1

An Overview of the Management of Osteoporosis

Salina LAM, Pharmacist, QEH

1. Introduction
1.1. Epidemiology
Osteoporosis () affects
over 75 million people in the United
States, Europe and Japan, and
causes more than 8.9 million
fractures annually worldwide.
1
It
affects both men and women, but
particularly common in
post-menopausal women, and its
prevalence increases with age.
2
It is
three times more common in
women than men as a result of the
decline in level of oestrogen usually
after menopause.
3
The annual
incidence of fractures is estimated
to rise markedly with the worldwide
increase in the aging population,
thus giving rise to significant
morbidity and mortality to some
extent.
4
The relevant clinical
consequences of osteoporosis are
fractures and their significant
complications such as pain,
physical limitation and other
psychological symptoms, most
notably depression and loss of
self-esteem.
5
The estimated lifetime
risk for a wrist, hip or vertebral
fracture is 30-40% in developed
countries, which is actually very
close to that for coronary heart
disease.
1

Osteoporosis is a silent disease
which is asymptomatic and is not
clinically evident until fractures
take place, causing medical and
personal burdens on aging
individuals as well as an economic
burden to the society.
3,5
It is
associated with three categories of
adverse outcomes: mortality,
morbidity, and cost.
4
The fractures
of the vertebrae (spine), proximal
femur (hip) and distal forearm
(wrist) have been identified to be
the most typical fracture sites, in
which the hip fractures have been
regarded as the most serious,
resulting in 10-20% excess
mortality in the first year after
fracture.
4,5
In addition, a hip fracture
is associated with a 2.5-fold
increased risk of future fractures at
the same site whereas a vertebral
fracture is associated with a 10-fold
increase in subsequent vertebral
fractures.
4, 5

1.2. Pathogenesis
According to the World Health
Organisation (WHO), Osteoporosis
is a systemic skeletal disease
characterised by low bone density
and microarchitectural deterioration
of bone tissue, leading to enhanced
bone fragility and a consequent
increase in fracture risk.
1,3
The
microarchitecture of bone tissues of
a young female compared with an
elderly woman is shown in Figure 1,
illustrating many of the plate-like
structures converted to thin rods in
older age.
6

Ask Yourself
1 How can osteoporosis
affect us?
2 What elements are
important for maintaining
bone health?
3 What pharmacological
and non-pharmacological
interventions can be used
for preventing and
treating osteoporosis?
Figure 1

Scanning electron micrographs to show
the structure of L3 Vertebra in a 31
year old woman (top) and in a 70 year
old woman (bottom).
6

2

Bone loss occurs as a result of
imbalance between the activity of
osteoclasts (; bone cells
that break down bone) and
osteoblasts (; bone cells
responsible for bone formation) in
which there is an increase in
osteoclasts activity and decreased
bone formation by osteoblasts.
4,6

Such imbalance leading to skeletal
fragility can be resulted from:
(i) failure to produce a skeleton of
optimal mass and strength
during growth;
(ii) excessive bone resorption
(breakdown of bone) resulting
in decreased bone mass and
microarchitectural
deterioration of the skeleton;
and
(iii) an inadequate formation
response to increased
resorption during bone
remodelling.
7

The bone remodelling in an adult is
a process in which skeleton is
continually remodelled in an
orderly sequence of bone resorption
followed by bone formation.
4,7
As
illustrated in Figure 2, bone
remodelling process occurs on the
surface of trabecular bone (spongy
bone) and it begins with the
activation of hematopoietic
precursors through interaction with
cells of the osteoblast lineage or
with inflammatory cells,
particularly T-cells, to become
osteoclasts. Upon formation of
osteoclasts, there is a resorption
phase of limited duration and a brief
reversal phase, during which the
bone formation has not yet begun.
The formation phase is then
initiated, possibly by factors
produced by the osteoclast or
reversal cells or released from the
bone matrix.
7
The formation phase
is substantially longer than the first
3 phases and involves the
production of matrix and osteocytes
embedded in the bone.
7
Since the
resorption and reversal phases of
bone remodelling are relatively
short and the period required for
bone formation is long, increase in
the rate of bone remodelling will
result in imbalance between
resorption and formation processes
and cause loss of bone mass.
4,7
The remodelling process is
controlled by systemic and locally
produced cytokines and imbalance
between bone resorption and
formation results in net bone loss,
leading to osteoporosis.
Osteoporosis can result from
inadequate intake of nutritional
calcium, vitamin D or protein,
deficiency of sex hormone, primary
hyperparathyroidism (
), hyperthyroidism (
) or exposure to excess
glucocorticoid.
3

