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Essential
ORTHOPEDICS
(Principles and Practice)

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Essential
ORTHOPEDICS
(Principles and Practice)
2 Volumes

Editor
Manish Kumar Varshney
MS (Orth) DNB (Orth) MNAMS MRCS (Glasgow)
Senior Consultant Orthopedic Surgeon
Tata Motors Hospital
Jamshedpur, Jharkhand, India

The Health Sciences Publisher


New Delhi | London | Philadelphia | Panama

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Essential Orthopedics (Principles and Practice) (2 Volumes)
First Edition: 2016
ISBN: 978-93-5250-175-5
Printed at

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Dedicated to
My loving children Siddhant and Mrigank
and my life partner giving strength
to my devotion, Neeta Verma.
The blessings of my parents and my sister have always helped
in maintaining the spark of learning and dissemination.

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CONTRIBUTORS
Abheek Kar  MBBS MS (Orth) MRCS (Edinburgh) Ayush Kumar  MBBS DNB Trainee
Shoulder Unit Senior Medical Officer
Department of Orthopedics Tata Motors Hospital
Apollo Gleneagles Hospital Jamshedpur, Jharkhand, India
Kolkata, West Bengal, India E-mail: akk324802@tatamotors.com
E-mail: abheekkar@gmail.com
Jaydip Patel  MBBS DNB
Aditya Soral  MS Orth (AIIMS) Orthopedic Surgery
Fellow 3rd Year Resident
Bone and Cartilage Transplantation and Joint Revision Surgery Tata Motors Hospital
Brisbane, Australia Jamshedpur, Jharkhand, India
Senior Consultant, Department of Orthopedics E-mail: jaydip_shyani_88@yahoo.co.in
Eternal Hospital
Jaipur, Rajasthan, India Manish Kumar Varshney 
E-mail: aditya.soral@gmail.com MS (Orth) DNB (Orth) MNAMS MRCS (Glasgow)
Senior Consultant Orthopedic Surgeon
Alok Sud  MS Tata Motors Hospital
Commonwealth Fellow Jamshedpur, Jharkhand, India
Pediatric Orthopedic and Spinal Deformities E-mail: drmkvarshney@gmail.com
Royal Hospital for Sick Children
Edinburgh, Scotland Palak Mehta  MD FIPP
Professor, Department of Orthopedics Director
Lady Hardinge Medical College and Associated Hospitals Pain Care Clinic
New Delhi, India Ahmedabad, Gujarat, India
E-mail: avimukta2@gmail.com E-mail: pbm_111@yahoo.co.in

Amit Singh  MBBS D Orth S Pavan MS


Senior Resident Senior Consultant and Head
Maharishi Valmiki Hospital Department of Orthopedics
New Delhi, India Tata Motors Hospital
E-mail: drnamitanmch@gmail.com Jamshedpur, Jharkhand, India
E-mail: pavan.sudarshan@tatamotors.com
Ankit Data  MBBS DNB
General Medicine Sachin Bharti  MBBS DNB
2nd Year Resident General Medicine
Tata Motors Hospital 3rd Year Resident
Jamshedpur, Jharkhand, India Tata Motors Hospital
E-mail: adata12@gmail.com Jamshedpur, Jharkhand, India
E-mail: bharti_sachin@rediffmail.com
Ashok Jadon  MD DNB MNAMS FIPP (USA)
Chief Consultant and Head Sanjay L Srivastava  MD (Medicine)
Department of Anesthesia Chief Consultant and Head
In-Charge, Pain Relief Service Department of Medicine
Tata Motors Hospital Tata Motors Hospital
Jamshedpur, Jharkhand, India Jamshedpur, Jharkhand, India
E-mail: ashok.jadon@tatamotors.com E-mail: sanjay.srivastava@tatamotors.com

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viii Essential Orthopedics (Principles and Practice)

Somdatta B Datta  MD DPB DNB Swapnil Sharma  MBBS DNB


Senior Consultant and Head Orthopedic Surgery
Department of Pathology 3rd Year Resident
Tata Motors Hospital Tata Motors Hospital
Jamshedpur, Jharkhand, India Jamshedpur, Jharkhand, India
E-mail: somdattad@tatamotors.com E-mail: swapnil917@yahoo.com

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PREFACE

Orthopedics like other medical faculties is a growing branch. The growth is, however, much faster than other fields. Till
the beginning of last century, the orthopedics as a discrete was nonexistent to this world but the efforts of pioneers in
the field gave birth to the baby that boomed possibly the fastest to become one of the most favored surgical branches to
new entrants in the postgraduation. Orthopedics is the most glamorous and preferred surgical faculty for all youngsters
aspiring to quickly gain sort of “superspecialization” as not much is available or required after one does his postgraduation
in orthopedics, the region-wise faculty development into knee, shoulder, hip, pediatric orthopedics, orthopedic oncology
and spine surgery are mostly fellowship dependent.
The scenario in orthopedics was not similar when the faculty started and in the beginning most of the evidences were
mere “possibilities” as propounded in the replete literature of the older times written by the eminent persons in the field.
Soon it came to be realized that opinions do not count and are often deleterious to general practice that may be true only
for certain circumstances, so the era of “evidence-based practice” gradually evolved. With a few hitches then dawned the
time where evidence was sought for most of the prevailing practices that were repeatedly questioned by surgeons around
the world. This was pioneered by efforts of Association for Osteosynthesis (AO) foundation and others and did help to
some extent. In the beginning, however, the evidence was more of confusion rather than leading and the laid down facts
had to be constantly changed and adjusted more due to poverty in exactness of the previously laid principles and less
also to the emerging evidence as is evident from changing AO philosophy and the glaring failure of metal-on-metal hips.
As a postgraduate, it became difficult for me to comprehend the historical errors and practice, changing philosophy and
emerging new evidence and importantly remember them all. It was even more difficult to be accurate in orthopedic
examinations to rationalize my understanding and teachings to that of the senior examiners who had started the practice
even in a more bleak and confused environment prevailing at their time. However, I did realize during the course that some
fundamentals were constantly getting lost in these times of evolution that could not be passed on to the youngsters and
clinical examination has by now become a mere formality due to higher dependence/pervasiveness on advanced imaging
and some illicit activities. The beginning of this century was marked by two major developments I feel—the development
of improved implants and instrumentation (particularly the locked plate screw constructs) and higher importance laid
down for minimally invasive surgery. It became quickly evident to me that we need a text that encompasses all these facts
so that the student gets a “One Stop” text where he can refer to most of his queries. This encouraged me to write down
the current text and incorporate the most significant of previous practices and the current developments, some attempts
have been made to incorporate the futuristic techniques but it is limited by unavailability of “evidence-based practice”,
so I have personally restricted that.
I feel that the future of orthopedics lies in correct and prudent diagnosis (aided solidly by sound knowledge and clinical
examination) and ethical practice (not just money making as is considered an important practice nowadays); the basis of
which should be correct and true literature and not polluted one. I found some youngsters in the race of just publishing
even resort to unethical practice and publish skewed and incorrect findings that pollute the sacred literature which has
access to all and even amateur people who may not be able to rationalize and fall prey to wrong practice. This, I feel, also
is the reason that newer meta-analysis and even systematic reviews are unable to yield evidence in favor of one or the
other method rather often end in saying “no statistically significant different in practice”.
The current text will help a practicing surgeon to acquaint himself with the alternatives available for a particular
condition. I have tried to integrate most of the methods that are in practice or known currently for different orthopedic
conditions and also organize the text in the form of answers to common theory questions for use to a postgraduate
student. I tried to make a sincere effort in producing a text that can give an orthopedic surgeon insight into the orthopedic
practice importantly the basic sciences and how diseases are based on faults in them. The textbook has been organized
in the form of regional disposition to capture the region-specific conditions. There is vast emerging evidence and will
keep emerging even at the time of this writing in the form of modern and new molecular markers that aim to diagnose

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x Essential Orthopedics (Principles and Practice)

disorders correctly and fast. The future for treatment of some of these disorders might also lie in the molecular level by
using microinstruments like nanotechnology and gene therapy, so I tried to cover that topic also comprehensively.
I would like to thank from my heart to all those who have contributed to the text. Particularly Prof Alok Sud from
Lady Hardinge Medical College and Associated Hospitals, New Delhi, India, who stood by the commitment once
made and put constant efforts in providing me the text in pediatric orthopedics and helped till end in organizing some
photographs despite ourselves being only formally introduced and worked for a short duration together. The other
person who has helped in preparing the text is Dr S Pavan, who stood always by my side whenever required and also
relieved me of my duties often at even hectic times to prepare the text. My juniors Dr Jaydip Patel, Dr Amit Singh and
Dr Swapnil Sharma have provided help at difficult times when I needed them for text correction and improvement
despite some of them being engaged in their own academic work. Especially, I would thank Dr Jaydip, who even woke-
up untiringly at nights despite his duties to correct the text and add to the base work done by others and Dr Swapnil,
who provided support regardless of his examinations going on. The contribution of others is not nevertheless small and
Dr Ashok Jadon, Dr Sanjay L Srivastav, Dr Ankit Data and Dr Sachin Bharti have contributed thoroughly to the
nonorthopedic topics and Dr Aditya Soral, Dr Ram Kinkar Jha and Dr S Dutta, without their help the text could never be
completed. My family had been very supportive in displaying immense courage to face social restrictions and my untimely
absence from home due to writing work, sometimes when my kids needed me most to play, read, learn and enjoy and my
wife missing me sometimes altogether in important festivals and ceremonies. There are, however, some sour memories
also and it is also important to mention that the writing had not been easy at all, with minimal help coming from persons
I thought would contribute the most. The most respected and dear ones from my earlier relations in the field got too busy
or otherwise to provide any help but this was to my best use and possibly advantage that it made me write all the topics
by myself, which gave me further knowledge and confidence in areas where I was lacking in my training.
Lastly, I am highly thankful to Shri Jitendar P Vij (Group Chairman), Mr Ankit Vij (Group President), Mr Tarun Duneja
(Director–Publishing), Ms Samina Khan (Executive Assistant to Director–Publishing), the artists and all the team members
who untiringly worked to bring out this wonderful text despite various delays and hitches from my end. It is only with the
help of the publishing team at M/s Jaypee Brothers Medical Publishers (P) Ltd, New Delhi, India, that I could produce
the text with confidence. Especially Shri Jitendar P Vij has grown in respect and stature in my thoughts who gave me the
opportunity and initiated me for writing giving timely broad outlines, similarly Mr Tarun Duneja has constantly assisted
me in sorting out nitty-gritty problems that an author would usually encounter.
Providing an updated and correct text is always a challenge and some concepts would keep changing over time—is
a fact. To this end, I reiterate all the readers of this text to kindly keep posting me in case they find fundamental errors in
the text or some critical updates that should be incorporated so that we can help all others in their future reading. I am
open to all the criticism as they are bound to arise by difference of opinion that should be freely communicated to me
at my e-mail—drmkvarshney@gmail.com. One may also reach me at the so-called in fashion social sites like Facebook®
or WhatsApp. In the name of Almighty I present the text as an endeavor to promote the proficiency of both the neophyte
and experienced orthopedic surgeon, bearing in mind to the truest of an attempt to present contradictory accumulation
of discernment into logical concepts and the fact that condensing the mountain of knowledge may not be possible in the
lifetime with ever-evolving concepts.

Manish Kumar Varshney

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ACKNOWLEDGMENTS

I heartily acknowledge the contribution of my teachers Dr PP Kotwal and Dr S Rastogi (Professors, Department of
Orthopedics, All India Institute of Medical Sciences, New Delhi, India) for providing clinical photographs and radiographs
representative of typical disorders as a learning resource used at various places in the chapters on pediatric upper and
lower limb disorders, rheumatoid arthritis, etc. and various clinical and operative learning representative photographs
and radiographs for chapter on bone neoplasia respectively.
I also acknowledge the contribution from Dr Neelam Jain (Radiologist, Discovery Imaging Center, Jamshedpur,
Jharkhand, India) for providing representative MRI pictures for chapter on magnetic resonance imaging (MRI).

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CONTENTS

Clinical Presentation and Evaluation of Osteoporosis  71


VOLUME-1
‰‰
‰‰ Prevention and Treatment of Osteoporosis  78
‰‰ Calcium, Vitamin D and Minerals  80
‰‰ Estrogen 82

Section 1: Bone Anatomy, Physiology, ‰‰ Future Approaches  93


‰‰ Atypical Forms of Osteoporosis  94
Pathology and Diseases Osteopetrosis 96
‰‰ Etiology and Pathophysiology  96
‰‰ Epidemiology and Clinical Features  97
1 Structure and Function of Bones and Joints 3 ‰‰ Investigations 97
Manish Kumar Varshney ‰‰ Differential Diagnosis  98
‰‰ Treatment 98
‰‰ Bone Structure  3
‰‰ Classification of Bone by Appearance  4 Rickets 98
‰‰ Gross Features of Bone  5 ‰‰ Definition 98
‰‰ Microscopic Anatomy  6 ‰‰ Pathophysiology 98
‰‰ The Cellular Elements of Bone  7 ‰‰ Clinical Features  99
‰‰ The Composition and Structure of Bone Matrix  14 ‰‰ Radiological Signs  99
‰‰ Blood Supply of Bone  17 ‰‰ Nutritional Deficiency of Vitamin D  100
‰‰ Nerve Supply of Bone  18 ‰‰ Secondary Vitamin D Deficiency  102
‰‰ Bone Development  19 ‰‰ Vitamin D-dependent Rickets Type 1  102
‰‰ The Process of Bone Mineralization  24 ‰‰ Vitamin D-dependent Rickets Type 2  103
‰‰ Bone Remodeling  25 ‰‰ Rickets in Chronic Renal Failure  103
‰‰ Regulation of Bone Metabolism  27 ‰‰ Calcium Deficiency and Rickets  103
‰‰ Growth Factors in Regulation of Bone Metabolism  31 ‰‰ Hypophosphatemic Rickets  104
‰‰ Endocrinopathies and Bone Involvement  32 ‰‰ Fluorosis 106
‰‰ Gaucher’s Disease  108
2 Fracture Repair 35 ‰‰ Mucopolysaccharidoses 109

Manish Kumar Varshney


4 Infections of Bone 114
‰‰ Definition and Classification  35
‰‰ Important Determinants of Fracture Repair  42 Manish Kumar Varshney
‰‰ Laws Associated with Fracture Repair and Bone ‰‰ Osteomyelitis 114
Remodeling 45 ‰‰ History and Epidemiology  117
‰‰ Methods to Enhance Fracture Repair  48 ‰‰ Pathogenesis 118
‰‰ Bone Banking  60 ‰‰ Modern Concept and Understanding of Osteomyelitis  120
‰‰ Bacteriological Factors  122
3 Metabolic Diseases of Bone and Effect of ‰‰ Environmental Influence  125
Glucocorticoid Therapy on Bone 64 ‰‰ Diagnosis 127
‰‰ Functional Imaging  130
Manish Kumar Varshney, Swapnil Sharma ‰‰ Principles of Therapy  132
Osteoporosis 64 ‰‰ Management of Chronic Osteomyelitis  133
‰‰ Definition 64 ‰‰ Tissue Debridement  134
‰‰ Natural History of Bone Mass Changes in Human ‰‰ Bone Stabilization  136
Body, Operational Definition of Osteoporosis and its ‰‰ Local Antibiotic Therapy  137
Classification 64 ‰‰ Biodegradable Systems  139
‰‰ Prevalence, Incidence and Problem Statement  66 ‰‰ Reconstruction of the Soft Tissue  145
‰‰ Genetics of Osteoporosis  67 ‰‰ Adjuvant Therapies for Treatment of Osteomyelitis  146
‰‰ Risk Factors for Low Bone Mineral Density and Fracture Risk ‰‰ Prevention of Exogenous Bone Infection  146
Assessment 68 ‰‰ Some Special Forms of Osteomyelitis  147

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xiv Essential Orthopedics (Principles and Practice)

‰‰ Actinomycosis 151 ‰‰ Joint Classification  329


‰‰ Mycetoma (Maduramycosis)  153 ‰‰ Kinematic Classification and Movements at
‰‰ Surgical Site Infection  155 Different Types of Joints  330
‰‰ Staphylococcal Colonization  156
‰‰ Operating Room Personnel Associated Risk Factors  156 8 Synovial Joint: Anatomy and Physiology 334
‰‰ Modifiable Patient Risk Factors  156 Manish Kumar Varshney
5 Bone Tumors 159 ‰‰ Synovial Joint  334
‰‰ Detailed Anatomy and Physiology of Synovial Joint  334
Manish Kumar Varshney ‰‰ Traumatic Arthrotomy  335
‰‰ Introduction and General Principles  159 ‰‰ Synovial Fluid  336
‰‰ Staging 159
‰‰ Clinical Evaluation  162 9 Disorders of Synovium 340
‰‰ Physical Examination  162 Manish Kumar Varshney
‰‰ Radiographic Evaluation  163
‰‰ Lesion Location and Size  163 ‰‰ Tenosynovial Giant Cell Tumors  340
‰‰ Lesion Margin  164 ‰‰ Pigmented Villonodular Synovitis (Synovial Xanthoma,
‰‰ Cortical Destruction  166 Villous Synovitis)  340
‰‰ Matrix 166 ‰‰ Synovial Chondromatosis  342
‰‰ Bone Reaction  166 ‰‰ Synovial Sarcoma  343
‰‰ Complex Periosteal Pattern  168
‰‰ Grading of Bone Tumors  170
10 Articular Cartilage: Structure,
‰‰ Adjuvant Therapy  175 Composition and Function 346
‰‰ Benign and Malignant Bone Neoplasms  181 Manish Kumar Varshney
‰‰ Cartilage Forming Lesions  202
‰‰ Structure and Composition  346
‰‰ Fibrous Lesions  214
‰‰ Chondrocytes 347
‰‰ Vascular Lesions of Bone  235
‰‰ Intercellular Matrix  348
‰‰ Metastatic Disease of Bone  239
‰‰ Metabolism and Regulation  349
‰‰ Musculoskeletal Soft Tissue Tumors  251
‰‰ Tumor and Tumor-like Conditions of Fibroblasts/ ‰‰ Biomechanics of Articular Cartilage  350
Myofibroblasts 252 ‰‰ Lubrication and Wear (Synovial Joint Lubrication)  351
‰‰ Common Fibrous Tumors of Infancy and Childhood  255 ‰‰ Effects of Injury  352
‰‰ Fibrohistiocytic Tumors  257 ‰‰ Methods to Repair or Reconstruct Focal Cartilage Defects  355
‰‰ Heterotopic Ossification  258 ‰‰ Mosaicplasty 359
‰‰ Allografts 360
6 Osteonecrosis and Osteochondrosis 264 ‰‰ Autologous Cartilage Implantation  360
‰‰ Chondrocyte Culture and Co-culture Systems  363
Manish Kumar Varshney
‰‰ Scaffolds 363
‰‰ Osteonecrosis 264 ‰‰ Third-Generation Chondrocyte Grafting  366
‰‰ Femoral Head Osteonecrosis  267
‰‰ Osteonecrosis of the Distal Femur (Femoral Condyles)  287 11 Joint Disorders Including Inflammatory
‰‰ Osteonecrosis of Talus  292 and Noninflammatory Arthritis
‰‰ Arthrodesis 295
‰‰ Ankle Arthroplasty  299 and Infection 367
‰‰ Kienbock’s Disease (Lunatomalacia)  302 Manish Kumar Varshney
‰‰ Preiser’s Disease  312 ‰‰ Arthritis 367
‰‰ Osteochondrosis 315
Osteoarthritis (OA, Osteoarthrosis, Arthrosis,
‰‰ Osteochondritis Dissecans of the Talus  322
Degenerative Joint Disease)  367
‰‰ Caisson Disease  324
‰‰ Epidemiology 368
‰‰ Etiology 368
Section 2: Joint—Structure, Function and ‰‰ Pathophysiology and Pathogenesis  371

Related Disorders ‰‰ Stages of Progression of Osteoarthritis  372


‰‰ Clinical Features and Diagnosis  372
‰‰ Clinical Staging of Osteoarthritis  374
‰‰ Investigations 375
7 Classification of Joints 329
‰‰ Differential Diagnosis  376
Manish Kumar Varshney ‰‰ Acute Complications of Osteoarthritis  376
‰‰ Definition 329 ‰‰ Variants of Primary Osteoarthritis  377
‰‰ Functions 329 ‰‰ Treatment 379

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Contents xv

Total Knee Arthroplasty  388 Gout (“Podagra”) (Big Toe Involvement), Rich Man’s
‰‰ History 388 Disease, Disease of the Kings  453
‰‰ Contemporary Knee Designs  389 ‰‰ Pathophysiology 454
‰‰ Contemporary CR Design  389 ‰‰ Clinical Features  455
‰‰ Contemporary PS Design  389 ‰‰ Differential Diagnosis  457
‰‰ Special Design Features  389 ‰‰ Treatment 457
‰‰ Goals of Total Knee Replacement  390
‰‰ Principles of Total Knee Replacement  390
‰‰ Complications of TKR  392
Section 3: Basic Sciences
Calcium Pyrophosphate Dihydrate Crystal Deposition
Disease (CPPD Disease or Arthropathy, Pseudogout, 12 Biostatistics, Ethics and Research
Chondrocalcinosis, Pyrophosphate Arthropathy)  397
Hemophilic Arthropathy  401
Methods 463
Ochronosis (Alkaptonuria)  402 Manish Kumar Varshney
‰‰ Clinical Features  402 ‰‰ The Measurement Scales  463
‰‰ Treatment 402 ‰‰ Derived Data  464
Rheumatoid Arthritis  402 ‰‰ Censored Data  465
‰‰ Etiology 403 ‰‰ Bias 465
‰‰ Pathogenesis 403 ‰‰ Biostatistics 467
‰‰ Clinical Features and Diagnosis  405 ‰‰ Randomization 474
‰‰ Differential Diagnosis  407 ‰‰ Blinding/Masking 476
‰‰ Treatment 408 ‰‰ Data Collection  478
‰‰ Pharmacotherapy 408 ‰‰ Descriptive Statistics  478
‰‰ Newer Modalities and Advances in ‰‰ Levels of Evidence  480
RA Management  410 ‰‰ Type of Distributions  481
Seronegative Spondyloarthropathies  416 ‰‰ Defining Statistics and Describing the Parametric
‰‰ Ankylosing Spondylitis (Marie-Strumpell Disease,
and Non-Parametric Tests  483
Morbus Bechterew Disease)  416 ‰‰ Analysis of Continuous Variable  484
‰‰ Psoriatic Arthritis (PSA) 420
‰‰ Nonparametric Analysis (Analysis of Categorical
‰‰ Enteropathic Arthritis (ENA), Reactive Arthritis
Variable) 486
(REA), and Undifferentiated and Juvenile-Onset ‰‰ Sampling 488
Spondyloarthropathy 422 ‰‰ Ethics 489
‰‰ Neuropathic Arthropathy [Charcot’s Joints, Charcot’s ‰‰ Informed Consent  489
Arthropathy (CA), Charcot’s Neuroarthropathy]  423
13 Biomechanics in Orthopedics:
Septic Arthritis  426
‰‰ Pathophysiology 427
General Principles 492
‰‰ Clinical Features  428 Manish Kumar Varshney, Jaydip Patel
‰‰ Septic Arthritis of Hip in Children and its Sequel  429 ‰‰ Statics 492
‰‰ Late Sequel of the Septic Arthritis Hip in Infants  431 ‰‰ Dynamics 495
‰‰ Principles and Algorithm of Reconstructive
Procedures 433 14 Gait 497
Prosthetic Joint Infection (PJI) 435 S Pavan
‰‰ Classification 435
‰‰ Microbiology and Pathophysiology  435
‰‰ Definition 497
‰‰ Diagnosis 436
‰‰ Phases of Gait  497
‰‰ Treatment 437
‰‰ Factors Affecting Gait  499
‰‰ Types of Pathological Gait  499
Mycobacterial Arthritis  439
‰‰ Microbiology 439
‰‰ Pathology and Pathogenesis  439 Section 4: Surgical and Medical
‰‰ Clinical Types of Tubercular Arthritis  440
‰‰ Clinical Features  440
Complications of Fractures
‰‰ Radiologic Findings  440
‰‰ Diagnosis 440
‰‰ Treatment 442
15 Nonunion of Long Bones 507
‰‰ Essential First-Line Drugs  444 Manish Kumar Varshney
‰‰ TB of Hip Joint  447 ‰‰ Epidemiology 508
HIV Associated Musculoskeletal Conditions  452 ‰‰ Classification 508

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xvi Essential Orthopedics (Principles and Practice)

‰‰ Pathogenesis 510 ‰‰ Clinical Presentation  567


‰‰ Diagnosis 511 ‰‰ Diagnosis 568
‰‰ Investigations 511 ‰‰ Complications 568
‰‰ Treatment 512 ‰‰ Treatment 568
‰‰ The Principle of Distraction Osteogenesis and Its Application ‰‰ Prophylaxis 570
to Nonunion of Long Bones  515
‰‰ Physiological Aspects of Distraction Osteogenesis  516 19 Fat Embolism Syndrome 571
‰‰ Some Technical Pearls  520 Sanjay L Srivastav, Ankit Data
‰‰ Causes 571
16 Compartment Syndrome 521
‰‰ Pathophysiology 571
Manish Kumar Varshney ‰‰ Presentation 572
‰‰ Etiopathogenesis 521 ‰‰ Diagnosis 572
‰‰ Natural History and Diagnosis  526 ‰‰ Laboratory Studies  573
‰‰ Measurement of Intra­compartmental Pressure  527 ‰‰ Imaging Studies  573
‰‰ History and Physical Examination  529 ‰‰ Treatment 573
‰‰ Differential Diagnosis  531 ‰‰ Medication 574
‰‰ Management 531 ‰‰ Prognosis 574
‰‰ Surgical Technique  531
‰‰ Chronic Compartment Syndrome  533 20 Neurogenic Bladder 575
‰‰ Indications for Prophylactic Fasciotomy  535 Jaydip Patel, Manish Kumar Varshney
‰‰ Postoperative Management and Rehabilitation  535 ‰‰ Definition 575
‰‰ Complications 535 ‰‰ Epidemiology 575
‰‰ Anatomy of the Bladder  575
17 Complex Regional Pain Syndrome 537 ‰‰ Neuroanatomy of the Bladder  575
Ashok Jadon, Amit Singh ‰‰ Pathophysiology and Etiology  576
‰‰ Definition 537 ‰‰ Classification 577
‰‰ History and Nomenclature  537 ‰‰ Investigations 577
‰‰ Epidemiology 538 ‰‰ Treatment and Management  578
‰‰ Types of Complex Regional Pain Syndrome  538
‰‰ Pathophysiology 538
21 Acute Respiratory Distress Syndrome 580
‰‰ Symptoms/Clinical Presentation  539 Sanjay L Srivastav, Ankit Data
‰‰ Diagnosis 540 ‰‰ Background and Definition  580
‰‰ Differential Diagnosis of Complex Regional Pain ‰‰ Pathophysiology 580
Syndrome 542 ‰‰ Etiology 580
‰‰ Treatment 542 ‰‰ Presentation 581
‰‰ Prognosis 546 ‰‰ Physical Findings  581
‰‰ Complex Regional Pain Syndrome in Children  546 ‰‰ Work Up  581
‰‰ Diagnostic Criteria  581
18 Deep Vein Thrombosis 548 ‰‰ Treatment 581
Manish Kumar Varshney, Jaydip Patel
22 Systemic Inflammatory Response
‰‰ Definition 548
‰‰ History 548
Syndrome 583
‰‰ Epidemiology 548 Jaydip Patel, Ankit Data
‰‰ Anatomy and Pathophysiology  549 ‰‰ Etiology 583
‰‰ Development of Thrombosis and Balancing ‰‰ Pathophysiology 583
Mechanisms 549 ‰‰ Multi-Hit Theory  584
‰‰ Pathogenesis of Deep Venous Thrombosis: The Tilt of ‰‰ Clinical Examination  584
Balance of Thrombosis  550 ‰‰ Laboratory Evaluation  584
‰‰ Location of Deep Venous Thrombosis  551 ‰‰ Treatment 584
‰‰ Etiology of Deep Venous Thrombosis  552 ‰‰ Complications 585
‰‰ Clinical Features  552
‰‰ Diagnosis 553 23 Multiple Organ Dysfunction Syndrome
‰‰ Differential Diagnosis  556 [Multiple Organ Failure (MOF) and
‰‰ Treatment of Deep Vein Thrombosis  556
‰‰ Prophylaxis of Deep Venous Thrombosis  559
Multisystem Organ Failure (MSOF)] 586
Upper Extremity Deep Vein Thrombosis  566 Ankit Data, Ayush Kumar
‰‰ Pathogenesis and Risk Factors  566 ‰‰ Definition 586

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‰‰ Etiology 586 ‰‰ Melorheostosis 647
‰‰ Pathophysiology 586 ‰‰ Osteopoikilosis (Osteopathia Condensans
‰‰ Clinical Features  587 Disseminata) 648
‰‰ Other Systems  587 ‰‰ Osteopathia Striata  648
‰‰ Diagnosis 587 ‰‰ Dysplasia Epiphysealis Hemimelica  649
‰‰ Prevention 588
‰‰ Prognosis 588 27 Poliomyelitis 651
‰‰ Treatment 588 Alok Sud, Manish Kumar Varshney
‰‰ Pathology 651
24 Transfusion Medicine 589 ‰‰ Clinical Features of an Acute Attack of Polio  653
Sanjay L Srivastav, Ankit Data, Sachin Bharti ‰‰ Management 654
‰‰ Blood Group Systems  589 ‰‰ General Rules for Tendon Transfer in Foot  657
‰‰ Detection of Blood Group Antibodies  590 ‰‰ Paralysis of Specific Muscle and Muscle Groups and Functio
‰‰ Blood and Blood Products  591 Laesa (Modified from Peabody)  657
‰‰ Clinical Use of Blood and Blood Components  591 ‰‰ Paralysis of Inversion  657
‰‰ Adverse Reactions to Blood Transfusion  593 ‰‰ Paralysis of Dorsiflexion and Inversion (Tibialis Anterior,
‰‰ Nonimmunologic Reactions  595 Tibialis Posterior and Toe Extensors)  658
‰‰ Alternatives to Blood Component Therapy  596 ‰‰ Paralysis of Dorsiflexion, Inversion and Eversion  659
‰‰ Blood Substitutes  597 ‰‰ Paralysis of Eversion  659
‰‰ Paralysis of Plantar Flexion (Triceps Surae)  659
25 Shock 599 ‰‰ Stabilization of Joints of Foot and Ankle  660
‰‰ Claw Toes  661
Ankit Data, Sachin Bharti, Sanjay L Srivastav
‰‰ Dorsal Bunion  663
‰‰ Definition 599 ‰‰ Cavus Deformity and Claw Toes  664
‰‰ Classification and Causes  599 ‰‰ Talipes Equinus  668
‰‰ Pathophysiology 600 ‰‰ Talipes Equinovarus  671
‰‰ Shock Manifestations  601 ‰‰ Talipes Cavovarus  672
‰‰ Endpoints of Resuscitation  607 ‰‰ Talipes Equinovalgus  672
‰‰ Talipes Calcaneus  673
Section 5: Pediatric Orthopedics 28 Cerebral Palsy 675
Alok Sud, Manish Kumar Varshney
26 Congenital, Genetic, Syndromic and
‰‰ Classification of Activity Limitation  676
Miscellaneous Disorders 611 ‰‰ Clinical Assessment of a Cerebral Palsy Child  679
Manish Kumar Varshney ‰‰ Principles of Management of Child with Cerebral Palsy  683
‰‰ Ehlers-Danlos Syndrome  612 ‰‰ Treatment for Spasticity in Cerebral Palsy  683
‰‰ Osteogenesis Imperfecta  614 ‰‰ Management of Hip Deformities in Cerebral Palsy  684
‰‰ Marfan Syndrome  620 ‰‰ Management of Foot and Ankle in Cerebral Palsy  688
‰‰ Trisomy 21 (Down Syndrome)  624
‰‰ Turner Syndrome  625
29 Anomalies of Pediatric Lower Limb 695
‰‰ Disorders Caused by Abnormalities in Manish Kumar Varshney
Tumor-related Genes  625 ‰‰ Development of Lower Limb  695
‰‰ Achondroplasia and Related Disorders  627 ‰‰ Congenital Femoral Deficiency  695
‰‰ Disorders Related to Type II Collagen Abnormalities  630 ‰‰ Coxa Vara  698
‰‰ Disorders Caused by Abnormalities in Genes Important in ‰‰ Rotational and Angular Alignment of Lower Limb,
Normal Skeletal Development  631 Common Pathologies and Principles of Correction
‰‰ Disorders Caused by Abnormalities in Genes that Play a Role of Deformity in Children  700
in the Processing of Proteins  633 ‰‰ Genu Varum  712
‰‰ Other Skeletal Dysplasias  633 ‰‰ Tibia Vara  717
‰‰ Some Miscellaneous Syndromes  635 ‰‰ Genu Valgum (Knock-Knees)  720
‰‰ Fetal Alcohol Syndrome  642 ‰‰ Congenital Angular Deformities of Tibia and Fibula  723
‰‰ Prader-Willi Syndrome  642 ‰‰ Congenital Deficiencies of the Tibia  727
‰‰ Angelman Syndrome (Happy Puppet Syndrome)  643 ‰‰ Fibular Hemimelia  728
‰‰ Beckwith-Wiedemann Syndrome  643 ‰‰ Congenital Dislocation of the Knee  729
‰‰ Trichorhinophalangeal Syndrome  643 ‰‰ Leg-Length Discrepancy  731
‰‰ Progeria (Hutchinson-Gilford Syndrome)  644 ‰‰ Patellar Instability  744
‰‰ Rubinstein-Taybi Syndrome  644 ‰‰ Congenital Vertical Talus (Convex Pes Valgus,
‰‰ Congenital Constriction Band Syndrome  645 Rigid Rocker Bottom Flatfoot)  752

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xviii Essential Orthopedics (Principles and Practice)

‰‰ Congenital Metatarsus Adductus (Metatarsus Varus, ‰‰ Differential Diagnosis (Clinical and Radiological)  829
Metatarsus Adductovarus)  756 ‰‰ Some Procedural Descriptions  835
‰‰ Tarsal Coalition  758
‰‰ Skewfoot (Z-Foot, Serpentine Foot, Metatarsus 33 Perthes Disease 839
Adductovarus, Congenital Metatarsus Varus)  760 Manish Kumar Varshney, Alok Sud
‰‰ Flexible Flatfoot  761
‰‰ Etiology and Pathogenesis of Disease  839
‰‰ Accessory Navicular (Os Tibiale Externum, Navicular
‰‰ Pathophysiology and Pathoanatomy of the Disease  840
Secundum and Prehallux)  763
‰‰ Clinical Features  841
‰‰ Slipped Capital Femoral Epiphysis (Slipped Upper Femoral
‰‰ Differential Diagnosis  842
Epiphysis) 764
‰‰ Radiological Workup  842
30 Anomalies of Pediatric Upper Limb 768 ‰‰ Staging and Classification of Disease  843
‰‰ Prognostic Factors  844
Manish Kumar Varshney ‰‰ Treatment Principles and Methods  845
‰‰ Development of Upper Limb  768 ‰‰ Some Notes on Surgical Containment Procedure  849
‰‰ Birth-related Brachial Plexus Palsy  768
Sprengel’s Deformity (Congenital Elevation of Scapula)  775
‰‰
‰‰ Glenoid Hypoplasia  777 Section 6: Sports Medicine
‰‰ Congenital Pseudarthrosis of the Clavicle  777
‰‰ Congenital Radial Head Dislocation  778
‰‰ Congenital Proximal Radioulnar Synostosis  780 34 Sports Medicine: Knee 853
‰‰ Radial Longitudinal Deficiency  781 Manish Kumar Varshney
‰‰ Madelung’s Deformity  786 ‰‰ Tibiofemoral Articulation  853
‰‰ Central Deficiency  789 ‰‰ Cruciate Ligaments  864
‰‰ Syndactyly 790 ‰‰ Patellofemoral Articulation  867
‰‰ Polydactyly 792 ‰‰ Patellar Tendon  870
‰‰ Camptodactyly (Bent Finger)  794 ‰‰ Biomechanics of Knee Joint  874
‰‰ Clinodactyly 795 ‰‰ Knee Instability  878
‰‰ Thumb Hypoplasia or Aplasia  795 ‰‰ Tibial Collateral Ligament Injury  884
‰‰ Congenital Trigger Thumb or Digits  797 ‰‰ Lateral Collateral Ligament Injury  888
‰‰ Anterior Cruciate Ligament Injury  888
31 Clubfoot—Congenital Talipes
‰‰ Posterior Cruciate Ligament Injury  894
Equinovarus 799 ‰‰ Posterolateral Corner Injuries  897
Manish Kumar Varshney ‰‰ Combined Ligament Injuries and Knee Dislocation  900
‰‰ Definition and Problem Statement  799 ‰‰ Meniscal Lesions  900
‰‰ Historical Perspective  800 ‰‰ Pathophysiology and Pathoanatomy  901
‰‰ Etiology of Clubfoot  800 ‰‰ Sports Related Peroneal Nerve Injury  905
‰‰ Biology of Developing Clubfoot  801 ‰‰ Bursitis 906
‰‰ Clinical Examination and Characteristic Findings  802 ‰‰ Baker’s Cyst  908
‰‰ Characteristic Bony Changes and Radiological ‰‰ Infrapatellar Fat Pad Syndrome (Hoffa’s Disease, Hoffa’s Fat
Examination 803 Pad Syndrome, and Liposynovitis Prepatellaris)  909
‰‰ Radiology 804 ‰‰ Patellofemoral Pain Syndrome and Anterior Knee Pain  911
‰‰ Types of Congenital Talipes Equinovarus  806 ‰‰ Patellar Tendinitis (Jumper’s Knee)  913
‰‰ Classification of Congenital Talipes Equinovarus  806 ‰‰ Runner’s Knee (Iliotibial Band Friction Syndrome and Pes
‰‰ Treatment 807 Anserinus Tendinitis or Bursitis)  914
‰‰ Evaluation of Deformity Correction in Congenital Talipes ‰‰ Sinding-Larsen-Johansson Disease (Larsen-Johansson
Equinovarus 819 Syndrome and Sinding-Larsen Disease)  915
‰‰ Treatment of Resistant Deformity and Relapsed Congenital ‰‰ Osgood-Schlatter Disease  916
Talipes Equinovarus  820
35 Sports Medicine: Foot, Ankle and Leg 919
32 Dysplastic Development of Hip Manish Kumar Varshney
[Developmental Dysplasia of Hip (DDH), ‰‰ Achilles Tendon  919
Congenital Dysplasia of Hip, Congenital ‰‰ Tibialis Posterior Tendon  921
Dislocation of Hip (CDH)] 821 ‰‰ Peroneal Tendon Disease  922
‰‰ Stress Fractures  923
Alok Sud, Manish Kumar Varshney ‰‰ Plantar Fasciitis (Plantar Fasciosis, Calcaneal Plantar
‰‰ Clinical Presentation  824 Enthesopathy) 928
‰‰ Imaging Studies  826 ‰‰ Posterior Ankle Impingement Syndrome  932

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36 Sports Medicine: Hip and Thigh 935 Section 7: Regional Orthopedics—


Manish Kumar Varshney Shoulder
‰‰ Hip Arthroscopy Indications and Principles  935
‰‰ Acetabular Labral Tears  939
‰‰ Femoroacetabular Impingement (Acetabular Rim 42 Shoulder—Functional Anatomy 1005
Syndrome, Cervicoacetabular Impingement)  947 Manish Kumar Varshney, Abheek Kar
‰‰ Snapping Hip (Coxa Saltans)  955
‰‰ Piriformis Syndrome (Deep Gluteal Syndrome, Pelvic Outlet ‰‰ The Rotator Cuff Anatomy and Pathoanatomy  1007
Syndrome, Infrapiriform Foramen Syndrome)  959
‰‰ Meralgia Paresthetica (Bernhardt-Roth Syndrome,
43 Biomechanics of Shoulder Joint 1011
Lateral Cutaneous Nerve Neuralgia)  963 Manish Kumar Varshney
‰‰ Trochanteric Bursitis (Greater Trochanteric Pain ‰‰ The Glenoid Labrum  1011
Syndrome) 966 ‰‰ Stability Ratio  1012
‰‰ Osteitis Pubis  968 ‰‰ The Glenoidogram  1012
‰‰ Hip Stress Fractures  971 ‰‰ Anterior Restrictors  1012
‰‰ Groin Pain (Athletic Pubalgia and Sports Hernia)  972 ‰‰ Posterior Restrictors  1013
‰‰ Scapulohumeral Rhythm  1013
37 Sports Medicine: Elbow 977
Manish Kumar Varshney 44 History and Clinical Examination 1016
‰‰ Elbow Arthroscopy  977 Abheek Kar, Manish Kumar Varshney
‰‰ Terrible Triad Injury of Elbow (Hotchkiss Triad, 1996)  979 ‰‰ Age 1016
‰‰ Sex 1016
38 Sport Medicine: Hand and Wrist 983 ‰‰ Instability 1017
Manish Kumar Varshney ‰‰ Physical Examination  1017
‰‰ Jersey Finger  983 ‰‰ Special Tests  1017
‰‰ Mallet Finger  984
‰‰ Boxer’s Knuckle (Boxer’s Fracture)  985 45 Investigations 1027
‰‰ Jammed Finger  986 Manish Kumar Varshney
39 Head Injuries in Sports 988 46 Rotator Cuff Disease 1028
Manish Kumar Varshney Manish Kumar Varshney
‰‰ Pathophysiology 988 ‰‰ Subacromial Impingement Syndrome  1028
‰‰ Spectrum of Head Injuries  988
‰‰ Concussion (Commotio Cerebri)  990 47 Shoulder Instability 1038
40 Doping (Drugs and Legal Aspects) 994 Abheek Kar, Manish Kumar Varshney
Manish Kumar Varshney ‰‰ Anterior Instability  1039
‰‰ Superior Labrum Anterior and Posterior Lesion
‰‰ Definition 994 and Internal Impingement  1048
‰‰ Testing 995
‰‰ Consequences of Anti-doping Rule Violations  995 48 Calcific Tendinopathy 1051
41 Skeletal Muscle: Structure and Function 996 Manish Kumar Varshney
Manish Kumar Varshney ‰‰ Etiopathogenesis 1051
‰‰ Radiologic Appearance and Classification  1052
‰‰ Cytology 996
‰‰ Clinical Course of Disease  1052
‰‰ Motor Unit  998
‰‰ Treatment 1052
‰‰ Sarcoplasmic Reticulum  998
‰‰ Structural Proteins of Muscle  999 49 Lesions of Biceps Tendon 1053
‰‰ Sliding Filament Model of Contraction  999
‰‰ Muscle Twitch and Tetanus  999 Manish Kumar Varshney
‰‰ Fiber Types and Muscle Adaptability  1001 ‰‰ Bicipital Tendinosis  1053
‰‰ Length-Tension Relationship  1002 ‰‰ Subluxating Biceps Tendon  1053
‰‰ Force-Velocity Relationship  1002 ‰‰ Rupture of the Long Head of Biceps  1054

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xx Essential Orthopedics (Principles and Practice)

50 Atraumatic Osteolysis of the Distal Clavicle 56 Tuberculosis of Shoulder Joint 1075


(Idiopathic Clavicle Osteolysis, Wrestlers Manish Kumar Varshney
Syndrome, Weightlifters Shoulder) 1056 ‰‰ Pathoanatomy and Clinical Forms  1075
Manish Kumar Varshney ‰‰ Clinical Features  1075
‰‰ Radiology 1075
‰‰ Pathogenesis 1056
‰‰ Differential Diagnosis  1076
‰‰ Pathoanatomy 1056
‰‰ Treatment 1076
‰‰ Clinical Features  1056
‰‰ Differential Diagnoses  1057
‰‰ Radiological Findings  1057 VOLUME-2
‰‰ Treatment 1057
‰‰ Complications of Surgical Procedures  1057

51 The Stiff Shoulder 1059 Section 8: Regional Orthopedics—Hip


Manish Kumar Varshney
‰‰ Adhesive Capsulitis  1059 57 Surgical and Functional Anatomy 1079
52 Hemorrhagic Shoulder (Milwaukee Manish Kumar Varshney
Shoulder, L’epaule Senile ‰‰ Anatomy of the Hip  1079
Hemorragique) 1063 58 Surgical Approaches to Hip Joint 1092
Manish Kumar Varshney Manish Kumar Varshney
‰‰ Pathogenesis 1063 ‰‰ Classification of Approaches to Hip Joint  1092
‰‰ Pathoanatomy 1063 ‰‰ Techniques of Various Surgical Approaches to the Hip
‰‰ Epidemiology 1063 Joint 1093
‰‰ Clinical Features and Radiology  1064
‰‰ Diagnosis 1064 59 Biomechanics of Hip Joint 1105
‰‰ Differential Diagnosis  1064
Manish Kumar Varshney
‰‰ Treatment 1064
‰‰ Functional Anatomy  1105
53 Osteoarthritis of Shoulder Joint 1065 ‰‰ Forces Transmitted Across Hip Joint  1106
‰‰ Clinical Applications  1110
Manish Kumar Varshney
‰‰ Clinical Features  1065 60 Tribology and Bearing Surfaces for Hip
‰‰ Differential Diagnosis  1065 (Including Ceramics) 1113
‰‰ Radiology 1065
‰‰ Treatment 1066 Manish Kumar Varshney
‰‰ Arthrodesis of Shoulder Joint  1066 ‰‰ Historical Perspective  1113
‰‰ Arthroplasty of Shoulder Joint  1067 ‰‰ Problem Statement  1114
‰‰ Tribology of Articulating Surfaces  1114
54 Scapular Instability 1071 ‰‰ Bearing Surfaces for Total Hip Arthroplasty  1127
Manish Kumar Varshney ‰‰ Materials Bearing Against Polyethylene  1128
‰‰ Polyethylenes 1129
‰‰ Etiology 1071
‰‰ Metal-on-metal Bearings  1132
‰‰ Clinical Feature  1071
‰‰ Ceramic Bearings  1135
‰‰ Treatment 1072
‰‰ New Horizons in Bearing Surfaces  1140
55 Suprascapular Nerve Syndrome 1073 61 Polymethyl-methacrylate (PMMA,
Manish Kumar Varshney Plexigas, Bone Cement, Acrylic Bone
‰‰ Anatomy 1073 Cement) 1142
‰‰ Etiology 1073
‰‰ Clinical Presentation  1073 Manish Kumar Varshney
‰‰ Investigations 1074 ‰‰ History of Development of Bone Cement  1142
‰‰ Differential Diagnosis  1074 ‰‰ Effect of Various Factors on Cement
‰‰ Treatment 1074 Polymerization 1144

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Contents xxi

‰‰ Mixing Techniques  1144 ‰‰ Clinical Assessment and its Impact  1178


‰‰ Physical Properties of Cement  1146 ‰‰ Level of Osteotomies  1178
‰‰ Adverse Effects/Complications of Bone Cement  1147 ‰‰ Milch-Bachelor Osteotomy  1179
‰‰ Removal of Bone Cement  1150 ‰‰ Mcmurray’s Osteotomy  1180
‰‰ Lorenz Bifurcation Osteotomy  1181
62 Osteoarthritis of Hip Joint 1151 ‰‰ Schanz Osteotomy (Low Subtrochanteric
Manish Kumar Varshney Osteotomy) 1181
‰‰ Risk Factors  1151 ‰‰ Trochanteric Osteotomies  1181
‰‰ Classification of Hip Osteoarthritis  1154 ‰‰ Subtrochanteric Osteotomies  1187
‰‰ Clinical Features and Evaluation  1154 ‰‰ Derotational Osteotomy  1187

63 Protrusio Acetabuli [Otto-Chrobak 66 Total Hip Replacement Arthroplasty


Pelvis, Otto Pelvis, Arthrokatadysis (Rationale, Design, Complications
(Greek—Subsidence of Joint), and Revision) 1189
Osteoarthritis Deformans, Manish Kumar Varshney, Aditya Soral
Osteoarthritic Protrusion of ‰‰ Principle of Total Hip Arthroplasty  1189
‰‰ History of Total Hip Arthroplasty  1189
the Acetabulum] 1158 ‰‰ Components of a Modular Hip Prosthesis  1191
Manish Kumar Varshney ‰‰ Fixation Methods of Prosthesis: Cemented versus
‰‰ Historical Considerations  1158 Uncemented 1199
‰‰ Classification 1158 ‰‰ Goals of Total Hip Arthroplasty  1201
‰‰ Biomechanics of Protrusio  1159 ‰‰ Indications for Total Hip Arthroplasty  1201
‰‰ Clinical Features  1159 ‰‰ Contraindications for Hip Arthroplasty  1202
‰‰ Radiographs 1159 ‰‰ Clinical Results and Possible Complications  1203
‰‰ Laboratory Workup  1161 ‰‰ Complications of Arthroplasty  1203
‰‰ Management of Protrusio  1161 ‰‰ Cement-in-cement Revision  1215

64 Transient Synovitis of Hip (Transitory 67 Intertrochanteric Resection Osteotomy/


Coxitis, Acute Transient Epiphysitis, Arthroplasty of Girdlestone (and its
Coxitis Fugax, Coxitis Serosa Seu Modifications) 1217
Simplex, Phantom Hip Disease, Toxic Manish Kumar Varshney
Synovitis, and Observation Hip) 1164 ‰‰ Indications 1217
‰‰ Technique (Classical Girdlestone)  1217
Manish Kumar Varshney
‰‰ Modifications of Girdlestone Arthroplasty  1217
‰‰ Epidemiology 1164 ‰‰ Postoperative Course  1218
‰‰ Etiology 1164 ‰‰ Complications 1218
‰‰ Diagnosis 1164
‰‰ Differential Diagnosis  1165 68 Hip Arthrodesis 1219
‰‰ Treatment 1166 Manish Kumar Varshney
‰‰ Natural History and Prognosis  1166
‰‰ History of the Procedure  1219
65 Osteotomies Around the Hip Joint 1167 ‰‰ Biomechanics and Natural History of the Procedure  1221
‰‰ Classification of Hip Arthrodesis Procedures  1222
Manish Kumar Varshney ‰‰ Contraindications for Hip Arthrodesis  1222
‰‰ Definition 1167 ‰‰ Surgical Technique of Cobra-Head Plate Arthrodesis  1223
‰‰ Classification and Types of Proximal Femoral ‰‰ Postoperative Course  1224
Osteotomies 1168 ‰‰ Total Hip Replacement in an Arthrodesed Hip  1225
‰‰ General Work-up for Osteotomy  1169
‰‰ Clinical Examination  1169 69 Surgical Dislocation of the Hip (Ganz
‰‰ Radiological Evaluation of the Involved Hip  1169 Surgical Dislocation of Hip, Open
‰‰ Intertrochanteric Osteotomy  1170
Dislocation of Hip) 1226
‰‰ The Various Commonly Performed Osteotomies  1172
‰‰ Curved Varus Osteotomy for Osteonecrosis  1175 Manish Kumar Varshney
‰‰ Pelvic Support Osteotomy [Resection Angulation Osteotomy ‰‰ Principles 1226
(RAO), Pedicle Subtraction Osteotomy (PSO)] 1176 ‰‰ Technique 1227
‰‰ History of Pedicle Subtraction Osteotomy  1177 ‰‰ Complications 1228

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xxii Essential Orthopedics (Principles and Practice)

Section 9: Foot and Ankle Disorders 76 Inflammation of Foot and Ankle, and
Neuropathic Foot 1269
70 Ankle Anatomy 1233 Manish Kumar Varshney
‰‰ Rheumatoid Affection of Foot  1269
Manish Kumar Varshney
‰‰ Tibia 1233 77 Deformities of the Hallux 1275
‰‰ Fibula 1233 Manish Kumar Varshney
‰‰ Talus 1233
‰‰ Ligaments of Ankle Joint  1234 ‰‰ Bunion or Hallux Valgus  1275
‰‰ Tendons and Neurovascular Structures  1236 ‰‰ Crossover Second Toe  1283
‰‰ Hallux Rigidus  1284
71 Biomechanics of the Ankle Joint ‰‰ Hallux Flexus  1285
and Related Examination 1237 ‰‰ Rigid Hammer Toe  1286
‰‰ Flexible Hammer Toe  1287
Manish Kumar Varshney ‰‰ Claw Toe  1287
‰‰ Foot 1239 ‰‰ Mallet Toe  1287
‰‰ Ankle Joint Movements  1240 ‰‰ Tailor’s Bunion or Bunionette  1288
‰‰ Neurological Examination  1241 ‰‰ Ingrowing Toenail (IGTN, Onychocryptosis)  1288
‰‰ Measurements 1243
78 Acquired Flatfoot (Pes Planus) and
72 Arches of the Foot 1244 Charcot Flatfoot (Neuropathic
Manish Kumar Varshney Osteoarthropathy) 1290
‰‰ Bones of the Arches  1244 Manish Kumar Varshney
‰‰ Mechanisms of the Arch Support  1245
‰‰ Maintenance of the Medial Longitudinal Arch  1245 Acquired Flatfoot (Pes Planus)  1290
‰‰ Maintenance of the Lateral Longitudinal Arch  1245 ‰‰ Etiology 1290
‰‰ Maintenance of the Transverse Arch  1245 ‰‰ Pathoanatomy 1290
‰‰ Propulsive Action of the Foot  1245 ‰‰ Symptoms 1290
‰‰ Forefoot 1247 ‰‰ Physical Examination  1291
‰‰ Sole of the Foot  1248 ‰‰ Radiology of Flatfoot  1291
‰‰ Tripod Action of the Foot  1249 ‰‰ Ancillary Studies  1291
‰‰ Movements at Foot  1249 ‰‰ Stages of Development of Flatfoot  1292
‰‰ Flexible Pes Planus  1293
73 Examination of the Foot and Ankle 1251
‰‰ Etiology 1293
Manish Kumar Varshney ‰‰ Clinical Examination  1293
‰‰ Inspection 1251 ‰‰ Radiograph 1294
‰‰ Posture 1252 ‰‰ Treatment 1294
‰‰ Medial Arch  1252 ‰‰ Rigid Pes Planus  1294
‰‰ Heels 1252 ‰‰ Peroneal Spastic Pes Planus  1295
‰‰ Shoes 1252
Charcot Flatfoot (Neuropathic
‰‰ Club Foot Deformity  1254
Osteoarthropathy) 1296
‰‰ Palpation 1255

74 Tarsal Tunnel Syndrome 1257 79 Pes Cavus 1298


Manish Kumar Varshney Manish Kumar Varshney
‰‰ Anatomy 1257 ‰‰ Etiology 1298
‰‰ Etiology 1258 ‰‰ Pathogenesis of Deformity  1299
‰‰ Clinical Features and Examination  1258 ‰‰ Types of Deformity  1300
‰‰ Investigations 1259 ‰‰ Natural History of Pes Cavus and Clinical
‰‰ Differential Diagnosis  1259 Relevance 1301
‰‰ Treatment 1259 ‰‰ Principles of Treatment  1301

75 Ligament Injuries Around Ankle 1261 80 Hindfoot Deformities 1305


Manish Kumar Varshney Manish Kumar Varshney
‰‰ Classification 1263 ‰‰ Hindfoot Valgus Deformity  1305
‰‰ Chronic Instability after Injury  1266 ‰‰ Hindfoot Varus Deformity  1305

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81 Foot Drop 1307 ‰‰ White Matter and Spinal Cord Tracts  1336
‰‰ Blood Supply of the Spinal Cord  1337
Manish Kumar Varshney
‰‰ Pathophysiology 1308 86 Low Back Pain and Intervertebral Disk
‰‰ Clinical Presentation  1308 Degeneration 1339
‰‰ Diagnosis 1308
‰‰ Treatment 1308 Manish Kumar Varshney
‰‰ Complications 1309 ‰‰ Investigations 1339
‰‰ The Concept of Pain Generator and Common
82 Avascular Necrosis of the Metatarsal Recognized Pain Generators in Lumbar Spine  1340
Head (Freiberg’s Disease) 1310 Intervertebral Disk Degeneration  1345
Manish Kumar Varshney ‰‰ Pathoanatomy 1345
‰‰ Pathobiomechanics 1346
‰‰ Etiology 1310
‰‰ Degenerative Processes  1347
‰‰ Clinical Features  1310
‰‰ Production of Pain and Radicular Symptoms in
‰‰ Investigations 1310
Degenerative Disk Disease  1349
‰‰ Differential Diagnosis  1311
‰‰ Etiology of Disk Degeneration  1350
‰‰ Staging by Smillie  1311
‰‰ Pathophysiology of Disk Degeneration  1353
‰‰ Surgical Algorithm  1312
‰‰ Classification of Pathology of Disk Degeneration  1355
‰‰ Diagnosis of Internal Disk Disruption  1355
83 Tendo-Achilles Rupture 1313
‰‰ Treatment of Discogenic Pain  1356
Manish Kumar Varshney ‰‰ Chemonucleolysis 1357
‰‰ Site and Mechanism of Tear  1313 ‰‰ Gene Therapy/Cell-based Therapies  1360
‰‰ Pathoanatomy and Pathophysiology  1314 ‰‰ Augmentation of Nucleus Pulposus/Nucleus
‰‰ Clinical Features  1314 Replacement 1361
‰‰ Investigations 1315 ‰‰ Regeneration of the Cartilage Endplate  1362
Lumbar Spondylosis and Lumbar Degenerative Disk
84 Morton’s Metatarsalgia (Morton Toe, Disease 1362
Interdigital Neuroma) 1319 ‰‰ Epidemiology 1362
Manish Kumar Varshney ‰‰ Clinical Features  1362
‰‰ Diagnostic Imaging  1363
‰‰ Pathogenesis 1319
‰‰ Diagnosis 1364
‰‰ Pathoanatomy 1319
‰‰ Treatment 1364
‰‰ Clinical Features  1319
‰‰ Facet Replacement  1369
‰‰ Investigations 1320
‰‰ Treatment 1320 87 Interventional Techniques for Diagnosis
‰‰ Complications 1320
and Treatment of Back Pain 1370
Ashok Jadon, Palak Mehta
Section 10: Regional Orthopedics—Spine
‰‰ Role of Interventional Pain Management in the
Management of Low Back Pain  1371
85 Anatomy of the Spine and Spinal Cord 1323 ‰‰ Red Flags and Yellow Flags—A Caution Before
Intervention 1371
Manish Kumar Varshney, S Pavan ‰‰ Facet Joint Injection and Medial Branch Block  1373
‰‰ Vertebral Column  1323 ‰‰ Myofascial Pain and Trigger Point Injection  1374
‰‰ Curvatures of Vertebral Column  1324 ‰‰ Epidural Steroid Injection  1375
‰‰ Vertebral Joints  1325 ‰‰ Approaches for Epidural Steroid Injection in Back Pain  1376
‰‰ The Intervertebral Disk  1326 ‰‰ Lumbar Interlaminar Approach  1376
‰‰ Molecular Composition of the Intervertebral ‰‰ Caudal Epidural  1377
Disk 1326 ‰‰ Epidurography and Epiduroscopy  1378
‰‰ Functions of Intervertebral Disk  1328 ‰‰ Epidurolysis/Epidural Adhesiolysis/Neuroplasty  1379
‰‰ Changes in the Intervertebral Disk with Age  1329 ‰‰ Provocative Discography  1379
‰‰ Biomechanics of Intervertebral Disk  1329 ‰‰ Percutaneous Disk Decompression/Discectomy  1379
‰‰ Blood Supply of Intervertebral Disk  1330 ‰‰ Ozone Nucleolysis  1379
‰‰ Innervation of Vertebral Disk  1330 ‰‰ Sacroiliac Joint Steroid Injection/Radiofrequency
‰‰ Blood Supply of Spine  1330 Neurotomy 1380
‰‰ The Spinal Cord  1331 ‰‰ Percutaneous Vertebroplasty and Kyphoplasty  1381
‰‰ Structure of the Spinal Cord  1333 ‰‰ New Techniques  1381

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xxiv Essential Orthopedics (Principles and Practice)

‰‰ Annuloplasty 1382 ‰‰ Sagittal Plane Deformity of Spine  1454


‰‰ Gray Ramus Block  1382 ‰‰ Cervical Kyphosis  1459
‰‰ Spinal Cord Stimulator  1383
‰‰ Indication of Surgery  1384 91 Lumbar Spondylolysis and
Spondylolisthesis 1467
88 Lumbar Disk Herniation and
Manish Kumar Varshney
Spinal Stenosis 1385
Spondylolysis 1467
Manish Kumar Varshney
‰‰ Pathophysiology 1468
Lumbar Disk Herniation  1385 ‰‰ Symptoms 1468
‰‰ Pathoanatomy 1385 ‰‰ Natural History  1468
‰‰ Terminology of Disk Pathology  1385 ‰‰ Clinical Features  1468
‰‰ Pathophysiology 1386 ‰‰ Imaging 1468
‰‰ Epidemiology 1387 ‰‰ Differential Diagnosis  1469
‰‰ Pathoanatomy 1387 Spondylolisthesis 1469
‰‰ Natural History of Lumbar Disk Herniation  1387 ‰‰ Classification System  1469
‰‰ Clinical Features  1387 ‰‰ Natural History  1469
‰‰ Diagnostic Imaging  1389 ‰‰ Congenital or Dysplastic Spondylolisthesis  1471
‰‰ Treatment 1390 ‰‰ Isthmic Spondylolisthesis  1471
‰‰ Comparing Nonoperative and Operative ‰‰ Degenerative Spondylolisthesis  1475
Management 1391 ‰‰ Traumatic Spondylolisthesis  1478
‰‰ Failure of Discectomy (Failed Back)  1391 ‰‰ Pathologic Spondylolisthesis  1478
‰‰ Indications for Fusion after Discectomy  1392 ‰‰ Iatrogenic Spondylolisthesis  1478
‰‰ Management of Cauda Equina Syndrome  1392
‰‰ Recurrent Herniation and Revision  1392 92 Diffuse Idiopathic Skeletal Hyperostosis
‰‰ Disk Herniation in Pediatric Patients  1392
(DISH, Forestier Disease, Ankylosing
Lumbar Spinal Stenosis  1393
Hyperostosis, Generalized Juxta-articular
‰‰ Pathoanatomy 1393
‰‰ Pathophysiology 1393 Ossification of Vertebral Ligaments, and
‰‰ Clinical Features  1394 Spondylosis Hyperostotica) 1479
‰‰ Diagnostic Imaging  1394
Manish Kumar Varshney
‰‰ Treatment 1395
‰‰ Etiology 1480
89 Failed Back Surgery Syndrome 1397 ‰‰ Prevalence 1480
‰‰ Clinical Presentation  1480
Manish Kumar Varshney ‰‰ Spinal Manifestations  1480
‰‰ Incidence 1397 ‰‰ Extraspinal Manifestations  1481
‰‰ Etiology of Failed Back Surgery Syndrome  1397 ‰‰ Radiology 1482
‰‰ Classification of Patients with FBS  1398 ‰‰ Differential Diagnosis  1483
‰‰ Patient Evaluation  1399 ‰‰ Treatment 1484
‰‰ Prevention and Management  1400
‰‰ Medial Branch Radiofrequency Lesionning  1402 93 Rheumatoid Affection of Spine 1485
‰‰ Spinal Endoscopy (Epiduroscopy)  1402 Manish Kumar Varshney
90 Deformities of Spine 1404 ‰‰ Epidemiology and Natural History  1489
‰‰ Clinical Presentation  1489
Manish Kumar Varshney
‰‰ Diagnostic Evaluation  1490
‰‰ Scoliosis 1404 ‰‰ Atlantoaxial Subluxation  1490
‰‰ Historical Perspective  1406 ‰‰ Cranial Settling/Superior Migration of the Odontoid  1491
‰‰ Idiopathic Scoliosis  1408 ‰‰ Subaxial Subluxation  1492
‰‰ Adolescent Idiopathic Scoliosis  1409 ‰‰ Diagnostic Strategy  1493
‰‰ Clinical Features  1411 ‰‰ Management 1493
‰‰ Physical Examination and Diagnosis  1412 ‰‰ Types of Surgical Stabilization  1494
‰‰ Curve Classification  1419 ‰‰ Outcome and Complications  1496
‰‰ Management 1434
‰‰ Fusion Surgery  1434 94 Vertebral Discitis and Osteomyelitis and
‰‰ Congenital Scoliosis  1436 Other Spinal Infections 1497
‰‰ Adult Scoliosis and Deformity  1442
‰‰ Evaluation and Investigations  1445 Manish Kumar Varshney
‰‰ Neuromuscular Scoliosis  1451 ‰‰ Tuberculosis of Spine (Pott’s Spine, Pott’s Disease)  1497

