Secondary Fracture Prevention: Consensus Clinical Recommendations from a Multistakeholder Coalition.

Meta-analyses conducted >15 years ago reported that improvements in bone mineral density (BMD) were associated with reduction in vertebral and nonvertebral fractures in osteoporosis trials. Numerous studies have been conducted since then, incorporating new therapies with different mechanisms of action and enrolling many more subjects. To extend these prior analyses, we conducted a meta-regression of 38 placebo-controlled trials of 19 therapeutic agents to determine the association between improvements in BMD and reductions in fracture risk. We used a linear model to examine the relationship between mean percent difference in BMD change between treatment and placebo groups and the logarithm of the relative risk. We found that greater improvements in BMD were strongly associated with greater reductions in vertebral and hip fractures but not nonvertebral fractures. For vertebral fracture, the r2 values for total hip, femoral neck, and lumbar spine BMD change were 0.56, 0.54, and 0.63, respectively (p ≤ 0.0002). For a 2% or 6% improvement in total hip BMD, we might expect a 28% or 66% reduction, respectively, in vertebral fracture risk. For hip fracture, the r2 values for total hip, femoral neck, and lumbar spine BMD change were 0.48 (p = 0.01), 0.42 (p = 0.02), and 0.22 (ns), respectively. For a 2% or 6% improvement in total hip BMD, we might expect a 16% or 40% reduction in hip fracture risk. In conclusion, our results extend prior observations that larger improvements in dual-energy X-ray absorptiometry (DXA)-based BMD are associated with greater reductions in fracture risk, particularly for vertebral and hip fractures. Although these results cannot be directly applied to predict the treatment benefit in an individual patient, they provide compelling evidence that improvements in BMD with osteoporosis therapies may be useful surrogate endpoints for fracture in trials of new therapeutic agents. © 2019 American Society for Bone and Mineral Research.

Bone strength and surrogate markers: The first, second, and third fiddle

Sequelae after an osteoporosis-related fracture include significant morbidity and mortality. Preventing repeat fractures is an important aspect of mitigating these sequelae. As highlighted in the American Society for Bone and Mineral Research multistakeholder coalition's Secondary Fracture Prevention: Consensus Clinical Recommendations, nurse practitioners play an important role in secondary fracture prevention. With a focus on education, longitudinal relationships with patients, and expertise in coordinating and managing care, nurse practitioners are uniquely qualified to run Fracture Liaison Services and help close the gap to care in secondary fracture prevention.

Dual-energy X-ray absorptiometric bone mineral density (DXA BMD) is a strong predictor of fracture risk in untreated patients. However, previous patient-level studies suggest that BMD changes explain little of the fracture risk reduction observed with osteoporosis treatment. We investigated the relevance of DXA BMD changes as a predictor for fracture risk reduction using data from the FREEDOM trial, which randomly assigned placebo or denosumab 60 mg every 6 months to 7808 women aged 60 to 90 years with a spine or total hip BMD T-score < −2.5 and not < −4.0. We took a standard approach to estimate the percent of treatment effect explained using percent changes in BMD at a single visit (months 12, 24, or 36). We also applied a novel approach using estimated percent changes in BMD from baseline at the time of fracture occurrence (time-dependent models). Denosumab significantly increased total hip BMD by 3.2%, 4.4%, and 5.0% at 12, 24, and 36 months, respectively. Denosumab decreased the risk of new vertebral fractures by 68% (p < 0.0001) and nonvertebral fracture by 20% (p = 0.01) over 36 months. Regardless of the method used, the change in total hip BMD explained a considerable proportion of the effect of denosumab in reducing new or worsening vertebral fracture risk (35% [95% confidence interval (CI): 20%–61%] and 51% [95% CI: 39%–66%] accounted for by percent change at month 36 and change in time-dependent BMD, respectively) and explained a considerable amount of the reduction in nonvertebral fracture risk (87% [95% CI: 35% – >100%] and 72% [95% CI: 24% – >100%], respectively). Previous patient-level studies may have underestimated the strength of the relationship between BMD change and the effect of treatment on fracture risk or this relationship may be unique to denosumab. © 2012 American Society for Bone and Mineral Research