Oestrogen has been shown to play a
critical role in the normal
physiology of bone remodelling. A
deficiency in oestrogen after
menopause, accelerates the rate of
bone turnover, upsetting the balance
between bone formation and bone
resorption.
3,4,7
Oestrogen causes a
reduction in the proinflammatory
cytokines, such as interleukin-1
(IL-1), interleukin-6 (IL-6) and
tumour necrosis factor- (TNF-),
released by the bone marrow and
Figure 2

The bone remodelling unit.
7

3

Table 1 - Risk factors for
osteoporosis
Non-modifiable Increased age
Female gender
Asian, Caucasians
Early menopause
Family history of
osteoporosis
Modifiable Low BMI
Smoking
Physical inactivity

Learning Points
1. Osteoporosis is an
asymptomatic systemic
skeletal disease which is
common in
post-menopausal women.
2. Osteoporosis is
characterised by low bone
density and
microarchitectural
deterioration of bone
tissue.
3. Fractures are clinical
consequences of
osteoporosis, which lead
to pain, physical limitation
and other psychological
symptoms.
4. Bone loss occurs as a
result of imbalance
between bone resorption
and bone formation.
hence oestrogen deficiency
increases the production of these
cytokines which further enhance
formation of osteoclasts to
resorb bone, causing progressive
loss of trabecular bone.
3,4
1.3. Risk Factors
2,3,5,6,8-10

Table 1 lists different risk factors,
non-modifiable and modifiable,
causing an increase in risk for
development of osteoporosis.
The causes of osteoporosis can be
primary or secondary to other
conditions, in which are listed in
tables 2 and 3 respectively. Some
medications can induce
osteoporosis and corticosteroid is
being the most well understood
example. Examples of drug-related
osteoporosis are outlined in table 4.
Pharmacists are placed in a
prominent role to recognize
medicationinduced osteoporosis
and take part in the prevention of
fractures.
2. Screening and Diagnosis of
Osteoporosis
The measurement of bone mineral
density (BMD) has been
well-established in confirming
diagnosis of osteoporosis,
prediction of fracture risk and
identification of individuals who are
at higher risk of fracture.
5, 11

Table 2 - Causes for primary osteoporosis
Trauma e.g. falls
Low bone density Menopause
Age-related conditions
Reduced calcium absorption from the gut
Secondary hyperparathyroidism
Previous fracture
Genetics Family history of fragility fracture, particularly hip fracture
Nutrition Deficiency of calcium, vitamin D, vitamin K, protein
High dietary intake of phosphate
Physical inactivity Immobility
Cigarette smoking
Alcohol consumption 3units/day
Low body mass index < BMI of 19kg/m
2

Sex hormone deficiency Primary hypogonadism ()
Oestrogen deficiency at the menopause

4


Table 4 - Examples of drug-induced osteoporosis
Thyroid replacement
hormone
Excess thyroid replacement hormone
Causes hyperthyroidism and suppresses TSH, resulting in bone loss
Anticonvulsants e.g. Phenytoin, Phenobarbital
CYP induction increases the metabolism of vitamin D, leading to reduction in
calcium absorption
CYP induction lowers circulating oestrogen and testosterone, causing bone loss
Anticonvulsants inhibit osteoblasts to decrease bone formation
Antidepressants e.g. Selective serotonin reuptake inhibitors (SSRI)
e.g. Tricyclic antidepressants (TCA)
Antipsychotics Increase in prolactin concentrations lowers oestrogen and testosterone
concentrations, leading to bone loss
Thiazolidinediones e.g. Pioglitazone
Glucocorticoids With prolonged use
Drugs that cause
hypogonadism
Parenteral progesterone
Methotrexate
Gonadotropin-releasing hormone agonists
Lithium
Heparin Long-term use in particular with unfractionated heparin
Aromatase inhibitors Drugs e.g. Anastrozole, exemestane, letrozole used in treatment of
oestrogen-receptor positive breast cancer lowers oestrogen level
Proton pump inhibitors High dose and long term use

