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The goal of osteoporosis management is to prevent fractures. Several pharmacological agents are available to lower fracture risk, either by reducing bone resorption or by stimulating bone formation. Bisphosphonates are the most widely used anti-resorptives, reducing bone turnover markers to low premenopausal concentrations and reducing fracture rates (vertebral by 50–70%, non-vertebral by 20–30%, and hip by ~40%). Bisphosphonates bind avidly to bone mineral and have an offset of effect measured in months to years. Long term, continuous use of oral bisphosphonates is usually interspersed with drug holidays of 1–2 years, to minimise the risk of atypical femoral fractures. Denosumab is a monoclonal antibody against RANKL that potently inhibits osteoclast development and activity. Denosumab is administered by subcutaneous injection every 6 months. Anti-fracture effects of denosumab are similar to those of the bisphosphonates, but there is a pronounced loss of anti-resorptive effect from 7 months after the last injection, which can result in clusters of rebound vertebral fractures. Two classes of anabolic drugs are now available to stimulate bone formation. Teriparatide and abaloparatide both target the parathyroid hormone-1 receptor, and are given by daily subcutaneous injection for up to 2 years. Romosozumab is an anti-sclerostin monoclonal antibody that stimulates bone formation and inhibits resorption. Romosozumab is given as monthly subcutaneous injections for 1 year. Head-to-head studies suggest that anabolic agents have greater anti-fracture efficacy and produce larger increases in bone density than anti-resorptive drugs. The effects of anabolic agents are transient, so transition to anti-resorptive drugs is required. The optimal strategy for cycling anabolics, anti-resorptives, and off-treatment periods remains to be determined.

Key Points Bisphosphonates—the most widely used treatment for osteoporosis—are safe and effective, but are usually only given for ∼5 years followed by a drug holiday to reduce the risk of atypical femoral fractures Denosumab is a potent antiresorptive, with an antifracture efficacy comparable to that of potent bisphosphonates; BMD changes with long-term use of denosumab seem to be more positive than those with bisphosphonates Teriparatide—the most widely used anabolic agent—is well-tolerated and early concerns related to osteosarcoma have not been substantiated; effects of teriparatide on BMD are additive to those of antiresorptives Strontium has marginal antifracture efficacy and its use is declining owing to concern about its cardiovascular safety profile Cathepsin K inhibitors and sclerostin antibodies are anti-osteoporotic agents in development, which show great promise Osteoporosis is a process operative in almost all individuals past middle age and results in fractures in a large proportion of men and women. In this Review, Ian Reid reflects on the nature of the osteoporotic process and its implications for treatment indications, and considers the pros and cons of available interventions to reduce fracture risk. Progress continues to be made in the development of therapeutics for fracture prevention. Bisphosphonates are now available orally and intravenously, often as inexpensive generics, and remain the most widely used interventions for osteoporosis. The major safety concern associated with the use of bisphosphonates is the development of femoral shaft stress fractures and, although rare, this adverse event affords the principal rationale for restricting bisphosphonate therapy to those individuals with femoral T-scores <−2.5, and for providing drug holidays in those individuals requiring therapy for >5 years. Newer antiresorptive therapies, in the form of denosumab and cathepsin K inhibitors, might increase efficacy and possibly circumvent some of the safety concerns associated with bisphosphonate use (for example, gastrointestinal and renal complications). The combination of teriparatide with antiresorptives markedly increases effects on BMD; new anabolic agents are also very promising in this regard. However, whether or not these changes in BMD translate into improved efficacy of fracture prevention remains to be determined. Vitamin D is important for the prevention of osteomalacia, but does not influence BMD or fracture risk in patients not deficient in vitamin D. The balance of risks and benefits of calcium supplementation is contentious, but patients should be encouraged to adhere to a balanced diet aimed at maintaining a healthy body weight. Consideration of a patient's risk of falling, and its mitigation, are also important. In this Review, I summarize the short-term and long-term effects of osteoporosis therapies.

