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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 for your Attention!