Best Practice & Research Clinical Obstetrics and Gynaecology 23 (2009) 73–85
Contents lists available at ScienceDirect
Best Practice & Research Clinical
Obstetrics and Gynaecology
journal homepage: www.elsevier.com/locate/bpobgyn
6
Bone health and osteoporosis in postmenopausal women
Tobias Johannes de Villiers, MBChB, MMed (O&G), MRCOG, FCOG (SA),
Consultant Gynaecologist *
Suite 118, Panorama MediClinic, 1 Rothschild Boulevard, Parow, 7500, South Africa
Keywords:
menopause
osteoporosis
fractures
Osteoporosis-related fractures affect one-third of postmenopausal
women, resulting in significant morbidity, mortality and cost. Bone
strength is compromised if bone remodelling favours resorption by
osteoclasts over bone formation by osteoblasts. Understanding the
regulation of remodelling holds the key to the management of
osteoporosis. Postmenopausal women should be encouraged to
embrace lifestyle changes that benefit bone health. Pharmacological intervention should be reserved for patients at risk of fracture,
determined with the 10-year probability of fracture using an
integrated model of risk factors (FRAX). Randomized controlled
trials have shown that oestrogen/progestin hormone therapy,
selective oestrogen receptor modulators, bisphosphonates, teriparatide and strontium ranelate are effective in the prevention of
osteoporotic fractures. No head-to-head comparative data are
available. Compliance with therapy is poor and treatment monitoring relies on surrogate markers. Every effort must be made to
prevent osteoporotic fractures.
Ó 2008 Published by Elsevier Ltd.
Bone health and the prevention of osteoporosis-related fractures are key elements in the
management strategy of the menopause and menopausal transitional period. A detailed knowledge of
bone health and related diagnostic and therapeutic options falls within the domain of the gynaecologist as part of a multidisciplinary approach.
Osteoporosis is defined as a systemic skeletal disorder that reduces the strength of bone, resulting in
an increased risk of fracture.1 Fractures can occur as a result of minimal trauma, such as a fall from one’s
own body height. The most common osteoporosis-related fractures are fractures of the vertebrae.
Major non-vertebral osteoporosis-related fractures are fractures of the hip, wrist, pelvis, sacrum, ribs,
* Tel.: þ279304433; Fax: þ279308348.
E-mail address: [email protected]
1521-6934/$ – see front matter Ó 2008 Published by Elsevier Ltd.
doi:10.1016/j.bpobgyn.2008.10.009
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T. Johannes de Villiers / Best Practice & Research Clinical Obstetrics and Gynaecology 23 (2009) 73–85
sternum, clavicle and humerus. All these fractures are important in terms of disability and pain.
Osteoporosis-related fractures result in significant morbidity and increased mortality.2
Osteoporosis-related fractures are common and will affect at least one-third of women >50 years of
age.3 It is estimated that osteoporosis affects 75 million people in Europe, the USA and Japan, and this is
estimated to increase by 240% by 2050.4 It is estimated that more than 2 million osteoporosis-related
fractures occurred in the USA during 2005, at a cost of $19 billion. Hip fractures accounted for 72% of
these costs.5
Our understanding of the pathophysiology of osteoporosis, diagnostic methods and treatment
modalities has improved significantly over the past two decades. Dissemination of this knowledge is of
vital importance as many osteoporosis-related fractures are preventable.
Pathophysiology
Bone is living tissue, structured around three basic elements. An organic matrix of protein is laid
down by osteoblasts. The newly formed matrix is mineralized over time by calcium and phosphate in
the form of hydroxyapatite. Typically, bone has an outer casing of cortical bone connected to an inner
trabecular structure of interconnecting plates and rods. This structural arrangement gives bone the
strength required for normal activity, without a significant weight penalty.
Osteoblasts, osteocytes and osteoclasts are cells that cover all bone surfaces. Osteoclasts remove old
bone (resorption) and osteoblasts replace this with new bone (formation). This continuous process of
remodelling maintains normal skeletal size and bone strength, and provides a mechanism for the
repair of damaged bone. These changes occur within a basic multicellular unit. Under circumstances of
normal bone turnover, resorption and formation are closely linked and do not result in any loss or gain
of bone. Increased bone turnover, as found in the postmenopausal state and with advancing age, results
in incomplete refilling of resorption cavities that manifests as a loss of bone mineral density (BMD),
decreased cortical thickness, increased cortical porosity and loss of trabecular interconnectivity. A
combination of these changes results in decreased bone strength with an increased risk of fragility
fracture when falling from one’s own body height.