Abstract Leptin originates in adipocytes, including those in bone marrow, and circulates in concentrations 20 to 90 times higher than those in the cerebrospinal fluid. It has direct anabolic effects on osteoblasts and chondrocytes, but it also influences bone indirectly, via the hypothalamus and sympathetic nervous system, via changes in body weight, and via effects on the production of other hormones (e.g., pituitary). Leptin's role in bone physiology is determined by the balance of these conflicting effects. Reflecting this inconsistency, the leptin-deficient mouse has reduced length and bone mineral content of long bones but increased vertebral trabecular bone. A consistent bone phenotype in human leptin deficiency has not been established. Systemic leptin administration in animals and humans usually exerts a positive effect on bone mass, and leptin administration into the cerebral ventricles usually normalizes the bone phenotype in leptin-deficient mice. Reflecting the role of the sympathetic nervous system in mediating the central catabolic effects of leptin on the skeleton, β-adrenergic agonists and antagonists have major effects on bone in mice, but this is not consistently seen in humans. The balance of the central and peripheral effects of leptin on bone remains an area of substantial controversy and might vary between species and according to other factors such as body weight, baseline circulating leptin levels, and the presence of specific pathologies. In humans, leptin is likely to contribute to the positive relationship observed between adiposity and bone density, which allows the skeleton to respond appropriately to changes in soft tissue mass.

Findings from recent meta-analyses of vitamin D supplementation without co-administration of calcium have not shown fracture prevention, possibly because of insufficient power or inappropriate doses, or because the intervention was not targeted to deficient populations. Despite these data, almost half of older adults (older than 50 years) continue to use these supplements. Bone mineral density can be used to detect biologically significant effects in much smaller cohorts. We investigated whether vitamin D supplementation affects bone mineral density. We searched Web of Science, Embase, and the Cochrane Database, from inception to July 8, 2012, for trials assessing the effects of vitamin D (D3 or D2, but not vitamin D metabolites) on bone mineral density. We included all randomised trials comparing interventions that differed only in vitamin D content, and which included adults (average age >20 years) without other metabolic bone diseases. We pooled data with a random effects meta-analysis with weighted mean differences and 95% CIs reported. To assess heterogeneity in results of individual studies, we used Cochran's Q statistic and the I2 statistic. The primary endpoint was the percentage change in bone mineral density from baseline. Of 3930 citations identified by the search strategy, 23 studies (mean duration 23·5 months, comprising 4082 participants, 92% women, average age 59 years) met the inclusion criteria. 19 studies had mainly white populations. Mean baseline serum 25-hydroxyvitamin D concentration was less than 50 nmol/L in eight studies (n=1791). In ten studies (n=2294), individuals were given vitamin D doses less than 800 IU per day. Bone mineral density was measured at one to five sites (lumbar spine, femoral neck, total hip, trochanter, total body, or forearm) in each study, so 70 tests of statistical significance were done across the studies. There were six findings of significant benefit, two of significant detriment, and the rest were non-significant. Only one study showed benefit at more than one site. Results of our meta-analysis showed a small benefit at the femoral neck (weighted mean difference 0·8%, 95% CI 0·2–1·4) with heterogeneity among trials (I2=67%, p<0·00027). No effect at any other site was reported, including the total hip. We recorded a bias toward positive results at the femoral neck and total hip. Continuing widespread use of vitamin D for osteoporosis prevention in community-dwelling adults without specific risk factors for vitamin D deficiency seems to be inappropriate. Health Research Council of New Zealand.

Objective To determine whether increasing calcium intake from dietary sources affects bone mineral density (BMD) and, if so, whether the effects are similar to those of calcium supplements.Design Random effects meta-analysis of randomised controlled trials.Data sources Ovid Medline, Embase, Pubmed, and references from relevant systematic reviews. Initial searches were undertaken in July 2013 and updated in September 2014.Eligibility criteria for selecting studies Randomised controlled trials of dietary sources of calcium or calcium supplements (with or without vitamin D) in participants aged over 50 with BMD at the lumbar spine, total hip, femoral neck, total body, or forearm as an outcome.Results We identified 59 eligible randomised controlled trials: 15 studied dietary sources of calcium (n=1533) and 51 studied calcium supplements (n=12 257). Increasing calcium intake from dietary sources increased BMD by 0.6-1.0% at the total hip and total body at one year and by 0.7-1.8% at these sites and the lumbar spine and femoral neck at two years. There was no effect on BMD in the forearm. Calcium supplements increased BMD by 0.7-1.8% at all five skeletal sites at one, two, and over two and a half years, but the size of the increase in BMD at later time points was similar to the increase at one year. Increases in BMD were similar in trials of dietary sources of calcium and calcium supplements (except at the forearm), in trials of calcium monotherapy versus co-administered calcium and vitamin D, in trials with calcium doses of ≥1000 versus <1000 mg/day and ≤500 versus >500 mg/day, and in trials where the baseline dietary calcium intake was <800 versus ≥800 mg/day.Conclusions Increasing calcium intake from dietary sources or by taking calcium supplements produces small non-progressive increases in BMD, which are unlikely to lead to a clinically significant reduction in risk of fracture.