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Contents xxv

‰‰ Vertebral Pyogenic Osteomyelitis (VPO) 1517 ‰‰ Movements at Elbow Joint  1572


‰‰ Pyogenic Epidural Abscess  1524 ‰‰ Constraints of Elbow Joint  1572
‰‰ Biomechanics of Throw  1572
95 Spinal Cord Injury 1526
Manish Kumar Varshney 99 Tendon Disorders of Elbow 1574
‰‰ Etiology 1526 Manish Kumar Varshney
‰‰ Epidemiology 1526 Lateral Epicondylitis  1574
‰‰ Mechanisms of Injury  1531 ‰‰ History 1574
‰‰ Vascular Insult and Oxidative Overload  1533 ‰‰ Etiology 1574
‰‰ Spinal Cord Injury  1534 ‰‰ Associations 1575
‰‰ Excitotoxicity 1534 ‰‰ Pathogenesis 1575
‰‰ Immunological Mechanisms  1535 ‰‰ Clinical Features  1576
‰‰ Role of Mitochondria  1535 ‰‰ Provocative Tests  1577
‰‰ Miscellaneous Mediators Implicated in Secondary ‰‰ Differential Diagnosis  1577
Spinal Cord Injury  1536 ‰‰ Investigation 1577
‰‰ Early Immobilization and Stabilization of the Spine  1536 ‰‰ Treatment 1578
‰‰ Glutamate Receptor Antagonists (Anti-excitotoxic ‰‰ Complications 1581
Agents) 1539 Medial Epicondylitis  1581
‰‰ Definitive Management  1542 ‰‰ History 1581
‰‰ Complications of Spinal Cord Injury  1544 ‰‰ Biomechanics 1581
‰‰ Prognosis of Spinal Cord Injury  1544 ‰‰ Anatomy and Pathomechanics  1581
‰‰ Pathophysiology 1582
96 Spinal Dysraphism (Spina Bifida, Myelocele, ‰‰ Clinical Features  1582
Meningomyelocele, Diastemetomyelia) 1546 ‰‰ Differential Diagnosis  1582
Manish Kumar Varshney ‰‰ Investigations 1582
‰‰ Treatment 1583
‰‰ Epidemiology 1548
‰‰ Postoperative Management  1583
‰‰ Clinical Features (in General for Spinal Dysraphism)  1548
‰‰ Embryological and Developmental Aspects  1548 Distal Biceps Tendon Rupture  1584
‰‰ Anatomy 1584
‰‰ Anomalies of Development  1551
‰‰ Pathophysiology 1584
‰‰ Malformations of Neurulation  1552
‰‰ Epidemiology 1585
‰‰ Malformation During the Second Phase (Canalization,
‰‰ Clinical Presentation  1585
Stages XLLL-XX) and the Third Phase (Retrogressive
‰‰ Investigations 1585
Differentiation, Stages XX Thereafter) 1554
‰‰ Treatment 1585
‰‰ Tethered Cord Syndrome  1557
Triceps Tendon Rupture  1587
97 Vertebra Plana and CT-Guided Biopsy 1559 ‰‰ Anatomy 1587
‰‰ Pathophysiology 1587
Manish Kumar Varshney
‰‰ Clinical Presentation  1588
‰‰ Features and Diagnosis  1559 ‰‰ Investigation 1588
‰‰ Radiological Features  1559 ‰‰ Treatment 1588
‰‰ Management 1560 ‰‰ Complications 1589
‰‰ Computed Tomography-guided Biopsy  1562
‰‰ Historical Perspective  1562 100 Elbow Instability 1590
‰‰ Causes of False Negative Biopsies  1564
Manish Kumar Varshney
‰‰ Complications of Spinal Biopsy  1564
‰‰ Intervertebral Disk Calcification  1564 ‰‰ Classification of Elbow Instability  1590
‰‰ Etiology 1590
‰‰ Pathomechanics 1591
Section 11: Regional Orthopedics—Hand ‰‰ Evaluation of the Patient with Chronic Instability  1592
and Upper Extremity (Except Shoulder) ‰‰ Differential Diagnosis  1593
‰‰ Management of Elbow Instability  1593
‰‰ Chronic Valgus Elbow Instability  1595
98 Elbow Anatomy and Biomechanics 1569 ‰‰ Management 1598
‰‰ Erosive Arthropathies  1599
Manish Kumar Varshney ‰‰ Terrible Triad Injuries  1599
‰‰ Bony Anatomy  1569 ‰‰ Recurrent Dislocation of Elbow  1599
‰‰ Ligaments 1569 ‰‰ Valgus-Extension Overload Syndrome  1599
‰‰ Functions of Elbow  1571 ‰‰ Radiocapitellar Overload Syndrome  1601

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xxvi Essential Orthopedics (Principles and Practice)

‰‰ Posterolateral Rotatory Instability  1601 ‰‰ ECU Tendon Problems and ECU Tendinitis 1681
‰‰ Recurrent Isolated Radial Head Instability  1603 ‰‰ Vaughan-Jackson Syndrome  1684
‰‰ Ulnocarpal Impaction/Abutment Syndrome and
101 Stiff Elbow 1606 Ulna Impingement Syndrome  1685
Manish Kumar Varshney ‰‰ Ulnocarpal Impaction Syndrome Secondary to
Ulnar Styloid Nonunion  1687
‰‰ Etiology 1606
‰‰ Ulnar Impingement Syndrome  1687
‰‰ Classification 1606
‰‰ Clinical Features  1608 106 Volkmann Ischemic Contracture 1689
‰‰ Investigations 1608
‰‰ Management 1608 Manish Kumar Varshney
‰‰ Operative Management  1609 ‰‰ Pathogenesis 1689
‰‰ Ectopic Ossification Around Elbow  1612 ‰‰ Classification of Volkmann Ischemic Contracture  1690
‰‰ Management 1612 ‰‰ Assessment of Patient  1692
‰‰ Radial Head Excision  1614
‰‰ Elbow Arthroplasty Procedures  1614 107 Compressive and Entrapment
Neuropathies of Upper Limb 1696
102 Hand Anatomy and Function 1619
Manish Kumar Varshney
Manish Kumar Varshney
‰‰ Carpal Tunnel Syndrome  1696
‰‰ Positions of the Hand  1621 ‰‰ Anterior Interosseous Nerve (AIN) Compressive Neuropathy
‰‰ Anatomy 1622 (Anterior Interosseous Nerve Syndrome)  1706
‰‰ Anatomy of Tendons  1630 ‰‰ Pronator Syndrome  1708
‰‰ Cubital Tunnel Syndrome  1709
103 Carpal Instability 1635
‰‰ Ulnar Tunnel Syndrome  1714
Manish Kumar Varshney ‰‰ Radial Tunnel Syndrome (RTS, Supinator Syndrome)  1716
‰‰ Definition 1635 ‰‰ Wartenberg Syndrome  1721
‰‰ Pathomechanics 1636 ‰‰ Posterior Interosseous Nerve Compression Syndrome  1722
‰‰ Classification of Carpal Instability  1637
‰‰ Management of Carpal Instability  1638 108 Peripheral Nerve Injuries 1723
‰‰ Dissociative Carpal Instability  1639 Manish Kumar Varshney
‰‰ Dissociative Distal Carpal Instability (Distal CID) 1645 ‰‰ Anatomical Considerations  1723
‰‰ Carpal Instability Complex  1647
‰‰ Neuron 1724
104 Common Miscellaneous Conditions ‰‰ Structure and Function of a Peripheral Nerve  1725
‰‰ Gross Fascicle Organization of Nerve Structure  1727
of Hand 1651 ‰‰ Myoneural Junction  1728
Manish Kumar Varshney ‰‰ Neuron Action Potential  1728
‰‰ De Quervain’s Stenosing Tenosynovitis (De Quervain’s ‰‰ Axonal Transport  1729
Tenovaginitis, De Quervain’s Disease, Washerwoman’s Sprain, ‰‰ Blood-Nerve Interface  1729
Stenosing Peritendinitis)  1651 ‰‰ Biomechanical Properties of Peripheral Nerve  1730
‰‰ Intersection Syndrome (Abductor Pollicis Longus Bursitis, ‰‰ Peripheral Nerve Injury  1731
Crossover Tendinitis, Squeaker’s Wrist, and Peritendinitis ‰‰ Factors Affecting Wallerian Degeneration and the
Crepitans) 1654 Effect of Slow Wallerian Degenerations Protein and
‰‰ Trigger Finger  1654 Nicotinamide Mononucleotide Adenylyltransferase  1734
‰‰ Congenital Trigger Thumb  1657 ‰‰ Clinical Features  1735
‰‰ Dupuytren’s Contracture  1657 ‰‰ Nerve Pinch or Stretch Syndromes  1736
‰‰ First Metacarpophalangeal Joint Ulnar Collateral Ligament ‰‰ Classification of Nerve Injury  1736
Injury (Gamekeeper’s Thumb and Skier’s Thumb)  1664 ‰‰ Diagnosis of Nerve Injury  1737
‰‰ Thumb CMC Joint Arthritis (Basal Joint Arthritis)  1666 ‰‰ Nerve Conduction Velocity  1739
‰‰ Strength-Duration Curve  1739
105 Distal Radioulnar Joint Disorders ‰‰ Management 1740
and Ulnar Wrist Pain 1671 ‰‰ Nerve Repair (Neurorrhaphy)  1740
‰‰ Augmentation of Nerve Repair  1742
Manish Kumar Varshney ‰‰ Management of Nerve Defects  1742
‰‰ Anatomy 1671 ‰‰ Special Scenarios  1745
‰‰ Pathology at DRUJ and Pathogenesis  1673 ‰‰ Injection Nerve Palsy  1746
‰‰ Diagnosis 1674 ‰‰ Management of Old and Late Presenting Cases  1748
‰‰ Treatment 1676 ‰‰ Early Tendon Transfers—“Internal Splints”  1749

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Contents xxvii

‰‰ Indications 1749 ‰‰ Knee Disarticulation  1802


‰‰ Individual Upper Limb Nerve Palsies of Upper Limb  1749 ‰‰ Hip Disarticulation  1803
‰‰ Combined Nerve Palsies of Upper Limb  1754 ‰‰ Hand Amputations  1807
‰‰ Thumb Reconstruction  1815
109 Rheumatoid Hand 1756 ‰‰ Pollicization 1815
Manish Kumar Varshney ‰‰ Wrist Disarticulation  1816

‰‰ Finger Deformity in Rheumatoid Arthritis  1758 Prostheses 1824


‰‰ Boutonniére Deformity  1761 ‰‰ Lower Limb Prosthesis  1824
‰‰ Metacarpophalangeal Joint Involvement in ‰‰ Joints 1827
Rheumatoid Arthritis  1762 ‰‰ Components for Interposing Joints  1833
‰‰ Rheumatoid Affection of the Wrist Joint  1763 ‰‰ Externally Powered Prostheses  1834
‰‰ Thumb Deformities in Rheumatoid Arthritis  1764 ‰‰ Orthotics 1835

110 Infections of the Hand 1767 113 Biomaterials in Orthopedics 1843


Manish Kumar Varshney S Pavan
‰‰ Principles of Treatment of Hand Infections  1767 ‰‰ Metals and their Alloys  1845
‰‰ Complications of Hand Infections  1767 ‰‰ Polymers 1846
‰‰ Nail Bed Infections  1767 ‰‰ Ceramics 1847
‰‰ Bite Wounds of Hand  1772 ‰‰ Composits 1847
‰‰ Deep Space Infections  1773 ‰‰ Osteointegration of Biomaterials  1847
‰‰ Web Space Infection (Collar-Button Abscess/
Hourglass Abscess)  1773 114 Pain Management in Orthopedic
‰‰ Midpalmar Space Infection  1774 Patient 1849
‰‰ Thenar Space Infections  1774 Ashok Jadon
‰‰ Hypothenar Space  1775
‰‰ Flexor Tenosynovitis (Pyogenic Flexor Tenosynovitis or ‰‰ Definition 1849
Suppurative Flexor Tenosynovitis)  1775 ‰‰ Pain Threshold, Perceptual Dominance and Pain
Tolerance 1849
111 Tendon Injuries of Hand and ‰‰ Types of Pain  1849
Pathways of Pain  1850
Management 1777 ‰‰
‰‰ Gate Control Theory (Pain Production and Modulation
Manish Kumar Varshney Theory) 1851
‰‰ Historical Perspective  1777 ‰‰ Postoperative Pain and its Management  1851
‰‰ Anatomical and Biomechanical Considerations  1778 ‰‰ Assessment of Pain  1852
‰‰ Causes of Tendon Injuries  1781 ‰‰ Systemic Effects of Poor Pain Control  1853
‰‰ Clinical Features  1781 ‰‰ Barriers to Effective Pain Management  1854
‰‰ Postoperative Protocol  1786 ‰‰ Strategies for Adequate Postoperative Pain Control  1855
‰‰ Treatment of Tendon Ruptures  1787 ‰‰ Methods for Postoperative Pain Control  1855
‰‰ Extensor Tendon Ruptures  1787 ‰‰ Drugs Used for Postoperative Pain Control  1859
‰‰ Way Forward  1863
Section 12: General Topics 115 Necrotizing Fasciitis 1864
S Pavan
112 Amputations and Rehabilitation 1791 ‰‰ Etiology 1864
S Pavan ‰‰ Pathophysiology 1864
‰‰ Clinical Features  1864
Amputations 1791 ‰‰ Treatment 1865
‰‰ Indications and Principles  1791
‰‰ Dressing Technique  1795 116 Robotics and Computers in
‰‰ Immediate Postoperative Prosthesis and Orthopedics 1867
Physiotheraphy 1795
‰‰ Pain Management  1796 Jaydip Patel
‰‰ Rehabilitation 1797 ‰‰ Haptic Robotic Systems  1867
‰‰ Complications of Amputation Surgery  1797 ‰‰ Autonomous Robotic Systems  1868
‰‰ Lower Limb Amputations  1798 ‰‰ Robotic Surgery: Pitfalls and Limitations  1868
‰‰ Amputations Around Ankle  1799 ‰‰ Role of Computers in Orthopedics  1868

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xxviii Essential Orthopedics (Principles and Practice)

117 Gene Therapy in Orthopedics 1871 ‰‰ Complications 1912


‰‰ Contraindications for Use of Tourniquets  1913
Jaydip Patel, Manish Kumar Varshney ‰‰ Systemic and Local Effects of Tourniquet Usage  1913
‰‰ The Use of Different Vectors and Strategies for ‰‰ Systemic Adverse Effects  1913
Gene Transfer in Orthopedics  1871 ‰‰ Tourniquet Pain and Tourniquet-induced
‰‰ Newer Approach: Nanoparticles and Hypertension 1915
Nanotechnology 1876 ‰‰ Alteration in Drug Kinetics Due to Tourniquet
‰‰ Gene Therapy Using RNAI  1877 Application 1915
‰‰ New Vectors or Strategies for Stable and Safe Gene
Modification 1877 122 Replantation 1916
‰‰ Targeted Gene Delivery  1879
S Pavan
‰‰ Gene Therapy Applications for the Musculoskeletal
System 1880 ‰‰ Level of Amputation  1916
‰‰ Mechanism of Injury  1916
118 Thoracic Outlet Syndrome 1886 ‰‰ Condition of the Vessels  1916
‰‰ Transport of Amputated Part  1917
Swapnil Sharma, Jaydip Patel, Amit Singh
‰‰ Preoperative Preparation  1917
‰‰ History 1886 ‰‰ Order of Replantation  1917
‰‰ Definition 1886 ‰‰ Postoperative Care and Outcomes  1918
‰‰ Anatomy 1886
‰‰ Epidemiology 1887 123 Isotope Bone Scan 1919
‰‰ Etiology 1887
S Pavan
‰‰ Clinical Presentation  1887
‰‰ Physical Examination  1888 ‰‰ Hybrid Scanning Techniques  1919
‰‰ Differential Diagnoses for Thoracic Outlet Syndrome  1889
‰‰ Diagnostic Studies  1889 124 Lasers in Orthopedics 1921
‰‰ Treatment 1889 S Pavan
‰‰ Complications 1890 ‰‰ Therapeutic Lasers  1921
‰‰ Surgical Lasers  1921
119 Wound Ballistics 1891 ‰‰ Pitfalls 1922
Manish Kumar Varshney, Swapnil Sharma
‰‰ Classification 1892 125 Magnetic Resonance Imaging 1924
‰‰ Soft-Tissue Wound Management  1894 S Pavan
‰‰ Wound Infection  1895 ‰‰ Fast Spin-echo Technique  1924
‰‰ Pathophysiology of Lead Toxicity  1895 ‰‰ Gradient-echo Technique  1924
‰‰ Principles of Management  1895 ‰‰ Short TAU Inversion Recovery Enhanced Images  1925
‰‰ International Humanitarian Law  1895 ‰‰ Fluid-attenuated Inversion Recovery  1925
‰‰ Blast Injuries  1896 ‰‰ Functional MRI (FMRI) 1925
‰‰ Multinuclear Imaging  1926
120 Polytrauma, Mass Casualties and
‰‰ Contrast Magnetic Resonance Imaging  1926
Disaster 1899 ‰‰ Contraindications of Magnetic Resonance Imaging  1927
Manish Kumar Varshney ‰‰ Knee 1927
‰‰ Definitions 1899 ‰‰ Shoulder 1929
‰‰ Principles of Management of Polytrauma  1899 ‰‰ Spine 1930
‰‰ Damage Control Orthopedics (DCO) versus ‰‰ Foot and Ankle  1932
Early Total Care (ETC) 1904 ‰‰ Hip 1933
‰‰ Principles of Managing Disasters  1906 ‰‰ Wrist 1934
‰‰ Tumor Imaging  1934
121 Tourniquet in Orthopedics 1909
126 Role of Ultrasonography in
Manish Kumar Varshney
Orthopedics 1936
‰‰ Tourniquet Safety  1909
‰‰ Size of Tourniquets and Application Technique  1910 Jaydip Patel, Manish Kumar Varshney
‰‰ Tourniquet Pressure (Occlusion Pressure) and Size Pressure ‰‰ Advantages of Ultrasonography  1937
Relationship 1910 ‰‰ Uses of Ultrasonography in Orthopedics  1937
‰‰ Duration of Tourniquet Use (Ischemic Time)  1911 ‰‰ Neonatal Conditions  1938
‰‰ The Use of Esmarch Tourniquet and Martin Rubber Sheet  1912 ‰‰ Interventional Procedures  1941

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Contents xxix

127 Instruments and Implants 1942 ‰‰ Sir Robert Jones (1857–1933)  1968
‰‰ Thomas Porter Mcmurray (1888–1949)  1968
S Pavan ‰‰ Willis C Campbell (1880–1941)  1968
‰‰ Awls 1942 ‰‰ Gerhard Küntscher (1900–1972)  1969
‰‰ Chisels/Osteotomes/Gouges 1942 ‰‰ Martin Kirschner (1879–1942)  1969
‰‰ Bone-holding Clamps  1943 ‰‰ Sir Reginald Watson-Jones (1902–1972)  1969
‰‰ Bone Cutters/Nibblers  1943 ‰‰ Austin T Moore (1899–1963)  1970
‰‰ Periosteal Elevators  1943 ‰‰ Gavriil A Ilizarov (1921–1992)  1970
‰‰ Curettes 1946 ‰‰ Sir John Charnley (1911–1982)  1971
‰‰ Retractor/Levers 1946
‰‰ Cartilage/Tendon Instruments  1947 129 Wound Healing and Principles of
‰‰ General Instruments  1948 Wound Care 1973
‰‰ General Trauma Instruments  1950
Manish Kumar Varshney
‰‰ Nails 1953
‰‰ Plates 1955 ‰‰ Epithelialization 1973
‰‰ Screw 1958 ‰‰ Wound Contraction  1974
‰‰ Choice of Suture Material  1978
128 History of Orthopedics 1964 ‰‰ Factors Affecting Wound Healing  1978
‰‰ Soft Tissue Coverage in Orthopedics  1981
Swapnil Sharma, Manish Kumar Varshney
‰‰ Reconstruction of Proximal Third Leg  1988
‰‰ Ambroise Paré (1510–1590)  1964 ‰‰ Reconstruction of Soft Tissue Defects in
‰‰ Nicolas Andry (1658–1742)  1965 Middle Third Region of Leg  1990
‰‰ Percivall Pott (1714–1788)  1965 ‰‰ Reconstruction of Distal Third Region of the Leg  1992
‰‰ John Hunter (1728–1793)  1966 ‰‰ Microvascular Free Flaps  1992
‰‰ Abraham Colles (1773–1843)  1966 ‰‰ Pressure Sores (Bed Sores, Pressure Ulcers)  1995
‰‰ Antonius Mathijsen (1805–1878)  1967
‰‰ Hugh Owen Thomas (1834–1891)  1967 Index 1997

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SECTION 1
Bone Anatomy, Physiology,
Pathology and Diseases

Structure and Function of Bones and Joints


Fracture and Fracture Repair
Metabolic Diseases of Bone and Effect of Glucocorticoid Therapy on Bone
Infections of Bone
Bone Tumors
Osteonecrosis and Osteochondrosis

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Chapter

1 Structure and Function of


Bones and Joints
Manish Kumar Varshney

BONE STRUCTURE •• The inorganic portion comprises of crystalline calcium


phosphate salts, present in the form of hydroxyapatite
Bone is a composite tissue (in engineering sense discussed [Ca 10 (PO 4 ) 6 (OH) 2 ] with minor contribution from
below) consisting of organic matrix, inorganic minerals, carbonates, fluorides and other magnesium salts.
cells and water. Biologically, it is a dynamic mesenchymal •• The organic component is dominated by type I
(specialized connective) hard tissue that undergoes collagen that forms the basic architecture of bone
continuous formation and remodeling throughout life. The on which inorganic portion is deposited. Support to
size of bone increases by growth (skeletal modeling) during collagen is provided by derived protein components
initial life till physeal closure and the shape of bone changes like proteoglycans, glycoproteins, phospholipids
through remodeling. The remodeling process occurs in and phosphoproteins that serve specific functions
adulthood and is essentially a mechanism that differentiates (discussed below).
living tissue from non-living tissue. Remodeling gives Both the components give bone its unique mechanical,
capacity to bone to repair itself and renew the lost internal biological and electrical properties. Loss or inadequacy
structures from wear and tear process. It also enables of mineral component (osteomalacia or rickets) or
bone to adapt itself to changing environment resulting organic component (like osteogenesis imperfecta)
from altered activity levels and aging. Both modeling and produces structurally weak bones that fail easily. The
remodeling occur via “coupling” of bone resorption and bones comprise (Figs 2A to E) of typical distribution of
bone formation that occurs simultaneously. The bone per hard (“compact”) bone outside, supported internally by
se consists of (Fig. 1) predominant inorganic component biologically more active (“cancellous”) bone that has nine
(60%) and organic component (40%). times the metabolic activity (Table 1). This distribution

Fig. 1: Broad constituents of bone

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4 Section 1:  Bone Anatomy, Physiology, Pathology and Diseases

A C
D

B
E
Figs 2A to E: The gross appeareance (A to C) to microstructure (D and E) of bone. The cortex forms a cylinder encircling the medullary cavity
(A) and is in turn covered by the periosteum (green envelop here). Illustrated are the dispositions of cortical and cancellous components (B) of
human bone in a typical long bone (tibia here), the cancellous bone typically occupies the epiphysis and metaphysis of a long bone while cortical
bone predominates in the diaphysis. The microstructure of mature cortical (compact) bone comprises of concentric rings around Haversian
(longitudinal) and Volkmann (transverse) canal system within the osteoid (C), also shown are the osteocytes arranged in the lamellations (D)
that form the largest network of cells connecting skeletal system to the outside environment through their processes (E) and also maintains
homeostasis within bone

TABLE 1: Difference between cortical and cancellous bone


Cortical bone Cancellous bone
Forms the outer part or “shell” of bone Contained within shell
Predominantly found in diaphyseal region Predominantly seen in metaphyseal and epiphyseal regions
Concentric lamellar structure around Haversian system—osteonal formation Contains lamellae, but osteons are missing
Provides compressive strength to bone Provides tensile strength to bone and resilience
Provides attachment to tendons, ligaments and periosteum Provides scaffolding to marrow cavity and space for osteoprogenitor cells
Metabolically less active Nine times more metabolically active than cortical bone
Slow remodeling. Thickening occurs on the concave side (compression), Complete trabecular structure changes with continuous remodeling. Tra-
while convex side (tensile side) undergoes thinning and resorption becular hypertrophy under compressive forces and even with tensile forces.
They atrophy and disappear with reduction of these forces
Usually minimal change in osteoporosis Undergoes great amount of resorption in osteoporosis
When used as a graft mainly provides strut support and compressive Preferred in bone grafting for higher osteogenic potential and remodels by
strength—less osteogenic potential creeping substitution

of hard and weak components gives bone mechanical Long Bones


advantage of discrete rigidity and flexibility. Such a structure
is called a “composite” mentioned initially. The long bones are formed by endochondral ossification.
The bones of arm, forearm, thigh and legs, viz. femur, ulna,
tibia, radius, humerus and fibula, are typical examples.
CLASSIFICATION OF BONE BY These have two ends (epiphysis), a cylindrical tube in
APPEARANCE the middle (diaphysis) and a transitional zone between
them (metaphysis). The long bones develop from cartilage
The human body has five different types of bones (Figs 3A enlage through a process of endochondral ossification.
to E): The ossification centers for epiphysis and the diaphysis

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Chapter 1:  Structure and Function of Bones and Joints 5

A B D E
Figs 3A to E: The five types of bones in human body. Long bones here exemplified by tibia and fibula (A) have expanded metaphysis at both
the ends capped by epiphysis that is separated by physis from metaphysis in an immature bone, and a cylindrical shaft in middle. Flat bones
are typified by skull (B) bones that have an outer and an inner table. The carpal and metatarsal bones (C) represent the small irregular bones
like pebbles of different shapes. Vertebrae (D) are best examples of irregular bones with multiple irregular processes and parts. Sesamoid bones
develop later in life commonly at the wear and tear sites of tendons or where the tendons need some mechanical advantage for their action,
here are shown the sesamoid bones in the tendon of flexor hallucis brevis beneath the first metatarsal of foot (E)

are different and are separated by growth plate also known Sesamoid Bones
as physis which is basically a layer of hyaline cartilage
organized into different layers. These bones also resemble short bones, but form without
ossification center (except patella) due to undue stress in the
region. They are found embedded in tendons or ligaments
Flat Bones and serve specific functions.
The flat bones as against long bones develop from a discrete The bone functions to:
process called intramembranous ossification. Scapula and •• Provide a rigid framework of all vertebrates to support
sternum are the representative examples. The flat bones the body
have an inner and an outer table of cortical bone intervened •• Act as levers for muscles
by trabecular bone as is exemplified by skull bones. •• Give shape to soft tissues and protect vital organs of body
by forming rigid or flexible cavities
•• Provide minerals in time of need as it has mineral
Short Bones reserve for calcium and phosphate.
Carpal and tarsal bones are representative examples. They
are predominantly composed of trabecular bone that is
shelled by a thin layer of cortical bone.
GROSS FEATURES OF BONE
As evident from the above classification the bones are
either shaped as a hollow tube (long bones) or bilaminar
Irregular Bones plate of bone (flat bones) containing variable cortical or
They are like short bones in cut sections, but unlike them trabecular structures. Cortical (compact) bone is dense
they have no smooth structure resembling any geometrical and calcified bone forming hard outer structure of bone
shape (hence irregular). Vertebrae are classic examples. providing most of the mechanical strength. It is also

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6 Section 1:  Bone Anatomy, Physiology, Pathology and Diseases

referred to as “cortex” commonly by surgeons and consists from the contained progenitors. The marrow gradually
of aggregations of concentric lamellar bone in the form of changes from red (hematopoietic) in adolescents to
osteons. Osteons at their center contain Haversian and yellow or white (fatty) in adults. The red marrow persists
Volkmann vascular canal systems, individual nerves and in the vertebrae, some metaphyseal regions and flat
one or two lymphatic channels (discussed below). One bones in adults.
can say that well developed osteons define cortical or •• Periosteum—It is a thick fibrous membrane that
compact bone and its presence is the hallmark. The marrow covers the bone like a laminating membrane (except
cavity is the space inside the cortical walls that contains articular cartilage and dense tendon attachments).
hematopoietic marrow tissue, fat and bony spicules. The membrane is divided histologically into outer
Trabecular bone consists of these slender spicules and fibrous (collagen) and inner cellular layer. The latter is
trabeculae (not more than 0.2–0.4 mm) that are separated important structure responsible for bone repair and is
by marrow spaces. Trabeculae of bone support the marrow referred to as “cambium” layer. It contains totipotent
elements by increasing surface area and providing scaffold, (young children) or multipotent (adolescents and
also they lighten the bone. It fills the metaphyseal and adults) cells that serve as osteoprogenitor cells capable
epiphyseal region of bones. They are composed of lamellar of forming new bone and callus with traumatic
bone with longitudinal arrangement of lamellae, but the disruption. Periosteum also serves to add thickness to
osteons are not formed (Table 1). These spongier regions bone by appositional bone deposition; this is especially
develop according to the lines of stress giving bone ability true at the sites of tendon attachment through sharpey’s
to deform (elastic nature) before failing (tensile strength). fibers that give a traction force on bone. Sharpey’s fibers
By virtue of outer cortex bone resists compression also are thick collagen bundles that anchor the periosteum
avidly (composite design). to circumferential lamellae and dominate in the regions
The bone can be divided into following parts of tendon attachment.
(anatomically and functional distinct units, Fig. 2): •• Endosteum—There is no microscopic or macroscopic
•• Epiphysis—Part of bone that lies between physis or structure distinctly seen inside the bone that can be
physeal scar and articular cartilage. The part is usually referred to as endosteum. The outer resting layer of
intra-articular and takes part in joint formation and marrow and its interface with bone is what is referred
function. The periosteum in intra-articular region lacks to as endosteum. Electron microscopically there is a
the cambium layer that has totipotential cell rests. thin arrangement of highly cellular osteoblastic and
•• Physis—The growing structure consisting of flat portion osteoclastic elements devoid of characteristically
adding length to bone and circumferential portion distinguishable membrane.
adding to width of bone and physis itself as it grows
(discussed below for detailed structure).
•• Metaphysis is the funnel-like part at ends of diaphysis
MICROSCOPIC ANATOMY
that predominantly comprises of trabecular bone. The Based on collagen fiber arrangements, bones have two
metaphysis lies between physis and diaphysis and distinct histological appearances—woven bone and the
is quite susceptible to osteoporotic fractures being lamellar bone.
deficient in cortical bone that undergoes less resorption. •• Woven Bone is also called immature bone, coarse
Being metabolically active it is also susceptible to bundled bone or sometimes fiber bone. It is made
remodeling defects like multiple osteochondromatosis. from randomly oriented collagen fibers in interlacing
Radiologically, the extent of metaphysis is defined by a or “burlap” fashion, with numerous osteoblasts and
square drawn from epiphysis from a line having greatest osteoprogenitor cells (so-called immature). When
horizontal dimension at metaphysis. viewed under polarized light, it shows haphazard
•• Diaphysis—This is the predominant central tubular structural organization. Woven bone is much more
portion of long bones giving them the characteristic cellular than the organized lamellar bone and has
form. Most cortical bone is found on this region giving higher number of cells per unit area. Woven bone is the
tensile and compressive strength to the region. It is major bone type in the developing fetus that matures to
the strongest part of bone and susceptible to fractures lamellar bone in adult. In adults, immature bone is still
by virtue of extreme levered forces being transmitted found at remodeling sites, in the alveolar socket (mouth),
through it. Also, it is subject to direct trauma in the fracture repair (callus) and at tendinous intersection. It
center of limb. occurs pathologically in osteosarcoma, fibrous dysplasia
•• Bone marrow—It fills the medullary cavity and is and several other tumors. The synthesis of woven bone
responsible for most of the hematopoietic activity is triggered by platelet-derived growth factor (PDGF A

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Chapter 1:  Structure and Function of Bones and Joints 7

and PDGF B) and insulin-like growth factor (IGF I and mesenchymal stem cells, the osteoclasts are related to
IGF II) and is seen in areas of fast bone growth. monocyte or macrophages, and hence derived from
•• Lamellar (thin plate) bone (mature bone) on polarized hematopoietic stem cells. Bone mineralization is a chemical
light microscopy has characteristic well-organized process that is facilitated by the cellular elements, so we can
arrangement of collagen fibers seen as parallel bundles call it biochemical process. The bone resorption and bone
(2–4 µm) of deposited bone. Lamellar bone develops formation are to be tightly coupled with favorable chemical
during remodeling of immature bone by replacement milieu (controlled by various extraneous and intrinsic
of the latter. Continuous secondary organization processes) to result in proper physiological mineralization.
(remodeling) is pathognomonic of mature lamellar
bone. Lamellar bone is deposited in slow growing Osteoblasts
regions, but the control mechanisms have not been fully
understood. In the cortex, the lamellae have concentric Osteoblasts are derived from pluripotent mesenchymal
tubular arrangement containing 5–15 concentric stem lineage. These mesenchymal progenitors can
lamellae. Outer circumferential lamellae (Fig. 2) lie next differentiate into various cell types including fibroblast,
to the periosteum, while inner circumferential lamellae chondrocytes, adipocyte (PPARγ2 stimulant), myoblasts
lie near endosteum. The interstitial lamellae (Fig. 2) (MyoD stimulant) and bone marrow stromal cells. Under
represent archaic remnants of old concentric lamellae. appropriate stimulation [by Cbfa1 (core-binding factor
These variable size (thick or thin) tubes of concentric α1) and/or runt-related transcription factor 2 (Runx2)],
lamellar arrangement are called osteon and a number the stem cells first differentiate into osteoprogenitor cells
of them are closely packed with few gaps, if any to form (pluripotent cells) and then into osteoblasts (Fig. 4). The
compact bone. The fibers of each lamella run in a spiral osteoblast pathway can be induced by bone morphogenetic
fashion rather than concentric cylinders around the protein (BMP) 2, 4 and 7 that upregulate the Cbfa1 mRNA.
canal. The osteons (Haversian systems—after Clopton
Havers who defined it in 1691) are cylindrical units that
surround a central Haversian canal (Fig. 2) that contains
vascular bundle of capillaries and venules and also
nerves, lymphatic canals and a loose connective tissue
encompassing osteoprogenitor cells. It is a branching
system of cylinders arranged longitudinally in the bone.
Volkmann’s canals (transverse perforating canal system)
are vascular channels that interconnect Haversian
canals and also the Haversian system to periosteal
blood vessels and intramedullary vascular supply (Fig.
2). Osteocytes are located in the interlaminar regions
with their processes arranged in a radial pattern into
the canaliculi. The osteons act like fibers of bamboo that
resist deformation.

THE CELLULAR
ELEMENTS OF BONE
Osteoblasts, osteocytes and osteoclasts are predominant
cells in bone. Osteoblasts serve the purpose of bone Fig. 4: The differentiation pathway for mesenchymal stem cell
formation (osteogenesis), while osteoclasts are mainly and generation of osteoblasts. Note the stem cell can transform
into different cells under appropriate influences. For generation of
accountable for bone resorption; their combined action
osteoblasts the stem cells first differentiate into osteoprogenitor
contributes to progressive mineralization and remodeling.
cells (pluripotent cells) induced by BMP 2,4,7 that upregulate the
The osteocytes maintain the milieu of bone and its Cbfa1 mRNA. There is also a possible flux mechanism that operates
homeostasis through vast network of canalicular system simultaneously and it has been found that inhibitor of PPARγ that
that communicates with external environment through reduces adipocytogenesis increases osteoblastogenesis, and hence
Haversian system. The three types of cells have different bone formation. This may find therapeutic utility in future management
origins; while osteoblasts and osteocytes originate from of osteoporosis.

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8 Section 1:  Bone Anatomy, Physiology, Pathology and Diseases

The osteoprogenitor cells are disperced into various bone parathyroid hormone (PTH) and 1, 25-dihydroxyvitamin
elements and this has a purpose. They are found in: D3 present on mature cells
•• The inner layer of the periosteum (predominant •• Paracrine activity by secretion of various cytokines like
source)—responsible for callus formation IL-6 and IL-11, and granulocyte colony-stimulating
•• Bone marrow (regenerative and intramedullary callus factor (GM-CSF) and macrophage colony-stimulating
formation) factor (M-CSF) (thus play a role in myelopoiesis also).
•• The endosteum—endosteal callus formation The osteoblasts also secrete a number of growth factors
•• Haversian and Volkmann’s canals—direct or primary like transforming growth factor-β (TGF-β), IGF, BMP
healing of bone and remodeling and PDGF
•• Perivascular tissue adjacent to bone—ill-defined •• Differentiation of osteoclasts—this is now considered
function, but may form ectopic bone as after surgery or a primary function with increasing understanding of
pathologic bone formation in myositis ossificans. osteoporosis. The osteoblasts secrete receptor activator
Osteoblasts measure 15–20 µm in diameter and contain of nuclear factor kappa B (RANK) ligand to regulate the
copious cytoplasm. They are cuboidal to columnar, and activation and differentiation of osteoclasts that then
form a single layer of cell over bone surface where new effect remodeling. The pathway is also the culprit for
matrix is being laid down. The cells deposit new bone or new increased bone resorption in osteoporosis and drugs
osteoid (the osteoid seam) along the surface adjacent to bone targeting the same are increasingly becoming popular.
only—a property called polarization, bone is not deposited
at the free or superficial surface. The mineralization front lies The Process of Mineralization as a Function of
deeper to the osteoid seam, where organized mineralization Osteoblasts (Fig. 5)
of the newly formed osteoid is being carried out. Osteoblasts
Alkaline phosphatase (ALP) produced by the osteoblast
are connected to each other by adherens type tight
acts as a pyrophosphatase and is the primer for initiation
junctions (established by major transmembrane protein
of the mineralization process. The matrix vesicles secreted
cadherins) that also help in communication between cells
actively by osteoblasts (discussed above) are the centers
(communicating junctions) other such junctions include
for synthesis of crystalline hydroxyapatite from amorphous
the desmosomes and tight junctions. The high metabolic
calcium phosphate though this also takes place outside
activity of osteoblasts is suggested by presence of abundant
of vesicles after mineralization has been initiated. The
rough endoplasmic reticulum and bulky Golgi apparatus
crystals within vesicles act as needle to rupture the
(involved in protein synthesis) and abundant mitochondria
membrane of vesicles when they come in contact. These
required for fulfilling energy requirements and staining
free crystals induce further the precipitation of crystalline
basophilic with hematoxylin and eosin stain.
hydroxyapatite over the entire organic matrix surface
Osteoblasts serve two main functions:
which is lying in a supersaturated solution of calcium and
1. They produce the organic component of bone matrix—
phosphate.
the osteoid by synthesizing and secreting type I collagen
along with proteoglycans or glycosaminoglycans. Each
Markers of Osteoblastic Activity
new layer is laid down upon existing layer of osteoid
(appositional growth) separated by a distinct cementing •• Alkaline phosphatase enzyme levels and activity is
or watermark line. increased with osteoblast activity
2. Osteoblasts facilitate subsequent mineralization •• The non-collagenous proteins (discussed above) also
of osteoid by secreting matrix vesicles. They create mark osteoblast phenotype and are expressed uniquely
a conducive milieu for deposition of calcium and during osteoblast differentiation.
phosphate in the organic matrix. Osteocalcin secretion Growth and evolution of osteoblast activity: With growth
is at its peak during mineralization. and proliferation the molecular activity and development
The accessory functions (also important) of osteoblasts pathways keep changing as the cell is destined to achieve
include: a unique functionality. The progressive changes can be
•• Production of non-collagenous proteins including described in a flow diagram as follows:
the osteocalcin, osteopontin, bone sialoprotein and Expression of cell cycle and histone genes (initial
osteonectin that takes part in bone mineralization and proliferative phase) → upregulation of genes linked to
maintenance formation of bone matrix (viz. for type I collagen and ALP)
•• Regulating bone metabolism—this is made possible → expression of genes for osteocalcin and bone sialoprotein
by responding to alteration in levels of hormones that are associated with mineralization (final stage of
involved in calcium metabolism through receptors for osteoblast maturation).

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Chapter 1:  Structure and Function of Bones and Joints 9

Fig. 5: Role of osteoblasts in bone mineralization. Also depicted is the complex interaction of the
alkaline phosphatase and pyrophosphate along with the role of vesicles

It is observed that with osteoblast maturation the •• Osterix basically acts further downstream of Runx2
proliferative capacity keeps constantly decreasing. pathway and is also responsible for osteoblast
differentiation affecting mineralization.
Osteoblast Differentiation and Regulation Other regulators of osteoblast differentiation and
Osteoblast proliferation or differentiation is under function include:
paracrine and endocrine control, with the predominant •• Dickkopf (Dkk1)—This is a negative regulator of bone
control of the former. There is a fine control of relative formation. Reduced Dkk1 (gene deletion) increases
strengths of opposing signaling pathways within a complex trabecular and cortical bone thickness and volume.
system. Osteoblasts respond to chemical and mechanical •• Osteocalcin (gamma-carboxyglutamic acid protein),
stimuli (Wolff ’s law). The chemical regulators include osteopontin (secreted phosphoprotein 1) and
growth factors (usually proliferation and maturation osteonectin (secreted acidic cysteine rich protein)—
factors) like TGF-β, BMPs, fibroblast growth factors (FGFs) osteopontin and osteocalcin are negative regulators of
and transcription factors (differentiation factors) like bone formation deficiency of former leads to ectopic
Runx2/cbfa-1 [core-binding factor alpha (1)] and osterix calcification of medial layer of arteries and resistance to
predominantly. estrogen deficient bone resorption, while deficiency of
•• Runx2 transcription pathway target genes include latter produces higher bone mass of improved functional
osteocalcin, bone sialoprotein, osteopontin and collagen quality without impairing bone resorption. Osteonectin
a1 that are responsible for mineralization front mainly is a positive regulator and its deficiency produces severe
and also somewhat for production of cartilage anlage. osteopenia, cataracts and weak lens capsule.
Mutations causing dysfunction or loss of function of •• Wnt/β-catenin pathway: Signaling by the Wnt family
the Runx2 gene causes cleidocranial dysplasia. The of secreted glycolipoproteins via the transcription
disease is characterized by absent or hypoplastic coactivator β-catenin controls embryonic development
clavicles and prolonged opening of cranial sutures and adult homeostasis (canonical pathway). This
(delayed ossification). Osteoblasts fail to differentiate in pathway promotes osteoblast commitment and
mice with targeted deletion of the Runx2 gene and the proliferation, finally culminating into its differentiation.
skeleton comprises exclusively of unossified cartilage. The survival of osteoblast and osteocyte is also improved
Due to lack of any stimulation from absent osteoblasts by Wnt/β-catenin pathway even in adverse conditions.
these mice also lack osteoclasts. Wnt binds to a coreceptor low-density lipoprotein

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10 Section 1:  Bone Anatomy, Physiology, Pathology and Diseases

receptor-related protein (LRP5 or LRP6) activating the Rheumatoid arthritis (RA)—Osteoclasts are the major
pathway which is comediated by one of the frizzled culprit cells for rheumatoid arthritis and cause three types
family member (Fz). The activity and binding of LRP5/6 of bone changes:
is antagonized by sclerostin (product of osteocytes) and 1. Focal bone loss—seen at the joint margins producing
the Dickkoppf (Dkk) family, thus they are now being the characteristic erosive changes and cysts.
targeted for osteoporosis therapy and prevention by 2. Periarticular osteopenia—seen more prominently
inhibiting their action. around inflamed small joints of hands and feet.
•• Leptin has long known to be synthesized by adipocytes. 3. Generalized bone loss—this involves the axial and
It is a peptide having its receptor in the hypothalamus. appendicular skeleton and is cytokine mediated—
Leptin mediates its effects of osteoblast differentiation property of systemic involvement. Tumor necrosis
and mineralization by inhibiting glycogen synthase factor-α (TNF-α) is the predominant inflammatory
kinase-3β (GSK-3β).This mechanism seems to be cytokine in rheumatoid arthritis. This is responsible
centrally regulated, but overall effect is negative for reduction in ALP activity, decreased osteocalcin
regulation on bone formation. The leptin-hypothalamic expression and perturbed collagen type I synthesis that
axis control pathway is not fully elucidated as to prohibits mineralization of tissue, while bone resorption
how it controls bone deposition or bone mass. It is is continued. It also directly inhibits the osteoblast
a common finding that patients with generalized function in RA.
lipodystrophy (absence of adipocytes and white Osteoporosis and glucocorticoid related to osteoblast
fat) develop osteosclerosis and accelerated bone function: osteoprotegerin (OPG)/RANK/Receptor activator
growth, this has also been reproduced in laboratory by of nuclear factor-kappa B ligand (RANKL) system represents
producing leptin or leptin receptor deficient mice that the main regulatory factors of bone remodeling and are
develop higher bone mass. involved in the pathogenesis of osteoporosis though
all the mechanism are not fully clear. DKK-1 mRNA is
Mechanical Regulation of Osteoblast Function overexpressed in osteoblasts treated with glucocorticoid
Osteoblasts also respond to mechanical stress to mediate suppressing the mineralization function.
changes in bone size and shape, a property that has Smoking and alcohol effect on osteoblast—Moderate
been exploited in some treatment forms like Ilizarov amount of nicotine and alcohol both seem to stimulate
osteosynthesis and possibly also in electrical or sonological osteoblast to produce bone. Moderate alcohol consumers
stimulation of bone formation. Calcium hydroxyapatite have low levels of osteoporotic fractures. Excess of everything
crystals have a piezoelectric effect possibly modulating though is bad and leads to increased bone resorption.
the osteoblast activity, but complete understanding and
science behind this effect is lacking. This process is essential Osteocytes
component of bone remodeling.
In adult and aging bone where many of the bone Around 10% of the embryonic osteoblastic population is lost
surfaces are inactive, osteoblasts become flattened by getting trapped and enclosed in their own synthesized
resembling squamous cells lining bone surfaces (quiescent matrix. These then become osteocytes (Fig. 6). Their
osteoblasts). This quiescent reservoir gets reactivated into cytoplasm also contains spherical granules stainable with
functional forms during remodeling, fracture repair and periodate-leukofuchsin like osteoblasts suggesting common
neoplasia when active bone formation occurs. origin. The spaces which they occupy are known as lacunae.
The lacunae (L. “pit or depression”) are flat to oval cavities
Role of Osteoblasts in Various Disorders containing fine apertures called canaliculi (L. “tiny dust”)
Osteoarthritis (OA)—subchondral bone metabolic changes through which cytoplasmic processes of osteocytes pass
have been suggested as a major pathogenic factor for (Fig. 2). Baud and Auil classified the lacunae into four types
development of osteoarthritis. There is five-fold increase as follows:
in leptin expression in osteoarthritis that modulates 1. Inactive: Small lacunae with smooth borders largely
the osteoblasts to actively produce reactive bone at the seen in cortical bone.
degenerated ends. This effect is observed in the form of 2. Osteolytic: Large lacunae with irregular borders present
elevated levels of bone formation markers (osteocalcin in cancellous bone.
and ALP) seen in osteoblasts of osteoarthritic bone. Type I 3. Osteoplastic: Large lacunae with recently formed matrix
collagen levels synthesis is also increased in osteoarthritis present at sites of remodeling and fracture repair.
producing subchondral sclerosis that is a radiological 4. Empty: Lacunae only containing cellular debris
hallmark of osteoarthritis. following death of osteocytes.

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Chapter 1:  Structure and Function of Bones and Joints 11

accumulates on bone surface and binds to N-syndecan


(receptor for OSF-1) located on osteoblast progenitor
cells
•• Osteocytes similar to osteoblasts are also known as
mechanosensory cells. The thin layer of unmineralized
matrix around osteocyte cell body and processes
mediate the mechanical influence by loading derived
flow of interstitial fluid across the osteocyte membrane.
This affect translation of mechanical stress to cellular
events culminating in bone formation and remodeling.

Regulation of Bone Metabolism and


Mineralization as a Function of Osteocytes
•• The bone-renal axis for bone mineral metabolism:
Patients with autosomal recessive hypophosphatemic
rickets display a hypomineralized bone phenotype
manifesting as rickets or osteomalacia. There is
isolated renal phosphate wasting associated with
elevated fibroblast growth factor 23 (FGF23, a
phosphatonin) levels and normocalciuria. Similar,
phenotype is displayed in animal models having
deficient dentin matrix protein 1 (DMP1) which is
otherwise highly expressed in osteocytes. In patients
Fig. 6: Formation of osteocytes: These cells are none other than with hypophosphatemic rickets there is a mutation
osteoblasts that get entrapped in the bone matrix with deposition affecting the DMP1 start codon, while some patients
of it around the cells. The cells then develop and communicate with display a seven base pair deletion damaging the
other cells through processes functional C terminus of DMP1. These findings suggest
close relation of renal function and osteocyte in bone
Osteocytes are not dead or nonfunctional cells and their mineral metabolism.
vitality is essential to the maintenance of bone. When •• Osteocytes possess receptors for PTH, which regulates
the osteocyte dies, the bone around it also becomes mineral ion homeostasis
nonfunctional and is eventually removed. Osteocytes live •• Human osteocytes secrete sclerostin that inhibits bone
within the substance of bone unlike surface cells such as formation. In the absence of sclerostin a disorder called
osteoblasts and comprise 90–95% of all bone cells. The sclerosteosis develops in which the skeleton develops
processes of osteocytes intercommunicate and these high bone mass characterized by increased osteoblast
cells are also connected to surface osteoblasts through activity. Uninhibited osteoblastic activity results from
the network of canaliculi, hence in all they form a large loss of the SOST gene product, sclerostin.
network inside the bone. Unlike osteoblasts the processes
of osteocytes are joined by gap junctions which help them
“talk” to each other and with cells far off and outside of the
Osteoclasts
bone matrix. They serve following functions: Osteoclasts are multinucleated cells related to the monocyte/
•• Cell signaling (because of vast network) and maintaining macrophage lineage found at bone remodeling site. Their
the viability of bone matrix. Osteocytes also have cytoplasm is acidophilic and contains β-glucuronidase.
N-methyl-D-aspartate (NMDA) neural receptors and They are derived from hematopoietic progenitor cells unlike
may be involved in central mechanisms of bone mineral the osteocytes or osteoblasts. Despite having discrete
metabolism like bone resorption in reflex sympathetic origin for osteoclasts their differentiation requires the
dystrophy (RSD) presence of osteoblasts at various steps. Differentiation
•• Regulates the mineral exchange between the and maturation of osteoclasts also need a variety of
extracellular fluid (ECF) and bone by means of the hematopoietic cytokines, such as TNF, interleukins 1, 3,
widespread canalicular system 6 and 11, stem cell factor and colony stimulating factors
•• Osteocytes express osteoblast-specific factor-1 (OSF-1) (CSF). Development of osteoclasts and their maturation
that serves to stimulate osteoblasts. The secreted OSF-1 (the osteoclastogenesis) needs hormonal support from PTH

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12 Section 1:  Bone Anatomy, Physiology, Pathology and Diseases

and 1,25-dihydroxyvitamin D3 and cytokines like TGF-α, their path which is followed by mineralization front lead
and epidermal growth factor (EGF). Osteoclastogenesis by osteoblasts recreating bone (coupled bone resorption
is inhibited by calcitonin, estrogen and TGF-β (Fig. 7). and formation).
The main function of osteoclasts is bone resorption that
Regulation of osteoclastic bone resorption: The process
is in contrast to osteoblasts at first glance, but in fact both
is highly regulated otherwise all the bone of body will
processes are complementary in normal physiology of bone.
dissolve away in an uncontrolled manner. Osteoclasts
The characteristic features of osteoclasts are as follows:
are stimulated primarily by IL-6 and RANKL (and are the
•• They are found within pits called Howship’s lacunae—
targets for antiresorptive therapy). These cytokines are
These are the sites of active bone resorption or may
represent quiescent cavities where bone resorption has
already occurred.
•• Osteoclasts like osteoblasts are highly polarized cells
with only one site of activity where bone resorption is
occurring. The nuclei gather away from the resorbing
bone surface (Fig. 8) as the space near to resorptive site
will be occupied by vesicles and organelles involved in
active resorption.
•• “Ruffled border”—It is the cell surface in direct
apposition to the bone with numerous infoldings
of the plasma membrane (Fig. 8). Ruffled border
disappears when the cell is in the resting state. The
cytoplasmic region between the conglomerated nuclei
and the ruffled border (site of bone resorption) is rich
in carbonic anhydrase and in tartrate resistant acid
phosphatase (TRAP), lysosomes, mitochondria, vesicles
and free ribosomes.
•• Clear zone—At the site of active bone resorption
osteoclast attach to bone matrix in a ring-like fashion
sealing the area. This ring-like area of the cell membrane
that forms the perimeter of the ruffled border is called Fig. 7: Role of various cytokines and factors in production of osteoclasts
“clear zone” or “sealing zone”. This attachment to the (osteoclastogenesis). Osteoclastogenesis is inhibited by calcitonin,
bone matrix involves participation of actin filaments estrogen and TGF-β
and the alpha-v beta-3 (αVβ3) integrin.

The Osteoclast-mediated Bone Resorption


Bone resorption is a systematic process that involves
sequential steps as follows:
Mineral resorption: Bone resorption requires the creation
of acidic media via secretion of hydrogen ions (aided by
ATP driven proton pump) around the ruffled border of
osteoclasts in the sealed off clear zone. The process requires
the enzyme carbonic anhydrase II to generate hydrogen
ions. Acid phosphatase is produced by osteoclasts. These
dissolve the alkaline mineral phase of bone.
Removal of organic matrix: Lysosomes release acid
hydrolases into the acidified extracellular space and
collagenase. Degradation of collagen may also be helped
by oxygen-derived free radicals. There is disruption of
mineralized matrix to a depth of 1–2 μm. Osteoclasts migrate
over the bone surface (migration front lead by osteoclasts Fig. 8: Illustration depicting the structure and function of
followed by osteoblasts), creating many resorption pits in osteoclasts

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Chapter 1:  Structure and Function of Bones and Joints 13

produced locally by the osteoblast under the influence negatively modulated by the c-Fos that sets up a negative
of PTH, Vitamin D3, TGF-β, IL-1 and TNF-α. Osteoclasts feedback loop, thus RANKL induced IFN-β induces its
have calcitonin receptors that can directly influence the own inhibitor.
cells, but PTH or vitamin D receptors are missing from
osteoclasts so their influence is indirect. Osteoclastic Regulation of Osteoclast Differentiation
stimulation resulting in bone resorption is also influenced The RANK/RANKL/OPG axis: The proliferation and survival
by interactions of the cell membrane integrins and of osteoclast precursors, cells of the monocyte-macrophage
bone matrix proteins that contain amino acids RGD lineage is dependent on M-CSF secreted by osteoblasts (Figs
(arginine, glycine, asparagine) like the type I collagen, 7 and 9) and marrow stromal cells. Osteoblasts under the
fibronectin, bone sialoprotein II and osteopontin. These influence of PTH, vitamin D, PGE2 or IL-11 express RANKL
proteins bind to cell membrane integrins and initiating mRNA. Both osteoblasts and stromal cells produce RANKL
outside-in signaling pathways that finally culminate in that binds to the RANK receptor on osteoclast precursors.
bone resorption. In pathological state like in giant cell M-CSF primes hematopoietic progenitor cells to become
tumor (osteoclastoma), the osteoclasts are stimulated for osteoclasts that are activated by RANKL to differentiate into
bone resorption by IL-6, this has been documented by mature or functional osteoclasts. The RANK and RANKL
perturbation of osteoclastic activity in osteoclastoma by interaction on osteoclast precursors and on osteoblasts
anti-IL-6 antibodies; however, physiological role of IL-6 or stromal cells, respectively, requires cell-to-cell contact
antibodies has not been documented for osteoclastogensis. for further development of osteoclast precursors and
Pathological bone resorption: TNF-α and IL-1 secreted by maturation (Fig. 9). In the cytoplasm, RANK undergoes
T-cells and macrophages in rheumatoid arthritis and other complex interaction with TNF receptor associated factor
pathological conditions also stimulate bone resorption. (TRAF). TRAF have different effects, while TRAF2 induces
These cytokines bypass the normal cell-to-cell contact osteoclast differentiation TRAF6 is involved in osteoclast
required for osteoclast formation (in physiological state) activation. Osteoblasts also secrete soluble protein OPG
instead they directly stimulate osteoclast progenitors to that prevents osteoclast activation by interfering with above
differentiate and mature into osteoclasts. This type of RANK/RANKL interaction as it falsely attaches to RANKL
bone resorption leads to loss of bone mass and produces (hence it acts as a decoy receptor). OPG, thus, modulates
uncoupling of the process of bone resorption and formation. the process of osteoclastogenesis and it strongly blocks
osteoclastic bone resorption.
Regulation of Osteoclastogenesis
•• Interferon-gamma (IFN-γ) suppresses osteoclastogene- Clinical Implication
sis. The T-cell mediated osteoclastogenesis is supported As the RANKL/RANK interaction is so important to
by suppressor of cytokine signaling 1 (SOCS1) which in- osteoclast activation, differentiation and maturation, it is a
hibits cytokine signaling. SOCS1 counteracts inhibitory hot target to prevent increased bone resorption in metabolic
cytokines such as IFN-γ so it is a positive regulator for bone diseases such as rheumatoid arthritis and osteoporosis
osteoclastogenesis, but not always. The osteoclast pre-
cursor cells that lack SOCS1 are more susceptible to the
inhibitory effects of IFN-γ. SOCS1 is induced by RANKL
stimulation during osteoclastogenesis. It is interesting
to note that the osteoclast precursor cells develop toler-
ance or resistance to IFN-γ mediated inhibition only if
they are first stimulated by RANKL that induces SOCS1.
This order of stimulation suggests that the ultimate fate
of osteoclast precursor cells is determined not only by
the balance of cytokines, but also by the cytokine first
encountered.
•• Osteoclastogenesis is negatively regulated by
interferon-β (IFN-β). RANKL induces IFN-β in osteoclast
precursors. IFN-β inhibits the expression of c-Fos which
is an essential transcription factor for osteoclastogenesis. Fig. 9: The bone resorption-synthesis coupling due to interaction
It is interesting to note that the influence of IFN-β on between osteoclasts and osteoblasts mediated by RANK-RANKL
cells and RANKL mediated induction of IFN-β is further interaction and OPG protein that is essential for remodeling

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14 Section 1:  Bone Anatomy, Physiology, Pathology and Diseases

and even neoplasia (like GCT). In recent studies, it has TABLE 2: Different types of collagen and characteristics
been also found to be involved in bone resorption in
Type of Remarks Disorder
osteoclastoma. It has been conjured that inhibiting the collagen
RANKL/RANK interaction or RANK mediated signals would
I Most abundant, bone, teeth, Osteogenesis
prevent pathological bone loss by tipping the balance to tendon, skin, vessels, cornea and imperfecta, Ehlers-
mineralization. In laboratory mouse knockouts for RANK fibrocartilage Danlos syndrome,
and RANKL have been found to develop osteopetrosis. Caffey’s disease
These mice have absence of osteoclasts and there is II (fibrillar) Hyaline cartilage, vitreous humor Chondrodysplasias and
complete failure of tooth eruption. The other models are of eye and nucleus pulposus of collagenopathy type II
transgenic mice that overexpress OPG (discussed above) intervertebral disk disorder (IVD) and XI
in the liver. These mice also develop severe osteopetrosis III (fibrillar) Granulation tissue, skin, intestines Ehlers-Danlos syndrome,
due to prevention of RANK/RANKL interaction. Patients and large vessels (30%) Dupuytren’s contracture
from familial Paget’s disease of bone have been found to IV Lens of eye, renal glomeruli and Alport syndrome and
have altered first exon of RANK. Denosumab, a novel drug basement membranes Goodpasture disease
is found to be effective in preventing attachment of RANKL V (fibrillar) Interstitial tissue associated with Ehlers-Danlos syndrome
to RANK receptor, hence opening the possible role in above collagen I and large vessels (5%)
mentioned diseases. VI Short chain collagen of interstitial Atopic dermatitis and
tissue ulrich myopathy

THE COMPOSITION AND VII Anchoring fibrils of


dermoepidermal junctions
Epidermolysis bullosa
dystrophica

STRUCTURE OF BONE MATRIX VIII Endothelial cells Corneal dystrophy type II


IX Fibril associated collagens with Multiple epiphyseal
Collagen interrupted triple helix (FACIT) dysplasia type 2 and 3
collagen, cartilage (10–20%)
Bone is a connective tissue. Like all other connective tissues it X Mineralizing cartilage Schmid metaphyseal
also contains varying amounts and combination of collagen, dysplasia
elastin (a related fibrous protein), glycosaminoglycans XI (fibrillar) Cartilage Collagenopathy type II
and proteoglycans. Collagen is the most abundant protein and XI
component in all these. Collagens have a unique triple XII FACIT collagen
helix composed of three component polypeptide alpha
XIII Transmembrane collagen
chains. There are several subtypes each produced by a
different gene and differ in their biochemical structure. XIV Undulin
Some 28 different types of collagen have been identified, XVII Transmembrane collagen Bullous pemphigoid and
important ones are listed in detail in Table 2. Type I collagen junctional epidermolysis
bullosa
is the most abundant type of collagen in bone (easy to
remember; b-one). Type I collagen, also known as alpha-1
type I collagen, is a protein that in humans is encoded by commonly proline and hydroxyproline and only to a lesser
the COL1A1 gene. It is a fibrillar type collagen that is also extent lysine/hydroxylysine. The Gly-X-Y is organized in a
present in other tissues like skin, menisci, tendon and left handed supertwisted helix (the “α” chain) contributing
ligaments, intervertebral disk annulus fibrosus and synovial majorly to the strength of collagen. As a comparison of
joint capsules. Most (≈90%) of bone organic matrix is made strength collagen fibers are said to have tensile strength
up of type I collagen. Type I collagens have several subtypes. greater than steel wire of equivalent cross-section. Collagen
The type I collagen specific to bone has predominantly synthesis is controlled by over 20 genes. The single collagen
galactosyl-hydroxylysine amino acid configuration in fibril is made of three polypeptide chains arranged in a
contrast to glucosyl-galactosyl-hydroxylysine predominant helical fashion making up the fundamental units. Aggregate
conjugate found in dermal collagen. Also hydroxylation of three units of these fundamental collagen fibril forms
and glycosylation as post-translational modifications of tropocollagen. This tropocollagen then aggregates in a
collagen are found only in bone specific collagen that staggered fashion to form a collagen microfibril. A collagen
partly explains mineralization property of this tissue and fibril is formed by removal of N- and C-propeptides
not at other places where type 1 collagen is found. The type from collagen microfibrils causing their rearrangement.
I collagen is composed of basic structure comprising of Between two tropocollagen molecules there is electron
repeating tripeptide sequence (Gly-X-Y). The X and Y are microscopically identified “dark area” which is termed a

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Chapter 1:  Structure and Function of Bones and Joints 15

“hole”. It measures about 41 nm and is considered to be the in collagen) and other products of collagen degradation
site where mineralization is initiated (Fig. 10). The cross- (such as pyridinoline and deoxypyridinoline) are assessed
linking of collagen fibrils imparts stability and improves in osteoporosis. These are markers of collagen breakdown
structural integrity. Cross-linking in collagen is a chemical and the level of collagen degradation by these degradation
process involving aldol reaction. Initially, aldehyde is products in urine or serum indirectly reflect amount of bone
generated by an amino oxidase enzyme which condenses turnover.
with a lysyl or hydroxyl group to produce a Schiff base
forming a cross-link. The aldehyde may also condense with Other Non-collagenous Matrix Proteins
a similar aldehyde in an aldol reaction to generate a stronger
bond. The amino oxidase enzyme can be blocked by nitriles. Calcium Binding Proteins
These nitriles are alkyl cyanide substances responsible for Osteopontin: Osteopontin is a sialylated and highly
producing the disorder lathyrism. Poor collagen quality phosphorylated phosphoprotein, which exists in multiple
of collagen in lathyrism leads to development of various forms and is important in cell attachment. This protein is
spinal coronal and sagittal plane deformities, demineralized regulated by substances such as 1, 25-dihydroxyvitamin D,
bone, recurrent joint dislocations, aortic aneurysm and TGF-β, PTH, etc. Osteopontin binds to the integrin receptor
various nervous system manifestations. On the other hand, on osteoclasts and activates the phospholipase C pathway
extensive “cross-linking” between α-chains as is found in resulting in increased intracellular calcium through Src
aging individuals gives a rigid and brittle character to the tyrosine kinase. Osteopontin is found in high amounts in
connective tissue. Penicillamine prevents collagen cross- the extracellular matrix of developing intramembranous
linking and is administered to patients with scleroderma. and endochondral bones, and is present in good amount
Defective cross-linking renders collagen susceptible to in osteoblasts, osteocytes, osteoclasts and chondrocytes.
collagenases. The genetic collagen defects produce various
disorders like: Bone sialoprotein II (BSP II): BSP II is a bone specific protein
•• Osteogenesis imperfecta [clinically presenting with having cell attachment properties due to its RGD sequence
brittle bones that fracture easily, characterized by a (but less than osteopontin).
glycine to cystine change though various other varieties Osteonectin: This is a 32 kilodalton (kD) phosphorylated
are found (discussed later)] glycoprotein that regulates the extracellular calcium
•• Ehler-Danlos syndrome (clinically present with loose hydroxyapatite formation and mineralization. Osteonectin
joints that frequently dislocate and also relocate, has various other names like SPARC that stands for its
characterized by a glycine to serine substitution). description—“secreted protein acidic rich in cysteine”,
Clinical marker—For estimating bone turnover, culture shock protein or basement membrane-40
urinary excretion of hydroxyproline (found exclusively (BM-40), and is encoded by SPARC gene. Osteonectin links
mineral to collagen (by binding to both to Ca2+, collagen
type I and hydroxyapatite) and thrombospondin. It also
promotes mineralization by initiating hydroxyapatite crystal
growth. Recently, osteonectin has been found to have
involvement in pleotropic functions like morphogenesis,
tissue remodeling, angiogenesis and cell migration. The
last function may be explained by its function as an anti-
adhesive protein by virtue of involvement in cell matrix
interactions that is possibly linked to prostate carcinoma
metastasis. Osteonectin is expressed in various tissues,
but its concentration is particularly high in osseous tissue
(up to 10,000 times compared to other tissues). The second
peculiarity is that it is the most abundant non-collagenous
bone protein and quantitatively it increases with bone
maturity. The functions of this protein for bone tissue are:
•• Mineralization of nascent bone
•• Support to osteoblasts in development, maturation and
Fig. 10: Illustration of the structure of collagen fibril distribution survival
(organic phase of bone) and concept of hole zone that is the space •• Crystallization of inorganic solutes and binding to
available for mineralization (inorganic phase) collagen matrix

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16 Section 1:  Bone Anatomy, Physiology, Pathology and Diseases

•• Cell migration, proliferation and possibly differentia­ factor and takes part in prominent role in organization of the
tion. extracellular matrix by binding substrates at various binding
sites. It also mediates platelet aggregation. TSP is deposited
Gamma-carboxyglutamic acid proteins (“Gla” proteins):
into the bone matrix, where it regulates the extracellular
Osteocalcin (bone Gla protein) comprises significant
matrix proteins. It is also expressed by osteoblasts and
portion of about 20% of the total non-collagenous proteins
chondrocytes besides platelets.
in bone. It is the second most predominant non-collagenous
protein of bone. Osteocalcin is an osteoblast-specific Connective tissue growth factor: Connective tissue growth
protein with characteristic 3-gamma carboxyglutamic acid factor (CTGF) also called CCN2 is matricellular protein
residues (Gla) that serves to negatively regulate osteoblasts of the CCN family of extracellular matrix associated with
itself (self-check mechanism). Its synthesis is vitamin heparin binding proteins that regulates various cellular
K-dependent and is enhanced by 1, 25-hydroxyvitamin functions like cell adhesion, migration, proliferation and
D3. The circulation and excreted protein concentration differentiation. It also regulates matrix production and
indirectly reflects metabolic cellular activity. Osteocalcin cell survival. CTGF is involved in bone cell (especially
serves following functions: osteoblast) differentiation and maturation. The angiogenic
•• Regulates crystal growth and osteoclast recruitment activity (chemotaxis of endothelial cells and vascular smooth
•• Inhibitor of osteoblast function muscle cells) of CTGF is responsible for neovascularization
•• May attract osteoclast progenitors in the area for of the mineralized cartilage in the process of endochondral
maturation into osteoclasts, thus acting as chemo- ossification. CTGF stimulates the production of extracellular
attractant. matrix (ECM) proteins in fibroblasts and osteoblasts like
Osteocalcin is encoded by BGLAP gene. It is synthesized by type I collagen and fibronectin. It is also mitogenic for
osteoblasts following stimulation from 1, 25-hydroxyvitamin fibroblasts and chondrocytes and also promotes their
D3 regulated by TGF-β and secreted into the osteoid differentiation. CTGF blocks apoptosis where cell adhesion
during mineralization. Osteocalcin is required to stimulate is prevented so supports cell migration and improves cell
bone mineral maturation. Hence, it serves as a marker survival. This feature especially gathers importance in
for mineralized tissue (like ALP) and increased bone various tumorigenesis (cartilaginous tumors), development
turnover. Apart from ALP it is a good and specific marker of atherosclerosis and other fibrotic diseases.
for increased osteoblastic activity. It should, however, be Osteoactivin: Osteoactivin (OA) expression increases during
clearly understood that both these markers do not correlate matrix maturation and mineralization. OA is expressed
with each other as they are synthesized by osteoblasts during in various malignant tumors such as in glioma and
different stages of development. The early differentiation hepatocellular carcinoma facilitating tumor invasiveness.
marker is ALP, while osteopontin and osteocalcin are late
Alkaline Phosphatase: This enzyme is a hydrolase that causes
differentiation markers. Clinical utility lies in following the
dephosphorylation in alkaline medium. It is produced by
progress of patients with osteosarcoma, and as a marker
osteoblasts in bone and has three related isozymes. The
for its recurrences or metastases in patients with anabolic
isozymes are tissue related and are associated with three
therapy for osteoporosis the serum levels correlate well
separate genes. These are:
with bone turnover and increases in bone marrow density
1. The placental (regan isozymes)
(BMD). Other than bone osteocalcin acts as a hormone that
2. Intestinal form (ALP-3) is seen in a variety of tissues
stimulates pancreatic β cells to secrete insulin and increases
such as bone (ALP-2), liver (ALP-1), kidney (proximal
synthesis of testosterone that may have a role in male fertility.
convoluted tubules) and skin.
Fibronectin and thrombospondin: These proteins contain an 3. Tissue nonspecific form—Found in bone osteoblasts is
arginine-glycine-aspartic acid (RGD) amino acid sequence associated with a single gene at chromosome 1. ALP is
(like osteopontin) and mediate the attachment to integrins, adhered to the cell membrane, via. phosphatidylinositol
located on cell surfaces. Fibronectin (FN) is prominent and that can be broken by phospholipase C and the enzyme
versatile extracellular matrix glycoproteins. FN is involved is released free from cell membrane.
in cell adhesion, development and growth, proliferation, All three isozymes require zinc and magnesium ions
differentiation and cell migration. It is responsible for wound for their activity. ALP is a glycoprotein that catalyzes the
healing, development of carcinoma lung, embryonic growth splitting (by hydrolysis) of phosphates (such as pyridoxal-5’-
and development of various tissues. FN mutation and phosphate) at an alkaline pH between 8 and 10. This makes
deficiency are incompatible with life. Thrombospondin (TSP enzyme inactive in blood. Bone specific ALP reflects the
1, 2, 3, 4 and 5) is an antiangiogenic protein first isolated biosynthetic activity of osteoblasts. The synthesis of tissue
from α-granules of platelets. TSP acts as an autocrine growth nonspecific ALP is increased by Vitamin D and thyroxin,

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Chapter 1:  Structure and Function of Bones and Joints 17

whereas glucocorticoids and PTH inhibit its production. with deficiencies only in the region of capsular attachments
In physiological states, the expression of ALP is cell cycle and nutrient vessels. The periosteum has an inner cellular
dependent, where its activity is high in G1 through S phases, osteogenic layer (cambium) containing osteoprogenitor
and reduces in G2 through M phases. The most interesting cells. This layer serves to increase bone girth by appositional
fact is that despite such a long period of identification of bone deposition before skeletal maturity. The outer layer of
this enzyme the exact role of ALP in bone mineralization periosteum consists of fibrous tissue that is predominantly
is still not fully understood and most explanations are supportive and imparts stiffness to it. The periosteum is
theories. The enzyme has been demonstrated in matrix thick in children due to the presence of active cambium
vesicles, but its role is elusive and may involve degradation (cellular layer) with blood supply in the form of longitudinal
of pyrophosphate that is otherwise an endogenous inhibitor arterioles incorporated within. However, with aging the
of apatite crystal formation by precipitation. Serum ALP cambium gets hypotrophied and becomes thin, also the
activity is raised in various orthopedic and non-orthopedic vascularity reduces with absence of prominent longitudinal
conditions as follows: arterioles. This has important surgical implications with
Orthopedic conditions where serum ALP is raised: respect to higher incidence of nonunion and delayed union
•• Growing children (physiological rise) in fractures fixed after ripping periosteum, especially in
•• Primary and secondary hyperparathyroidism adults. Over most of the surface of long bones in an adult
•• Rickets and osteomalacia the periosteum is loosely attached beneath muscle bellies.
•• Healing fractures The only periosteal blood vessels in those areas are venules
•• Neoplasias like osteosarcoma and capillaries. Periosteal supply is a low pressure system
•• Paget’s disease compared to intramedullary system of blood supply. So,
•• Osteoblastic metastasis from prostate the normal flow in mature bone is centrifugal with excess
•• Treatment of osteoporosis by anabolic agents blood exiting from the periosteal venules. In vascular stress
•• Hyperthyroidism situations like acute embolism of the intramedullary system
•• Herpes zoster or reaming of intramedullary canal, the blood flow of the
Non-orthopedic causes of raised ALP: periosteum increases many fold compensating for the loss
•• Neoplasias—Leukemia and hodgkin’s lymphoma in blood supply. In such situations, the blood flow becomes
•• Pregnancy centripetal.
•• Oral contraceptives
•• Hepatitis
•• Hepatic malignancies
•• Amyloidosis
•• Inflammatory bowel disease
•• Septicemia
•• Sarcoidosis
•• Myocardial and pulmonary infarctions (acute injuries)
•• Pancreatitis.
The ALP serum levels are reduced in hypophosphatasia.

