OSTEOPOROSIS

• Osteoporosis is the most common bone disease. It has been • Fractures in pa4ents with osteoporosis can affect any bone but
es4mated that > 8.9 million fractures occur annually worldwide common sites are the forearm (Colles’ fracture), spine (vertebral
and most of these occur in pa4ents with osteopenia or fractures), humerus and hip. All of these fractures become more
osteoporosis. common with increasing age.
• About 1/3 of all women and 1/5 of men aged 50 and above • Hip fractures are the most serious and have an immediate
suffer fractures at some point in life. mortality of about 12% and a con4nued increase in mortality of
• The burden of osteoporosis-related fractures is predicted to about 20% when compared with age-matched controls.
increase by two- to threefold by 2050 on a worldwide basis, due Treatment of hip fracture accounts for the majority of the
to ageing of the popula4on. health-care costs associated with osteoporosis.
• Osteoporosis is under-diagnosed and under-treated in Asia and
the Indian subcon4nent, par4cularly in rural areas, due to low
provision of technologies like Dual-energy X-ray absorp4ometry
(DXA), which are required to make the diagnosis.
Pathophysiology

• The defining feature of osteoporosis is reduced bone density,

which causes micro-architectural deteriora4on of bone 4ssue
and leads to an increased risk of fracture, in response to minor
trauma.
• The risk of fracture increases markedly with age in both genders.
This is mostly aWributable to an increased risk of falling with age
but is also due in part to an age-related decline in bone mass,
especially in women.
• Bone mass increases during growth to reach a peak between the
ages of 20 and about 45 years, but falls thereaZer in both
genders with an accelerated phase of bone loss aZer the
menopause in women due to oestrogen deficiency.
• The loss of bone with ageing is caused by an imbalance in the
bone remodelling cycle, whereby the amount of new bone
formed by osteoblasts cannot keep pace with the amount that is
removed by osteoclasts.
• The reduc4on in bone forma4on is thought to be partly due to
differen4a4on of bone marrow stem cells to adipocytes, as
opposed to osteoblasts.
• Osteoporosis some4mes occurs because of failure to aWain
adequate levels of peak bone mass but is more commonly due
to age-related bone loss.
• Osteoporosis is a complex disease that can occur in associa4on
with a wide variety of risk factors.
• Gene4c factors account for up to 80% of varia4on in bone
density, and genome-wide associa4on studies have shown that
suscep4bility is determined in part by a large number of
common variants, some of which are involved in the RANK and
Wnt signalling pathways. Rarely, osteoporosis may be caused by
muta4ons in single genes.
• Environmental factors, such as exercise and calcium intake
during growth and adolescence, are important in maximising
peak bone mass and in regula4ng rates of post-menopausal
bone loss.
• Smoking has a detrimental effect on BMD and is associated with
an increased fracture risk, partly because female smokers have
an earlier menopause than non-smokers.
• Heavy alcohol intake is a recognised cause of osteoporosis and
fractures but moderate intake does not substan4ally alter risk.
Idiopathic osteoporosis

• The term idiopathic osteoporosis is frequently used to describe • It is slightly misleading, since most, if not all, pa4ents in this
the occurrence of osteoporosis in pa4ents with no specific category have age-related osteoporosis or osteoporosis
underlying cause. associated with inheritance of gene4c variants that regulate
bone density.

Secondary osteoporosis

• Osteoporosis can occur in associa4on with a variety of diseases • Secondary causes of osteoporosis are par4cularly common in
and drug treatments, and in many cases > 1 disease or risk factor men, occurring in up to 50% of pa4ents.
is opera4ve. • Hypogonadism, glucocor4coid use and alcohol excess are the
most important predisposing factors.