Knowledge of the mechanisms involved in the coupling of resorption and formation holds the key
to understanding the aetiology and treatment of osteoporosis. The remodelling cycle is controlled by
systemic hormones such as oestrogen, androgen, parathyroid hormone, follicle-stimulating hormone
and thyroid-stimulating hormone, as well as local cellular pathways of interaction between osteoblasts
and osteoclasts involving cytokines and growth factors.
The interaction between receptor activator of nuclear factor-kappaB (RANK) and RANK ligand
(RANKL) is the pathway used by osteoblasts to control bone resorption. Osteoblasts produce RANKL,
a cytokine of the tumour necrosis factor (TNF) family. RANK (the receptor) resides on the cell surface of
osteoclasts and pre-osteoclasts. RANK–RANKL binding stimulates the formation, activation and
maturation of osteoclasts. The catabolic effects of RANKL are opposed by osteoproteregin (OPG), which
is also a member of the TNF family that acts as a decoy receptor for RANKL, thus inhibiting RANK–
RANKL binding. The relative balance between RANKL and OPG is a major determinant of osteoclast
activity.6 Activated osteoclasts need to produce enzymes such as the lysosomal protease, cathepsin K
that is necessary for the degradation of bone matrix. The nature of cellular cross talk between activated
osteoclasts and osteoblasts is less well understood. There is evidence that it involves, amongst others,
a complex family of proteins called the Wnt pathway (Fig. 1).7
Prevention and treatment
Until the first fracture occurs, osteoporosis is a silent disease without any symptoms or increased
morbidity. Once the first fracture has occurred, the risk of subsequent fractures doubles with every new
fracture, with a resultant increase in morbidity and mortality.8 The aim of any osteoporosis prevention
strategy must be the prevention of the first and any subsequent fractures. It must be clearly stated that
the aim of any intervention or programme should be fracture prevention and not the treatment (or
improvement) of a single risk factor, such as BMD. As the disease affects such a large proportion of the
postmenopausal female population, a broad-based approach involving all menopausal women seems
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Fig. 1. Communication between osteoblasts and osteoclasts via receptor activator of nuclear factor-kappaB (RANK), RANK ligand
(RANKL) and osteoprotegerin (OPG). Adapted from Khosla et al. Endocrinology 2001; 142: 5050.
attractive. This is only possible when using non-pharmacological strategies such as lifestyle changes
and exercise. When using pharmacological strategies, cost-effectiveness, compliance and possible
adverse events dictate that a case-specific approach be followed. This means that only patients at
significant risk of fracture must be targeted.
Preventative measures for all postmenopausal women
Lifestyle changes
Management of the first visit after the last menstrual period (menopause) should always include
reference to lifestyle changes that can promote bone health.
All possible bone toxic substances should be avoided. The most common bone toxic substance is
nicotine derived from cigarette smoking. A recent study confirmed that former and current smoking
increased the risk of hip fracture in a population of postmenopausal women.9 Smoking has been shown
to reduce BMD and cortical thickness in young men.10
Excessive intake of alcohol is also a common source of bone toxicity. A recent study reported that
alcohol intake (2 units daily) was associated with a significant increase in all osteoporotic fractures.11
Medical history should review the use of any chronic medication toxic to bone, such as high-dose
systemic glucocorticoids or anticonvulsants. Bone loss is one of the most important side-effects of
glucocorticoids, even at low doses. The main effect of glucocorticoids on bone is inhibition of osteoblast
function, most likely by a process of apoptosis, leading to a decrease in bone formation. Several studies
and reports have shown a decrease in BMD and an increased risk of fractures associated with prior and
current exposure to glucocorticoids. Bone loss starts promptly after initiation of glucocorticoids and is
greatest in the first 6 months of treatment. Bone loss is predominantly evident in bone with high
trabecular content, such as vertebrae. The risk of glucocorticoid-induced osteoporosis can be reduced
by general measures such as prescribing glucocorticoids in a low dose and for the shortest period of
time. Furthermore, pharmacological intervention for prevention of glucocorticoid-induced osteoporosis is needed depending on glucocorticoid dose, expected duration of glucocorticoid treatment, age
and gender of the patient, and BMD at the start of glucocorticoid treatment.12
Inactivity favours osteoclastic activity with a resultant loss of BMD. On the other hand, weightbearing exercise stimulates osteoblastic activity with a resultant gain in BMD. Daily walking as well as
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specific weight-bearing exercise slows down the normal bone loss experienced by women in the early
postmenopausal years, and should be encouraged in all postmenopausal women.13 Patients in institutions need special precautions to avoid the negative effects of inactivity on bone.