BLOOD SUPPLY OF BONE


Bone receives around a fifth (10–20%) of the cardiac output.
The two predominant vascular systems for blood supply
include (Fig. 11):
1. The periosteal system.
2. The endosteal system (misnomer as there is no
endosteum, better called intramedullary system).
Minor contributions come from:
1. Epi-metaphyseal system.
2. Articular ligaments (like obturator ligament in hip). Fig. 11: Illustration depicting the blood supply of bone, nutrient
The Periosteal System (also called accessory nutrient artery—diaphyseal circulation, metaphyseal and epiphyseal vessels
arterioles) supplies only the outer third of the cortex. Entire supply the respective zones; periosteum supplies the peripheral one-
long bone except its cartilage ends is covered by periosteum third of the cortex

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18 Section 1:  Bone Anatomy, Physiology, Pathology and Diseases

Intramedullary system: Diaphyseal nutrient arteries (one through foramina near the articular ends of the bones
or two) enter through the cortical bone often in an oblique commonly. Lymphatic vessels are also abundant in the
direction. The common ports of nutrient artery entry are periosteum.
the fascial regions firmly attached to the diaphysis of long
bones or along anatomical bony ridges like linea aspera Direction of Blood Flow
of the femur. Perivascular fat supports and protects the
afferent blood vessels in these regions so that the vessels The intramedullary system of vessels represents a high
can approach directly the cortical surface and enter. The pressure system within the long bone. This system is
principal nutrient artery to bone is formed of these afferent derived from the nutrient artery that is a branch of systemic
vessels. The afferent vessels after entering the intramedullary circulation, so the intravascular pressure is higher in
system divide into ascending and descending branches that the medulla or marrow of bone than in the periosteal
supply inner two-thirds of the cortex (outer thirds being system, where vasculature mainly comprises of venules
supplied by periosteal supply, discussed above) and whole and capillaries. As is commonly known from laws of
of the medullary cavity. The above system holds true for physics fluid that current flows from high to low pressure
most long bones, except large irregular bones, flat bones region, consequently, the direction of normal blood flow
and some short bones that receive a major blood supply in physiological state in bone through the diaphyseal
from the periosteum superficially or otherwise from large cortex of a long bone is centrifugal, i.e. from medulla to
nutrient arteries that directly penetrate into the medullary periosteum (inside-out). Under some pathologic conditions
bone. The intramedullary and periosteal systems of blood the intramedullary vascular pressure may get diminished
supply anastomose freely. resulting in reversal of blood flow through the vascular
channels of the diaphyseal cortex, so that it becomes
Metaphyseal and epiphyseal arteries: This system supplies
outside-in or centripetal. This flow reversal can happen with:
blood to the ends of bones, diaphysis being supplied by
•• Occlusive vascular disease
the above mentioned systems. They arise as principle
•• Osteoarthritis
branches from adjacent articular supply or periarticular
plexus. This system also freely anastomoses with the •• Displaced fracture
diaphyseal or intramedullary system terminating in bone •• Reaming of intramedullary canal.
marrow, trabecular bone, cortical bone and articular Under above conditions, the blood flow reversal
cartilage. In immature skeleton, growth plate (end plates primarily occurs through existing normal vascular channels
of cartilage component of physis) separates these arteries though studies demonstrate opening up and development
from intramedullary system. Near the growth plate (physis) of new vascular channels.
a few vessels make hairpin bend and retreat back upon
themselves, while most enter into an open circulation. In
the past, this arrangement of hairpin bends was considered
NERVE SUPPLY OF BONE
to reduce the rate of blood flow to cause localization Bones have rich nerve supply, especially at the articular
of blood-borne bacteria and serve as focus of onset of ends of the long bones, the vertebrae and larger flat bones.
hematogenous osteomyelitis, especially in children. This The nerve fibers supplying bones accompany nutrient blood
concept is challenged now (discussed under bone infection vessels to reach the interior of bones and Haversian system.
section). After closure of growth plate in adult, the entire Also, accompanying the arteries inside the Haversian system
expanded end of the long bone becomes the metaphysis. are vasomotor nerves that control blood flow through them
This metaphysis receives superficial blood supply from as in physiological state in most other body systems by
periosteal arteriolar vessels entering all over, except in vascular constriction or dilation. The periosteal nerves have
regions covered by articular cartilage. The longitudinal nociceptive ends so it is pain sensitive (common experience
afferent arterioles seen in periosteum of immature is needed for anesthetizing periosteum, while placing
skeleton in metaphysis and diaphysis disappear with age Steinman pin). Bones are also innervated by sympathetic
related atrophy of the cambium layer of the periosteum. fibers originating from the sympathetic ganglion that again
Throughout life of individual this layer remains dormant enters bone along with nutrient vessels. Blood flow in
and atrophic until activated by specific stimulus like trauma. bones reduces by 80% in stressful conditions and shock.
Neurotransmitters released by various nerve endings not
only regulate the blood flow, but also they have a role in
Venous and Lymphatic Drainage bone development and remodeling. Dopamine transporter
From bone the blood is drained by collateral venous system gene DAT (-/-) deletion mice demonstrated 30% reduction
that accompanies the afferent arteries. These veins leave in bone mass and strength.

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Chapter 1:  Structure and Function of Bones and Joints 19

The endogenous cannabinoids (anandamide, bones of the entire axial and appendicular skeleton develop
2-arachidonoylglycerol) have been found to regulate bone through either intramembranous or endochondral bone
remodeling to some extent. They activate the G protein- formation (ossification). The two processes differ in absence
coupled; central and peripheral cannabinoid receptor type or presence of a cartilaginous intermediary. A cartilage
1 (CB1) and type 2 (CB2), respectively. CB1 is responsible model is first formed and which ossifies in latter process
for the typical cannabinoid associated psychotropic and (Fig. 13), while it is conspicuously absent in former. A third
analgesic effects, but CB2 is of interest and plays role in mode of physiological bone formation during development
liver fibrosis and atherosclerosis. Endocannabinoids inhibit is appositional ossification.
lipogenesis (effect opposite that of corticosteroids and Non-physiological bone formation: Bone can also form in
alcohol). So they have trophic effect on bone formation various other forms and processes, but not involving the
and remodeling (Fig. 12). CB2 receptor null mice show skeletal development. Callus formation and regenerate
accelerated age-related trabecular bone loss with minimal development are physiological forms of bone formation
change in cortical thickness (osteoporosis like changes). that occur in specific conditions and are not a part of
This is partly explained by increased osteoclast number developmental ossification process. Similarly, ectopic
in the trabecular bone. CB2-specific agonist increases ossification and myositis ossificans are pathological forms
osteoblast number and activity, while simultaneously of bone formation.
restraining osteoclastogenesis in trabecular bone. They
inhibit proliferation of osteoclast precursors directly and also
restrict the differentiation and maturation of osteoclasts by
Intramembranous Bone Formation
suppressing expression of receptor activator of NF-κβ ligand In this process like the endochondral ossification a cartilage
in bone marrow-derived osteoblasts or stromal cells. Thus, anlage forms, but it is not ossified and for new bone to
it appears that endocannabinoid system maintains normal be formed the anlage needs to be completely resorbed.
bone mass by CB2 signaling. In addition to other modalities The flat bones of the skull and face are typical examples
being tried, CB2 receptor system may serve a molecular target of intramembranous (membranous) ossification. On the
for the diagnosis and treatment of osteoporosis in future. preformed scaffold of cartilage the osteoprogenitor cells
aggregate at the sites of new bone formation (preosseous
BONE DEVELOPMENT condensation) that are usually centrally located and
differentiate into osteoblasts that actively synthesize new
In human embryo bone appears after 7th week. Typically bone matrix advancing radially peripherally. Osteoblasts
two forms of bone formation are evident in the system. The then lay the bone successively on this scaffold in layers, a

Fig. 12: The endocannabinoid system and its effect on bone formation

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20 Section 1:  Bone Anatomy, Physiology, Pathology and Diseases

Fig. 13: The illustration depicting process of endochondral bone formation from a cartilage model

process called apposition (deposition upon prior bone). First stage—this stage begins with differentiation of
Ossification centers develop within the bone and enhance mesenchymal stem cells to become cartilage progenitors.
the rates of mineralization. The surrounding mesenchyme At molecular level this involves expression of transcription
condense into periosteum and lays down bone beneath factors, Pax1 and scleraxis by activation of cartilage-specific
it. The bones take on a lamellar character gradually. In genes.
the adult, similar process is called Haversian remodeling.
Second stage (the precartilaginous state)—this stage
Chondroid bones of the skull (wormian bones) that are
involves condensation of the committed mesenchymal stem
seen in association with suture closure are developmentally
cells to form compact nodules and these cells differentiate
intermediate between cartilage and bone. They contain both
into chondrocytes by the progression of activity of Pax1
types I and type II collagen. Here the scaffold is formed by
and scleraxis in stage one. The condensation of committed
chondroid bone upon which lamellar bone is deposited. It
cells is affected by N-cadherin. This precartilaginous
is not replaced by bone as in the endochondral ossification.
state also involves expression of SOX9 gene (sex reversal
Many factors (all not known) play potential roles regulating
Y-related high-mobility group box protein) that encodes
bone formation. Core-binding factor alpha-1 (cbfa-1)
a DNA-binding protein. SOX9 expression is an essential
or Runx2 transcription pathway (discussed above) is
step that is required for proper organization of further
responsible for osteoblast differentiation and binding to the
complex interactions. Mutations of the SOX9 gene are
osteocalcin promoter. This causes osteocalcin expression
generally incompatible with life and it has been found that
essential for processing of mineralization front. This
infants with specific mutations of the SOX9 gene die from
pathway is also responsible partly for formation of cartilage
respiratory failure due to poorly formed tracheal and rib
anlage. Cbfa-1 mutation causes cleidocranial dysplasia in
cartilages.
which there is delayed ossification of cranial sutures and
absent or hypoplastic clavicles. Third stage is marked by chondrocytes proliferation
forming the cartilage model (pre-cartilage condensation).
Endochondral Bone Formation Chondrocytes secrete a cartilage-specific extracellular
matrix.
Here a cartilage tissue first forms as a model (cartilage
anlage) from aggregated mesenchymal cells and is In the fourth stage, the chondrocytes hypertrophy
subsequently ossified. The appendicular skeleton, vertebral and produce collagen type X and fibronectin, so that
column and pelvis develop via endochondoral ossification. mineralization can proceed by calcium carbonate.
This discrete complex process can be divided into five Fifth stage is marked by vascular invasion of the cartilage
stages. model and apoptosis of hypertrophic chondrocytes. The

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Chapter 1:  Structure and Function of Bones and Joints 21

osteoprogenitor cells after proper stimulation differentiate growth plate in the human long bone typically comprises
into osteoblasts that begin to lay down osseous matrix on of various anatomically discrete tissues acting together as
the mineralized cartilage remnants that have been partially a composite unit to perform one specialized function, and
degraded. This process occurs in the cartilage model first thus is referred as an organ by many researchers. The physis
at the region forming future diaphysis of long bone and for physio-anatomical description can be divided into three
is known as the primary center of ossification. From the components (Fig. 14):
primary ossification center the endochondral ossification 1. The cartilaginous component of growth plate contains
spreads vertically along the axis of the developing bone in three predominant regions:
both directions. Secondary centers of ossification form at a. Reserve zone—contains spherical, single or paired
the ends of each bone (the epiphysis) eventually leaving chondrocytes involved in matrix production.
an area of cartilage between the primary and secondary They are full of glycogen and have predominantly
ossification centers called growth plate or physis. It is here anaerobic environment due to low PO2.
that continued growth in length occurs at both ends of the b. Zone of chondrocyte proliferation—This zone
developing bone. serves three purposes—matrix production, cellular
proliferation and longitudinal growth. Latter is equal
Structure of Physis (Figs 14 and 15) to the combination of former two. It has flattened
chondrocytes arranged in distinct columns. The
The term epiphyseal plate or epiphyseal growth plate endoplasmic reticulum occupies progressively
so commonly used actually confuses with the term increasing percent of the cytoplasmic area that rises
“epiphysis” and should not be used. Rubin introduced the from 14.9% at the top of the zone to 40.1% at the
term “physis” or “physeal segment” and is preferable. Two bottom of the zone of chondrocyte proliferation.
forms of growth plates exist in long bones one horizontal Biochemical analysis reveal that this zone contains
and the other spherical. The horizontal growth plates the highest content of hexosamine, inorganic
are responsible for increase in length of bone, while the pyrophosphate and has highest lysosomal activity.
spherical growth plates take part in growth of epiphysis The chondrocytes in this zone are the only cells of
and the physis itself circumferentially and contributes also growth plate that divide (proliferate). Longitudinal
to thickness of bone. The fully developed cartilaginous growth in the physis is directly proportional to the

Fig. 14: Structure of physis and involvement in various disorders

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22 Section 1:  Bone Anatomy, Physiology, Pathology and Diseases

Fig. 15: Structure of growth plate of bone—the physis, the illustration depicts various zones and associated disposition of vasculature

product of rate of production of new chondrocytes in the middle of the hypertrophic zone. The following
at the top of the proliferating zone to maximum sequence of events occurs for final calcification:
size of the chondrocytes in the lowermost layer of • Mitochondrial calcification
the hypertrophic zone. Due to heavy demand and • Reduction of nutrients and oxygen supply to the
consumption oxygen tension is maintained higher hypertrophic chondrocyte with mitochondrial
in the proliferating zone of physis at mean of 57 mm death
Hg (± 5.8 mm Hg) compared to any other zones. • Anaerobic glycolysis (this occurs due to distance
c. Zone of chondrocyte hypertrophy—This zone has from vascular supply, and hence oxygen tension
three discrete functional and histological regions this hypertrophic zone is very low to a mean of
namely the maturation zone, degenerative zone and 24.3 ± 2.4 mm Hg). All the stored glycogen is
zone of provisional calcification. The function of consumed
this zone is to prepare the matrix for calcification • Calcium is released from mitochondria
and to calcify the matrix. The chondrocytes show • Nucleation of mineralization in matrix vesicles
progressive vacuolation and increase in size with • Matrix calcification.
disintegration. The mitochondria instead of forming The cartilaginous matrix gets calcified as the cells
adenosine triphosphate (ATP) start to accumulate hypertrophy. This calcified cartilage then serves as a
calcium. The initial calcification (“seeding”) occurs scaffold for bone matrix deposition by osteoblasts. The
at the bottom of the hypertrophic zone (zone of lacunae that remain after apoptosis of hypertrophic
provisional calcification) within physis. This is chondrocytes are utilized by blood vessels. Abnormalities
initiated by matrix vesicles around which then in chondrocyte development or function can disrupt this
mineralization progresses. As noted above, matrix organized sequence of physeal growth and maturation
vesicles are rich in ALP that destroys pyrophosphate producing abnormal bones usually stunted in growth
which is an inhibitor of calcium phosphate and having crooked shape. Achondroplasia is such a
precipitation. Destruction of pyrophosphate tips the condition causing dwarfism and possibly involves a
balance to precipitation of calcium and phosphate, mutation in FGF.
and hence facilitates mineralization. Matrix vesicles 2. The bony component or metaphysis serves few important
also simultaneously accumulate calcium from the functions—it is involved in vascular invasion of
calcium lost through mitochondria at the same level transverse septa at the bottom of cartilaginous

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Chapter 1:  Structure and Function of Bones and Joints 23

portion of growth plate providing blood supply, the These vessels do not pass across the proliferative zone into
other functions are new bone formation and bone hypertrophic zone. The nutrient supply for hypertrophic
remodeling. It has two predominant components, the zone instead comes indirectly from terminal branches
primary spongiosa and the secondary spongiosa. There of nutrient artery which is also supplied by metaphyseal
is internal (histologic) remodeling with removal of arteries or plexus of vessels at places. The nutrient artery is
calcified cartilage bars (primary spongiosa) and lamellar the main supply for the central metaphyseal region and as
bone deposition (secondary spongiosa). The external or much as four-fifths of the metaphysis receives nutrition and
anatomic remodeling gives funnel shape to metaphysis oxygen through it. The metaphyseal blood vessels supply
(funnelization). Near the transverse septa separating only peripheral portions of the metaphysis, especially
metaphyseal from cartilage component there is low through the periosteum. As mentioned earlier also, the
oxygen tension (19.8 ± 3.2 mm Hg) and high degree of nutrient and metaphyseal arteries terminate into vascular
rouleaux formation of RBCs due to vascular stasis. High loops or capillary tufts. The terminal branches pass vertically
levels of phosphoglucoisomerase (enzyme compatible toward the bone-cartilage junction of physis and turn back
with anaerobic metabolism) are found in this region. The sharply forming hairpin bends just below the last intact
low oxygen tension inhibits WBC activity which is highly transverse septa at the base of the cartilage portion of the
oxygen dependent, while is favorable for pathogens. This plate. The venous branches from hairpin bends descend
may explain the reason for hematogenous osteomyelitis via several progressively larger veins to finally drain into
in ends of bone and not vascular stasis per se; the the large central vein of the diaphysis. Here again we see
concept is still however challenged). that no vessels penetrate the bone (metaphysis) cartilage
3. A fibrous sheath surrounds the growth plate at periphery (hypertrophic zone) junction beyond the last intact
that comprises of perichondrial ring of LaCroix and transverse septa, hence, hypertrophic zone is not directly
the ossification groove of Ranvier. These two structures penetrated by any vessel and most nutrients reach it via
are structurally different and serve different functions. diffusion or open circulation. Hence, in a fully developed
It appears that the groove of Ranvier contributes growth plate, hypertrophic zone is entirely avascular.
chondrocytes to the physis for the growth in diameter Compared to above the groove of Ranvier and the fibrous
(appositional growth or latitudinal growth) of the plate. perichondrial ring of LaCroix are richly supplied from
There are three distinct cell groups in the Ranvier’s perichondrial arteries.
ossification groove:
a. Progenitor cells for osteoblasts—this is a group of Regulation of Growth Plate (Physis)
densely packed cells that forms the bony band in
the perichondrial ring. The chondrocytes elsewhere in body are not responsible
b. Undifferentiated cells and fibroblasts contribute to for organ growth as in bone. So the chondrocytes of the
appositional chondrogenesis and are responsible for growth plate are functionally different from articular
diametrical growth of physis. cartilage cells. Even the chondrocytes within different
c. Fibroblasts cover the groove and serve to firmly parts of the growth plate show different response to similar
anchor the perichondrium of hyaline cartilage to stimuli. Growth plate is regulated by a host of systemic
growth plate. and local factors.
The perichondrial ring provides mechanical support for •• Systemic factors regulating the metabolism and
the otherwise weak bone-cartilage junction of the growth development of growth plate include growth hormone,
plate. It is a dense fibrous band that encircles the growth vitamin D and glucocorticoids, IGF I, thyroid hormone
plate at the bone-cartilage junction and in which collagen and estrogens (in females). These factors affect the
fibers run vertically, obliquely and circumferentially. linear growth of bone and also maturation of physis
(maturation is enhanced by estrogen so females grow
longer earlier and physis closes also faster terminating
Blood Supply of the Physis the linear growth earlier)
The three components of growth plate have distinct blood •• PTH, IGF and vitamin C influence the whole cartilage
supply. The proliferative zone receives blood supply from component
branches of epiphyseal vessels that penetrate the top four •• The growth hormone and thyroid hormones are trophic
to ten columns. These vessels arise perpendicular to the to reserve, proliferative zone and the maturation region
main perichondrial epiphyseal artery and pass through of hypertrophic zone
micro spaces in the reserve zone to finally terminate •• Gonadal hormones stimulate the hypertrophic and
in the proliferative zone at the summit of cell columns. metaphyseal regions

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24 Section 1:  Bone Anatomy, Physiology, Pathology and Diseases

•• Local factors that influence the growth and function of (invertebrates contain calcium carbonate, whereas plants
physis include TGF-β, PTHrP, Indian hedgehog (IHH) have oxalate) that is deposited along the long axis of the
and FGF receptor type 3 (FGFR3) (Fig. 16). collagen fibrils. The inorganic matrix is deposited in the hole
–– TGF-β inhibits chondroc yte proliferation, zone of collagen matrix created by the space left between
hypertrophic differentiation and matrix mineralizatio staggered arrangement of fibrillar structure. The individual
–– Indian hedgehog (IHH) induces the expression of collagen macromolecules are staggered by one-fourth
PTH related protein (PTHrP) in the perichondrium. of their length leaving around 400 Å long and 15 Å wide
PTHrP inhibits chondrocyte differentiation, thus hole zones. The mineral is initially deposited as randomly
acting as a negative feedback loop and poorly oriented amorphous calcium phosphate. The
–– Proliferative zone is controlled by FGF, PDGF and amorphous phase undergoes a series of organized solid
TGF-β. The maturation of chondrocytes occurs phase transformations that ultimately lead to production of
under the influence of prostaglandins and IGF. crystalline hydroxyapatite which is the stable solid phase.
Various factors are important in mineralization (Table 3).
The initiation of mineralization is caused by
Appositional Ossification heterogeneous nucleation. There is active binding of
The enlargement of bone in diameter occurs by appositional calcium, phosphate and calcium phosphate complexes at
bone growth. The osteoblasts deposit additional bone on the the nucleation site and not just simple precipitation of the
existing bone surface. There is continuous bone resorption mineral. Matrix vesicle provides the requisite environment
from inside until the desired bone thickness is reached. for this process. The physiologic state of extracellular
fluids is supersaturated with respect to octacalcium
phosphate. Pyrophosphate and serum proteins act as
THE PROCESS OF BONE crystal inhibitors. Phosphatases and proteases are essential
MINERALIZATION to locally remove these inhibitors and facilitate apatite
formation. Still crystallization would need local increase
Calcification of cartilage and osteoid as a physiologic in concentration of substrates (calcium and phosphate)
process is called mineralization. The inorganic matrix is far beyond supersaturation levels to overcome the energy
laid down in a specific pattern along the organic matrix. of the reaction of crystal formation and real mechanism is
The process is complicated and poorly understood. Calcium elusive. Many theories have been propounded by eminent
hydroxyapatite predominates mineral phase in humans researchers for explaining mineralization initiation and

Fig. 16: The effect of various growth factors and cytokines locally on the different zones of physis

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Chapter 1:  Structure and Function of Bones and Joints 25

TABLE 3: Role of various constituents in bone mineralization The Urist Triphasic Hypothesis
Component Remark In first phase, a soluble calcium protein substrate is formed.
Collagen Provides support to crystal deposition. Collagen can The calcium disrupts hydrogen bonds in collagen and reacts
initiate crystal precipitation. Facilitates formation of to form calcium complexes. These anionic complexes in
solid phase crystals from solution. Does not nucleate phase two react with phosphate to form soluble protein
crystal deposition
calcium phosphate complex. In phase three, the neutralized
Calcium-bind- These phosphoproteins may nucleate crystal deposi- calcium-protein-phosphatase complex reacts with Ca2+ and
ing protein tion and promote polymerization
HPO42- depending on the solubility product which is kept
Proteoglycan inhibit calcification by sequestering the
calcium ions or shielding collagen at metastable state (supersaturated) at the mineralization
front.
Gla proteins Osteocalcin and other Gla proteins bind calcium by
virtue of Gla residue
The Glimcher Hypothesis
Pyrophosphate Inhibits calcification and increases the solubility of
calcium phosphate preventing precipitation Proposes the stereochemical disposition of collagen
Alkaline phos- Possibly degrades pyrophosphate to aid in crystal components to be primarily responsible for nucleation. The
phatase precipitation and mineralization nucleation occurs with respect to the physical organization
of the collagen physical and chemical properties.
propagation, but for that the role of matrix vesicles should
be understood first. Pathological Calcification
Unlike the physiological calcification of bone described
The Role of Matrix Vesicles in Initiation above there are lots of pathological conditions where
calcium deposition occurs:
Matrix vesicles are the membrane bound cell free structures
derived from chondrocytes and osteoblasts serve these •• Damaged tissues have pathologic extracellular or
requisites and initiate mineralization. The trilamellar intracellular “dystrophic” calcification. The calcium
membrane bound matrix vesicles secreted by chondrocyte deposition within the soft tissues (both dystrophic
seed the calcium phosphate salt in matrix. Probably derived and metastatic) in myeloma, metastases, fat necrosis,
from mitochondria, they can either store calcium or ATP. trauma, sarcoidosis, scleroderma, hyperparathyroidism,
In the proliferative zone with high oxygen availability, the etc. is caused by calcium hydroxyapatite.
mitochondria synthesizes ATP for cellular requirement. •• “Metastatic” calcification occurs in association with
While progressing down to hypertrophic zone, the altered serum levels of calcium and phosphate.
oxygen concentration falls and the mitochondria store •• Crystal deposition in joints—This deposition is rarely
calcium instead of ATP. These are extruded out at zone of massive and simulates tophaceous deposits, hence
provisional calcification with degeneration of cells and burst called tophaceous pseudogout. The linear calcification
releasing microcrystals of calcium phosphate (possibly seen along menisci and articular cartilage or in the
hydroxyapatite also). Under supersaturated conditions the intervertebral disk radiographically, is mostly due to
mineralization is hence initiated. calcium pyrophosphate deposition (CPPD disease).

Mineralization Propagation BONE REMODELING


After nucleation hydroxyapatite crystal formation undergoes Remodeling is a process that involves tight coupling of bone
propagation (multiplicative proliferation) leading to resorption and formation to adjust to constantly changing
progressive ossification of calcification. These are matrix requirements with activity and aging (Fig. 17). It is essential
vesicle mediated and collagen mediated hydroxyapatite for the bone to change its form in response to stress and
precipitation. strain else, it will never leave its infantile form or be able to
For theories regarding bone mineralization one school bear the increasing weight with growth. Persons doing active
of thought gives primacy to matrix vesicles. The other school labor need to have stronger bones supporting muscles so on
gives bone matrix the primacy for initiating and propagating and so forth. Also, remodeling acts like regular maintenance
mineralization. These two theories have tried to explain the work healing the microtrauma and fractures that keep
intermediate mechanisms between calcium, phosphate and occurring in this “hard” tissue. Bone undergoes remodeling
hydroxyl ions in blood stream and eventually formation of throughout life which is primarily a function of trabecular
hydroxyapatite. bone arrangement, but is actively also seen in healing

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26 Section 1:  Bone Anatomy, Physiology, Pathology and Diseases

Fig. 17: Concept of bone remodeling as a function tight coupling of two alternating opposing processes, the bone
formation and bone resorption. Also shown is the effect of various growth factors and cytokines

compact bone of immature bone fractures, while minimally osteon (where bone formation is initiated). The resorption
in adult compact bone. To put it in figures nearly 25% of front of cutting cone does not follow osteonal arrangement
the metabolically active cancellous bone and some 3% of and progresses randomly, so that in a single go it can take
the cortical bone gets renewed each year. It is an essential down multiple osteons. With mineralization front, the
process as without remodeling (that also entails repair of osteons are partially repaired and form new interconnected
microfractures) bone would exceed its elastic tolerance channels depending on the stress pattern. The lamellae that
limits within a short period of time. The remodeling is not remain as reminiscent of cutting cone activity persist as
constantly occurring throughout the skeleton at once, but interstitial lamellae and keep accumulating over the age of
it occurs in discrete packets termed bone remodeling units person. The interstitial lamellae are less active metabolically
(BRU) by Frost, scattered throughout the skeleton. Each and are, hence unable to repair promptly. This is partly
packet takes 3–4 months to complete. There is, however, responsible for senile osteoporosis.
some quantitative bone loss with age (senile osteoporosis) Bone formation is a function of osteoblasts taking
as bone formation always lags temporally and quantitatively approximately 3 months. The osteoblastic activity is
from bone resorption possibly due to decreased number mediated by differentiation regulators like TGF-β, PDGF,
of osteoblasts. The process of remodeling of bone involves IGF and Gla proteins (discussed above). More important
three discrete steps of activation, bone resorption and is, however, the linking or “coupling” of bone resorption
bone formation that need discrete cellular and molecular and bone formation and this is immensely complex. We
components to complete. Bone remodeling is prominent understand at least three mechanisms that explain this
at endosteal and periosteal surfaces and is also seen within coupling:
Haversian canal systems that contain osteoprogenitor cells. 1. The current postulated model is that “osteoclastogenic”
The width of tubular bones and also the bone mass are and “osteoblastogenic” cytokines are stimulated
controlled by cortical bone remodeling. simultaneously by the same signal transduction
Resorption of bone is interestingly activated by pathway mediated by glycoprotein 130. Glycoprotein
stimulatory cytokines IL-1 and IL-6 produced by osteoblasts 130 is increased by the influence of PTH and vitamin
(that are ironically really meant for bone formation) and D, whereas sex steroids inhibit it.
also involves modulation of the integrin RGD sequence 2. During the osteoclastic process some osteoblast
interaction. Bone resorption takes approximately 10 days stimulating factors such as IGF I and IGF II and
carried out by a “cutting cone” of osteoclasts. The defect TGF-β are released that would stimulate formation of
created after resorption, is filled in by fibrovascular tissue osteoblasts from the osteoprogenitor cells by the time
containing pericytes (later forming Haversian and Volkman’s bone resorption process is completed.
canals), monocytes or macrophages, mesenchymal stem 3. The most fascinating and studied mechanism for
cells and undifferentiated osteoprogenitor cells in loose coupling bone resorption and formation is the RANK/
connective tissue. Histopathologically, basophilic line—the RANKL interaction, where osteoblasts regulate
“cement” or the “reversal” line marks the outer edge of the osteoclastogenesis.

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Chapter 1:  Structure and Function of Bones and Joints 27

Whatever the mechanism, coupling has been exploited altered cellular metabolism. A “piezoelectric” effect
by giving intermittent PTH therapy to treat osteoporosis so produced due to compression of the hydroxyapatite crystal
successfully. that has been so commonly highlighted is actually much
Why and how osteoclastic activity precedes osteoblastic less important in signaling, but may be responsible for the
activity always? The most logical answer to this is that the coupling of mechanical-electrical phenomena in bone.
ground needs to be cleared by osteoclastic activity for new
Strain response: Osteoblast proliferation in response to
bone to form in an organized robust way by osteoblasts
strain is mediated by the inositol 1, 4, 5-trisphosphate
rather than just a namesake patch work to be done—the
system. Neomycin mediated inhibition of phospholipase C
body systems are more honest, organized and authentic.
blocks inositol trisphosphate production, and hence
The osteoclasts are fast workers, so they finish their work
subsequent osteoblast proliferation.
early and bone synthesis should be more meticulously and
gradually done so osteoblasts come late, it is apparently Common mechanism (for stress and strain): Cells maintain
perceived that the bone resorption occurs early even though a constant milieu or basal equilibrium state for stress.
both started the race at same time. Also, the RGD sequence This equilibrium is defined by the number and quality of
may be directly stimulated in response to stress or strain intercellular focal adhesions, intracellular cytoskeleton
(discussed below) stimulating the osteoclasts first followed polymerization and the amount of externally applied
by osteoblasts. deformation (stress-strain equilibrium). The mechanism
involves activation of G proteins and other kinase cascade
Effect of Stress and Mechanosensory by load stimulus detected by mechano-electrochemical
sensory system. This specific sensory system includes
Systems on Remodeling (Wolff’s Law) stretch sensitive ion channels, integrin cytoskeletal
Wolff ’s law described by Julius Wolff in 1882 in strict machinery and load-conformational sensitive receptor
accordance with mathematical laws states, “every change tyrosine kinase. Integrins form important components of
in form and function of bones is followed by changes in the this mechanical sensory system. The αvβ3 integrins bind
internal architecture and external conformation”. Since to RGD sequence of osteopontin that triggers osteoclastic
long it has been known that mechanical forces influence resorption. The matrix proteins having RGD sequence
morphology of skeleton. If the stresses on a limb are taken undergo conformational change in response to tension
off say in immobilization the tissues undergo atrophy and strain. The matrix tension is then “communicated” to bone
the bones undergo “disuse” osteoporosis. On the other cells via previously detailed osteocyte network. Nitric oxide
hand, it is seen that children with malunited fractures of (NO) might also be a part of this signaling process.
long bones nearly always remodel into almost normal
appearing bones (except for some rotational under REGULATION OF BONE
correction), while poliomyelitis limbs with poor stress on
bones stay malunited. Similarly, weightlessness in space METABOLISM
causes rapid decrease in bone mass, equivalent to the
reduced amount of stress on them reflecting the need for Endocrine Control (Fig. 18)
constant force in maintaining skeletal health. Systemic and local factors maintain:
•• Balance between bone formation and loss
Pathways Affecting the Wolff’s Law •• Homeostasis in calcium levels in the body for various
Stress response: Under conditions of load there is an altered physiological functions, especially muscle contraction
bone metabolism and DNA synthesis. These responses are •• Maintenance of a reservoir of phosphate required for
mediated by electrical or chemical messengers (cytokines). generating energy.
Two separate components mediate this stretch sensory
pathway. The cell network consisting of osteocytes and their
processes communicate with surface cells. Osteoblasts
Parathyroid Hormone
and fibroblasts exhibit stretch sensitive ion channels. The Parathyroid hormone produced from the parathyroid gland
mineralized matrix is responsible for stream generated is a polypeptide hormone synthesized from pro-PTH.
potentials when fluid flowing through the matrix carries PTH maintains calcium homeostasis by stimulating bone
along particular ions (in the presence of different ones resorption. In fetal and neonatal animals, PTH is required
attached to the matrix). These stretch sensitive and stream for normal formation and development or remodeling of
generated potentials may be responsible for the signaling cancellous bone. PTH also impacts intestine and kidney

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28 Section 1:  Bone Anatomy, Physiology, Pathology and Diseases

Fig. 18: Illustration depicting the endocrine control of bone calcium and phosphate metabolism.
Shown are the effects of PTH and vitamin D on intestine and bones

function. Reduced serum calcium is the strongest stimulator osteoclast activation, initiation of bone resorption and
of PTH release from parathyroid glands. The physiologic maintaining adequate blood calcium levels for optimal
role of PTH includes: functioning of dependent organs like contractile tissues
•• Increase in osteoclastic activity which results in by calcium release from bone. Simultaneous osteoblast
calcium and phosphate release from the bony skeleton stimulation might be a check mechanism preventing
(mediated through osteoblasts and RANK and RANKL). too much bone resorption and “policing” the action of
•• In kidney, PTH reduces calcium excretion, but increases osteoclasts against excessive calcium stealth. Clinical
phosphate excretion. It also stimulates 1, 25-dihydroxy use of PTH analog has demonstrated that in certain
vitamin D production. situations PTH stimulates bone formation. It has been
These measures increase serum calcium concentration shown that in continuous administration of PTH there
which suppresses the secretion and synthesis of PTH. is increased osteoclastic resorption with simultaneous
PTH controls the serum calcium levels on a minute to suppression of bone formation. The effect reverses to
minute basis probably because we live in low calcium– bone formation instead when PTH is administered in low
high phosphate environment and the calcium levels are doses, intermittently. This anabolic effect is also probably
important with respect to sustaining life. Interestingly, indirectly mediated via IGF I and TGF-β. Constant high
despite being bone resorptive hormone receptors for PTH serum PTH levels, initiate osteoclast formation resulting
are found on preosteoblasts, osteoblasts and chondrocytes, in bone resorption that overrides the effects of activating
but absent from osteoclast which supports the notion that genes that direct bone formation indicating that osteoclast
PTH mediates osteoclastogenesis and bone resorption function and formation requires persistently high PTH
is osteoblast-dependent and mediated via cytokines levels due to indirect action. The action on osteoblasts
(discussed above). The ultimate effect of this action is is more direct, but possibly the bone resorption is much

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Chapter 1:  Structure and Function of Bones and Joints 29

more efficient process than the slower bone formation includes cholecalciferol (diet & even the drug supplements);
so that persistent elevated levels produce predominantly 1, 25-dihydroxyvitamin D = calcitriol. Vitamin D can
bone resorption. PTH-related protein (PTHrP) is expressed be synthesized in skin epithelial cells, and therefore by
early in the osteoblast progenitor cells and regulates bone definition it is not a vitamin. The predominant source
formation in a paracrine manner. This process persists of vitamin D normally is synthesis within skin and
longer so that pulsatile stimulation by even low doses of depends on the conversion of 7-dehydrocholesterol
PTH will stimulate osteoblasts escaping bone resorption to vitamin D3 (cholecalciferol) from UV-B radiation
that needs high persistent levels. (wavelength 290–320 nm). Ergosterol (naturally derived)
and 7-dehydrocholesterol (derived from cholesterol and
stored in skin) are the precursors for vitamin D. In the
Calcitonin skin, they are activated by ultraviolet light to previtamin
Calcitonin is a peptide hormone synthesized by parafollicular D that is thermally converted to ergocalciferol (D2)
(C) cells of thyroid. Its secretion is regulated by extracellular and cholecalciferol (D3). The reaction involves rapid
calcium levels and gastrin. The calcitonin acts to tone formation of previtamin D3 (photochemical reaction),
down calcium from blood maintaining normocalcemia which is then slowly converted to vitamin D2 or D3.. These
by removing excess calcium. Calcitonin blocks PTH- compounds are transported in the body via an alpha-
mediated bone resorption by osteoclasts. This is done globulin binding protein also known as vitamin D-binding
through increased adenylate cyclase and cyclic adenosine protein (DBP or Gc protein). DBP is vital in maintaining
monophosphate (cAMP) or as mitogen acting on bone stable serum levels for vitamin D and its metabolites. It
cells. It promotes renal calcium excretion. Calcitonin acts also modulates the rate of bioavailability, activation and
as an “emergency hormone” protecting against sudden end organ responsiveness of vitamin D. If the exposure to
hypercalcemia. The hypocalcemic effects of calcitonin UV light is prolonged then previtamin D3 gets converted
are temporary and with continuous infusion of calcitonin to lumisterol and tachysterol that are photoisomers and
“escape phenomenon” is seen where the effects of PTH do not bind to DBP. They get wasted with skin slough.
supersedes that of calcitonin. The actions of calcitonin are Vitamin D2 and D3 undergo hydroxylation in liver to
independent of vitamin D levels. Calcitonin receptors are yield 25-hydroxyvitamin D in the presence of magnesium.
present on osteoclasts and its precursors, and certain tumor This is the most abundant circulatory form of vitamin D.
cells. Increased levels result in a temporary fall in plasma The hydroxylation in liver is not stringently regulated so
calcium. measurement of 25-hydroxyvitamin D3 is the standard
The physiological role of calcitonin on bone morphology method for determining a patient’s vitamin D status. Further
and ultimate function is not fully clear. Decline or hydroxylation is done in proximal convoluted tubule (PCT)
overproduction of calcitonin does not have any significant of kidney forming 1, 25-dihydroxyvitamin D (calcitriol) and
alterations in bone density. The uncertainty may arise 24, 25-dihydroxyvitamin D (less active and produced under
from possible recently identified dual action of calcitonin the influence of calcitonin). The most active form of vitamin
bone formation and resorption. Calcitonin and alpha D is 1, 25-dihydroxyvitamin D. The normal plasma level of
calcitonin gene-related peptide (alpha-CGRP) deficiency 25-hydroxycholecalciferol is about 30 ng/mL, and that of
(Calca-/- -) exhibits high bone mass mediated by increased 1,25-dihydrocholecalciferol is 0.03 ng/mL. This hormone
bone formation with normal bone resorption in animals. (calcitriol) has various functions including:
However, with only alpha-CGRP (alphaCGRP-/-) deletion •• Calcium and phosphorus metabolism:
osteopenia was seen. These may explain why alterations of –– Stimulates synthesis of calcium binding protein
calcitonin serum levels in humans do not result in major (cholecalcin—transports calcium from luminal to
changes in bone mineral density. Calcitonin does, however, basal layer in intestine)
has some therapeutic role, it is used in management of –– Affects osteocalcin production
hypercalcemia of malignancy, pain control in osteoporosis –– Osteoid mineralization
(the effect on bone mineral alteration is meagre if any) and –– Osteoclastic bone resorption and maintenance of
in Paget’s disease (Osteoclasts from Paget’s patients are blood calcium levels
hyperresponsive to calcitonin). –– Increased active transcellular absorption of calcium
from proximal part of intestine
–– Increased phosphorus absorption from distal part
Vitamin D of small intestine
Vitamin D2 = ergocalciferol and Vitamin D3 = cholecalciferol. –– Reduced calcium and phosphorus excretion from
The common layman term for vitamin D refers to and kidney

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30 Section 1:  Bone Anatomy, Physiology, Pathology and Diseases

•• Skin growth of vitamin D receptor (VDR) gene has been recently


•• Insulin secretion portended to be responsible for postmenopausal
•• Reproduction osteoporosis making it genetically predetermined. Vitamin
•• Combating tuberculosis, viral infections and influenza D receptor (VDR) manifests most of the functions—calcium
by stimulation monocyte maturation. transportation, prodifferentiation, antiproliferative and
Deficiency of calcitriol is related to: immunomodulatory activities. The vitamin D receptor
•• Precipitation of autoimmune diseases and death due type II (VDR II) especially has a role for vitamin D in
to heart disease bone metabolism. The VDR II deficiency or mutation may
•• Stroke secondary to hypertension also be responsible for progressive alopecia. The marrow
•• Inflammatory bowel disease mononuclear cells fuse to form osteoclasts on exposure to
•• Muscle weakness and falls vitamin D only in the presence of osteoblasts as only the
•• Fractures latter contain vitamin D receptors and not the osteoclast
•• Cancers of colon, breast and prostate. precursors. PTH has synergistic action to that of vitamin
Calcitriol is primarily responsible for controlling D mediating this activity.
calcium metabolism in the intestine, proximal tubule of
kidney and bone. 1, 25-dihydroxyvitamin D [1, 25-(OH)2
D3] production is in turn regulated by other metabolic
regulators like PTH and calcium concentration itself.
Formation of calcitriol is facilitated by PTH when the plasma
Ca2+ level is low. Low calcium levels actually increase the
PTH levels responsible for majority effect. When the plasma
Ca 2+ level is high, renal 1-α hydroxylation is inhibited
producing only little 1, 25-dihydroxycholecalciferol and
instead majority is directed at producing the relatively
inactive metabolite 24,25-dihydroxycholecalciferol instead
(Fig. 19). The production of 1, 25-dihydroxyvitamin D3
[1,25-(OH)2 D3] is also increased by low levels of plasma
PO43– while high levels inhibit the same which is mediated
by a direct inhibitory effect of PO43– on 1-α-hydroxylase.
The third route for control of 1, 25-dihydroxycholecalciferol
formation is the direct negative feedback effect of
the metabolite [1, 25-(OH) 2 D3] on 1α-hydroxylase, a
positive feedback effect on 24-hydroxylase producing
24, 25-dihydroxycholecalciferol and a direct effect on the
parathyroid gland to inhibit the production of mRNA for
PTH.
Lack of vitamin D results in rickets in children and
osteomalacia in adults due to impaired mineralization of
newly formed bone. There is accumulation of excessive
proteinaceous bone matrix which fails to mineralize.
Excessive vitamin D would instead increase bone
resorption and cause hypercalcemia. Vitamin D activity
is mediated by vitamin D receptor present on several cell
types. The vitamin D receptor is complex arrangement
that forms homodimers or heterodimers with members
of the steroid hormone receptor superfamily of which
the retinoic acid receptor (RXR) is most notable. Vitamin
D receptor (VDR) ultimately forms a transcription
factor. Rickets has been reported to result from errors or
mutations in genes that code for this steroid hormone
receptor superfamily of nuclear receptors. Polymorphism Fig. 19: The formation and metabolism of vitamin D in body

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Chapter 1:  Structure and Function of Bones and Joints 31

Role of Vitamin D in Osteogenesis doses will produce a growth spurt, but it will be soon
arrested due to premature fusion of physis. Reduced
As noted above, calcitriol acts to resorb bone by stimulating
estrogen leads to bone loss by directly affecting osteoblasts
the formation of osteoclasts. That involves close association
and possibly osteoclasts, and may be mediated via PTH
of osteoblasts containing the VDR. Vitamin D3 is responsible
and calcitonin. In hypogonadism, the physes remain open
for stimulation of osteoblast differentiation through
and produce a long, slender and poorly muscled person
induction of osteocalcin and expression of ALP. Osteocalcin
(eunuchs are typical example). Androgens maintain
and ALP serve as markers of mature osteoblasts. Osteoblast
bone mass via receptors on osteoblasts and possibly by
differentiation through release of ALP is mediated via
strain from strong and developed muscles, so common
intermediary MAPK (mitogen activated protein kinases)/
in androgen abusers. Excess growth hormone causes
ERK (extracellular signal regulated kinase) signaling
rapid growth without having any effect of maturation of
(also known as Ras-Raf-MEK-ERK pathway) pathway.
physis. The actions are likely mediated on bone primarily
Osteoclast formation is stimulated via cell-cell contact
by IGF. Gonadal hormones though may exert direct effect
between osteoblasts and osteoclast precursor cells
through growth hormone receptors found on osteoblasts
involving the RANK/RANKL pathway upregulation that
and chondrocytes.
represents osteoclast differentiation factor. It also involves
downregulation of osteoprotegerin (OPG) expression which
is an inhibitor for osteoclastogenesis via “decoy” RANK
receptor mechanism (discussed above). 1, 25-(OH)2 D3
GROWTH FACTORS IN REGULATION
mediates bone resorption and remodeling by secondary OF BONE METABOLISM
stimulation of osteoclasts. In addition, 1, 25-(OH)2 D3 also
inhibits osteoblast proliferation and may instead stimulate Transforming Growth Factor-Beta
its apoptosis through induction of TNF-α. 1α-hydroxylase
system (mainly renal) responsible for synthesis of calcitriol Transforming growth factor exists in two forms, TGF-α
is also seen in macrophages, monocytes, keratinocytes and and β. TGF-α is now called epidermal growth factor
lymphocytes which are not regulated by negative feedback and is not present in bone. TGF-β increase synthesis of
mechanisms and amount to hypercalcemia seen in various DNA, plays important osseous metabolic effects like it
conditions. Mutations in the human 1α-hydroxylase gene enhances the synthesis of bone matrix proteins like type
cause pseudovitamin D deficiency rickets. I collagen and fibronectin, proteoglycans and it also
reduces the activity of ALP. TGF-β plays an important role
in intramembranous and endochondral ossification and
Vitamin A also enhances fracture and wound healing. The effects are
Vitamin A decreases the formation of bone and cartilage mediated by inhibiting production of hydrogen peroxide,
matrix. These effects are mediated by retinoic acid (RA—the deactivating proteolytic enzymes and upregulating integrin
most active metabolite of vitamin A). RA is a potent regulator receptors for extracellular matrix proteins. TGF-β1 enhances
of osteoblast growth and differentiation. RA acts on nuclear the proliferation and early differentiation of osteoblasts
receptors that belong to the steroid hormone receptor and a high rate of collagen synthesis, but inhibits terminal
superfamily (wide above in description and functioning of differentiation and mineralization of culture matrix. TGF-β
VDR). Alterations in RA levels during embryonic skeletal binds to TGF-β specific type I and type II receptors initiates
development result in prominent abnormalities of the a sequence of events → phosphorylation of SMADs 2 and
appendicular and craniofacial skeleton. RA increases 3 → complex formation of SMADs 2/3 with SMAD 4 →
levels of osteopontin and osteocalcin mRNA in osteoblasts, translocation of SMAD 2/3/4 complex into the nucleus →
hence acting trophic to its formation. The retinoid signaling finally transcriptional activation of specific target genes.
pathway also prominently affects the expression of the TGF-β1 specifically increases intracellular calcium ion
skeletogenic regulatory factors like Sox9 and Cbfa1 that act transport which enhances expression of a5 integrin that
like band masters for bone formation and development in is necessary for osteoblast adhesion. Following osteoblast
the embryological ossification process. adhesion its proliferation is also enhanced by TGF-β1 by
inhibiting p57 cyclin-dependent kinase inhibitory protein
(CKI) that is negative regulator of the cell cycle. TGF-β1
Gonadal Hormones and Growth Hormone also increases production of collagen, while suppressing
Estrogen promotes longitudinal growth and excess of it its maturation in effect increasing the collagen content
leads to premature fusion of the physis. So therapeutic quantitatively.

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32 Section 1:  Bone Anatomy, Physiology, Pathology and Diseases

Bone Morphogenetic Proteins (BMPs, ENDOCRINOPATHIES AND BONE


see Chapter 2 on Fracture Repair) and INVOLVEMENT
Osteogenesis
Primary Hyperparathyroidism
Bone morphogenetic proteins are osteotrophic factors that
belong to TGF-β superfamily. BMP-2 is responsible for Increased circulating levels of PTH with consequential
gene expression and synthesis of osteoblast differentiation effects on body.
markers, viz. ALP and osteocalcin, in preosteoblast cells
in the developing fetus. BMP-2 exposure for a very short Causes
duration itself are sufficient to induce cellular effects most Parathyroid adenoma, less commonly parathyroid
of which are signaled through specific type I and type II hyperplasia, rarely parathyroid carcinoma and as part of
serine/threonine kinase receptors. BMP receptor type IB multiple endocrine neoplasia (MEN) syndrome.
(BMPR-IB) plays an essential role in osteoblast commitment
and differentiation. BMP signals to inhibit myogenic Associated Mutations
differentiation and facilitate osteoblast differentiation in Mutations in MPRT2 gene and retinoblastoma gene.
mesenchymal stem cells that is mediated through BMPR-I
acting through SMAD 1, 5 and 8. Additionally, BMP-2 Epidemiology
induces osteoblast differentiation through Runx2 that as
Asymptomatic cases represent around 1% of population;
previously detailed is a global mediator for osteogenesis.
patients more than 60 years represent 0.2% of the incident
Runx2 and BMP-2-induced SMAD proteins together lead
disease. Asymptomatic cases are increasingly detected due
to osteoblast differentiation.
to multiple point screening commonly done while visiting
physician (serum calcium levels, PTH levels for osteoporosis
Insulin-like Growth Factors: IGF I and II management, etc.).
Insulin-like growth factors are final pathways for many
cell lines to promote proliferation, differentiation and Signs and Symptoms
matrix production of bone and cartilage. Osteoblasts and Classical patients with “stones (renal), abdominal groans,
chondrocytes produce them and the activity of growth psychiatric moans, bones” are rare to find and most
hormone has been closely linked to them. Growth hormone patients are now asymptomatic at detection. The classical
binds to specific receptors in target tissues that then produce manifestations are mentioned below:
IGF I. IGF I in turn has endocrine, paracrine and autocrine
Renal manifestations—Deposition of calcium in renal
effects on the stimulated cells and mesenchymal stem
parenchyma (nephrocalcinosis) or recurrent nephrolithiasis,
cells. For its endocrine actions IGF I has to be transported
diabetes insipidus and renal failure.
by IGF-binding proteins (IGFBPs carrier proteins). IGFBP
III appears to be the most important of them and it is Abdominal groans—Constipation, vomiting, peptic ulcer
postulated that deficiency of IGF or IGFBP III may be disease (may be associated with Zollinger-Ellison syndrome
responsible for Laron-type dwarfism. (MEN)] and acute pancreatitis.
Psychiatric moans—Result from memory loss, fatigue,
Other Growth Factors depression and delirium.
Platelet-derived growth factors have been competed Bones—The characteristic findings are osteitis fibrosa
to be one of potent osteogenic growth factors and have cystica (Brown tumor), which occurs in 10–20% of
been diversely utilized in orthopedic disorders from patients. Histologically, there are increased giant
osteonecrosis to nonunion (effects though have never been multinucleated osteoclasts in scalloped areas on
fully substantiated). PDGF are important mitogens for the surface of the bone (Howship’s lacunae) and the
osteoblasts and also have a chemotaxic effect. PDGFs are normal cellular and marrow elements are replaced by
typically thought to play important role in bone remodeling. fibrous tissue. Radiological changes usually include
The role of FGFs in osseous development and metabolism areas of subperiosteal cortical resorption which is
are not fully elucidated, but mutations of FGF are thought evident radiologically replacement of the usual sharp
to induce certain skeletal deformities like Pfeiffer syndrome, cortical outline of the bone in the digits by an irregular
Apert syndrome, achondroplasia, Jackson-Weiss syndrome, outline. There is also resorption of the phalangeal tufts.
and Crouzon syndrome. Other findings include loss of lamina dura dentes,

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Chapter 1:  Structure and Function of Bones and Joints 33

mineralization of soft tissues, development of bone cysts Secondary hyperparathyroidism may also arise
and an overall reduction in bone density. due to calcium malabsorption (as in malabsorption
Some people add to this “thrones” referring to polyuria syndromes, bariatric surgery, chronic pancreatitis and
and constipation. nutritional deficiency) and osteomalacia, but these cases
are rare. Especially important is identification of secondary
Diagnosis hyperparathyroidism in patients of osteoporosis (due to
•• Elevated immunoreactive PTH level in asymptomatic associated vitamin D deficiency) who are to be started on
hypercalcemia teriparatide as the effect will be blunted in these patients
•• Hypercalcemia, hypophosphatemia, increased urinary due to baseline elevated PTH levels.
phosphate, increased alkaline phosphate and increased
excretion of hydroxyproline in the urine. Treatment
This disease differs from primary hyperparathyroidism
Treatment : Usually, the asymptomatic patients are in the fact that the hormonal secretion and hyperplasia
managed conservatively with adequate hydration and of the gland can be suppressed by appropriate therapy.
reduced calcium intake. The patients should be followed The patients should be given calcitriol (0.25–2 µg/day)
annually for serum calcium levels, BMD test and serum and phosphate restricted diet. Calcimimetics (cinacalcet)
creatinine. There is a growing concern for cardiovascular have been introduced and approved for use in patients
deterioration, neuropsychiatric dysfunction, the adverse on dialysis. They act by allosteric activation of calcium
effects of osteoporosis and reduced bone quality favoring sensitive parathormone receptors. Long-term management
early surgery. Prophylactic parathyroidectomy is, however, and maintenance of normocalcemia depends on renal
debated and there is no clear consensus. Currently, surgery transplantation, but even then a few patients may develop
is indicated in patients with sustained serum calcium more tertiary hyperparathyroidism.
than 1 mg/dL above normal, creatinine clearance less than
60 mL/min, age less than 50 and bone density t-score less
than –2.5 at any of the three sites. Pseudohyperparathyroidism
Surgical removal of the functional parathyroid lesion This results from excessive PTH-like polypeptides secreted
results in a rapid decrease in circulating PTH levels, due to in circulation from malignant tumors of nonparathyroid
rapid bone formation by uninhibited osteoblasts (“hungry origin. Characteristic findings include persistent
bone”). It may acutely result in severe hypocalcemic tetany hypercalcemia and hypophosphatemia, absence of bone
since the half-life of PTH in plasma is approximately 20 metastasis, atrophy of parathyroid glands and remission
minutes. Postoperatively, if hypercalcemia persists for a of hypercalcemia on extirpation of tumor which is also the
week or more or recurs after showing initial improvement treatment.
one should suspect a second adenoma or metastases from
carcinoma.
Acromegaly
Secondary Hyperparathyroidism This is due to excess pituitary growth hormone (GH)
secretion (primary or due to excess GH release hormone).
This is a condition of increased (but not autonomous) PTH
secretion in response to hypocalcemia. The most common
Causes
cause of increased PTH secretion by parathyroid glands
is secondary to chronic renal failure. The mechanism is Pituitary adenoma ( > 98% cases), MEN1, growth hormone
not very clear and though on initial thought 1, 25-(OH)2 cell carcinoma and metastasis, McCune-Albright syndrome,
D3 deficiency appears to be the cause; the real picture is ectopic sphenoid or parapharyngeal sinus pituitary
much broader: adenoma, excess growth hormone release hormone
•• There is resistance to normal levels of PTH in blood secretion—hypothalamic hamartoma, choristoma, etc.
resulting in hypocalcemia
•• There is increased phosphatonin (FGF23) secretion Clinical Findings
by osteocytes that inhibits 1α-hydroxylase that is The patients are usually diagnosed after 10 years of age.
responsible for reduced 1, 25-(OH)2 D3 levels. Characteristic features include:
Patients usually have chondrocalcinosis at knee and •• Increased hand and foot size (increased shoe and glove
pubic symphysis, bone pains, joint pains, deformities and size)
pathological fractures (renal osteodystrophy), ectopic •• Prognathism and increased mandibular size
calcification and pruritus. •• Frontal bossing

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34 Section 1:  Bone Anatomy, Physiology, Pathology and Diseases

•• Broad chest
•• Pituitary gigantism if hypersecretion occurs before
CONCLUSION
physeal closure •• The human skeleton is made of a strong and stable
•• Increased heel pad thickness framework of bones that are finely engineered composite
•• Carpal tunnel syndrome tissue present in various shapes and forms.
•• Macroglossia •• Bone is a living tissue with active synchronization and
•• Increased gap between lower incisors evolution of its cellular elements chiefly composed
•• Broad joints (due to increased growth of epiphysis and of osteoblasts, osteoclasts and osteocytes. The
cartilage hypertrophy). osteocytes form the largest network of connecting cells
In adults, the bones are thickened due to appositional throughout the body. Osteoblasts and osteoclasts act in
bone deposition while in children the bone length also synchronization to form and reform the bone.
increases. Bones that develop late ossification centers like •• The basic framework of the bone is formed by the
scapula, sternum, mandible and ischium are unusually collagen molecules and a lot of them are available
enlarged as they are in the influence of increased hormonal serving minutely different purposes but type 1 collagen
level for longer duration. The joints of these individuals predominates in bone. Mineralization of collagen
due to unusual biomechanics and shape are prone to is specific and unique to bone giving it the ‘hard’
osteoarthritis. consistency a property found only for bone.
•• Bone is an active metabolic tissue with quite
Treatment predominant blood supply and like other tissues
The goal is to control the growth hormone and IGF also has neural supply that has trophic influences.
I hypersecretion, arrest tumor growth and reduce In immature skeleton the bone grows at the ends for
comorbidities. Surgical resection (transsphenoidal and increase in length while perimetric growth also occurs
high cure rate) is preferred modality for most patients. by appositional bone formation. Physis or growth plate
Somatostatin analogs (octreotide and lanreotide) are used of the bone is a specialized tissue which is very sensitive
for patients with invasive macroadenomas (for tumor to metabolic influences and genetic factors—any error
shrinkage) and for those requiring immediate control of at some or the other stage is responsible for various
symptoms or those who cannot undergo surgery for various malformations and osseous defects.
reasons. Other drugs like bromocriptine or growth hormone •• The process of bone formation, remodeling and calcium
antagonist (pegvisomant) are indicated for patients who metabolism is highly regulated by local and systemic
cannot tolerate somatostatin analogs. Latter is highly factors chiefly hormones (endocrinopathies have their
effective, but cost is a concern. Radiation therapy is reserved discrete manifestations on skeleton), but one of the
for indicated patients only and has disadvantage of late unique influences comes from mechanical factors like
onset hypopituitarism and inability to control IGF I levels. the stress on the skeleton (Wolff’s law).