The gold standard technique used
to assess bone mass, bone mineral
or other related aspects of skeletal
mass or structure is the dual-energy
x-ray absorptiometry (DXA), which
measures bone mineral at sites such
as the spine and hip and total body
bone mineral.
3
BMD is expressed in
terms of grams of mineral per
square centimetre scanned (g/cm
2
)
and in relationship to two norms: (i)
Z-score in which patients BMD
compared to the expected BMD for
a gender, ethnicity and age-matched
population, or (ii) T-score in which
patients BMD compared to the
expected BMD for a gender and
ethnicity-matched young adult
healthy population.
5, 11

Standard deviation (SD) above or
below the mean is applied as an
expression of the difference
between the patients score and the
norm.
3,5,11
Table 5 illustrated the
WHO diagnostic classification,
which adopts the DXA devices for
BMD measurement at the femoral
neck.
1,3
This classification applies
to postmenopausal women and men
aged 50 and above. Other central
sites (e.g. lumbar spine, total hip)
can also be used for diagnosis in
clinical practice.
Table 3 - Causes for secondary osteoporosis
Chronic medical
and systemic
diseases
Chronic obstructive pulmonary
disease
Inflammatory bowel diseases
Liver disease (severe)

Renal failure
Rheumatoid arthritis
Systemic lupus
erythematosus

Endocrine and
metabolic
disorders
Diabetes mellitus, Type 1
Hyperparathyroidism (primary)
Hyperthyroidism

Hypogonadism (primary
and secondary)
Hypophosphatasia
Cushings syndrome






5

Key Points
DXA (Dual-energy X-ray
Absorptiometry) is a
technique for measuring the
bone mineral density (BMD).
FRAX is a tool for calculating
the 10-year probability of
bone fracture.
Other clinical and biological tests
Other clinical and biological tests
should be performed to: (i) exclude
a disease which can mimic
osteoporosis; (ii) establish the
causes of osteoporosis and the
contributory factors; (iii) assess the
severity of osteoporosis and
determine the risk of subsequent
fractures; (iv) select the most
appropriate treatment; and (v)
establish baseline measurements for
subsequent monitoring of
treatment.
3
A list of other screening
tests are described in table 6.
8
The FRAX, a fracture risk
assessment tool adopted by the
WHO, is used to calculate the
10-year probability of a hip fracture
and the 10-year probability of a
major osteoporotic fracture which is
defined as clinical vertebral, hip,
forearm or proximal humerus
fracture. The FRAX tool uses sex,
age, body mass index, prior fracture,
parental hip fracture, usage of
glucocorticoid, rheumatoid arthritis,
current smoking status, alcohol
intake (three or more units daily)
and BMD of the femoral neck for
estimation of the fracture risk.
5, 12

3. Pharmacological
Interventions
Therapeutic options for
osteoporosis have increased
considerably in recent years and
recommendations for choices of
treatment vary among individuals.
In summary, postmenopausal
Table 5 - WHO diagnostic classification for osteoporosis
by measurement of BMD
Normal BMD within 1 SD of the young adult reference mean
T-score -1.0
Low bone mass
(osteopenia)
BMD is between 1.0 and 2.5 SD below that of the
young adult mean
-2.5 < T-score < -1
Osteoporosis BMD is 2.5 SD or more below that of the young adult
mean
T-score -2.5
Severe osteoporosis
(established
osteoporosis)
BMD is 2.5 SD or more below that of the young adult
mean in the presence of one or more fragility fractures
T-score -2.5

Table 6 - other biological and chemical screening tests for diagnosis of osteoporosis
8