Glucocor4coid-induced osteoporosis

• Glucocor4coid-induced osteoporosis is a common problem in • Glucocor4coids mainly cause osteoporosis by inhibi4ng bone
pa4ents with systemic inflammatory and chronic pulmonary forma4on and causing apoptosis of osteoblasts and osteocytes.
diseases. • Other contributory mechanisms include inhibi4on of intes4nal
• The risk of osteoporosis is related to dose and dura4on of calcium absorp4on, increased renal excre4on of calcium and
glucocor4coid therapy and increases substan4ally in pa4ents secondary hyperparathyroidism, which s4mulates osteoclas4c
who have taken > 7.5 mg of prednisolone daily for > 3 months bone resorp4on.
(or an equivalent dose of another glucocor4coid).
• Inhaled glucocor4coids can reduce bone density but the risk of
osteoporosis is much lower than with systemic therapy.

Pregnancy-associated osteoporosis

• This is a rare form of osteoporosis that typically presents with • The cause is unknown but may relate to an exaggera4on of the
back pain and mul4ple vertebral fractures during the second or bone loss that normally occurs during pregnancy in pa4ents with
third trimester. pre-exis4ng low bone mass.

Clinical features

• Osteoporosis does not cause symptoms un4l a fracture occurs. • The presenta4on of vertebral fractures is variable. Some pa4ents
• Non-vertebral fractures are almost always caused by a trauma4c present with acute severe back pain. This may radiate to the
event, most usually a simple fall. anterior chest or abdominal wall and be mistaken for a
• The term ‘fragility fracture’ is used to describe a fracture that myocardial infarc4on, aor4c dissec4on or intra-abdominal
occurs as the result of a fall from standing height or less. These pathology. In others the presenta4on is with height loss and
are typical of osteoporosis. kyphosis in the absence of pain or with chronic back pain.
• It is important to remember that the majority of people who • Some4mes the presenta4on of osteoporosis is with radiological
suffer a fragility fracture do not have osteoporosis; some have osteopenia or as a vertebral deformity on an X-ray that has been
normal bone density but most have osteopenia. performed for other reasons.
• The clinical signs of fracture are pain, local tenderness and
deformity.
• In hip fracture, the pa4ent is (with rare excep4ons) unable to
weight-bear and has a shortened and externally rotated limb on
the affected side.

Inves;ga;ons

• The most important inves4ga4on is DXA at the lumbar spine and

hip.
• This should be considered in pa4ents age over 50 who have
already suffered a fragility fracture, and in those with clinical risk
factors when a fracture risk assessment tool has returned an
elevated value.
• The risk at which DXA should be performed remains a subject of
debate but a 10-year risk of over 10% has been suggested, since
there is evidence of benefit from treatment at this level.
• Other indica4ons for DXA are in pa4ents under 50 years who
have very strong risk factors, such as premature menopause or
high-dose glucocor4coids.
• A history should be taken to iden4fy any predisposing causes,
such as early menopause, excessive alcohol intake, smoking and
glucocor4coid therapy. Signs of endocrine disease, neoplasia and
inflammatory disease should be sought on clinical examina4on.
• A falls history should be taken and a ‘get up and go’ test
performed, especially in older pa4ents.
• Screening for secondary causes of osteoporosis should be
performed.
Management
The aim of treatment is to reduce the risk of fracture and this can be achieved by a combina4on of approaches.

Non-pharmacological interven4ons

• Advice on smoking cessa4on, modera4on of alcohol intake, • Those with recurrent falls or unsteadiness on a ‘get up and go’
adequate dietary calcium intake and exercise should be given. test should be referred to a mul4disciplinary falls preven4on
team