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Chapter

2 Fracture Repair

Manish Kumar Varshney

Definition and classification Table 1: Classification of open fractures


Gustilo and Anderson (1976) classification [modified by Gustilo, Risk of
Fracture is a break in the continuity of a bone along with Mendoza and Williams (1984)] infection
partial or complete disruption of blood supply to the
Grade I: Clean wound smaller than 1 cm in diameter or puncture 0–12%
region, visible radiologically as a uni- or bicortical break. wound that appears clean with a simple fracture pattern, no skin
Philosophically experts define fractures as a soft tissue crushing or internal degloving
injury in which bone is incidentally involved—highlighting Grade II: A laceration larger than 1 cm but < 10 cm, without 2–12%
the importance of soft tissue handling and preservation for significant soft-tissue crushing, including no flaps, degloving,
optimal results of fracture management. or contusion. Fracture pattern may be more complex. High
velocity trauma
To describe fracture complete information need to be
deciphered from the information provider to the others. Grade III: An open segmental fracture or a single fracture with 9–55%
extensive soft-tissue injury (> 10 cm). Injuries older than 8 hours,
This should also be documented comprehensively. A useful farm injuries, gunshot injuries, segmental fractures, and fractures
guide is provided to fracture description including following with diaphyseal bone loss are also included in this type. Type III
headings: injuries are subdivided into three subtypes:
•• Side and bone involved—left/right femur, humerus 1. Type IIIA: Adequate soft-tissue especially periosteal coverage
of the fracture despite high-energy trauma or extensive
•• Condition of skin—open fracture (Gustilo-Anderson— laceration or skin flaps
Table 1)/closed fracture 2. Type IIIB: Inadequate soft-tissue coverage with periosteal
•• Location within bone—proximal third or middle or stripping and bone damage or bone loss. There is often gross
distal third or otherwise metaphyseal or diaphyseal contamination. Soft-tissue reconstruction is necessary
3. Type IIIC: Any open fracture (irrespective of wound size or
fracture. In skeletally immature bone epiphyseal and/or bone loss/type of fracture) that is associated with vascular
physeal involvement should be communicated (Salter- injury that mandates repair
Harris classification—Table 2, fig. 1)
•• Extent of involvement—complete/incomplete fracture Fractures can be “incomplete” where the fracture line
•• Displacement (distal fragment with respect to proximal, is not seen to pass through the opposite cortex, viz.
fig. 2)—anterior, posterior, medial, lateral, overlapping •• “Stress fracture” (fatigue fracture) occurring due to
(bayonetting) and distraction. excessive compressive stress (usually) or tensile loading
•• Angulation (defined by the direction of apex, fig. 2)— •• “Greenstick fracture” of immature skeleton where cortex
anterior/posterior, medial/lateral and periosteum are intact on concave side
•• Rotation (distal fragment with respect to proximal, •• “Cortical rupture” in bone tumors
fig. 2)—internal or external rotation •• Other types of incomplete fractures “may not show break
•• Fracture pattern (fig. 3)—transverse, oblique, spiral, in bone” structure at all viz. “impaction fractures” due
comminuted, greenstick, torus, etc. to compression force at cancellous bone and “torus
•• Condition of joint—intra-articular, extra-articular fracture” in immature skeleton.
•• Duration—fresh fracture or old fracture (more than or “Complete fractures” can be closed (with skin intact) or
equal to 3 weeks). “open” (“compound” is misnomer) with a break in overlying

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36 Section 1:  Bone Anatomy, Physiology, Pathology and Diseases

Table 2: Salter and Harris classification (1963) of physeal skin that can occur from outside in (trauma force) or inside
fractures out (sharp bone spike).
Type I A transverse fracture through the growth plate typically “Pathological fractures” occur in structurally abnormal
through the hypertrophic zone. This manifests as increased bone like neoplastic and metastatic lesions, infection,
width of physis. As the germinal portion remains intact metabolic bone disease (radiopenic bone) or osteopetrosis
there is no growth disturbance
and bisphosphonate associated fractures (radiodense
Type II A fracture through the growth plate and the metaphysis,
bone).
sparing the epiphysis
Fractures occurring near bone can be termed “juxta-
Type III A fracture through growth plate and epiphysis, sparing the
metaphysis. The line of fracture passes from hypertrophic articular” (just near the articular surface), “intra-articular”
zone of physis and exits through epiphysis damaging the (fracture line communicating with joint space) or “extra-
germinal layer. Being intra-articular prompt reduction and articular” (outside joint altogether).
fixation is mandatory. Tillaux fracture is a typical example Corner or bucket-handle fractures occur in child abuse
Type IV A fracture through all three elements of the bone, the resulting from violent shaking of the extremity.
growth plate, metaphysis and epiphysis. The straight
“Fracture dislocation” results when the joint surfaces
fracture line passes through the whole width of physis
and is prone to growth disturbances at healing by virtue also separate in association with fracture of one or both
of linear bony bar formation bones.
Type V A compression fracture of the growth plate due to crushing Sometimes bone may shatter into pieces at the fracture
force. This results in a decreased height of the growth plate site into more than two pieces resulting in a “comminuted
radiologically. The growth disturbance is very common and fracture”.
has a poor prognosis
“Avulsion fractures” (traction fractures) occur at the
Type VI (Rang, Injury to the peripheral portion of the physis (zone of
attachment site of ligaments, tendons or capsule, here the
1968) Ranvier) and a resultant bony bridge formation which may
produce an angular deformity bone fragment is pulled with the soft tissue.
Type VII Isolated injury of the growth plate only—no involvement Fractures impose lot of added physiological demand
(Ogden, 1982) of epiphysis or metaphysis on body, also there can occur complications if the fractures
Type VIII Isolated injury of the metaphysis at the primary and are not treated properly (table 3). Conventionally fractures
(Ogden, 1982) secondary spongiosa region with possible impairment of were stabilized by cast treatment or prolonged splinting that
endochondral ossification led to development of local and systemic complications
Type IX Injury of the periosteum (periosteal avulsion—usually collectively called “fracture disease” (table 4). Modern
(Ogden, 1982) iatrogenic) which may impair intramembranous ossification
orthopedics deals predominantly with reducing the

Fig. 1: The Salter-Harris classification of physeal injuries in skeletally immature patients

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Chapter 2:  Fracture Repair 37

A B C D E
Figs 2A to E: Illustration depicting the common displacements incurred in fractures of long bones

Fig. 3: Illustration showing various fracture patterns

morbidity of fractures by rationally using operative and influences of local and systemic factors. For a successful
various stabilization procedures that are still evolving. fracture repair appropriate cells need to be recruited with
“Fracture repair” [if not augmented {by fixation or simultaneous activation of appropriate genes at a right time
bone morphogenic protein (BMP)} or interfered (gross in a correct anatomical location. Fracture repair is essentially
displacement, loss of vascularity, etc.)] is a systemic and a “regenerative” process rather than healing as the defect
organized cascade of regenerative tissue formation with is actually replaced by new bone and not by scar tissue (so

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38 Section 1:  Bone Anatomy, Physiology, Pathology and Diseases

Table 3: Complications of fractures and repair process Table 5: Local and systemic factors influencing fracture repair
Local Systemic Local factors Systemic factors
Vascular injury Shock •• Type of bone (reduced with •• Age
pathologic fractures) •• Activity level (immobilization
Orgonal and muscle injury Fat embolism
•• Type of fracture (open and in the form of bed rest, “space”
Neural injury Deep vein thrombosis and comminuted, bone loss) flight!)
thromboembolism •• Intra-articular fracture •• Nutritional status
Ligament and capsular injury SIRS •• Surrounding soft tissue injury •• Hormonal factors
and devascularization •• Vitamin and mineral deficiencies
Compartment syndrome and ARDS •• Single or both bone fracture •• Diseases like diabetes mellitus,
volkmann’s ischemic contracture (maintained fibula can anemia, neuropathies
Nonunion, malunion Septicemia produce tibial nonunion!) •• Drugs (NSAIDs, cytotoxic
•• Soft tissue interposition and chemotherapy, fluroquinolones,
Fracture disease Gangrene and tetanus (open
distraction phenytoin, calcium channel
fractures)
•• Local bone pathologies blockers, steroids and
Myositis ossificans (heterotopic Pulmonary complications like cysts, fibrous dysplasia, tetracyclines)
ossification) (atelectasis and pneumonitis) for malignancies (neoplastic cells •• Smoking
bed-ridden patients keep eating away the repair •• Alcohol abuse
Reflex sympathetic dystrophy response and cells) •• Head injury
(CRPS) •• Infection (misdirection of
energy and inflammatory cells
Osteomyelitis to counter infection rather
Growth disturbances than healing of bone)
Pressure ulcers •• Venous stasis
•• Type of treatment and fixation
SIRS, systemic inflammatory response syndrome; ARDS, adult respiratory distress
(rigid, soft tissue stripping, etc.)
syndrome; CRPS, complex regional pain syndrome

Table 4: Fracture “disease”


George Perkin coined the term fracture disease for morbidity following
prolonged immobilization and nonweight bearing
•• Stiffness Of joints by fibrosis and capsular contracture and
synovial adherence
•• Muscle atrophy Disuse atrophy
•• Skin atrophy Due to immobilization and altered sympathetic
stimulus, associated with hyperhidrosis later
•• Circulatory Predominantly due to sympathetic dysfunction,
dysfunction if excessive sympathetic stimulus results RSD can
develop
•• Osteopenia Under remodeling due to released stress according
to Wolff’s law
RSD, reflex sympathetic dystrophy

fracture “healing” could be a misnomer). Surrounding soft


tissue injury is an important determinant to fracture repair
by virtue of maintaining good blood supply to the region.
Repair may be disrupted at start (slow union), or initially
(delayed union) or interrupted (nonunion) anytime during
the process depending on healing of surrounding soft
tissue and synchronization of bone repair. Colloquially it
is said that fracture is a soft tissue injury where the bone is Fig. 4: Illustration showing repair of fracture defect by a bone modeling
incidentally broken. Various other local and systemic factors unit (primary bone healing) that works across a well-apposed fracture
are also responsible for proper fracture repair (table 5, fig. with less than critical fracture defect
4). Three types of fracture repair are noted:
1. Intramembranous repair (direct bone healing, gap haversian remodeling): There is no callus formation
healing, osteonal remodeling, contact healing and (primary fracture repair) and the bone heals directly

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Chapter 2:  Fracture Repair 39

without any intervening tissue or callus mainly 3. Repair with bone callus formation (enchondral repair,
due to rigid fixation. Bones when apposed together secondary bone healing, indirect bone healing) is the
anatomically under physiological compression loads most common and is typical of diaphyseal fractures.
heal without any intervening tissue. This is the ideal Probably we have been so engrossed by seeing fracture
situation for fracture repair and is the natural course callus in patients treated with cast immobilization and
when the gap is below critical limit of 400 µm (some from our classical teaching that we think this to be
take it to 500 µm). The cutting cones cross from one the standard method of fracture repair. However, this
side to another across the fracture (fig. 4) and following is not so; most probably as this requires formation of
ossification front heals the fracture in turn. The healing extraneous tissue (cartilage) and takes longer time to
passes through the following stages (see also below in heal. Callus is a preossification cartilage tissue that forms
the determinants of fracture repair): in response to controlled motion rather micromotion at
–– Resorption of bone ends: Compression at fracture, the fracture site. Enchondral fracture repair process is
damage to blood supply at the fracture site causes also termed secondary bone repair (because there is
partial resorption of the bone ends. need for “intermediate tissue” the callus) and can be
–– Fibrous tissue formation: fibrous tissue forms broadly classified into three main “R” stages (fig. 5) as
from the healing hematoma or lying down of below (modified from Cruess-Dumont).
inflammatory tissue at the gap. It is a very thin layer –– Reactive stage (inflammatory stage): This stage is
and predominantly comprises of collagen. The akin to inflammatory response seen in response to
stages of inflammation after granulation tissue are tissue injury and comprises of two phases:
not followed in this type of healing and by virtue 1. Hematoma formation and induced inflammation:
of absolute stability the bone assumes as if it is not hematoma immediately forms due to blood
broken at all. leak into surroundings from disrupted vessels,
–– Maturation to lamellar bone—because of the close periosteum and endosteum. Blood in a free
apposition of bone ends the normal process of state (outside vessels) is a reactive tissue and
haversian remodeling occurs across the fracture immediately induces local inflammation. This
site. The advancing osteoclastic migration front hematoma is vastly responsible for further stages
in the form of cutting cones cross the fracture site and osteogenesis as demonstrated by Mizuno
and the fibrous tissue followed by the osteoblastic et al. They demonstrated that as early as 4th
ossification front and thin capillary vessels that seal day the hematoma has “osteogenic power” that
the gap. progressively increases. Hematoma at fracture
2. Second type is “creeping substitution” (term site lifts periosteum and underlying cells die, also
first used by Phemister) and is primarily seen in pressure effect of hematoma produces ischemia.
cancellous bone. It is typical of intra-articular and The fibroblasts survive bone necrosis the extent
periarticular fractures stabilized by rigid fixation of which is determined by degree of impact.
anatomically. Creeping substitution is also seen Cellular toxicity induces chemotactic cytokine
during incorporation of cancellous bone graft. response and is responsible for the “regional
Creeping substitution is the process of resorption acceleratory phenomenon” (RAP) as described
of the trabecular network of bone and lying of new by Frost. Complicated cellular process of cellular
bone by appositional ossification on the surface of recruitment, migration, multiplication, osteoblast
the scaffold hence left (both processes occurring and osteoclast differentiation, mineralization
simultaneously). The inside of the newly laid control and remodeling control ensues as part
bone microtubes is hollow filled with resorptive of RAP. Osteoblast progenitors are recruited
material and is gradually replaced with bone. The by osteogenic induction of undifferentiated
inflammatory cells and granulation tissue creeps cells from bone marrow and mesenchymal
into the tubes and new bone formation occurs. cells from “cambium” layer of periosteum.
They provide the pluripotent cells needed for new Osteoclasts come from hemopoietic cells of
bone formation and remodeling. This sandwich bone marrow. Bone morphogenic proteins help
architecture of necrotic bone surrounded by viable in differentiation of cells to osteoblasts, clasts
new bone is remodeled by osteoblastic activity from and cytes. These cells then migrate to fracture
granulation tissue. Gross architecture of the bone is focus. Under the influence of platelet-derived
maintained hence the scaffold (dead trabecular bone) growth factor (PDGF) and transforming growth
is copy-pasted (substituted) by new living bone. factor-β (TGF-β); the progenitor cells proliferate

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40 Section 1:  Bone Anatomy, Physiology, Pathology and Diseases

Fig. 5: Illustration of fracture repair by callus formation (secondary bone healing), note this is not the primary mode of fracture healing,
formation of callus shows a compromised state wherein bone has to take help of complementary tissue (callus) for healing the defect

into colony forming unit fibroblasts (CFU-F), all type II collagen. This stage lasts some 2 weeks.
collectively forming granulation tissue. Other This is biochemically “mesenchymal” step and
cytokines and paracrine influences on the is predominated by collagen type 1, 2, 3 and 5.
cells are derived from inhibin, activing, BMPs, Access to substrate molecules (oxygen, glucose
nodal related genes, glial derived neurotropic and amino acids) and clearance of metabolic
factor, αFGF, βFGF and IGF-1. Most of these are products (CO2, lactate and urea) are of critical
mitogenic (some authors have cited uncontrolled importance to cell survival. The processes by
activation from these factors to cause “tumor which molecules are moved in and out of a fracture
formation and neoplasia development” later—as or graft site are collectively referred to as “mass
a practicing orthopedic surgeon we so commonly transport”. This process may be mediated by fluid
find trauma at the site related by the patients flow (convection, e.g. with muscle contraction)
to neoplasia. Personally I am unsure of this or by diffusion of molecules along concentration
relationship but true is the fact that many gradients or in response to electromagnetic forces.
patients do report local trauma months/weeks At distances greater than 200 μm, the transport
ago and logical could be the derivation that of oxygen and other nutrients rapidly becomes a
uncontrolled activation of mitogens could limiting factor for cell survival. As a general rule,
cause neoplasia formation). Mineralization is there is an inverse square relationship between
controlled by systemic factors regulating calcium cell concentration and the depth of cell survival,
and phosphorus metabolism. Inflammation such that fourfold reduction in the concentration
usually reaches its peak at 48 hours and then is of implanted cells will double the depth of their
modulated according to the treatment a fracture survival within an implant.
is receiving. –– Reparative stage: this stage essentially comprises of
2. Granulation tissue formation: The hematoma is reparative tissue deposition and can be divided into
infiltrated by developing vessels from surrounding following phases:
healing tissue under effect of vascular endothelial ◊ Callus formation: Callus is the bone regenerative
growth factor (VEGF) and fibroblast growth tissue that forms in response to micromotion at
factor (FGF). The proliferating fibroblasts (that the bone injury site aimed to naturally unite the
survive ischemia) along with ingrowing vessels two opposed stabilized bone ends. Formation
evolve into fibrovascular granular tissue rich in of callus reduces the interfragmentary strain by

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Chapter 2:  Fracture Repair 41

increasing surface area and thus improving local important in fracture repair as absence of the
environment towards healing. The formation of same has been cited as one of the reasons
callus is a combined effect of four distinct healing for nonunion of distal third tibial fractures.
responses as outlined by Einhorn emanating These four types of callus responses have been
from the bone marrow, the periosteum (most incorporated in the philosophy of “fracture
important), bone cortex proper and external healing process” propounded by McKibbin
soft tissues (response mounted by surrounding (see below). Differentiation of progenitor cells
muscles and mesenchymal tissue). There are two depends on type of strain delivered (see also
histologically varied forms of callus that can be Parren Theory below) and oxygen tension.
recognized: High strain and/or low oxygen produce
1. Soft callus (primary callus): After 2 weeks fibrogenic differentiation and fibrous tissue.
the periosteal derived cells few millimeter Rigid fixation with low strain and high oxygen
p rox i ma l f ro m f ra c tu re d e ve l o p i nto promotes direct woven bone formation
chondroblasts to form hyaline cartilage, (intramembranous ossification); intermediate
distally somehow the cells from cambium strain and low oxygen promotes cartilage
layer develop into osteoblasts and deposit formation (endochondral ossification).
the organic matrix (osteoid substance with Mobile regions (relative stability, e.g. with
disorganized collagen fibers) and woven bone nailing) with hydrostatic loading (compressive
rapidly. This is biochemically “chondroid- stress) at fracture produces cartilaginous
osteoid” step predominated by collagen type differentiation, while tensile loading produces
1, 2 and 10. In contact with periosteum the fibrocartilaginous differentiation. The
bone lamina forms proximally forming bone mineralization progresses from immature
bridge. At the fracture site the cells deposit bone bridge towards focus. The fracture during
hyaline cartilage, and as the focus solidity this stage is “sticky”, i.e. it is deformable (can be
increases the cartilaginous cells hypertrophy angulated) but not displaceable (ends cannot
and cartilage progressively mineralizes by be separated) by physiologic loads. Supervised
enchondral ossification. This is biochemically mobilization can begin during this stage.
“chondroid” step predominated by type 2 2. Hard callus: As the immature bone grows
and 9 collagen. There are three types of callus strong the woven bone gradually transforms
formation at the site of fracture. (1) “Periosteal into primary lamellar bone. This bone,
bridging callus” typically develops in the above however, grows in many directions. The
described fashion. It should be realized that transformation usually commences in 4th
amount of periosteal callus has no relation week and finishes around 16th week. The
to the size of initial hematoma, but reflects amount of callus formation is dependent
the need for ancillary stabilization required primarily on oxygen tension but also on strain
if blood supply is adequate and is inversely pattern (treatment) at the fracture site.
related. In addition to the periosteal callus ◊ Consolidation (lamellar bone deposition): There
a slowly developing (2) “intramedullary is resorption of bone ends with bridging callus
callus” is laid down from inside the bone formation. The fracture line becomes vague. The
supplied by medullary arterial system. This initially deposited collagen is predominantly
has double concave shape with periphery type 2 that is gradually replaced by type 1
adhered to endosteum and is the predominant collagen on which mineral phase quickly deposit.
response during “gap repair”. (3) Third type is This is biochemically “osteoid” step and is
the “intercortical uniting callus” occupying predominated by type 1 collagen. The process of
the space between the opposed cortices of formation of lamellar bone in hyaline cartilage is
fractured ends. Its size is totally dependent termed enchondral ossification while formation
on reduction and apposition of bone ends so of lamellar bone from woven bone is called
that it is absent in compressed plating. Apart bony substitution and both processes occur
from above a fourth type of tissue is also seen simultaneously in consolidation. Mineralization
called “external soft tissue” response (not of fracture callus is an essential step in bone
a true callus) that develops from vascular formation that depends on degradation of
mesenchymal tissue like muscles and is proteoglycans affected by endopeptidase and

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42 Section 1:  Bone Anatomy, Physiology, Pathology and Diseases

deposition of crystals affected by alkaline movement; it also is predominant response in total


phosphatase. rigidity.
–– Remodeling: remodeling is the process of slow 2. External bridging callus (incorporates the periosteal
restoration of normal bone structure, passing through bridging callus and external soft tissue response): by far
stages of primary lamellar bone (multidirectional this is the most predominant callus response manifested
osteons) to secondary lamellar bone (longitudinal by extensive callus tissue formation and clinically
osteons). The stage starts during reparative stage palpable swelling at the fracture site by 2–3 weeks and
and continues even after clinical bone union (up later. This is the predominant response of osseous tissue
to 7 years). Remodeling is based on the special in closed treatment methods and cast immobilization.
units called “bone modeling units” described by Periosteal totipotent and pluripotent cells take part in
Frost. This is spearheaded by osteoclasts covering the callus response. It forms fast (less than previous
the bonnet shape capillary vessels cutting into response) but has marvellous ability to bridge the
the previous bone resorbing the bone in areas of fracture gap. If total rigidity (rigid fixation) prevails
depression called “howship lacunae”. These “cutting this response will be absent absolutely. The external
cones” are followed by osteoblasts depositing new bridging callus develops in accordance with Wolff’s law.
mature bone (concentric lamellar). This structural Larger the diameter higher is the torsional and bending
modification continues indefinitely according to resistance. Torsional resistance is proportional to four
the functional load and stress pattern on the bone times the radius (4x R) so increased callus diameter as
(Wolff’s law). Strength at the fracture site gradually seen in functional cast bracing of long bones due to
improves over time and is further classified into cyclic muscular movements will have higher resistance
four progressive stages depending on the physical to strain and loading.
strength gained at the fracture site: 3. Late medullary callus (involves intramedullary callus):
1. Stage 1: torsional testing causes failure at the this is a combination of appositional and endochondral
fracture site in a low resistance pattern ossification and is an essential step to formation of hard
2. Stage 2: similar to stage 1 but in a high-resistance callus. It is slow to develop but has the best ability to
pattern bridge the fracture gap. The response is seen both in
3. Stage 3: in torsional testing the bone fails partly at closed treatment of fractures and rigid fixation.
the original fracture site and partly in the previous 4. Primary cortical response (involves intercortical callus):
intact bone. this is slowest to develop and is dependent on rigid
4. Stage 4: failure does not occur at the original fixation and hard callus formation. It is seen by 50–80
fracture site. days and progresses very slowly at the rate of 1 mm every
Apart from above commonly accepted flow of fracture 3 weeks.
repair, “Frost” also proposed stages of fracture repair that
delineates five stages, viz. Important determinants of
1. Stage of hematoma formation
2. Stage of granulation tissue (inflammation and cellular fracture repair (fig. 6)
proliferation) •• Method of treatment (see also the interpretation of
3. Stage of callus mechanical theories below): Stability at the fracture site
4. Stage of remodeling determines the differentiation of progenitor cells and
5. Stage of modeling the amount of callus formation. Different modalities
The “fracture healing process” as propounded by used provide for different types of repair and knowledge
McKibbin. This incorporates the basis of four types of callus can be used for our clinical use (table 6). With absolute
responses described above to explain the process of fracture stability, rigid fixation and low strain environment
repair. there is no movement (500–2,000 microstrain) at the
1. Primary callus response (involves part of periosteal fracture site and fracture heals with “primary fracture
bridging callus and intercortical callus): viable repair” at diaphyseal site (even where secondary bone
osteoblasts from apposed bone fragments incorporate repair usually is the rule). Primary fracture repair
in the soft callus. Unable to bridge the fracture gap (intramembranous repair) does not pass through
completely and failure will produce horse hoof above-mentioned stages. Primary fracture repair is not
nonunion. This response is very swift to initiate inferior or superior method of repair but is essential
and progress and quickly resolves the tolerance to normal process of fracture repair in dense cancellous

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Chapter 2:  Fracture Repair 43

Fig. 6: Determinants and various inhibitory influences on fracture healing

Table 6: Type of stabilization and its impact on fracture repair (it is assumed that no nonunion results)
Type of stabilization Predominant type of repair
Plaster of Paris cast Enchondral ossification
DCP plating •• Gap repair without compression
•• Primary cortical repair (Haversian remodeling) with compression
•• Enchondral repair can occur on opposite side
Locked plating in rigid mode and compression Primary cortical repair
Open reduction and locked plate in “elastic mode” Combination of primary cortical repair and enchondral repair (predominates)
MIPPO Enchondral repair
Intra-articular fractures fixed with plate Creeping substitution at cancellous surface and primary cortical repair (no callus)
Intramedullary nail Early periosteal callus and enchondral repair. Late intramembranous repair
External fixator •• Elastic: enchondral repair through periosteal bridging callus
•• Rigid: primary cortical repair
Wire loops Creeping substitution at cancellous bone and endochondral repair at diaphysis
MIPPO, minimally invasive percutaneous plate osteosynthesis

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44 Section 1:  Bone Anatomy, Physiology, Pathology and Diseases

bone (no or minimal callus forms) and intracapsular ◊ Delay in onset of periosteal reaction (due to
fractures where cambium layer of periosteum is periosteal and its cambium layer atrophy)—
deficient as in fracture neck of femur. With plating a decreased number of progenitor cells and
fracture and establishing absolute stability we remove delayed response to TGF-β and vitamin D.
the local hematoma and create a periosteal wound this ◊ Delay in cell proliferation due to aging effect on
suppresses callus formation. This is desired in intra- cells—decrease in the division capacity of cells.
articular fractures where callus would disturb intra- ◊ Decreased bone formation—lower osteoinductive
articular congruity. There are two fate of this fixation, capacity of bone matrix, increased ratio of RANKL
if a gap is left between the fracture ends a gap repair to OPG.
occurs; else with compressed ends a primary contact ◊ Delayed angiogenic invasion of cartilage—
repair ensues. decreased blood vessel formation. There is
1. Gap primary fracture repair (gap < 400 µm): reduced expression of PDGF-BB in endothelial
Intramedullary callus plays a predominant role in progenitor cells in elderly. Hypoxia-inducible
this repair. By 6 weeks marrow callus completely factor-1α protein and transcripts of “vascular
occupies the canal and vessels grow from it up to the endothelial growth factor” are expressed promptly
cortical gap surrounded by granulation tissue. Over in young patients early in course of fracture repair.
this the osteoid and woven bone is laid out filling This is partly mediated by expression of MMP9 and
the gap. This immature bone is continuous with the 13 that are also expressed early (3–7 days) in the
marrow callus and is oriented transversely to the young but take 21 days in elderly.
longitudinal axis of bone and Haversian system. ◊ Protracted period of endochondral ossification—
In the second stage that takes months, haversian changed local and systemic milieu of signaling
longitudinal remodeling occurs and normal bone molecules. Decreased antioxidant levels and
structure is restored. This second stage consists of higher oxidative damage to regenerating cells.
“cutterheads” passing from one side of fracture to ◊ Impaired bone remodeling—apoptosis of
other (diaphyseal cortex) according to ARF scheme osteoblasts with aging and glycation of matrix
(activation, resorption and formation), welding the disturbs bone healing.
fracture. –– Depending on location of fractures, the metaphyseal
2. Contact primary repair (primary cortical healing, fractures heal faster than diaphyseal fractures and
haversian remodeling): With compression at upper limb fractures unite faster than lower limb
fracture site the osteons at both ends are opposed fractures.
so close that the first stage of gap repair is omitted
and “cutterheads” follow the ARF scheme from Table 7: Endocrine and paracrine influence on fracture repair
start “osteonal remodeling”. Tunneling produced by Growth factors / hormones Action
“cutterheads” is followed by capillaries and activated TGF-β (platelets, inflammatory Progenitor cell stimulation
osteoblasts eventually forming the Haversian cells, chondrocytes, osteoblasts)
system. This also explains why we should achieve BMPs (chondrocyte, Cartilage formation, recruitment,
compression of fracture ends if we are aiming for osteoblasts) proliferation, differentiation,
absolute stability. It should be, however, recognized enhancement
that the side opposite to plate fixation still can FGF (inflammatory cells, Mesenchymal cell proliferation
produce secondary bone repair by callus formation chondrocytes, osteoblasts)
commonly seen as it is difficult to achieve “absolute” PDGF (platelets, inflammatory Stimulation of type-I collagen synthesis
stability and uniform compression always. cells, endothelial cells)
•• Endocrine influence and effect of local growth factors IGF chondrocytes, osteoblasts) Production of type-I collagen stimulation
on fracture repair (table 7). Cortisone Decreased callus proliferation
•• Effect of age and site of fracture:
ACTH Reduce or stop consolidation
–– Fracture healing is faster in younger patients
Thyroxine Stimulates consolidation
(children and adolescents) by a factor of 1.5–2 times,
i.e. the time required for fracture to heal in elderly Growth hormone Stimulates callus formation
(older than 60 years) will be 1.5–2 times than that PTH Stimulates consolidation and remodeling
required for children for similar fracture. The causes TGF-β, transforming growth factor beta; BMP, bone morphogenetic protein; FGF,
for this difference have been studied and are possibly fibroblast growth factor; PDGF, platelet-derived growth factor; IGF, insulin-like growth
as follows: factor; ACTH, adrenocorticosteroid hormone; PTH, parathyroid hormone

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Chapter 2:  Fracture Repair 45

•• Effect of smoking and radiation: Cigarette contains about on “graphic mechanics” and pointed out that the
109 known chemicals including nicotine, benzene, tar, lines in Meyer’s drawings resembled the principle
etc. which harm bone. Nicotine depresses osteoblast stress trajectories in cantilever beams. His student
activity, may inhibit revascularization of bone graft, made a crane with a curved beam stimulated by
has a negative impact on fracture repair and inhibits Meyer’s drawings of internal bone structure of
the expression of a wide range of cytokines including cancellous bone.
those associated with neovascularization and osteoblast 2. There is statical importance and necessity of the
differentiation. It increases the risk of bone fractures by trajectory structure of the bone.
inducing osteoporosis, reduces estrogen effectiveness, 3. Bone growth can occur only in the interstitial space
and can counter the antioxidant properties of vitamins (proved wrong).
C and E. Radiation produces long-term suppressive 4. The compact bone is nothing but a compressed
effects on Haversian system by reducing the vascularity cancellous bone (proved wrong).
and cellularity. Postoperative radiation reduces bone Wolff concluded from his observations that increased
graft incorporation and should be delayed for 3 weeks. compressive and distraction forces stimulated
High dose radiation also reduces the structural integrity bone osteoblasts, whereas reduced compressive
of bone. Radiation also affects the bone structure, and distraction forces inhibited them. Moreover he
function and metabolism. Exposing bone to radiation considered compressive forces to be more important and
can result in four major types of complications: (1) was impressed by the callus formation at the concave
osteoradionecrosis, (2) fractures, (3) bone growth (compression) side of angulated fractures. “Wolff’s law
changes, and (4) radiation-induced cancers. Radiation of bone transformation” is related to remodeling and
itself is called a “complete carcinogen”, in that it can cause states that the bone’s trabecular structure adapts to the
the four phases of cancer’s formation: (1) initiation, (2) types of stress it is subjected to, so that structure of bone
promotion, (3) progression and (4) metastatic activity is dictated by the functional demands. Taking it further
of transformed cells. The minimum latency period for a fully developed bone hence must serve the function
radium-caused tumors is around 3 years with a peak at that part of body as it has developed in response to
time of about 8 years. Children who receive radiation the functional demands there. So, in short, Wolff’s law
for cancers (other than those of bony origin) are at can also be extended to simply state that “form dictates
particular risk if their growing bones receive large doses function” (fig. 7).
of radiation (see section on bone tumors). •• Hüter Volkman theory (1862): This is relevant to the
physis (growth plate) and physeal growth; it should
not be misinterpreted with Wolff’s law that applies to
Laws associated with bone remodeling. According to this principle excessive
fracture repair and bone compression leads to tissue atrophy and inhibits the
physeal growth, whereas decreased compression and
remodeling
•• Wolff’s law: Meyer demonstrated that the spongiosa of
cancellous bone shows a well-motivated structure which
is closely connected with the statics and mechanics of
bone (his drawings stimulated not only orthopedic
surgeons but even engineer’s like Culmann). Wolff was
influenced by Meyer’s ideas and in 1869 he claimed
that some physiological properties of bone that can
be proven by the concept that “Bone aligns itself along
directions of principle stresses”. The principle directions
of a stress tensor at any given point are orthogonal and
the trabeculae in bone seem to intersect at right angles.
He proposed four principles based on the mechanism
of which the last two have been proven wrong:
1. There is perfect mathematical correspondence
between the structure of cancellous bone in the
proximal femur and trajectories of Culmann’s crane. Fig. 7: Wolff’s law: in accordance with this law the trabeculae in the
Carl Culmann was a German engineer who worked bones are distributed.

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46 Section 1:  Bone Anatomy, Physiology, Pathology and Diseases

moderate distraction enhances osteogenesis promoting “Interfragmentary Strain Theory”, which related the
bone growth. The effect is such that a physis subjected tissue response to the local mechanical environment.
to angulatory forces will show retarded growth at the The theory was initially devised to explain the
compression side (fig. 8) and increased growth at the mechanism of “gap healing” or “contact healing”
distraction side (tensile forces). Finely analyzed the bone without formation of fracture callus based on
is adapting itself in the direction of applied force finally longitudinal strain. But the gap deformation involves
and is in congruence with Wolff’s law. So essentially both numerous strain mechanisms operating in different
laws tell the same thing that bone develops according directions, still understanding the concept is useful
to applied forces. Classic relation of Hüter Volkman for basic understanding. Perren’s theory postulates
theory can be seen with the development of congenital changes in fracture gap tissue related to strain
scoliosis (and Blount’s disease) where the vertebral magnitudes in the fracture gap. Perren theorized
physis develops according to compression and tensile that the magnitude of interfragmentary strain would
forces and hence wedge vertebrae with bent spine result. determine the subsequent differentiation of fracture
•• Mechanical effects on fracture repair: The two main gap tissue. The interfragmentary strain was defined
theories relating mechanical stimuli to fracture repair as the ratio of the relative displacement of fracture
are one due to Perren and one due to Blenman and ends versus the initial gap width.
Carter. ◊ Interfragmentary strain (ε gap) = fracture gap
1. Perren interfragmentary strain theory: Perren displacement/initial gap width
(1979) proposed a brilliant hypothesis, the ◊ Δu/L
This definition of gap strain corresponds to a small
deformation definition of strain. Perren theorized
that interfragmentary strains above 100% would
lead to nonunion. Strains between 10% and 100%
would lead to sustain initial fibrous tissue formation
(fig. 9). Strains between 2% and 10% would lead
to cartilage formation and an endochondral
ossification formation. Strains under 2% would lead
to direct bone formation and primary fracture repair.
Perren believed that once set in progress that tissues
once formed would stiffen the fracture gap, which in
turn, would lead to lower strains, which would allow
Fig. 8: The Hueter-Volkmann law for physeal growth (see text for formation of the next stiffest tissue and the cycle
description) would repeat until all bone was formed.

Fig. 9: Perren interfragmentary theory (see text for description)

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Chapter 2:  Fracture Repair 47

2. Carter and Blenman theory: Their theory differs cartilage. With growing stability at fracture site over
from Perren’s theory in that it not only predicts that time and reducing mobility due to callus formation the
the magnitude of mechanical stimulus will affect cartilage undergoes metaplasia into bone.
fracture tissue differentiation, but also the type of •• If there is no mobility then cartilage does not develop
mechanical stimulus. Carter and Blenman believed and with gap less than critical defect the bone heals
that vascular supply to tissues was the primary factor directly by remodeling. This healing is nine times faster
determining tissue differentiation. Based upon than healing through callus intermediary.
the level of vascularity, they believed that both the •• Compression at fracture has dual effects. Physiological
magnitude and type of mechanical stress, basically compression stimulates bone formation (like thickening
hydrostatic pressure versus octahedral shear stress, of cortex on the concave side of bone—in accordance
would affect the type of tissue within fracture sites. with Wolff’s law). However, as demonstrated by Hüter-
If a good vascular supply was available to tissues, Volkmann excessive compression produces bone
Carter and Blenman believed that the following atrophy and tensile force stimulates bone growth
sequence would occur: though this is more suited to growth plate. Also Ilizarov
◊ Fracture elicits osteogenic stimulus demonstrated that moderate distraction and reduced
◊ If minimal cyclic stresses are present with good compression supports bone formation in tissue and
blood supply, bone will form directly osteogenesis. Influence of compression also varies with
◊ If high hydrostatic compressive stresses were the type of bone—compression is useful for spongy bone
present, fibrocartilage would form while harmful for diaphyseal bone.
◊ If high tensile or shear stresses were present, •• Compressive stress (not exceeding the elastic limits
fibrous tissue would form of bone) produces endochondral ossification—
osteogenesis at fracture site. Continuous physiological
◊ If fibrocartilage forms, subsequent shear stresses
compressive loading with good vascularity produces
would lead to bone formation
bone hypertrophy (as seen with tibialization of
Carter and colleagues developed the osteogenic
fibula)—this process will fail if vascularity is inadequate.
index:
c Reduced compression with maintained vascularity
I = ∑ ni (Si + kDi ) produces osteopenia (as in space walkers). Reduced
i =1 load and vascularity both retards bone formation (as
where “I” is the scalar value of the index, i is a in poliomyelitis).
given load case, c is the total number of different •• Intermittent compressive stress or minimal shear
load cases, ni is the number of loading cycles for stress in a stabilized fracture (controlled micromotion)
a given load case, Si is the cyclic octahedral shear promotes osteogenesis.
stress (always positive), Di is the cyclic hydrostatic •• Intermittent compressive hydrostatic stress (pressure) at
stress (negative if compression, positive if tension), fracture site “without” controlled motion/stabilization
and k is an empirical factor weighing the relative produces gross chondrogenesis (pseudoarthrosis) that
contributions of hydrostatic and shear stress to tissue does not ossify.
differentiation. The higher the value of “I”, the more •• Constant excessive loading of the fracture site
likely that the tissue will ossify. (compressive stress) forms cartilage at the fracture site
and inhibits endochondral ossification due to bone
necrosis (this is the rationale for “accordion maneuver”
Interpretation where the compression is released intermittently
From above theories it can be inferred that a combination alternating with distraction).
of “vascularity”, “stability” at fracture and “stress/strain” •• Tensile stress (as in distraction histiogenesis) produces
modulate the biological tissue formation. The combinations intramembranous ossification.
of factors influence tissue formation as follows: •• Strain at fracture site, i.e. shear stress favors
•• As a rule the fracture repair and consolidation is fibrogenesis—fibrous nonunion or fibrous ankylosis.
inversely proportional to the amount of mobility at •• Low levels of mechanical stimuli (micromotion) at the
fracture site. Higher the mobility greater is the cartilage fracture site:
formation. Callus and cartilage as intermediary stage of –– G ood vas cular ity s ettles into ossification
fracture union are commonly perceived, this is due to (osteogenesis)
the fact that conventional cast immobilization permits –– Poor vascularity at fracture site produces chondroid
fragment mobility and hence formation of intermediary tissue.

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48 Section 1:  Bone Anatomy, Physiology, Pathology and Diseases

METHODS TO ENHANCE electronegativity at the compression site (electrons grouped


nearer) while it becomes electropositive at the tension
FRACTURE REPAIR side (electrons deviate farther). Reverse piezoelectric
effect (an applied current produces material compression)
Before embarking on the methods of enhancing fracture
is a property exhibited by some materials exhibiting
healing the physical and electrical properties of bone should
piezoelectric effect like bone. This piezoelectric property
be understood. The compact bone is required to bear stress
implies that a voltage could be applied to the bone and the
of muscular contractions and loading stress of the body
bone itself would compress (develops strain). Compression
weight continuously. It also serves to protect the internal
across fracture improves healing (mechanical property
soft organs. This entails requirement of good compressive
of bone). But the dielectric property (capacitance) would
and tensile strength. The compact bone has specific gravity,
lead to generation of current with the applied voltage and
1.92–1.99; tensile strength, 13,000–17,000 psi; compressive
could damage the cells if it exceeds the impedance. So it is
strength, 18,000–24,000 psi (compressive strength parallel
imperative that standard protocols must be used. Compact
to the long axis, 7,150 psi; and at right angles to the long
bone in addition exhibits a permanent electric polarization
axis, 10,800 psi). The strength of cancellous bone has
as well as “pyroelectricity” (which is a change of polarization
linear relationship to its elastic modulus. The strength is
with temperature) determined by polar structure of
proportional to strain rate raised to power 0.06. Range for
collagen and orientation in bone. Electric properties
values is wide for cancellous bone depending on the method
and variation with fracture occurrence (development of
of testing, size of bone, origin, etc. shear strength ranges
electronegativity) and restoration (of electrical properties)
from 1–17 MPa. The cancellous bone is less stiff in tension
with healing have been exploited to develop impedance
than compression so the tensile strength is less than its
imaging that may possibly indicate development of
compressive strength and tensile strength of compact bone.
nonunion or delayed union early. Conductance measures
The “electrical properties” of bone depend on a number
indicate fracture healing at 8 weeks but the values depend
of factors. The bone is “dielectric” (applying voltage produces
tremendously on the cross-sectional area and volume of
current across ends determining the “capacitance”) and
bone. Inductance though independent of these variables
“anisotropic” (charge flowing in all directions in a branching
is still not standardized.
pattern rather than unidirectional flow in a metal wire/rod)
Fracture repair may not progress the ideal way always
with respect to its electrical properties. This means that they
and various methods are utilized to improve or enhance the
are semi-conductive (dielectric) themselves but properties
fracture repair. These are broadly classified into:
differ, “impedance” is lowest in the longitudinal direction
and highest in the radial direction. The electrical properties •• Biophysical stimulation (mechanical and electrical
of fully hydrated bone are significantly different from those methods)
of dry and partially wet bone and these properties are highly •• Biological methods.
frequency-dependent, they also vary with moisture content, The various “biophysical methods” rely on the
methods of measurement, temperature and pH of the fluid. interactions between biophysical stimuli and cellular
In general the cancellous bone has lower resistance than responses to effect bone repair or enhance the callus
cortical bone. The metaphysis of long bones is negatively maturation. The basis of using various methods is the effect
charged in relation to diaphysis. The fracture site is more of mechanical stimulation on induction of fracture repair or
electronegative than surrounding bone. “Conductance” is at least alteration of its pathway. Repetitive loading under
a property of the bone marrow and a normal value indicates small strain and high frequency or overloading through
establishment of intramedullary canal. Piezoelectricity excessive exercise causes bone hypertrophy. This was also
is a coupled field effect meaning application of stress/ influenced by the direction and magnitude of mechanical
strain are coupled to electrical field generating current stimulation. It is envisaged that mechanical stimuli possibly
and polarization (like thermoelasticity—application of alter cytoplasmic processes or paracrine influences on
heat produces expansion and vice versa). These gradient the cells and if it is so then mechanical stimulation can
effects are now referred to as “flexoelectric”, however, the consistently produce desirable effects. The commonly used
term piezoelectric effect will be used here for common methods are discussed as follows:
understanding. Bones exhibit “piezoelectric properties” •• Ultrasound: This is a noninvasive method transmitting
meaning that when stress is applied to the bone, the bone mechanical energy through skin. High-intensity
produces a current within itself—the piezoelectric effect, ultrasound (500 mW–3 W/cm2) induces an intense
this is due to deformation of hydroxyapatite (HA) crystals. warming of tissues. This form is effective for reducing
Under the effect of a tensile strain the bone develops pain and controlling muscular spasm. Initially same

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Chapter 2:  Fracture Repair 49

high-intensity waves were employed for treatment of resorption. This mechanism is altered with fracture
nonunion in Germany (1960s) but it carries risk of bone and the fracture site itself becomes negatively charged.
necrosis. Low-intensity pulsed ultrasound (LIPUS) has Yashuda demonstrated that externally applied charge
minimal if any heating effects and accelerates fracture (electricity) can induce or stimulate new bone formation
repair in normal and osteoporotic bone by controlling around cathode (negative electrode) that mimics
inflammation and enhancing differentiation of cells. compression induced bone charges (compression
–– The mechanical strength of callus improves causes electronegativity while tensile forces produce
along with torque and stiffness possibly through electropositivity). Typically they are indicated for
piezoelectric effect. delayed union of a well-positioned diaphyseal fracture,
–– Osteoprogenitor cells favorably respond to in a patient who has undergone many surgeries. This has
mechanical energy transmitted by ultrasound, also been shown to be useful for nonunions especially
possibly by alteration in ionic permeability of cell those with hypertrophic callus formation.
membrane and changes in the second messenger Mechanism (Fig. 10): Like most incidental findings
activity. in medical science the mechanism of new bone
–– There is increased incorporation of calcium in formation through electrical or magnetic field is largely
cultured cartilage and bone cells, improvement in unknown. cAMP and alteration in intracellular calcium
local blood flow (angiogenesis) and stimulation of levels have been implicated but never consistently
expression of numerous genes involved in repair confirmed. Stimulation by “direct current” stimulates
process like aggrecan, IGF and TGF-β. neo-osteogenesis by direct effect of current, release
The modern LIPUS consists of 1.5 Mhz sine wave of hydroxyl ions locally (chemical reaction), reducing
administered in a burst of 200 µs, with a pause of 800 vicinity PO2 and increased pH. Low PO2 stimulates new
µs (pulsed 1:4), repeated 1000 times per second (rate bone growth and higher pH favors calcium deposition.
of 1 KHz). The average intensity over space and time The mechanisms of “inductive coupling” and “capacitive
is 30 mW/cm2 and the average intensity over the “on” coupling (CC)” are even more unclear but possibly
period is 150 mW/cm2. It is administered daily through related to direct effect of the current.
a nonmoving transducer for 20 minutes. LIPUS has –– Direct current (fig. 10A): Constant application of
been found to be effective for fresh cases, delayed 20 µA at 1 V to cathode applied directly to the bone
unions and nonunions with healing rates of 94%, 90% surface (Dwyer/Wickham) induces bone by electric,
and 83% respectively. They have been approved by FDA chemical and mechanical effect. The anode is placed
in 1994 for treatment of fresh fractures. Recently these in the adjacent soft tissue or skin surface. Electric
have been found effective for treatment of infected and current is the primary stimulator but the production
noninfected nonunion. of hydroxyl ions (electrochemical) locally increases
•• Electrical stimulation: “Electrical properties of bone the pH and lowers pO2 at cathode. This prevents
and cartilage” can be modulated to enhance fracture bone resorption and increases bone formation
repair. “Stress-generated potentials” are produced by stimulating the osteoblastic activity. There is
in calcified matrix by virtue of piezo-electric effect of additionally production of H2O2 at cathode which
deformed dry collagen molecules and HA crystals. enhances osteoclast differentiation. Osteoclast bone
Streaming potentials are generated by interstitial resorption additionally stimulates the osteoblasts.
fluids forced through calcified matrix by dilation/ The H 2 O 2 may also stimulate the macrophage
compression. Both the dry and hydrated bone has to secrete VEGF that indices angiogenesis and
electrical properties, when mechanically stimulated fracture healing. Direct current stimulation may
the bone cells produce electrical field that mediates induce formation of BMP 2, 6 and 7 by osteoblasts
cell proliferation. Friedberg/Brighton introduced the to stimulate bone formation. Mechanical effects
concept of “bioelectric steady state potential” generated of cathode insertion and electrode movement
in areas of active growth and repair in “nonstressed” can possibly help bone formation. Inflammatory
bones. Compression site in a stressed bone and area reaction (stage I of fracture repair) is produced
of active bone growth is electrodense (electronegative) in the tissue. The method is invasive and vigilant
while the tension side in a stressed bone or areas of measures and regular monitoring needs to be done
minimal osseous activity are electropositive. There is to prevent infection. Direct current leads to warming
bone deposition on the compression side as it becomes effect in tissues and blistering at anode while
slightly alkaline while the tensile side shows mineral pitting at cathode. This may also be responsible to

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50 Section 1:  Bone Anatomy, Physiology, Pathology and Diseases

A B C
Figs 10A to C: Mechanism of electrical and magnetic stimulation of bone formation as used in various contemporary
methods to stimulate bone formation

inflammatory effect at fracture site at low strengths. bone formation (HOXA10, AKT1), collagenous and
Brighton used similar DC current but applied to noncollagenous matrix proteins (COL1A, SPARC),
percutaneous electrodes reporting bone union genes for cytoskeletal component (FN1, VCL), and
in 84% uncomplicated (no infection or synovial genes at transductional level (CALM1, p2RX7) in
pseudoarthrosis) cases. in-vitro cell culture of osteoblasts. They are also found
–– Inductive coupling or pulsed electromagnetic field to downregulate the genes related to degradation of
(PEMF) developed by Bassett et al.: Here a time extracellular matrix (MMP-11, DUSP4). PEMF has
varying electric field is applied to a pair of coils direct inhibitory influence on parathyroid hormone
placed on opposite sides of fractured extremity. (PTH) signalling. The PEMF prevents store of cAMP
This produces time-varying magnetic field between to buildup inside cell normally associated with PTH
coils and in turn secondary time-varying electric activity. This increases increased calcium uptake by
field of 10 µA/cm 2 at 20 mV gets generated in the cell. Also there is direct increase in intracellular
the tissues. PEMF acts by both electrical and levels by a mechanism different from CC. This is
mechanical influence on the bone (fig. 10B). a noninvasive method but requires frequent and
Electrical current helps as described in the direct prolonged sittings and visits to hospital. Double
current, while pulsed electrical field generates blinded studies have shown efficacy of PEMF on
piezoelectric effect compressing and relaxing the osteotomy healing and delayed union.
fracture site. This generates micromotion and –– Capacitive coupling (CC): A time-varying electric
compressive strain at the fracture site. This induces field is applied to paired electrodes (not coils),
calcification of fibrocartilage and hyaline cartilage generating time-varying electric field (capacity
(fibrous tissue is not induced at all). PEMF has coupled generators) across tissue in a symmetrical
also been found to upregulate the genes related to sine wave pattern with peak-to-peak amplitude of

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Chapter 2:  Fracture Repair 51

5 V and frequency of 60 kHz. This is due to dielectric adjusted to the size of the skeletal segment—for large
property of bone. This produces average electric bones the power is 2 kV using electrohydraulic devices,
field of 80 mV/cm (range 20–150) at 5–10 mA in the 0.6–1 mJ/mm2 using electromagnetic devices.
fracture callus. Here the role of any magnetic field •• Mechanical stimulation:
(as in inductive coupling) is negligible. CC causes an –– Distraction histiogenesis (osteogenesis): Developed
increase in cytosolic calcium through voltage gated by GA ilizarov, this concept entails use of controlled
calcium channels increasing intracellular calcium distraction to new tissue genesis/formation.
(fig. 10c). This enhances calmodulin stores and Theoretically indefinite amount of tissue can
induces cell proliferation and callus formation and form with the technique, if applied to bone then
maturation. CC also enhances bone formation by osseous tissue will form. One should realize that
activation of bone formation through expression of tissue should be present from beginning that can
mRNA for BMP 2, 4, 5, 6 and 7. Collagen synthesis be stretched rather “distracted” not to confuse
and production of cAMP is induced in the tissues with fractures initially fixed in distraction (gap)
enhancing calcification on reparative stage. that are actually the cause of nonunion. Under
Indications of electrical stimulation: optimal conditions the “regenerate” that forms is
–– Hypertrophic nonunion distracted somewhere 1 mm/day till the desired
–– Stable fixation with fracture in acceptable alignment length is achieved. Bone forms in “intramembranous
–– Patient who does not want surgical procedures or ossification” (so it is not called callus) fashion else
unfit for surgical procedure, having untreatable skin with unstable environment pseudoarthrosis results.
disease at the site of nonunion or poor skin condition The tissue is left to consolidate for twice as long
(grafted skin), coexisting infection. as the distraction phase while physiologic stress
Contraindications for electrical stimulation: bearing can be allowed anytime during treatment.
–– Pseudoarthrosis For optimal results 5–7 days latency followed by
–– Avascular nonunion continuously applied distraction (ideally motorized)
–– Coexisting deformity throughout the day and stable fixation is mandatory.
–– Nonunion of upper limb as need for simultaneous The technique has been successfully utilized
immobilization may compromise function at joints for treatment of nonunions, limb lengthening,
permanently. deformity correction, and segmental bone loss,
–– Humerus and femur fractures with large gaps (gaps primary fixation of comminuted fractures and open
equal to width of the bone) and also possibility of fractures, varicose ulcers, trophic ulcers, arthrodesis
pseudoarthrosis in these bones is inherently high. of joints. Carrying the fixator and cosmesis is the
Additionally it is difficult to immobilize the humerus primary concern.
completely. –– Controlled axial micromotion: Controlled axial
Complications: (mechanical) stimulation (by using Wagner type
–– Infection with implanted electrodes frame) had been used by few authors for treatment
–– Skin irritation at position of electrodes of tibial fractures and had shown reduced time to
–– Incorporation of the electrode in the new bone union and secondary surgeries.
requiring surgical removal –– Intermittent pneumatic soft tissue compression: In
•• Extracorporeal shock wave therapy (ESWT): Relatively animal model (rabbit) the method has been found
newer mode studied for mechanical enhancement to increase callus area. Though elusive and not
of fracture repair, this requires higher frequency and substantiated, reduced venous stasis and increased
energies for stimulation of repair. Breaking down of interstitial fluid return to circulation may increase
stones in kidney that have same structure as HA might NO and local prostacyclin levels improving callus
have similar effects of microstimulation (creating density.
microfissures, cavitation with liberation of energy, –– Functional cast bracing of Sarmiento—this is based
increased local blood flow) at the osteogenic and on the concept of maintaining the limb in near
nonunion sites. Mechanism though is still not clear and physiological state throughout the fracture repair
some attribute the benefit to be biased by prolonged process. The brace is applicable to nearly cylindrical
immobilization itself. It was first used in Bulgaria (1980s) body parts like the arm and leg where free motion
by Valchanov and Michailov. This is given by means is allowed at the proximal and distal joints. The
of electrohydraulic or electromagnetic devices under concept of Wolff’s law is mostly applicable to the
C-arm control. The power of trains of shock waves is method as early weight bearing is begun and also

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52 Section 1:  Bone Anatomy, Physiology, Pathology and Diseases

cyclic muscular movements have been found around 20 types have been recognized, BMP2–7
to enhance the development of external callus belongs to TGF-β superfamily while BMP 1 is a
response along with trophic effect on periosteal metalloproteinase. These proteins are secreted as
callus thus enhancing the fracture repair. It should homodimers or heterodimers of 110–140 amino acid
be remembered that the brace should be a “total peptides linked by one disulfide bond (molecular
contact brace” else fracture would displace during weight of approximately 30 kd). They are now
weight bearing and may even fail. Total contact brace found not to be responsible only for bone formation
forms a closed compartment that prevents fracture from cartilage but constitute important pathway
displacement by maintaining the hydrostatic signaling in morphogenesis since birth, throughout
pressures within compartment exceeding the the body (so “BMP” may be a misnomer). BMP
displacing forces at the fracture site. The other signaling plays critical roles in heart, neural and
concern is that this bracing is ineffective and may cartilage development. BMP 3 has in fact shown
complicate the venous drainage when there is acute to be an inhibitor of osteoinductive activity in the
swelling at the site and in the limb. For a typical rat, and ironically this is the most abundant BMP in
functional knee brace the proximal portion is body. The signal triggered by BMPs is transduced
trimmed to resemble a PTB prosthesis with anterior through serine/threonine kinase receptors, type I
portion at the level of inferior pole of patella, the and II subtypes. Three type I receptors have been
posterior wall extends one fingerbreadth below the shown to bind BMP ligands, namely: type IA and
anterior impression of patellar tendon anteriorly. IB BMP receptors and type IA activin receptors.
Lateral wings of the brace remain high for providing BMPs seem to be involved in the regulation of cell
rotational stability. proliferation, survival, differentiation and apoptosis,
•• Biological methods (table 8): Osteoinduction (introduced but their hallmark is their ability to induce bone,
by Marshall R Urist) is a process that supports the cartilage, ligament, and tendon formation at both
mitogenesis of undifferentiated mesenchymal cells, heterotopic and orthotopic sites. rhBMP-2 blocks
leading to the formation of osteoprogenitor cells that the differentiation of osteoblast precursor cells into
form new bone. Osteoconduction is a property of a myoblasts or adipocytes. Sampath and collaborators
matrix that supports the attachment of bone-forming demonstrated that when OP-1 (BMP-7) is added
cells for subsequent bone formation. Osteogenic to cultures of bone cells enriched with osteoblasts
property can be defined as the generation of bone from at different stages of differentiation it stimulates
bone-forming cells. cell proliferation, collagen synthesis, induction of
–– bone morphogenic protein: A bone inducing alkaline phosphatase, PTH-mediated production
principal was first postulated in 1952 by Marshall of cAMP, and osteocalcin synthesis. Clinically
Urist et al. He pioneered the concept of presence of a
substance naturally present in the bone responsible
for regeneration and repair activity in the bone, Table 9: Historical evolution of development in understanding
he called this substance BMP. They are a group of BMP (the wonder molecule)
of growth factors also known as cytokines and as 1965 Marshall Urist has discovered that demineralized bone
matrix (DBM) can induce bone formation
metabologens. The evolution in understanding
of BMP is represented in (table 9). Till now 1971 Urist conceptualizes bone morphogenic proteins (BMPs)
1981 Extraction and reconstitution of BMP activity for bioassay
1991 First use of BMP with demineralized bone matrix (DBM)
Table 8: Biological methods to improve bone regeneration
October 2001 FDA grants humanitarian device exemption (HDE)
Osteoconductive approval for osteogenic protein-1 (OP-1; rhBMP-7)
•• Bone graft substitutes
Osteoinductive July 2002 FDA approves rhBMP-2 (INFUSE) for a single level spine
•• Bone morphogenic proteins fusion (L4-S1)
•• Platelet rich plasma April 2004 FDA grants HDE approval for OP-1 putty for revision spinal
•• Conditioned plasma fusion.
Osteogenic
May 2004 FDA approves rhBMP-2 (INFUSE) for treating acute open
•• Bone grafts
tibial shaft fractures
•• Bone marrow infiltration
Systemic agents 2008 FDA approval to rhBMP-2 for treatment of posterolateral
•• Prostaglandins lumbar pseudoarthrosis.
•• Fibronectin FDA, Food and drug Administration

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Chapter 2:  Fracture Repair 53

rhBMP-7 (OP-1) has been approved as alternative various modifications and refinements. Bone
to allograft for treatment of nonunion which marrow aspirate (BMA) from “red active marrow
was extended in 2004 to its use as an alternative (RAM)” (typically posterior iliac crest) contains
to allograft for posterolateral spine fusion. The mesenchymal stem cell (MSC) in the strength of
rh-BMP-2 (Infuse) has been approved for use in 1:100,000. Volumes ranging from 15–150 ml have
anterior lumbar interbody fusion with a fusion all been used. Aspiration is done in volumes of
device (LT cage—lumbar tapered titanium interbody less than 4 ml (ideally 2 ml) from every 2–3 mm
fusion device). In 2008 this has been extended to depths in a fan like fashion to capture as many MSCs
its use for posterolateral lumbar pseudoarthrosis, without dilution. It is estimated that typical BMA
open tibia shaft fractures with intramedullary from RAM contains 70 million marrow cells of which
nail fixation. There is, however, extensive off label 700 would be MSCs. It is postulated that MSCs act
use of BMP (cervical discectomy and fusion, etc.) synergistically with BMP to produce effective fracture
which has recently raised concern particularly as repair response (osteoinductive and osteogenic)
to hypertrophic bone formation at the site and and can also be used for delayed and nonunions.
induction of colon cancer and Barrett’s esophagus. Transpedicular harvest from vertebral bodies has
Various delivery systems have been evaluated notable also been described. For optimum clinical efficacy
of which are demineralized bone matrix, poly lactic it is recommended that a high-degree open pore
and glycolic acid, hyaluronic acid gel, ceramics, scaffold with interconnected geometry is used
calcium phosphate based cements, depot injectable to deliver the BMA. Ceramic HA, β-tricalcium
carriers, viral vectors and gene guns. Carrier for BMP phosphate (TCP) and ultraporous β-TCP have
needs to maintain a critical threshold concentration been studied to be effective. The BMA can be
of BMP at implantation site for the required period ultracentrifuged to yield high concentration of stem
(Temporal distribution), act as scaffold over which cells in a lower volume that can be incorporated
bone growth can occur and contain the BMP at with scaffolds to produce similar effects. Composite
the localized site and prevent extraneous bone grafting of BMA with BMP is found to yield better
formation (Spatial containment). Apart from bone results. Recently the isolated MSCs have been
formation BMP could help in cartilage regeneration induced by dexamethasone in vitro to enhance
in osteochondral defects and reverse diabetic renal the ability of BMP-2 modified MSCs in osteogenic
disease. For anterior interbody fusion a total dose conversion as part of stem cell therapy.
of 4.2–12 mg of rhBMP-2 at concentration of 1.5 Platelets are a source of a variety of growth factors
mg/ml is recommended. The recommended total many of which are relevant to fracture repair.
dose of OP-1 as humanitarian device exemption for Some 15 different factors and cytokines have been
recalcitrant posterolateral fusion nonunion is 7 mg identified like platelet-derived growth factor (PDGF-
for both sides. The recommended dose of OP-1 for bb, -ba,-aa isoforms), TGF-β (β1, β2 isoforms),
recalcitrant long bone nonunions is 7 mg. Recent platelet factor 4, IL-1, VEGF, EGF, IGF, osteocalcin,
studies have identified specific BMP antagonists (i.e. osteonectin, thrombospontin-1, etc. Platelet rich
noggin and chordin) and members of the DAN family plasma (PRP) is used as a liquid from 50–100 ml
(i.e. gremlin and follistatin). These antagonists may of full blood passed through two-stage centrifuge
be used therapeutically in pathological conditions process yielding 1/10th the original volume with
characterized by excessive bone formation. platelet concentrated of 1,000,000 platelets/µl.
–– Prostacyclins: These are mainly only research This is mixed with bovine thrombin and CaCl2 for
molecules and clinical utility is still not substantiated. activation in vivo. Although in vitro stimulation of
PGE1-increase cortical thickening (limbs/ribs of mitogenic (i.e. transforming) response to PRP in
neonates) and PGE2–increase bone formation. human trabecular bone is found the same has not
Normal fracture healing is demonstrably impaired been translated into clinical efficacy in vivo, though
by PG inhibitors. CP 533, 536 are nonprostanoid EP2 its supportive role to fracture repair cannot be fully
receptor selective PGE2 agonist that stimulates local denied and is under study. PRP has also been used
bone formation/enhance fracture healing. to treat chronic elbow tendinosis (tennis elbow) and
–– Platelet concentrate and bone marrow injections diabetic foot ulcers with some success.
and stem cells: After Goujon reported formation –– Parathyroid hormone: PTH and PTH-related
of ectopic bone in 1869 with the application of peptide (PTHrP) have been documented to be
bone marrow, the technique has been used with potent in the expansion of progenitor populations

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54 Section 1:  Bone Anatomy, Physiology, Pathology and Diseases

and in the regulation of differentiation of these grafts incorporate by different mechanisms and have
cells. Recent research indicates that both PTH and fundamental differences (table 11).
PTHrP play an important role in regulating the
Biological mechanism of effect of bone grafting: the bone
pool of undifferentiated MSCs available for growth
grafts tend to improve bone healing or fracture repair by
plate expansion and fracture callus formation. It
one or combination of following mechanisms:
appears that PTH or PTHrP is required to prevent
•• Osteoinduction: It is the property by which the
the depletion of progenitor cells needed in the
graft causes stimulation of osteoprogenitor cells to
formation of the growth plate or fracture callus. Thus,
differentiate into osteoblasts that then begin new bone
it would be expected that exogenously administered
formation. BMP is a typical example. Autogenous bone
PTH may have an important biologic function at
especially cancellous bone carries with it the factors
sites of healing bone. Moreover, recent reports
and cellular elements that can act for “osteoinduction”
have documented that PTH can reverse the effect
in paracrine manner. These grafts serve as a scaffold
of aging on depleting osteoblast progenitor cells.
for currently existing osteoblasts and also trigger
Both chondrogenic and osteogenic precursor cells
the formation of new osteoblasts promoting faster
seem to be targets of PTH. Because both cell types
integration of the graft. Bone reamings are example of
contribute to normal fracture repair, it is likely that
pure osteoinductive grafts.
PTH has a beneficial effect on fracture repair. Cost is
•• Osteoconduction: It is the property where the bone graft
a deterring factor and studies have yet to document
material serves as a scaffold (framework) for new bone
the low cost to benefit ratio.
growth. Osteoblasts from the host bone use the bone
–– Ultraconcentrate of centrifuged blood: This is
graft material as a framework upon which it generates
composed of leukocytes and platelets and is often
new bone.
referred to as PRP or autologous conditioned
•• Osteogenesis: It is the process of bone formation by
plasma. There is little clinical evidence for its use
the osteoblasts from bone graft itself in addition to the
from centrifuged blood. There is a recent concern
bone formation by osteoblasts of host bone. For this the
about enhancement of bone healing due to high
bone graft should be sufficiently vital enough and free
concentration of leukocytes that have been found to
of immunological response. Though exact interval time
inhibit bone formation in animal studies.
for bone graft to remain outside and retain its osteogenic
–– Anabolic supplementation and minerals: High protein
activity is not known but this should be minimized and
diet promotes fracture healing in animal models;
done immediately if possible.
there is some weak evidence of improved fracture
•• Osteopromotion: It is enhancement of osteoinduction
repair with essential amino acid supplemented diet
without the possession of osteoinductive properties.
rich in arginine. Zinc supplementation also similarly
Demineralized bone matrix could fall into this category
increases bone protein component but is more
to some extent.
effective at later stages of fracture repair.
–– Bone grafts and bone graft substitutes: Bone grafts Theories of bone graft incorporation: Phemister introduced
provide a latticework for ingrowth by host bone the term “creeping substitution” which is the mechanism
and supply living osteogenic cells to the host and for cancellous bone graft incorporation (and even
growth factors induce bone formation. History dates cancellous bone repair). Granulation tissue invades the
back to 1668 and first bone graft was a xenograft areas of resorption and pluripotential mesenchymal cells
(no more used today) where the skull of a soldier differentiate into osteoblasts laying seams of new osteoid
was reconstructed using a dog’s skull by Job van
Meekeren. After Lane and Sandhu introduced Table 10: Stages of bone graft incorporation
internal fixation, Albee, Kushner, Henderson, Stage Description
Campbell and others added principle of osteogenesis Inflammation Bone resorption and chemotaxis by necrotic
to develop bone grafting for nonunion. Bone grafting tissue and inflammation
is in principle a surgical procedure that replaces Osteoblast differentiation From cells in graft or marrow precursors
missing bone in bone defects due to complex
Osteoinduction Support and growth of bone cells
fractures or to augment bone healing/repair/
strength when it fails to heal properly (delayed and Osteoconduction Scaffold to guide cells for bone formation
nonunion). Bone graft incorporation occurs through Remodeling Graft modification to the innate bone
five stages (Urist) (table 10). Cancellous and cortical structure

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Chapter 2:  Fracture Repair 55

along the dead trabeculae of the bone graft forming an •• Cancellous: predominantly cancellous bone.
“osteoid tube” on the existing scaffold. The surface cells of the •• Cortical: predominantly cortical bone.
trabecular bone from graft survive and take part in actively •• Corticocancellous: combination of both for faster repair
forming the new bone (Abott). The necrotic tissue in marrow and structural integrity.
spaces and Haversian canals is removed by macrophages. •• Autograft: obtained from same individual.
The debris and necrotic bone inside the tube is resorbed by •• Syngraft (prev. isograft): obtained from twin.
migrated macrophages that differentiate into osteoclasts •• Allograft (prev. homograft): obtained from different
converting them into “hollow tubes”. These tubes are then person from same species.
invaded by granulation tissue and form new bone inside. In •• Xenograft (prev. heterograft): obtained from different
cortical bone the process is much slower as the osteoclasts species usually bovine.
have to resorb the dense bone along Haversian system. •• Synthetic: synthesized completely in laboratory or
This is invaded by the granulation tissue and new bone is industrially.
laid (reverse creeping substitution). The bone grafts can be “Autogenous bone grafts” (better called “transplants”)
classified according to the type of bone or the type of source are still the “gold standard” and can be used in various forms
and vary in their basic structural or compositional properties according to the need. Advantages and disadvantages of
(table 12). Following are the common terms used: autograft versus allograft bone are provided in table 13.