Tests Possible aetiology
Alkaline phosphatase (ALP) High level in Pagets disease, immobilisation
Calcium Vitamin D deficiency, malabsorption
Liver or kidney function Liver or kidney disease
Complete blood count Bone marrow malignancy, malabsorption
Estradiol (pre- or perimenopausal women) Hypogonadism
Thyroid-stimulating hormone Hyperthyroidism
Total testosterone (in men) Hypogonadism
25-hydroxyvitamin D Vitamin D deficiency
Parathyroid hormone Hyperparathyroidism
Serum protein electrophoresis Multiple myeloma ()

6

women and men aged 50 and above
presenting with the following
should be considered for treatment:
(i) A hip or vertebral fracture;

(ii) T-score -2.5 at the femoral
neck or spine after appropriate
evaluation to exclude
secondary causes;

(iii) low bone mass (osteopenia)
with a T-score between -1.0
and -2.5 at the femoral neck or
spine and a 10-year probability
of a hip fracture 3% or a
10-year probability of a major
osteoporosis-related fracture
20% based on the WHO
FRAX fracture risk assessment
tool.
5
3.1. Bisphosphonates
3.1.1. Indications
Bisphosphonates (alendronate,
risedronate, ibandronate and
zoledronic acid) are licensed in the
prevention and treatment of
postmenopausal osteoporosis and
osteoporosis in men.
3.1.2. Pharmacological action
Bisphosphonates are synthetic
analogues of naturally-occurring
inorganic pyrophosphate.
13,14

Pyrophosphate itself is a natural
circulating inhibitor of
mineralisation in the blood and
urine but cannot diffuse into the
bones.
14
Bisphosphonate
accumulates in bone where it exerts
its actions by binding to
hydroxyapatite crystals in bone
mineral and thus inhibiting
mineralisation. It is because
bisphosphonates adsorb to bone
mineral especially at sites of bone
resorption during the bone
remodelling process. They inhibit
and induce apoptosis (cell death) of
osteoclasts, contributing to the
reduction of bone turnover rate and
increase of bone mineral mass.
15
The relative anti-resorptive potency
of different bisphosphonates is
stated in table 7.
14

3.1.3. Adverse effects
The common adverse effects and
the management to reduce
incidence of developing such
effects are described in table 8.
5,16,17
It is important to note that other rare
and serious complications such as
osteonecrosis of the jaw, atypical
fractures and oesophageal cancer
have been reported and addressed
as safety concerns by the FDA.
18

Bisphosphonate-associated
osteonecrosis of the jaw has been
defined as exposed or necrotic bone
in the maxillofacial region, which
has persisted for more than 8 weeks
in those receiving bisphosphonates
without history of irradiation of the
jaw.
17,19
Osteonecrosis occurs more
frequently in cancer patients
receiving IV bisphosphonates and is
associated with dental surgery in
many cases.
17
Recommendations to
reduce the development of
osteonecrosis of the jaw are that any
dental procedures are ought to be
completed before initiation of
bisphosphonates, and during
treatment, patients should be
advised to maintain good oral
hygiene, have regular check-ups,
and report any oral symptoms.
17,19

Long-term use of bisphosphonate
has been associated with atypical
femur fractures, defined as atypical
by their location in the
subtrochanteric region and femoral
shaft with minimal or no associated
trauma and absence of comminution
(breakage of bones into several
pieces).
17
Table 7 - The
anti-resorptive
potency of different
bisphosphonates
14

Drug Potency
Etidronate 1
Clodronate 10
Tiludronate 10
Pamidronate 100
Alendronate 1000
Risedronate 5000
Ibandronate 10000

7

In addition, the use of oral
bisphosphonates has been linked
with an increased risk of
oesophageal cancer.
17,18
There have
been conflicting findings from
studies evaluating this risk and a
review by the FDA is still ongoing.
Nevertheless, bisphosphonates,
especially etidronate, alendronate
and risedronate, are still most
widely used in prevention and/or
treatment of osteoporosis at present
as the benefits of bisphosphonates
outweigh the risk.
3.2. Strontium ranelate
20,21