Postmenopausal women should be encouraged to implement changes that can reduce the risk of
falling.14 Special attention must be given to all household flooring surfaces as well as the choice
of appropriate footwear. Balance can be improved by the correction of eyesight and the treatment of
middle ear pathology. Special attention should be given to medication that can promote falls such as
tranquilizers. In some instances, this can be addressed by lowering the dose to appropriate levels.
Depression is common in postmenopausal women. Depressed women are more likely to follow
a lifestyle that can compromise bone health. A recent study found that depressed women treated with
selective serotonin re-uptake inhibitors were associated with an increased rate of bone loss at the hip
and an increased risk of clinical fragility fractures.15 These effects are not seen with tricyclic
antidepressants.
Diet and supplementation
Caregivers and patients are well aware of the important role of calcium and vitamin D in bone
health. The role of a well-balanced diet is often overlooked. Bone has an extensive protein matrix which
needs to be maintained. Normal muscle mass around bone acts as fracture protection. Normal muscle
function is needed to keep balance intact, and depends on a well-balanced diet that is often lacking in
the older patient.16 The health-related benefits of a high intake of potassium-rich, bicarbonate-rich
foods (e.g. fruits and vegetables) on indices of bone health have been gaining increasing attention in
the literature. However, no randomized controlled data are available to support the recommendation
that postmenopausal women should concentrate on a diet rich in fruit and vegetables, with minimum
fat intake.17 Protein supplementation should be considered, especially in the frail and following
a fracture. A recent study indicated that protein-rich supplementation given to lean elderly female hip
fracture patients increased total body BMD.18 The association between low body mass index (BMI) and
increased risk of fracture is well known.19
Normal body homeostasis depends on the maintenance of appropriate serum calcium levels. Bone
acts as a reservoir of calcium. In the event of low availability of calcium (such as low dietary intake or
absorption), calcium is mobilized from bone by the effect of parathyroid hormone (secondary hyperparathyroidism). This leads to increased bone fragility. Postmenopausal women need a total recommended dietary allowance (RDA) of 1200 mg of elemental calcium.20 The best dietary source of calcium
is dairy products because of the favourable elemental calcium content, absorption ability and costeffectiveness.21 A recent meta-analysis of 17 clinical trials with fractures as outcomes found that
calcium supplementation is associated with a 12% reduction in all types of fractures in people aged 50
years. In patients with 80% compliance, fractures were reduced by 24%.22 According to a recent
consensus view of leading European experts, routine dietary calcium supplementation to the general
population as a global strategy cannot be justified in terms of efficacy and health economics.23 They
suggested a clearer rationale for supplementing patients who are at increased risk of osteoporosis and
those who have developed osteoporosis, including those already taking other treatments for osteoporosis. The dosage of supplemental calcium (500–1000 mg of elemental calcium) will depend on the
routine daily dietary content of the individual. There are no routine blood tests to detect calcium
insufficiency, but low levels of 24-h urinary secretion may be indicative of low calcium intake. Daily
intake of elemental calcium <1500 mg will not promote the formation of renal calculi.
