Transcript Postmenopausal Osteoporosis

Postmenopausal Osteoporosis
BY:r.Narimani
1395
References
1)Postmenopausal Osteoporosis
Dennis M. Black, Ph.D., and Clifford J. Rosen, M.D. NEJM 374;3 nejm.org
January 21, 2016
2)WILLIAMS TEXTBOOK OF ENDOCRINOLOGY, 13TH
EDITION
3)European guidance for the diagnosis and
management of osteoporosis in postmenopausal
women Osteoporos Int (2013) 24:23–57
4) Overview of the management of osteoporosis in
postmenopausal women UpToDate® 2016
A 73-year-old asymptomatic white woman with
a history of a Colles fracture of the left radius
10 years earlier presents for evaluation. Dualenergy x-ray absorptiometry reveals a bone
mineral density (BMD) T score of −2.8 in the
lumbar spine and −2.5 in the total hip. How
should this case be managed?
BONE QUALITY
Bone strength is determined by bone mineral density (BMD)
and other properties of bone that are often collectively
called “bone quality”.
Non-BMD determinants of bone strength include bone
turnover, architecture (size and shape, or bone geometry),
microarchitecture (eg, trabecular thickness, trabecular
connectivity, trabecular perforation, cortical thickness, and
cortical porosity), damage accumulation, matrix properties,
mineralization, and mineral properties (eg, crystal size and
orientation).
Investigation of bone quality has provided insight into the
pathogenesis of osteoporosis and a better understanding of
the mechanism of action of medications used to treat
osteoporosis, but with the exception of bone turnover
markers it is not yet possible to measure these routinely in
clinical practice.
Osteoporosis is characterized by low bone mass,
microarchitectural disruption, and skeletal fragility,
resulting in decreased bone strength and an increased risk
of fracture.
Decreased bone strength is related to many factors other than
bone mineral density (BMD), including rates of bone
formation and resorption (turnover), bone geometry (size
and shape of bone), and microarchitecture .
The World Health Organization (WHO) has defined diagnostic
thresholds for low bone mass and osteoporosis based upon
BMD measurements compared with a young-adult
reference population (T-score).
The majority of postmenopausal women with osteoporosis
have bone loss related to estrogen deficiency and/or age.
Osteoporosis or low bone mass (osteopenia) occurs in about 53 million
American men and women, accounting for 55 percent of the
population age 50 years and over
There are approximately two million fragility fractures in the United
States each year:
There were an estimated nine million osteoporotic fractures
worldwide in 2000, of which 1.6 million were hip, 1.7 million
forearm, and 1.4 million clinical vertebral fractures .
Some estimates predict a continued increase in the number of hip
fractures over the next 40 years .
However, other epidemiologic studies suggest a changing trend .
In one study from Finland, review of a national discharge registry
revealed a decline in hip fracture rates between 1997 and 2004 .
Possible reasons for the decline include a healthier aging
population, improved functional ability, increased body weight, and
greater use of calcium, vitamin D, and pharmacologic therapy for
osteoporosis.
Fractures of the hip and spine are associated with
an increased mortality rate of 10 to 20 percent.
Fractures may result in limitation of ambulation,
depression, loss of independence, chronic pain,
deformity, depression, disability, and death.
About 50 percent of patients with hip fractures will
never be able to walk without assistance and 25
percent will require long-term care.
The mortality rate five years after a fracture of the
hip or a clinical Vertebral Fx is about 20 percent
greater than expected.
The direct cost of incident osteoporotic fractures in
the United States was about $17 billion per year
in 2005.
Osteoporosis has no clinical manifestations until there is a
fracture.
This is an important fact because many patients without
symptoms incorrectly assume that they must not have
osteoporosis. On the other hand, many patients with
achy hips or feet assume that their complaints are due
to osteoporosis.
This is unlikely to be true in the absence of fracture. In
comparison, pain is common in osteomalacia in the
absence of fractures or other bone deformities.
Vertebral fracture is the most common clinical
manifestation of osteoporosis. Most of these fractures
(about two-thirds) are asymptomatic; they are
diagnosed as an incidental finding on chest or
abdominal x-ray .
Other fractures — Hip fractures are relatively
common in osteoporosis, affecting up to 15
percent of women and 5 percent of men by 80
years of age.
Subchondral insufficiency fractures of the femoral
head, which may lead to a rapid loss of cartilage
space and eventual destructive secondary
osteoarthritis, have also been observed.
In addition, distal radius fractures (Colles fractures)
may occur. Colles fractures are more common in
women shortly after menopause, whereas the
risk of hip fracture rises exponentially with age.
A clinical diagnosis of osteoporosis may be made in the
presence of a fragility fracture, particularly at the spine,
hip, wrist, humerus, rib, and pelvis, without measurement
of bone mineral density (BMD). Fragility fractures are those
occurring from a fall from a standing height or less, without
major trauma such as a motor vehicle accident.
Certain skeletal locations, including the skull, cervical spine,
hands, feet, and ankles, are not associated with fragility
fractures.
Stress fractures are also not considered fragility fractures, as
they are due to repetitive injury.
