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osteoporosis

Osteoporosis is the most common


metabolic bone disease and has
been defined as a systemic bone
disease characterized by low bone
mass and microarchitectural
deterioration of bone tissue, leading
to enhanced fragility and a
consequent increase in fracture risk.
Bone consists of an organic matrix (collagen and
noncollagenous proteins) and an inorganic
mineral component (calcium and phosphate in
hydroxyapatite crystals).
Normally, bone turnover is tightly coupled with
osteoclast-mediated bone resorption followed
by osteoblast stimulated bone formation.
This delicate balance in bone remodeling results
in no net change in skeletal mass.
Osteoporosis results from an
imbalance between bone resorption
and formation.
The hallmark of osteoporosis is the
loss of bone mineral and bone
matrix that results in maintenance
of a normal mineral-to-matrix ratio.
Scanning electron micrograph of the trabecular
structure of cancellous bone from a (A) normal
subject and a patient with osteoporosis (B).
Osteoporosis was previously thought to be a silent
disease that was part of the normal aging process.
However, the advent of bone densitometry has
made it possible to accurately identify patients at
risk for osteoporosis so that prevention and
treatment strategies can be instituted to reduce
fractures.
Pathophysiology
Osteoclasts originate from the colony-forming
unit granulocyte-monocytes, are attracted
to the bone surface, attach to bone matrix,
and resorb bone tissue.
Generally, bone resorption is rapid, and a
resorption pit is formed within 10 to 14 days.
Pathophysiology
After resorption is complete, osteoblasts,
derived from the bone marrow stromal
cells, attach to the resorbed bone surface and
produce osteoid, which is then mineralized.
Bone formation can take up to 3 or 4 months.
Therefore a normal bone remodeling cycle in
adults can last 4 to 6 months.
Pathophysiology
A number of metabolic changes such as
estrogen deficiency, immobilization, metabolic
acidosis, hyperparathyroidism, and systemic and
local inflammatory diseases can increase
osteoclast number and activity, uncoupling bone
turnover.
This results in greater bone resorption than
bone formation and a net loss of bone tissue.
Pathophysiology
A number of local factors in bone affect the
regulation of bone formation and resorption and
the coupling of these processes.
These include insulin-like growth factors (IGFs),
interleukins (IL-1, IL-6, and IL-11), tumor
necrosis factor (TNF), receptor activator of
nuclear factor κB ligand (RANKL),
and transforming growth factor (TGF).
Bone remodeling cycle
Osteocytes most likely release chemicals to the
bone surface that attract osteoclasts.
Osteoclasts attach to the bone matrix, create a
tight ring, and release acid that lowers the pH
and dissolves the mineral from the bone matrix.
After the mineral is released, the demineralized
matrix is broken down. The osteoclast leaves the
bone surface, and an osteoblast is attracted to
the area of the bone that was resorbed.
Bone remodeling cycle
The resorption phase is about 10 to 14 days.
Osteoblasts produce new bone, or osteoid, that
fills in the resorption pit. Also, some of the
osteoblasts are left within the bone matrix as
osteocytes. The osteoid mineralizes over about 3
months, and the bone remodeling cycle is
complete.
Post-menopausal osteoporosis
Estrogen deficiency is associated with the
release of cytokines including RANKL, IL-1, IL-6,
and TNF, which leads to the recruitment and
stimulation of osteoclasts in the bone marrow
and increased production of bone- resorptive
cytokines, which may contribute to menopause-
related bone loss.
Post-menopausal osteoporosis
Estrogen deficiency increases osteoblast
production of RANKL, which stimulates
maturation and activity of osteoclasts by
attaching to RANKL on the surface of immature
and mature osteoclasts. Simultaneously,
estrogen deficiency decreases osteoblast
production of OPG (osteoprotegerin), the
decoy receptor that reduces RANKL production
and activity.
Male osteoporosis
Osteoporosis is less common in men and a
secondary cause can be identified in about 50% of
cases.
The most common are hypogonadism,
corticosteroid use and alcoholism.
In hypogonadism, testosterone deficiency results in
an increase in bone turnover and uncoupling of
bone resorption from bone formation.
Genetic factors are probable important in the 50%
of cases with no identifiable cause.
Corticosteroid-induced osteoporosis
This is an important cause of osteoporosis that
relates to dose and duration of corticosteroid
therapy, the risk increases when the dose of
prednisolone exceeds 7.5 mg daily and
is continued for more than 3 months.
Corticosteroids have adverse effects on calcium
metabolism and bone cell function.
Corticosteroid-induced osteoporosis
A key abnormality is reduced bone formation due to a
direct inhibitory effect on osteoblast
function and steroid-induced osteoblast and osteocyte
apoptosis.
Corticosteroids also inhibit intestinal calcium
absorption and cause a renal leak of calcium, and this
tends to reduce serum calcium, leading to secondary
hyperparathyroidism with increased osteoclastic bone
resorption.
Osteoporosis in Rheumatic Diseases
Recently, studies have reported significant bone
loss in patients with systemic inflammatory
diseases such as rheumatoid arthritis, systemic
lupus erythematosus (SLE), and ankylosing
spondylitis. Patients with rheumatoid arthritis
experience periarticular and generalized bone
loss, with an increased incidence of fractures
compared with the general population.
Osteoporosis in Rheumatic Diseases
T lymphocytes, macrophages, and
synovial-like fibroblasts release inflammatory
cytokines (IL-1, TNF, IL-6) which stimulate
preosteoclasts in the bone marrow and
synovium to actively resorb bone; in addition,
osteoblast maturation is altered.
Additional factors include decreased mobility,
glucocorticoid therapy, and systemic
inflammation.
Risk factors of osteoporosis
Primary
Previous fracture after age 30
Family history of hip fracture
Cigarette smoking
Low body weight
Low bone mineral density
Risk factors of osteoporosis
Secondary
Non-modifiable:
White race
Advanced age
Frailty or poor health
Dementia
Secondary
Modifiable:
Low calcium intake
Eating disorder
Low testosterone levels (men)
Premenopausal estrogen deficiency (amenorrhea >1 yr
or
menopause at age <45 yr)
Excessive alcohol intake
Physical inactivity
Impaired vision
Neurologic disorder
Lack of sunlight exposure
Diseases associated with osteoporosis
Endocrine diseases
• Hypogonadism • Hyperthyroidism
• Hyperparathyroidism • Cushing’s syndrome
Inflammatory disease
• Inflammatory bowel disease • Ankylosing spondylitis
• RA
Gastrointestinal disease
• Malabsorption • Chronic liver disease