Approximately 50% of women experience at least one bone fracture postmenopause. Current screening approaches target anti-fracture interventions to women aged >60 years who satisfy clinical risk and bone mineral density criteria for osteoporosis. Intervention is only recommended in 7–25% of those women screened currently, well short of the 50% who experience fractures. Large screening trials have not shown clinically significant decreases in the total fracture numbers. By contrast, six large clinical trials of anti-resorptive therapies (for example, bisphosphonates) have demonstrated substantial decreases in the number of fractures in women not identified as being at high risk of fracture. This finding suggests that broader use of generic bisphosphonates in women selected by age or fracture risk would result in a reduction in total fracture numbers, a strategy likely to be cost-effective. The utility of the current bone density definition of osteoporosis, which neither corresponds with who suffers fractures nor defines who should be treated, requires reappraisal.Osteoporosis interventions are currently recommended in a small proportion of postmenopausal women, of whom ~50% will experience bone fracture. This Perspectives proposes that broader use of generic bisphosphonates would result in reductions in total fracture numbers and suggests that the current bone density definition of osteoporosis requires reappraisal.

Osteonecrosis of the jaw (ONJ) is associated with high-dose bisphosphonate therapy in patients with cancer, and has also been linked to bisphosphonate use in patients with osteoporosis. In this Review, the authors examine the epidemiology and pathogenesis of ONJ. Osteonecrosis of the jaw (ONJ) is defined as exposed bone in the oral cavity that persists despite appropriate therapy. Over the past decade, ONJ has been reported in about 5% of patients with cancer receiving high-dose intravenous bisphosphonates, and more recently in similar patients treated with denosumab, another potent inhibitor of osteoclastic bone resorption. The condition has also been described in patients treated with bisphosphonates for benign diseases, such as osteoporosis, but whether bisphosphonates or denosumab increase the incidence above that seen in untreated patients of comparable age and frailty is yet to be established. The pathogenesis of ONJ is uncertain: the toxic effects of bisphosphonates in a wide variety of cells could increase susceptibility to infections in the oral cavity or impair mucosal healing, and denosumab might interfere with monocyte and macrophage function. Local osteolysis is an important defense against infection on bone surfaces that is blocked by both bisphosphonates and denosumab. Preventive dentistry prior to high-dose antiresorptive therapy is a critical measure in cancer patients, but is not usually justified in patients with osteoporosis. The management of established ONJ lesions is problematic: the greatest success seems to come from vigorous antimicrobial therapy with judicious use of surgical debridement. Key Points Osteonecrosis of the jaw (ONJ) is defined as the presence of exposed bone in the mouth that persists despite appropriate therapy ONJ is primarily a problem encountered in patients with cancer receiving high-dose intravenous bisphosphonates for the prevention of skeletal-related events, of whom about 5% develop the condition ONJ has now been reported at a similar frequency in patients with cancer treated with denosumab, a monoclonal antibody against RANKL ONJ has also been reported in patients treated with bisphosphonates for osteoporosis, but it is not yet established whether bisphosphonates increase the incidence above that seen in untreated patients of comparable age and frailty The pathogenesis of ONJ is uncertain, but local toxicity from bisphosphonates or blockade of the normal osteolytic response to infection on a bone surface might be important factors Preventive dentistry prior to initiation of high-dose antiresorptive therapy is important in patients with cancer, but is not usually justified in patients with osteoporosis