In the absence of a fragility fracture, BMD assessment by dualenergy x-ray absorptiometry (DXA) is the standard test to
diagnose osteoporosis, according to the classification of the
World Health Organization (WHO)
EVALUATION
The goal of the evaluation is to exclude causes
of low bone mass other than age and estrogen
deficiency, such as osteomalacia,
hyperthyroidism, and hyperparathyroidism,
and to detect potentially remediable causes or
other contributing factors to osteoporosis
Initial evaluation
The evaluation should begin with a history of clinical risk
factors for fractures (underlying medical conditions
and/or medications that cause bone loss), physical
examination, and basic biochemical testing.
Fracture risk can be assessed with the World Health
Organization (WHO) Fracture Risk Assessment Tool
(FRAX), a computer-based calculator which estimates
the 10-year probability of hip fracture and major
osteoporotic fracture (hip, clinical spine, proximal
humerus, or forearm) for untreated patients between
ages 40 and 90 years, using easily obtainable clinical
risk factors for fracture, with or without femoral neck
bone mineral density (BMD)
A history of a fragility fracture is an important risk
factor for a subsequent fracture.
In women who have a vertebral fracture,
approximately 19 percent will have another
fracture in the next year.
A meta-analysis of 11 cohorts (15,259 men and
44,902 women) showed that a previous fracture
was associated with an increased risk of any
fracture compared with those without a prior
fracture (relative risk [RR] 1.86, 95% CI 1.751.98).
Thus, individuals with a history of a fragility fracture
are a high-risk group that requires evaluation and
treatment.
Most of the conditions causing osteoporosis
can be excluded with a careful history and
physical examination
Laboratory evaluation may help to diagnose secondary
causes of osteoporosis such as renal or liver disease,
hyperthyroidism, hyperparathyroidism, Cushing's syndrome
or subclinical hypercortisolism, early menopause, celiac
disease and other forms of malabsorption, idiopathic
hypercalciuria, or rarely, connective tissue disorders.
We suggest that postmenopausal women with low BMD (Tscore below -2.5) and/or fragility fracture have the
following basic tests:
●Biochemistry profile (especially calcium, phosphorous,
albumin, total protein, creatinine, liver enzymes including
alkaline phosphatase, electrolytes).
●25-hydroxyvitamin D (25[OH]D).
●Complete blood count (CBC).
●If the diagnosis of osteoporosis is based upon the presence
of a fragility fracture, we also obtain a BMD (dual-energy xray absorptiometry [DXA]), performed on a nonurgent
basis, for quantitative assessment of bone density and to
monitor response to therapy.
ASSESSMENT OF FRACTURE RISK
Screening for osteoporosis involves fracture risk
assessment and measurement of bone mineral
density (BMD)
We recommend assessing risk factors for
fracture in all adults, especially
postmenopausal women, men over 60 years,
and in any individual who experiences a
fragility or low-trauma fracture
Risk factors
Most fractures occur in women and men who do
not have osteoporosis by dual-energy x-ray
absorptiometry (DXA) criteria.
Individuals with osteoporosis are at the highest
relative risk of fracture, but there are more
fractures in patients with low bone mass or
osteopenia (T-score between -1.0 and -2.5)
because there are so many more patients in this
category. Therefore, assessment of risk factors
that are independent of BMD is important for
fracture prediction.
Validated risk factors that are independent of BMD
include the following:
●Advanced age
●Previous fracture
●Long-term glucocorticoid therapy
●Low body weight (less than 58 kg [127 lb])
●Family history of hip fracture
●Cigarette smoking
●Excess alcohol intake
The most robust non-BMD risk factors are age and
previous low trauma fracture
When combined with country-specific economic
analyses, FRAX can provide guidance for both
BMD testing (assessment threshold) and
treatment (intervention threshold).
In countries with limited or no access to DXA, the
FRAX algorithm can potentially be used to
identify individuals in whom measurement of
BMD would influence management decisions. As
an example, measurement of BMD may be
indicated in those with an intermediate fracture
probability, in whom the selective addition of
BMD testing may result in intervention.
Biochemical markers of bone remodeling
Biochemical markers that reflect the overall
rates of bone resorption and formation are
currently available clinically and have been
used extensively in research to help
understand the pathogenesis of osteoporosis
and responses to therapy.
The mean values of these markers are generally
higher in patients with osteoporosis than in
matched normal subjects, but there is
substantial overlap
BONE DENSITY
Bone density measurements are used in
conjunction with fracture risk assessment for
osteoporosis screening.
Low bone mineral density (BMD) is associated
with increased risk of fracture, regardless of
the technique used for measurement
We suggest BMD testing (dual-energy x-ray
absorptiometry [DXA]) in women 65 years of
age and older and in postmenopausal women
younger than 65 years of age with clinical risk
factors for fracture
Dual-energy x-ray absorptiometry
DXA is the most widely used method for
measuring BMD because it gives very precise
measurements at clinically relevant skeletal
sites (ie, those with major clinical
consequences when a fracture occurs).
Quantitative computerized tomography (QCT)
QCT measures volumetric bone density of the spine and
hip and can analyze cortical and trabecular bone
separately. This method is quite useful in clinical
research and may be used in individual patients to
follow therapeutic responses to therapy, where large
changes may be observed.