3.2.1. Indications
Strontium ranelate, available as a
sachet to be mixed with water and
taken daily, has a therapeutic
indication for treatment of
osteoporosis in postmenopausal
women to reduce the risk of
vertebral and hip fractures.
3.2.2. Pharmacological action
Strontium is adsorbed onto the
crystal surface and only slightly
substitutes for calcium in the apatite
crystal (composition of bone
mineral) of newly formed bone,
without modifying the bone crystal
characteristics. By this action, it
reduces bone resorption by
decreasing osteoclast differentiation
and resorbing activity. Moreover, it
also increases bone formation
Table 8 - Adverse effects of bisphosphonates
5,16,17

Type Examples Management
Mineral metabolism Hypocalcaemia
Hypophosphataemia
Existing hypocalcaemia should be treated before
starting bisphosphonates
Adequate intake of calcium and vitamin D
Gastrointestinal Oesophagitis
Peptic ulceration
Abdominal pain, nausea and
vomiting
Diarrhoea or constipation
Swallow tablets whole with plenty of water (not less
than 200mL)
Stay in an upright position (standing or sitting) for
at least 30mins after taking tablets
Tablets should be taken on rising for the day, on an
empty stomach, at least 30mins before breakfast or
any other oral medication
Musculoskeletal Severe bone, joint, and/or
muscle pain reported
Aetiology unknown
Renal Renal toxicity Associated with IV infusion of zoledronic acid
especially with rapid infusion rate
Monitor renal function before and during treatment
Maintain appropriate hydration
Recommended to infuse over 15 mins
Contraindicated in CrCl < 35 ml/min
Acute-phase reaction Fever, arthralgia (),
headache, myalgia()
Associated with IV zoledronic acid
Usually transient
Patients may be pre-treated with paracetamol to
reduce the risk
These symptoms occurred in 32% of patients after
first dose, 7% after the second dose and 3% after the
third dose

8

through stimulation of osteoblast
precursor replication and collagen
synthesis in bone cell culture. As a
result, strontium rebalances the
bone turnover, in which favouring
the process of bone formation.
3.2.3. Adverse effects
Adverse reactions associated with
the use of strontium ranelate were
usually mild and transient, with
nausea and diarrhoea being the
most common ones, which were
generally reported at the beginning
of treatment. Phase III clinical trials
showed that, compared with
placebo, strontium ranelate was
associated with an increased annual
incidence of venous
thromboembolism (;
VTE) of 0.7% but the mechanism is
still unknown. Therefore, it should
be used with caution in patients at
increased risk of VTE.
Food, milk and derivative products,
and medicinal products containing
calcium reduce the bioavailability
of strontium ranelate by
approximately 60-70%. Therefore,
administration of strontium ranelate
and such products including
antacids should be at least two
hours apart, preferably at bedtime.
Co-administration of strontium
ranelate with oral tetracycline or
quinolone antibiotics can form
poorly soluble chelates at the
gastrointestinal level, thereby
reducing their absorption.
Treatment of strontium ranelate
should be suspended during
treatment with these antibiotics.
It is an alternative treatment option
to bisphosphonates, particularly in
patients for whom these drugs are
contraindicated or not tolerated.
3.3. Raloxifene
8, 21,22

3.3.1. Indications
Raloxifene is indicated for the
treatment and prevention of
osteoporosis in postmenopausal
women to reduce the risk of
vertebral fractures but not hip
fractures. It is indicated to decrease
the risk of invasive breast cancer in
postmenopausal women with
osteoporosis.
3.3.2. Pharmacological action
Raloxifene, a selective oestrogen
receptor modulator (SERM), has
selective agonist or antagonist
activities on tissues responsive to
oestrogen. It has oestrogen agonist
activity on the bones and lipids,
whereas oestrogen antagonist effect
on the breast and uterus. It
decreases bone resorption and
normalises bone turnover to the
pre-menopausal range, which
manifests as reductions in serum
and urine levels of bone turnover
markers, increases in bone mineral
density and decreases in incidences
of fractures. Additionally,
significant reduction in total
cholesterol and LDL cholesterol
were shown in clinical trials but
raloxifene did not significantly
affect the risk of cardiovascular
events. However, raloxifene is
associated with a three-fold increase
in the risk of venous
thromboembolism (VTE) and
therefore it is contraindicated in
people with a history of VTE.
3.3.3. Adverse effects
The most common adverse effects
are vasomotor symptoms such as
hot flushes. Raloxifene is not
recommended as the first-line
treatment option for primary
prevention and treatment of
osteoporosis as bisphosphonates
can reduce the risk of fractures in
all sites whereas raloxifene has
been proven to reduce vertebral
fractures only. Perhaps, it can be
considered as a treatment option in
postmenopausal patients with
osteoporosis, who are unable to
tolerate bisphosphonates, have no
vasomotor symptoms or history of
VTE, and have a high breast cancer
risk score.
3.4. Hormone replacement
therapy
5,23