The role of vitamin D in bone homeostasis has been redefined in the past years.24 It has been known
for many years that vitamin D is essential for calcium absorption, and the RDA for vitamin D was
previously set at 400 international units (IU). It is possible to determine vitamin D status directly by
measuring the blood level of 25-hydroxyvitamin D, and indirectly by observing the inverse relationship
with the level of parathyroid hormone. Based on the available evidence, expert opinion has set a target
serum level of 25-hydroxyvitamin D of at least 75 nmol/L (30 ng/mL) to be at lower risk of fracture. In
order to achieve this target, the RDA in older people has to be raised to 800–1000 IU of vitamin D3.25 If
this is not done, approximately 60% of older patients will have inadequate levels of vitamin D. This is due
to age-related inability of the skin and kidney to produce the active form of vitamin D. Supplementation
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is the only option as it is impossible to correct the deficit by normal dietary measures. Vitamin D
supplementation has been shown to independently lower the risk of falling in elderly patients.26
Vitamin D is currently under the spotlight for other possible benefits on the inflammatory
response, carcinogenesis and total mortality.27
Fracture risk assessment
The use of pharmacological agents in the treatment and prevention of osteoporosis must be based
on a case-specific approach aimed at treating patients at highest risk of fracture. An integrated risk
analyses model (FRAX) has been developed by the World Health Organization Collaborating Centre for
Metabolic Bone Disease at the University of Sheffield, UK.28 The FRAX algorithms express the fracture
risk of patients as the 10-year probability of a hip fracture or a major osteoporotic fracture (clinical
vertebral fracture or fracture of the forearm, hip or shoulder). It is based on individual patient models
that integrate the risks associated with clinical risk factors as well as BMD at the femur neck. If BMD is
not available, the model can still be used using clinical risk factors alone. The FRAX models have been
developed from studying population-based cohorts from Europe, North America, Asia and Australia.
Individual charts exist for certain ethnic groups. The FRAX tool is available as a computer-driven online
tool or a paper-based version (Fig. 2).
Individual risk factors for fracture29
The following risk factors are incorporated in the FRAX tool.
Advanced age
The risk of any osteoporotic fracture increases with age. For example, a BMD T-score of –2.5 at 75
years of age implies a greatly increased risk of fracture compared with the same value at 50 years of
Fig. 2. The FRAX website allows the calculation of fracture risk, taking a number of risk factors into account.
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age. The FRAX tool accepts ages between 40 and 90 years. If older or younger ages are entered, the
programme will compute probabilities at 40 and 90 years, respectively.
Gender
Females have an increased risk of fracture compared with males.
Low BMI
A low BMI (<21 kg/m2) is associated with lower BMD and increased risk of fracture, and may be
indicative of dietary deficiencies.22
Presence of a fracture or the history of fracture after 50 years of age30
Any prevalent vertebral fracture doubles the risk of subsequent fractures. The risk of a subsequent
fracture is 20% in the first year after vertebral fracture, and is increased by the presence of multiple
fractures. Vertebral fractures may be asymptomatic and only detectable by lateral X-ray of the lumbar
and cervical spine, or by lateral vertebral assessment by dual X-ray absorpsiometry (DXA).31 The
semiquantitive method of Genant et al should be used for evaluation of the vertebral body, and requires
at least a 20% decline in the anterior, mid or posterior height of the vertebral body.32
Parental history of fractured hip33
Fracture risk is increased in the presence of a history of hip fracture in the individual’s mother or
father.
Use of substances toxic to bone
Current smoking34, the intake of 3 or more units of alcohol daily11 and exposure to oral glucocorticoids
for more than 3 months at a dose of prednisolone 5 mg daily or more35 increase the risk of fracture.
Conditions associated with osteoporosis
The following disorders are strongly associated with osteoporosis: rheumatoid arthritis, hyperparathyroidism, vitamin D deficiencies, type 1 diabetes mellitus, osteogenesis imperfecta in adults,
untreated long-standing hyperthyroidism, hypogonadism, premature menopause, chronic malnutrition, malabsorption (especially coeliac disease), chronic liver disease and Cushing’s disease.
