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In postmenopausal women, osteoporotic fractures are more common than stroke, myocardial infarction, and breast cancer combined, and fractures can be costly and result in disability or death. Because there are no signs or symptoms of osteoporosis other than fracture, risk assessment is necessary to identify those at higher risk for clinical events. For women, a clinical fracture risk assessment (FRAX) is appropriate at menopause. Bone mineral density (BMD) measurement is recommended for women at age 65, and earlier for those who have risk factors. Adequate calcium, vitamin D, and weight-bearing exercise are important for bone health at all ages, and those at high risk for fracture based on BMD or FRAX should be offered medical therapy to reduce fracture risk after an appropriate medical evaluation. Bisphosphonates can accumulate in bone, so after a period of treatment, lower risk patients may be offered a period off drug therapy. However, the effects of denosumab are not sustained when treatment is discontinued, so there is no “drug holiday” with denosumab. Anabolic therapy can be offered to those with higher risk for fracture. Although rare safety concerns regarding atypical femoral fracture and osteonecrosis of the jaw have received prominent attention, for patients who are appropriately treated according to National Osteoporosis Foundation guidelines, the benefit of hip fracture risk reduction far outweighs the risk of these uncommon side effects. Accurate information for patients and shared decision-making are important for acceptance and persistent with appropriate treatment. [ABSTRACT FROM AUTHOR]

The first bisphosphonate (etidronate) was approved by the FDA in 1977; alendronate was approved in 1995 for the prevention and treatment of osteoporosis. Bisphosphonates have emerged as the agents of choice for the treatment of osteoporosis and have proved useful in the treatment of skeletal complications of malignancy (hypercalcemia, bone metastases) and have been used long-term in millions of patients. Osteonecrosis of the jaw (ONJ) is a newly described condition (2003) defined as exposed bone in the maxillofacial area, not associated with radiation or any other known cause and not healing for 8 weeks. Most cases have followed dental extraction, another invasive dental procedure, or poorly fitting dentures. Although most cases are painful and it can be progressive, approximately one-third of cases are painless and some do resolve. Although ONJ occurs exclusively or almost exclusively in patients receiving bisphosphonate therapy, a causal association has not been shown, and the mechanism is not clear. In patients receiving high-dose IV bisphosphonates for malignant diseases, ONJ may occur in 5 to 10% over 3 years. It does occur in patients receiving oral or IV bisphosphonates for osteoporosis, but is rare in that setting; about 1 case per 100,000. Treatment is conservative (antimicrobial mouthwash, antibiotics for secondary infection, limited debridement). Preventive strategies should include good dental hygiene for all patients and completion of elective invasive dental procedures before initiating high-dose IV bisphosphonate therapy for cancer. Patients with osteoporosis receiving lower-dose bisphosphonate therapy do not require special precautions, but should be informed of the low risk of this complication. [ABSTRACT FROM AUTHOR]

Osteoporosis is a major public health problem but is underdiagnosed and undertreated. A new randomized controlled trial indicates that population screening for osteoporosis by BMD assessment resulted in improved treatment and reduced risk of fractures in postmenopausal women. [ABSTRACT FROM AUTHOR]

Abstract: Bisphosphonates are effective in reducing bone turnover, increasing BMD and reducing fracture risk in postmenopausal women with osteoporosis. The licensed bisphosphonates exhibit some differences in potency and speed of onset and offset of action. These differences mean that different agents may be more advantageous in different situations. Uncertainties still exist around the optimum duration of treatment and treatment holidays, how best to use bisphosphonates with anabolic treatments, and the benefits of treatment in patients who do not have a BMD T-score below −2.5. This article is part of a Special Issue entitled Bisphosphonates. [Copyright &y& Elsevier]