Oestrogen deficiency is considered
to be a major factor predisposing to
osteoporosis. Hormone replacement
therapy (HRT), oestrogen with or
without progesterone, is approved
for the prevention of osteoporosis,
relief of vasomotor symptoms and
vulvovaginal atrophy associated
with menopause.
The Womens Health Initiative
(WHI) randomised clinical trial
demonstrated that 5 years treatment
with oestrogen plus progesterone
increase BMD and reduces the risk
of clinical vertebral fractures and
hip fractures by 34% and other
9

Counselling Points

1. When taking
bisphosphonate tablets,
swallow with plenty of
water and stay in an
upright position for at
least 30mins afterwards.

2. Products containing
calcium reduce the
absorption of strontium
ranelate, which should be
taken at least 2hrs apart.
osteoporotic fractures by 23%.
However, the WHI reported
increased risks of myocardial
infarction, stroke, invasive breast
cancer, and VTE during 5-year
treatment with conjugated
oestrogen and medroxyprogesterone.
The benefit of fracture reduction
does not outweigh the risks of
cardiovascular disease and breast
cancer, even in women at higher
risk of fracture.
Therefore, given the overall
unfavourable risk-benefit ratio and
the availability of other agents for
prevention and treatment of
osteoporosis, HRT should not be
recommended as first-line agent for
prevention or for treatment of
osteoporosis in women without
vasomotor symptoms.
3.5. Calcitonin (Salmon)
8,12,21,24,25

3.5.1. Indications
Calcitonin is approved in the
treatment of established
post-menopausal osteoporosis to
reduce the risk of vertebral fractures
but a reduction in hip fractures has
not been demonstrated in clinical
trials. It is not considered as a first
line agent for osteoporosis unless
first line treatment with
bisphosphonates is not tolerated.
3.5.2. Pharmacological action
Calcitonin is a naturally occurring
32-amino acid polypeptide hormone
that is produced by the
parafollicular cells of the thyroid.
Synthetic or recombinant calcitonin
has been derived from a number of
different species and salmon
calcitonin is the most widely used
preparation as it is 50 to 100 times
more potent than human calcitonin.
Calcitonin secretion is stimulated
by high plasma concentrations of
calcium. Calcitonin binds to
calcitonin receptors on osteoclasts,
resulting in diminished osteoclastic
binding to mineralised bone and
decreased osteoclast activity, hence
inhibiting bone resorption and
markedly reducing bone turnover.
3.5.3. Dosage recommendation
It is available commercially as
subcutaneous injection and nasal
spray preparations. Calcitonin nasal
spray (Miacalcic) can be given at a
dosage of 200 IU in alternating
nostril each day.
3.5.4. Adverse effects
The use of parenteral calcitonin was
significantly limited by the common
adverse effects of nausea, flushing
of the face and hands, and local
injection sites reactions, which
affects patients compliance and
acceptability. The most common
adverse effect of nasal calcitonin is
rhinitis which is usually mild and
not a major cause for drug
discontinuation. The safety of nasal
preparation has therefore been
considered as an advantage.
3.6. Recombinant parathyroid
hormone
6,8,26,27