However, it is not recommended for screening, largely
because the application of Tscores to predict the risk of
fracture has not been validated with QCT.
In addition, this method is more costly and results in
greater exposure to radiation than DXA.
Peripheral measurements
Because of the high cost and lack of portability of
DXA, other techniques to measure peripheral
sites have been developed.
These include ultrasound, peripheral DXA (pDXA),
radiograph absorptiometry, and peripheral QCT
(pQCT) of the heel, radius, or hand.
The World Health Organization (WHO) criteria for
the diagnosis of osteoporosis are based upon
BMD measured by DXA and, therefore, do not
apply to these other technologies
Ultrasound
Quantitative ultrasound appears to be a good
predictor of fractures in men and women, and
is at least as good as clinical risk factors for
identifying patients at high risk for
osteoporosis.
Skeletal site to measure
For screening site of measurement, we suggest DXA of hip and
spine.
Measurement of the hip alone could be sufficient in older
individuals.
Although overall fracture risk can be predicted by
measurement or estimation of BMD at many skeletal sites ,
the risk for fracture at a particular skeletal site is best
estimated by measuring BMD at that skeletal site. As an
example, hip BMD is superior to BMD measured at other
skeletal sites in predicting hip fracture.
Therefore, since hip fracture is often associated with
significant morbidity and mortality compared with other
fractures, DXA of the hip is generally regarded as the best
site for diagnosis of osteoporosis.
In contrast, the lumbar spine is often considered
the best skeletal site to monitor because it
shows less variability and can detect
responses to therapy earlier than hip BMD.
when measurements of different skeletal sites
are performed, the diagnosis of osteoporosis
is based upon the lowest T-score for BMD
assessed at one of these sites.
Measuring more than one site generally
increases the number of individuals
categorized as osteoporotic
in younger postmenopausal women with risk
factors for fracture, we suggest DXA
measurements of both the spine and hip because
early menopause is associated with greater BMD
loss at the spine than the hip.
In addition, interference from osteophytes and
vascular calcifications on the spine measurement
is usually minimal in women less than 65 years of
age.
In contrast, spinal osteophytes are common in
aging women and men, which interferes with the
assessment of BMD at this site. In this setting,
measurement of hip BMD alone could be
sufficient.
In the presence of degenerative changes of the
spine, BMD can be monitored at another
skeletal site, such as the hip or radius,
although the sensitivity for detecting changes
at these locations is lower.
Bone mineral density
T-score — The WHO established a classification of BMD (by
DXA) according the standard deviation (SD) difference
between a patient's BMD and that of a young-adult
reference population (T-score).
A BMD T-score that is 2.5 SD or more below the young-adult
mean BMD is defined as osteoporosis, provided that other
causes of low BMD have been ruled out (such as
osteomalacia). A T-score that is 1 to 2.5 SD below the
young-adult mean is termed low bone mass (osteopenia).
Normal bone density is defined as a value within 1 SD of
the mean value in the young-adult reference population .
Individuals with T-scores of ≤-2.5 have the highest risk of
fracture. However, there are more fractures in patients with
a T-score between -1.0 and -2.5 because there are so many
more patients in this category
Z-score — The Z-score is a comparison of the
patient's BMD to an age-matched
population. A Z-score of -2.0 or lower is
considered below the expected range for age .
Thus, the presence of Z-score values more than
2 SD below the mean should prompt careful
scrutiny for coexisting problems (eg,
glucocorticoid therapy or alcoholism) that can
contribute to osteoporosis
Contraindications
DXA should not be done in women who are pregnant or
may be pregnant because ionizing radiation, albeit it in
very small doses, is used. DXA should be postponed
until pregnancy is completed. As with any medical test,
DXA should not be done unless the results are likely to
play a role in the management of the patient.
It may not be possible to do a DXA of the hip and spine in
some patients due to inability to get on the table. BMD
measurement may not be valid in some situations due
to skeletal structural abnormalities, such as severe
osteoarthritis, surgical hardware, or scoliosis.
Assessment of fracture risk
Whereas BMD provides the cornerstone for the
diagnosis of osteoporosis, the use of BMD alone
is less than optimal as an intervention threshold
for several reasons.
Firstly, the fracture risk varies markedly in different
countries, but the T-score varies only by a small
amount.
Secondly, the significance of any given T-score to
fracture risk in women from any one country
depends on age and the presence of clinical risk
factors.
FRAX® is a computer-based algorithm
(http://www.shef.ac.uk/FRAX) that calculates the
10-year probability of a major fracture (hip,
clinical spine, humerus or wrist fracture) and the
10-year probability of hip fracture .
Fracture risk is calculated from age, body mass
index and dichotomized risk factors comprising
prior fragility fracture, parental history of hip
fracture, current tobacco smoking, ever use of
long-term oral glucocorticoids, rheumatoid
arthritis, other causes of secondary osteoporosis
and alcohol consumption (Fig. 2).
Femoral neck BMD can be optionally input to
enhance fracture risk prediction
A general approach to risk assessment is shown in
Fig. 4. The process begins with the assessment of
fracture probability and the categorization of
fracture risk on the basis of age, sex, BMI and the
clinical risk factors.
On this information alone, some patients at high
risk may be considered for treatment without
recourse to BMD testing.