Table 11: Difference between cancellous and cortical bone grafts


Cancellous bone graft Cortical bone graft
Consists predominantly of soft spongy bone Consists predominantly of hard cortical bone
Contains higher number of living bone cells Contains more of bone matrix and less cells
Mainly acts as a filler to obliterate cavities Mainly acts as structural support
Poorly resists compression or bending force Good compressive strength and provides tensile strength also
Cannot be used to augment strength of bone Can be used to augment bone strength as in fixation of osteoporotic
fractures
Provides biological support to healing as in cases of comminuted fractures Less of biological support but is used to fill bone gaps in diaphyseal defects
primary bone grafting with cancellous bone supports fracture repair
These grafts gather strength over time They tend to become weaker with time
Incorporates faster (3–9 months) Slow incorporation and is often incomplete (union to parent bone takes 3–6
months while complete incorporation of graft may take 2 years to even a
decade depending on the length of graft)
Creeping substitution is the primary mode of incorporation Reverse creeping substitution and a process similar to remodeling is the way
this graft incorporates
Can be used in places that have potential for being infected as the graft will Should not be used at infected sites as there is a high chance of organisms
be quickly resorbed if infection prevails making these metabolically inactive grafts their home gathering shelter and
complicating treatment

Table 12: Structural properties of bone grafts


Grafts type Osteoconduction Osteoinduction Osteogenesis Structural integrity
Cancellous autograft +++ ++ +++ ± (fair if impaction bone grafting done)
Cortical autograft + + ± +++
Allograft + + - ++
Calcium phosphate + - - +
Demineralized bone matrix + ++ - ±
Xenograft + - - ++
Bone marrow - - ++ -

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56 Section 1:  Bone Anatomy, Physiology, Pathology and Diseases

Table 13: Advantages and disadvantages of autograft versus spinal fusion. Typically local tibia, fibula, ribs or iliac
allograft methods crest are used.
Autograft Allograft
•• H-grafts: Typically used for anterior cervical spine in past
and uncommonly for scaphoid nonunion.
Advantages: Advantages:
•• Readily available •• Quick and easy to use
•• Dowel grafts and peg grafts: Corticocancellous grafts
•• Quick and reliable incorporation •• Available now in various sizes used in past for treatment of nonunions in regions where
•• No immunogenicity and shapes for different use onlay grafting is not possible. For neck of femur ilium
•• No clearance hassles for •• Cortical vs. cancellous can be was used in conjunction with screw fixation (now people
authority chosen use fibula as curvature of ilium limits practical utility).
•• No risk of “transmitting” •• Large amount for massive
infections as with allografts reconstruction available
Carpal scaphoid nonunion have also been treated by
•• Different forms—cortical, •• Shortens operative time cancellous pegs prepared from dense bone. Nowadays
cancellous, combined available Disadvantages: vascularized pedicle or free grafts are commonly used.
for various use •• Requires set-up and •• Medullary grafts: Used to augment screw purchase in
Disadvantages: maintenance osteoporotic bones, commonly humerus. Intramedul-
•• Increase time of surgical •• Not readily available in India
procedure •• Various regulatory clearances
lary fibula provides two additional cortices for screw
•• Limited in amount for large needed purchase. With locked screw plate constructs the utility
reconstructions and defects •• Risk of infection especially the has reduced.
•• Pain at operative site, morbidity clostridial and viral infections •• Hemicylindrical grafts: Massive cortical hemicylindrical
and increased length of stay has still not been eliminated grafts supplemented with cancellous bone are placed to
•• Increased cost of surgery •• Weak osteogenic potential
•• “second’” surgery and potential though provides good
bridge the defect. As with most other grafting techniques
risks like infection structural support this is also hardly ever used (may be used in some cases
•• Chronic pain may persist (osteoconductive) of bone tumor excision).
•• Possibility of hernia and •• Procurement, processing and •• Fibular head graft: this is typically used to recreate distal
secondary complications preservation need expertise and radius articular surface. In cases where distal radius
dedication
is sacrificed as in giant cell tumor same side fibula is
harvested and fixed in a reversed fashion.
A brief description of various common forms of usage is •• Vascularized pedicle grafts: These grafts carry their
as follows: own vascular supply so that the incorporation and
•• Multiple cancellous (or corticocancellous) chips: Most remodeling is faster. Local rotation pedicle grafts are
widely used for stacking, stuffing voids, filling defects, more popular as they are easy to use like periosteal
nonunion, delayed union, fusion, etc. in onlay fashion. and muscle pedicle based grafts for hip, scaphoid
Has highest osteogenic potential. Can be morcellized (pronator quadratus based), intercompartmental
and used for impaction bone grafting (amount is the supraretinacular artery based bone pedicle for scaphoid.
limiting factor). Ilium is the most common site for Free microvascular fibular grafts can be placed at remote
procurement proximal and distal femur, proximal and site for femoral neck and other diaphyseal defects
distal tibia, distal radius and olecranon can be used as following tumor excision, infection or traumatic bone
required. loss are popular but require expertise.
•• Single onlay cortical grafts: Treatment of nonunions •• Intercalary graft: usually allografts are used for large
before development of good internal fixation methods. diaphyseal defects; however, vascularized fibula can be
Tibia or split fibula was commonly used. Spinal fusion used along with bridge plate fixation with better results.
(rare) is the only modern use, principally because of The various sites for obtaining cancellous bone graft are:
donor site morbidity and development of fixation. •• Iliac crests (anterior and posterior): usually cancellous
•• Dual onlay cortical bone graft (of Boyd 1941): Classically chips are obtained from the inner table and cancellous
described for congenital pseudoarthrosis tibia. portion of anterior ilium, however, sometimes
No indication in modern orthopedics, however, requirement for tricortical graft necessitates removal
modified allograft can be used for augmenting cortical of a wedge. Bicortical chips are harvested after lifting
insufficiency in revision arthroplasty in this fashion. the iliac crest cap. The graft is taken from the outer
•• Inlay bone grafting: Principally described as a sliding and table and cancellous bony region underneath the
graft reversal inlay technique to treat nonunion tibia by gluteus maximum muscle when harvesting is done from
Albee (superseded now by rigid fixation and cancellous posterior iliac crest.
bone grafting). Extended indications in current practice •• Proximal tibia
are typically utilized for ankle arthrodesis and anterior •• Trochanteric region of femur

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Chapter 2:  Fracture Repair 57

•• Distal condylar region of femur •• Shell allografts: Biologic resurfacing of articular defects
•• Olecranon process of ulna using devascularized osteoarticular graft with a small
•• Distal radius styloid process. bony component.
The cortical autografts are obtained from: •• Large composite allografts: Usually required for excision
•• Fibula: entire proximal two-thirds bone may be utilized of large tumors or reconstruction of defects in revision
but care should be taken to avoid injury to the peroneal arthroplasty after freeze thawing.
nerve and peroneal muscles. Distal fourth fibula must be
Indications for use of allograft: Reconstruction of massive
left in place to maintain a stable ankle joint. Middle third
bone defects arising from trauma, infection (debridement),
fibula is commonly used as a vascularized graft also.
osteolysis or revision arthroplasty and resection of bone
•• Tibia proximal half region (Phemister graft).
tumors requiring amount of bone that cannot be supplied
“Allografts, allogenic bone grafts” (better called
by extended autografting procedures. The following are the
“implants” differs from transplant as the bone is nonviable)
typical common procedures for which allografts are used
are available in various forms. Supply in our country is
(some are common indications for bone grafting in general):
limited for awareness and lack of banking facilities. A graft
•• Reconstruction of skeletal defects following tumor
may be orthotopic (transplanted to the same site in the
resection
recipient that it occupied in the donor, e.g. distal femur to
•• Reconstruction of bone defects as a result of primary
distal femur); heterotopic (transplanted to a different site
joint arthroplasty osteolysis
but one occupied by the same tissue as in the donor, e.g.
•• Reconstruction of extensor mechanism of knee
fibula to spine); or ectopic (transplanted to a site normally
•• Reconstruction of congenital or developmental bone
occupied by a different type of tissue, e.g. fascia lata as a
and joint defects (protrusio acetabuli, dysplastic
tendon graft). Ectopic sites are mainly investigational for
hip) and deformities. Acetabular plastical arthrosis
bone grafting. The various types of allografts are as follows:
(remodeling) is required to improve coverage of the
•• Fresh—no clinical use due to high immunogenic femoral head
potential. •• Obliteration of cystic cavities of bone
•• Fresh-frozen—less immunogenic but needs secondary •• Repair of fresh comminuted fractures with bone loss
procedure for sterilization. Preserves BMP. •• Treatment of nonunion and complicated osteoporotic
•• Freeze-dried (lyophilized)—bone should be extracted fractures
from donor within 8–12 hours of death. The bone •• Arthrodesis of large joints
loses its inductive factors and BMP due to enzymatic •• To provide bone blocks for limiting joint motion
autodigestion by intracellular and extracellular (arthrorisis), e.g. flail joint in poliomyelitis
enzymes. Antigen-extracted allogeneic (AAA) bone •• Treatment of scoliosis and spinal fusion
as advised by Urist may retain inductive factors. Here, •• Repair of massive segmental bone defects
chloroform-methanol is used to extract lipids and cell •• Repair of periodontal osseous defects.
membrane lipoproteins (4 hours); hydrochloric acid “Xenografts (heterogeneous bone grafts)” have been
extracts acid-soluble proteins and demineralizes the used but are now out of favor because of easier access to
surface in 24 hours; and neural phosphate buffer is used allografts. Bovine bone xenograft is harvested and washed
to remove endogenous intracellular and extracellular in water, extracted with peroxide to oxidize proteins
transplantation antigens. The bone is then frozen and and washed with acetone to remove fats. After gamma
freeze dried and stored at −60°C. sterilization the product (kiel bone) mainly serves to be
•• Demineralized bone matrix (DBM or bone matrix osteoconductive scaffold.
gelatin, BMG): This is a digested source of BMP, used as “Bone graft substitutes (Alloplastic bone grafts)”
bone graft extender. DBM is available in two forms, dry are material that can be used in place of bone grafts but
or injectable. DBM is mixed with a carrier. Carriers (inert are purely osteoconductive unless they act as carrier
with regards to bone generation) include hyaluronic for delivery of some inductive materials like BMP (see
acid, collagen, glycerol, gelatin, and actual derivatives elsewhere). Typically they are comprised of silicon, calcium
of DBM itself. Second generation DBM putties (carrier or aluminium.
is loaded with BMP) have higher concentrations of BMP •• Calcium based products are widely used:
and are possibly better. –– Calcium phosphate based grafts (tricalcium
•• Osteochondral allografts: Bony chunk with cartilage phosphate): Calcium phosphate naturally occurs
cover, used for large articular defects in osteochondroses in bone as HA [(Ca5(PO4)3OH or Ca10(PO4)6OH2)].
of knee. Synthetic HA is osteoconductive but very slow

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58 Section 1:  Bone Anatomy, Physiology, Pathology and Diseases

to absorb taking years to incorporate. Calcium and histopathological features of bone formation
phosphate based grafts are hence synthesized in equivalent to autogenous bone graft. “Synthetic
different forms to improve biological characteristics hydroxyapatite” is a crystalline calcium phosphate
and are available as ceramics, powders and cements. osteoconductive bone substitute not commonly
“Ceramics” are highly crystalline structures used for slow bone formation. Calcium phosphate
created by a process known as “sintering” (heating can also be manufactured as “cement”, by adding an
nonmetallic mineral salts at temperatures greater aqueous solution (containing sodium carbonate)
than 1,000°C). Sintering increases the strength of to dissolve the calcium, which is followed by
mineral substitute but reduces the resorption and a precipitation reaction in which the calcium
remodeling capacity. These phosphate materials phosphate crystals grow (in the presence of calcium
have variable rates of osteointegration based on carbonate—premixed) and the cement hardens. The
their crystalline size and stoichiometry. They have primary advantage of cements over blocks, granules,
the advantage of incorporating at a slower rate or powders is the ability to custom-fill defects and
than calcium sulfate materials but faster than HA. increased compressive strength (55 MPa), but has
Pore size is important and defines the integration the disadvantage of leaking through the fracture
properties. Recommended pore size is 100–150 and into joint from where the resorption is poor and
µm. Higher pore size permits faster ingrowth but can lead to functional deficit, difficulty in extraction
reduces strength. This results in a faster degradation if infection occurs, poor resistance to torsion and
of the mineral substitute. Mineral substitutes sheer forces.
with a smaller pore size allow the platelets and –– Coralline ceramics are formed by thermochemically
leukocytes to congregate within the pores and treating coral with ammonium phosphate, leaving
secrete cytokines to induce and implement bone TCP with a structure and porosity that are similar to
formation. Mineral substitutes are osteoconductive those of cancellous bone. Pore size and porosity are
only; however, they may be combined with DBM important characteristics of bone graft substitutes.
(osteoinductive) or BMA (osteogenic) to form a No osseous ingrowth occurs with pore sizes of
composite bone graft substitute. TCP is one such 15–40 µm. Osteoid formation requires minimum
bioceramic that is available in alpha and beta pore sizes of 100 µm, with pore sizes of 300–500 µm
forms. TCP absorbs faster than synthetic HA but is reported to be ideal for osseous ingrowth. Calcite
less strong. The alpha form resorbs faster than beta (magnesium containing calcium carbonate) is
which is (β-TCP) preferred. β-TCP is available as obtained from sea urchins having characteristics
blocks, granules and powders. The resorption rates similar to bone HA.
vary from 6 months to 2 years. β-TCP is available for –– Calcium sulfate and calcium carbonate are not
dental procedures, posterolateral spinal fusion and very popular for bone grafting. Calcium sulfate is
as bioresorbable screws. Basic calcium phosphates commonly known as “plaster of Paris” as it was used
are defined mixes of bioceramics to balance in Paris for coating walls to make them fire resistant.
biomechanical properties and absorption rates, Calcium sulfate (CaSO4. 2H2O) partially dehydrates
e.g. BoneSave® (Stryker corporation) is a 80-20 parts to produce a hemihydrate (CaSO4. ½H2O). Calcium
by weight mix of β-TCP and HA. Ion substituted sulfate rapidly absorbs within few weeks following
ceramics—HA of native bone is not a pure form of insertion and has been used clinically as autograft
HA and contains various impurities. To increase extender in short segment posterolateral spinal
the biological activity there is interest in producing fusions.
ceramics that resemble native impure as closely as •• Bioactive composites:
possible. The “phase purity” of bioceramics refers –– Silicate based grafts: available as bioactive glasses
to these substitutions and relative distributions are usually now available for carrier purpose and
of different phases in the material. A number of have good structural strength.
materials have been produced by substituting ions –– Bioactive composite of polyethylene reinforced
like silicate, carbonate, fluoride, magnesium and with HA has been used for orbital floor repair and
strontium. Silicate substituted calcium phosphate as middle-ear implants.
results from substitution of the phosphate ions by –– Newer materials being studied include biodegradable
silicate ions. The impurity substitutes only 0.8% polymers like polylactic and glycolic acids that
by weight of the material and has been shown in are completely degraded by hydrolysis later into
animal studies to cause more rapid bone formation nontoxic metabolites eliminated as CO2 and water.

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Chapter 2:  Fracture Repair 59

•• Aluminium based grafts like aluminium oxide binds to tissues in donor. Varied infections have been reported
bone in response to stress and strain between implant form implanted allograft bone including viral [hepatitis B
bone interfaces. and C, human immunodeficiency virus (HIV)], bacterial
Engineering principles for synthesis of bone graft substitutes: [Clostridium species, S aureus, (group-A beta hemolytic
the bone grafts to be successful must have some architectural streptococci (GABHS), Pseudomonas, Enterococcus
and surface properties that provide it strength and biological organisms] and fungal. Aseptic processing of allografts has
viability (allow penetration of nutrients, removal of by- improved but does not completely sterilize the tissue from
products and cell migration and colonization) to use as organisms or spores. Even practice of submerging the bone
bone growth. Some technical concerns are as follows: in antimicrobial solutions does not ameliorate the spores.
•• Reproduce the highly porous architecture of cancellous To destroy the spores, gamma radiation and treatment
bone for homing and colonization by MSCs. This is with ethylene oxide or a low-temperature chemical
very important as changing pore size alters response sterilization should be done at the time of implantation
of cells—pore diameters of 15–50 μm stimulate (at the cost of decreased integrity of the graft and possible
fibrovascular growth, 50–150 μm causes osteoid synovitis). Irradiation has been proposed to reduce bacterial
formation, 150–500 μm pores are the most optimal size transmission and may also inactivate HIV but the efficacy
resulting in mineralized bone. has not been quantitatively studied. Strict guidelines for
•• Surface properties need to be so reproduced that fibrin processing the bone grafts and establishing standards for
clot is well-stabilized and osteoprogenitor cells become testing aerobic and anaerobic organisms and fungi as well
associated with matrix scaffolds. as reporting of infections should be laid down.
Over the past years, the use of “antibiotic-impregnated
Complications of bone grafting (autograft and allograft): bone grafts (AIBGs)” has become a popular procedure
•• Additional surgical and anesthesia time in the treatment of bone and joint infections. A major
•• Added costs advantage of AIBGs involves the possibility of impregnation
•• Morbidity in the form of pain and delayed mobilization of various antibiotics depending on the sensitivity profile
•• Development of incisional hernia of the causative organism, and also an additional surgery
•• Vascular injury for removal of the antibiotic carrier is not necessary, as in
•• Neurological injury: posterior iliac grafting—cluneal the use of antibiotic-loaded bone cement. Vancomycin is
nerves, anterior iliac grafting—lateral femoral cutaneous the most common antibiotic used (VAN-BG) but others
grafting like tobramycin, gentamycin, clindamycin, cephalothin
•• Fracture of donor bone and rifampicin have also been used. Antibiotics are
•• Hematoma and seroma formation incorporate by manual mixing or by placing the bone
•• Additional site for potential infection grafts into antibiotic-containing solutions. Better of the two
•• Logistic—limited amount of bone available for grafting methods is, however, unknown. There is a higher amount
•• Cosmetic concern and chronic pain of antibiotic uptake in demineralized bone compared to
•• Ureteral injury native one. Furthermore, there exist great discrepancies
•• Transmission of infection (allograft) regarding the exact antibiotic/bone graft ratio. From
•• Very rarely tumor cell transplantation. various studies vancomycin is found to significantly
Infections associated with bone allografts: Use of allografts better elute from cancellous bone in comparison with
has increased tremendously over last decade especially with tobramycin. Rifampicin elutes longest; for up to 21 days
the availability of bone banking facility and standardization. while betalactamase are the shortest to do so. Although
Allografts act as porous, noncellular and avascular high local concentrations are eligible for a successful
foreign bodies that are prone to bacterial adhesion. Upon eradication of the infection, it should be borne in mind
attachment bacteria protect themselves by secreting a thick that such high concentrations might be associated with an
glycocalyx matrix rendering them inaccessible to immune accompanying toxic effect on cells. High concentrations
surveillance and local cellular defence mechanisms. The of vancomycin have been reported to substantially reduce
issue of allograft associated sepsis rose after identification osteoblast replication and even cause cell death. In case of
of a 23-year-old man with Clostridium sordellii sepsis was a biantibiotic combination, a synergistic effect has been
attributed to allograft transplantation. By 2002, the Center described between aminoglycosides and glycopeptides
for Disease Control (United States) had reported 26 cases when eluted from acrylic bone cement. However, the
of clostridial infections associated with musculoskeletal amount of vancomycin eluted from vancomycin-netilmicin-
tissue allografts probably a result of decomposition of loaded grafts was significantly reduced compared with

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60 Section 1:  Bone Anatomy, Physiology, Pathology and Diseases

those loaded only with vancomycin, whereas the release of function autonomously. There are lots of advantages for
netilmicin is not hampered. Moreover, the addition of blood the use of allografts (table 13), but there needs to be strict
significantly slowed down the antibiotic elution over the first regulatory mechanisms for development and induction of
7 days in vitro. In clinical practise, AIBGs might be used in bone banking facility like the use of blood products.
the prophylaxis as well as in the treatment of bone and joint
Need for constant updation in screening methods and
infections. The prophylactic use of antibiotic-loaded bone
regulation: With the initial use there was not much focus
grafts for prevention of wound infections after orthopedic
on screening the donors. This came into focus with
surgery has been though only sparsely done.
transmission of hepatitis B infection in a medical student
Rejection of allograft: Allografts can induce immune who received bone from above knee amputee (Shutkin
response and are liable for rejection. The rejection process, 1954). Then other infections like transmissions of HIV
however, is not as prominent as that of other soft tissue infection in 1984, hepatitis C virus in 1992 and 1995 and
transplantation. Allografts possess cell surface glycoproteins new infections like SARS in 2004 have been reported. Thus
typically from the contained bone marrow cells, endothelial the screening methods need to be constantly updated to
cells and retinacular activating cells. These are recognized by incorporate unusual and new infections. Also like other
innate “cell-mediated immunity” of the host. T-lymphocytes organ transplantation unethical activities like “trafficking”
recognize class I and II antigens to mount host immune can ever become prominent so regulation of all human
response. Collagen possibly incites mild cell-mediated tissues should be strict and traceable. This also encourages
and humoral immune response, while noncollagenous registration of complications.
portion (proteoglycans, osteopontin, osteocalcin, etc.) The bone banking protocol: Ideally a protocol should be
produce cell-mediated immunity but to even a lesser extent. developed by the responsible person from department of
Mineral phase (HA) is nonimmunogenic. The implanted orthopedics (preferably the HOD), organ donation and
graft is surrounded by inflammatory cells restricting the retrieval unit or a bone banking administrator, operation
incorporation. Inflammatory cells also get sensitized theater nurse, hematological laboratory technician,
and may possibly lead to increased reaction on future pathologist and microbiologist in a combined effort
implantation but the effects have not been specifically depending on the needs and availability of resources for
studied. The degree of the host response is related to the that center and surroundings. They also comprise the team
antigen concentration and total dose which is significant or organizational unit of bone bank. The bone banking
in fresh allografts. Modern allograft processing kills most of administrator need not be a medical personnel but should
the resident cells and washes away the surface proteins to a have adequate training to handle the bone bank.
large extent. This is the cause of frequent seroma formation
and persistent serous discharge from the operative site as
the incorporation is dependent on cellularity and MHC
Donor Selection
compatibility between host and donor following massive Informed consent from the person is a must before
allograft transplantation. retrieving the tissue if says he is undergoing hip arthroplasty
(for obtaining femoral head). For cadaveric bone retrieval
it is ideal if the person has expressed his wish for donation
Bone banking premortem but deviation may be legally obtained if closest
A bone bank provides usable bone grafts (implants) on of the relatives freely and voluntarily give consent to do so
demand that serve predictable function, and are free (depending on state laws) postmortem. The criteria used to
from transmissible disease. An increase in the demand judge if bone can be reasonably obtained from the patient
of bone grafts due to higher number of complex (spinal are tabulated in table 14.
fusion, tumor resection reconstruction) and revision
surgeries have pressed the need for developing storage Excision of graft bone, processing and
and procurement facilities for allograft bone. Autograft
alone cannot specifically supply the demand in large
storage
tumor excisions, complicated articular and extra-articular The removed femoral head is inspected and capsule and
reconstructions in revision arthroplasty, etc. Several centers synovial tissue are cultured on aerobic and anaerobic
are storing bone using nonuniform methods in our country bacteria. In order to exclude malignancies, autoimmune
as a central regulatory authority does not exist. Also there inflammatory processes, or infections, a biopsy of 1 cm3 of
is no intercommunication between the centers and they representative bone and capsule is sent for histopathological

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Chapter 2:  Fracture Repair 61

Table 14: Criteria used for excluding patient from bone donation (not a comprehensive list and can be modified from center-to-center)
Specific exclusion criteria:
•• No consent
•• HIV, HBsAg, HCV, CMV positive patient (serologically and clinically proven)
•• Men having homosexual intercourse after 1977
•• Immigrants (after 1977) from countries in which heterosexual intercourse is an important factor for HIV transmission
•• Persons indulging in or suspected to be involved in prostitution (or their partners) since 1977
•• Intravenous medication/narcotics use (documented or suspected)
•• Hemophilic patients who received clotting factor concentrates
•• Individuals who received blood transfusion before 1980
•• Individuals who had a skin tattoo or did piercing less than 6 months ago
•• Individuals who stayed in a SARS epidemic area or individuals who had face-to-face contact with a SARS patient
General exclusion criteria:
•• Language barrier or patient unable to understand and give consent for any reason (mental retardation, psychiatric patients)
•• Age less than 18 years
•• Active or recent systemic infection
•• Patients with severe burns or contaminated wounds
•• Meningitis/encephalitis
•• Tubercular infection of bone or joints
•• Leprosy
•• Active ‘‘slow-virus’’ infection (suspected or documented) or patients suffering from dementia
•• Previous undocumented infection with hepatitis B or C, HIV
•• Active or past syphilis infection
•• Recent (less than 4 weeks) vaccination with live vaccine (measles, yellow fever, mumps, polio, oral typhoid, rubella)
•• Patients with rheumatoid arthritis or connective tissue disorders/autoimmune diseases
•• Documented or suspected metabolic disorders
•• Patients with insulin dependent diabetes mellitus or those treated with growth hormones in past
•• Patients on chronic medication (phenytoin, corticosteroids)
•• Recent exposure to toxic substances (lead, aluminium or other substances known to home bone)
•• Patients with malignancies and those treated with anti-cancer chemotherapy
•• Significant radiation exposure to bone as in radiotherapy.

examination (though histopathological examination as condition, the unprocessed allogenic bone tissue can be
a routine standard procedure is debated by agencies and preserved for a maximum of 5 years. Blood samples are
really not mandatory for lacking literature support of utility). collected simultaneously while harvesting the bone graft
The dimensions are noted and it is wrapped using double to determine blood type and routine hemogram (table 15).
jar technique (described by Nather). The graft is washed During surgery, bacterial culture swab samples from the soft
in normal saline or biofiltered water followed by hydrogen tissues (hip capsule) are collected. Serological screening for
peroxide to remove grossly visible fat and debris and dipped infectious diseases is re-performed 6 months after surgery
in 2% aqueous iodine solution for 15–30 minutes followed to exclude infections with window period. This takes care
by a thorough repeat wash with normal saline. The excess of persons that might be recently infected.
water is then drained and the graft put in a smaller sterile For harvesting cadaveric bone, the donor’s limbs are
glass jar with a screw-on cap. This is then put in a larger prepped and draped using standard surgical principles,
glass bottle with air seal lock, both the jars are sterile. Due and the tissue is recovered by trained persons. Bones are
labeling of the graft is done with dimensions and it is sent commonly retrieved from ilium, femur, humerus, tibia, ribs
to storage deep-freezer within 30 minutes. The freezer has a and vertebrae. Many other types of tissues can be recovered,
temperature of −80°C and that has a continuous temperature including stem cells, soft tissues (tendon, ligament) and
registration device charting temperature changes round the skin. Fresh articular cartilage is initially refrigerated and
clock. The ambient storage temperature range is between then placed in a culture medium to maintain its viability
−90°C and −70°C to protect against temperature-induced for up to 28 days. Small bones and soft tissues are collected
damage to the tissue. As a back-up measure nitrogen tank using the described “double jar” technique while long bones
should be installed in case the freezer fails. In any case if should be triple wrapped in sterile packaging. The three
the cold chain for storage fails at any time then the whole layers consist of inner gamma irradiated polyethylene bag,
batch of bone graft has to be discarded. In deep frozen middle layer of autoclaved linen where the bone is tied at

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62 Section 1:  Bone Anatomy, Physiology, Pathology and Diseases

Table 15: Recommended tests that should be performed on water (with or without pressurization) followed by
donor’s blood sample and tissues pasteurization (shaker bath at 60°C for 3 hours) and
•• Blood and rhesus typing
centrifugation with alcohol (70% for 3 hours) or detergent
•• Hemogram including erythrocyte sedimentation rate (ESR) and C- solution. Pasteurization (not necessarily required and
reactive protein should be omitted if asceptic precautions are followed)
•• Viral (hepatitis) removes most bacteria, fungi and viruses including
■■ HBsAg, hepatitis B core antigen and hepatitis B antibody HIV (heating greater than 60°C damages the healing
■■ Anti-HCV antibody (repeat after 180 days for living donors)
■■ Viral nucleic acid properties of bone so should be avoided). Alternatively
•• Viral markers for aqueous solution of iodine may be used to similar effect
■■ HIV1 and HIV2 (repeat for living donors after 180 days) but prolonged exposure is cytotoxic. Alcohol therapy is
■■ HTLV (repeat for living donors after 180 days) effective against HIV, bacteria and spores. Antibiotics have
■■ CMV
•• Syphilis (VDRL, veneral disease reaction laboratory)
not been shown to give an additional benefit in reduction
•• Microbiology (of soft tissue specimen and bone) of contamination. Some authors have even demonstrated
■■ Gram stain, ZN stain adverse effects of some antibiotics. The lyophilized graft
■■ Aerobic culture (nutrient agar, blood agar, chocolate agar) after terminal sterilization (see below) is stored at room
■■ Anaerobic culture (thioglycolate broth)
•• Histopathological examination
temperature.
Terminal sterilization is usually done by gamma
irradiation. Gamma radiation is effective in killing bacteria,
ends with cotton tape and outer again a sterile polyethylene fungi, spores, and, to a lesser degree, viruses. Depending
bag. The dimensions of bones should be measured and on the dose, however, gamma radiation can weaken the
put on the label (to match in future with recipient). All graft. Doses below 1.5 mrad do not adversely affect the
obtained graft material is swab cultured immediately upon tissue strength. A minimum dose of 2 mrad is required
retrieval prior to processing. The periosteum is immediately to kill bacteria and 4 mrad for killing viruses. After such
stripped, cleaned as above and the grafts from hereon are high dose irradiation the bone is discolored and fibrillar
kept frozen at −80°C for all further processing and storage network of bone is destroyed. Solubility of collagen and
(fresh frozen graft). The method for lyophilization is proteoglycans increase reducing structural strength and
different (preferred for cadaver allografts) and is described inductive capacity is greatly reduced. A dose of 2.5 mrad is
below. If gross bacterial contamination is identified or chosen for processed bone giving priority to sterilization
suspected the material is kept under surveillance and newer and is given by Co60 gamma generators. After processing
techniques, such as bacterial extraction, are used to confirm the grafts are sent to quarantine for final storage. Grafts
the results. There is high chance of both false, positive and are stored at the tissue bank during the quarantine period
false, negative results with swab culture. All the material (6 months) until the second stage serologic and bacteriologic
is discarded if bacterial contamination is confirmed or test results and autopsy reports (when required) are
suspicion unsettled. For cadaveric donors as it is not received and cleared. The graft is then released for human
possible to re-obtain blood samples after 6 months, the use after proper labeling and sent to definite storage.
blood samples are also stored with the grafts and serological
Choice of freeze dried versus fresh frozen graft: The shelf life in
tests re-performed at 6 months before release into storage
storage depends on the method of processing and storage;
facility.
commonly either Freeze Drying (lyophilization—infinite)
Sterilization of graft: The sterilization techniques differ or deep freezing (5 years) is used. Fresh frozen grafts are
at various setups and keep evolving. Regardless of the obtained under strict sterile conditions and may not be
technique used, the objective is to remove all infectious processed (though most units process them with above
elements with minimal impact on the performance of the method to minimize chances of infection). Freezing an
allograft. Tissue can either be processed aseptically or be allograft has little impact on the mechanical properties and
secondarily “sterilized”. In all the safest method appears reduces its immunogenicity; however, it does reduce viability
to be aseptic harvesting with strict monitoring. To be of articular cartilage unless cryopreserved. Lyophilization
considered sterile, allografts should have fewer than 10 6 removes more than 95% of the water enabling biological
microorganisms; for medical devices, the requirement material (arresting the enzymatic lysis) to be stored for long
is fewer than 103 microorganisms. For fresh frozen grafts periods of time even at room temperature. This process is
the above described method is followed. For freeze-dried achieved by first freezing the graft and then sublimated in
allograft preparation the method is as follows. Commonly vacuum; the drying is achieved by water evaporation from
the harvested graft bone is cut and washed with biofiltered the specimen and condensation in the condenser. Freeze

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Chapter 2:  Fracture Repair 63

drying further diminishes the immunogenicity of the graft recommend HPE. Thus, a HPE of bone grafts should
and also eliminates the bacterial contamination but does be carefully institutionalized. We would recommend
alter mechanical properties (especially if not rehydrated HPE only when there is critical suspicion that cannot
properly). Freezing at −15°C to −30°C is not recommended be settled otherwise.
as ice crystals develop very fast. •• Culture swab: this is a mandatory requirement.
All fre eze—dr ie d and frozen tissue re quires The culture specimen obtained at the time of graft
“reconstitution”. The length of reconstitution time varies implantation and usage serves purpose of quality
according to the type of tissue. Reconstitution of lyophilized control check on banking procedure. The policy decision
bone grafts is done aseptically at 4º temperature before use. needs to be determined for the use of better culture
Sterile normal physiological saline or Hartmann Ringer— methods as swab cultures have been often found to show
lactate solution is commonly used. Some surgeons use false-negative results. There are two ways one by taking
antibiotic solution (amoxicillin and cloxacillin solution) but multiple specimens and culturing them after processing
the efficacy and need is unknown. Any bone which requires or otherwise using routine antibacterial processing of
modification before use or is intended for load-bearing the graft before surgical use.
purposes should be reconstituted for longer periods of time
preferably 24 hours. Freeze-dried tissue is brittle (lack of
water) which can be reduced by prolonged reconstitution. CONCLUSION
All reconstituted grafts must be used within 24 hours. Graft •• Fracture is a break in continuity of otherwise normal bone
incorporation usually follows the steps as for an autograft. (fracture in abnormal bone will be termed pathological
The fresh frozen grafts intended to be used are allowed to fracture) that induces a host of inflammatory and
thaw in operation theater in situ for 1 hour before surgery. reparative processes to incite metabolic changes in this
It is then soaked in 1 liter of normal saline and prepared by hard tissue of body.
removing all soft tissues and remaining periosteum if any. •• The process of osseous repair is primarily a direct
The articular cartilage should be removed before cutting healing which is possible in exact apposition of the
or morcellization of the graft. This is then again washed fractured fragments under compression.
thoroughly before surgical use. Culture swabs should be •• If the fragments are not apposed well then fracture repair
obtained at the time of graft usage also. occurs by indirect or secondary healing involving the
Quality control of bone banking: As stated above as lot many intermediary tissue called callus.
procedures are involved in bone banking so a stringent •• The repair process in either case is stereotyped and
protocol should be followed that needs regular monitoring follows a predetermined path governed genetically
a few are discussed below. and discrete cellular processes, however, extrinsic
•• Histopathological screening: The histopathological control is exercised in the form of mechanical, cytokine
examination (HPE) establishes good quality bone (paracrine) and hormonal (endocrine) influences; any
being stored and used. HPE has not been mandated discrepancy of which would produce abnormal process
by all agencies and few centers omit it altogether. The resulting in slow, delayed repair or nonunion.
rationale is that it has never been documented to be •• In modern day practice the treatment variable has
cost effective and makes hardly any difference in patient specific influence on the fracture repair and it is of
management or to recipient. Most of the findings have utmost importance not do disturb the local biology of
been over-diagnostic for suspicion of malignancy or fracture healing and maintain vascularity for optimal
inflammatory disorders that got hardly documented outcome whatever the method used for fracture fixation.
in the donors on follow-up. Also it has been found that •• In case the fracture repair does not follow the desired
with 100% sensitivity and 99.9% specificity surgeon path constitutionally or due to treatment variables,
can preoperatively and during surgery with gross various, methods are available for improving the
examination rule-out exclusions. There have been a few possibility of fracture repair that broadly fall into
instances on the contrary where malignancies in early biological and non-biological methods. Bone grafting is
stages have been found that were missed on routine the most widely accepted method of improving fracture
hematological or clinical examination. Equalizing repair.
evidence exists that suggest presence of occult findings •• Due to increased number of surgeries being performed
(B-cell lymphoma, myeloma, sarcoma, Paget’s disease, the need of bone grafts is constantly increasing
ochronosis, metabolic disease, osteonecrosis and necessitating the deployment of bone banking
Gaucher’s disease) to a significant instance and facilities.

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Chapter
Metabolic Diseases of Bone and
3 Effect of Glucocorticoid Therapy
on Bone
Manish Kumar Varshney, Swapnil Sharma

OSTEOPOROSIS •• Bone strength refers to a vague general term that


combines, BMD and bone quality taken together
Manish Kumar Varshney •• Bone density is primarily a derivative of mineral
component, and hence reflects bone mass
DEFINITION •• Bone size is probably a constitutional and genetic
function with secondary environmental and lifestyle
Osteoporosis is both a qualitative and quantitative defect influences
of bone that usually affects all the bones of the body. It •• Bone quality is an accrual term that varies with age.
can be more precisely defined as a “progressive (often), It is determined by architecture, turnover, damage
systemic (commonly) and skeletal disease characterized accumulation (e.g. microfractures) and mineralization.
by overall low bone mass (quantitative) predominated
by microarchitectural (qualitative) deterioration of bone
tissue that results in increased bone fragility, and hence NATURAL HISTORY OF BONE
susceptibility to fracture”. World Health Organization
(WHO) definition for osteoporosis is more objective and MASS CHANGES IN HUMAN
is detailed below and stresses solely on the bone mineral BODY, OPERATIONAL DEFINITION
density (BMD) that has ingrained in the minds of physicians.
Newer definition of osteoporosis considers it to be a skeletal OF OSTEOPOROSIS AND ITS
disorder characterized by low bone strength and increased
risk of fracture (National Institutes of Health Consensus
CLASSIFICATION
Development Panel on Osteoporosis Prevention, Diagnosis Peak adult bone mass reaches at about the age of 35 years for
and Therapy) which puts into perspective the changing cortical bone (varying by genetic and environmental factors
scenario of a relation much larger and varied than BMD. by a couple of years) and a little earlier for trabecular bone.
When considered with respect to total number of persons Bone mass is accumulated from age of 8 years till the end of
affected osteoporosis ranks as number one metabolic 2nd decade. In cortical bones, the bone mass subsequently
bone disease that affects population and its prevalence at declines with aging at the rate of 0.3–0.5% per year in both
any given point of time exceeds the collective prevalence men and women. This is a universal phenomenon occurring
of major medical diseases (diabetes, breast cancer and in all races. At menopause the loss of bone mass accelerates
hypertension) combined together. The term osteoporosis in females not taking hormone replacement therapy from
and osteomalacia were coined by Pommer in 1885 and he an average of 1% initially to 5% over the decade which then
also avidly differentiated between them. A restrictive and again slows. At any given period of time, women have less
inappropriate definition commonly followed by clinicians bone mass than do men and the difference gets accentuated
in general practice is “fragility fractures”—fractures in with aging. Riggs and Melton classified osteoporosis into
bones occurring with nonviolent trauma (such as falling primary and secondary types (Table 1). The primary type
with standing height). This definition essentially does not is further classified into type 1 or postmenopausal and
indicate or refer to primary prevention and should not be type 2 or senile forms. The senile and postmenopausal
used to clinically define osteoporosis. Some terms should forms differ conceptually (Table 2) giving some insight
be clarified before using in common practice as they are into the process of disease development. Senile form
commonly wrongly referred is also referred as involutional osteoporosis. Similar to

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Chapter 3:  Metabolic Diseases of Bone and Effect of Glucocorticoid Therapy on Bone 65

TABLE 1: Classification of osteoporosis TABLE 2: Conceptual differences in types of primary


Primary: osteoporosis
•• Type 1 (postmenopausal) Type 1 (postmenopausal Type 2 (senile osteoporosis)
•• Type 2 (senile or involutional) osteoporosis)
•• Type 3 (“postclimacteric”, it is not a part of original classification, but is
Age > 50 years Age > 75 years
similar to type 1 osteoporosis but occurring in males)
Secondary: Female to male ratio around 5:2 Female to male ratio around 2:1
•• Hormonal: Hypogonadism, thyrotoxicosis, Cushing’s, Involves mainly trabecular Proportionately involves both trabecular
hyperprolactinemia and diabetes mellitus bone and cortical bone
•• Drugs: Steroids, phenobarbital, anticonvulsants, anticoagulants,
cytotoxic agents, etc. Usually high turnover Usually low turnover osteoporosis
•• Nutritional: Calcium deficiency, vitamin C and vitamin D deficiency, osteoporosis
malabsorption, alcohol intake and malnutrition Predominantly vertebral Predominantly proximal femoral
•• Metabolic diseases: Osteogenesis imperfecta, homocystinuria, Marfan’s fractures fractures
syndrome, etc.
PTH normal to low PTH increased
•• Chronic liver and renal disease
•• Miscellaneous disorders: Multiple myeloma, rheumatoid arthritis, Estrogen withdrawal main Age related reduced bone turnover is
mastocytosis, thalassemia, Wilson’s disease, hemochromatosis, etc. etiology the main cause

(Source: Modified from Riggs and Melton)

postmenopausal osteoporosis men have “postclimacteric” and epidemiologic data that relate “incidence of fracture
osteoporosis as seen in gradual testicular failure. This differs to BMD” in white women was observed. It was seen that
from postmenopausal form only in the sense that clinical when BMD of more than 2.5 standard deviation below
evidence of osteoporosis develops some 15 years later and peak bone mass was associated with significant increase
is slow to develop. in fracture incidence in study population so a value of 2.5
T h e o p e r a t i o n a l d e f i n i t i o n o f o s t e o p o ro s i s was chosen. There is still controversy regarding proper
(densitometric definition) given by WHO is in terms of BMD cutoff values (as logically these values cannot be
BMD (bone mass). Although BMD is not the only factor universally applied) in other ethnic and gender groups. One
that determines fracture risk, but it is the strongest must remember that these values represent densitometric
predictor identified for fracture. Hence, osteoporosis criteria only for diagnosing osteoporosis and do not provide
is defined (Fig. 1) for diagnostic and communication any differential diagnosis of the causes of low bone mass.
standardization (Table 3) as a BMD more than or equal Because BMD is a continuous measure of fracture risk, the
to 2.5 standard deviations below the peak BMD of gender chosen cutoffs are of course a bit arbitrary and not that
and ethnicity matched 30-year-old healthy Caucasian person with value at 2.4 standard deviation is safe against
women (T-score; discussed below). To define these, criteria an osteoporotic fracture.

Fig. 1: BMD assessment and defining osteoporosis

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66 Section 1:  Bone Anatomy, Physiology, Pathology and Diseases

TABLE 3: The densitometric definition of osteoporosis (WHO)


DEXA T-score (note Bone mineral density Interpretation
indicated t-scores are
negative here so > and <
are truly mathematical)
T-score > –1 BMD value within 1 standard Normal
deviation below mean peak
bone mass for a young adult
reference population
Between –1 and –2.5 Between 1 and 2.5 standard Low bone
deviation below that of the mass
mean level for a young adult (osteopenia)
reference population
T-score ≤ –2.5 (i.e. BMD value more than Osteoporosis
“numerical values” higher or equal to 2.5 standard
than 2.5 say 3 or 3.2, etc.) deviation below mean peak Fig. 2: Change of bone mass with age (pink, females; blue, males)
bone mass of a young adult
reference population
years and 70 years and around 70% older than 80 years have
T- score ≤ –2.5 and BMD value more than or Severe or
osteoporosis (rest have osteopenia).
osteoporotic fracture(s) equal to 2.5 SD below mean established
peak bone mass of a young osteoporosis Common fractures that occur in osteoporosis are (Figs 3A
adult reference population to C):
with fractures •• Fractures of distal radius
•• Fracture of proximal femur—femoral neck and
intertrochanteric
•• Fracture of vertebral bodies
PREVALENCE, INCIDENCE AND •• Other fractures related to low BMD are of metatarsals,
PROBLEM STATEMENT proximal humerus, ribs, toes, leg, pelvis, hand and
clavicle.
Osteoporosis is a pandemic. Over a lifetime a female loses Ninety percent of all hip and spinal fractures in old
30% of cortical bone and 50% of trabecular bone; males age are related to osteoporosis. Thoracolumbar junction
lose two-thirds of above values. Endosteal diameter of (T12 and L1) and mid thoracic spine are the most frequent
bone increases rapidly than periosteal diameter due to areas for vertebral fractures. The lifetime risk of having one
increased trabeculation of cortical bone. Peak bone mass or more vertebral fractures in females over age of 50 years
is achieved in second decade (20% > in men), with age the are one in three compared to one in five for males of same
bone mass is lost gradually in both sexes more in females age. In white women and men aged 50 years or older, the
(females:males = 4:1). After 80 years of age, there is no lifetime risk of any osteoporosis related fracture in the hip,
gender related difference in prevalence of osteoporosis (Fig. spine or distal forearm is nearly 40% and 13% respectively
2). With increased life expectancy the “old baby boomers” as commonly reported in contemporary literature. With
are just exploding entering into osteoporotic age group increasing age the incidence of osteoporotic related
and suffering from complications. Primary undesirable fractures increase, it has been observed that the incidence
consequence of osteoporosis is fragility fracture. Fracture of hip fractures which is nearly 2 per 1,000 patient-years
would occur only if a failing force is applied to bone. The between ages 65 and 69 years in women increases to
magnitude of failing force required is inversely proportional approximately 26 per 1,000 patient-years by age 80–84
to bone strength. Weaker the bone, hence higher will be years. Osteoporotic fractures are less common in nonwhite
chance of fracture. This is at best a rough correlation. Elderly females and in men. Osteoporosis and consequent fractures
people gradually lose balance during walk and later may fall are major public health concerns and pose immense
even during standing. Fall from standing height has been economic burden. The costs of burden for fractures are
cited the most common cause of osteoporotic fractures. But estimated to be USD 21,000 during the first year of a hip
there are a variety of factors influencing each of the three fracture, USD 1,200 for a vertebral fracture and USD 820 for
variables (bone strength, the fall and the impact of fall) a wrist fracture (Indian data not available). This indicates
intrinsic to cause a fracture. These explain the significantly that cost of osteoporosis related hip fracture is similar to that
less prevalence of fractures despite widely prevalent incurred for stroke (relative comparison for highlighting
osteoporosis. Nearly one-third of women aged between 60 severity). Other untoward effects of an osteoporotic

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Chapter 3:  Metabolic Diseases of Bone and Effect of Glucocorticoid Therapy on Bone 67

A B
A C
Figs 3A to C: Osteoporotic fractures: (A) Shows the osteoporotic wedge compression fracture of 3rd lumbar vertebra. (B) Shows the Colles
fracture of distal radius with fracture of ulnar styloid. (C) Demonstrates the intertrochanteric fracture of left femur

fracture include reduced height, poor functional status, TABLE 4: Standardized mortality ratio after a spine fracture
residual pain, loss of independence, reduced tidal volume
Age-standardized mortality ratio
(thoracic spine fractures), reduced metabolism, frailty, poor
Fracture Women Men
remaining quality of life, and fear and depression. The irony
is that within 1 year of hip fracture 50% of survivors never Proximal femur 2.2 3.2
fully recover, 20% die within a year, 30% have permanent Vertebral 1.7 2.4
disability, 40% are unable to walk independently and 80% Other major 1.9 2.2
are unable to carry out at least one independent activity of Other minor 0.8 1.5
daily living (Fig. 4). Not only the functional disabilities but
mortality associated with vertebral fractures is also greater
than expected in the general population (Table 4). Vertebral as the former exceeds hip fractures in the mean number of
fracture related mortality exceed that of hip fracture despite bed days and limited-activity days.
a much higher mortality ratio associated with hip fractures
GENETICS OF OSTEOPOROSIS
Half of the BMD is attributable to inherited factors
and some 62 genome-wide loci have been attributed
to development of osteoporosis of which 15 genes are
identified as causative. Genes for the TCIRG1 (encodes
the APT6i subunit of the osteoclast-specific proton pump),
vitamin D receptor (VDR), the Wnt/β-catenin signaling
pathway, CLCN7 (encodes chloride channel), the estrogen
receptor, transforming growth factor (TGF-α), interlukin-6,
collagen type I, Cbfa1 [(core binding factor alpha 1) or Runt-
related transcription factor 2 (Runx2)—regulates osteoblast
differentiation] and collagenase are a few. Most of the genes
are located in the estrogen pathway, the Wnt/β-catenin
signaling pathway and the receptor activator of nuclear
factor kappa-B ligand (RANKL)/RANK/osteoprotegerin
(OPG) pathway. Mutations in a gene coding for the type 2a
sodium-phosphate cotransporter (NpT2a) predisposes to
both osteoporosis and kidney stones. A partial form of the
Fig. 4: Morbidity of an osteoporotic hip fracture fragile X mutation leads to early menopause and increases

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68 Section 1:  Bone Anatomy, Physiology, Pathology and Diseases

risk of osteoporosis. Lifestyle risk factors (discussed below), 3. CAROC produced by the Canadian Association of
however, modify the genetic influence significantly on BMD. Radiologists and Osteoporosis Canada.
Fracture risk assessment tool (FRAX®) is a web-based
RISK FACTORS FOR LOW calculator that includes a number of clinically identified
risk factors (BMD can be optionally included). FRAX® has
BONE MINERAL DENSITY AND been developed to calculate the 10-year probability of a
hip fracture taking into account the femoral neck BMD and
FRACTURE RISK ASSESSMENT clinical risk factors shown in Table 6. It can also be used to
A number of risk factors have been identified and used to calculate the 10-year probability of other major osteoporotic
predict the risk of developing osteoporosis and associated fractures (defined as clinical vertebral, hip, forearm or
fracture. It is found that these factors predict risk of proximal humerus fracture) using the mentioned clinical
fracture much better than solely making the diagnosis risk factors. FRAX® tool is most useful in patients with low
of osteoporosis based on BMD. The risk factors can be BMD at femoral neck, when the same is included. It has
categorized into modifiable and nonmodifiable ones (Table been found, however, that FRAX® underestimates the fracture
5). Using some of these validated risk factors and clinical risk in patients with multiple osteoporosis-related fractures,
assessment tools the risk to fracture in a patient can be recent fractures and those at increased risk for falling. Also,
estimated as low (< 10% chance to fracture in next 10 years), when FRAX® underestimates risk when applied to patients
moderate (10–20% in next 10 years) or high (> 20% in next 10 with low BMD at vertebral body but relatively normal BMD
years). Three such tools are available developed by different at femoral neck. The WHO algorithm is not validated for use
agencies to give an approximate measure of chance to suffer of lumbar spine BMD. The specific applications are:
from osteoporosis related fracture over next 10 years (10- •• FRAX® is intended to use in postmenopausal women and
year fracture risk in a given patient). men aged 50 or older
1. FRAX® tool (accessible at http://www.shef.ac.uk/FRAX/ •• FRAX® may be calculated with total hip BMD or femoral
tool.aspx), developed by the WHO. neck BMD, but the latter is preferred. Other sites are not
2. The QFractureScores. recommended.

TABLE 5: Risk factors for possible development of osteoporosis


Nonmodifiable Modifiable
Advanced age Hyperthyroidism and hyperparathyroidism
Frailty BMI < 20 kg/m2 in women (< 25 in men)
Parental history of fragility fracture Low body weight [< 127 lb (57.6 kg) in women, <154 lb (69.9
Early menopause (< 45 years) kg) in men]
Primary androgen (males) and estrogen (females) deficiency Glucocorticoid intake
Hypogonadal states: androgen insensitivity, anorexia nervosa, athletic amenorrhea, Secondary estrogen and androgen deficiency
hyperprolactinemia, panhypopituitarism, premature menopause (< 40 years), Turner and Smoking
Klinefelter syndrome Alcohol consumption > 3 units (1 unit = 5 oz. spirits, 12 oz.
Ethnicity beer)
Genetic factors (discussed later)—cystic fibrosis, Ehlers-Danlos syndrome, Caffeine intake > 4 cups/day
Gaucher’s disease, glycogen storage disorders, hemochromatosis, homocystinuria, Inadequate calcium and vitamin D intake
hypophosphatasia, Marfan syndrome, Menkes steely hair syndrome, osteogenesis Prolonged immobility
imperfecta, parental history of hip fracture, porphyria and Riley-Day syndrome Lack of sunlight exposure (indoor work)
Small stature Sedentary lifestyle
Rheumatologic and autoimmune diseases—Rheumatoid arthritis, ankylosing spondylitis Excessive exercise (impaired hypothalamic-pituitary axis)
and systemic lupus Excess protein intake
Gastrointestinal disorders—Peptic ulcer disease, celiac disease, gastric bypass, Anorexia nervosa
gastrointestinal surgery, inflammatory bowel disease, malabsorption, pancreatic disease Medications [aluminum in antacid preparations, anticoagulants
and primary biliary cirrhosis (heparin), antiepileptics, aromatase inhibitors, barbiturates,
Endocrine disorders—diabetes mellitus type 1 and type 2, central obesity, Cushing’s depot medroxyprogesterone (premenopausal contraception),
syndrome, hyperparathyroidism, thyrotoxicosis and acromegaly chemotherapeutic and cytotoxic agents, glucocorticoids
Hematological disorders—Hemophilia, leukemia and lymphoma, monoclonal (≥5 mg/day prednisolone or equivalent for ≥3 months),
gammopathy, multiple myeloma, sickle cell disease, systemic mastocytosis, other lympho gonadotropin-releasing hormone (GnRH), tacrolimus,
and myeloproliferative disorders methotrexate, proton pump inhibitor (PPI) (omeprazole,
Neurological and musculoskeletal risk factor—Spinal cord injury, epilepsy, multiple etc.), lithium, methotrexate, parental nutrition, tamoxifen,
sclerosis, muscular dystrophy, parkinson’s disease and stroke thiazolidenediones and selective serotonin reuptake inhibitor
Chronic liver and renal disease (SSRI), etc.]
Epidermolysis bullosa Space travel and prolonged low gravity exposure

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Chapter 3:  Metabolic Diseases of Bone and Effect of Glucocorticoid Therapy on Bone 69

TABLE 6: Risk factors included in WHO fracture risk assessment osteoporosis as in WHO definition. As a significant impact
model of BMD, the vertebral fracture risk is inversely correlated
Clinical risk factors included
to bone mineral content. It is estimated that roughly for
in WHO FRAX® tool a decline of 1 standard deviation in bone mass, there is a
Current age Gender
1.3-fold to 2.5-fold increase in risk of osteoporosis related
fracture. One percent increase in BMD decreases fracture risk
Rheumatoid arthritis Secondary causes of osteoporosis type
1 – type 1 DM, osteogenesis imperfecta
by about 4%. But the expectation and relation is nonlinear
in adults, untreated long-standing and nonuniversal. National osteoporosis foundation (NOF)
hyperthyroidism, hypogonadism or study itself revealed that 82% of postmenopausal females
premature menopause (< 40 years), that presented with a fracture within 1 year had a T-score
chronic malnutrition, malabsorption and above –2.5, and 67% had a T-score above –2.0 as measured
chronic liver disease
with peripheral densitometry. Each standard deviation
Prior osteoporotic fracture Parental history of hip fracture decrement in femoral neck BMD has been found to increase
Femoral neck BMD Current smoking the risk of fracture 2.6-fold. BMD at the femoral neck is a
Low BMI (kg/m2) Alcohol intake (3 or more drinks per day) better predictor of hip fracture than BMD at other places.
Oral glucocorticoids ≥ 5 mg Patient with previous fracture and current low BMD would
prednisolone per day for 3 have additive influence and is more likely to suffer with a
months fracture than either factor alone. The risk of fractures in
women with two fractures is 75-fold greater, if their BMD
currently is less than –2.5 standard deviation compared to
those with no fractures and normal BMD.
•• FRAX® has not been validated for use in currently or
previously treated patients with pharmacotherapy for
osteoporosis. Patients off the pharmacotherapy for 1–2 Epidemiological Factors
years may be considered untreated. Bone mineral density decreases with age in both sexes. The
QFractureScores do not require laboratory measure­ risk of hip fractures exponentially rises in older age. The
ment. It utilizes simple parameters that are known to the lifetime risk of fracture is approximately twice in women
individual and without rigorous testing like age, sex, height, than in men. In females, the risk of distal forearm and
weight, previous fracture, parental history of hip fracture, vertebral fracture increases after menopause. Though often
current smoking, glucocorticoid treatment, rheumatoid linked to osteoporosis and increasing age the incidence of
arthritis, secondary osteoporosis and use of alcohol (> 3 Colles’ fracture actually plateaus with age. Osteoporotic
units/day). It is a good tool for primary care or for individual fractures are twice more common in whites than in blacks.
self-assessment. This tool also shows some improved White women are more prone (1.5-fold to 4.0-fold) to have
discrimination and calibration compared with the FRAX a hip fracture than African-Asian women after 40 years
algorithm. Being simple there is likelihood of its use as a of age.
systematic population based program to identify high risk
patients. Body Weight and Composition
The CAROC takes into account age, sex, fracture history
and glucocorticoid use to determine a 10-year absolute risk Higher body mass protects from osteoporosis partially that
of all osteoporotic fractures. Here, BMD is mandatory to may be explained by the protective effect of fat on bone
calculate risk. tissue mediated, via leptin. Weight gain during adult life
Some important risk factors for osteoporotic fractures would, hence protect against hip fracture, but voluntary
are discussed below. or involuntary weight loss would predispose to fragility
fracture at all sites. Voluntary weight loss has not been linked
that decisively to hip fracture.
Low Bone Mineral Density
Bone mineral density has been considered the strongest History of Prior Fractures
predictor of sustaining a primary osteoporotic fracture A previous insufficiency fracture is the most important
(secondary and future fractures are better predicted by predictor of future fractures (Fig. 5). Single site vertebral
having a primary fracture itself). The bone strength variation fracture increases the risk of an additional vertebral fracture
is dependent on BMD, but in only 50% or less of the cases as by 4-fold to 5-fold, while the risk increases by 12-fold with
the strongest predictor cannot be the sole measure to define more than two such fractures as mentioned in Table 7.

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70 Section 1:  Bone Anatomy, Physiology, Pathology and Diseases

Pregnancies, however, appear to have a protective factor for


BMD, lowering the risk of fracture ultimately. Menopause in
females has a significant association with osteoporosis onset
and progression. The longer the time to menopause, the
higher is the ultimate bone mass. When measured at distal
radius each 5-year delay in menopause has been found to
be associated with 1.3% higher bone mass.