3.6.1. Indications
Teriparatide, a recombinant
parathyroid hormone, is indicated in
the treatment of osteoporosis in
postmenopausal women and in men
at increased risk of fracture.
Teriparatide is associated with a
significant reduction in incidence of
vertebral and non-vertebral
fractures but not hip fractures. It is
also approved in the treatment of
osteoporosis associated with
sustained systemic glucocorticoid
therapy in women and men at
increased risk for fracture.
3.6.2. Pharmacological action
Teriparatide, an anabolic steroid,
acts predominantly on osteoblasts to
increase bone formation on
trabecular and cortical surfaces by
more selective stimulation of
osteoblastic activity over
osteoclastic activity. It exerts its
10

effect by increasing the lifespan of
osteoblast through reduction of
osteoblast apoptosis and induction
on recruitment and formation of
new osteoblasts. Skeletal mass and
bone strength are also increased.
3.6.3. Dosage recommendation
The recommended dosage of
teriparatide is 20 micrograms
administered once daily by
subcutaneous injection in the thigh
or abdomen and the maximum total
duration of treatment should be 24
months. The 24-month course of
teriparatide should not be repeated
over a patients lifetime as the
safety and efficacy of teriparatide
have not been evaluated beyond 2
years of treatment. Patients may be
continued on other osteoporosis
treatment after stopping 24 month
treatment with teriparatide therapy.
3.6.4. Adverse effects
Dizziness, leg cramps, nausea,
injection site reactions and
headache are the most commonly
reported side-effects which are
generally mild and not requiring
discontinuation. Increase of uric
acid concentration without the
development of acute gout and
small increases in urinary calcium
excretion without nephrolithiasis
( ) have been reported.
Increased risk of osteosarcoma (
)is seen in rats exposed to high
doses. Consequently, teriparatide is
contraindicated in patients with risk
of osteosarcoma, such as those with
Pagets disease, previous skeletal
radiation, or unexplained elevation
of alkaline phosphatase level.
Due to its high cost, teriparatide is
generally reserved for those with
severe osteoporosis who are unable
to tolerate or seem to be
unresponsive to other treatments.
3.7. Denosumab
12,28,29

3.7.1. Indications
Denosumab is approved in the
treatment of osteoporosis in
postmenopausal women at
increased risk of fractures and it
significantly reduces the risk of
vertebral, non-vertebral and hip
fractures.
3.7.2. Pharmacological action
Denosumab, a human monoclonal
antibody (IgG2), targets and binds
with high affinity and specificity to
RANK-L, preventing activation of
its receptor RANK on the surface of
osteoclast precursors and
osteoclasts. Activated
RANK-L/RANK pathway (a cell
signalling pathway) is associated
with enhanced bone resorption,
resulting in bone loss. Denosumab
inhibits this pathway, thus
inhibiting osteoclast formation,
function and survival, thereby
decreasing bone resorption in
cortical and trabecular bone.
3.7.3. Dosage recommendation
The recommended dosage of
denosumab is 60mg administered as
a single subcutaneous injection
once every 6 months into the thigh,
abdomen or back of arm.
3.7.4. Adverse effects
The most common adverse effects
include infections of the urinary and
respiratory tract, cataract,
constipation, rashes and pain in
extremities. The increase in
infections under denosumab
treatment might be related to the
role of RANK-L in the immune
system. Denosumab is
contraindicated in hypocalcaemia
which must be corrected by
adequate intake of calcium and
vitamin D before starting therapy
with denosumab. Similar to
bisphosphonates, osteonecrosis of
the jaw has been reported in
patients treated with denosumab. To
minimise the risk of osteonecrosis
of the jaw, patients who are
scheduled to start denosumab
should be seen by a dentist if they
have additional systemic
(glucocorticoid therapy,
chemotherapy) or local risk factors
(radiation, dental disease). In
addition to recommending
improved oral hygiene, invasive
dental procedures should be
avoided during denosumab
treatment.
According to the practice guidelines
for the management of osteoporosis
published by the Canadian Medical
Association, denosumab can be
used as first-line therapy for
prevention of hip, non-vertebral and
vertebral fractures in menopausal
women requiring treatment of
osteoporosis. There are several
11