Lung disease
• COPD • Cystic fibrosis
Drugs associated with osteoporosis
• Corticosteroids
• Gonadotrophin-releasing
hormone (GnRH) agonists
• Aromatase inhibitors
• Thyroxine over-replacement
• Thiazolidinediones
• Sedatives
• Anticonvulsants
• Alcohol intake > 3 U/day
• Heparin
Clinical features
Patients with osteoporosis are asymptomatic until a
fracture occurs. Osteoporotic spinal fracture may
present with acute back pain or gradual onset of
height loss and kyphosis with chronic pain.
Peripheral osteoporotic fractures present with local
pain, tenderness and deformity, often after an
episode of minimal trauma. In patients with hip
fracture, the affected leg is shortened and
externally rotated.
Investigations
The pivotal investigation is dual energy X-ray
absorptiometry (DEXA) at the lumbar spine and hip.
WHO has published criteria for osteoporosis on the basis
of bone density:
1. Normal bone density: if the t score is greater than −1.
2. Osteopenia: a bone density measurement between 1
and 2.5 SD below the young-adult mean (t score between
−1 and −2.5).
3. Osteoporosis: a bone density measurement
less than 2.5 SD below that of young, healthy controls
(t score < 2.5).
Indications of DEXA scan:
• Low trauma fracture age > 50 years
• Clinical features of osteoporosis (height loss, kyphosis)
• Osteopenia on plain X-ray
• Corticosteroid therapy (> 7.5 mg prednisolone daily for
> 3 mths)
• Family history of hip fracture
• Low body weight (BMI < 18)
• Early menopause (< 45 yrs)
• Diseases associated with osteoporosis
• Increased fracture risk on risk factor analysis (FRAX or
QFracture)
• Assessing response of osteoporosis to treatment
Other investigations:
Renal function, liver function, thyroid function,
immunoglobulins and ESR, with screening for coeliac
disease should be performed.
Serum 25(OH) vitamin D and PTH measurements are
useful to exclude vitamin D deficiency and secondary
hyperparathyroidism.
Levels of sex hormones and gonadotrophins should be
measured in men with osteoporosis and women under
the age of 50.
Transiliac bone biopsy is sometimes required in early-
onset osteoporosis of unknown cause or when coexisting
osteomalacia is suspected.
Management:
Non-pharmacological interventions:
Advice on smoking cessation, moderation of alcohol
intake, adequate dietary calcium intake and exercise
should be given.
Drug treatment:
Drug treatment should be considered in patients
with BMD T-score values below −2.5 or below −1.5
in corticosteroid-induced osteoporosis, and in
vertebral fractures, irrespective of BMD, unless they
resulted from significant trauma.
Bisphosphonates
Bisphosphonates are synthetic analogues
of pyrophosphate with a high affinity for
hydroxyapatite crystals in bone,
suppressing bone turnover and increasing
BMD at the lumbar spine and other sites
via inhibition of osteoclast-mediated bone
resorption.
Alendronate and risedronate are usually
administered once weekly for greater convenience.
Ibandronate is a monthly therapy
at a dose of 150 mg and is also available as a 3 mg
intravenous injection every 3 months.
Alendronate and risedronate reduce the incidence
of vertebral, nonvertebral, and hip fractures.
Both etidronate and ibandronate have
been shown to reduce the incidence of vertebral
fractures, but their impact on non-vertebral and hip
fractures is less clear.
The use of bisphosphonates in patients receiving
chronic glucocorticoid therapy is beneficial for
both the prevention and treatment of
osteoporosis. The use of alendronate 5 mg/day
(35 mg/week) as prevention or 10 mg/day (70
mg/week) as therapeutic dose, while
risedronate 5 mg/day (35 mg/week) as
preventive and therapeutic doses.
Zoledronic acid is licensed for the treatment of
osteoporosis in both men and women as a 5 mg
intravenous infusion once yearly.
It has been shown to significantly reduce the risk
of vertebral and non-vertebral fractures and
mortality in both men and women following
surgical repair of hip fracture
Adverse effects of bisphosphonates
Common
• Upper gastrointestinal intolerance (oral)
• Acute phase response (intravenous)

