Osteoporosis

PATHOGENESIS DIAGNOSIS TREATMENT

Robert D. Auerbach, M.D. FACOG Senior VP & Chief Medical Officer CooperSurgical, Inc.

Two components of the bone

Cortical Bone

Dense and compact Runs the length of the long bones, forming a hollow cylinder
Has a light, honeycomb structure Trabeculae are arranged in the directions of tension and compression Occurs in the heads of the long bones Also makes up most of the bone in the vertebrae

Trabecular bone

Osteons

Principal organizing feature of compact bone

Haversian canal place for the nerve blood and lymphatic vessels Lamellae collagen deposition pattern Lacunae holes for osteocytes Canaliculi place of communication between osteocytes

Bone cells

Osteocytes - derived from osteoprogenitor cells

Osteoblasts Osteoclasts

Osteocytes

Trapped osteoblasts

In lacunae

Keep bone matrix in good condition and can release calcium ions from bone matrix when calcium demands increase

Osteocytic osteolysis

Osteoblasts
Make collagen Activate nucleation of hydroxyapatite crystallization onto the collagen matrix, forming new bone As they become enveloped by the collagenous matrix they produce, they transform into osteocytes Stimulate osteoclast resorptive activity

Osteoclasts
Resorbe bone matrix from sites where it is deteriorating or not needed Digest bone matrix components Focal decalcification and extracellular digestion by acid hydrolases and uptake of digested material Disappear after resorption Assist with mineral homeostasis

Chemistry of the bone

Matrix Mineral

Matrix - osteoid
Collagen type I and IV Layers of various orientations (add to the strength of the matrix) Other proteins 10% of the bone protein

Direct formation of fibers Enhance mineralization Provide signals for remodeling

Mineral
A calcium phosphate/carbonate compound resembling the mineral hydroxyapatite Ca10(PO4)6(OH)2 Hydroxyapatite crystals

Imperfect Contain Mg, Na, K

Mineralization of the bone

Calcification occurs by extracellular deposition of hydroxyapatite crystals

Trapping of calcium and phosphate ions in concentrations that would initiate deposition of calcium phosphate in the solid phase, followed by its conversion to crystalline hydroxyapatite

Mechanisms exist to both initiate and inhibit calcification

Bone remodeling process

Proceeds in cycles first resorption than bone formation The calcium content of bone turns over with a half-life of 1-5 years

Bone remodeling process

Coordination of Resorption and Formation

Phase I
Signal from osteoblasts Stimulation of osteoblastic precursor cells to become osteoclasts Process takes 10 days

Coordination of Resorption and Formation

Phase II
Osteoclast resorb bone creating cavity Macrophages clean up

Phase III

New bone laid down by osteoblasts Takes 3 months

Pathways of differentiation of osteoclasts and osteoblasts

Hormonal Influence
Vitamin D Parathyroid Hormone Calcitonin Estrogen Androgen

Vitamin D

Osteoblast have receptors for (1,25-(OH)2-D) Increases activity of both osteoblasts and osteoclasts Increases osteocytic osteolysis (remodeling) Increases mineralization through increased intestinal calcium absorption Feedback action of (1,25-(OH)2-D) represses gene for PTH synthesis

Parathyroid Hormone

Accelerates removal of calcium from bone to increase Ca levels in blood PTH receptors present on both osteoblasts and osteoclasts Osteoblasts respond to PTH by

Change of shape and cytoskeletal arrangement Inhibition of collagen synthesis Stimulation of IL-6, macrophage colony-stimulating factor secretion

Chronic stimulation of the PTH causes hypocalcemia and leads to resorptive effects of PTH on bone

Calcitonin
C cells of thyroid gland secrete calcitonin Straight chain peptide - 32 aa Synthesized from a large preprohormone Rise in plasma calcium is major stimulus of calcitonin secretion Plasma concentration is 10-20 pg/ml and half life is 5 min

Actions of Calcitonin
Osteoclasts are target cells for calcitonin Major effect of clacitonin is rapid fall of plasma calcium concentration caused by inhibition of bone resorption Magnitude of decrease is proportional to the baseline rate of bone turnover

Other systemic hormones

Estrogens

Increase bone remodeling

Increase bone formation

Androgens

Other systemic hormones

Growth hormone

Increases bone remodeling

Inhibit bone formation

Glucocorticoids

Thyroid hormones
Increase bone resorption Increase bone formation

Local regulators of bone remodeling

Cytokines
IL-6 IL-1

Prostaglandins Growth factors

IGF-I TGF-

Osteoporosis
A disease characterized by:
low bone mass microarchitectural deterioration of the bone tissue

Leading to:
enhanced bone fragility increase in fracture risk

WHO guidelines for determining osteoporosis

Normal: Not less than 1 SD below the avg. for young adults Osteopenia: -1 to -2.5 SD below the mean Osteoporosis: More than 2.5 SD below the young adult average

70% of women over 80 with no estrogen replacement therapy qualify More than 2.5 SD below with fractures

Severe osteoporosis

Osteoporosis - epidemiology
Disorder of postmenopausal women of northern European descent Increase in the incidence related to decreasing physical activity Over 27 million or 1of 3 women are affected with osteoporosis Over 5 million or 1of 5 men are affected with osteoporosis

Bone Mass

Statistics

Prevalence of Osteopenia and Osteoporosis in Postmenopausal Women by Ethnicity

Pathogenesis of Estrogen Deficiency and Bone Loss

Estrogen loss triggers increases in IL1, IL-6, and TNF due to:
Reduced suppression of gene transcription of IL-6 and TNF Increased number of monocytes Increased cytokines lead to increased osteoclast development and lifespan