Medications
A lot of medications are known to reduce BMD.
Glucocorticoids, carbamazepine and phenytoin (barbiturates
and valproic acid may induce hyperparathyroidism by
accelerating metabolism of vitamin D causing rickets
and osteomalacia), heparin, warfarin, thiazide diuretics,
aromatase inhibitors, methotrexate, depo progesterone,
proton pump inhibitors (interfere with calcium absorption)
and thiazolidinediones (pioglitazone and rosiglitazone) all
Fig. 5: Previous osteoporotic fracture is the strongest predictor for have been implicated to cause osteoporosis.
next fracture. This patient had osteoporotic right intertrochanteric
fracture fixed 20 months ago came back with a “fall” and fracture at Smoking and Alcohol Abuse
neck of left femur
Compared to nonsmoking twins, the females who smoke
TABLE 7: Probable risk of subsequent fracture in an osteoporotic one or more pack per day have a 5–10% reduction in
patient who has sustained a prior osteoporotic fracture perimenopausal bone mass. Smoking causes increased
Risk of subsequent fracture hydroxylation of estradiol in liver with a decrease in
bioactive content. Ethanol in alcohol directly inhibits
Site of prior fracture Hip Spine Forearm Minor fracture
osteoblast proliferation and function reducing bone
Hip 2.3 2.5 1.4 1.9
formation, maintenance and mineralization, if used over
Spine 2.3 4.4 1.4 1.8 long period (chronic abuse).
Forearm 1.9 1.7 3.3 2.4
Minor fractures 2.0 1.9 1.8 1.9 Role of Beverages
Caffeine consumption has a mild but definite effect on
Hormonal Influence bone mass. Consumption of 10 cups of coffee per day for
Estrogen deficiency increases osteoclast number and bone 30 years is associated with a 1.1% decrease in distal radial
resorption by secondarily elevated blood cytokine levels bone mass. In contrast to coffee, high 10-year tea intakes
like interleukins-6 and tumor necrosis factor-α (TNF-α). increase BMD possibly due to a benefit from flavonoids,
Oral contraceptives used for more than or equal to 6 years fluoride or phytoestrogens found in tea. Phosphorated
have been found to increase BMD at the vertebral and and carbonated drinks leach out calcium from bones and
femoral neck regions reducing the risk of hip fracture by produce calciuria. Chocolates and high sugar containing
half. Estradiol hormone body concentrations less than meals also have similar effect. Dark chocolates may have
5 pg/mL is associated with higher risk of osteoporosis some protective effect in contrast.
related vertebral and hip fractures as is the higher sex
hormone binding globulin concentrations (≥ 1.0 µg/ Calcium and Other Minerals
dL) as this reduces free hormone levels. This effect is not Aluminum intake in antacid preparations or in dialysis
seen at distal wrist. Tubal ligation interestingly has been patients, cadmium toxicity and patients consuming lithium
associated with estrogen deficiency, but not low BMD or for metered dose inhaler (MDI) are at increased risk of
fractures. Amenorrhea as is commonly seen in athletes and osteoporosis. Higher teenage calcium and milk intake
individuals with anorexia nervosa (psychogenic dietary was associated with higher BMD at the spine and hip.
disorder), is associated significantly with decreased BMD. Similar effect is noted in adults. Protein is traditionally
In contrast to the proposal made by some researchers, there considered bad for bones due to its calciuric effect, but
is no evidence to support that breast-feeding or the number may be beneficial, if it is consumed with sufficient calcium.
of pregnancies is directly associated with alteration in BMD. Routine fluoridation of drinking may decrease the fracture

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Chapter 3:  Metabolic Diseases of Bone and Effect of Glucocorticoid Therapy on Bone 71

risk. Boron, magnesium and selenium have been found to TABLE 8: Causes of falls in elderly
have trophic influence on BMD.
Personal intrinsic factors Extrinsic and environmental factors

Vitamin D, Vitamin A and Vitamin B Balance and gait: Personal hazards:


•• Joint disease •• Inappropriate footwear
For obvious reasons vitamin D deficiency impacts BMD •• Reduced proprioception •• Clothing
negatively and is associated with fractures. Vitamin D •• Cerebrovascular disease Sedatives and hypotensive drugs
deficiency when associated with low calcium intake •• Neuropathy Psychotropic medications
•• Parkinson’s disease Hazards at home:
produces secondary hyperparathyroidism resulting in bone Aging: •• Bad lighting
resorption and weakening. Vitamin D excess, however, has •• Poor postural control •• Slippery floors
a toxic effect and is associated with low BMD. Excessive •• Kyphosis •• Obstacles in the walking path
vitamin A also is deleterious to bone. Deficiency of vitamin •• Weakness of muscles/sarco- •• Loose rugs
B in elderly has been associated with higher homocysteine penia •• Lack of railing
•• Slow reaction time •• Uneven pavements
levels. Also in patients with homocystinuria due to metabolic •• Defective proprioception
defect there is early onset of osteoporosis. Elevated plasma Visual impairment:
homocysteine levels are associated with higher risk of •• Cataract
fracture, but not completely associated to low BMD. Low •• Glaucoma
vitamin B levels and higher homocysteine levels stimulate •• Retinal degeneration
Cognitive impairment:
osteoclasts, while inhibiting osteoblasts simultaneously •• Alzheimer’s disease
shifting bone metabolism toward resorption. In addition, •• Stroke
homocysteine inhibit the enzyme lysyl oxidase responsible •• Depression
for collagen cross-linking. These may explain the higher •• Deconditioning
than normal risk of fractures in osteoporosis with vitamin •• Previous falls and fear of falling
Hypoglycemia
B deficiency and raised homocysteine levels despite minor Postural hypotension
effects on BMD. Arrhythmia
Dehydration
Activity Levels Vitamin D deficiency
Anxiety and agitaion
Regular workouts and weight-bearing exercises improve Epilepsy
BMD in accordance with Wolff’s law. Disuse osteoporosis
is common in long-term immobilization, space travelers
and even absolute sedentary inactive population. However, fracture. Other morphological features that have also
athletes may develop premature osteoporosis due to been identified to independently predict fracture risk
excessive stress on bone beyond reparative capacity as (but are not commonly used due to availability of less
has been seen in marathon runners. In female athletes, cumbersome and more standardized measures) include
prolonged amenorrhea due to deranged hypothalamic- thickness of the femoral shaft and/or neck cortex
pituitary axis may contribute. (reduced thickness predicts fracture), tensile trabecular
index (reduced numbers or quantity predicts fracture)
Falls and width of trochanteric region (wider trochanter is
related to osteoporotic fracture). Femoral neck width or
Factors predisposing to falls are predictors of osteoporotic
neck/shaft angle do not have any correlation.
fractures not osteoporosis (Table 8). A fall in the last year
strongly independently predicts possibility of fall and
consequent fracture. CLINICAL PRESENTATION AND
Bone Morphology EVALUATION OF OSTEOPOROSIS
Bone geometry and variations by themselves also predict Awareness, knowledge and commitment are required to
fracture risk. manage this pandemic. The dismal part of medical care
•• Hip axis length (HAL) is positively correlated with hip is that only 20% of patients who had a previous fragility
fracture. It is defined as the distance from the greater fracture would receive treatment for osteoporosis ever. There
trochanter to the pelvic brim. With one point increment are no specific clinical signs or symptoms for osteoporosis.
in standard deviation of HAL, the risk of femoral neck Patients generally have nonspecific, nonlocalized and mild
and trochanter fracture nearly doubles. This implicates bone pains usually in central skeletal system that slowly
that tall thin women will be at highest risk of hip progress in intensity and distribution. The back pain is due

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72 Section 1:  Bone Anatomy, Physiology, Pathology and Diseases

to microfractures and ligament stretching and in late cases –– Brown tumor


due to iliocostal impingement from kyphotic deformity. –– Osteomyelitis.
Kyphosis is usually the earliest sign associated with loss
of height (Fig. 6). Loss of 2 inches in height sensitively Laboratory Tests
indicates vertebral compression. The number of missing
teeth has also been correlated with reduced BMD. All older These primarily help in evaluating or excluding secondary
persons should be evaluated for fall risk. They should be causes of osteoporosis and are never required for primary
observed as they stand up from chair without using arms evaluation or diagnosis. Protein electrophoresis and urine
and walk few steps and return (get up and go test). Those Bence-Jones proteins help in excluding multiple myeloma.
who have difficulty need assessment for fall circumstances, Serum calcium, phosphorus and parathyroid hormone
medications, medical problems, vision, gait and balance, (PTH) assay are useful to evaluate hyperparathyroidism
lower extremity evaluation (proprioception, reflexes), (high PTH and serum calcium) and are also advised
mobility tests, basic neurological function (cortical, before starting recombinant human parathyroid hormone
pyramidal and extrapyramidal, cerebellar), mental status (rhPTH) treatment. Serum calcium may be obtained
and cardiovascular functions. before giving zoledronic acid to exclude hypocalcemia
Differential diagnosis of osteoporosis: that may precipitate tetany. High calcium may be seen in
•• Vertebral deformity: metastasis, but PTH is normal to decreased. Renal panel
–– Osteomalacia is used to exclude renal impairment and dose adjustment
–– Paget’s of injectable bisphosphonates and homocysteine levels
–– Pott’s spine may be estimated for suspected homocystinuria. Thyroid-
–– Metastasis stimulating hormone (TSH), free T4, 24-hour free cortisol,
–– Myeloma free testosterone may be ordered to evaluate suspected
–– Traumatic fracture early in life endocrine pathology. Vitamin D deficiency is quite
–– Histiocytosis prevalent and levels can be estimated to initiate proper
•• Low-trauma fracture: treatment. It has been suggested that low levels of insulin-
–– Metastasis like growth factor I (IGF I) in women around 40 years
–– Myeloma of age could identify at-risk patients for low bone mass
–– Bone cyst and osteoporosis. Serum IGF I levels below 1.5 standard

Fig. 6: With osteoporosis there is gradual and progressive loss of height

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Chapter 3:  Metabolic Diseases of Bone and Effect of Glucocorticoid Therapy on Bone 73

deviation may indicate BMD measurement by dual-energy –– Finally they help to determine duration of “drug
X-ray absorptiometry (DEXA). holiday” and also as to when the medication should
be restarted.
Bone Turnover Markers
These give an assessment of dynamic aspects of skeletal
metabolism and can also be used to monitor the effectiveness
Analysis of the Bone Mineral Density
of instituted therapy. Finally, they also provide insight The BMD is measured predominantly at cancellous sites.
to evaluate fracture risk. The markers of bone formation The cancellous component of bone being highly metabolic
include (all serum markers) the procollagen I carboxyl is considered a more sensitive measure of estimating
and amino terminal propeptide (P1CP and P1NP), bone bone loss and regain. The bone transforms early and due
specific alkaline phosphatase (ALP) and serum osteocalcin to rapid turnover represents the disorders of metabolism
(bone Gla protein). The markers for bone resorption include early. Cortical bone loss on the other hand determines
plasma tartarate resistant acid phosphatase (TRAP), severity of bone loss (total accrued loss). The skeleton can
amino and carboxyl terminal telopeptide of type I collagen be subdivided into (for DEXA purposes) central (spine and
(COL1A1) (so-called serum sNTx and sCTx), cross-linked proximal femur) and peripheral (heel and forearm).
C-telopeptide of type 1 collagen (ICTP) and urinary Very importantly it should be understood that bone
N-telopeptide (uNTx), bone sialoprotein, urinary collagen mass testing (especially DEXA) is indicated only when the
[pyridinoline (uPYR) and deoxypyridinoline (uDPD)] cross- results will influence a treatment decision and should not be
links, urinary hydroxylysine glycosides, urinary calcium used as a business tool as is the common practice. Following
and hydroxyproline. Circulating microRNAs (miRNA) are are the recommendations for deciding who should undergo
being studied for their utility in identifying the patients with BMD analysis according to US FDA given in 1998.
osteoporosis. The miR-133a in circulating monocytes is a •• Estrogen deficient women at clinical risk of osteoporosis,
potential biomarker under evaluation and quantification especially for assessment of early postmenopausal
for postmenopausal osteoporosis. osteoporosis as an indication to start estrogen
Utility of bone markers: replacement therapy
•• These predict quite reliably the rapidity of bone loss in •• Radiological vertebral abnormalities that suggest diag-
untreated patients nosis of osteoporosis (osteopenia and vertebral fracture)
•• Bone markers may predict fracture risk in untreated •• Glucocorticoid treatment both quantity and duration of
patients (independent of BMD) treatment are important to this respect. Prednisolone
•• Bone markers can categorize an individual as having given in dose more than or equal to 7.5 mg for more
fast or slow bone turnover. Fracture risk is higher in the than 3 months places patient at high risk to developing
former. osteoporosis. Other high risk patients include prolonged
–– During treatment follow-up, reduction in markers amenorrhea, anorexia nervosa, alcoholism, atraumatic
of bone resorption indicate reduced bone fractures, etc.
turnover with antiresorptive therapy. This effect •• Primary hyperparathyroidism
is considered parallel to reduced fracture risk •• Monitoring response to an FDA approved medication
independent of changes in BMD. Specifically for osteoporosis
studies report that decreased urinary pyridinoline •• Repeat BMD evaluations at more than 23 months
and deoxypyridinoline cross-links after 6 months interval, or more frequently, if medically justified.
on alendronate therapy have been associated with It is recommended by the US Preventive Services Task
increases in BMD at the hip and spine after 2.5 years Force that routine screening for osteoporotic fractures
of treatment. could begin at age 60 for females at increased risk. The
–– Bone markers can be used as a check mechanism recommendations, however differ from other organizations,
on the patients on antiresorptive therapy. The viz. the International Society for Clinical Densitometry
compliance with antiresorptive therapies can be recommends BMD testing (2003) for all females who are
monitored by using these markers as minimal or no 65 years or older; all males aged 70 years or older; anyone
reduction in urinary N-telopeptide concentrations with a diagnosed fragility fracture; anyone with a disease,
suggest poor compliance, though this effect may also medical condition or on medication more than likely to
arise with impaired drug absorption that should be be associated with osteoporosis; anyone going to be put
considered. Urinary N-telopeptide of COL1A1 has on therapy for osteoporosis; and females taking HRT for
shown the most significant association between prolonged periods. I feel one can justifiably follow the
BMD and response to hormone replacement therapy current recommendations as provided by the national
(HRT). osteoporosis foundation (2014) that are detailed in Table 9.

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74 Section 1:  Bone Anatomy, Physiology, Pathology and Diseases

TABLE 9: Indications for BMD testing (NOF, 2014) An incident vertebral fracture is defined by McCloskey-
Kanis method as a minimum height decrease of 4.6 mm
Bone material density testing should be considered in following individu-
als: and a decrease of 15% in absolute height on a subsequent
•• Women aged 65 years and older, men aged 70 years and older, regard- film. The Singh index, classifies five different trabecular
less of clinical risk factors patterns in the hip. It correlates with histologic grading
•• Younger postmenopausal women, women in menopausal transition of the iliac crest, but has not been found to predict BMD
and men aged 50–69 years with clinical risk factors for fracture
of the proximal femur accurately. It has a low sensitivity,
•• Adults who have fracture at or after age 50
•• Adults with a condition (like rheumatoid arthritis) or taking a medica- but a relatively high specificity. Various other methods
tion (like glucocorticoids) associated with low bone mass or bone loss have also been proposed to predict the fracture risk and
include HAL (discussed above), reduced thickness of the
femoral shaft cortex, diminished index of tensile trabeculae
Conventional Radiography and Vertebral and wide trochanteric region or a combination of these
measurements.
Imaging
The current indications for vertebral imaging according to Spinal Deformity Index
NOF are provided in Table 10. Bone loss must exceed 30–40%
before it is visible by radiography so plain radiographs are It incorporates both number and severity of fractures by
insensitive method and due to wide variability in evaluation adding the severity grades of spine from T4 to L4 described
and non-standardization; often inaccurate (Figs 7A to C). on lateral spine radiographs. It was described by Minne, et
al. and Genant, et al. For each vertebra a semiquantitative
grade is assigned after visual evaluation. There are three
TABLE 10: Indications for vertebral imaging grades: (1) grade 1 is 20–25% decrease in vertebral height,
(2) grade 2 (moderate) is 25–40% reduction in height and
Vertebral imaging should be considered for following individuals:
•• All women aged 70 years or older and all men aged 80 years or older, if (3) grade 3 (severe) is more than or equal to 40% reduction
BMD t-score at the spine, total hip or femoral neck is < –1.0 in height, while grade 0 is normal vertebra (Figs 8A and B).
•• Women aged 65–69 and men aged 70–79, if BMD t-score at the spine, The scores are then added up for T4–L4 vertebrae. The spinal
total hip or femoral neck is < –1.5 deformity index (SDI) value ranges between 0 and 39, higher
•• Postmenopausal women and men age ≥ 50 years with specific risk
the SDI greater is chance of incident fracture. Appreciate the
factors:
■■ Low trauma fracture during adulthood (age 50 and older) osteopenia on a radiograph based on following patterns:
■■ Historical height loss of 1.5 inch or more (4 cm) •• Change in radiolucency: compare with adjacent soft
■■ Prospective height loss of 0.8 inch or more (2 cm) tissues, amount of trabeculation and overall estimate
■■ Recent or long-term ongoing glucocorticoid therapy of osteopenia.

A B
A C

Figs 7A to C: The (A) AP and (B) lateral view of spine and pelvis showing gross osteopenia and washed out appearance of bone with only
silhouette appearance. The vertebrae have biconcave appearance but no osteoporotic fracture is seen. (C) The radiograph shows multiple
osteoporotic fractures in spine falling into definition of severe osteoporosis (once BMD is done)

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Chapter 3:  Metabolic Diseases of Bone and Effect of Glucocorticoid Therapy on Bone 75

•• Change in trabecular pattern: increased vertical


striations and thin subchondral plate (superior and
inferior endplates)
•• Change in shape: normal difference in anterior
and posterior heights of vertebral body is taken
as 1–3 mm, a difference of more than or equal to
4 mm is abnormal. The shape changes could be
wedge-shaped compression, central compression or
pancake compression. Wedge compression is when
the posterior portion of body (central column) is
intact compared to burst fracture when both anterior
and posterior portions of body get compressed.
The biconcave pattern of vertebrae commonly
referred to as fish vertebrae resemble the normal
biconcave shape of vertebral body of fish (though
this is abnormal for humans). Fish vertebrae are seen
A B in osteoporosis, Paget’s disease, osteomalacia and
Figs 8A and B: (A) SDI—grade the vertebrae from T4 to L4 and add hyperparathyroidism.
the grades. This X-ray has osteoporotic “central wedge” fracture of
L1 with grade 2 deformity. L3 and L4 had been fused previously for Singh Index
unrelated disorder. (B) It is imperative to understand the fact that
“anterior wedging” may be seen even in normal spine even up to Based on the completeness and presence of tensile and
25% of the posterior body height as in 12th dorsal vertebra in this compressive trabeculae in proximal femur the index divides
asymptomatic patient femurs radiologically into six grades (Fig. 9):

Fig. 9: Singh’s index. Note the trabecular disposition in normal femur that gets progressively thinned and disappear sequentially with
progression of osteoporosis. Grade 6 is normal interestingly while the lower grade represent higher severity of the disease

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76 Section 1:  Bone Anatomy, Physiology, Pathology and Diseases

•• Grade 6: All normal trabecular groups are visible of healthy population (without any increased risk of
•• Grade 5: Prominent Ward triangle; principle tensile fracture, while reference from male population will
trabeculae attenuated, while principle compressive fallaciously put even some of normal females into
trabeculae normal. Attenuated secondary compressive. osteoporotic category). T-scores are used to both predict
Trochanteric trabeculae vanish fracture risk and classify disease status as in WHO
•• Grade 4: Marked reduction, but continuous tensile definition. This score was suggested to avoid confusion
trabeculae. Secondary compressive trabeculae lost between different BMD measurement technologies. The
•• Grade 3 (definite osteoporosis): Definite break in the score is calculated by the formula:
continuity of tensile trabeculae
mBMD − YN
•• Grade 2: primary tensile trabeculae remnants visible t = score =
along lateral cortex, rest vanish. Principal compressive SD
trabeculae present and prominent Where, mBMD is the measured bone density, YN is the
•• Grade 1: Attenuation of even principal compressive normal value from young population (reference) and SD is
trabeculae, essentially empty proximal femur. the standard deviation of young adult population.
Quantitatively, a change of 1 standard deviation in
Dual-energy X-ray Absorptiometry either the t-score or z-score corresponds to a change of
approximately 0.06 g/cm2 (about 10% BMD). DEXA can
Dual-energy X-ray absorptiometry involved very limited be used to measure bone mass at central (vertebral and
radiation exposure. It affords fast, reliable and accurate proximal femur) and peripheral sites, the choice of site(s)
measurement of bone mass so is commonly used in being primarily guided by the anticipated or expected rates
screening population and also defining osteoporosis of change in bone mass within these skeletal locations. The
according to WHO criteria. DEXA has replaced dual-photon choice is also influenced by precision of the testing device
and single X-ray absorptiometry and is now the most widely at these discrete sites. The central DEXA sites of the hip and
used bone mass measurement tool sort of becoming the spine are commonly preferred because it has:
currently gold standard for diagnosis, evaluation and follow- •• Higher precision
up of osteoporosis patients (discussed above in indications •• The quantity of trabecular bone at central sites is usually
of DEXA). Soft tissue radiation exposure and attenuation is indicative of the osteoporosis burden, and hence
compensated in DEXA by using a combination of high and fracture risk
low X-ray energies. Both pencil-beam and fan-beam (cone •• Bone loss begins early in the trabecular bone as it is
beam, C-arm) devices are currently in use. Pencil beam has highly metabolically active compared to cortical bone
less scatter, require less dose (≈1 µSv) and reduces operator and is predominant in central skeleton
or patient radiation compared to cone pencil-beam or fan- •• Ward’s triangle has lowest BMD, but is much less
beam systems, where the required dose is around 18 µSv. predictive or reproducible, so BMD at other locations
However, the fan-beam systems improve image quality and like the femoral neck (preferred), trochanter or total hip
possibly the accuracy of measurement also. DEXA gives a should be measured.
two-dimensional measure of BMD. It does not, however, Regular follow-up with serial DEXA scan to monitor
measure true volume density as with quantitative computed therapy is controversial. One school of thought recommends
tomography. Bone mass is reported as an absolute value in yearly scan, while others site benefits of osteoporosis
grams per square centimeter in DEXA and is then presented therapy beyond change in BMD and inability to discern
as t-score and z-score as defined below. true change by relative insensitivity of DEXA as precluding
•• Z-score compares patient’s value to an age-matched factors to its use. This is substantiated by the fact that
and sex-matched reference range. The z-score is of minimum 2.77% change in BMD is required between two
less clinical value and is used in young adults and successive DEXA studies to reach statistical significance
postmenopausal females less than 50 years of age, for estimating difference with 95% confidence (p < 0.05).
z-scores significantly deviating from normal may indicate Not only this, but the measured changed value needs to
an alternative cause of a metabolic bone disease. be multiplied by the “precision error” of the measuring
•• T-score is a comparison to mean bone mass of young device. If the device has a 2% precision error, a change in
adult normal individuals defined as healthy women BMD of about 5.6% is needed to substantiate BMD change
population 20–40 years of age. Thus, t-score may not by chance. Any clinician would know that no currently
be called young adult z-score. Women are chosen available modality would achieve this improvement by
specifically as they represent the lower normal values 1 year of treatment making repeat estimation futile.

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Chapter 3:  Metabolic Diseases of Bone and Effect of Glucocorticoid Therapy on Bone 77

Pitfalls in Dual-energy X-ray Absorptiometry computed tomography are newer variants with even better
Measurement analytic capability.
Osteoporosis though systemic occurs inhomogeneously
across the body with significant discordance between sites, Ultrasound
especially in the elderly. Imaging only one site may thus be
Quantitative ultrasound is an underutilized technique to
misleading. Osteophytes due to high prevalence of facet and
measure bone mass. It has advantages of portability, lower
posterior element spinal osteoarthritis in elderly may yield
cost, simple instrumentation and absence of ionizing
a falsely elevated bone mass in anteroposterior projection.
radiation. Ultrasound has distinct advantage of providing
This is circumvented by measurement of the spine BMD
additional information about bone quality that is not
in lateral projection or measuring hip DEXA. Lateral spine
possible with other methods. The typical measurements
scan is still limited in accuracy by soft tissue attenuation
include speed of sound (SOS) and broadband ultrasound
due to greater thickness and nonuniformity of soft tissues
attenuation (BUA). Stiffness or quantitative ultrasound index
in this projection.
is a combination of SOS and BUA, but it does not reflect a
biochemical property of bone so is ineffective. Ultrasound
Peripheral Dual-energy X-ray Absorptiometry
assessment is most commonly performed for calcaneus and
It is commonly used as a cheaper substitute or mass it has been found that validated heel ultrasound predicts
promotion for DEXA. It measures real bone density at vertebral, hip and overall fracture risk in postmenopausal
either forearm, finger or heel as per machine calibration. women and hip and nonvertebral fractures in men more
Measurement by validated peripheral DEXA (pDEXA) than or equal to 65 years. The advantages for calcaneus
devices can help predict vertebral and overall fracture risk ultrasound are that it has two nearly parallel sides and is
in postmenopausal women, but the prediction in men is not surrounded only by a thin layer of soft tissue minimizing
proven or supported. The radiation risk is trivial. It is not a errors. The calcaneus consists mainly of trabecular bone
good method to monitor BMD after therapy. and is easily accessible weight-bearing bone that reflects the
trabecular bone changes quite accurately. The fracture risk
Trabecular Bone Score doubles for 1-standard deviation reduction in BUA or SOS
when measured in standard conditions. The fall in BUA of
This is available in some densitometers. It measures the the calcaneus after menopause parallels the decrement in
microarchitectural structure of bone tissue and may vertebral BMD (related to complementary trabecular bone
improve the ability to predict the risk of fracture, the specific loss). In general, ultrasonic measurements of the calcaneus
role is, however, unknown due to non-standardization. are better for identifying patients with fracture of the hip
than of the spine. The limitations of ultrasound include
Quantitative Computed Tomography inferior precision of ultrasound measurements, changes
in ultrasonic properties of bone with age and slow rate of
Quantitative computed tomography (QCT) gives an accurate
bone mass change with treatment needing long intervals
assessment of fracture risk and measurement of bone loss,
for documentation.
but is seriously limited by radiation dose and running cost.
Quantitative magnetic resonance imaging (QMRI) and
QCT uses standard computed tomography scan machine
structural analysis are research tools only.
to measure volumetric integral, trabecular and cortical
bone density and gives a true three-dimensional view of Novel early detection techniques for osteoporosis: The
BMD. Its precision measurements are used to calibrate following are currently research based investigations, but
other modalities. QCT is best done for spine, but marrow may soon be available for early detection of osteoporosis.
fat increases with age and glucocorticoid use giving an The details are beyond the scope of current text and reader
overestimation for the extent of bone loss in these two can refer dedicated text for details.
clinical settings. pQCT (peripheral) is done at the forearm •• Bone fracture detection microsensor—assesses the
bones or tibia and high-resolution pQCT (HR-pQCT) mechanosensitivity of bone cell and stress in bone.
provides accurate and reproducible measures of bone Newer techniques study the brittleness of bone
architecture, volumetric density and microarchitecture. •• Microfluidic channels (uses biomarkers)—analyzes and
QCT measure of spine trabecular BMD predicts vertebral assesses total ALP
fractures in postmenopausal women, while pQCT of •• Biochemical based BioMEMS (Microelectromechanical
forearm and ultradistal radius predicts hip, but not vertebral system) chip—detects osteoprotegerin (OPG) based on
fractures. Volumetric computed tomography and extreme gold nanoparticles

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78 Section 1:  Bone Anatomy, Physiology, Pathology and Diseases

•• BioMEMS based sensors—uses electrochemical


immunoassay with microfluidic system to study ALP
•• Spectroscopic techniques:
–– Fourier transform infrared spectroscopy (FTIR)
–– Ultraviolet-visible spectroscopy (UV-Vis).

PREVENTION AND TREATMENT OF


OSTEOPOROSIS
Supportive Treatment for Fractured A B
Figs 10A and B: Shoulder arthroplasty
Patients: Pain Control and Bracing
Nonsteroidal anti-inflammatory medications, non-narcotic •• The rate of bone union is not affected by osteoporosis per
analgesics (paracetamol, tramadol, etc.), low dose tricyclic se, but due to old age the prolongation of healing process
antidepressants and other neurotropic agents (such as is possibly due to age related blunting of reactionary
carbamazepine and gabapentin) should be judiciously process. However, it is the implant holding strength that
used on individual basis. Localized nerve blocks can be influences stabilization of fracture and union. Implants
used in refractory situations. Transcutaneous electrical may fail as they have to maintain fracture for prolonged
nerve stimulation, fomentation of heat and cold, and the periods due to longer healing time and poor holding
use of therapeutic ultrasound have been variably suggested. strength. Locked screw plate constructs at variable angle
Calcitonin and some bisphosphonates have been suggested are preferable to dynamic compression plates (Figs 11A
to relieve pain from compression fracture, however, the to D). Absolute stability and lag screw techniques are
effect of calcitonin is weak and may not last long. Bracing not effective in osteoporotic bones. Focus should be
of the spine for osteoporosis pain control is commonly strain reduction by utilizing relative stability techniques.
prescribed despite lack of objective data on effectiveness. Providing wide buttress to juxta-articular fractures
Excessive reliance on bracing can adversely lead to
muscular weakness and loss of postural support. Weight-
bearing exercises are important elements of osteoporosis
management. Stress-induced or exercise-induced bone
mass improvement is most commonly seen in weight-
bearing sites such as the tibia (runners), and in the spine
(weight lifters). Spinal extension exercises are preferred
over flexion exercises as the latter may predispose to spinal
compression fractures and deformities.

Principles of Surgical Management of A B


Osteoporotic Fractures and Effect of
Pharmacotherapy
•• Manage not just the fracture, but the geriatric patient as
a whole, so balance the outcome of inflicting surgical
trauma on biology of body system
•• Quick and precise surgeries by expert in the field
are preferable. Also one should focus on modalities
that afford quickest mobilization, for example in
octogenarians with even minimally fracture of femoral
neck doing a quick hemiarthroplasty is beneficial over C D
screw fixation (Figs 10A and B). For relatively younger Figs 11A to D: (A and B) Proximal humeral locking plate. (C and D)
patients with osteoporosis total hip replacement would Bilateral proximal humerus fractures in a patient treated with proximal
be better humerus locking plate osteosynthesis

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Chapter 3:  Metabolic Diseases of Bone and Effect of Glucocorticoid Therapy on Bone 79

mechanical strength has been observed in animal


studies. Improved implant fixation and strength has
also been observed. As regards the concern on retarding
remodeling they have not been found to have any
adverse effect. Scheduling first dose is the controversy.
Oral drugs can be given at any time, however, delaying
by 3 weeks is considered better for compliance issues
and theoretical concern of formation and organization
of fracture callus. Injectable drugs should be preferably
delayed for 3–4 weeks or more or withheld (oral drugs
are preferable) as drugs like zoledronic acid have
localizing effect so they may concentrate at the fracture
site immediately after administration and systemic
advantages on other bones may be lowered till next
dose
A B C •• Teriparatide has not been shown to alter fracture healing
and although anabolic has also not been definitely
Figs 12A to C: (A) Patient with osteoporotic proximal femoral fracture.
The femur was treated with ORIF 20 years ago elsewhere for treatment
shown to improve fracture healing though the effect
of fracture of shaft. (B) The implant was removed and intramedullary is overall positive. Sclerostin and Dickkopf-1 (DKK1)
nailing with (C) reconstruction nail was done that led to complete antibodies (discussed below) have also been shown to
union have beneficial effect on fracture healing.

is also a good option rather than fixing the fracture Vertebroplasty and Kyphoplasty
fragment
•• Plating is beneficial at juxta-articular and intra-
(Discussed in Chapter Vertebra Plana)
articular fractures, however, for diaphyseal fractures Impregnation of polymethyl methacrylate into the vertebral
intramedullary nailing should be preferred (Figs 12A body (vertebroplasty) provides improved pain relief and
to C) for biology preservation, dynamic load sharing, rehabilitation (Fig. 13). The dreaded complications of
relative stability and less invasive nature vertebroplasty are extradural extravasation of bone cement
•• Augmentation with bone cement to improve screw that would cause neurological compromise and formation
purchase at trabecular bone (delta bolt for hip, of cement emboli that may migrate in the spinal canal.
cannulated screws with side openings for humerus,
femoral condyle and vertebrae) could be considered
to improve strength of fixation. Hydroxyapatite coated
implants with deliverable growth factors, like bone
morphogenetic proteins (BMP), TGF-β could provide
improved fixation in future
•• Some people prefer intramedullary fibula graft to
improve screw purchase, but the published literature
on this method is scanty
•• Comminuted fractures at metaphyseal or periarticular
regions could be better managed by arthroplasty,
for example proximal humerus and proximal femur.
Pharmacotherapy in surgery: Bisphosphonates and
anabolic therapy—patients on bisphosphonates can
definitely undergo fracture fixation. The question is
for those patients who are osteoporotic and identified
with a fracture. Though bisphosphonates suppress bone
resorption, and hence the coupled process of bone
formation, but they have not been primarily found to
alter the rate of fracture healing. Increased callus size
and mineralization, reduced remodeling and improved Fig. 13 : Vertebroplasty

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80 Section 1:  Bone Anatomy, Physiology, Pathology and Diseases

Kyphoplasty is considered to be a more effective procedure •• Pedicle is localized under fluoroscopy


as it involves inflating a balloon inside the vertebra restoring •• After making stab incision, 11-gauge biopsy needle
vertebral height and then bone cement is injected into the is advanced into the fractured vertebral body by
balloon. This potentially ameliorates cement extravasations. transpedicular approach
Pain relief is prompt and lasting, however, there are •• Working cannula is introduced and needle is removed
concerns of compression fractures of adjacent vertebrae •• Inflatable balloon tamp is introduced under the
and cost with kyphoplasty. collapsed end plate
Balloon kyphoplasty can be performed by orthopedic •• Balloon tamps are then inflated under fluoroscopic control
surgeon or interventional radiologist. The majority of measuring the pressure through inbuilt manometer
vertebral osteoporotic compression fracture occurs at •• Maximum fracture reduction is achieved and inflation
the thoracolumbar junction. The primary indications for is stopped when the balloon reaches the cortical wall or
balloon kyphoplasty are: one obtains the “balloon kissing” position (two balloons
•• Painful fractures with a back pain score of 4 points or introduced through each pedicle touching each other in
more on a 0–10 scale not responding to conservative the vertebral body center)
treatment for 6 weeks •• Cement is prepared and loaded in syringes
•• Compression fracture due to osteoporosis (primary or •• At semisolid state (3–5 min after mixing, depends on
secondary), osteolytic metastatic tumors (D5-L5 levels), product), the cement is introduced carefully under
multiple myeloma fluoroscopy control
•• Junctional lesions: “Adjacent vertebra” of a fractured •• At cement setting the cannula is removed and wound
and treated one at the level of D12 or L1 in severely closed.
osteoporotic patient, older than 75 years of age with Complications of balloon kyphoplasty procedure:
good Karnofsky performance status score (> 70). This is •• Minor—transient bradycardia and desaturation are
preventive treatment as it has been found that at D12-L1 most common
level if one of the vertebra is treated then the other one •• Serious—cement pulmonary embolus (0.01–1%),
shows a fracture within 18 months. extravasation to epidural space (7–10%). To prevent the
Contraindications for balloon kyphoplasty: latter one should push cement only when it is semisolid
•• Age less than 21 years and cannula should be removed in a rotating maneuver
•• Previous vertebroplasty of the same vertebra slowly.
•• Pedicular fracture
•• Severe disease: Reduction of Risk Factors and Nutritional
–– Radicular pain Modifications
–– Neurological deficit Risk reduction: Patient education is primary mechanism to
–– Evident spinal cord compression modify the environmental factors at home and elsewhere.
•• Patients on uninterruptible anticoagulation therapy Thorough review of the medications should be made and
•• Allergy to any of kyphoplasty instrumentation necessary adjustments made. Identification of hypogonadal
•• Nonambulatory before fracture state and thyrotoxicosis by laboratory tests, orthostatic
•• Fractures due to primary bone tumors, osteoblastic hypotension by clinical methods and treatment of visual
metastasis and high energy trauma. impairment are some of the key measures. It is imperative
Principles of procedure: The procedure is performed as to encouraging patients to quit smoking and limiting alcohol
short admission of 24 hours. The success relies on regular intake.
expansion of the vertebral body that can be stabilized by
intraosseous cement. Injection pressure and the cement CALCIUM, VITAMIN D AND
viscosity are hence the most important parameters. It has
been identified that higher viscosity and lower injection MINERALS
pressures are important for uniform expansion of the bone Calcium alone may somewhat reduce, but not fully
and optimal filling. prevent bone loss. Calcium may be most beneficial for
postmenopausal and elderly women. Despite unclear
Operative Technique mechanism of benefit, several controlled clinical trials of
•• The surgery is done under local anesthesia. The patient treatment with calcium given concomitantly with vitamin D
lies prone and best worked under O-arm or two C-arms have documented decrease in osteoporosis related fractures
to give continuous anteroposterior and lateral views (20–30% risk reduction). Bone loss in men is not modified

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Chapter 3:  Metabolic Diseases of Bone and Effect of Glucocorticoid Therapy on Bone 81

or controlled by calcium and vitamin D intake significantly, cirrhosis of liver and postmenopausal osteoporosis.
however. The choice of supplementing patient with calcium Patients are rarely, if ever deficient in magnesium due
and vitamin D is more empirical than definitive as all recent to its high availability in diet, but some patients with
studies of effect of various pharmacologic agents on fragility malabsorption syndrome may need supplementation.
fractures have been conducted with supplementation of Phytoestrogens derived primarily from soy products and
calcium and vitamin D replacement. Thus, it is standard legumes have recently gained interest available in various
practice to ensure an adequate calcium and vitamin D ayurvedic preparations and have shown beneficial effects
intake in patients with osteoporosis irrespective of other for improving BMD. Of the various plant extracts studied, a
anti-osteoporosis treatment. There has been an oft-repeated natural isoflavone genistein has been found to reduce bone
question of impact of calcium supplementation on stone resorption, while simultaneously increase bone formation
formation in urinary tract. In patients with a history of in postmenopausal women. Zinc, copper, manganese and
nephroureterolithiasis, it has been found that high intake boron have trophic influence on osteoblasts and collagen
of dietary calcium reduces the risk of stone formation so could be included in various preparations though strong
marginally, whereas intake of high doses of supplemental evidence of clinical effect is lacking.
calcium may modestly increase risk (weak relation). Dietary
Pharmacotherapy and biological agents: The various class
calcium exerts its beneficial effects by binding to oxalate,
of medicines used for treatment of osteoporosis act at
and hence preventing the formation or precipitation of
different stages of intercellular interaction for their effect
calcium oxalate—a primary ingredient in most renal stones.
(Fig. 14). The usage of the specific drugs should be expertly
It is recommended that these patients (positive history
advocated for different patients. In general, the indication
of renal stones) should be evaluated by 24-hour urinary
of pharmacotherapy, various class of drugs, their pros
calcium determination before starting supplementary
and cons are provided below. The drugs basically fall into
calcium to avoid hypercalciuria. The recommended daily
antiresorptive and anabolic groups with a few having
dosage of elemental calcium is:
overlapping functions also.
•• 1,200–1,500 mg/day in postmenopausal women not
Postmenopausal women and men aged more than or
on HRT
equal to 50 years with following clinical features have been
•• 1,000–1,200 mg/day in premenopausal women, men
indicated to undergo pharmacotherapy as recommended
and postmenopausal women on HRT.
by the NOF:
The role of vitamin D is more obscure. Studies failed to
•• Hip or vertebral fracture
show beneficial effects of vitamin D on osteoporosis related
•• Other prior fractures and low bone mass (t-score
fractures. Also, the hypercalciuria and hypercalcemia
between –1.0 and –2.5 at the femoral neck, hip and
associated with vitamin D preparations limits their
spine)
routine use (not to mention they are still used as essential
•• T-score less than or equal to 2.5 at the femoral neck,
supplementation without documented indication in most
hip or spine after appropriate evaluation to exclude
prescriptions). If calcitriol is used in proper indications,
secondary causes
it is important to reduce calcium supplementation. The
•• Low bone mass (t-score between –1.0 and –2.5
current recommendation stands at supplementing 600–
at the femoral neck, hip or spine) and secondary
800 IU of vitamin D3 per day for older adults with discrete
causes associated with high risk of fracture (such as
indications. It has been, however, my experience that
glucocorticoid use or immobilization)
creating iatrogenic vitamin D toxicity is quite uncommon
despite irrational use. Individuals with documented
vitamin D deficiency should be supplemented with higher
doses of vitamin D.
Vitamin K supplementation has been shown to improve
BMD possibly due to role in carboxylation of osteocalcin.
Vitamin K2 (menaquinone) itself includes many types of
vitamin K2. Menaquinone-4 (MK-4) and menaquinone-7
(MK-7) are most studied as pertinent for osteoporosis.
Vitamin K1 in the testes, pancreas and arterial walls is
converted to MK-4. MK-4 has been approved for the
prevention and treatment of osteoporosis as it has been
shown to reduce fracture risk by 87%. MK-4 also prevents Fig. 14: The interaction of various bone cells and typical sites of action
bone loss and fractures caused by steroid therapy, anorexia, of chief class of drugs commonly used in treatment of osteoporosis

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82 Section 1:  Bone Anatomy, Physiology, Pathology and Diseases

•• 10-year probability of hip fracture more than or equal increased risk for breast cancer. In addition to a fracture
to 3% or a 10-year probability of any major osteoporosis benefit, estrogen lowers the risk of colorectal cancer by 24%
related fracture more than or equal to 20% based on and reduces mental stress, estrogen plus progestin however
FRAX. increases probable dementia. Addition of progesterone
Some specific risk factors have been elucidated by NOF (HRT) diminishes the increased risk of endometrial cancer
that should be looked in a patient who is considered a likely and cardiovascular events, but increases possibility of
candidate for osteoporotic fracture. These include: developing breast cancer and might also partially blunt
•• History of fracture (especially vertebral body) as an adult the already modest benefit of estrogen on bone. High dose
•• First-degree relative sustaining any fragility fracture estrogens are not a preferred initial pharmacotherapy for
•• Low body weight (< 127 pounds) osteoporosis and also there are issues of compliance. HRT
•• Current smoker may have a role in postmenopausal women in combination
•• Glucocorticoid use for more than 3 months therapy with bisphosphonates.
•• Visual impairment
•• Dementia Selective Estrogen Receptor Modulators
•• Poor health and morbidities
Tamoxifene is the first generation selective estrogen
•• Estrogen deficiency in late adulthood (before age 45 in receptor modulator (SERM), but not indicated or preferred
females) for treatment or prevention of osteoporosis. Raloxifene
•• History of recent falls suggesting poor balance (second generation SERM) is a benzothiopene derivative
•• Poor or inadequate calcium intake (lifelong) with estrogenic effects on the skeleton and lipid profile
•• Restricted physical activity especially in early years of and anti-estrogenic effects on the breast and uterus. It has
life that changes to sedentary work later been shown to lower the biochemical markers of bone
•• Alcohol intake more than 2 drinks per day. remodeling and it also increases lumbar spine BMD. It
also reduces LDLs, total cholesterol and triglycerides
ESTROGEN while raising HDLs. Raloxifene therapy for 4 years appear
to reduce cardiovascular events in higher risk women as
Now largely historical only, FDA has withdrawn the approval against estrogen therapy. Important drawbacks to use of
of hormone replacement with estrogen for osteoporosis raloxifene, however, are its relative inefficiency to reduce
prevention, except in selected cases of postmenopausal fracture risk at nonvertebral sites and that the beneficial
osteoporosis. Estrogen replacement therapy (ORT) effects of raloxifene on BMD dissipate after withdrawal. It
historically has been commonly used in postmenopausal reduces the risk of invasive breast cancer, however, there is a
women to prevent osteoporosis based on the premises roughly threefold increased risk of deep venous thrombosis.
that there is accelerated bone loss in postmenopausal Arzoxifene development has been withdrawn by Lily though
women. ORT improves bone mass through receptors on it met primary end points of reduction in vertebral fractures
osteoclasts lowering bone turnover and resorption. ORT and breast cancer, but failed to meet the secondary end
is most effective in decreasing bone loss when initiated points of reduction in nonvertebral fractures. Bazedoxifene
soon after menopause and used continuously. There is (third-generation non-steroidal, indole based SERM) is
increased lumbar spine BMD of 1–4% at 1 year in women approved in Europe for treatment of postmenopausal
receiving conjugated estrogen at 3.0–0.625 mg/day in osteoporosis and may have a beneficial role in dyspareunia
combination with calcium. Compared to other available and painful sexual intercourse. Lasofoxifene is potent
agents the effect is however modest. ORT raises high-density third-generation SERM (naphthalene derivative) with good
lipoproteins (HDLs) and lowers low-density lipids (LDLs) oral bioavailability and higher potency. It is different from
to the extent of 10% in postmenopausal women, however, first-generation (raloxifene and tamoxifen) and second-
there has been an increase in coronary heart disease (CHD) generation (clomiphene or idoxifene) SERMs. Lasofoxifene
and thromboembolic events in the first 2 years of therapy. specifically binds to human ERα (similar to other SERMs)
Venous thromboembolic events are 2.7–4.0 times more with high affinity (10 times higher than raloxifene). It
common among estrogen users than among nonusers. has been found to reduce the bone turnover markers
In heart and estrogen or progesterone replacement study significantly as well as the symptoms of dyspareunia and
(HERS), some of the women were hypercoagulable, vaginal atrophy.
manifest by prothrombotic gene mutations. There are The combination of raloxifene with alendronate result
also important concerns like hyperplasia of endometrium in greater increase in BMD, but the effect on fracture
(potentially leading to endometrial cancer), and an prevention is unknown.

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Chapter 3:  Metabolic Diseases of Bone and Effect of Glucocorticoid Therapy on Bone 83

Calcitonin Pharmacokinetics and Dynamics


Calcitonin is a naturally occurring peptide hormone Bisphosphonates are sparingly absorbed and only 1% of the
produced by the parafollicular C cells of thyroid gland and administered dose enters circulation. If taken along with a
it directly inhibits osteoclasts. The antiresorptive effects divalent cation the absorption will be completely blocked.
are however mild. A synthetic preparation—the Salmon So, they must be taken on an empty stomach to maximize
calcitonin is 40–50 times more potent than human calcitonin absorption. To reduce gastrointestinal irritation and
and has also the longest half-life amongst all synthetic maximize absorption, the pills should be swallowed with 250
preparations. Salmon calcitonin can be administered either mL of water on an empty stomach, remaining upright for 30
subcutaneously or intranasally (preferred) in a dose of 200 min (60 min for ibandronate) after swallowing the tablet, and
IU daily. It is recommended that calcitonin should always having nothing to eat or drink for 30 min (60 min for monthly
be administered with adequate calcium (at least 1 g) and ibandronate) after ingesting each pill. Of the absorbed
vitamin D (400 IU/day). The clinical effects of intranasal amount, 50% binds to bone and rest is excreted by kidney
calcitonin have been reported to be modest only and it is unchanged. The bisphosphonates are not metabolized in
unsure as to whether they represent the effect of drug of the body due to unfamiliar and strong P-C-P linkage. The
supplemental calcium. Long-term administration leads to phosphonate groups serve two functions. Firstly, they are
development of calcitonin-specific antibodies. Neutralizing required both for binding to bone mineral for executing
antibodies may retard the long-term effects of this agent. cell-mediated antiresorptive activity. Secondly, varying
Interestingly, many studies have reported analgesic effect the R2 substituents result in differences in antiresorptive
for acute compression fracture pain. potency of several orders of magnitude (Fig. 15), while the
R1 side chain substituents (hydroxyl or amino) enhance
chemisorption to mineral. Although plasma half-life is short,
Bisphosphonates 30–180 min, once incorporated into bone they can remain
They are the current first line drugs for prevention and bound to exposed hydroxyapatite crystals and active for up to
treatment of osteoporosis. The bisphosphonates are 10 years (property conferred by R1 side chain). The variations
analogs of pyrophosphates (P-O-P) characterized by a in efficacy and potency are determined by the structure of
phosphorus-carbon-phosphorus bond (so, P-C-P instead the amino side chains (Table 11).
of P-O-P). They evolved from industrial use (the textile
and oil industries) where it was used as an antiscaling and
anticorrosive agent for over a century. They have the basic
property of inhibiting precipitation of calcium carbonate.
The medical use initiated with the identification of naturally
occurring polyphosphate (inorganic pyrophosphate) in
urine and plasma that prevent calcification of tissues and
stone formation by Fleisch et al. This pyrophosphate (PPi)
is a known by-product of many biosynthetic reactions in
the body and its concentration is regulated by hydrolytic
enzymes predominantly the ALP. Deficiency of ALP as in
hypophosphatasia is associated with increased PPi and
mineralization defects. The elementary problem with the
use of synthetic pyrophosphates and polyphosphates was
Fig. 15: Bisphosphonate structure
that they were effective only when injected and ineffective
orally due to hydrolysis in gastrointestinal tract (GIT). TABLE 11: Antiresorptive potency of different bisphosphonates
It was during this search for stable pyrophosphates that
Drug Relative potency
attention got diverted to bisphosphonates (wrongly called
Etidronate 1
diphosphonates) that had good osseous affinity and prevent
calcification both in vitro and in vivo. The carbon atom Clodronate 10
connecting the two phosphate atoms (P-C-P) imparts them Tiludronate 10
stability from chemical and enzymatic hydrolysis. Their Pamidronate 100
clinical use, however, began only with the identification Alendronate 1000
of their unique property of inhibiting dissolution of Risedronate 5000
hydroxyapatite crystals. Bisphosphonates are potent Ibandronate 10000
inhibitors of bone resorption. Zoledronate 100000

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84 Section 1:  Bone Anatomy, Physiology, Pathology and Diseases

Fig. 16: Mechanism of action of bisphosphonates

Classification and Mechanism of Action leading to cytoskeletal alterations, disappearance of


ruffled border and premature osteoclast cell death,
Bisphosphonates can be classified into two groups
via apoptosis. Inhibition of this enzyme interferes
regarding their routes of administration—oral (alendronate,
with the prenylation (a process of addition of 15- and
risedronate and tiludronate) or intravenous (pamidronate
20-carbon side chains that anchor GTP-binding proteins
and zoledronic acid) or both (ibandronate and clodronate).
to osteoclast cell membrane). This reduces not only
The other classification divides them based on the presence
the resorptive capacity of osteoclasts, but also induces
or absence of nitrogen.
apoptosis.
There are two basic categories of bisphosphonates:
1. The non-nitrogen-containing bisphosphonates, for
example clodronate, etidronate and tiludronate—they
are metabolized in the cell to compounds that replace
the terminal pyrophosphate moiety of adenosine
triphosphate (ATP), and thus get incorporated into
intracellular analogs of ATP directly. They inhibit
osteoclastic activity by producing toxic analogs of ATP
(that competes with natural ATP) and cause cell death
(thus, apoptosis is the primary effect).
2. The nitrogen-containing bisphosphonates (alendronate,
neridronate, olpadronate, pamidronate, risedronate,
ibandronate and zoledronate)—they inhibit the
prenylation and function of (GTP) guanosine
triphosphate-binding proteins required for osteoclast
formation, function and sur vival (osteoclast
dysregulation is primary effect). They alter cholesterol
metabolism in osteoclast by inhibiting the enzyme Fig. 17: The overall effect of prolonged administration of
farnesyl diphosphate synthase (Figs 16 and 17), bisphosphonates

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Chapter 3:  Metabolic Diseases of Bone and Effect of Glucocorticoid Therapy on Bone 85

The main effect of bisphosphonates, be it of any group, contraception. Achalasia and esophageal strictures are
is to reduce bone resorption and bone turnover, required absolute contraindications to oral bisphosphonate therapy.
for treatment of osteoporosis. The secondary effects are Clinical uses (General uses are also mentioned here to
reduction of angiogenesis by depression of blood flow utilize the opportunity to describe them):
and a significant reduction in vascular endothelial growth •• Osteogenesis imperfecta: Quite significantly it has been
factor (VEGF). Inhibition of epithelial keratinocytes is also demonstrated that the bone strength is improved by
observed. The net effect of these actions is reduced healing administration of bisphosphonates and it constitutes
capacity and the bone sort of becomes metabolically an important therapy in this disease irrespective of age
inactive (metabolic freeze). They reduce the recruitment or clinical presentation.
and activity of osteoclasts reducing their lifespan. The rank •• Osteoporosis: Second-generation bisphosphonate
order of potency for inhibiting farnesyl pyrophosphate alendronate was the first aminobisphosphonate
synthase is zoledronate > risedronate > ibandronate > approved by the US FDA for the treatment and
alendronate (Table 11), with the more potent heterocyclic prevention of osteoporosis. Alendronate inhibits
bisphosphonates (zoledronate and risedronate), being bone resorption without much deleterious effects
more potent than the compounds with an alkyl side chain on mineralization. Spinal BMD shows continuous
(alendronate and ibandronate) though this does not have improvement after alendronate therapy up to 7 years
equivalent bearing on the antiresorptive capacity. Over of daily therapy. A once-weekly dosing is most popular,
prolonged administration, a regional paracrine effect of but has been randomly decided. Risedronate is a third-
continuously deposited and recycled bisphosphonates generation pyridinyl bisphosphonate with somewhat
may have persistent effect seen on discontinuation of inferior antiresorptive effect compared to alendronate,
medication. Bisphosphonates with higher mineral binding but similar fracture reduction efficacy. Tiludronate
affinity, such as alendronate and zoledronate, are associated is ineffective when administered intermittently.
with greater reduction of bone turnover and have a longer Zoledronate (third-generation bisphosphonate) has
duration of effect after treatment is stopped as conferred by highest potency and very good efficacy similar to or
R1 side chain (Fig. 18). Bisphosphonates with lower mineral better than alendronate. It is given as a yearly injection.
binding affinity, such as risedronate and etidronate are less Ibandronate is effective in reducing fracture risk at
effective and their effect is more readily reversible when vertebral sites, however, nonvertebral fracture reduction
therapy is stopped. Though unclear and not identified, but is not as good. Alendronate, risedronate and zoledronate
they may also have additional unrecognized anabolic effects have been shown to be effective at both vertebral and
which would correlate to the findings of persistent increase nonvertebral sites (predominantly hip). Bisphosphonate
in BMD realized even beyond stopping the drug after first therapy acts by various mechanisms (discussed above)
year of therapy. that primarily lower activation frequency slowing the
They should be used cautiously in patients with deterioration in bone architecture. Bisphosphonates
chronic kidney disease. They are not recommended in cause bone metabolic freeze reducing bone turnover,
women of childbearing age who are not using adequate of which there is an earlier decrease in bone resorption
than bone formation improving bone strength. The
magnitude of response depends on the type and route
of administration of the drug. The increase in BMD
results from filling in of the remodeling space, and hence
relative increase in mineralization of bone tissue. When
associated with biological effects and improvement in the
bone quality there is also reduction in fracture risk. The
effect is more marked in postmenopausal women with
osteoporosis. Despite wide usage of the drug there is still
uncertainty about the optimum duration of treatment of
antiresorptive therapy and treatment holidays (if any).
The other questions that cannot be definitely answered
are how best to combine bisphosphonates with anabolic
treatments and if there are any benefits of treatment in
patients who do not have a BMD T-score below −2.5.
Fig. 18: Mechanism of action of strontium ranelate (SR) in •• Hypercalcemia of malignancy and antiresorptive effect
osteoporosis in cancer patients: Bisphosphonates are the drug of

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86 Section 1:  Bone Anatomy, Physiology, Pathology and Diseases

choice for all patients with multiple myeloma and Adverse effects:
radiologically confirmed bone metastases from breast •• Approximately 30% of the patients experience influenza-
cancer. Bisphosphonates are to be started in these cases like illness (pyrexia, chills, myalgia and arthralgia)
immediately as soon as the diagnosis is made and are that tend to resolve within 3–7 days. Treatment with
continued indefinitely. Other bone metastasis should acetaminophen is sufficient for concerned patients and
also be treated with bisphosphonates when appropriate. symptomatic relief.
The effects of bisphosphonates have been two-fold: •• Ocular inflammation: Conjunctivitis, uveitis, iritis,
–– Reducing pain episcleritis and scleritis occur in less than 1%. Treat
–– Prevention of pathological fractures. It should be with corticosteroids and avoid use, especially of the
remembered that they are approved only for cancer intravenous agents.
with metastasis. •• Gastrointestinal adverse effects: Gastritis, esophageal
•• Paget’s disease of bone: Interestingly, the antiresorptive ulceration, etc.
effect of bisphosphonates was first demonstrated in •• Atrial fibrillation: Though with unknown mechanism
Paget’s disease. Use of bisphosphonates showed dose the bisphosphonates have been shown to induce atrial
dependent inhibition of bone resorption, and hence fibrillation.
remodeling. As good efficacy has been established since •• Bone joint and muscle pains: Shift to lower potency
1980s the treatment with bisphosphonate class of drugs bisphosphonate and give supportive care.
for Paget’s disease is currently the preferred modality. •• Bisphosphonate-related osteonecrosis of the jaws
The primary drug used for the treatment of Paget’s (BRONJ): Osteonecrosis of jaw (ONJ) now better called
has been alendronate, intravenous. Palmidronate painful exposure of mandible and maxilla has been
(preferred), oral residronate and tiludronate usually mainly reported in cancer patients receiving intravenous
along with calcitonin. preparations and very rarely from patients on oral
•• Pediatric uses: therapy. Bisphosphonates produce osteopetrosis like
–– Fibrous dysplasia and McCune-Albright syndrome: picture (“freeze” the skeleton) that leads to osteonecrosis.
R a d i o l o g i c a l i m p rov e m e n t h a s n o t b e e n Injectable bisphosphonates inhibit neoangiogenesis
demonstrated, but pain relief has been reported by and inhibit VEGF induced vessel sprouting leading
most patients. Definitive role is not known to avascular necrosis. Also, bisphosphonates get
–– Perthes disease: Studies have been sparse, but concentrated in the jaws as teeth need continuous
there is a suggestion that possibly they may restrict remodeling at sockets. Inhibition of osteoclast activity
deformation of the head and collapse similar to inhibits the remodeling and bone is not resorbed. This
osteonecrosis inhibits new osteoblasts to come and the resident cells
–– Osteoporosis in children: Primary osteoporosis die as they have limited life (150 days for osteoblasts
is unknown, but secondary osteoporosis does and osteoclasts). The osteon, hence, become necrotic
respond to the effects of bisphosphonates. It reduces and the vessels involute causing osteonecrosis. Patients
occurrence of fractures and increase BMD. should undergo dental checkup before initiation of
•• Other uses: the therapy as dental infection has been linked to
–– Postsurgical: In enhancing implant fixation development of ONJ and all required dental procedures
–– Prevention of bone collapse in osteonecrosis at should be completed before bisphosphonate therapy.
various sites, but commonly used at hip joint Treatment by debridement and coverage by flap have
–– “Bone scanning”: Bisphosphonates by virtue of their been all ineffective including hyperbaric oxygen. These
strong affinity for bone mineral get accumulated patients have to live with exposed bone sadly as of now.
at sites of increased bone turnover acting as bone •• Atypical insufficiency fractures: These have been found
scanning agents. Also, their ability to be linked to to occur at sacrum, femoral shaft and proximal femur
a gamma-emitting technetium isotope serves an (more likely bilateral). Lot of reports have creeped up
important advantage for detecting bone metastasis mentioning “atypical” fractures associated with the
and other bone lesions long-term use of bisphosphonates. A task force was
–– Prevent heterotopic ossification following hip created by American Society for Bone and Mineral
replacement surgery Research (ASBMR) to identify and categorize these
–– Treatment for calcification in renal failure and fractures and address key questions associated with
vascular disease. their finding. They defined major and minor features of
•• Pamidronate has been used most commonly for the incomplete and complete atypical femoral fractures and
treatment of lytic bone metastases, Paget’s disease and recommended the following major features (all should
osteogenesis imperfecta. be present to call a fracture as “atypical”):

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Chapter 3:  Metabolic Diseases of Bone and Effect of Glucocorticoid Therapy on Bone 87

–– Location in the subtrochanteric region and femoral raloxifene. The specific advantage is that alendronate
shaft can diminish the loss of BMD seen after stopping HRT.
–– Transverse or short oblique orientation •• Current recommendation is to start antiresorptive
–– Minimal or no associated trauma drugs, such as bisphosphonates as first line agents for
–– A medial spike when the fracture is complete reducing fracture risk in patients with osteoporosis. In
–– Absence of comminution. patients with severe osteoporosis (that have enhanced
The minor features include: risk of fracture during antiresorptive therapy), starting
–– Cortical thickening anabolic agents is recommended. This is based on the
–– A periosteal reaction of the lateral cortex strategy that starting with a bone anabolic substance
–– Prodromal pain (like teriparatide) at early stages of osteoporosis and
–– Bilaterality sealing the benefit with antiresorptive agent could first
–– Delayed healing improve the bone mass rapidly, while keeping bone
–– Comorbid conditions microarchitecture intact (or better). Such combination
–– Concomitant drug use, including bisphosphonates studies are underway.
or other antiresorptive agents, glucocorticoids and
proton pump inhibitors. Thiazide Diuretics
Bisphosphonate-induced subtrochanteric fractures are
a serious complication. Due to the bone “freezing” effect Low dose thiazide diuretics reduce calcium excretion and
of bisphosphonates the microcrack keep accumulating lead to a significant increase in BMD. They have adverse
in the bone and do not get repaired for absence of effects on lipid profile and can cause electrolyte imbalance.
remodeling. These are low turnover fractures due to Compliance is poor due to intolerable side effects by
reduction in bone remodeling induced by long-term the normotensive patient and with their relatively weak
bisphosphonate therapy. The stress fractures develop effects on bone in nonhypercalciuric patients, they are not
over time on the tensile side of femur (lateral cortex). commonly prescribed.
Such fractures typically accumulate in the dense cortical
bone. Subtrochanteric region of femur near isthmus Receptor Activator of Nuclear Factor
contains highest percentage of compact bone so gets
weakened enough to fail under repeated stress. These are Kappa-B Ligand Inhibitors
transverse fractures without thickening of the cortices Denosumab (AMG 162) is a recombinant human
(stress fractures usually have thickened cortex). The risk immunoglobulin G2 (IgG2) antibody functionally similar
to fracture reduces rapidly as the treatment with drug to OPG with affinity and specificity for RANKL (Fig. 19).
is discontinued. This suggests that a process other than Denosumab inhibits the RANKL/RANK formation on
inhibition of remodeling is involved. A causal association the osteoblast, and hence preventing the osteoblast-
between bisphosphonates and atypical fractures has not
been established. However, recent observations imply
that the risk rises with increasing treatment duration.
Bisphosphonate are known to accumulate at the fracture
site so continued dosing leads to inhibition of repair of
microfractures. However, with drug withdrawal and no
new drug available for binding further new fractures, if
any will heal in standard way. The tendency to unite after
fixation is also subdued having high chances of delayed
or nonunion, if treatment is continued. The fractures are
treated in a standard way as for shaft femur fracture with
strict withholding of the drug.
Combination approaches to osteoporosis therapy are
constantly emerging:
•• Alendronate is superior to ORT and combination
therapy of both is better than either therapy alone. This
additive effect is more prominently seen for those on
ORT when alendronate is added later. The effect is also Fig. 19: RANKL inhibitor prevent stimulation and proliferation of
seen for patients in whom alendronate is combined with osteoclasts, inhibiting bone resorption

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88 Section 1:  Bone Anatomy, Physiology, Pathology and Diseases

osteoclast interaction decreasing bone resorption. One postmenopausal women at high risk of fracture. The other
might recall that RANKL produced by osteocytes and indication is treatment of steroid-induced osteoporosis
osteoblasts regulate osteoclast number and activity. The (approved in 2009). The “high risk” has been defined by the
effect is an increase in bone mass and strength in both Hodsman et al. proposed criteria as follows:
cortical and trabecular bone primarily by antiresorptive •• Preexisting osteoporotic fractures
action and minimal, if any anabolic effect (it is hence not •• Very low bone density (T-score < –3.5)
an anabolic agent). Suppression of bone resorption is •• Above and/or an unsatisfactor y respons e to
seen within first 24 hours. The freedom trial, development antiresorptive therapy.
of new morphometric vertebral fractures was chosen as Continuous infusions of PTH and analogs cause
the primary end point where by Denosumab showed persistent elevation of the serum PTH concentration and
significant reduction in the new vertebral fractures at 3 years result in bone resorption, the usual effect of PTH. However,
(7.2% vs 2.3%, –68%, p < 0.0001). The incidence of hip and interestingly and contrary to the conventional thinking,
nonvertebral fractures was chosen as secondary end points. exogenously administered intermittent PTH is a potent
It was demonstrated in the freedom trial that denosumab anabolic agent that stimulates skeletal remodeling and
additionally reduced the nonvertebral fractures also at 3 improves BMD. RhPTH (1-34) has significant effect on
years (1.2% vs 0.7%, –40%, p = 0.04 and 8.0% vs 6.5%, –20%, reducing the risk of vertebral fractures and nonvertebral
p = 0.01, respectively), so in essence there was an overall fractures in postmenopausal women. The increase in BMD
reduction in the fracture risk. The efficacy of denosumab to is, however, noted most prominently at vertebral sites than at
reduce fracture risk has been shown to be consistent across nonvertebral sites when given in a dose of 20 µg/day. There
patients with varying degrees and types of osteoporosis and is an initial reduction in cortical bone density possibly due
fracture risk. Denosumab is generally well tolerated, but to initial increase in intracortical porosity. The appositional
some notable adverse events are: new bone formation is also stimulated that increases the
•• Osteonecrosis of the jaw cross sectional area of bone and cortical bone strength. Due
•• Risk of hypocalcemia to its unique efficacy profile some even recommend the use
•• Potentially increased risk of severe infections of teriparatide as first line treatment for postmenopausal
•• Atypical fractures and delayed fracture healing women and for men with severe osteoporosis. The effect
•• Pancreatitis of teriparatide are mediated in a multifactorial manner
•• Neoplasia of the breast, reproductive system and possibly involving Wnt pathway (stimulating Wnt10b and
gastrointestinal system are seen more frequently with inhibiting sclerostin), IGF I mediated anabolic effect, etc.
denosumab treatment although the causal relationship A recently developed teriparatide-coated microneedle
has not been established. patch system (ZP-PTH) demonstrated increase in
ALX-0141 is another RANKL inhibitor, currently under biochemical markers of bone formation in a phase II dose-
clinical development. finding study. This was also substantiated by increase
Anabolic agents: This is a new approach altogether as in lumbar spine BMD. Though the effect of combining
none of the antiresorptive agents activate new bone osteoanabolic therapy with antiresorptive agents is unclear
formation. This is due to the tight coupling of osteoblastic as to BMD measurements, there appears to be an enhanced
and osteoclastic activity, and hence bone formation will effect on bone mass when PTH is sequentially followed by
be inhibited, if osteoclast is inhibited. The anabolic agents alendronate or estrogen. Overall there is a greater BMD
try to improve the bone formation primarily rather than increase seen with PTH than with bisphosphonates alone
inhibiting bone resorption. and also there is indication of less improvement in BMD
with simultaneous use of teriparatide and alendronate
than teriparatide alone. BMD increases with PTH occur
Parathyroid Hormone even in the presence of bisphosphonates, but the initial
When first introduced (November 2002, FDA approval) the effect is delayed and latency of effect is increased, if PTH
therapy with PTH was hyped as a “cure for osteoporosis” that administration follows antiresorptives followed by less
is only partially true. Currently, the recombinant human than a complete effect. Full length 1-84 PTH is available in
full length PTH, rhPTH (1-84), its N-terminal segment Europe.
rhPTH (1-34) and PTH related protein (PTHrp) analogs Parathyroid hormone-related protein (1-36) is
are all available (in different parts of world) that exert their an equipotent protein analog to 1-84 PTH which has
anabolic effect (osteoanabolic therapy) on bone by binding physiological functions, like stimulation of bone resorption,
to the PTH receptor on osteoblasts. Only teriparatide— control of calcium metabolism in lactating women and
the N-terminal segment rhPTH (1-34) is, however, allowing tooth eruption. It uses similar receptors and
approved for treatment of osteoporosis by FDA in men and intracellular signaling pathways as that of PTH. Interestingly,

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Chapter 3:  Metabolic Diseases of Bone and Effect of Glucocorticoid Therapy on Bone 89

however, while the continuous administration of PTH (or extracellular fluid, soft tissue and superficial zone of bone
even rhPTH) leads to bone resorption (a net loss of bone tissue, and bone itself. Within bone and calcified tissues
mass, discussed above), the continuous administration of it is adsorbed on surface of hydroxyapatite crystals and
PTHrP preferentially stimulates bone formation suggesting may participate in bone mineralization. Higher amounts
that PTHrP could most likely be the endogenous skeletal of strontium are found in cancellous bone than in cortical
ligand for the PTH or PTHrP receptor acting as bone bone. It has both anabolic and modest antiresorptive affects,
anabolic agent. This apparently contradictory finding so it is actually a dual action compound rather than being
could be possibly explained by existence of two different only anabolic one. Strontium ranelate decreases osteoclast
activated states of PTH receptor one of which involves differentiation and activity (Fig. 18). Strontium appears to
continuous cyclic adenosine monophosphate (cAMP) result in uncoupling of bone remodeling (by competing with
secretion following PTH binding and the other has burst calcium at the calcium binding site) and increases bone
cAMP secretion after PTHrP binding. This latter receptor formation by separate mechanism (Fig. 18). It stimulates
type mimics the effects of intermittently administered PTH preosteoblast replication and increases matrix synthesis. In
possibly explaining anabolic action. The interest in use of spinal osteoporosis therapeutic intervention (SOTI) study,
PTHrP for use in osteoporosis has risen due to this pure the risk of new vertebral fractures was found to be halved in
anabolic effect that is different from the mixed anabolic and strontium group. Salt like taste and high doses are concerns
catabolic effect of PTH. This anabolic effect is maintained for compliance, as are the most common side effects—
even at very high dose (750 μg/day), and surprisingly at nausea and diarrhea. Nausea and diarrhea disappear after
such doses it also stimulates 1, 25-dihydroxyvitamin D third month of treatment. Some also doubt that higher
production. weight of the cation might spuriously raise the BMD.
Adverse effects of teriparatide:
•• Tiredness and depression Prostaglandins
•• Palpitation, nausea, vomiting and constipation or
diarrhea They have a local paracrine action. They show the effect and
•• Leg cramps are metabolized in the tissue, where they are synthesized
•• Joint pains (from arachidonic acid by cyclooxygenase pathway).
•• Osteosarcoma [therapy > 2 years in rats only, not Prostaglandin production is regulated by mechanical stress,
demonstrated in monkeys or humans (three cases cytokines, growth factor and systemic hormones. They have
reported, but not linked definitively)] both inhibitory and stimulatory effect on bone structure.
•• Hypercalcemia. Prostaglandin E2 (PGE2) stimulates bone resorption
Contraindications to use of rhPTH include: and formation through the cell surface E4 receptor.
•• Children with open epiphysis Systemic PGE2 administration stimulates proliferation of
•• Patients with history of prior radiation exposure osteoblast precursors or differentiation of osteoprogenitor
•• Unexplained elevations of serum ALP cells in bone marrow (Fig. 20). Misoprostol a methylene
•• Paget’s disease of bone. analog of prostaglandin E1 (PGE1) (used for treatment
of gastric ulcer for its inhibitory effect on acid and pepsin
secretion and cytoprotective effect) when administered to
Tibolone oophorectomized rats, significantly reduced oophorectomy
Tibolone is a synthetic steroid with estrogenic, androgenic related bone loss at site of lumber spine. This is, hence,
and progestin properties. There are reported increases in quite significantly useful in treatment of postmenopausal
lumbar BMD in early postmenopausal women. The use is osteoporosis where HRT is not feasible or contraindicated.
not very common due to other available effective drugs. Misoprostol is administered in dose of 800 µg/day.