Pharmacological interven4ons
Bisphosphonates

• Bisphosphonates are the first-line treatment for osteoporosis. • Oral bisphosphonates are poorly absorbed from the
• These are a class of drugs with a central core of P-C-P atoms, to gastrointes4nal tract and should be taken on an empty stomach
which various side-chains are aWached. with plain water; no food should be eaten for 30–45 minutes
• Following administra4on, they target bone surfaces and are aZer administra4on. They are contraindicated in pa4ents with
ingested by osteoclasts during the process of bone resorp4on. oesophageal stricture or achalasia, since tablets may s4ck in the
The bisphosphonate is released within the osteoclasts and oesophagus, causing ulcera4on and perfora4on. Upper
impairs bone resorp4on. gastrointes4nal upset occurs in about 5% of cases.
• This in turn causes an increase in bone density but this is • Oral bisphosphonates can be used in pa4ents with gastro-
principally due to increased mineralisa4on of bone, rather than oesophageal reflux disease but may cause worsening of
an increase in bone mass. symptoms.
• Bisphosphonates reduce the risk of fracture in pa4ents with • The most common adverse effect with IV bisphosphonates is a
osteoporosis but do not completely prevent fractures occurring. transient influenza-like illness typified by fever, malaise, anorexia
• Oral bisphosphonates are typically given for a period of 5 years, and generalised aches, which occurs 24–48 hours aZer
at which point the need for con4nued therapy should be administra4on. This is self-limi4ng but can be treated with
evaluated, with a repeat DXA if possible. paracetamol or NSAIDs if necessary. It predominantly occurs
• If pa4ents have remained free of fractures aZer 5 years and if aZer the first exposure and tolerance develops thereaZer.
BMD levels have increased and no longer remain in the • Osteonecrosis of the jaw is characterised by the presence of
osteoporo4c range, it is usual to ins4gate a 5-year spell off necro4c bone in the mandible or maxilla, typically occurring
therapy. aZer tooth extrac4on when the socket fails to heal. This
• Treatment may be con4nued for up to 10 years in pa4ents complica4on is very rare in osteoporosis but pa4ents receiving
whose BMD levels remain in the osteoporo4c range aZer 5 bisphosphonates should be advised to pay aWen4on to good oral
years. hygiene. There is no evidence that temporarily stopping
• A change in treatment should be considered in pa4ents who bisphosphonates for tooth extrac4on alters the risk of
have lost BMD despite oral bisphosphonates (> 4%). Most osteonecrosis of the jaw.
commonly, this will be a switch to parenteral zoledronic acid but • Atypical subtrochanteric fractures have been described in
teripara4de (TPTD) can also be considered in those with severe pa4ents who have received long-term bisphosphonates and
spinal osteoporosis. appear to be the result of over-suppression of normal bone
• With IV zoledronic acid, 3 years of therapy is equivalent to 6 remodelling.
years in terms of fracture risk reduc4on and many experts • In the vast majority, the benefits of bisphosphonate therapy far
recommend periods of 3 years on and 3 years off treatment to outweigh the risks but it is important for treatment to be
reduce the risk of over-suppression of bone turnover. targeted to pa4ents with low BMD who are most likely to
benefit.

Denosumab

• Denosumab is a monoclonal an4body that inhibits bone • Denosumab may rarely cause osteonecrosis of the jaw and
resorp4on by neutralising the effects of RANKL. atypical subtrochanteric fractures.
• It is administered by SC injec4on of 60 mg every 6 months in the • If it is stopped, there is a rebound increase in bone turnover that
treatment of osteoporosis and has similar efficacy to zoledronic can be associated with a greater risk of fracture and even
acid. hypercalcaemia.
• One poten4al adverse effect is hypocalcaemia but this can be • Because of this, many experts advise giving a bisphosphonate
mi4gated by calcium and vitamin D supplements. following cessa4on of denosumab.

Calcium and vitamin D

• Combined calcium and vitamin D supplements have limited

efficacy in the preven4on of osteoporo4c fractures when given
alone but are widely used as an adjunct to other treatments.
• A typical daily dosage is 1000 mg calcium and 800 IU vitamin D.
• Calcium and vitamin D supplements have efficacy in preven4ng
fragility fractures in elderly or ins4tu4onalised pa4ents who are
at high risk of deficiency.
• Vitamin D supplements alone do not prevent fractures in
osteoporosis but there is evidence that the response to
bisphosphonates is blunted in pa4ents with vitamin D deficiency.
If the pa4ent’s dietary calcium is sufficient, stand-alone vitamin
D supplements (800 IU daily) can be prescribed as an adjunct to
an4-osteoporosis therapies.