For example, many guidelines in Europe
recommend treatment in the absence of
information on BMD in women with a previous
fragility fracture (a prior vertebral or hip fracture
in North America)
Intervention thresholds
The use of FRAX in clinical practice demands a
consideration of the fracture probability at
which to intervene, both for treatment (an
intervention threshold) and for BMD testing
(assessment thresholds). Many approaches
have been used to set intervention thresholds
with FRAX.
Since many guidelines recommend that women
with a prior fragility fracture may be considered
for intervention without the necessity for a BMD
test (other than to monitor treatment), a prior
fracture can be considered to carry a sufficient
risk that treatment can be recommended.
the intervention threshold in women without a
prior fracture can be set at the age-specific
fracture probability equivalent to women with a
prior fragility fracture and therefore rises with
age from a 10-year probability of 8 to 33 % in the
UK.
Assessment thresholds for BMD testing
The assessment thresholds for making recommendations
for the measurement of BMD.
There are, in principle, two assessment thresholds: A
threshold probability below which neither treatment
nor a BMD test should be considered (lower
assessment threshold) A threshold probability above
which treatment may be recommended irrespective of
BMD (upper assessment threshold)
When patients have a fracture probability that is 20 % or
more than the intervention threshold, almost no
individuals will be reclassified (from high to low risk)
when probabilities are recomputed with the addition
of BMD to FRAX
Treatment is recommended in patients in whom
the 10-year probability of a major fracture
exceeds 20 % or when the 10-year probability
of a hip fracture exceeds 3 %.
The treatment of osteoporosis consists of
lifestyle measures and pharmacologic therapy
LIFESTYLE MEASURES — Lifestyle measures
should be adopted universally to reduce bone
loss in postmenopausal women. Lifestyle
measures include adequate calcium and
vitamin D, exercise, smoking cessation,
counseling on fall prevention, and avoidance
of heavy alcohol use. In addition, affected
patients should avoid, if possible, drugs that
increase bone loss, such as glucocorticoids.
General management Mobility and falls
Immobilisation is an important cause of bone loss.
Immobilised patients may lose as much bone in a
week when confined to bed than they would
otherwise lose in a year.
For this reason, immobility should, wherever
possible, be avoided. The amount of weightbearing exercise that is optimal for skeletal health
in patients with osteoporosis is not known, but
exercise forms an integral component of
management
Physiotherapy is an important component of
rehabilitation after fracture. At all times,
increased strength may prevent falls by
improving confidence and coordination as well
as maintaining bone mass by stimulating bone
formation and by decreasing bone resorption,
and by preserving muscle strength.
Modifiable factors such as correcting decreased
visual acuity, reducing consumption of
medication that alters alertness and balance
and improving the home environment
(slippery floors, obstacles, insufficient lighting,
handrails) are important measures aimed at
preventing falls
Some randomised trials have shown that
wearing hip protectors can markedly reduce
hip fracture risk, particularly in the elderly
living in nursing homes.
Nutrition
At every stage of life, adequate dietary intakes of key
bone nutrients such as calcium, vitamin D and
protein contribute to bone health and reduce
thereby the risk of osteoporosis and of fracture later
in life.
Dietary sources of calcium are the preferred option,
and calcium supplementation should only be
targeted to those who do not get sufficient calcium
from their diet and who are at high risk for
osteoporosis.
Calcium-rich foods such as dairy products contain
additional nutrients that may also contribute to
bone health .
The Recommended Nutrient Intakes (RNI) are at
least 1,000 mg of calcium and 800 IU of vitamin D
1 g/kg body weight of protein per day in men and
women over the age of 50 years.
As calcium is mainly provided in dairies, calciumand vitamin D fortified dairy products (yoghurt,
milk) providing at least 40 % of the RNI of calcium
(400 mg) and 200 IU of vitamin D per portion are
valuable options (e.g. yoghurt, such as Danone
Densia/Danaos, or milk, such as Valio Plus Hyla)
that are likely to improve long-term adherence.
There is a high prevalence of calcium, protein
and vitamin D insufficiency in the elderly.
Combined calcium and vitamin D supplements
in a daily dose of 0.5–1.2 g and 400–800 IU,
respectively, are generally recommended in
patients receiving bone protective therapy,
since most randomised controlled trial
evidence for the efficacy of interventions is
based on co-administration of the agent with
calcium and vitamin D supplements
Calcium and vitamin D supplements decrease
secondary hyperparathyroidism and reduce
the risk of proximal femur fracture,
particularly in the elderly living in nursing
homes.
Vitamin D supplements alone may reduce the
risk of fracture and of falling provided the
daily dose of vitamin D is greater than 700 IU.
In contrast, studies with large annual doses of
vitamin D have reported an increased risk of
hip fracture and, in one study, also of falls.
Metaanalyses also indicate that vitamin D may
have a small beneficial effect on
cardiovascular risk and mortality
Whereas a gradual decline in caloric intake with
age can be considered as an appropriate
adjustment to the progressive reduction in
energy expenditure, the parallel reduction in
protein intake may be detrimental for
maintaining the integrity and function of
several organs or systems, including skeletal
muscle and bone.