Strontium Ranelate Statins


Strontium is a divalent alkaline element that is combined These 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-
with ranelic acid to make it more palatable. The compound CoA) reductase inhibitors are primarily used as effective
contains two atoms of nonradioactive strontium. Strontium cholesterol lowering agents for cardiovascular diseases. As a
usually acts as calcium agonist in most of physiologic side effects, these drugs have bone anabolic effects as shown
process. It is absorbed from the GIT by either passive in several observational studies. Osseous effects are possibly
diffusion or carrier mediated absorption. The carrier system mediated by suppressing the formation of the mevalonate.
is common to calcium and strontium, but has greater affinity This compound is an important precursor for osteoclastic
for former. After absorption, it is distributed into plasma activity, and hence reduced substrate controls the bone

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90 Section 1:  Bone Anatomy, Physiology, Pathology and Diseases

is observed. There is increased incidence of stress fractures


of weight-bearing bones, lower extremity pain syndrome,
osteomalacia, arthralgia and arthritis, and an increased risk
of femoral neck fractures. The routine use of fluoride is not
recommended. Recently, a different formulation of fluoride
the monofluorophosphate has been suggested which when
administered in lower doses produce lesser GI side effects.

Androgens
Synthetic androgens, such as nandrolone and stanozol
have been tried, however, virilizing side effects in females,
lowering of HDL, hepatotoxicity and the need for parenteral
administration limit their utility.

Growth Factors
Growth hormone modulates longitudinal bone growth
and when studied in vitro and in vivo it has been found
to regulate both bone formation and bone resorption.
Fig. 20: Mechanism of action of prostaglandins in bone metabolism Administration of biosynthetic growth hormone cyclically
with or without calcitonin has been found to significantly
resorption as seen with bisphosphonates. Additionally, the increase central BMD, especially in IGF I deficient
important anabolic effects are mediated by stimulation of patients (Fig. 21). Combination therapy of biosynthetic
VEGF expression from osteoblasts by hydrophobic statins growth hormone with estrogen, calcium and vitamin D
such as simvastatin, atorvastatin and cerivastatin. This also improves BMD in postmenopausal women. Growth
effect is affected through reduced protein prenylation and hormone increases bone formation by:
the phosphatidylinositide-3 kinase pathway which also •• Direct interaction with GHRs on osteoblasts
promotes osteoblastic differentiation. The effect of statins is •• Induction of endocrine and autocrine or paracrine IGF I.
an added advantage to patients’ primarily on lipid lowering Recombinant human Growth Hormone (rhGH) has
therapy, but mass usage for osteoporosis may not be cost effects on bone mineral metabolism in postmenopausal
effective. females. Growth hormone, however, also results in
increased bone resorption, but over a period of time bone
mineralization is predominant. It is speculated that the
Sesamin
Obtained from sesame seeds this is a lignin compound
having direct effects on osteoblasts. It stimulates
expression of essential genes and key enzymes of the bone
mineralization. Also osteoblast differentiation is stimulated
by activation of the p38 and ERK/MAPK (mitogen-activated
protein kinase) pathway. The alternative pathway (indirect)
could also be through osteoclast development, via the
expression of OPG and RANKL in osteoblasts. Studies are
needed to prove clinical efficacy, however.

Sodium Fluoride
Fluoride is an anabolic agent that stimulates new bone
formation via a mitogenic effect on the osteoblast. It typically
leads to a rapid increase in vertebral BMD. However, there is
usually a BMD loss in peripheral bones. The increased BMD Fig. 21: Effect of growth hormone on bone metabolism and IGF-1 as
does not translate into reduced fracture risk and in fact a intermediary. The left part of figure shows osteoclast bone resorption
heightened risk of both vertebral and nonvertebral fractures while the right part shows bone formation by osteoblasts

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Chapter 3:  Metabolic Diseases of Bone and Effect of Glucocorticoid Therapy on Bone 91

predominant effects of growth hormone are mediated Oxytocin


through modulation of IGF I.
Bone is the second richest source of IGF I in the body. It increases osteoblastic bone formation. The effect is
IGF I may have more rigorous effect in men with idiopathic prominent during pregnancy and lactation where they not
osteoporosis, however, there is relatively high incidence of only enhance bone resorption by increasing the number of
unacceptable experiences, like gynecomastia and edema. osteoclasts to make maternal calcium (shunted to the fetus
There is also a theoretical concern of potentiation of prostate or infant), but also prevent unrestricted bone removal by
and breast cancer with its use. Despite these concerns it has inhibiting the activity of mature osteoclasts. Their anabolic
been found that low levels of IGF I may result in greater risk action may have potential role in human osteoporosis.
of hip and spine fractures. The beneficial effects on bone
metabolism may outweigh the side effects (especially, when Lithium
given in low doses) and is better than growth hormone in
the following ways: Therapy with lithium carbonate may improve BMD and
•• More direct stimulation of bone formation bone mass. It has been found that in patients treated with
•• Bypass of skeletal growth hormone resistance that can lithium the serum total ALP, serum osteocalcin and serum
be present CTX were lower representing a reduced bone turnover.
•• A reduction in growth hormone-induced side effects, There is higher bone density reported at spine, femoral neck
such as carpal tunnel and diabetes mellitus. and trochanter in these patients.
Low doses of rhIGF I may directly increase osteoblastic
function with only a minimal increase in bone resorption. Calcilytics
Low levels of IGF I may identify at risk patients for
Calcilytics (CaR antagonists) are unique agents that
osteoporosis (discussed above).
modulate PTH secretion by antagonizing the calcium
receptor (CaR) found on parathyroid cells and shifting the
Bortezomib set point up (thus reducing endogenous PTH secretion at
This targets osteoblast proteasome. Proteasome inhibitor even subnormal calcium concentrations). Though available
bortezomib (Bzb) is anabolic to skeleton in patients with for over 10 years these are still under development. The
multiple myeloma. The mechanism is, however, unclear. most focused compounds are oral calcilytics, such as
Bzb with lenalidomide or thalidomide has been proposed JTT-305/MK-5442 and SB-423557 that have been shown to
to increase bone formation by stimulating osteoblast activity stimulate endogenous transient PTH secretion, and hence
and inhibiting osteoclastic bone destruction (Fig. 22). bone formation. The effect of reducing bone loss was also
seen in ovariectomized rats. These may represent future
therapeutics for osteoporosis. However, the development
of MK-5442 was halted in 2011 for unreported reasons in
phase III trials.

Antagonists of Wnt-inhibitors (Inhibitors


of Endogenous Inhibitors)
The Wnt signaling pathway has three components, the
Wnt/β-catenin or canonical pathway, the Wnt/Ca2+ pathway
and the planar polarity cell pathway of which the first
one is specific to bone. The canonical pathway (Fig. 23)
is strongly osteoblastogenic and reduces the osteoclast
activation and activity. The binding of Wnt proteins to the
LRP5/6-frizzled co-receptor on osteoblast cell membrane
causes stabilization of intracellular beta-catenin. This in
a way regulates gene transcription and promotes bone
formation by osteoblasts. It is also responsible for reduced
adipocytogenesis and redirecting the mesenchymal cells
to osteocyte lineage rather than becoming adipocytes.
Sclerostin (encoded by SOST gene) and Dkk1 are
Fig. 22: Effect of Bortezomib in patients with multiple myeloma endogenous inhibitors of the above mentioned canonical

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92 Section 1:  Bone Anatomy, Physiology, Pathology and Diseases

Fig. 23: The Wnt canonical signaling pathway—{right hand side, liganded state} When Wnt (name derives from wingless drosophila and int-1
mouse) bind to Frizzled protein (FZL) and LRP5/6 (LDL receptor related protein) in a ternary complex at the cell surface, GSK-3b (Glycogen
synthase kinase 3b) is inhibited and β-catenin is stabilized. This inhibition is affected by Frat (mamalian homolog of GSK3b) and GBP (GSK
binding protein) when Dvl (Disheveled) receive signal from Fzl/LRP complex. β-Catenin then accumulates in the nucleus and activates lymphoid
enhancer factor (LEF)/T-cell factor (TCF)-mediated gene transcription of Runx-2 and cbfa-1 responsible for further effects on osteoblasts (+)
and (-) RANKL. In the absence of Wnts {left hand side}, β -catenin is phosphorylated by mainly glycogen synthase kinase 3b (GSK-3b), leading
to proteosomal degradation. This phosphorylation and degradation is affected through axin which serves as a scaffolding protein to assemble
APC (adenomatous polyposis coli) and Casein kinase (not shown) required to phosphorylate β-catenin. When Wnt binds to LRP the axins are
recruited to membrane disturbing the complex formation and preventing the phosphorylation. Inhibitors of Wnt signaling are responsible
for reduced bone formation. The inhibitors include Sclerostin/wise (encoded by SOST, sclerosteosis gene responsible for sclerosteosis and van
Buchem disease). Sclerostin is synthesized by osteocytes. It inhibits BMP-stimulated bone formation in a pathway different from BMP antagonists.
Mechanical stimulation and PTH treatment reduces sclerostin secretion. Mutation in sclerostin or inhibition of this protein leads to release of
inhibition of Wnt pathway and increased osteogenesis. The Dkk (Dickpofs)/Kremen are secreted glycoprotein developmental regulators. The
Dkk forms a complex with Kremen (a transmembrane protein) that binds to and internalizes LRP, removing it from cell surface. Both Dkk1 and
2 have high affinity for Kremen but complete absence of Dkk2 (or its inhibition) results in osteopenia and increased unmineralized osteoid
surprisingly suggesting that it is required for final mineralization and may not be a true inhibitor of the pathway only. Secreted frizzled-related
proteins (sFRPs) are expressed by osteoblasts. They are capable of binding Wnt and preventing it from binding to the LRP5/6 -frizzled receptor.
They also have effect similar to OPG that prevent the binding of RANKL and regulate osteoclasts. Wnt inhibitory factor-1 (WIF-1) is a secreted
protein that binds to Wnt proteins and inhibits their activities

(β-catenin-dependent) Wnt/β-catenin pathway which is and anabolic to bone. The subcutaneous administration of
found only in bone. These inhibitors prevent exposure of a single dose of AMG 785 (high affinity IgG2 monoclonal
the osteoblast precursors to a Wnt signal. In the absence antibody), a human recombinant sclerostin antibody
of this signal or stimulation, osteoblast differentiation has shown dose related improvement in bone formation
and recruitment is stopped. Antibodies against sclerostin markers and decrease in serum C-telopeptide, CTx a bone
or Dkk1 would, hence prevent this inhibition to bone resorption marker. This suggests an anabolic effect on
formation pathway and work being trophic to osteoblasts bone and potential therapeutic agent. These biochemical

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Chapter 3:  Metabolic Diseases of Bone and Effect of Glucocorticoid Therapy on Bone 93

changes were supplemented by BMD increases at the and resorption possibly due to suppression of osteoclast
lumbar spine and hip within 3 months after the single function and viability resulting from suppression of cathepsin
dose. A dose-finding randomized placebo-, teriparatide- K without altering bone formation. Unlike the generalized
and alendronate-controlled 12-month phase II study suppression of bone resorption seen with bisphosphonates,
in postmenopausal women with low BMD has recently odanacatib displays site specific effects on trabecular and
completed, and AMG 785 has been found to be as effective cortical bone formation preferentially improving the more
as teriparatide and alendronate. Nonspecific hepatitis and deranged form. ONO-5334 is a new cathepsin K inhibitor
neutralizing antibodies to the agent have been reported, with little or no suppression on bone formation markers
but in general it is well tolerated. The most notable effect is while reduction in the bone resorption markers. There are
that this bone formation is not related to amount of bone no clinically relevant safety concerns. With a significant
resorption or its influence. The development of sclerostin increase in BMD ONO-5334 is a new potential agent for
antibodies, hence unfolds the perspective of uncoupling treating osteoporosis. Balicatib (less selective cathepsin K
bone formation and resorption and of restoring bone inhibitors) development was stopped due to the appearance
microarchitecture. This would prove to be a unique method of scleroderma-like skin lesions.
in the future management of osteoporosis where influence
of related factors is minimal. The concern is, however, that
of neoplasia, the Wnt signaling pathway has been associated FUTURE APPROACHES
with many forms of cancer, like gastric, kidney, liver, lung, MicroRNAs (miRNA)—regulate a number of bone formative
ovarian and bone cancer itself. Sclerostin inhibition may pathways by double inhibition. These regulate the BMP,
increase susceptibility to osteosarcoma. This theoretical TGF-β and Wnt/β-catenin signaling pathways of osteoblast
concern needs to be fully analyzed before mass usage of formation and differentiation by suppressing the inhibitory
the sclerostin antibody. Antibodies specifically directed signaling mechanisms. The miR-218 is upregulated during
against Dkk1 which might have anabolic effects on bone osteoblastogenesis, while miR-148a is upregulated during
as serum Dkk1 concentrations are significantly higher in osteoclastogenesis. Lot of osteogenic mi-RNAs are found
patients with low BMD and in women with postmenopausal to be downregulated during pathological conditions
osteoporosis. The concept is also interesting in light of the and abnormal osteoblast differentiation while others get
recent finding that waning effect of teriparatide treatment upregulated. Defining and identifying the specific miRNA
on bone turnover has been shown to be associated with an may help synthesize the strategies for future diagnostic
increase in serum Dkk1. and treatment methods. Free circulating miRNA, like
miR-21, miR-23a, miR-24, miR-25, miR-100 and miR-125b
Cathepsin K Inhibitors have been found to be significantly elevated in the serum
of osteoporotic patients and can serve as biomarkers for
Odanacatib is a highly selective orally bioactive cathepsin K development of osteoporosis. Circulating monocytes
inhibitor reversibly binding to cathepsin K. Cathepsin K is the develop into osteoclasts; higher levels of miR-133a and miR-
primary osteoclast produced protease that is involved in the 382 have been found in these cells from postmenopausal
degradation of COL1A1 during bone resorption (congenital osteoporosis, especially the former and have been
absence of this enzyme produces pycnodysostosis—an implicated for use as diagnostic assay [real-time reverse
autosomal recessive disorder with increased bone mass). transcription polymerase chain reaction (qRT-PCR)].
Odanacatib is a powerful, reversible and neutral (unlike basic Inhibition of these and stimulation of “osteosynthetic”
inhibitors) nonpeptidic biaryl inhibitor of cathepsin K that miRNAs may help to treat the disease in future also.
inactivates the proteolytic activity. This neutral inhibition Summary of Current recommendations to prevent
prevents its accumulation in acidic lysosomes, and hence and treat osteoporosis (based on National Osteoporosis
avoiding nontargeted inhibition of cathepsin K. The efficacy Foundation).
of odanacatib has been proven in clinical trials that reported
50% lower urine N-terminal telopeptide (NTx) resorption
marker compared with placebo at doses of 50 mg once Universal Recommendations
weekly, whereas the formation markers were increased by •• Counsel on the risk of osteoporosis and related fractures
18% at 3 years. The effect is, however, reversible with return on •• Advise on diet that includes adequate amounts of total
increased bone turnover at 1–2 years after stopping therapy. calcium intake (1,000 mg/day for men aged 50–70,
The increases in spine and hip BMD with odanacatib have 1,200 mg/day for women age 51 and older and men 71
been comparable to those observed with zoledronate or and older), incorporating dietary supplements, if diet
denosumab. There is a decoupling between bone formation is insufficient

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94 Section 1:  Bone Anatomy, Physiology, Pathology and Diseases

•• Advise on vitamin D intake (800–1,000 IU/day),


including supplements, if necessary for individuals age
ATYPICAL FORMS OF
50 and older OSTEOPOROSIS
•• Recommend regular weight-bearing and muscle-
These are not grouped with classical osteoporosis discussed
strengthening exercises to improve agility, strength,
above which is a systemic disease. Most of these atypical
posture and balance, maintain or improve bone
forms are localized osteopenic conditions containing
strength, and reduce risk of falls and fractures
the term “osteoporosis” that is actually a misnomer. The
•• Assess risk factor for falls and offer appropriate
following are some of them:
modifications
•• Immobilization and disuse related (atrophic
•• Advise on cessation of tobacco smoking and avoidance
osteoporosis)
of excessive alcohol intake.
•• Sudeck’s osteodystrophy (RSD; discussed later)
•• Regional migratory osteoporosis (RMO): First described
Diagnostic Assessment by Duncan et al. in 1969 it is a sequential polyarticular
•• Measure height annually, preferably with wall mounted arthralgia of the weight-bearing joints associated with
stadiometer severe focal osteoporosis. RMO primarily affects the
•• Bone mineral density testing as mentioned in Table 9 lower limbs in middle aged men, but combined axial
•• Vertebral imaging as mentioned in Table 10. skeleton involvement has also been described. Regional
osteoporosis is a distinctive feature of the disease. Its
presentation and clinical course are identical to those
Monitoring Patients of transient osteoporosis (TO). This clinical entity
•• Perform BMD testing 1–2 years after initiating medical involves the lower extremities, especially the knee,
therapy for osteoporosis and every 2 years thereafter: ankle and foot, with lesser involvement of the hip joint,
–– More frequent BMD testing may be warranted in differentiating it from transient osteoporosis. Migration
certain clinical situations may occur in the same or a different joint and in an
–– The interval between repeat BMD screenings may inconsistent time interval after the onset of the first
be longer for patients without major risk factors and symptoms. Usually, the joint nearest to the diseased one
who have an initial t-score in the normal or upper is the next to be affected. There is generalized tenderness
low bone mass range with decreased range of motion due to severe pain.
•• Biochemical markers can be repeated to determine, if The overlying skin is characterized by inflammatory
treatment is producing expected effect. changes and muscle atrophy is frequently found which
differentiate it from transient osteoporosis. “Transient
regional osteoporosis” is a term used by some authors
Pharmacological Treatment that combines both RMO and transient osteoporosis
•• Initiate treatment in: •• Malignancy related osteoporosis
–– Those with hip or vertebral fractures •• Disuse osteoporosis: The primary trophic component to
–– Those with t-scores less than or equal to –2.5 at the bone remodeling and maintenance is stress. Prolonged
femoral neck, total hip or lumbar spine by DEXA immobilization takes away the muscular and pulling
–– Postmenopausal women and men age 50 and older stress from the bone. This leads to bone resorption and
with low bone mass (t-score between –1.0 and –2.5) attenuated bone formation so that there is a net loss of
at the femoral neck, total hip or lumbar vertebra by bone mass. This is commonly seen in polio limb, stroke,
DEXA score and a 10-year hip fracture probability plaster disease, etc.
more than or equal to 3% or a 10 year major •• Transient osteoporosis (transient osteoporosis of hip,
osteoporosis related fracture probability more than abortive osteonecrosis of hip and bone marrow edema
or equal to 20% based on FRAX® tool syndrome): Transient osteoporosis is an idiopathic
•• No pharmacological therapy should be considered condition mostly affecting young and middle aged
indefinite in duration. After initiation of treatment a males and rarely females in third trimester or immediate
comprehensive risk assessment should be done. The postpartum period. Transient osteoporosis involves
decisions are individualized only the lower extremities, especially the hip joint and,
•• In adults age 50 and older after a fracture, institute less frequently, the knee, ankle and foot. Transient
appropriate risk assessment and treatment measures osteoporosis of hip and other local osteoporosis
for osteoporosis as indicated. syndromes are subtypes of transient osteoporosis. There

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Chapter 3:  Metabolic Diseases of Bone and Effect of Glucocorticoid Therapy on Bone 95

is sudden onset, spontaneous pain of the affected joint disease. Histologic examination of the lesion is necessary
which increases on weight-bearing and is associated only when these other pathologies are suspected.
with limping and disability. These symptoms gradually Conventional radiography: Radiographs may be normal
subside within 4–9 months. Recurrence may involve in the early stages of transient osteoporosis. Usually at 3–6
the same or adjacent joints. Physical examination is weeks from the onset of symptoms there is periarticular
quite unremarkable and there is minimal restriction osseous demineralization manifest as osteopenia. These
of range of movement and pain only at the extremes of findings may persist even weeks after the symptoms
range. The disjunction between physical examination have resolved (sometimes up to 2 years). The joint
and disability may help in diagnosing this self-limiting space remains intact with preserved bony margins and
condition, avoiding unnecessary diagnostic and there are no subchondral erosions. In advanced stages
therapeutic measures. of transient osteoporosis, the femoral head may seem
to completely disappear in osseous architecture—the
Pathogenesis “phantom appearance” of the femoral head. The trochanter,
acetabulum and iliac wings are rarely affected.
The cause and pathogenesis remain obscure till date.
Various inclusive theories are presented in literature, like Bone scintigraphy: Though nonspecific, the findings of
Curtiss and Kincaid neurogenic compression theory and technetium Tc-99m methylene diphosphonate scintigraphy
the venous obstruction and secondary localized hyperemia are useful in the early diagnosis of transient osteoporosis.
proposed by Rosen. Based on electromyographic findings Increased uptake (seen in all three phases) in the affected
indicative of denervation during pain attacks of transient joint usually precedes radiologic features and can appear
osteoporosis pathology of the proximal nerve roots has within a few days after the onset of symptoms. Bone
been proposed as a possible pathogenic mechanism scanning is sensitive, but not specific for detection of
of transient osteoporosis. This is possibly due to some transient osteoporosis and can be used in symptomatic
undefined ischemia in the small vessels proximal to period when radiographs are normal. Scintigraphy,
nerve roots and later restoration of blood flow may be however, appears to be very useful both for monitoring
responsible for the limited clinical course of transient the progression of the disease and therapeutic response.
osteoporosis, which usually lasts less than or equal to 9 It is also helpful in differentiating transient osteoporosis
months. Repetitive occurrence of such ischemic events from other conditions that are characterized by regional
elsewhere may explain the migratory character of RMO. osteopenia. With subsidence of symptoms reduced activity
Regional accelerated phenomenon (RAP) activation has on the perfusion and blood pool phases are noted that
been shown to be a recent possibility. RAP is a process indicate resolution of disease. Increased activity in the
by which the rate of bone modeling and remodeling in delayed bone phase may still persist for many months
local areas may be accelerated up to 10 times the normal due to repair activity. Differential diagnosis includes
rate in response to noxious stimuli. The pathogenesis osteonecrosis of the femoral head, trauma or stress fracture
is unclear, however, it is thought that bone tissue of the femoral neck and infection (tubercular infection or
microdamage and consequent microfracture may trigger osteomyelitis).
RAP. Prolonged activation of bone foci where normal bone Computed tomography: Not a useful investigation for
repair mechanisms are most active may result in transient transient osteoporosis, however findings such as spotty
osteoporosis. Supported by other investigators these defects without any cortex involvement may be useful for
findings may support Frost’s theories of prolonged active distinguishing transient osteoporosis from other clinical
bone foci as a cause of transient osteoporosis explaining entities.
the influence of local and systemic factors in both causing
and reversing osteoporosis. Bone marrow edema (BME), Magnetic resonance imaging: It is the modality of choice.
as shown on MRI and focal osteopenia, as shown on On MRI, BME is characterized by increased signal intensity
plain radiographs, are typical findings in the patient with on fat-suppressed T2-weighted and short tau inversion
transient osteoporosis. recovery images. These are complemented by low signal
intensity on T1-weighted images. BME is, however, a
nonspecific finding and enhancement of the BME area after
Laboratory Tests intravenous administration of contrast agents is indicative
As such no utility for contextual diagnosis; blood tests are of hypervascularity and increased permeability of the
done to distinguish transient osteoporosis from aggressive capillary bed. Vasodilation and increased permeability
clinical entities, such as metastatic or metabolic bone may constitute a result rather than a cause of the BME

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96 Section 1:  Bone Anatomy, Physiology, Pathology and Diseases

disclosed on MRI. Differentiation from osteonecrosis is •• Variants:


important as early stages may mimic transient osteoporosis –– Osteopetrosis associated with renal tubular acidosis
lesion. The lack of subchondral changes other than BME and cerebral calcification (carbonic anhydrase II
on both T2-weighted and contrast-enhanced T1-weighted deficiency)
highly suggests transient lesions. Subchondral area of –– Osteopetrosis associated with neuronal storage
low signal intensity at least 4 mm thickness on either disease
T2-weighted or contrast-enhanced T1-weighted images –– Drug-induced osteopetrosis
suggests osteonecrosis. Presence of contour deformity and –– Syndromic form: Osteopetrosis, lymphedema,
areas of subchondral low signal intensity further support anhidrotic ectodermal dysplasia and immuno­
osteonecrosis. deficiency syndrome.

Treatment ETIOLOGY AND


Transient osteoporosis is a self-limiting disease and PATHOPHYSIOLOGY
treatment is mainly supportive primarily aimed to reduce
pain and protect the bone due to reduced mechanical The disease basically results from modeling and remodeling
strength. Protected weight-bearing, mild analgesics and defects arising out of osteoclast dysfunction. The osteoclasts
administration of nonsteroidal anti-inflammatory drugs fail to resorb bone due to defects at various levels resulting
are main therapeutic approaches. Glucocorticoids are from genetic mutations affecting discrete gene products in
not found to be effective for remineralization though they different forms. For a single form different mutations may
improve pain symptoms. Sympathetic blockade provided result in the phenotype so the disease is heterogeneous. The
no improvement of results in the treatment of transient following are some identified mutations:
osteoporosis. Bisphosphonates (especially intravenous) •• Adult type I osteopetrosis results from activating
may help in reducing pain and improving bone strength. mutations of LRP5 gene. This indicates that the form may
Calcium and corrective doses of vitamin D should be not be true osteopetrosis as this mutation does not result
started. Iloprost, a prostacyclin analog, has shown pain in osteoclast dysfunction. The set point (threshold)
relief in patients with transient osteoporosis of hip and bone for bone resorption and remodeling in response to
marrow edema syndrome by possibly dilating the vessels mechanical loading is increased so that the process does
and reducing permeability. not get initiated at physiological loading.
•• Half of the cases of adult type II osteopetrosis (the
form originally described by Albers-Schonberg in
OSTEOPETROSIS 1904) are attributed to mutations of CLCN7, the type 7
Manish Kumar Varshney chloride channel. The chloride channel is responsible
for acidification of extracellular resorption lacuna
Synonyms: Marble bone disease, Albers-Schonberg disease necessary for bone resorption.
(refers to an adult autosomal dominant type 2 milder form •• Some patients with malignant infantile osteopetrosis
of disease) and stone bone. (autosomal recessive) have a mutation in the TCIRG1
gene encoding the osteoclast-specific α3 subunit
Definition: Osteopetrosis is a group of heterogeneous
to which H+ATPase of the vacuolar proton pump is
inherited sclerosing bone disease characterized by
anchored. Others have CLCN7 and OSTM1 mutations
generalized increase in the bone mass (osteosclerosis)
that together form a chloride channel or chloride/
primarily resulting from osteoclast dysfunction.
proton-exchanger. These are responsible for acidification
Classification and types of osteopetrosis: At least eight of the milieu and bone resorption. In contrast, above few
different types have been recognized based on various patients have been found to have mutations in TNFSF11
genetic mutations and clinical presentations. Important gene encoding for the osteoclast differentiation
ones are mentioned below— factor RANKL, this results in decreased number of
•• Classical types: osteoclasts itself. Mutations in the RANK receptor also
–– Autosomal recessive (infantile and malignant) cause osteoclast poor osteopetrosis with additional
–– Autosomal dominant (adult and benign) type I and immunological abnormalities.
type II •• Intermediate form of autosomal recessive osteopetrosis
–– Autosomal recessive intermediate form may result from mutations in the PLEKHM1 gene. A

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Chapter 3:  Metabolic Diseases of Bone and Effect of Glucocorticoid Therapy on Bone 97

variant of autosomal recessive intermediate form result to touch end of first decade. Incidence varies from 1 in
from mutation of carbonic anhydrase II gene (Car2). 200,000 to 1 in 500,000 live births. The patients show failure
Carbonic anhydrase catalyzes the formation of carbonic to thrive and suffer from growth retardation. Cranial nerve
acid that acidifies the lacunae. neuropathies (multiple) are very common and progressive
The modeling defects are most pronounced in due to compression of nerves in narrow foramina resulting
autosomal recessive form and the phenotype develops by in deafness, blindness, proptosis, etc. Children have
second trimester itself. Modeling of bone is responsible sleep apnea, stuffy nose and recurrent sinusitis (due to
for expansion of medullary canal, foramina, etc. during paranasal sinus malformation) that may be associated
bone development, and hence hematopoiesis and giving with maxillomandibular osteomyelitis bringing them
the typical shape to bone metaphysis. The bone marrow to physician earliest and multiply. Bone marrow failure
develops inside the intramedullary cavity. Defect in bone results in pancytopenia, reduced incident immunity
modeling produces loss in hematopoietic function and and easy bruising due to thrombocytopenia. Children
resultant anemia and immunodeficiency, skull foramina have growth retardation due to skeletal defect, anemia,
fail to expand resulting in various cranial nerve palsies and recurrent infections and psychomotor retardation due to
blindness. Remodeling is the process of continued turnover hydrocephalus and general growth retardation. Dentition
of bone (resorption and reformation) in adult live that is is delayed and bones fracture with minimal impact.
influenced by various mechanical and endocrine factors Extramedullary compensatory hematopoiesis produces
(discussed in Chapter 1). Defective remodeling results hepatosplenomegaly and hypersplenism.
in accrual of microfractures in the bone and qualitative
weakness of bone to withstand stress. Such structurally
weakened bone though appearing radiodense fails under INVESTIGATIONS
mild stress and impacts. Laboratory findings: In infantile form the serum tartrate-
resistant acid phosphatase and creatine kinase-BB (CK-BB)
EPIDEMIOLOGY AND CLINICAL (brain isoform) are elevated due to release from defective
osteoclasts into systemic circulation. Nutritional calcium
FEATURES deficiency produces hypocalcemia, rickets and secondary
hyperparathyroidism. In adult benign form, the acid
Benign adult form: The adult type 2 autosomal dominant
phosphatase and CK-BB levels are often increased in type
form is the most common form that was recognized by
II but normal in type I form.
Albers-Schonberg with a prevalence of 5.5/100,000. This
is also the most common form in India. It is diagnosed Radiology: This has typical findings but differ in individuals
in late adolescence or early adulthood. Clinically, it due to heterogeneous nature of disease. Generalized
presents with bone pains, nontraumatic fractures of long osteosclerosis with thickening of both cortical and
bones, cranial nerve palsies (deafness and facial palsy), cancellous bones is common to all, but may vary in
carpal tunnel syndrome and osteoarthritis of the hip and extent of involvement, like predominant cranial vault
mandibular osteomyelitis. The serum acid phosphatase involvement in type 1 adult osteopetrosis without spine
levels are raised. Bone marrow function is normal. There involvement.
may be visual impairment due to retinal degeneration and •• Infantile form:
psychomotor retardation affecting school performance. –– Small and under pneumatized sinuses
The type I autosomal dominant form is characterized by –– Absent medullary canal
generalized osteopetrosis, especially of the cranial vault –– Cube-like bones (carpals and tarsals)
with normal acid phosphatase levels. Involvement of other –– Erlenmeyer flask deformity of metaphysis with
regions of skeleton, like spine and appendicular bones is broadening
not prominent. Fracture risk is increased, but not as high •• Adult form (type 2):
as in type II. These findings are present in about half of –– Alternating sclerotic and lucent bands:
the patients, other half are usually asymptomatic and the ◊ “Rugger-Jersey” spine
diagnosis is often made incidentally on radiographs taken ◊ Endobone formation (bone within bone
for other purpose. appearance) in iliac wings and subcristal sclerosis
Infantile malignant form: This has varied presentations ◊ Transverse banding of ends of long bones
and is uniformly fatal with some patients succumbing (metaphysis) this is pathognomonic of type 2 adult
in infantile period, while others fortunate just enough form differentiating from type 1 radiologically.

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98 Section 1:  Bone Anatomy, Physiology, Pathology and Diseases

DIFFERENTIAL DIAGNOSIS TABLE 12: Etiological classification of rickets


Vitamin D disorders:
All possible causes of diffuse osteosclerosis including •• Nutritional deficiency of vitamin D
pyknodysostosis, hypoparathyroidism, pseudohypopara­ •• Vitamin D dependent rickets type 1
thyroidism, Paget’s disease and myeloproliferative •• Vitamin D dependent rickets type 2
disorders, like leukemia, sickle cell disease, osteoblastic •• Congenital vitamin D deficiency
metastasis and poisoning (fluoride, lead and beryllium). •• Secondary vitamin D deficiency:
■■ Malabsorption
■■ Decrease liver 25-hydroxylase
TREATMENT ■■ Increase degradation
•• Chronic kidney disease
Infantile osteopetrosis is uniformly fatal and the only Renal losses:
chance to survival and cure is bone marrow transplantation. •• Autosomal dominant hypophosphatemic rickets
The treatment cannot be offered to all due to cost and •• Autosomal recessive hypophosphatemic rickets
•• X-linked hypophosphatemic rickets
logistic restraints and nonuniform success rates. The •• Hereditary hypophosphatemic rickets with hypercalciuria
allogeneic human leukocyte antigen (HLA)-matched •• Excess production of phosphatonin:
bone marrow transplant provides normal osteoprogenitor ■■ Neurofibromatosis
cells that form normal osteoclasts capable of resorbing ■■ Tumor induced rickets
■■ McCune-Albright syndrome
bone. The transplant should be done before age of 4 years. ■■ Epidermal nevus
Studies have documented good benefit from treatment •• Dent disease
with interferon γ-1β and high dose calcitriol. Calcitriol •• Fanconi syndrome
stimulates osteoclasts with low calcium intake. Low •• Distal renal tubular acidosis
calcium diet may stimulate osteoclasts, but restriction Calcium deficiency:
should be avoided if rickets develops. Interferon therapy •• Decrease intake
improves white blood cell function, increasing bone •• Malabsorption
marrow volume, and increases hemoglobin and platelet Phosphorous deficiency:
counts. Erythropoietin and corticosteroids have been used ■■ Premature infants (rickets of prematurity)
■■ Aluminum—containing antacids
to treat anemia.
Surgical treatment is required only to correct
the complications of disease, like fracture fixation,
decompression of cranial nerves, deformity correction and
features and prognosis that can be grouped into “varieties”
arthroplasty for degenerative joint disease. Osteomyelitis
or “type” of rickets, detailed below.
is treated on the principles laid in chapter on bone
infection. Very rarely surgical intervention may be asked
for correcting facial deformity and improving cosmesis. PATHOPHYSIOLOGY
Vitamin D undergoes successive hydroxylation in the
RICKETS liver and kidney to 1, 25-dihydroxycholecalciferol. Its
main action is to increase the absorption of calcium from
Swapnil Sharma
intestine (see regulation of bone metabolism in structure
and function of bone). PTH secreted by parathyroid
DEFINITION glands mobilizes calcium from bone and increases urinary
excretion of phosphate. The third hormone calcitonin
It is a defect in mineralization of osteoid matrix caused by
secreted by parafollicular cells (C cells), inhibits bone
inadequate calcium and phosphate deposition prior to
resorption. Although, the role of calcitonin seems to be
closure of physis. Rickets is a disease of growing bone that
relatively minor. All three hormones operate in concert to
occurs in children (before fusion of epiphysis) and clinical
regulate the calcium levels in body fluids. A fourth local
features arise from unmineralized matrix at the growth
hormone, PTHrP, acts on one of the PTH receptors and is
plate. Cartilage and osteoid continues to expand the growth
important in the skeletal development in utero.
plate that fails to mineralize. The growth plate thickens,
widens and increases in circumference of metaphysis. A brief review of Vitamin D and hydroxycholecalciferol (also
There are various causes of rickets (Table 12). A few of see endocrine and paracrine regulation of bone metabolism
them have their own set of clinical, laboratory, diagnostic in Chapter 1).

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Chapter 3:  Metabolic Diseases of Bone and Effect of Glucocorticoid Therapy on Bone 99

Vitamin D3 is produced in mammals from Spine


7-dehydrocholesterol by ultraviolet B radiation from the sun.
Vitamin D3 and its hydroxylated derivatives are transported •• Scoliosis (uncommon)
in the plasma bound to a globulin vitamin D binding protein •• Kyphosis (rachitic cat back)
or globulin (DBP), which is also known as Gc protein and •• Accentuation of lumbar lordosis.
binds G-actin. The affinity of DBP for previtamin D3 is low, but
for vitamin D3 is high. In the liver, 25-hydroxylase converts Limbs and Joints
vitamin D (cholecalciferol) to 25-hydroxycholecalciferol.
The final step occurs in kidney where 1α-hydroxylase adds •• Bone pain and tenderness
the second hydroxyl group and 25-hydroxycholecalciferol •• Coxa vara
is converted to 1, 25-dihydroxyvitamin D (calcitriol). •• Genu valgum or varum
There is upregulation of 1α-hydroxylase that occurs by •• Windswept deformity
PTH and hypophosphatemia; hyperphosphatemia and •• Bowing of tibia, femur, radius and ulna
calcitriol inhibit this enzyme. Most calcitriol circulates •• Widening of wrist, elbow, knee and ankle because of
bound to DBP. Calcitriol (1, 25-dihydroxycholecalciferol) enlargement of ends of long bones
is also synthesized in placenta, the keratinocytes in •• Rachitic saber shins
the skin, and in macrophages. Person with sarcoidosis •• Sausage like enlargement of ends of phalanges and
and pulmonary alveolar macrophages also produce 1, metacarpals, with regular constrictions corresponding
25-dihydroxycholecalciferol, on stimulation by interferon γ. of the joints string of pearls deformity
The less active metabolite 24, 25-dihydroxycholecalciferol •• Double malleoli sign.
is also synthesized in the kidneys.
General
CLINICAL FEATURES •• Failure to thrive
•• Protuberant abdomen
The following features are rarely seen in all cases, only
•• Apathy, listlessness and irritability
full blown cases with advanced deficiency that have been
•• Proximal muscle weakness
neglected for long present with such changes. Else most
•• Ligament laxity
patients present with a few of the features presented below.
•• Symptoms of hypocalcemia—tetany, seizures and
stridor due to laryngeal spasm
Head •• Bilateral lamellar cataract (Vitamin D deficiency in early
infancy).
•• Craniotabes—softening of cranial bones a sensation
The clinical features also vary depending on type of
similar to pressing a ping pong ball on applying pressure
deficiency:
on occiput or the parietal bones. Craniotabes can also
•• Lower extremity changes predominate in X-linked
be seen in osteogenesis imperfect, hydrocephalus and
hypophosphatemic rickets
syphilis
•• Rickets that is associated with decreased serum calcium
•• Frontal bossing
levels is associated with symptoms of hypocalcemia,
•• Delayed dentition and tooth caries
e.g. dietary vitamin D deficiency, vitamin D dependent
•• Delayed closure of fontanel
rickets (VDDR) type I and II, chronic kidney disease and
•• Craniosynostosis.
dietary calcium deficiency.

Chest
•• Rachitic rosary—widening of osteochondral junction,
RADIOLOGICAL SIGNS
feels like beads of rosary on moving finger along the On radiographic examination, rickets is characterized by:
osteochondral junction from rib to rib •• Generalized osteopenia
•• Harrison’s groove—occurs due to pulling of softened •• Bowing deformities of the long bones, particularly the
ribs in inspiration by diaphragm. Softened ribs also femur and tibia
predispose to atelectasis and pneumonia because of •• Widening of the growth plate (secondary to deficient
decreased air entry mineralization in the provisional zone of calcification)
•• Pectus carinatum (pigeon breast)—sternum projects and cupping or flaring of the metaphysis (Fig. 24),
forward. particularly in the proximal humerus, distal radius and

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100 Section 1:  Bone Anatomy, Physiology, Pathology and Diseases

Fig. 24: Radiographs of rickets

ulna, and distal femur as explained. Widened growth bone may produce Looser’s zone in proximal humerus.
plate is due to continued hypertrophy of cartilage cells. In severe rickets, the margins of tarsal and carpal
Normally, capillaries grow from metaphysis to epiphysis ossification centers may disappear.
via tunnels in the zone of provisional calcification. This •• Findings of healing rickets:
growth of capillaries destroys the cartilaginous cells –– Earliest finding the reappearance of the provisional
in zone of hypertrophy, thereby limiting the growth of zone of calcification, which gradually thickens into
epiphyseal plate. In rickets, tunnels are not formed in a transverse band
the zone of provisional calcification because of defective –– This is followed by recalcification of the spongiosa
mineralization, the cartilaginous cells continue to in the metaphysis
proliferate, but do not die, thus leading to thickened –– A dense line appears at the end of metaphysis
growth plates. The metaphysis is soft due to absent –– Epiphyseal shadow is clearly defined
mineralization, hence the epiphysis is pushed into –– The end of shaft and epiphysis become clearly
metaphysis with axial pressure causing cupping. The differentiated
metaphysis widens under axial pressure and defective –– Finally, the bone appears to be normal.
modeling of bone causing flaring. Irregular calcification
leads to fraying of metaphysis that instead of appearing
smooth takes the form of “trees on plateau top” viewed NUTRITIONAL DEFICIENCY OF
from a distance.
•• The radiographic findings in vitamin D resistant VITAMIN D
rickets are similar to those in infantile rickets. Bowing Globally, vitamin D deficiency remains the most common
deformities and shortening of the long bones are, cause of rickets. Most patients have a combination of risk
however, more pronounced in early rickets. They are factors that lead to vitamin D deficiency as vitamin D
best seen in the rapidly growing distal ends of radius and can be obtained from dietary sources or from cutaneous
ulna (more so in ulna). Changes in the shaft appear a synthesis.
few weeks later than metaphysis. The epiphysis is cloudy
and indistinct and periosteum is thick. The shaft shows
diffuse rarefaction, thin cortices with coarse texture of
Etiology
spongiosa. Sometimes Umbau zones (Looser’s zones) Deficiency of vitamin D most commonly occurs in infancy
are seen as sharply defined radiolucent transverse because of a combination of poor intake and inadequate
zones. The circumflex artery pulsating against soft cutaneous synthesis. Infants who receive formula receive

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Chapter 3:  Metabolic Diseases of Bone and Effect of Glucocorticoid Therapy on Bone 101

adequate vitamin D, even without cutaneous synthesis. Treatment


Transplacental transport of vitamin D, mostly 25-D,
provides enough vitamin D for the first 2 month of life unless Adequate intake of vitamin D, calcium and phosphorous
there is severe maternal vitamin D deficiency. Breast-fed is the main stay of treatment in nutritional vitamin D
infants, because of the low vitamin D content of breast milk deficiency rickets, which can be administered by the
as almost 90% females in India are vitamin D deficient; rely following methods:
on cutaneous synthesis or vitamin supplements. Cutaneous •• Stoss therapy: 300,000–600,000 IU of vitamin D is
synthesis can be limited due to the ineffectiveness of the administered orally or intramuscularly as 2–4 doses over 1
winter sun and cultural practices. day. Because the doses are observed, Stoss therapy is ideal
Most infants present in late winters and spring, support in situations where adherence to therapy is questionable.
the impact of winter sun in the causation of decreased •• Alternate therapy: High dose vitamin D, with doses
cutaneous synthesis of vitamin. Vitamin D deficiency rickets ranging from 2,000–5,000 IU/day over 4–6 weeks.
may also occur secondary to unconventional dietary habits, Either strategy should be followed by daily vitamin D
such as use unfortified soy milk or rice milk. intake of 400 IU/day, typically given as a multivitamin. It
is important to administer adequate dietary calcium and
phosphorus; common sources for which are milk, formula
Clinical Features diets, and other dairy products.
These children have an increased risk of pneumonia and For the symptoms of hypocalcemia, patient may need
muscle weakness, leading to a delay in motor development. intravenous calcium acutely, followed by oral calcium
The clinical manifestations are typical of rickets with a few supplements, which typically can be tapered over 2–6 weeks
presenting even with symptoms of hypercalcemia and in children receiving adequate dietary calcium. Transient
prolonged laryngospasm is life threatening. use of intravenous or oral calcitriol is often helpful in
reversing hypocalcemia in the acute phase by providing
active vitamin D during the delay as supplemental vitamin D
Laboratory Findings is converted to active vitamin D. Calcitriol doses are typically
Hypocalcemia is a variable as blood calcium levels are 0.05 μg/kg/day. Intravenous calcium is initially given as
kept normal by secondary hyperparathyroidism. The an acute bolus for symptomatic hypocalcemia (20 mg/kg
hypophosphatemia is due to PTH-induced renal loss of of calcium chloride or 100 mg/kg of calcium gluconate).
phosphate and also decrease in intestinal absorption of Alternatively, a continuous intravenous calcium drip may
phosphate. be tried in some patients, which is titrated to maintain the
The calcitriol levels may be low, normal or high may be desired serum calcium level followed by conversion to oral
secondary to the upregulation of renal 1α-hydroxylase due calcium of approximately 1000 mg/day.
to associated hypophosphatemia and hyperparathyroidism.
The serum levels of calcitriol are normally much less than
the levels of 25-D, there is still often enough 25-D present
Prognosis
to act as a precursor for calcitriol synthesis in the presence The prognosis of nutritional rickets is excellent provided the
of an upregulated 1α-hydroxylase. In severe vitamin D cases are diagnosed early and are followed up thoroughly.
deficiency, the level of calcitriol may be low. There may be The radiological signs of improvement start appearing
metabolic acidosis and generalized aminoaciduria. within a few months and the laboratory parameters
also normalize within few weeks. Children with severe
deformities are the ones that are diagnosed late or are
Diagnosis and Differential Diagnosis neglected; are the ones who sustain permanent deformities.
The diagnosis of nutritional vitamin D deficiency is based on An orthopedic intervention may only be required to correct
the combination of a history of poor vitamin D intake and these residual deformities, but is undertaken only after the
risk factors for decreased cutaneous synthesis, radiographic bone disease is healed.
changes consistent with rickets and typical laboratory
findings (Table 12). A normal PTH level almost never
occurs with vitamin D deficiency and suggests a primary
Prevention
phosphate disorder. Calcium deficiency may occur with or In breast-fed children, daily administration of multivitamin
without vitamin D deficiency. A normal level of 25-D and a containing 200–400 IU of vitamin D can prevent nutritional
dietary history of poor calcium intake support a diagnosis rickets, and for others the diet should ensure adequate
of isolated calcium deficiency. vitamin D.

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102 Section 1:  Bone Anatomy, Physiology, Pathology and Diseases

SECONDARY VITAMIN D IU/day), titrated based in serum vitamin D levels. Doses of


even up to 4,000 IU/day may be needed in some resistant
DEFICIENCY patients.

Etiology
Congenital Vitamin D Deficiency
The deficiency of vitamin D occurring from causes apart
from inadequate intake (nutritional deficiency) is termed Congenital rickets is seen with severe maternal vitamin D
as secondary vitamin D deficiency, which may be due to: deficiency during pregnancy. The maternal risk factors are
•• Inadequate absorption similar to nutritional vitamin D deficiency and include poor
•• Decreased hydroxylation in the liver dietary intake of vitamin D, closely spaced pregnancies and
•• Increased degradation. lack of adequate sun exposure. These newborns along with
Because vitamin D is fat-soluble and its absorption from classic rachitic changes have:
GIT is dependent on bile acids, a variety of diseases of GIT •• Decreased bone ossification
may decrease its absorption, such as defects in metabolism •• Symptomatic hypocalcemia
of bile acids, liver diseases, malabsorption syndromes, •• Intrauterine growth retardation.
cholestatic liver disease, cystic fibrosis, celiac and Crohn’s There may be a defect in the dental enamel, neonatal
disease. Malabsorption of vitamin D can also occur with bone density and birth weight. These infants are predisposed
intestinal lymphangiectasia and after intestinal resection. to hypocalcemic tetany. Treatment of congenital rickets
Apart from decreased vitamin D absorption a decreased includes vitamin D supplementation and adequate intake
vitamin D synthesis occurs in severe liver disease, (also of phosphorous and calcium.
associated with malabsorption), a decrease in 25-D
formation due to insufficient enzyme activity. The reserve
of 25-hydroxlase activity is large and requires a loss of more VITAMIN D-DEPENDENT RICKETS
than 90% of liver function for impact. TYPE 1
Vitamin D dependent rickets type I or pseudovitamin D
Treatment deficiency is a genetic disorder with an autosomal recessive
Treatment of vitamin D deficiency due to malabsorption mode of inheritance. The disorder is the result of mutation
requires high doses of vitamin D. 25-D (25–50 μg/day in 1α-hydroxylase gene causing reduction in the available
or 5–7 μg/kg/day) is superior to vitamin D3 as it is better enzyme for ultimate hydroxylation step. This prevents
absorbed. Alternatively, calcitriol may be used which is conversion of 25-D into calcitriol. Those patients who
better absorbed in the presence of fat malabsorption, or present within first 2 years of life, can have any of the classic
with parenteral vitamin D. The dose is adjusted based on features of rickets, including symptomatic hypocalcemia.
monitoring of serum levels of 25-D. The treatment is the Typical laboratory findings include elevated PTH levels,
same for children with secondary vitamin D deficiency due decreased serum calcium, low or undetectable serum
to activation of P450 in the acute stage, and is followed by concentrations of calcitriol 1, 25-(OH)2 D despite normal or
prolonged administration of high dose of vitamin D (> 800 increased concentrations of calcifediol (25OHD) (Table 13).

TABLE 13: Laboratory findings in various “varieties” of rickets


Disorder Ca Pi 25-OHD 1,25-(OH)2D PTH AlkPhos Urinary Ca Urine Pi
Vitamin D deficiency N, ↓ ↓ ↓ ↓, N, ↑ ↑ ↑ ↓ ↑
VDDR, type 1 N, ↓ ↓ N ↓ ↑ ↑ ↓ ↑
VDDR, type 2 N, ↓ ↓ N ↑↑ ↑ ↑ ↓ ↑
Dietary calcium deficiency N, ↓ ↓ N ↑ ↑ ↑ ↓ ↑
X-linked hypophosphatemic N ↓ N RD N ↑ ↓ ↑
Dietary Pi deficiency N ↓ N ↑ N, ↓ ↑ ↑ ↓
Chronic renal failure N, ↓ ↑ N N ↑ ↑ N, ↓ ↓
ADHR N ↓ N RD N ↑ ↓ ↑
HHRH N ↓ N RD N, ↓ ↑ ↑ ↑
Tumor-induced rickets N ↓ N RD N ↑ ↓ ↑
Abbreviation: RD, relative decrease.

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Chapter 3:  Metabolic Diseases of Bone and Effect of Glucocorticoid Therapy on Bone 103

Treatment deficiency, patients have hyperphosphatemia as a result of


decreased renal excretion. In addition, failure to thrive and
Long-term treatment with calcitriol is the treatment for growth retardation may be accentuated because of the direct
VDDR type I. Initial doses are 0.25–2 μg/day, with lower effect of chronic renal failure on the growth hormone axis.
doses used once the rickets has healed, with adequate
intake of calcium. The dose of calcitriol is adjusted to
maintain a low normal serum calcium level, a normal Treatment
serum phosphorus level and a high normal serum PTH level Calcitriol is the treatment of choice. This permits adequate
to prevent possible complications of hypercalciuria and absorption of calcium and directly suppresses the
nephrocalcinosis. Patient is monitored during the therapy parathyroid gland. Sevelamer hydrochloride, a phosphate
with urinary calcium excretion, with a target of less than 4 binder used orally, and dietary restriction of phosphate to
mg/kg/day. regulate serum phosphate levels, as hyperphosphatemia is a
stimulus for PTH secretion. In addition, metabolic acidosis
VITAMIN D-DEPENDENT RICKETS may be corrected with alkalis.

TYPE 2 CALCIUM DEFICIENCY AND


This occurs due to mutations in the gene encoding the
VDR an autosomal recessive disorder, preventing a normal RICKETS
physiologic response to calcitriol because of end organ
resistance. More severely affected patients present in
Pathophysiology
infancy whereas less severely affected patients may not •• Poor weaning: One of the common causes of calcium
be diagnosed until adulthood. A less severe disease is deficiency rickets especially occurs in children who are
associated with a partially functional VDR. In a percentage weaned from breast milk early. The diet of these children
of patients, it may be associated with alopecia (ranging is low in calcium content (juice, soda or calcium-poor
from alopecia areata to alopecia totalis), which tends soy drink, without an alternative source of dietary
to be associated with a more severe form of the disease. calcium), typically less than 200 mg/day. There is little
Epidermal cysts may be associated, but is a less common intake of dairy products or other sources of calcium.
manifestation. Levels of calcitriol are extremely elevated and Also, the diet may be rich in phytates, oxalates and
serve to differentiate type II from type I VDDR. phosphates, e.g. green leafy which decrease absorption
of dietary calcium from GIT
•• Calcium deficiency rickets may also develop in children
Treatment who receive intravenous nutrition without adequate
A 3–6 month trial of high dose of vitamin D 2, 25-D or calcium
calcitriol and oral calcium is given for less severe form of •• Malabsorption syndromes, like celiac disease, intestinal
disease, especially those without alopecia. This response abetalipoproteinemia, and after small bowel resection
is due to a partially functional VDR. The initial dose of predisposes to calcium malabsorption. Along with other
calcitriol should be 2 μg/day. Oral calcium doses range from micro- and macronutrients there may be concurrent
1,000–3,000 mg/day. Unresponsive patients may be treated malabsorption of vitamin D.
with long-term intravenous calcium with possible transition
to very high dose oral calcium supplements. Patient not
responding to vitamin D are difficult to treat.
Clinical Manifestations
Children have the classic signs and symptoms of rickets.
Classically, the diet is deficient in dairy products.
RICKETS IN CHRONIC RENAL Presentation may occur during infancy or early childhood.
FAILURE Because calcium deficiency occurs after the cessation of
breast-feeding, it tends to occur later than the nutritional
In chronic renal failure, the activity of 1α-hydroxylase in vitamin D deficiency that is associated with breast-feeding.
the kidney is decreased, leading to diminished production
of calcitriol. Along with inadequate calcium absorption
and secondary hyperparathyroidism, the rickets may be
Diagnosis
worsened by the metabolic acidosis of chronic renal failure. Laboratory findings include increased levels of PTH,
In chronic renal failure, unlike the other causes of vitamin D calcitriol and ALP (Table 13). Serum calcium levels may

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104 Section 1:  Bone Anatomy, Physiology, Pathology and Diseases

be normal or low, although symptomatic hypocalcemia is the secreted frizzled-related protein-4 (SFRP-4) and matrix
uncommon. The urinary excretion of calcium is decreased extracellular phosphoglycoprotein that have shown to
and due to secondary hyperparathyroidism serum reduce renal sodium-dependent phosphate transport. Also,
phosphorus levels may be low due to renal wasting of among the mentioned phosphatonins, FGF-23 and SFRP-4
phosphate, which may also cause aminoaciduria. In inhibit 1, 25-dihydroxyvitamin D synthesis, which leads to a
some children, there is coexisting nutritional vitamin D decline in absorption of phosphates from the intestine and
deficiency; 25-D levels would then be low. also its retention in the body.

Treatment X-linked Hypophosphatemic Rickets


Children with dietary calcium deficiency respond X-linked hypophosphatemic rickets (XLH) is the most
dramatically to oral calcium supplementation. Typically common genetic disorder among the genetic disorders
as a dietary supplement doses of 350–1,000 mg/day of causing rickets due to hypophosphatemia, with a prevalence
elemental calcium are effective. Vitamin D supplementation of 1/20,000. It is an X-linked dominant disorder, the
is necessary, if there is concurrent vitamin D deficiency. In defective gene lies on the X chromosome and so the female
cases of malabsorption syndrome, calcium supplementation carriers are also affected.
is done parenterally followed by high oral calcium
supplements. Prevention strategies include discouraging Pathophysiology
early cessation of breast-feeding and increasing dietary The defective gene is called PHEX because it is a phosphate
sources of calcium. regulating gene with homology to endopeptidases on the
X chromosome location Xp22.2-p22.1. The PHEX gene
HYPOPHOSPHATEMIC RICKETS produces a protein that regulates another protein called
FGF-23 produced from FGF-23 gene, which appears to
Phosphorous Deficiency have either a direct or an indirect role in inactivating a
phosphatonin or phosphatonins. If the PHEX gene is
Pathophysiology absent the degradation of the phosphatonin, thus leading to
Inadequate intake: As phosphorous is present in most of increase in phosphate excretion and decreased production
the foods dietary deficiency of phosphorous is extremely of calcitriol. Also, in the absence of PHEX enzymatic activity,
rare, except in conditions of prolonged starvation or severe osteopontin (mineralization inhibiting protein) may
anorexia. accumulate in the bone to contribute to the osteomalacia.
Laboratory investigations in XLH reveal hypophosphatemia
Malabsorption: In malabsorption syndromes there is and inappropriately low level of 1, 25-(OH)2 vitamin D3. A
decreased absorption of phosphates along with the person affected by this disease usually cannot touch both
decreased absorption of other minerals also. Rickets knees and ankles together. It also affects their equilibrium,
develop in these cases due to simultaneous malabsorption only to the effect of their balance, which their knee or ankle
of vitamin D and/or calcium. joints are farther, either outward or inward.
Isolated phosphorous malabsorption: Rare cases of isolated
malabsorption of phosphorus occur in patients with long- Clinical Features
term ingestion of aluminum containing antacids. Chronic The clinical features are that of rickets with abnormalities
aluminum exposure results in hypophosphatemia with of lower extremity more as compared to upper limb with
rickets in children and secondary osteomalacia in adults. poor growth. Delayed dentition and tooth abscesses are also
This entity responds to discontinuation of the antacid and common. Some patients have hypophosphatemia and short
short-term phosphorus supplementation. stature without clinically evident bone disease.
Role of phosphatonin in hypophosphatemic rickets:
Phosphate plays a vital role in a number of other biological Laboratory Findings
processes, such as signal transduction, nucleotide Patients have high renal excretion of phosphate,
metabolism and enzyme regulation, and also phosphate hypophosphatemia and increased ALP; PTH and serum
ions are critical for normal bone mineralization. Our calcium levels are normal. Hypophosphatemia upregulates
understanding on role of phosphate in calcium homeostasis renal 1α-hydroxylase, so it is logically expected that there
comes from the study of rare disorders associated with is increased calcitriol, but these patients have low or
renal phosphate wasting. A number of proteins have been inappropriately normal levels possibly due to normal PTH
discovered like fibroblast growth factor (FGF)-23, FGF-7, and calcium levels that are potent regulators.

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Chapter 3:  Metabolic Diseases of Bone and Effect of Glucocorticoid Therapy on Bone 105

Treatment testing confirms the diagnosis. Treatment is similar to the


approach used in XLH.
A combination of oral phosphorus and calcitriol is given to
get an appropriate response. The daily need for phosphorus
supplementation is 1–3 g of elemental phosphorus divided Hereditary Hypophosphatemic Rickets
into 4–5 doses. Frequent dosing helps to prevent prolonged with Hypercalciuria (HHRH)
decrements in serum phosphorus because there is a rapid
decline after each dose also the side effects of high dose It is a rare disorder that is mainly described in the Middle
phosphorous, such as diarrhea is avoided. Calcitriol is East. It is an isolated real phosphate wasting disorder
administered 30–70 ng/kg/day divided into two doses. leading to low serum phosphate levels. Inherited in an
There may be complications associated with treatment, if autosomal recessive form. The distinguishing feature of
an adequate balance between phosphorus supplementation HHRH from other forms of hypophosphatemia is that, in
and calcitriol is not maintained. Excess phosphorus, by HHRH the serum levels of 1, 25-dihydroxyvitamin D are
decreasing enteral calcium absorption, leads to secondary elevated which results in hypercalciuria.
hyperparathyroidism, with worsening of the bone lesions.
In contrast, excess calcitriol causes hypercalciuria and Pathophysiology
nephrocalcinosis; it may even cause hypercalcemia. Hence, On chromosome 9 the candidate region contained a
laboratory monitoring of treatment should include serum sodium-phosphate cotransporter gene, SLC34A3, which
calcium, phosphorus, ALP, PTH, and urinary calcium, as has been shown to be expressed in proximal tubules
well as periodic renal ultrasounds to evaluate patients for cells. Sequencing of this gene revealed disease-associated
nephrocalcinosis. Normalization of ALP levels is a useful mutations in five families, including two frame shift and
method of assessing the therapeutic response than serum one splice site mutation. Loss of function of the SLC34A3
phosphorous. Growth hormone is an effective option for protein presumably results in a primary renal tubular
children with significant short stature. Children with severe defect and is compatible with the HHRH phenotype. The
deformities may need osteotomies, but this should be done phosphaturic factor FGF-23, which is increased in X-linked
only when treatment has led to resolution of the bone hypophosphatemic rickets and carries activating mutations
disease. in ADHR, is at normal or low-normal serum levels in the
patients with HHRH, further supporting a primary renal
Prognosis defect.
Girls, generally, have less severe disease than boys, probably
due to the X-linked inheritance. The response to therapy Clinical Manifestations
is usually good, although frequent dosing may lead to The dominant symptoms are rachitic leg abnormalities,
problems with compliance. Short stature may persist muscle weakness and bone pain. Patients may have short
despite healing of the rickets. Adults generally do well with stature, with a disproportionate decrease in the length of
less aggressive treatment, with receiving some calcitriol the lower extremities. The severity of the disease varies and
alone. Adults with bone pain or other symptoms improve some family members have no evidence of rickets, but have
with oral phosphorus supplementation and calcitriol. kidney stones secondary to hypercalciuria.

Laboratory Findings
Autosomal Dominant
Like other phosphate wasting disorders, HHRH is
Hypophosphatemic Rickets characterized by reduced tubular reabsorption of phosphate
This disorder is much less common than XLH. There (TRP) and hypophosphatemia. However, in contrast to
is incomplete penetrance and variable age of onset. In the characteristics of XLH and ADHR, serum levels of
autosomal dominant hypophosphatemic rickets (ADHR), calcitriol in HHRH are appropriately elevated for low serum
the gene encoding for FGF-23 is mutated. The mutated phosphorus levels despite suppressed parathyroid, there is
FGF-23 escapes degradation by the proteases, thus elevating elevated calcium excretion in urine.
its concentration. The actions of FGF-23, i.e. decreased
reabsorption of phosphates in the PCT and inhibition Treatment
of 1α-hydroxylase are overwhelmed, thus leading to Therapy relies on oral phosphorus replacement (1–2.5 g/
hypophosphatemia and decreased levels of calcitriol. day of elemental phosphorus in five divided oral doses).
In ADHR, as in XLH, abnormal laboratory findings are Treatment of the hypophosphatemia decreases serum levels
hypophosphatemia, an elevated ALP level and a low or of calcitriol and corrects the hypercalciuria. The accurate
inappropriately normal calcitriol level. Molecular genetic diagnosis of HHRH has important therapeutic implications.

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106 Section 1:  Bone Anatomy, Physiology, Pathology and Diseases

Unlike for XLH and ADHR, phosphate supplementation the world. Fifty-six million people living in 200 districts are
alone can cause a complete remission of HHRH and an at risk of developing fluorosis. Skeletal fluorosis occurs
addition of vitamin D may lead to complications, like due to excessive intake of fluoride both from drinking
hypercalcemia, nephrocalcinosis and renal damage. The water and food. The optimum upper safe limit is not more
response to therapy is usually excellent, with resolution of than 6 mg/day. Epidemiological and experimental studies
pain, weakness and radiographic evidence of rickets. There on fluorosis have greatly helped in understanding the
is also an increase in growth. disease and provided a rational approach of management
of the menace of fluoride toxicity. States known to be
Overproduction of Phosphatonin endemic in various parts of India include Assam, Andhra
Pradesh, Bihar, Delhi, Gujarat, Haryana, Jammu & Kashmir,
Overproduction of phosphatonins is one of the pathogenesis Karnataka, Kerala, Maharashtra, Orissa, Punjab, Rajasthan,
in tumor-induced osteomalacia (TIO). It is more common Tamil Nadu, Uttar Pradesh, West Bengal. The first case
in adults than in children. It is a type of paraneoplastic report of endemic skeletal fluorosis was from Prakasam
syndrome. If at all it develops in children, the manifestations district, Andhra Pradesh in 1937, a province in south India.
are characteristic of hypophosphatemic rickets. Tumors There was also a report of neurologic manifestations of
associated with TIO are usually mesenchymal in origin, fluorosis, which usually occurs in the later stages of the
usually benign, small and located in bone. These tumors disease. The fluoride levels in these areas were surprisingly
secrete a number of different putative phosphatonins low, i.e. in a range of 1–3 ppm, which is unusual as skeletal
(FGF-23, frizzled-related protein 4 and matrix extracellular fluorosis rarely occurs at levels less than 6 ppm. The
phosphoglycoprotein), with different tumors secreting possible mechanisms through which fluorosis occurred in
different phosphatonins or combinations of phosphatonins. these areas are as follows:
These phosphatonins produce a biochemical phenotype that •• High atmospheric temperatures (115–116°F) during
is similar to XLH and ADHR, including urinary phosphate summer months so people drink lot of water
wasting, hypophosphatemia, low or inappropriately •• Hard physical labor activity again leads to increased
normal calcitriol levels and elevated ALP levels. Cure can water intake
be achieved by excision of the tumor. If the tumor is not •• Poor nutrition, deficient in calories and also vitamin C
resectable, the line of treatment is similar to that of XLH. •• Impaired renal function
Renal phosphate wasting leading to hypophosphatemia •• Abnormal concentrations of certain trace elements, like
and rickets (or osteomalacia in adults) is a potential strontium, silica, uranium, calcium, magnesium, etc. in
complication in McCune-Albright syndrome. Triad of high concentration in water and food could influence
McCune-Albright syndrome includes fibrous dysplasia, fluoride toxicity.
hyperpigmented macules, and polyendocrinopathy. There
are inappropriately low levels of calcitriol and elevated levels
of ALP. Patients have elevated levels of the phosphatonin
Clinical Features
FGF-23, presumably produced by the dysplastic bone. Clinical manifestations of fluoride toxicity have uniformity
The renal phosphate wasting and inhibition of calcitriol in the clinical presentation. Fluorosis in humans is
synthesis are related to the polyostotic fibrous dysplasia. predominantly dental and skeletal. Dental fluorosis occurs
Hypophosphatemic rickets can also occur in children early in the disease process followed by a prolonged
with isolated polyostotic fibrous dysplasia. Although a symptom free period of nearly 10–30 years which is
rare possibility, removal of the abnormal bone can cure ultimately followed by a crippling skeletal fluorosis and
this disorder in children with McCune-Albright syndrome. neurologic abnormalities. During the apparent symptom
The treatment is same as that for XLH. Additionaly, free stage, the body keeps on accumulating excess fluoride
bisphosphonate treatment decreases the fracture risk and and the patient suffers from vague gastrointestinal
pain associated with the bone lesions. It also decreases the symptoms. The neurological manifestations in skeletal
elevated ALP level. fluorosis are dominated by radiculomyelopathy that arise
primarily due to mechanical compression of the nerve
roots and also the spinal cord from osteophytes, sclerosed
FLUOROSIS vertebral column and ossified ligaments. The cervical cord
is involved earlier than the dorsal cord. The lumbar spine
Introduction is the first to show skeletal changes, but the involvement
Skeletal fluorosis is an endemic metabolic disease of bones, of cauda equina is rare. Minor trauma may precipitate
widely prevalent in India and many other countries around neurologic deficits.