BMD estimation by DXA
The diagnosis of osteoporosis historically required the presence of a fracture. Bone densitometry by
DXA has provided a non-invasive, reliable and reproducible index that is validated as a good risk factor
for fracture in the untreated patient without a fracture.36 There is a strong continuous relationship
between BMD and osteoporotic fractures, with a 1.5- to 2.6-fold increase in fracture risk for every
standard deviation decrease in BMD, depending on the site of BMD measurement and the site of
fracture.37 The operational diagnosis of osteoporosis as defined by the World Health Organization in
1994 requires a DXA BMD value of 2.5 standard deviations below the peak value for a young Caucasian
female (T-score –2.5).38 Although this definition is useful as an epidemiological tool, it is not a good
clinical intervention threshold value as it is based on a single risk factor. Using peripheral measurement
devices, it was found that 82% of postmenopausal patients with fractures had T-scores better than
–2.5.39 In nine population-based studies in which BMD and clinical risk factors were documented, the
gradient of risk for risk factors alone was smaller compared with BMD alone, but BMD combined with
risk factors gave the best gradient of risk.29 Routine DXA examination is advised for all postmenopausal
women considered to be at risk of fracture as well as women >65 years of age.
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Ethnicity
The FRAX model allows for different fracture risks in different ethnic groups since women of AfroCaribbean origin tend to have higher bone density than their Caucasian counterparts.
Pharmacological intervention threshold
The following are absolute indications for treatment:
DXA BMD of spine: T-score of 2.5 at three vertebrae L1–L4;
DXA BMD of hip: T-score 2.5 at femur neck or total hip; and
the presence of a fragility fracture irrespective of BMD.
The FRAX model does not indicate which patients need to be treated. This remains a clinical
decision based on the 10-year risk of fracture. It is expected that national guidelines will be developed
in many countries to incorporate local health economic factors in the decision tree. An early example
has been set by the National Osteoporosis Foundation (USA). They recommend treatment for osteopenic postmenopausal women with a 10-year risk of hip fracture of 3% or a major osteoporotic
fracture risk of 20%.
Clinical work-up of a patient with osteoporosis
Evaluation of a patient diagnosed with osteoporosis entails history taking, physical examination
and biochemical assessment to exclude secondary causes of loss of bone strength, and to diagnose any
prevalent vertebral fractures. The extent of routine special examinations varies between units and
clinical judgement is essential. The following investigations should be considered:
raised serum free calcium may be an indication of hyperparathyroidism;
raised serum parathyroid hormone may be indicative of primary hyperparathyroidism;
a low level of 25-hydroxyvitamin D is indicative of a vitamin D deficiency;
a low level of calcium in a 24-h urine sample may be indicative of poor calcium intake or
absorption;
nutritional status may be reflected in a full blood count;
a raised erythrocyte sedimentation rate may raise suspicion of an underlying malignancy;
abnormal serum protein electrophoresis may point to myelomatosis;
Paget’s disease is suspected if the serum alkaline phosphatase level is raised;
tests of kidney function should be considered before treatment;
serum antibodies specific for gluten-sensitive enteropathy are available;
biochemical markers of bone turnover have a limited role in routine practice; and
lateral X rays of the thoracic and lumbar spine are used to exclude prevalent vertebral fractures,
secondary malignancies and other skeletal conditions that may have contributed to a low or falsely
raised BMD.
Pharmacological agents available for the prevention of fracture
Agents inhibiting resorption (anti-osteoclastic activity)
Oestrogen/progestin hormone therapy (HRT)
Selective oestrogen receptor modulators (SERM)
Bisphosphonates
Agents stimulating bone formation
Teriparatide (PTH 1–34)
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Combination of antiresorption and formation
Strontium ranelate
Oestrogen/progestin HRT
The accelerated bone loss associated with the start of the menopause is directly related to the
abrupt loss of oestrogen caused by ovarian failure. Oestrogen has an antiresorptive effect on bone by
acting as an inhibitor of osteoclastic cell function and by stimulation of osteoclast apoptosis. In addition, oestrogen has a positive effect on calcium balance. It has been known for many years that the
menopause-associated bone loss can be prevented by the use of HRT and that HRT increases BMD in
patients with osteoporosis. The Women’s Health Initiative (WHI) study presented the first evidence in
a large randomized controlled trial that HRT or oestrogen alone (ORT) reduces the risk of all osteoporosis-related fractures, even in patients at low risk of fracture. However, it was concluded, based on
a non-validated global model, that when considering the negative effects of HRT or ORT on other
disease outcomes, there was no net benefit, even in women considered to be at high risk of fracture.40,41 The risk of fracture in women soon after the menopause is very low and the greatest risk is in
old age. Since the benefit of HRT is only during treatment, it means that women have to take the
preparation for a very long time to gain benefit. The risk of breast cancer increases with the duration of
use, and cardiovascular risk becomes appreciable in the older woman. Subsequently, the European
regulatory authorities withdrew HRT as first-line therapy for the treatment of osteoporosis. The
following adverse effects of HRT were documented in the WHI study.