Sufficient protein intakes are necessary to maintain
the function of the musculoskeletal system, but
they also decrease the complications that occur
after an osteoporotic fracture.
Correction of poor protein nutrition in patients with
a recent hip fracture has been shown to improve
the subsequent clinical course by significantly
lowering the rate of complications, such as
bedsores, severe anaemia, and intercurrent lung
or renal infection. The duration of hospital stay of
elderly patients with hip can thus be shortened
Major pharmacological interventions
Classes of Drugs Pharmacologic agents for the
treatment of osteoporosis
can be classified as either antiresorptive (i.e.,
targeting osteoclast-mediated bone
resorption) or anabolic (i.e., stimulating
osteoblasts to form new bone). Drugs of each
type have been shown to improve BMD and
reduce the risk of fractures.
The most commonly used agents in Europe are
raloxifene; the bisphosphonates alendronate,
ibandronate, risedronate and zoledronic acid;
agents derived from parathyroid hormone;
denosumab and strontium ranelate. Until
recently, hormone replacement treatment was
also widely used.
They have all been shown to reduce the risk of
vertebral fracture. Some have also been shown to
reduce the risk of non-vertebral fractures, and in
some cases, agents have been shown specifically
to decrease fracture risk at the hip
Estrogen and Selective Estrogen-Receptor Modulators
Estrogen treatment, with or without progesterone, has direct
effects on osteocytes, osteoclasts, and osteoblasts, leading
to inhibition of bone resorption and maintenance of bone
formation.
In the WHI trials, estrogen therapy significantly reduced the
incidence of new vertebral, nonvertebral, and hip fractures.
Both low-dose conjugated estrogens and ultra-low-dose
estradiol, which are often used in the short term for
postmenopausal symptoms, increase BMD, but their
antifracture efficacy has not been established.
Concerns about nonskeletal risks associated with estrogen use
(e.g., breast cancer and coronary, cerebrovascular, and
thrombotic events) have led to recommendations against
using estrogen as a first-line therapy for osteoporosis
Selective oestrogen-receptor modulators
(SERMs) are nonsteroidal agents that bind to
the oestrogen receptor and act as oestrogen
agonists or antagonists, depending on the
target tissue.
The concept of SERMs was triggered by the
observation that tamoxifen, which is an
estrogen antagonist in breast tissue, is a
partial agonist on bone, reducing the rate of
bone loss in postmenopausal women.
Raloxifene is the only SERM widely available for the
prevention and treatment of postmenopausal
osteoporosis.
Raloxifene prevents bone loss and reduces the risk of
vertebral fractures by 30–50 % in postmenopausal
women with low bone mass and with osteoporosis
with or without prior vertebral fractures as shown in
the Multiple Outcomes of Raloxifene Evaluation
(MORE) trial.
There was no significant reduction of non-vertebral
fractures. In women with severe vertebral fractures at
baseline (i.e. at highest risk of subsequent fractures), a
post hoc analysis showed a significant reduction of
non-vertebral fractures
In the MORE study and its placebo controlled 4-year
follow-up, the only severe (but rare) adverse
event was an increase of deep venous
thromboembolism.
Hot flushes and lower limb cramps are commonly
reported.
There was a significant and sustained decrease of
the risk of invasive breast cancer (by about 60 %)
that has been subsequently confirmed in two
other large cohorts, including the STAR study that
showed similar breast cancer incidences with
raloxifene and tamoxifen in high-risk populations
The efficacy of raloxifene has been shown in
women with osteopenia and is not dependent
on the level of fracture risk assessed by FRAX.
In summary, the overall risk benefit ratio of
raloxifene is favourable, and the drug is
approved widely for the prevention and
treatment of postmenopausal osteoporosis.
Bazedoxifene is a selective oestrogen receptor
modulator that has been approved in Europe but
is only available in Spain and Germany.
In phase 3 clinical trials, bazedoxifene was shown to
significantly reduce the risk of new vertebral
fracture, with favourable effects on bone mineral
density, bone turnover markers and the lipid
profile. In a subgroup of women at increased risk
of fracture, bazedoxifene significantly decreased
non-vertebral fracture risk.
In contrast to raloxifene, the efficacy of
bazedoxifene is dependent on the level of
fracture risk assessed by FRAX.
Bisphosphonates
Bisphosphonates inhibit bone remodeling.
Several oral and intravenous bisphosphonates
have been shown in randomized trials to
reduce the risk of fractures.
The bisphosphonates as a class represent the
vast majority of prescriptions for osteoporosis
treatment, and all are now available in generic
form.
Although data from randomized trials and clinical
experience indicate that they are generally safe,
mild hypocalcemia and muscle pain occur
infrequently. Two rare but more serious adverse
effects have also been observed.
These are atypical femoral fractures (i.e., fractures
in the subtrochanteric region that have a
transverse orientation and noncomminuted
morphologic features, show focal lateral cortical
thickening, occur with minimal trauma, and may
be bilateral) and osteonecrosis of the jaw, which
is defined as exposed bone in the maxillofacial
region that does not heal within 8 weeks
Use of bisphosphonates should be limited to
persons who have an estimated creatinine
clearance greater than 35 ml per minute and
normal serum vitamin D levels;
symptomatic hypocalcemia can develop in
patients with low levels of 25-(OH) D who
receive concomitant treatment with
bisphosphonates.