Practical Pearls
1. Adequate dietary intake of
calcium (at least 1200mg
per day) is important for
maintenance of bone
health.
2. Elderly people with
malabsorption, chronic
kidney disease or limited
sunlight exposure are at
risk of vitamin D
deficiency.
characteristics clearly separating
denosumab from bisphosphonates:
(i) reversibility of denosumab as it
targets RANK-L and is not
incorporated into the bone mineral;
(ii) lack of gastrointestinal
side-effects and convenient
bi-annual subcutaneous
administration which can improve
long-term adherence; and (iii)
potential use in impaired renal
function as it is not eliminated by
the kidneys. Although no dose
adjustment is required in patients
with renal impairment, patients with
severe renal impairment or on long
term haemodialysis are at greater
risk of developing hypocalcaemia.
3.8. Combination therapy
2,5,8

Combination therapy, usually a
bisphosphonate with a
non-bisphosphonate, can provide
additional small increases in bone
mineral density when compared
with monotherapy. However,
anti-fracture effectiveness of this
combination has not been shown
and there is currently a limited role
for combination therapy until
further supportive data is available.
4. Non-pharmacological
Interventions
4.1. Fall prevention
5,8

Vision deficits, balance and gait
abnormalities, cognitive impairment
and dizziness should be addressed
for fall prevention. In additions,
improving lighting, removing loose
rugs, and adding grab bars near
bathtubs, toilets, and stairways can
enhance safety. Medications such as
hypnotics and benzodiazepines,
which affect alertness and balance,
should be avoided.
4.2. Calcium and Vitamin D
5,8,30

An inadequate intake of either
calcium, vitamin D or both will
affect the calcium-regulating
hormones, particularly the
parathyroid hormone (PTH) which
is responsible for calcium and
phosphate balance in the body. A
deficiency of either calcium or
vitamin D will lead to reduced
calcium absorption and a lower
concentration of circulating ionised
calcium. When this occurs, PTH
secretion is stimulated and the
cumulative increase in the PTH
levels, secondary to low intake of
calcium and vitamin D, increases
the rate of bone remodelling
process and results in bone loss.
All individuals should be advised to
obtain an adequate intake of dietary
calcium (at least 1200mg per day,
including supplements if necessary)
for the acquisition of peak bone
mass and maintenance of bone
health. If supplementation is
required, it should optimally be
taken in doses containing 500mg or
less of elemental calcium at a time
to maximise absorption, because
absorption decreases with greater
calcium load. Calcium supplement
should be taken with meals as it is
better absorbed with food.
An intake of 800-1000 IU of
vitamin D per day for adults aged
50 and above is recommended as
vitamin D enhances calcium
absorption, maintains bone health
and muscle performance. For
patients with vitamin D deficiency,
vitamin D supplemented in amounts
sufficient to sustain the serum
25-hydroxyvitamin D level to
30ng/mL (75nmol/L) or higher is
needed. Suboptimal serum vitamin
D levels are common in elderly
with malabsorption, chronic renal
insufficient and housebound with
limited sun exposure. Serum
25-hydroxyvitamin D level should
be measured in these patients at risk
of deficiency. A higher intake of
vitamin D of up to 2000 IU may be
required in some elderly patients to
maintain optimal serum
25-hydroxyvitamin D level.
12

4.3. Regular weight-bearing
exercise
5

Weight-bearing and
muscle-strengthening exercises can
improve agility, strength, posture
and balance, which may reduce the
risk of falls and fracture. In addition,
exercise may increase bone density
modestly.
5. Conclusions
Osteoporosis is becoming more
common with the ageing population.
There are many different treatment
options available which are
effective but are not without
problems. Bisphosphonates have
been most widely used in both the
prevention and treatment of
osteoporosis in both men and
women. However, more rare and
serious complications such as the
atypical femur fractures,
osteonecrosis of the jaw have been
reported and causing safety
concerns. Other second line agents
such as calcitonin, raloxifene and
teriparatide have been linked with
reduction of vertebral fractures only,
but not hip fractures. The novel
target agents, RANK-L inhibitors,
are undergoing active development
but their long-term safety profiles
remain to be determined. Moreover,
long term follow-up after treatment
should be elucidated for further
evaluations on drug efficacy and
safety. In addition, other
non-pharmacological interventions
such as prevention of falls, adequate
intake of calcium and vitamin D to
maintain bone health, and increase
of weight-bearing exercises are also
of great importance in management
and prevention of osteoporosis.

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