An increased risk of venous thromboembolism (VTE). The excess risk is 18 cases per 10 000 women
treated per year and the risk increases with age. The effect is maximal in the first year of treatment.
Risk factors include a previous episode of VTE or a family history of VTE. The risk can theoretically
be diminished by use of the transdermal route, as this avoids the first-pass effect on the liver (no
evidence from randomized controlled trials).
An increased risk of stroke of approximately 8–12 events per 10 000 women per year. This risk is
maintained after the first year of treatment.
The risk of breast cancer is increased after 5 years of HRT (not ORT). This effect increases with
duration of treatment, as the natural occurrence of breast cancer increases.
The use of HRT in osteoporosis should be re-evaluated in view of newer subgroup analysis of the
WHI study that points towards a window of opportunity for the use of HRT. The initiation of HRT before
60 years of age poses very little risk and may even offer cardiovascular protection.42 Use of HRT will still
be restricted as it is not recommended to initiate EPHT after the age of 60 years.43 The continuation of
EPHT after the age of 60 years should take the risks into account, as well as the fact that the effect of
HRT on BMD is lost rapidly after cessation of therapy. Expert opinion presently suggests that HRT at the
lowest effective dose can typically be used in younger patients at current risk of fracture44, who may
also suffer from vasomotor symptoms, and that another agent may replace it after 60 years of age.
SERMs
The only SERM currently available for fracture protection is raloxifene, at an oral daily dose of
60 mg. Various newer SERMs are being developed (lasofoxifene, bazedoxifene and arzoxifene). This
complex group of synthetic molecules mimics the beneficial effects of oestrogen on bone and lipids,
without stimulating the oestrogen receptors in breast and endometrium.
Raloxifene was shown to reduce the risk of vertebral fracture by 34–51% in a large randomized
controlled trial45 and a recent meta-analysis46, in spite of a very modest increase in BMD. It failed to
demonstrate a protective effect on non-vertebral fractures (including hip fracture). Raloxifene reduces
the risk of invasive oestrogen-receptor-positive breast cancer by 76%.47 A recent randomized controlled
trial proved that raloxifene is as effective as tamoxifen in the prevention of breast cancer in nonosteoporotic patients.48 Unlike oestrogen, raloxifene does not treat the vasomotor symptoms of
menopause and may, in fact, cause hot flushes. The RUTH trial failed to show that raloxifene offers
protection against coronary heart disease in patients at high risk.49 In this trial, patients on raloxifene
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were at higher risk of venous thrombotic events (hazard ratio 1.44) and fatal stroke (hazard ratio 1.49).
Raloxifene is typically used in patients at risk of vertebral fracture and breast cancer.
Bisphosphonates
The bisphosphonates are a group of drugs that share a common bisphosphonate structure (P-C-P)
with different side chains. Bisphosphonates inhibit the activity of osteoclasts by blocking the mevalonic
acid pathway.
The following preparations are commonly used in menopausal osteoporosis.
Etidronate: 400 mg daily as oral dose for 14 days of a 90-day cycle followed by calcium carbonate
for the remaining 76 days reduces the risk of vertebral fracture by 41–47%.50
Alendronate: 70 mg weekly or 10 mg daily as oral dose reduces the incidence of vertebral, hip and
wrist fractures by approximately 50%.51
Risedronate: 35 mg weekly or 5 mg daily as oral dose reduces the incidence of vertebral fractures
by 41–49% and non-vertebral fractures by 36%.52
Ibandronate: 2.5 mg daily or 150 mg monthly as oral dose or 3 mg every 3 months intravenously
reduces the risk of vertebral fractures by approximately 50%.53
Zoledronic acid: 5 mg intravenously once yearly reduces the risk of vertebral fractures by 70%, hip
fractures by 41% and peripheral fractures by 25%.54
Oral bisphosphonates are poorly absorbed (<1%) and must be taken fasting with a glass of water.