All oral bisphosphonates have been tested in
large, randomized, placebo-controlled trials
with fracture end points, among women
receiving calcium and vitamin D and daily
doses of the bisphosphonates.
Oral bisphosphonates are now used in weekly
doses (alendronate and risedronate) or
monthly doses (ibandronate and risedronate);
comparability with daily dosing has been
established by assessment of comparative
changes in BMD and bone-turnover markers.
Minor gastrointestinal irritation may occur with
oral bisphosphonates and may be minimized
by adherence to dosing instructions.
Oral bisphosphonates should not be prescribed
for patients with clinically significant
esophageal disease (e.g., achalasia).
In the two Fracture Intervention Trials (FIT) of
alendronate, which were paired randomized
trials (with 3 to 4 years of follow-up) involving
postmenopausal women with a BMD T score
of −1.6 or less at the femoral neck, the rate of
vertebral fractures was significantly lower (by
approximately 50%) among those who
received alendronate (at a dose of 5 mg per
day for the first 2 years, followed by 10 mg per
day) than among those who received placebo.
In the first trial (involving women with existing
spine fractures), the rate of hip fractures was
significantly lower (by 51%) with alendronate,
and the rate of nonvertebral fractures was 20%
lower with alendronate than with placebo (P =
0.06).
In the second trial (involving women without
existing vertebral fractures), the rates of hip and
nonvertebral fractures were not significantly
lower with alendronate than with placebo overall
but were significantly lower (nonvertebral fractures
by 35% and hip fractures by 56%) in a
prespecified subgroup analysis of women with a
BMD T score of −2.5 or less at the hip.
Two randomized, controlled trials of risedronate (5
mg per day) in postmenopausal women with
existing vertebral fractures, low BMD in the
spine, or both showed that over a period of 3
years, the risk of vertebral fractures was lower
(by 41 to 49%) with risedronate than with
placebo, as was the risk of osteoporotic
nonvertebral fractures (by 33 to 40%)
A larger trial with a hip-fracture end point of
risedronate (2.5 or 5 mg per day) involving
women 70 years of age or older who were at
high risk for hip fracture showed a 30% lower
rate of such fractures over a period of 3 years
with risedronate than with placebo.
A trial of ibandronate (2.5 mg per day) showed a
62% lower rate of vertebral fractures with
ibandronate than with placebo but no
reduction in the rate of nonvertebral fractures
over a period of 3 years,although a post hoc
subgroup analysis of women with T scores
below −3.0 showed significantly fewer
nonvertebral fractures with ibandronate than
with placebo.
Ibandronate is also available in an intravenous
formulation
Adherence to oral bisphosphonates is low, and it is
estimated that less than 40% of persons who are
prescribed oral medications are still taking them
after 1 year.
Intravenous bisphosphonates (ibandronate and
zoledronic acid) are alternatives that do not
require frequent patient use.
In a large randomized trial involving women with
low BMD, existing vertebral fractures, or both,a
once-per-year infusion (≥15 minutes) of 5 mg of
zoledronic acid resulted in significantly lower
rates of vertebral fractures (by 70%), hip fractures
(by 41%), and nonvertebral fractures (by 25%)
than the rates with placebo.
In another trial involving women and men who were
randomly assigned to receive zoledronic acid or
placebo within 90 days after surgical repair of a hip
fracture, those who received zoledronic acid had a
significantly lower rate of subsequent clinical fractures
(by 35%).
Zoledronic acid causes an acute-phase reaction (flulike
symptoms) for up to 3 days after the first infusion in up
to one third of patients (and only rarely after
subsequent infusions);
coadministration of acetaminophen reduces both the
incidence of this reaction (by approximately 50%) and
the severity of symptoms.
An increased risk of atrial fibrillation has been reported in
some trials but not in others.
Denosumab
Critical molecules for the differentiation, activation
and survival of osteoclasts are the receptor
activator of nuclearfactor NFkB (RANK); its ligand
RANKL, a member of the tumour necrosis factor
superfamily , which acts as a decoy receptor for
RANKL.
A fully human antibody against RANKL has been
developed. This antibody, denosumab, has been
shown to specifically bind to RANKL with a very
high affinity, preventing its interaction with the
receptor RANK
A large trial involving women with a BMD T
score of less than −2.5 but not less than −4.0
at the lumbar spine or total hip showed that
treatment with denosumab (60 mg
administered twice yearly by subcutaneous
injection) resulted in a significantly lower risk
of vertebral fractures (by 68%), hip fractures
(by 40%), and nonvertebral fractures (by 20%)
than the risk with placebo
After completing the first 3 years of the study,
women from the denosumab group had two
more years of denosumab treatment (longterm group), and those from the placebo
group had 2 years of denosumab exposure
(cross-over group)
In the long-term group, lumbar spine and total
hip BMD increased further. Yearly fracture
incidences for both groups were below rates
observed in the placebo group of the 3-year
trial and below rates projected for a ‘virtual
untreated twin’ cohort.