Teripara4de

• Teripara4de (TPTD) is the 1-34 fragment of human PTH. • TPTD and oral bisphosphonates should not be given in
• It is an effec4ve treatment for osteoporosis, which works by combina4on, however, since the bisphosphonate blunts the
s4mula4ng new bone forma4on. anabolic effect.
• Although TPTD also s4mulates bone resorp4on, the increase in • The efficacy of TPTD for preven4on of non-vertebral fractures is
bone forma4on is greater, resul4ng in increased bone density, similar to that of bisphosphonates but it is superior to oral
par4cularly at sites rich in trabecular bone such as the spine. bisphosphonates in preven4ng vertebral fractures.
• It is given by a self-administered SC injec4on in a dose of 20 μg • The most common adverse effects are headache, muscle cramps
daily for 2 years. and dizziness.
• At the end of this period, bisphosphonate therapy or another • Mild hypercalcaemia may occur but it is usually asymptoma4c
inhibitor of bone resorp4on should be administered to maintain and does not require discon4nua4on of treatment.
the increase in BMD. • Monitoring of serum calcium is not required during TPTD
treatment.

Abalopara4de

• Abalopara4de is the 1-34 fragment of PTH-related protein. • Efficacy has been demonstrated for the preven4on of vertebral
• It works in a similar way to TPTD to s4mulate bone forma4on. fractures with effects similar to those of TPTD.
• It is given as a self-administered injec4on of 80 μg daily for 18 • Adverse effects are similar to those of TPTD.
months.
• At the end of this period an inhibitor of bone resorp4on should
be given to maintain the increase in bone mass.
Hormone replacement therapy

• Cyclical HRT with oestrogen and progestogen prevents post- • It is not recommended above the age of 60 because the risk of
menopausal bone loss and reduces the risk of vertebral and non- an increased risk of breast cancer, cardiovascular disease and
vertebral fractures in postmenopausal women. venous thromboembolic disease.
• It is primarily indicated for the preven4on of osteoporosis in
women with an early menopause and for treatment of women
with osteoporosis in their early fiZies who have troublesome
menopausal symptoms.

Raloxifene

• Raloxifene is a selec4ve oestrogen receptor modulator (SERM) • Adverse effects include muscle cramps, worsening of hot flushes
that acts as a par4al agonist at oestrogen receptors in bone and and an increased risk of venous thromboembolic disease.
liver, but as an antagonist in breast and endometrium. • Bazedoxifene is a related SERM that has similar effects to
• It is effec4ve in reducing the risk of vertebral fractures but does raloxifene.
not influence the risk of non-vertebral fracture and is seldom
used.

Tibolone

• Tibolone has par4al agonist ac4vity at oestrogen, progestogen • Treatment is associated with a slightly increased risk of stroke
and androgen receptors. but a reduced risk of breast cancer.
• It has been shown to prevent vertebral and non-vertebral
fractures in post-menopausal osteoporosis.

Other drugs

• Romosozumab is an4body directed against scleros4n, which is • Calcitriol (1,25(OH)2D3), the ac4ve metabolite of vitamin D, is
under development for the treatment of osteoporosis. licensed for treatment of osteoporosis but it is seldom used
• It increases bone forma4on, inhibits bone resorp4on and because the data on fracture preven4on are less robust than for
increases BMD. other agents.
• When given SC in a dose of 210 mg monthly, it reduces the risk
of vertebral fractures in pa4ents with postmenopausal
osteoporosis.

Surgery

• Orthopaedic surgery with internal fixa4on is frequently required • While randomised trials have shown that vertebroplasty
to reduce and stabilise osteoporo4c fractures. provides no beWer pain relief than a sham procedure, it is s4ll
• Pa4ents with intracapsular fracture of the femoral neck generally widely used, par4cularly in North America.
need hemiarthroplasty or total hip replacement in view of the • Kyphoplasty is used under similar circumstances, but in this case
high risk of avascular necrosis. a needle is introduced into the affected vertebral body and a
• Vertebroplasty is some4mes used in the treatment of painful balloon is inflated, which is then filled with MMA. It has similar
vertebral compression fractures. It involves injec4ng methyl efficacy to vertebroplasty but adverse effects are more common.
methacrylate (MMA) into the affected vertebral body under Adverse effects with both procedures include spinal cord
seda4on and local anaesthesia. compression due to leakage of MMA and fat embolism.