The patient must remain upright and fasting for 30 mins. Failure to do so may cause gastrointestinal
side-effects or inadequate absorption of the drug. Longer oral dosing frequencies reduce the possibility
of gastrointestinal side-effects and may increase compliance. Intravenous dosing avoids the gastrointestinal side-effects and ensures compliance, but may cause mild flu-like symptoms for a few days
after dosing.
The level of suppression of bone turnover varies between the different bisphosphonates, but may
last for long periods after cessation of therapy. Bisphosphonates bind tightly to hydroxyapatite on
bone surfaces and are retained in bone for long periods of time. When bone is resorbed, metabolically active bisphosphonate is released. This poses a potential risk of oversuppresion of bone
turnover with possible increased risk of fracture55,56, but 10 years of data in 247 women on
alendronate supports at least a maintained effect on BMD57 without any pointers towards
compromised bone quality in 18 bone biopsies.58 Osteonecrosis of the jaw (OJN), a condition
described as an area of exposed alveolar bone in the mandible or maxilla, has also been implicated
as caused by oversuppression of bone turnover by bisphosphonates. An analysis of 368 reported
cases provides insight into risk factors associated with ONJ.59 Ninety-four percent of cases had been
treated with intravenous bisphosphonates at much higher doses than that used for fracture
protection. Eighty-four percent of cases suffered from multiple myeloma or metastatic breast cancer,
and 60% of cases were preceded by tooth extraction or other dental procedures. Another risk factor is
poor oral hygiene. Although the risk of ONJ in the management of menopausal osteoporosis is very
rare (1:100 000), patients should be counselled and dental examination is advisable prior to starting
bisphosphonate treatment.
The ideal length of bisphosphonate therapy is not known. The Fracture Intervention Trial Long-term
Extension (FLEX) study provides some answers with regards to alendronate. It has been suggested that
alendronate should be stopped after 5 years for a drug-free holiday in patients that have a good
increase in BMD, with a T-score of >3.5 and no additional risk factors for fracture such as a prevalent
vertebral fracture.60 It has also been suggested that these patients should be followed-up by serial BMD
to detect possible fast losers of BMD.
The bisphosphonates have the most extensive track record in osteoporosis therapy, and are
likely to remain the most commonly prescribed drug for the prevention of fractures in the
immediate future. Care must be taken in women with premature ovarian failure, as the use of
bisphosphonates in the long term has not been studied fully, along with the impact on
a developing fetus in those who become pregnant (either naturally or following ovum
donation).
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Teriparatide (PTH 1–34)
PTH 1–34 is presently the only pure anabolic agent available. It is administered daily as a subcutaneous injection at a dose of 20 mg. It stimulates new bone formation on trabecular and cortical bone
surfaces by preferential stimulation of osteoblastic activity over osteoclastic activity. It significantly
reduces vertebral fractures by 65% and non-vertebral fragility fractures by 53% in treatment-naive
postmenopausal women who have previously suffered a vertebral fracture.61 Side-effects are generally
mild and include hypercalcaemia and raised uric acid levels as well as leg cramps, nausea and headaches. Early concerns regarding induction of osteosarcoma in rats have not been substantiated in
humans. Duration of therapy is presently limited to 18 months and should be followed by maintenance
therapy with an antiresorptive drug. The anabolic effect of PTH is blunted by prior treatment with
bisphosphonates.
The use of PTH is limited by high costs. Indications for PTH 1–34 treatment in preference to cheaper
therapies are presently based on expert opinion, as no evidence exists. A typical recommendation is
that PTH 1–34 should be reserved for cases with severe established osteoporosis as defined by low
BMD and at least two prevalent fractures, or failed antiresorptive treatment as defined by an incident
fragility fracture while compliant with antiresorptive treatment.62
Strontium ranelate
Strontium ranelate is registered outside the USA for the treatment of menopausal osteoporosis.