Osteoporotic fractures are one of the major causes of increased morbidity and mortality in postmenopausal women and the overall aging population. One of the major issues in the management of postmenopausal osteoporosis is to find a safe and effective treatment in the long term (>3 years) to achieve and maintain a reduction in the risk of fracture. Strontium ranelate (PROTELOS(®)) is a relatively novel drug, currently approved in Europe for the treatment of postmenopausal osteoporosis. Strontium ranelate is the first agent of a new therapeutic class in osteoporosis, capable of both promoting bone formation and, to a lesser extent, inhibiting bone resorption. This uncoupling in bone turnover results in a net gain in bone mineral density (BMD), bone quality improvement and reduction in risk of vertebral and nonvertebral fractures, as initially demonstrated in the preplanned long-term registrative trials SOTI (Spinal Osteoporosis Therapeutic Intervention) and TROPOS (Treatment of Peripheral Osteoporosis) at 5 years. Recently, open-label extensions of the SOTI and TROPOS trials up to 8 and, recently, 10 years have confirmed the sustained efficacy of strontium ranelate in increasing BMD, the long-term safety profile and the high compliance to treatment, independently from baseline BMD or other risk factors for osteoporotic fractures. Recent economic impact analyses have proved that long-term treatment with strontium ranelate is highly cost effective, especially in women older than 70 years of age. Histomorphometric analyses in animals and humans participating in the phase III trials have proved that the quality of mineralization is preserved in the long term and bone microarchitecture is ameliorated, with increased bone strength. Thus, strontium ranelate has been confirmed to be an effective compound for the long-term, chronic treatment of postmenopausal osteoporosis.

Bisphosphonates are the primary therapy for postmenopausal and glucocorticoid-induced osteoporosis. Case series suggest a potential link between prolonged use of bisphosphonates and low-energy fracture of subtrochanteric or diaphyseal femur as a consequence of oversuppression of bone resorption. Using health care utilization data, we conducted a propensity score–matched cohort study to examine the incidence rates (IRs) and risk of subtrochanteric or diaphyseal femur fractures among oral bisphosphonate users compared with raloxifene or calcitonin users. A Cox proportional hazards model evaluated the risk of these fractures associated with duration of osteoporosis treatment. A total of 104 subtrochanteric or diaphyseal femur fractures were observed among 33,815 patients. The estimated IR of subtrochanteric or diaphyseal femur fractures per 1000 person-years was 1.46 [95% confidence interval (CI) 1.11–1.88] among the bisphosphonate users and 1.43 (95% CI 1.06–1.89) among raloxifene/calcitonin users. No significant association between bisphosphonate use and subtrochanteric or diaphyseal femur fractures was found [hazard ratio (HR) = 1.03, 95% CI 0.70–1.52] compared with raloxifene/calcitonin. Even with this large study size, we had little precision in estimating the risk of subtrochanteric or diaphyseal femur fractures in patients treated with bisphosphonates for longer than 5 years (HR = 2.02, 95% CI 0.41–10.00). The occurrence of subtrochanteric or diaphyseal femur fracture was rare. There was no evidence of an increased risk of subtrochanteric or diaphyseal femur fractures in bisphosphonate users compared with raloxifene/calcitonin users. However, this study cannot exclude the possibility that long-term bisphosphonate use may increase the risk of these fractures. © 2011 American Society for Bone and Mineral Research.

Osteoporosis: Trials and tribulations

SummaryThis network meta-analysis assessed the efficacy of abaloparatide versus other treatment options to reduce the risk of fractures in women with postmenopausal osteoporosis. The analysis indicates that abaloparatide reduces the risk of fractures in women with postmenopausal osteoporosis versus placebo and compared with other treatment options.IntroductionThis network meta-analysis (NMA) assessed the relative efficacy of abaloparatide versus other treatments to reduce the risk of fractures in women with postmenopausal osteoporosis (PMO).MethodsPubMed®, Embase®, and the Cochrane Central Register of Controlled Trials were searched for randomized controlled trials published before December 20, 2017, that included women with PMO who were eligible to receive interventions for primary or secondary fracture prevention. The NMA was conducted by fracture site (vertebral [VF], nonvertebral [NVF], and wrist), with the relative risk (RR) of fracture versus placebo the main clinical endpoint. The NMA used fixed-effects and random-effects approaches.ResultsA total of 4978 articles were screened, of which 22 were included in the analysis. Compared with other treatments, abaloparatide demonstrated the greatest treatment effect relative to placebo in the VF network (RR = 0.13; 95% credible interval [CrI] 0.04–0.34), the NVF network (RR = 0.50; 95% CrI 0.28–0.85), and the wrist fracture network (RR = 0.39; CrI 0.15–0.90). Treatment ranking showed that abaloparatide had the highest estimated probability of preventing fractures in each of the networks (79% for VF, 70% for NVF, and 53% for wrist fracture) compared with other treatments. Individual networks demonstrated a good level of agreement with direct trial evidence and direct pair-wise comparisons.ConclusionsThis NMA indicates that abaloparatide reduces the RR of VF, NVF, and wrist fracture in women with PMO with or without prior fracture versus placebo, compared with other treatment options. Limitations include that adverse events and drug costs were not considered, and that generalizability is limited to the trial populations and endpoints included in the NMA.