Less common
• Atrial fibrillation (intravenous zoledronic acid)
• Renal impairment (intravenous zoledronic acid)
• Atypical subtrochanteric fractures
Rare
• Uveitis
• Osteonecrosis of the jaw
The most common adverse effect with
intravenous bisphosphonates is a transient
influenza-like illness characterised by fever,
malaise, anorexia and generalised aches, which
occurs 24–48 hours after administration. This is
self-limiting but can be treated with
paracetamol or NSAID if necessary.
Atypical subtrochanteric fractures have been
described in patients who have received long-
term bisphosphonates, and may be the result of
over-suppression of normal bone remodeling.
Osteonecrosis of the jaw
ONJ is characterised by the presence of necrotic bone in
the mandible or maxilla, typically occurring after tooth
extraction when the socket fails to heal. Most ONJ cases
have occurred in cancer patients with coexisting
morbidity, such as infection and diabetes, who have
received high doses of intravenous bisphosphonates.
All patients should be advised to pay attention to good
oral hygiene.
There is no evidence that temporarily stopping
medication in patients undergoing tooth extraction is
necessary or alters the occurrence of ONJ.
Other treatments:
Denosumab is a monoclonal antibody that
neutralises the effects of RANKL; it is
administered by subcutaneous injection every 6
months in the treatment of osteoporosis.
It has few adverse effects but there are isolated
reports of ONJ with long-term use.
Calcium and vitamin D have limited efficacy in the
prevention of osteoporotic fractures when given in
isolation but are widely used as an adjunct to other
treatments, most often as combination
preparations containing 500 mg calcium and 800 U
vitamin D.
They are of greatest value in preventing fragility
fractures in elderly or institutionalised patients who
are at high risk of calcium and vitamin D deficiency.
Strontium ranelate It has a weak inhibitory effect
on bone resorption, stimulates biochemical markers
of bone formation and is incorporated within
hydroxyapatite crystals in place of calcium.
It is contraindicated in patients with risk of
cardiovascular disease due to an increased
myocardial infarction. There is also an increased
risk of venous thrombosis. Rarely, a severe rash
occurs, and this is an indication to stop treatment.
Parathyroid hormone
PTH is an anabolic agent that works by stimulating new
bone formation. The most widely used preparation is the
1-34 fragment of PTH (teriparatide) given by single daily
subcutaneous injection of 20 μg.
It is also effective in corticosteroid-induced osteoporosis
and appears superior to alendronate in terms of BMD
gain and vertebral fracture reduction. It is also effective in
male osteoporosis.
PTH is expensive and is usually reserved for patients
with severe osteoporosis (BMD T-score of −3.5 to −4.0 or
below) and those who have failed to respond adequately
to other treatments.
Hormonal replacement therapy
cyclical HRT with oestrogen and progestogen prevents
post-menopausal bone loss and reduces the risk of
vertebral and non-vertebral fractures in post-menopausal
women.
It is primarily indicated for the prevention of
osteoporosis in women with an early menopause and for
treatment of women with osteoporosis in their early
fifties who have troublesome menopausal symptoms.
HRT should be avoided in older women with established
osteoporosis because it significantly increases the risk of
breast cancer and cardiovascular disease.
Raloxifene acts as a partial agonist at oestrogen
receptors in bone and liver but as an antagonist in
breast and endometrium, and is classified as a
selective oestrogen receptor modulator (SERM).
It increases the risk of VTE to a similar extent as
HRT but reduces the risk of breast cancer; it does
not influence the risk of cardiovascular disease.