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Chapter 3:  Metabolic Diseases of Bone and Effect of Glucocorticoid Therapy on Bone 107

In skeletal fluorosis, higher mental function defects random or morning samples. In normal individuals, urinary
and cranial nerve palsies are extremely rare. The motion of fluorides fluctuate widely between 0.1 and 2.0 ppm (average
the spine is restricted. Sodium fluoride has antimuscarinic 0.4 ppm) when the fluoride content of drinking water is 0.3
and curare like effect on myoneural tissue, although it has ppm. There is a linear relation between urinary fluoride
no effect on normal muscle membrane potentials even levels and fluoride intake.
in the endplate region. There is yet no evidence of direct Normal blood fluoride levels in nonendemic regions
neurotoxicity of fluoride. vary between 0.002 mg/100 mL and 0.008 mg/100 mL and
in endemic regions the levels range between 0.02 mg/100
Pathogenesis mL and 0.15 mg/100 mL, whereas in patients with skeletal
fluorosis the levels vary between 0.02 mg/100 mL and 0.19
Inorganic fluoride replaces the hydroxyl groups of calcium mg/100 mL. It is much less a useful reference for detecting
hydroxyapatite forming calcium fluorapatite and gets fluoride toxicity as major portion is mineral bound. Also,
deposited in bone. Osteons become irregular in shape, flash blood samples fail to capture the varying fluoride levels
size and distribution in compact bone and there is gross with bone metabolic activity that is better studied from 24-
reduction in spongiosa. The Haversian canals get enlarged hour urinary levels.
with concomitant irregular distribution of osteocytes and Retention of fluoride is measured by the bone fluoride
increased irregular interstitial lamellae. Excess fluoride levels and it can be used to monitor the fluoride treatment
makes invasion by capillaries difficult in the bone forming of osteoporosis. The value varies from 6,000 ppm to 8,400
uneven paths and resulting in isolated cartilage islands. ppm in bone ash in fluorosis, normal between 500 ppm and
Bone marrow becomes fibrous and poor in cells, while there 1,000 ppm or mg/kg.
is secondary hyperparathyroidism due to reduced systemic
calcium, producing a high bone turnover state. This may also
be aided by osteoblast activation from enhanced expression Radiology
of transcription factors such as activator protein-1 (AP-1) The radiographic findings are parallel to pathological
and Cbfa1, as well as upregulation of cytokines or growth changes. The bone tissue continues to be formed, but the
factors such as bFGF, BMP-2, IGF, transforming growth trabeculae thus formed have uncalcified borders and are
factor β (TGFβ), platelet-derived growth factor (PDGF) and resistant to reabsorption by osteoclasts.
osteoprotegerin ligand (OPGL). Radiological stages of skeletal fluorosis:
Although fluoride is known to stimulate bone •• Stage I—axial skeleton involvement and ground glass
formation, the underlying mechanisms are not fully appearance of cancellous bone.
understood. Recent studies have implicated the Wnt/β- •• Stage II—thick primary trabeculae merge with sclerotic
catenin pathway as a major signaling cascade in bone secondary trabeculae to make bone homogeneously
biology. The current study determined the involvement of dense, bone contours become uneven and calcification
Wnt/β-catenin signaling in fluoride-induced osteoblastic of paraspinous, sacrospinous and sacrotuberous
differentiation, fluoride significantly promoted osteoblasts ligaments is seen.
proliferation and ALP expression as well as the mRNA •• Stage III—axial skeletal bones demonstrate the typical
expression levels of bone differentiation markers, radiological features, marked calcification at the
including COL1A1, ALP and osteonectin. The positive insertion of muscles and tendons. There may be overlap
effect of fluoride on ALP activity and mRNA expressions of radiological features.
of COL1A1, ALP, osteonectin and Runx2 was abolished Osteosclerosis (dense bone) is the typical feature of
by DKK-1, a blocker of the Wnt/β-catenin receptor. Taken involved axial skeleton (spine, pelvis and ribs), whereas as
together, these findings suggest that fluoride promotes osteoporosis mainly involves the appendicular skeleton.
osteoblastic differentiation through Akt- and GSK-3B- Skeletal fluorosis produces a spectrum of bone changes,
dependent activation of Wnt/β-catenin signaling pathway including osteoporosis, exostoses, osteomalacia, changes
(see also osteoporosis). resulting from secondary hyperparathyroidism and their
combination.
Diagnosis Imaging: The best imaging modality to appreciate
bony pathology is computerized tomography. Computed
Urinary and Bone Fluoride tomography provides more details than plain radiographs.
Urinary fluoride levels are the best indicators of fluoride Calcified ligaments, spinal canal stenosis and root canal
intake. Since, fluoride excretion is not constant throughout stenosis are also better appreciated with computed
the day, 24-hour samples of urine are more reliable than tomography.

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108 Section 1:  Bone Anatomy, Physiology, Pathology and Diseases

A fluorotic vertebrae appears hypointense in both T1- •• A combination of these lesions. OPLL is very common
and T2-weighted images. in skeletal fluorosis.
Cord compression at the level of dorsal spine is of three
Prevention of Fluorosis types:
1. Localized posterior osteophytes spread over many
Prevention of fluorosis is better than cure, as no cure is vertebral levels, though technically feasible for excision,
possible once the disease sets in. the results are not so rewarding.
2. Localized posterior osteophitic or ossified ligamentous
Endemic Fluorosis compression, where results are likely to be excellent.
Defluoridation of drinking water supplies are based on 3. Diffuse, extensive where surgery is not beneficial.
Nalgonda method (named after the village in India where
the method was pioneered) of lime and alum, employs the
flocculation principle and uses domestic units. The method
GAUCHER’S DISEASE
is based on filtration of fluoride rich water with activated This autosomal recessive genetic disorder, first described
alumina (PAC granules). There is criticism to this technique by Gaucher over 100 years ago, is now known to be caused
for possibility of aluminum toxicity also aluminum has by lack of a specific enzyme glucosylceramide beta-
been incriminated in the causation of amyotrophic lateral glucosidase, which is responsible for the breakdown and
sclerosis (ALS) and Parkinson’s disease. Other methods of the excretion of the cell membrane products from defunct
defluoridation include electrochemical methods, cation cells. Persistent work on the understanding of pathogenesis
exchange resins, florex, etc. Nutrition has a crucial role in of disease has led to development of an effective treatment.
the severity of fluorosis, and hence a balanced diet having
adequate calcium and vitamins could reduce the toxicity Pathogenesis
to fluoride.
On the death of a cell in the body a glucocerebroside is
Industrial Fluorosis released from the cell membrane. Before the excretion of
the glucocerebroside, the glucoside bond is split by the
A monitoring of urinary fluoride levels should be done in
enzyme glucosylceramide beta-glucosidase, which releases
workers in industries and mining exposed to fluorides to
the glucose molecules. If there is deficiency of this enzyme,
keep the levels below 5 ppm. It is observed that skeletal
the glucocerebroside are not excreted out of the lysosomal
fluorosis does not occur in well-nourished individuals
bodies of macrophage of reticuloendothelial system and
unless the levels exceed more than 5,000 ppm.
keeps on accumulating, mainly in the marrow, spleen and
liver. These abnormally accumulated macrophages in the
Spine Surgery in Skeletal Fluorosis marrow, spleen and liver are mostly responsible for their
Surgery in spine fluorosis is beneficial in the early stage of enlargement and also secondary changes in the marrow
the disease when only a few spinal segments are involved. and bone.
The neurological deficits in fluorosis are mainly mechanical. Depending on the presence and absence of neurologic
The challenges encountered in operating a fluorotic spine involvement Gaucher’s disease is divided into three
include: subtypes:
•• Difficulty in positioning of the spine during surgery 1. Type 1: Non-neuronopathic form
•• Difficulty in intubation during anesthesia because of 2. Type 2: Acute neuronopathic form
the rigid cervical spine 3. Type 3: Chronic neuronopathic form
•• High risk for postoperative respiratory complications Most patients suffer from a chronic form of disorder, with
because of restricted chest movements and reduced changes predominantly in the marrow, bone, spleen and
vital capacity. varying degree of pancytopenia. A rare form of the disease
Operative outcomes with cervical spine operation are affecting central nervous system, appear in infancy and
better as compared to dorsal spine. Compression at lumbar usually causes death within a year.
vertebrae rarely requires decompression. Like other storage disorders, Gaucher’s disease is
Causes of cord compression at the level of cervical spine: transmitted as an autosomal recessive trait. Males and
•• Canal stenosis females are affected equally with relative high incidence
•• Calcification of ligamentum flavum in Jewish people of Ashkenazi descent. The phenotype is
•• Osteophytes compressing the cord anteriorly associated with a large number of different gene defects,
•• Ossification of posterior longitudinal ligament (OPLL) five of which appear in the majority of cases.

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Chapter 3:  Metabolic Diseases of Bone and Effect of Glucocorticoid Therapy on Bone 109

Clinical Features reverse the blood changes and reduce the size of liver and
the spleen. For acute episodes, analgesics and bed rest may
In the most common form of disease (type I), patients relieve the symptoms.
present in the childhood or adult life with anemia,
thrombocytopenia, hepatosplenomegaly or bone pain,
about two-thirds of affected people develop skeletal MUCOPOLYSACCHARIDOSES
abnormalities. Back pain due to vertebral osteopenia
and compression fractures may be the predominant Introduction
complaint in older patients. Femur neck fractures also Mucopolysaccharidoses (MPS) are a part of lysosomal
are not uncommon; however, diaphyseal fractures storage disease family which occurs due to deficiency
are rare. The hemoglobin concentration and platelet or malfunctioning of lysosomal enzymes required for
counts are usually diminished, there may be elevation breakdown of glycosaminoglycans (GAGs, formerly called
of serum acid phosphatase level which is present and is mucopolysaccharides). These GAGs help to build bone,
suggestive of diagnosis. The diagnosis can be confirmed by cartilage, tendons, corneas, skin, joint fluid and other
demonstrating low glucocerebrosidase activity in the blood connective tissues. People with MPS, either do not produce
or by identifying abnormal gene mutation in DNA tests. enough of one of the eleven enzymes required to breakdown
The orthopedic manifestations of Gaucher’s range from these sugar chains into simpler molecules or they produce
osteomyelitis to osteonecrosis. An orthopedic surgeon should defective enzymes resulting in accumulation of partially
recognize them early. Patients with Gaucher’s are at increased degraded GAGs in lysosomes and causing symptoms.
risk of pathological fractures and abnormal bone remodeling,
there is increased incidence of delayed and nonunion and
there may be increased intraoperative bleeding. Two most
Epidemiology
common complications of Gaucher’s are osteomyelitis It affects 1 in 25,000 babies and is autosomal recessive
and osteonecrosis of femoral head, femoral condyle and disorder, except MPS II which is inherited in X-linked
proximal humerus. The presentation of osteonecrosis and recessive manner. Over time GAGs collect in various organs
osteomyelitis may overlap, warranting an accurate diagnosis and connective tissues affecting their function.
and appropriate treatment at the earliest. The patients (usually
a child or adolescent) may present with an acute bone crisis, Clinical Features
with unrelenting pain, local tenderness and restriction
of movement, accompanied by pyrexia, leukocytosis and The clinical features are often not apparent at birth, but
elevated erythrocyte sedimentation rate (ESR). appear later with progressive storage of GAGs damaging the
target organs (bone, connective tissue and other organs).
Damage to neurons from compression of nerves or nerve
Imaging roots in the spinal cord or in the peripheral nervous system
X-ray shows a variable pattern of radiolucency or patchy causes pain and impaired motor function. CNS deterioration
density, more marked in cancellous bone. The distal end depends on MPS subtype and affected individuals may have
of femur may be expanded, producing Erlenmeyer flask normal intellect or variable retardation of mental functions.
appearance. A skeletal survey, may lead to reversal of Individuals also have variable hearing loss (conductive or
osteonecrosis of femoral head, femoral condyles, talus or sensorineural or both). Recurring respiratory infection
humeral head. are common and many affected individuals have cardiac
A radioisotope bone scan may help to distinguish a disease. Vision is affected by cloudy cornea along with
crises episode from infection, the former is usually “cold” degeneration of retina.
and the latter is “hot”. MRI is the most reliable way of Physical symptoms generally include:
defining marrow involvement. •• Coarse facial features (Fig. 25) (flat nasal bridge, thick
lips and enlarged mouth and tongue)
•• Thickened skin
Treatment •• Excessive body hair growth
Osteonecrosis of femoral head usually results in progressive •• Claw-like hands
deformity of the hip. However, most patients manage •• Joint stiffness
quiet with symptomatic treatment, and surgery should •• Carpal tunnel syndrome
be deferred for as long as possible. Bone pain may need •• Short stature with disproportionately short trunk
symptomatic treatment. Specific therapy in the form of (dwarfism), dysplasia (abnormal bone size and/or
alglucerase enzyme replacement. It has been shown to shape) and other skeletal irregularities

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110 Section 1:  Bone Anatomy, Physiology, Pathology and Diseases

years. There is progressive mental retardation, limited


language development (hearing loss and macroglossia)
and loss of physical skills. Vision loss occurs early due
to corneal clouding. Carpal tunnel syndrome and
restricted joint movement are common. Children
sometimes develop a short body trunk, hirsutism and
distinct coarse facial features. By age of 2 years, the
ribs have widened and are oar-shaped. Organomegaly
(hepatosplenomegaly and heart), feeding difficulty
and periodic bowel problems are common. Children
with Hurler’s syndrome often die before 10 years from
obstructive airway disease, respiratory infections and
cardiac complications.
Children may experience noisy breathing and recurring
upper respiratory tract and ear infections. Severe
form of the disease may present with dysostosis
Fig. 25: Rough facial features of mucopolysaccharidosis, also note multiplex showing severe skeletal abnormalities seen
the frontal bossing, gaped teeth and gingival hypertrophy with a on radiographs.
thickened protruding tongue. The patients are mentally retarded. There •• MPS IS (Scheie Syndrome): It is the mildest form of
is hypertelorism and depressed nasal bridge MPS I. The disease is diagnosed until adulthood as the
symptoms are very mild. The average age of presentation
is 10–20 years. Intellectually, the children may be normal
•• Hepatosplenomegaly
or may have mild learning disability or severe psychiatric
•• Hernia.
problems. The clinical features may include retinal
Various types of MPS have been described (MPS V and
degeneration, glaucoma, clouded corneas, short neck,
MPS VIII are no longer recognized): In general, the clinical
but normal stature, stiff joints, claw hands carpal tunnel
features of MPS can be grouped as under that present with
syndrome or other nerve compression, deformed feet,
varying severity.
sleep apnea and aortic valve disease.
•• Ophthalmologic disease: Corneal clouding, glaucoma,
•• MPS I H-S (Hurler-Scheie Syndrome): It is less severe
chronic papilledema and retinal degeneration
than Hurler’s syndrome alone. Caused by a homozygous
•• Vestibulocochlear system: Deafness
or compound heterozygous mutation in the gene
•• Central nervous system involvement: Hydrocephalus
encoding alpha-L-iduronidase on chromosome 4p16.
and myelopathy, especially in cervical spine due to
Symptoms generally start appearing between 3 years
stenosis
and 8 years. Children may have normal intelligence or
•• Cardiovascular disease: Hypertension, cardiomegaly,
moderate mental retardation and learning difficulties.
valvular dysfunction and congestive cardiac failure
Other symptoms include short stature, corneal clouding,
•• Abdominal: Hepatomegaly, umbilical hernia and
joint stiffening, umbilical hernia, dysostosis multiplex,
inguinal hernia
hepatosplenomegaly, micrognathia, progressive joint
•• Pulmonary disease: Airway obstruction, sleep apnea,
stiffness and compressed spinal cord, clouded cornea,
respiratory compromise, recurrent infections and cor
hearing loss, heart disease, coarse facial features and
pulmonale
umbilical hernia. Respiratory problems sleep apnea
•• Musculoskeletal disease: Short stature, joint stiffness
and heart disease may develop in adolescence. Some
and skeletal abnormalities
person with MPS I H-S, need continuous positive
•• Peripheral nervous system: Nerve root compression and
airway pressure during sleep, to ease breathing. The life
peripheral nerve compression neuropathies.
expectancy is generally limited till teens or late twenties.
MPS I: MPS I is further subdivided into three types (all MPS II [Hunter Syndrome, iduronate sulfatase deficiency,
three types result from an absence of or insufficient levels iduronate-2-sulfatase (IDS) deficiency, Sulfoiduronate
of enzymes, alpha-L-iduronidase) based on severity of the sulfatase deficiency, SIDS deficiency]. Incidence is 1 in
symptoms 100,000–150,000 male births.
•• MPS IH (Hurler’s syndrome): It is the most severe of •• MPS II is caused by lack of enzyme iduronate sulfatase
the MPS I subtypes and though normal at birth they and occurs almost exclusively in males (X-linked
usually stop developing between ages of 2 years and 4 recessive). Patients with Hunter syndrome are normal

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Chapter 3:  Metabolic Diseases of Bone and Effect of Glucocorticoid Therapy on Bone 111

at birth, but develop either of the two clinical subtypes Little clinical difference occurs between the four types,
by age 2–4 years. Since, it shows X- linked recessive but symptoms appear most severe with type A and they live
inheritance, the mother alone can pass the defective for 8 years to 10 years, following onset of symptoms. For
gene to a son. other subtypes, the patients live into their teenage years and
•• MPS IIA: Onset of the disease is at 2–4 years of age. It some even longer. The incidence of Sanfilippo syndrome is
is a more severe form of Hunter syndrome. The clinical about 1 in 70,000 births.
features are similar to that of Hurler’s syndrome (MPS MPS IV: MPS IV, Morquio syndrome is a progressive
I H), but with milder symptoms. Features resemble disease that occurs in 1 in 700,000 births and mainly
Hurler’s disease, but no corneal clouding is seen. Whitish affects skeleton. Its two subtypes result from the missing
skin lesions (Pebbly ivory skin lesions) may appear on or deficient enzymes, N-acetylgalactosamine-6-sulfatase
upper arms back and upper legs. Cardiomegaly, carpal (type A, mutation of GALNS gene) or beta-galactosidase
tunnel syndrome and cardiac valve abnormalities are (type B, mutation of GLB1 gene) which are required for
common in this disorder. Death from upper airway the breakdown of the keratin sulfate sugar chain. Clinical
disease or cardiovascular failure usually occurs by age features though similar in both types are milder in Morquio
of 15. Hydrocephalus and aggressive behavior seen. type B. Symptoms start appearing between age 1 year and
•• MPS IIB: Physical characteristics of MPS IIB are less 3 years. Skeletal abnormalities include a bell-shaped chest,
obvious and progresses at a much slower rate with no a flattened curvature of spine, dysplasia of hips, shortened
hydrocephalus. There is loss of hand function. Diagnosis long bones, knock knees and ankles and wrists. The joints
is often made in the second decade of life. Persons with are hypermobile, but some patients may have stiffness due
MPS IIB may live into their 50s or beyond. to contracture. In patients with odontoid hypoplasia and
MPS III (Sanfilippo syndrome): It is the most common MPS spinal cervical spine fusion is mandatory. Neurological
disorder characterized by severe neurological symptoms complications include spinal nerve root compression,
including progressive dementia, hyperactivity, seizures, conductive and neurosensory loss of hearing, and clouded
aggressive behavior and inability to sleep for more than a corneas. Intelligence is normal, but physical growth slows
few hours at a time and only minimal somatic involvement. and often stops between 4 years and 8 years. Restricted
Brain and spinal cord are the main targets. During early breathing, corneal clouding and heart diseases are also
disease the affected children show a marked decline in common.
learning between 2 years and 6 years, followed by eventual
loss of language skills and loss of some or all hearing. MPS VI: Maroteaux–Lamy syndrome, share physical
With growth the children acquire an aggressive behavior, features as in Hurler’s syndrome and usually has normal
hyperactivity, profound dementia and irregular sleep, intellectual development. The disease is progressive with
making them difficult to manage particularly those who organomegaly that become inflamed and scarred later. It is
retain physical strength. Later children become increasingly caused by mutations in ARSB gene, coding for the enzyme
unsteady on their feet and most are unable to walk by the arylsulfatase B. Complications include deafness, clouded
age of 10 years. Thickened skin and mild changes in facial corneas, thickening of the dura and pia compressing nerve
features, bone and skeleton structures become noticeable roots. Growth is normal at first, but stops suddenly around
with age, but are much less pronounced. By the age of 8 years. These patients also have dysostosis multiplex
10 years the growth usually stops. Mutations in the GNS, (multiple radiologically seen skeletal abnormalities). By
HGSNAT, NAGLU and SGSH genes occur in MPS III. There age of 10 years children have developed a shortened trunk,
are four distinct types of Sanfilippo syndromes. crouched stance and restricted joint movement. Nearly all
1. Sanfilippo A (mutation of SGSH gene): Most severe of children have some form of heart disease, usually involving
the MPS III and is caused by missing or altered enzyme valve dysfunction. An enzyme replacement therapy tested
heparan N–sulfatase. Children with Sanfilippo A have on patients with MPS VI had limited success in improving
the shortest survival rate among with those with MPS growth and joint movement.
III disorders. MPS VII: MPS VII, Sly syndrome, one of the least common
2. Sanfilippo B (mutation of NAGLU gene): Caused by forms of MPS, it is estimated to occur in less than 1 in
deficient alpha-N-acetylglucosaminidase. 250,000 births, but interestingly was the first autosomal
3. Sanfilippo C (mutation of HGSNAT gene): Results from MPS for which chromosomal assignment was achieved. It
mutations in the encoding gene for acetyl-CoA-alpha- is caused by deficiency of enzyme beta-glucuronidase. The
glucosaminide acetyltransferase. rarest of its forms, there occurs hydrops fetalis, in which
4. Sanfilippo D (mutation of GNS gene): Due to deficiency large amount of fluid is retained by the body. The fetus
of N-acetylglucosamine-6-sulfatase survives up to less than a month.

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112 Section 1:  Bone Anatomy, Physiology, Pathology and Diseases

MPS IX: Natowicz syndrome or online Mendelian inheritance prevent the disease progression, but limiting milk, sugar and
in man (OMIM) results from hyaluronidase deficiency dairy products has helped some individuals experiencing
arising out of heterozygous mutation in the HYAL1 gene on excessive mucus. Medical treatment is directed at treating
chromosome 3p21. It is an autosomal recessive disorder. systemic conditions and improving the person’s life quality.
Symptoms include nodular soft tissue masses located Enzyme replacement therapy has proved useful in reducing
around joints with episodes of painful swelling of the masses non-neurological symptoms and pain. Limited number of
and pain, the pain that ends spontaneously within 3 days. enzyme therapies has been introduced with partial benefits
These arise from the accumulation of nodular aggregates demonstrated in various disorders:
of histiocytes around and in joints, may be the result of the •• Laronidase is a recombinant human alpha-L-
failure of catabolism of hyaluronan by hyaluronidase. Pelvic iduronidase polymorphic variant that has been used
radiography, showed multiple soft tissue masses and some for treatment of MPS IH and MPS H-S forms. Improved
bone erosion. Other traits included mild facial changes walking capacity and pulmonary function have been
acquired short stature, as seen in other MPS disorders and reported in these patients.
normal joint movement and intelligence. •• Idursulfase is a purified form of human lysosomal IDS
and has been used in MPS II with limited success.
•• Elosulfase alfa is recently approved for treatment of
Diagnosis Moriquio A syndrome (MPS IVA). The treatment has
Diagnosis is usually established by clinical examination. been shown to improve the walking distance in these
Urine test [excess mucopolysaccharides are excreted in patients.
the urine, (Table 14)] and enzyme assays (Table 14) are Surgery can be done to repair hernia and ventriculo­
helpful in confirming the diagnosis. Prenatal diagnosis, peritoneal shunting to drain excessive cerebrospinal fluid
using amniocentesis (15th–16th week) and chorionic villus from the brain and decompress nerves (carpal tunnel
sampling (9th week), can verify the fetus either carries release) and nerve roots compressed by skeletal and other
a copy of defective gene or is affected with this disorder. abnormalities. Corrective osteotomy for deformity correction
Heterozygote identification in Hunter syndrome can be at knee and hip containment surgeries can be done in
done with hair root analysis and single cell cloning of specific patients. Spinal fusion can prevent progression of
fibroblast. Genetic counseling can help parents with history kyphosis and scoliosis. Corneal transplantation may improve
of MPS in family. vision among patients, with significant corneal clouding.
Bone marrow transplantation (BMT) and umbilical cord
blood transplantation (UCBT) have met with limited
Treatment success in treating MPS. Abnormal physical characteristics
At present there is no cure for these disorders. Physical other than for those affecting the skeleton and eyes may
therapy and daily exercises may delay joint problems and be improved, but neurological outcome may have varied
improve the ability to move. Changes to the diet will not improvement. BMT and UCBT are high risk procedure and

TABLE 14: The enzyme serum assays and urinary excretion of degradation products in various MPS
MPS type Enzyme deficiency Urinary excretion product
MPS IH (Hurler syndrome) α-L-Iduronidase Dermatan sulfate, heparan sulfate
MPS IS (Scheie syndrome) α-L-Iduronidase Dermatan sulfate, heparan sulfate
MPS I-H/S (Hurler-Scheie syndrome) α-L-Iduronidase Dermatan sulfate, heparan sulfate
MPS IIA (Hunter syndrome, severe and mild) Iduronate sulfatase Dermatan sulfate, heparan sulfate
MPS IIIA (Sanfilippo syndrome A) Heparan N–sulfatase Heparan sulfate
MPS IIIB (Sanfilippo syndrome B) N–acetylglucosaminidase Heparan sulfate
MPS IIIC (Sanfilippo syndrome C) Acetyl-coenzyme A: Alpha-glucosamine-N-acetyl transferase Heparan sulfate
MPS IIID (Sanfilippo syndrome D) N-acetyl alpha-glucosamine-6-sulfatase Heparan sulfate
MPS IVA (Morquio syndrome A) N-acetylgalactosamine-6-sulfatase Keratan sulfate
MPS IVB (Morquio syndrome B) β-galactosidase Keratan sulfate
MPS VI (Maroteaux-Lamy) N-acetylgalactosamine-4-sulfatase Dermatan sulfate
MPS VII (Sly syndrome) β-glucuronidase Dermatan sulfate, heparan sulfate

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Chapter 3:  Metabolic Diseases of Bone and Effect of Glucocorticoid Therapy on Bone 113

are usually performed only after family members receive be well versed in identifying and treating the disorder
extensive evaluation and counseling. meticulously to prevent associated morbidity and
mortality.
•• One must also try to keep abreast with the drug
CONCLUSION interactions and use of newer drugs for the management
•• Though bone is a hard tissue it is a metabolically active of osteoporosis as they are emerging.
tissue taking part actively in calcium and phosphate •• Rickets is a common disorder in India, especially
metabolism among others. in the underprivileged population and must be
•• The bone is subjected to various metabolic disorders handled in association with pediatrician for associated
by virtue of active participation in mineral metabolism. abnormalities and complete management.
Osteoporosis is probably the most rampant of the •• Metabolic disorders due to enzyme deficiencies are
disorder in the world and is the most common metabolic quite challenging to manage, however, supportive
disorder of bone. Every orthopedic surgeon, whether care should be provided to the patients as best as we
trauma specialist or reconstruction or sports physician can. Emerging therapies will possibly provide the
will encounter the disorder in his practice and should unfortunate patients with cure someday.

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Chapter

4 Infections of Bone

Manish Kumar Varshney

nonpurulent osteitis that is further subdivided into acute


¾¾ Osteitis and osteomyelitis (OM) the core difference and purulent, subacute purulent and chronic purulent osteitis
preferential terminology based on clinical findings. Hofmann proposed two clinical
¾¾ Definition of types, various classifications and a brief of subacute presentations of osteitis.
form 1. Acute postoperative osteitis: Here the bacterial infection
¾¾ History and pathogenesis. Older concepts (criticism), modern occurs within 8 weeks of trauma or an operation.
concept—including influence of implants, implant bacteria 2. Chronic osteitis: Here the infection in bone and
interface, biofilm model surrounding soft tissues occurs more than 8 weeks after
¾¾ Diagnosis, imaging and functional imaging treatment or injury.
¾¾ Principles of therapy for acute and chronic OM
¾¾ Various techniques used for local drug delivery, dead space OSTEOMYELITIS
management and tissue reconstruction
¾¾ Complications and prevention Osteomyelitis refers to a primary infection of the bone
¾¾ Discussing some atypical and uncommon unique forms of OM. marrow (myelitis) with subsequent affection of the bone
(cortex) and periosteum. The term was coined by Nelaton
in 1844 (also see history below). OM is generally categorized
INTRODUCTION into acute or chronic forms based on histopathological
findings. Using these pathological and anatomical
The infections of bone are broadly grouped under osteitis or criteria the differentiation between acute and chronic
osteomyelitis (OM). This differentiation is not very obvious hematogenous OM and acute and chronic exogenous (post-
clinically and also the treatment is mainly control of infection traumatic or postoperative) osteitis has been elucidated
in both. Central to understanding the distinction but is the by many authors. We will refer to infection of bone as OM
way of infection affects the bone in osteitis and OM. throughout the chapter and the book as distinction between
•• Centripetal progression of infection occurs in osteitis these two terms is very difficult in clinical practice and it
where the bone is affected at periphery first (usually hardly ever makes any difference in management. Also
periosteum) we feel that the distinction between acute and chronic
•• Centrifugal progression of infection from marrow forms is very important especially considering the different
(usually the first affected site) to periphery occurs in OM. treatment approaches, prognosis, length of treatment and
Osteitis is mostly a pyogenic bone infection (of the expectations. They strictly represent a spectrum (developing
whole bone including cortex) that may lead to the complete temporally) of bone infection that should be understood
destruction of the infected bone but also of the surrounding in continuity. Only rarely will chronic OM develop without
soft tissues. Rather than osteitis, periosteitis is more clearly acute form (except like in subclinical implant related OM).
recognized and is often the initial stage of developing osteitis. The distinction between acute and chronic forms is “strictly
Being excruciatingly painful this is promptly treated hence NOT based on duration”. However, as the chronic form takes
full blown osteitis rarely develops. In late stages osteitis some time (few weeks—6 weeks) to develop (recognized by
is similar to OM clinically and pathologically so current necrotic bone and reactive bone formation) so quite often
literature does not make any clear distinction between the surgeons refer to chronic form as developing after 6 weeks.
terms osteitis and OM. Some authors define purulent and The diagnosis of these forms is based on specific findings

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Chapter 4:  Infections of Bone 115

(Tables 1 and 2). We feel that as bone necrosis sets in 10 Chronic OM


days (histopathologically) following persistence of pus/ •• Infection present usually for more than 6 weeks.
acute OM, it should be considered that chronic form has •• Demonstrable sequestrum formation.
begun and practically also treatment alteration is required •• Symptoms are nonspecific but few characteristic ones
in patients with persistent symptoms after 10–14 days of should be looked for (Table 2).
treatment for acute OM. Chronic OM is defined with the •• Patients with associated morbidity like diabetes mellitus
identification of sequestrum that requires 4–6 weeks for (DM), immunosuppression, rheumatoid arthritis, etc.
identification on radiographs so this is the often quoted time are at higher risk for chronic OM.
duration for chronic OM to develop in various texts. The •• Treatment is surgical debridement of the infected bone
differentiation of acute from chronic can be summarized along with antibiotics and reconstruction of structural
under following clinical features: bone damage.
Acute OM Apart from the above two a third “primary subacute
pyogenic OM” (sometimes called “primary chronic OM”)
•• Infection present for less than 6 weeks.
has also been recognized (described by Harris and Kirkaldy-
•• Inflammatory symptoms and signs: Fever with or
Willis in 1965) that develops within one to several months.
without chills, malaise. Presence of pain, limited range
They described two types, one with abscess formation
of motion, and redness, warmth or swelling at infection
(metaphyseal) and the other without (diaphyseal, Fig. 1).
site.
The latter may have “onion skin” type periosteal reaction
•• Decompression, evacuation of pus and antibiotic
confusing with Ewing’s sarcoma. The classification by
treatment targeted to the specific infectious organism
Robert et al. (modified Denhill classification) classifies
is the primary treatment.
into six types depending on morphology, location and
bone reaction to infection (Table 3). Brodie’s abscess and
Garre’s OM (see below) are classic examples. Vertebral OM
TABLE 1: Diagnostic criteria for acute osteomyelitis
Peltola and Vahvanen’s criteria (Two of the listed findings must be present for
establishing the diagnosis):
•• Pus on aspiration from affected bone
•• Positive bacterial culture from bone tissue or blood (50% cases)
•• Clinical features (signs and symptoms) of acute osteomyelitis (OM) (often
absent in adults): Lethargy, irritability, fever, local bone tenderness,
local limb swelling, local erythema, local rise of temperature,
pseudoparalysis, effusion in nearby joint or reduced movements
•• Typical radiographic changes of OM
Morrey and Peterson’s criteria (Determine the likelihood of having OM):
•• Definite: Pathogen isolated from bone or adjacent soft tissue or there is
histologic evidence of OM
•• Probable: A blood culture is positive in the setting of clinical and
radiographic features of OM
•• Likely: Typical clinical settings and definite radiographic evidence of
OM are present and there is a response to antibiotic therapy

TABLE 2: Diagnostic criteria for chronic OM (the list represents


diagnostic ability of the characteristics in decreasing order)
•• Imaging studies demonstrating sequestrum and contiguous soft tissue
Fig. 1: Subacute osteomyelitis
infection
•• Clinical signs
■■ Discharge of bone pieces from sinus tract TABLE 3: Classification for subacute osteomyelitis (Roberts et al.)
■■ Exposed bone
■■ Persistent sinus tract with or without frank pus discharge •• Stage 1a—Solitary punched out radiolucency (margins normal)
■■ Necrosis tissue overlying bone •• Stage 1b—Localized radiolucent zone with sclerotic margins (Brodie’s
■■ Nonhealing wound exposing surgical hardware abscess)
■■ Nonhealing wound overlying fracture •• Stage 2—Large radiolucent usually metaphyseal with cortical erosion
•• Laboratory evaluation •• Stage 3—Localized cortical and periosteal reaction
■■ Positive blood cultures •• Stage 4—Linear single or multiple (Onion skin) periosteal reaction
■■ Increased C-reactive protein level •• Stage 5—Central lucency in epiphysis fine sclerotic margins
■■ Increased erythrocyte sedimentation rate •• Stage 6—Destructive process involving vertebral body

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116 Section 1:  Bone Anatomy, Physiology, Pathology and Diseases

(some forms) in adults is an example in modern world. This Investigation: “Laboratory investigations” are often not
disease is common in Africa and some 60% patients with helpful. On “radiographs” the characteristic lesion is
bone infection have this type of presentation. Increased host a lytic cavity surrounded by sclerosis (Fig. 1) and they
resistance and decreased virulence of bacteria have been can be classified according to Robert et al. (Table 3).
proposed to result into this form of disease. Initial homing Occasionally the communicating metaphyseo-diaphyseal
and proliferation of bacteria is quickly arrested by the local lesions grow as elongated “serpentine” lesions to epiphysis
immunity and host reaction walls off the lesion at variable (serpentine sign of Letts). The spinal lesions common
stage of evolution. Alternatively “trauma hypothesis” in adults require magnetic resonance imaging (MRI) for
states that local injury produces hypoxia and hematoma better characterization and differentiation. Radiographs
formation. This serves as a site for lodged bacteria to grow are nonsensitive and nonspecific, often healing is seen
and proliferate. The surrounding bone being relatively by the time they are appreciated on X-ray films. They are
healthy resists the infection and walls it off. The inciting differentiated from tuberculosis by sclerosis of vertebral
cause, however, is itself difficult to support let apart the body. “Contrast-enhanced MRI” are especially helpful.
evolution. In this type of disease there has been no acute “Penumbra sign” has been described characteristically for
attack and the patient has not received specific treatment Brodie’s abscess. In an otherwise doubtful case radionuclide
before presentation. The onset is insidious and as a rule imaging may help in localizing and differentiating the
the infection does not produce the systemic features of lesion in combination with other modalities. “Fine needle
infection. Pain, the most common presenting symptom, aspiration cytology (FNAC) or trephine biopsy” of the lesion
usually presents for months that remits spontaneously in is a must for documentation and diagnosis.
between for variable durations. Night pains and relief from
Treatment: Treatment is controversial and most people
acetylsalicylic acid is also frequently reported. Localized
opine for a prolonged course of antibiotic therapy in
tenderness and swelling are the only physical signs, though
children before proceeding to surgery. In adults, however,
even they “may” be absent. The symptoms and signs often
most agree that surgical treatment is preferable. We
are more prominent after activity and subside thereafter.
consider that formation of pus by itself is a hindrance to
Sequestrum formation and sinus are conspicuously
effective antibiotic therapy and hence simple incision and
absent. The distribution of subacute OM is much wider
drainage type treatment producing low morbidity should
than the acute type, and the disease occurs at various
be initiated early to reduce also the duration of antibiotics
sites (not all together but) within the affected bones. The
and associated complications. This approach would
lower limb is affected much more often than the upper
also ascertain the lesion diagnosis and patient returns
limb. The most commonly affected site is the metaphysis
to function faster. Surgical indications for subacute OM
and diaphysis is only occasionally affected in children
typically include:
but the distribution is equal in adults. Vertebral lesions
•• Poor response to antibiotic therapy
are more common in adults. Metaphyseal-equivalent
•• Doubtful lesions that appear as potential threats
locations are also commonly affected and include pelvis,
•• Impending joint involvement
the vertebrae, the calcaneum, the clavicle, and the talus.
•• Presence subperiosteal pus or synovitis.
In small bone like metacarpals, metatarsals and tarsals
Intralesional curettage of the lesion is adequate for
the lesion is usually subchondral. Multifocal subacute OM
small lesions (< 3 cm). For larger lesions or those with
is reported but occurrence is rare. Bacterial identification
weak bony wall support additional bone graft packing is
from the lesion is quite difficult and is absent in 30–50%
recommended. It is imperative that the drainage is done
cases. Identified organisms are similar to acute forms and
as far from the joint capsule as possible for epiphyseal and
include coagulase-positive Staphylococcus (most common >
metaphyseal lesions and where possible indirect approach
50%), Streptococcus, Pseudomonas and coagulase-negative
is better.
Staphylococcus.
The above classification of OM into acute, subacute and
Differential diagnosis (subacute OM): The lesions should chronic forms is an oversimplification but practical (for
be differentiated from Ewing sarcoma, Langerhans management perspective). The Lew and Waldvogel system
cell histiocytosis and osteosarcoma (diaphyseal lesion (Table 4) divides OM into the categories of hematogenous,
with onionskin periosteal reaction); chondroblastoma, contiguous and chronic. The other best known and popular
aneurysmal bone cyst, giant cell tumor, fungal OM, staging system is the University of Texas Medical Branch
tuberculous OM, pigmented villonodular synovitis (PVNS) (UTMB) clinical staging system for adult OM introduced
erosions, gout (epiphyseal lesions); nonossifying fibroma, by Cierny et al. (Table 5, Fig. 2). The Lew-Waldvogel system
chondromyxoid fibroma (metaphyseal eccentric lesions); classifies the affection of bone arising out of hematogenous
osteoid osteoma and intracortical hemangioma. seeding (endogenous) or contiguous spread (exogenous)

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Chapter 4:  Infections of Bone 117

TABLE 4: Lew and Waldvogel classification system for osteomyelitis


•• Hematogenous osteomyelitis (OM): Bacterial seeding of bone occurs from blood (bacteremia). More than 95% cases in children (discussed in detail in
pathophysiology) and 20% in adults. Metaphysis of long bones in children and vertebrae in elderly (> 50 years) are common sites on affection. Vertebral
OM could be pyogenic (10–15%, including diskitis) or chronic granulomatous (80–85% cases, often tubercular) and rarely fungal or actinomycotic. In IV
drug abusers (young adults) the common sites of affection are vertebra, pubic symphysis, sternoclavicular joints and sacroiliac joints
•• Osteomyelitis secondary to contiguous focus of infection (surgical procedure, trauma, open fractures, chronic soft tissue infection, decubitus ulcer,
diabetic foot and cellulitis)
■■ No generalized vascular disease
■■ Generalized vascular disease—usually diabetics and generalized atherosclerosis and neuropathic joints
•• Chronic OM (necrotic bone)

TABLE 5: Cierney-Mader system for classifying osteomyelitis (OM)


Anatomic type (Fig. 2)
•• Type 1: Medullary OM—limited to medullary cavity, usually single organism, hematogenous or intramedullary implants
•• Type 2: Superficial OM—involves cortex but not marrow or endosteum (akin to osteitis), contiguous soft tissue infection is the cause, often mixed
microbiology and local vascular compromise common
•• Type 3: Localized OM—involves a part of bone but in entire thickness (from cortex to medulla)
•• Type 4: Diffuse OM—involves whole diameter of bone and involvement could be extensive
Physiologic class
•• A host: Healthy with normal physiologic, metabolic and immune functions. Good prognosis
•• B host:
■■ Bs: Systemic compromise
■■ Bl: Local compromise
■■ Bls: Local and systemic compromise
•• C host: Treatment worse than the disease, health does not allow full treatment
Factors affecting immune surveillance, metabolism and local vascularity
•• Systemic factors (Bs): Anemia and hypoxemia, malnutrition, renal or hepatic failure, DM, chronic hypoxia, immune disease, extremes of age,
immunosuppression or immune deficiency and steroid abuse
•• Local factors (Bl): Chronic lymphedema, venous stasis, peripheral vascular disease, major vessel compromise, arteritis, extensive scarring, radiation fibrosis,
small-vessel disease, neuropathy, tobacco abuse

form. The Cierny and Madar system is a comprehensive


system that is based primarily on the part of affected bone,
physiological status of the patient and the risk factors that
affect immunity, metabolism and vascularity. Although it
does not recognize chronic form of bone infection but in
our view it is best suited for classifying chronic OM itself.
Few other authors have also classified the OM for their study
purpose but are not as popular (Table 6). The distinction
of OM into “primary” and “secondary” forms representing
endogenous and exogenous infection is practically succinct
but nondescriptive and confusing so should be dropped.

HISTORY AND EPIDEMIOLOGY


The oldest known evidence of OM is found in the fractured
spine of a dimetrodon Permian reptile, which existed
291–250 million years ago. Bromfield in 1773 used the term
Fig. 2: Anatomic types of osteomyelitis (see Table 5 for details)
“abcessus in medulla” and advised early decompression.
Smith used the term “necrosis” indicating the death of bone.
Nelaton introduced the term “osteomyelitis” in 1844. Pasteur
and the vascular insufficiency (ischemic form arising from used the term “a boil of bone” to describe bone infection.
traumatic, pathological or iatrogenic event). In common Winnett Orr is credited with the use of both conservative and
practice the diabetic foot may represent “ischemic form” radical measures to treat OM in preantibiotic era. Recently
of OM. The system recognizes chronic OM as a distinct the incidence of acute hematogenous OM is decreasing

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118 Section 1:  Bone Anatomy, Physiology, Pathology and Diseases

TABLE 6: Other less popular classification systems for


osteomyelitis (OM)
Author Classification and its basis
Ger R (1977) Soft-tissue condition
•• Type 1: Simple sinus
•• Type 2: Chronic superficial ulcer
•• Type 3: Multiple sinuses
•• Type 4: Multiple skin lined sinuses
Kelly et al. (1984) Etiopathogenesis
•• Hematogenous OM
•• Post-traumatic (united fracture)
•• Post-traumatic (nonunited fracture)
•• Postsurgical
Anatomopathological
•• Type 1: Open, without bone infection
•• Type 2: Circumferential, cortical and endosteal
infection
•• Type 3: Cortical and endosteal infection
associated with segmental bone loss Fig. 3: The common method of development and progression of
Weilan (1984) Weilan defined chronic OM as a wound with unchecked acute osteomyelitis
exposed bone, positive culture, findings and
drainage for more than 6 months.
•• Type I: Open exposed bone without evidence of
bone infection but positive soft tissue infection that acute OM developed in the metaphysis of long bones
•• Type II: Circumferential, cortical and endosteal because of “poor phagocytic activity” in metaphysis (Fig. 3).
infection with sequestration and involucrum He injected Chinese ink in the nutrient artery system that
formation was evenly distributed throughout for first 6 hours but
•• Type III: Cortical and endosteal infection with
after that the ink disappeared from diaphysis persisting in
segmental bone defect
metaphysis however. He concluded that phagocytosis is
Gordon et al. Bone defect
much active in diaphysis compared to metaphysis leading
(1988) •• Type A: Tibial defect and nonunion without
segmental loss to persistent bacteria developing OM. Other investigators
•• Type B: Tibial defect < 3 cm, intact fibula (Trueta), however, related these findings due to sluggish
•• Type C: Tibial defect > 3 cm, no intact fibula circulation through the “hair-pin bends” of arterioles at
Romano et al. Bone defect metaphysis (see criticism to this view below in modern
(2006) •• Type 1: Cavitary defect concept). The infection then develops in the “blood lakes”
•• Type 2: Epiphyseal defect of slow metaphyseal circulation.
•• Type 3: Segmental defect
“Starr from Toronto” explained the progression and
course of abscess (Fig. 4). He stated that the inflammatory
in incidence, whereas the incidence of OM due to direct reaction and abscess formation at metaphysis under
inoculation or contiguous focus of infection is increasing. pressure travels through Haversian and Volkmann’s canals
Possibly this is related to improvement in general health to erupt under the periosteum. The adjacent joints are
and increased vehicular trauma and orthopeedic surgery. protected by the tight attachment of periosteum to the
OM secondary to open fractures occurs in 3–25% of cases, growth ring. The periosteal vessels get thrombosed and
usually in young men. 15% of patients with diabetic foot intramedullary vessels are already disrupted thus the blood
develop OM. Osteomyelitic affection of spine occurs in 2–4% supply to the cortex is lost and the part of bone becomes
of all cases of OM and is usually hematogenous. Elderly men avascular. The pus then reenters the cortex at some other
are more commonly affected than women. place infecting the medullary cavity setting up another
focus. He also supported the concept that individual’s
PATHOGENESIS general resistance to bacterial aggression somehow
determines susceptibility to develop OM.
The older theories for development of OM have been
Wilenski concept : He proposed that the site of bone
traditionally engrained in the minds of orthopedic surgeons
involvement purely depends on the occlusion of blood
that it is imperative for a comprehensive text to mention them.
vessel at particular site by the septic embolus. If main artery
Hobo’s observations and hypothesis: Japanese researcher is involved then whole bone is affected (Fig. 5), however, if
Teruo Hobo published a paper in German which suggested upper or lower branch is involved then corresponding part

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Chapter 4:  Infections of Bone 119

will be affected. Embolism of terminal arterioles produces


lesion at bone ends and subperiosteal abscess results if
periosteal vessels are predominantly involved.
Trueta’s hypothesis: Trueta (1968) in his attempt to correlate
the clinical features with his hypothesis of underlying
pathology described three clinical stages.
1. Stage I: He described this as a “boil” in the bone. There
is severe constant pain described as “deep” or “in
the bone” and is often “not” localized (a bit diffuse)
at the focus of infection. Exquisite tenderness is but
accurately localized. The inflammatory signs are absent.
The exudate passes through the cortex but not to the
diaphysis.
2. Stage II: There is pus in the medulla and the subperiosteal
space. The symptoms and signs are more marked, and
systemic symptoms such as malaise, fever, other aches
Fig. 4: Pathways of progression of pus: (1) The usual route is for the pus and pains appear.
to break under periosteum reaching the space through the haversian 3. Stage III: The inflammation spreads to soft tissues with
system or perivascular space around nutrient vessels. If the periosteum characteristic signs of acute inflammation.
is thick and hard and does not give way; it gets lifted shutting the This prolonged development and subperiosteal
blood supply to underlying bone forming a cylindrical sequestrum appearance of pus from the formation of exudate and
as in infants and young children as seen in Figure 5. (2) In some joints slow transgress through the cortex has been challenged
(see text) the metaphysis is intra-articular and pus may enter the joint by consistent findings of pus within 48 hours beneath the
space also in younger children the joint capsule is not very strongly periosteum. Also his view of no or late involvement only of
adherent to the bone so that the pus under tension can track to joint
diaphysis is also not supported.
causing septic arthritis. (3) If the pus does not find its way underneath
He is also credited with the recognition of three types
periosteum and forms proximally in metaphysis it may directly track
into medullary canal causing extensive myelitis as depicted in Figure of OM (1959) based on the blood supply, the infantile,
3 also. (4) In infants and adolescents around puberty the transphyseal childhood and the adult form of disease. There is a
vessels are open paving a path for pus to travel to epiphysis and joint difference in OM in children and adults (summarized in
causing septic arthritis Table 7). The site of involvement varies in children according
to the blood supply that is described in detail by Trueta
presented briefly here:
•• In infants the metaphyseal blood vessels cross the
growth plate thus the infection can traverse the physis
involving the epiphysis in the process (see also Chapter
11: Septic Arthritis). This can quickly involve the joint
also. There is commonly a growth disturbance later as
a sequel (Fig. 6) to involvement and destruction of the
physis if treatment is not prompt (otherwise also the
morbidity is high). The bone is thin, weak and immature
giving way easily to the pus under pressure so extensive
devascularization and large sequestrum formation does
not occur. Pus is however copious. Cortical damage is
transient while a large involucrum forms due to high
regenerating potency of periosteum.
•• In childhood the growth plate and the epiphysis are
usually spared and the infection remains limited to
metaphysis and proximally. The subperiosteal extension
of pus and endosteal thrombosis produce extensive
Fig. 5: Whole humerus shaft becoming a sequestrum devascularization of the bone and large sequestrum

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120 Section 1:  Bone Anatomy, Physiology, Pathology and Diseases

TABLE 7: Difference in the osteomyelitis (OM) in children and


adults
Osteomyelitis in children Osteomyelitis in adults
Usually hematogenous Usually due to direct inoculation
Metaphyseal location •• Hematogenous (20%)—vertebral
commonly otherwise seen in IV
drug abusers
•• Traumatic or direct inoculation—
any site
Periosteal reaction—frequent Periosteal reaction—infrequent/
and copious subdued
Sequestrum formation is Bone is often resorbed forming a lytic
frequent cavity
Systemic features are common Less pronounced
Blood cultures often positive Blood culture often negative
Conversion to chronic form—less Commonly converts to chronic form
common
Organisms—infants: Group B •• Polymicrobial in 30–50% cases, Fig. 6: Postosteomyelitic deformity
streptococci coagulase positive and negative
Children: Staphylococcus aureus, staphylococci, Gram-negative
Streptococcus pyogenes, H. bacilli (vertebral OM)
that possibly leads to hematoma formation with local
influenzae •• IV drug abusers: P. aeruginosa,
Candida immune deficit where a lodged bacterium preferentially
•• Prosthetic infection: Staphylococcus localizes and thrives.
epidermidis

MODERN CONCEPT AND


(sometimes whole diaphysis—cylindrical sequestrum)
UNDERSTANDING OF
are seen in late presentations (Fig. 5). The cortical OSTEOMYELITIS
damage is hence extensive with prompt involucrum
The condition may arise from trauma, bacteremia (distant
formation. Growth disturbance is rare seen only with
focus of infection), contiguous focus of infection (nearby
extensive aggressive disease reaching the germinal
abscess or cellulitis) such as those associated with diabetic
layer of growth plate, else in common presentations
foot ulcerations and surgery, or orthopedic implants that
some growth stimulation is common due to increased
disrupt the integrity of the bone. Mere presence of bacteria
vascularity. Joint involvement is rare but can occur if:
but does not lead to development of bone infection. Once
–– Metaphysis is intracapsular—hip, proximal humerus,
the homeostasis (the equilibrium/stability in the normal
proximal radius and distal fibula.
body states) of the body has been altered even an innocuous
–– Iatrogenic seeding while drainage of pus/aspiration
bacteria can enter the body and proliferate.
–– Vessels cross to epiphysis from metaphysis (as in
infants) Pathogenesis of acute OM: The bacteria lodge adjacent to the
–– Some envisage weak adherence of periosteum to physis, probably in relation to terminal metaphyseal vessels.
growth ring as a reason for “leak” of pus beneath These vessels are “open-ended” (and NOT looped or “hair-
periosteum from metaphyseal to epiphyseal and pin bends” as visualized by Trueta and Hobo), as they tunnel
intra-articular region. between the columns of dividing and decaying physeal
•• The adult form: Osteomyelitis is often due to contiguous cartilage cells. The fact that the vessels enter into “open-
spread. Long bone involvement in hematogenous circulation” is important for chondrotropic pathogenic
spread is rare. Infected bone is resorbed leaving behind bacteria to adhere to cartilage cells at the junction between
a cavity (Figs 7A to D). Whole bone involvement and the physis and metaphysis (see “homing of bacteria” below
chronic OM developing is common. to understand localization of bacteria to these places). The
“Morrisey and Haynes” proposed the concept of trauma sluggish flow may not be important at all. With bone growth
(as focalizing influence) to delicate metaphyseal circulation the branches develop from the extended vessels and may

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Chapter 4:  Infections of Bone 121

A C

B D
Figs 7A to D: The patient is an elderly male having pain on anteromedial aspect of tibia. X-rays (A) appear unremarkable but on closer
examination one can see osteopenia with mild cortical scalloping on the fibular cortex of tibia in anteroposterior view and anteriorly on lateral
X-ray. Decompression had been attempted in the form of multiple drill holes (B) trying to drain pus but patient returned an year later with
chronic osteomyelitis, frank pus discharge (C) and intramedullary endosteal reaction (D) to myelitis that resulted in view of unchecked infection.
Patient also has nearby eczematous lesion on ankle

anastomose (that Hobo and Trueta visualized). The bacteria (except points 4, 6 and 7 below, where it may develop
here divide thriving on dead chondrocytes; produce acute de novo) and is a recurring condition difficult to treat
inflammation and tissue death secondary to ischemia from completely. It develops in one of the following ways
either venous or arterial obstruction. There is liquefactive (sometimes a combination of few):
necrosis of medullary tissue. The trabeculae of cancellous •• Incomplete treatment of acute OM (most common)
bone lose their vascularity and die remaining in the pus as •• Trauma (now increasing)
small sequestrae. Second concept is with respect to finding •• Implant related infection (probably the second most
of predominant periosteal supply in the animal bone model common now)
that hypothesizes the centripetal concept of developing •• A hematogenous type of OM
infection. This suggests lodging of bacteria in periosteal •• Compound fractures
circulation with subsequent development of subperiosteal
•• Infection with chronic persisting type of microbes
abscess. This then ruptures through or progresses and
Mycobacterium tuberculosis, Treponema species, fungal
involves the cortical circulation, thrombosis of the nutrient
•• Osteomyelitis associated with diabetic foot, vascular
artery and lead to development of characteristic acute OM.
disease, etc.
The concept is supported by finding of early subperiosteal
Modern system recognizes the “close interaction of
pus and predominant involvement of cortex than the
host factors, bacteriological factors and environment” in a
medulla in most cases of acute OM.
particular fashion that finally settles into infection (Fig. 8).
Pathogenesis of chronic OM: Chronic OM is usually (now Robson envisaged infection as an “imbalance between germ
direct inoculation at surgery with subacute smouldering and host” and was partially correct in suggesting that OM
type infection is increasing) the persistence of acute OM is due to certain predisposing factors.

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122 Section 1:  Bone Anatomy, Physiology, Pathology and Diseases

support is required in these patients. Various clinical,


laboratory and anthropometric measures should
be used to assess patient nourishment. Nutritional
index can be calculated by the Rainey-McDonald
formula = [(1.2*serum albumin) + (0.013*serum
transferrin)]—6.43. A value of 0 or negative indicates
malnourishment and high risk for sepsis. Survival
into adulthood living under poor hygiene may confer
increased immunological tolerance to infection due
to repetitive subcritical exposure to infectious agents
Fig. 8: The interaction of host, bacterial and environmental factors and conditioning of immunity.
determines the development of osteomyelitis (OM) not just the –– Role of exercise: Exercise helps the immune system
presence of bacteria by increasing natural killer cells, macrophage
count, cytokines, neutrophil count and lymphocyte
These “host factors” were grouped by Schmidt (modified count. There is a small time frame (open window)
here) into the two broad categories: when athletes are immunosuppressed after an
1. Endogenous factors [for a comprehensive list see also the intense physical activity, when ciliary action,
Bs physiological group of Cierny-Madar classification immunoglobulin A levels, natural killer cells,
(Table 4)]: T lymphocyte count, and CD4/CD8 ratio are
–– Age more than 65 years and infancy and childhood decreased. This susceptibility to infections in
–– Sex—male:female = 4:1 (?due to higher incident athletes in the past was called the “J-curve”, but has
trauma) been recently updated and termed the “S-curve”.
–– Obesity 2. Exogenous factors (see also Table 4 for BL physiological
–– Nicotine and alcohol abuse factors):
–– Diabetes –– Damage to soft tissue barriers (skin, fascia)
–– Vascular diseases –– Bacterial invasion by a virulent strain or hospital
–– Certain fevers like smallpox, scarlet fever, measles, acquired infection
diphtheria, influenza and typhoid. –– Super bugs
–– Immunosuppressive states: Neutrophil count –– Dead necrotic tissue (due to loss of vascularity from
less than 55/mm 3 predispose to staphylococci, trauma or surgery).
Candida, Aspergillus and Gram-negative bacilli.
Hypogammaglobulinemia and complement
deficiency predisposes to infection with streptococci,
BACTERIOLOGICAL FACTORS
Haemophilus and Neisseria, mycoplasma and The quantity and virulence of bacteria (ability to attach,
Ureaplasma urealyticum. Deficient cell-mediated reproduce and damage the host tissue) are important
immunity predisposes to mycobacterial and fungal determinants for infection. Most of the pathogenic
infections, herpes infection and P. carinii. bacteria have special features that help them circumvent
–– Congenital immunosuppressive states like the immunity, invade the tissues, attach to host tissues,
chronic granulomatous disease, sickle cell proliferate and grow even in hostile environment.
hemoglobinopathy (Salmonella infection), leukocyte •• Evasion of prophylactic antibiotic therapy: Half
adhesion deficiency are associated with acute OM. of the pathogenic Staphylococcus strains exhibit
–– Cancers and hematological malignancies like plasmid mediated resistance to antimicrobial agents.
lymphoma and leukemia: possibly also related to Development of superbugs due to prolonged use of
cachexia. antibiotics and misuse of antibiotics render prophylactic
–– Steroid and immunosuppressive therapy antibiotic therapy ineffective.
–– Poor hygiene and nutrition (leads to a suppression of •• Homing of bacteria: Most Staphylococcus species,
the cellular and humoral response): Albumin level Pseudomonas species, and Gram-negative bacteria have
less than 3.4 mg/dL, absolute lymphocyte count specific factors that mediate adherence to biomaterials.
less than 1,500, serum transferrin less than 150 –– Trauma to bone (iatrogenic or otherwise) or the
mg/dL, arm muscle circumference less than 80% “growing ends of bone” exposes the collagen matrix
of standard, anergy to a skin test battery indicate and acellular crystal faces, making it easier for
poor nutrition. For elective surgery nutritional bacteria to adhere to these surfaces.

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Chapter 4:  Infections of Bone 123

–– The bacteria exhibit specific ligands like sialoprotein, biofilm. Biofilm is typically quickly and copiously
laminin, von Willebrand factor, collagen, fibrinogen, produced by Pseudomonas aeruginosa, Staphylococcus
thrombospondin, osteopontin, vitronectin and aureus, and S. epidermidis. The glycocalyx is an
fibronectin that bind to above surfaces or surface of extracellular polysaccharide molecule that contains
implants in a receptor-ligand fashion. “host” molecules in an immunological sense. This
–– A family of proteins called adhesins (some include glycocalyx (exopolysaccharide) together with eDNA,
above proteins) have been recognized (fibronectin- proteins and lipids form the extracellular matrix
binding proteins, fibrinogen-binding proteins, commonly termed “slime” serves as protective physical
elastin-binding adhesin and collagen-binding barrier for microbes. The biofilm has a base layer that is
adhesion) that microbes use for colonization and near the implant and fosters adherence to target surface.
adhesion to biomaterials. The pH and local environment encourage formation
–– Bacterial adhesion to necrotic bone and implants of sessile variants of bacteria that collectively develop
is also mediated by charged properties and van der a colony. The outer layers form discrete structures
Waals forces between the bacteria tissue and implants. such as “columns” and “mushrooms”. “Streamers” can
•• Evasion of local host defence (the biofilm model to form in the outer layers that may break off to infect
explain the persistence of osteomyelitis): The body’s contiguous areas (Fig. 10). Intercellular signaling
own defence is rendered ineffective especially at the through the extracellular matrix occurs via “quantum
implant surfaces and within sequestrum. These being packets” that are transported via nanotubes formed
avascular the bacteria thrive uninhibitedly here far within matrix and these nanotubes are also involved
away from the influence of antibiotics and immunity. in conducting cell-to-cell electric signals. In chronic
Most bacteria and few fungi have ingenious capacity bone infections the common lifecycle of the infecting
to synthesise inert glycocalyx capsule (described in microbe (whether bacteria or fungi) passes through the
1984) that forms a “biofilm” (concept introduced in common sequence of single cell adhesion → incipient
1980) inert to host defence (see also prosthetic joint biofilm (immature, formed within 15 minutes of surface
infection). “Biofilm formation is a process whereby adhesion, “crowd behavior” causes aggregation of
microorganisms of the same species attach to and grow microbes and slime production) → mature sessile
on a surface and produce extracellular polymers that biofilm (within 48 hours there is altered molecular and
facilitate attachment and matrix formation, resulting cellular behavior, reduced cell replication, pillar and
in an alteration in the phenotype of the organisms mushroom formation increases vertical and horizontal
with respect to growth rate and gene transcription” thickness of the biofilm) → mature biofilm with genetic
(Figs 9 and 10). The polysaccharide intercellular diversity (every other opportunistic microbe from
adhesin (PIA) is mainly responsible for formation any strain, species or kingdom utilizes the produced
of extracellular polysaccharide matrix that makes biofilm and colonizes it with discrete close spatially
structured regions, there is fast horizontal genetic
transfer that occurs at a rate 10,000 times faster between
these groups than in planktonic form. This unique
combined genetic characteristic (pangenome) prevents
host from developing adaptive immune response) →
development of extended phenotype (the biofilm has
uniquely altered host and environmental factors that
cause variety of changes like altered pH, O2 tension and
ion concentration that are favorable only to biofilm and
host cells will not survive here) → surface dispersion
(microbes near the surface regularly detach and are free
to colonize other areas of host in remote places, also flow
of biofilm due to viscoelastic nature of the slime causes
streaming and spread of the biofilm to adjacent surface).
Following are some of the mechanisms responsible for
persistence of infection:
•• This mix-up of host and bacterial antigens hides the
specific bacterial antigens and is not recognized by host
Fig. 9: Biofilm formation and various influences on the same immunity.

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124 Section 1:  Bone Anatomy, Physiology, Pathology and Diseases

Fig. 10: The structure and formation of biofilm. The biofilm producing bacteria attach quickly to the implant surface or dead bone facilitated
by various factors. The attachment to extracellular matrix is mediated via Fbe/SdrG (fibrogen binding), GehD (collagen binding) and Embp
(fibronectin binding) while inhibited by higher concentration of β-lactams (partially justifies use of cocktail in implant arthroplasty). Attachment
to polymer surface is facilitated by SSP 1 and 2 (staphylococcal surface proteins-1 and 2) while inhibited by δ-toxin. Once this attachment
becomes permanent the next step is cell to cell adhesion having the common motive of thriving on surface this is mediated by polysaccharide
intercellular adhesin (PIA) and accumulation association protein. The cells then mature and have keen review of mechanisms for increased
proliferations. The colonies grow into mushrooms and columns into which planktonic and sessile variants thrive. The former are facilitated by
reduced immunity and absence of antibiotics while the latter suppressed forms develop in inhibitory milieu. To shorten the formation of colonies
the columns constantly release streamers that bypass the stage of temporary adhesion and intercellular interaction. The planktonic bacteria
keep getting released from the settled colonies and may lead to intermittent septicemia and or abscess formation

•• The biofilm is impermeable to antimicrobial agents •• The sessile forms keep coordination among themselves
typically the beta-lactams. by “quorum sensing” (lactone containing molecules
•• There is a reduced local immunity by inhibition of that establish communication between intra- and
phagocytes that cannot penetrate the biofilm and interspecies that regulate metabolic activity in response
in the process they lose their ability to phagocytose. to population density via signaling molecules) and
Also with excessive complement activation, release slowly develop increasing resistance to administered
of free radicals and proteases apoptosis results. The drugs. Quorum-sensing is also involved in production
highly water-soluble antibiotics like rifampicin can of toxins from the microbes that cause direct lysis of host
penetrate biofilms but resistance is quick to develop so lead inflammatory response cells like the neutrophils,
combination chemotherapy is advised. thus causing nearby tissue damage also. Once the local
•• The biofilm producing bacteria grow slowly due to immunity falls low the return to “planktonic form” (free-
highly anaerobic conditions reducing the metabolic floating, virulent, reproductive form, triggering host
activity so antibiotics targeting the replication process systems) can occur accounting for clinical recurrences
(fluroquinolones) are rendered ineffective (see also and acute on chronic episodes (Fig. 9). When planktonic
prosthetic infections). These organisms are called forms encounter a devitalized surface coated with
“persisters” or better the “sessile” variants. The sessile protein they quickly home in it. The host immunity
variants have 103 less sensitivity to antibiotics, restricted already “confused” about the method of dealing with
reproduction and are difficult to culture. them mounts a common inflammatory reaction that