The effects of denosumab on fracture risk are
particularly marked in patients at high fracture
probability
Adverse events did not increase with long-term
administration of denosumab. Two adverse
events in the cross-over group were adjudicated
as consistent with osteonecrosis of the jaw .
In a meta-analysis of four clinical trials, the relative
risk of serious adverse events for the denosumab
group compared with the placebo group was
1.33; of serious adverse events related to
infection, 2.10; of neoplasm, 1.11; of study
discontinuation due to adverse events, 1.10, and
of death, 0.78. These risks were all nonsignificant
Peptides of the parathyroid hormone family
The continuous endogenous production of parathyroid
hormone (PTH), as seen in primary or secondary
hyperparathyroidism, or its exogenous administration
can lead to deleterious consequences for the skeleton,
particularly on cortical bone.
However, intermittent administration of PTH (e.g. with
daily subcutaneous injections) results in an increase of
the number and activity of osteoblasts, leading to an
increase in bone mass and in an improvement in
skeletal architecture at both cancellous and cortical
skeletal sites.
The intact molecule (amino acids 1-84) and the
1-34 Nterminal fragment (teriparatide) are
used for the management of osteoporosis.
Based on their respective molecular weights,
the equivalent dose of the teriparatide,
relative to the 1-84 molecule, is 25 % (i.e. 20
and 40 μg of teriparatide is equivalent to 80
and 160 μg of 1-84 PTH, respectively).
Treatment with either agent has been shown to
reduce significantly the risk of vertebral
fractures, whereas teriparatide has been
shown to have an effect also on non-vertebral
fractures.
Treatment with PTH has been studied when
given for 18 to 24 months, and beneficial
effects on non-vertebral fracture with
teriparatide have been shown to persist for up
to 30 months after stopping teriparatide
Teriparatide is an anabolic agent that works
primarily by increasing bone formation rather
than by decreasing resorption.
In a 21-month trial involving women with low
BMD and previous vertebral fractures,
teriparatide (20 μg per day) was associated
with a lower risk of vertebral fractures (by
65%) and nonvertebral fractures (by 35%)
than the risk with placebo, but not with a
lower risk of hip fractures.
Teriparatide is administered by daily self-injection
and is approved for up to 2 years of use. Studies
of its use after bisphosphonate treatment have
shown that it retains its anabolic properties,
although its action is slightly blunted.
After teriparatide is discontinued, its benefits are
quickly lost, so it should be followed by an
antiresorptive agent.
There is a black-box warning about a risk of
osteosarcoma associated with teriparatide
treatment, on the basis of studies of long-term,
highdose teriparatide in rodents, but to our
knowledge only one documented case has been
reported in more than 1 million human users.
The most common reported adverse events in
patients treated with PTH or teriparatide are
nausea, pain in the limbs, headache and
dizziness.
In normocalcemic patients, slight and transient
elevations of serum calcium concentrations have
been observed following the injection PTH or
teriparatide.
Serum calcium concentrations reach a maximum
between 4 and 6 h and return to baseline 16 to
24 h after each dose. The change is small, and
routine monitoring of serum calcium during
therapy is not required.
Strontium ranelate
Strontium ranelate is registered and marketed for
the treatment of postmenopausal osteoporosis,
to reduce the risk of vertebral and hip fractures.
studies conducted up to 5 years have shown
fracture efficacy of strontium ranelate, at spinal
and non-vertebral sites, in a wide range of
patients, from osteopenia subjects to women
over the age of 80 years, including osteoporotic
patients with or without prior vertebral
fractures
In an open-label extension study, BMD increased
continuously with strontium ranelate over 10 years in
osteoporotic women.
Vertebral (−35 %) and non-vertebral (−38 %) fracture
incidence were lower between 5 and 10 years than
those in a matched placebo group studied over 5 years
The recommended daily dose is one 2-g sachet once daily
by mouth.
The absorption of strontium ranelate is reduced by food,
milk and its derivative products, and the drug should
be administered, therefore, between meals. Ideally,
it should be taken at bedtime, preferably at least 2 h
after eating.
Strontium ranelate is not recommended for patients with
severe renal impairment (creatinine clearance below
30 ml/min).
Adverse events observed with strontium ranelate
are usually mild and transient.
The most common adverse events are nausea and
diarrhoea which are generally reported at the
beginning of treatment and usually disappear
after the third month of treatment. An increase in
the incidence of venous thromboembolism (VTE)
However, strontium ranelate is contraindicated in
patients with a past history of thrombophlebitis.
Treatment should be stopped in patients in high-risk
situations for VTE such as prolonged
immobilisation without appropriate preventive
measures taken.
Other pharmacological interventions
Calcitonin
Calcitonin is an endogenous polypeptide
hormone that inhibits osteoclastic bone
resorption
For clinical use, it can be administrated either by
injection or nasal application, which provides
a biological activity of 25– 50 % compared
with the injectable formulation (200 IU nasal
calcitonin would be equivalent to 50 IU of the
injectable formulation).
Calcitonin modestly increases bone mineral
density at the lumbar spine and forearm
Calcitonin likely reduces the risk of vertebral
fracture.