Osteoclast Differentiation and Activation in Estrogen Deficiency

Impact of Estrogen on Osteoclastic Differentiation and Activation

National Osteoporosis Risk Assessment (NORA): Factors Associated With Increased Risk of Osteoporosis

NORA: Factors Associated With Reduced Risk of Osteoporosis

NORA: BMD and Fracture Rate

Osteoporosis

Mechanisms causing osteoporosis

Imbalance between rate of resorption and formation Failure to complete 3 stages of remodeling

Types of osteoporosis
Type I Type II Secondary

Osteoporosis - types

Postmenopausal osteoporosis (type I)

Caused by lack of estrogen Causes PTH to overstimulate osteoclasts Excessive loss of trabecular bone

Age-associated osteoporosis (type II)

Bone loss due to increased bone turnover Malabsorption Mineral and vitamin deficiency

Secondary osteoporosis

Osteoporotic vertebra

Normal vs. osteoporotic bone

Risk Factors

When to Measure BMD in Postmenopausal Women

All women 65 years and older Postmenopausal women <65 years of age:

If result might influence decisions about intervention One or more risk factors History of fracture

When Measurement of BMD Is Not Appropriate

Healthy premenopausal women Healthy children and adolescents Women initiating ET/HT for menopausal symptom relief (other osteoporosis therapies should not be initiated without BMD measurement)

Prediction of Fracture Risk

All techniques (DXA, QCT, QUS) predict fracture risk

American Association of Clinical Endocrinologists Endocrin Prac 2001; 7: 283-312

Osteoporosis can be Assessed by DXA

Relative Risk of Fracture per SD Decrease in BMD
3 2.5 2 1.5 1 0.5 0
re ar m Fo V er te br al A ll Si te s H ip

Relative Risk

Forearm Hip Spine

DXA-assessed content is a proven effective method for assessing osteoporosis related fracture risk. Population surveys and research studies demonstrate a decrease in bone density measured by DXA predicts fracture at specific sites. Marshall, D, et al: Meta-analysis of how well measures of bone mineral density predict occurrence of osteoporotic fractures. British Medical Journal. 312:1254-1259, 1996.

The McCue CUBA: Ultrasonometry Technology that can Assess Osteoporosis

BUA

110 Normal dB/MHz

40 dB/MHz Osteoporotic Bone Frequency

Heel BUA is Significantly Lower in Subjects With Future Hip Fracture.

60 50
BUA (dB/sq MHz)

40 30 20 10 0 Fracture No Fracture

Subjects who developed hip fracture showed significantly (p<0.001) lower heel BUA results in a two-year follow-up prospective study of 1,414 subjects. Porter, RW, et al: Prediction of hip fracture in elderly women: a prospective study. British Medical Journal. 301:638-641, 1990.

Discriminating Power of Heel BUA in Reflecting Vertebral Osteoporosis

When assessing vertebral osteoporosis, there was no statistically significant difference in the discriminating power of Heel BUA or Spine, Femur Neck or Trochanter BMD by DXA. Ohishi, T, et al: Ultrasound measurement using CUBA clinical system can discriminate between women with and without vertebral fracture. Journal of Clinical Densitometry. 3:227-231, 2000.
1 0.9
Area Under the Curve

0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.1 0

Heel BUA Spine BMD Neck BMD Trochanter BMD

Receiver Operator Characteristic Analysis of Hip Fracture Risk

0.9 0.85
Area Under the Curve

0.8 0.75 0.7 0.65 0.6 0.55 0.5

Heel BUA Fem ur Neck BMD

Schott, AM, et al: Ultrasound discriminates patients with hip fracture equally well as dual energy x-ray absorptiometry and independently of bone mineral density. Journal of Bone and Mineral Research. 10:243-249, 1995.

Increasing Relative Fracture Risk is Seen with Decreased BUA or BMD

Hans, D, et al: Ultrasonographic heel measurements to predict hip fracture in elderly women: the EPIDOS prospective study. Lancet. 348:511-514, 1996. Bauer, DC, et al: Broadband ultrasound attenuation predicts fractures strongly and independently of densitometry in older women. Archieves of Internal Medicine. 157:629-634, 1997. Frost, ML, et al: A comparison of fracture discrimination using calcaneal quantitative ultrasound and dual x-ray absorptiometry in women with a history of fracture at sites other than the spine and hip. Calcified Tissue International. 71:207-211, 2002.
3
Relative Risk of Fracture

2.5 2 1.5 1 0.5 0 Hans, et al Bauer, et al Research Study Frost, et al BUA BMD

Increased Relative Fracture Risk is Seen With Decreasing BUA

14,824 men and women were followed for an average of 1.9 years to relate BUA to future fracture risk. Subjects in the lowest 10th percentile of BUA showed a relative risk of fracture 4.44 times greater than those in the highest 30th percentile of BUA. Khaw, KT, et al. Prediction of total and hip fracture risk in men and women by quantitative ultrasound of the calcaneus: EPIC-Norfolk prospective study. Lancet. 363:197-202, 2004.
5 4.5 4 3.5 3 2.5 2 1.5 1 0.5 0 <10 10 to <40 40 to <70 70 to 100 Percentile Category

Relative Fracture Risk

Who Should Be Considered for Prevention or Treatment?

Postmenopausal women with T-score below 2.0 with no risk factors Postmenopausal women with T-score below 1.5 with one or more risk factors

NORA

NORA

Prevention of Bone Loss

Prevention of Bone Loss Calcium HRT SERMS Calcitonin Bisphosphonates

Calcium Supplementation

HOPE Trial

PEPI Trial

BMD

Spine BMD

Total Hip BMD

Forearm BMD

WHI Results

WHI Results

Summary