Calcitonin is an osteoclast inhibitor that has weak


anti-fracture efficacy but is no longer used in the
treatment of osteoporosis because of concerns
about an increased risk of cancer with long-term
use.
Duration of therapy
Oral bisphosphonates are usually given on a long-term
basis for osteoporosis with periodic review of the
continued need for therapy at 5-yearly intervals.
Other drug treatments, such as HRT, raloxifene and
denosumab, need to be given continuously for a
beneficial effect.
The optimal duration of treatment for strontium has not
been established.
For anabolic drugs such as PTH, a 2-year course
of treatment is given and followed by long-term
antiresorptive therapy.
Monitoring response
The response to drug treatment can be assessed
by repeating BMD measurements after 2–3
years.
Spine BMD is best for monitoring. To be sure
that a change has occurred, about 2% for spine,
5% for hip is required.
This means that, under normal circumstances,
at least 2 years should have elapsed before a
repeat scan is performed.
Markers of Bone Turnover
Biochemical markers of bone turnover, such as
N- telopeptide (NTX), or C- telopeptides (CTX)
which are sensitive indicators of bone
resorption, derived from the degradation of
mature collagen and respond more quickly than
BMD and can be used to assess adherence.
They increased in menopause, Paget’s disease,
osteoporosis, and RA.
Markers of Bone Turnover
Osteocalcin a noncollagenous matrix
protein in bone, it is produced exclusively by
osteoblasts; and its level reflects bone turnover.

Bone-specific alkaline phosphatase (BSAP) an


enzyme that is activated as osteoblasts
mature.