An effect on non-vertebral fractures remains
equivocal
In addition, calcitonin may have an analgesic
effect in women with acute vertebral fracture,
which appears to be independent of its effect
on osteoclastic resorption
Vitamin D derivatives
Alfacalcidol is a synthetic analogue of the vitamin
D metabolite calcitriol (1,25-dihydroxyvitamin
D3), and it is metabolized to calcitriol by its 25hydroxylation in the liver.
Several but not all studies show decreases in
vertebral fracture risk.
The effects on bone mineral density have been less
extensively studied.
A few reports have suggested that alfacalcidol and
calcitriol exert a direct action on muscle strength
and decrease the likelihood of falling in elderly
subjects
The major problem with the use of the vitamin
D derivatives is the risk of hypercalcaemia and
hypercalciuria.
Adverse effects of prolonged hypercalcaemia
include impairment of renal function and
nephrocalcinosis
Calcium supplementation of the diet should
be avoided or used with care.
Areas of Uncertainty
The relative importance of the two rare adverse
effects (atypical fractures and osteonecrosis of
the jaw) versus the benefits of antiresorptive
therapy is uncertain and remains controversial.
The concerns of many women regarding these
potential adverse effects have increasingly
become a substantial barrier to initiation of
antiosteoporosis therapy and to treatment
adherence.
Atypical fractures have been observed in rare
instances in women using bisphosphonates
and denosumab. Their pathophysiological
mechanisms are unclear.
Case–control and cohort studies and analyses of
a few randomized trials have examined the
relationship between atypical femoral
fractures and osteoporosis treatment
(primarily bisphosphonate agents);
in all the studies, the incidence of these fractures is
low, ranging from approximately 1 in 100,000 to
5 in 10,000 among bisphosphonate users.
Atypical fractures constitute only about 4 or 5 of
every 1000 femur fractures.
A recent meta-analysis estimated that the relative
risk associated with bisphosphonate use was 1.7
(95% confidence interval, 1.2 to 2.4), although
there was considerable heterogeneity among
studies,perhaps reflecting variations in study
design and case definition.
Several, but not all, studies have suggested an
increase in risk with more than 5 years of
bisphosphonate use
Calculations including results from recent
reviews and meta-analyses suggest a highly
favorable benefit-to-risk ratio associated with
treatment for up to 5 years in women with
osteoporosis, with fewer than 1 event caused
per 100 fractures prevented (Table 3).
The incidence of osteonecrosis of the jaw is
similarly very low (estimated at <1 case per
10,000 bisphosphonate users)
The incidence is much higher among patients
with cancer who are taking higher doses of
bisphosphonates or denosumab, and coadministration of glucocorticoids or
immunosuppressive agents may increase the
risk
The American Dental Association in 2011
recommended that osteoporosis therapy does
not require alteration before dental
procedures.
A recent review suggested that before major,
invasive dental surgery, consideration should
be given to stopping antiresorptive therapy;
the review also emphasized the importance of
good dental hygiene in reducing risk.
Given concerns about an increased risk of atypical
femur fractures with long-term treatment,the
possibility of a drug holiday (temporary
discontinuation for up to 5 years) has been
suggested, although the preferred timing and
duration of drug holidays with bisphosphonate
therapy are uncertain
Two randomized trials have indicated that with
discontinuation of alendronate after 5 years of
use or of zoledronic acid after 3 years of use,
benefits (as determined primarily by assessment
of BMD loss and changes in biochemical markers
of bone turnover as compared with those with
placebo) are generally retained for up to 5 years.
Although the trials were not sufficiently
powered to assess fractures, there was a
significantly lower incidence of vertebral
fractures (clinical vertebral fractures for
alendronate and morphometric vertebral
fractures for zoledronic acid) among
participants who continued bisphosphonate
therapy than among those who discontinued
therapy.
However, neither trial suggested a reduction in
nonvertebral fractures among those who
continued therapy.
Whereas more data are needed to guide criteria for
stopping and restarting therapy, it has been
suggested that temporary discontinuations be
considered in patients who are at lower risk, as
determined on the basis of assessment of hip
BMD and vertebral-fracture status at the time of
potential discontinuation,and that treatment
generally be reinitiated after no longer than 5
years.
The value of monitoring therapy after
discontinuation with the use of biochemical
markers of bone turnover or BMD to aid in
clinical decision making about restarting
bisphosphonates is controversial.
These recommendations regarding drug holidays
do not apply to risedronate or ibandronate,
because these agents have not been
systematically evaluated, or to other
osteoporosis therapies, whose benefits are
quickly lost after cessation.
• The woman in the vignette has a low BMD and
a fracture history, which are factors that are
consistent with osteoporosis. We would
recommend increased physical activity,
avoidance of smoking and excess alcohol
intake, a total calcium intake of 1000 to 1500
mg per day and a total vitamin D intake of 600
to 800 IU per day, and the use of an
antiresorptive agent.
We would generally recommend a
bisphosphonate as firstline therapy if there
are no contraindications;
we would discuss with the patient the rare
potential risks of atypical femur fracture or
osteonecrosis of the jaw but also the much
greater anticipated benefits in terms of overall
reduction in the risk of fractures.
Depending on the results of follow-up BMD
measurement, we would discuss the
possibility of temporarily discontinuing the
bisphosphonate after 5 years of treatment.
Thank you
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