This study examined patients' risk profiles and adherence to treatment in relation to the effect of risedronate and raloxifene on hip fracture incidence. Administrative billing data were used to follow two cohorts of women aged 65 and older after starting therapy with either risedronate (n = 86,735) or raloxifene (n = 37,726). The fracture risk profile was described using a 6-month history period before starting therapy. Effectiveness of each therapy was evaluated by comparing the incidence of hip fractures during the first 3 months with the subsequent 12 months among women adherent (medication possession ratio >80%) compared with those non-adherent to treatment. At the start of therapy, the raloxifene cohort was younger than the risedronate cohort (median age 73 vs. 76 years) and had fewer prior fractures (p < 0.01 for both). In the first 3 months of therapy, hip fracture incidence was lower in the raloxifene group (0.51 per 100 person-years) compared with the risedronate group (0.94 per 100 person-years). In the subsequent 12 months, the incidence of hip fractures decreased among patients adherent to the risedronate regimen [relative risk (RR) 0.70, 95% CI 0.59-0.84, p < 0.01] and did not change significantly among patients adherent to the raloxifene regimen (RR 1.02, 95% CI 0.73-1.44). In poorly adherent patients, neither drug decreased hip fracture risk. Risedronate treatment in adherent patients rapidly decreased the risk of hip fractures, whereas raloxifene treatment did not. [ABSTRACT FROM AUTHOR]

The bisphosphonates (BPs) are well established as the treatments of choice for disorders of excessive bone resorption, including Paget's disease of bone, myeloma and bone metastases, and osteoporosis. There is considerable new knowledge about how BPs work. Their classical pharmacological effects appear to result from two key properties: their affinity for bone mineral and their inhibitory effects on osteoclasts. Mineral binding affinities differ among the clinically used BPs and may influence their differential distribution within bone, their biological potency, and their duration of action. The inhibitory effects of the nitrogen-containing BPs (including alendronate, risedronate, ibandronate, and zoledronate) on osteoclasts appear to result from their inhibition of farnesyl pyrophosphate synthase (FPPS), a key branch-point enzyme in the mevalonate pathway. FPPS generates isoprenoid lipids used for the posttranslational modification of small GTP-binding proteins essential for osteoclast function. Effects on other cellular pathways, such as preventing apoptosis in osteocytes, are emerging as other potentially important mechanisms of action. As a class, BPs share several common properties. However, as with other classes of drugs, there are obvious chemical, biochemical, and pharmacological differences among the various individual BPs. Each BP has a unique profile that may help to explain potential important clinical differences among the BPs, in terms of speed of onset of fracture reduction, antifracture efficacy at different skeletal sites, and the degree and duration of suppression of bone turnover. As we approach the 40th anniversary of the discovery of their biological effects, there remain further opportunities for using their properties for medical purposes. [ABSTRACT FROM AUTHOR]

Most osteoporosis treatments have proven efficacy in reducing the risk of vertebral fractures, whereas evidence is less straightforward for prevention of non-vertebral fractures. Conclusions as to the efficacy of a treatment should be based primarily on analyses of the intention to treat (ITT) population rather than on exploratory subgroup analyses; however, non-vertebral anti-fracture efficacy has been largely derived by post-hoc subgroup analyses. This review and meta-analysis was performed to assess non-vertebral anti-fracture efficacy of several osteoporosis therapies, including a more stringent assessment of the ITT populations. Data on non-vertebral anti-fracture efficacy, a defined endpoint of the ITT analyses and confirmed by radiographs, were obtained from randomized, placebo-controlled, phase III clinical trials of at least 3-year duration. Meta-analyses were performed for the two bisphosphonates, alendronate and risedronate. Relative risks (RR), 95% confidence intervals (CI) and statistical significance for active treatment compared with placebo were calculated. Eleven clinical trials met the criteria for review, three of which showed statistically significant ( P ≤0.05) non-vertebral anti-fracture efficacy in the ITT population: two trials with risedronate and one trial with strontium. A meta-analysis showed significant reductions in the relative risk of non-vertebral fracture for both alendronate (RR=0.86; 95% CI: 0.76–0.97, P =0.012) and risedronate (RR=0.81; 95% CI: 0.71–0.92, P =0.001). Risedronate and strontium ranelate were the only treatments to show non-vertebral anti-fracture efficacy in this robust assessment of anti-fracture efficacy of osteoporosis therapy using ITT populations in trials of 3 years or more in duration. Risedronate was the only agent shown to demonstrate efficacy in more than one trial. Meta-analysis showed that both alendronate and risedronate provide non-vertebral anti-fracture efficacy. [ABSTRACT FROM AUTHOR]