Romosozumab and denosumab are monoclonal antibodies for the treatment of osteoporosis. Both have a rapid offset of effect resulting in loss of bone density (BMD) gained on-treatment and, in some cases, multiple vertebral fractures following treatment cessation. We recently reported disappointing results from transitioning patients from denosumab to intravenous zoledronate at the time the next denosumab injection is due. The present report re-assesses the role of bisphosphonates following the use of denosumab. In the FRAME trial, osteoporotic women were randomized to romosozumab or placebo for 1 year, then both groups were provided with open-label denosumab for the subsequent 2 years. In women completing this study at our center, we offered treatment with either oral or intravenous bisphosphonates. In the eleven women opting for intravenous treatment, zoledronate was given after a median delay of 65 days from trial-end, in the hope that this might increase skeletal uptake of the drug and, thereby, its efficacy to maintain bone density. In these women, spine BMD was 17.3% above baseline at trial-end, and still 12.3% above baseline a year later, a 73% (CI: 61%, 85%) retention of the treatment benefit. The comparable BMD figures for the total hip were 10.7 and 9.2% above baseline, a 87% (CI: 77%, 98%) retention of treatment effect. In contrast, those not receiving treatment after the conclusion of the FRAME trial lost 80–90% of the BMD gained on-trial in the following 12 months. Women treated with risedronate showed an intermediate response. In the zoledronate group, mean PINP 6 months post-FRAME was 23 ± 4 µg/L and at 12 months it was 47 ± 8 µg/L, suggesting that repeat zoledronate dosing is needed at 1 year to maintain the BMD gains. In conclusion, delaying administration of intravenous bisphosphonate when transitioning from short-term denosumab appears to increase the extent to which the gains in BMD are maintained.

Many older adults do not achieve recommended intakes of calcium and there is some concern over the potential impact of this on bone health. The objective of this review was to examine evidence from cohort studies on the relationship between calcium intake and change in bone mineral density (BMD) in older adults, something not undertaken in the last two decades. Data sources included Ovid Medline, Embase, and PubMed and references from retrieved reviews and articles. The final search was performed in February 2021. We included cohort studies of calcium intake in participants aged >50 years with change in BMD over ≥1 year as an outcome. We identified 23 studies of women and 7 of men. Most studies found no association between calcium intake and change in BMD in women (71%) or men (71%). Among women, five studies reported high rates (>30% of participants) of hormone treatment or osteoporosis therapy (HT/OT) use; 80% of these studies reported a positive association between calcium intake and change in BMD, compared with 10% of studies in which HT/OT use was low. No study in women in which the mean age was >60 years reported a positive association between calcium intake and change in BMD. We conclude that calcium intake across the ranges consumed in these studies (mean intake in all but one study >500 mg/day) is not an important determinant of bone loss, particularly among women >60 years. The positive findings in studies with high rates of HT/OT use are likely to arise from confounding as a result of co-administration of calcium supplements with these medications.

In this double-blind, placebo-controlled trial, women with postmenopausal osteoporosis received an infusion of either zoledronic acid (5 mg) or placebo at baseline and at 1 and 2 years and were followed for 3 years. Zoledronic acid significantly reduced the risk of vertebral, hip, and other fractures. Adverse events were similar in the two study groups, except for serious atrial fibrillation, which was more frequent in the zoledronic acid group. This drug may provide a promising approach to reducing fracture risk. In women with postmenopausal osteoporosis, zoledronic acid significantly reduced the risk of vertebral, hip, and other fractures. This drug may provide a promising approach to reducing fracture risk. Fractures are an important cause of disability among postmenopausal women, and the costs of medical care associated with osteoporosis are estimated to be more than $18 billion annually in the United States alone. 1 Bisphosphonates, the most commonly used treatment for established osteoporosis, inhibit osteoclast-mediated bone resorption and reduce the risk of vertebral fracture. Two bisphosphonates, alendronate and risedronate, also have been shown to reduce nonvertebral and hip fractures in women with osteoporosis. 2 – 6 However, adherence to oral treatment is problematic, and about half of patients for whom oral treatment is prescribed do not adhere to it after 1 year. 7 , . . .