Strontium ranelate is provided as 2 g of powder that is suspended in water and taken as a daily oral
dose. This agent has a unique double action. Based on bone marker studies, strontium ranelate
moderately decreases resorption and increases formation. This action is mediated by the RANK ligand
system as well as by a calcium-sensing receptor.63 Two large randomized controlled trials (SOTI64 and
TROPOS65), as well as extension studies, have yielded robust data over 8 years. Strontium ranelate
treatment results in significant increases in BMD and reduction in the risk of vertebral fractures (41%).
In a post-hoc analysis, hip fracture was reduced significantly in a subset of patients >74 years of age
with a T-score 2.5. A significant reduction in peripheral fractures was also demonstrated. Antifracture efficacy was demonstrated in subgroups of patients with osteopenia as well as patients >80
years of age.
Bone biopsy data over 5 years of therapy confirm bone safety and beneficial effects on threedimensional micro-architecture.66
Choice of therapy
Present data are insufficient to compare the relative efficacy or safety of available therapies.67
Choice is an individual clinical decision based on the data available for a specific drug, and may be
influenced by cost and compliance.
Monitoring of therapy
The monitoring of treatment by serial measurement of BMD has serious pitfalls such as individual
variations in precision of operators and devices. Typically, a change in BMD of at least 3.8% (hip) and
2.4% (spine) is needed to be of any significance. Follow-up measurements for patients on treatment
should be performed at intervals of at least 2 years. Regression to the mean predicts that patients with
unusual responses to treatment on serial BMD may represent outliers who are likely to have more
typical responses if treatment is continued without change. Even patients who lose bone on treatment
have a lower fracture risk compared with patients on no treatment. BMD does not take into account
effects on cortical thickness, cortical porosity or trabecular connectivity.
Bone turnover markers can indicate suppression of bone turnover as early as 3 months before
changes in BMD occur. Although early suppression may correlate with fracture risk reduction, the
information is more useful as an indicator of early adherence to therapy and may be used to improve
persistence.
Vertebral fracture assessment by DXA is the most meaningful monitoring tool available at present,
as an accurate assessment of incident vertebral fractures can be made.
T. Johannes de Villiers / Best Practice & Research Clinical Obstetrics and Gynaecology 23 (2009) 73–85
83
Summary
Osteoporosis-related fractures affect one-third of postmenopausal women, resulting in significant
morbidity, mortality and cost. In view of the rapidly increasing age of society and the spiraling cost of
treating fractures, the burden of disease will increase dramatically in future. Gynaecologists are in
a very good position to make a difference. Bone strength is compromised if bone remodelling favours
resorption by osteoclasts over bone formation by osteoblasts. Understanding the regulation of
remodelling holds the key to the management of osteoporosis. All postmenopausal women should be
encouraged to embrace lifestyle changes that will benefit bone health. Patients at risk of fracture
should be identified using the FRAX model. Pharmacological interventions should be reserved for
patients at risk of fracture, determined using the 10-year probability of fracture. All secondary causes of
bone loss should be investigated and treated. Randomized controlled trials have shown that HRT,
SERMs, bisphosphonates, teriparatide and strontium ranelate are effective in the prevention of osteoporotic fractures. No head-to-head comparative data between these agents are available. Compliance
with therapy is poor and the monitoring of treatment relies on surrogate markers. Every effort must be
made to prevent osteoporotic fractures.
Practice points
all perimenopausal and postmenopausal patients should be counselled regarding lifestyle
and dietary changes of benefit to bone health
fracture risk assessment should be done according to the FRAX model
BMD by DXA should be estimated in patients at high risk of fracture
secondary causes of osteoporosis should be established and treated
patients at high risk of fracture should be treated with an approved pharmacological agent
the choice of agent will be determined by the individual needs of the patient
every effort must be made to ensure compliance with therapy
Research agenda
development of new non-invasive, in-vitro determinants of bone strength
data on optimal duration of treatment
long-term effects of suppression of bone turnover
microcellular regulation of osteoblasts with a view to new pure anabolic agents
the following drugs are presently in clinical development: RANKL inhibitor, combination of
oestrogen and SERM, selective calcium sensor receptor antagonist and cathepsin K inhibitor
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