Assessment of Medication Adherence and Factors Contributing to Non-Adherence to Calcium and Vitamin D as Mainstay in Treatment and Prophylaxis of Osteoporosis

Studies on the fracture risk in presarcopenic and sarcopenic patients report contradictory results. The objective was to assess whether presarcopenia and sarcopenia are associated with an increase in fracture risk. We conducted a retrospective study using the UK Biobank cohort and the European Working Group on Sarcopenia in Older People 2 (EWGSOP2) criteria. Muscle strength was evaluated using hand-grip strength (HGS) and muscle mass using the skeletal muscle index (SMI; from bioimpedance analysis). Presarcopenia was defined through the two definitions available in the literature, as low HGS with normal SMI and as normal HGS with low SMI, and sarcopenia as low HGS and low SMI. Fracture events were recorded as "fracture" (location compatible with an osteoporotic origin) and "major osteoporotic fracture" (MOF), as listed in the FRAX tool. Associations were assessed using Cox proportional hazards models, adjusted for sarcopenia and osteoporosis risk factors. Adjusted hazard ratios (HRa ) and their 95% confidence intervals (CI) were reported. A total of 387,025 participants (women 54.4%; median age 58.0 years; interquartile range [IQR] 51.0-63.0 years) were included. At baseline, there were 18,257 (4.7%) presarcopenic participants-subgroup 1 (low HGS only), 7940 (2.1%) presarcopenic participants-subgroup 2 (low SMI only), and 1124 (0.3%) sarcopenic participants. Over a median follow-up of 12.0 years (IQR 11.4-12.6 years), 18,300 (4.7%) participants were diagnosed with at least one incident fracture. Presarcopenic (subgroups 1 and 2) and sarcopenic status were significantly associated with a higher risk of fracture (respectively adjusted HRs: HR = 1.26 [1.19-1.33], HR = 1.20 [1.11-1.30], HR = 1.30 [1.08-1.56]) and with a higher risk of MOF (respectively adjusted HRs: HR = 1.30 [1.21-1.40], HR = 1.19 [1.08-1.72], HR = 1.18 [0.93-1.49]). In a middle-aged population, the fracture and MOF risks were higher in both presarcopenic and sarcopenic participants compared with nonsarcopenic participants. © 2023 The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research (ASBMR).

Literature review. Review updated criteria that categorize patients' bone health for operative and nonoperative patients. Osteoporosis is common in spine patients including those with fragility fractures and in the elective surgery population. Untreated osteoporosis is associated with secondary spine fractures and increased likelihood of osteoporotic bone-related complications after elective surgery. Recently, the definition of osteoporosis is expanded beyond use of bone mineral density (BMD) to also include fracture history and fracture risk. Most spine practitioners are not aware of this definition. Recent clinical guidelines and recommendations for the diagnosis of osteoporosis are reviewed. Included are the use of dual x-ray absorptiometry (DXA), adjuncts such as trabecular bone score and vertebral fracture assessment, and other factors such as comorbidities, fracture history, and opportunistic use of other imaging studies. The use of the clinical diagnosis based on BMD, fracture history, and fracture risk increases the diagnosis of osteoporosis in spine patients. BMD is measured using DXA, which is sensitive and precise, although errors in analysis and interpretation are common. Fracture history is a strong predictor of secondary fracture and poor surgical outcomes. Reducing fracture risk is the goal of medical treatment, but it is rarely performed by spine practitioners. Fracture risk can be stratified into low, high, and very high-risk groups. High and very high-risk patients are candidates for medical management. Other clues to the presence of osteoporosis that should prompt further bone health assessment are based on history, height loss, risk factors, and opportunistic use of plain radiographs, CT, and MRI. Spine practitioners should be aware of newer concepts in the diagnosis of osteoporosis. Utilizing the clinical diagnosis of osteoporosis based on BMD thresholds, fracture history, and fracture risk will identify patients who should be considered for further health assessment and treatment.

Overdiagnosis and Overtreatment of Osteoporosis: A Wolf in Sheep's Clothing.

The primary goal of treatment for post-menopausal osteoporosis (PMO) is reduction in fracture risk. Therefore, clinicians must recommend therapies that are safe and have proven anti-fracture efficacy. Bisphosphonates have long been established as first-line therapy for osteoporosis and several of these drugs significantly reduce osteoporotic fracture risk. However, choosing among different bisphosphonates can represent a difficult clinical decision. This review outlines the pharmacology of various bisphosphonates, discusses how their pharmacological characteristics affect their efficacy, and summarizes clinical safety and efficacy data. Clinical trial data and the opinions of expert bodies suggest that alendronate, risedronate, ibandronate and zoledronic acid all provide fracture protection for patients with PMO. However, there are differences among these agents. For example, all four agents have demonstrated efficacy in preventing vertebral fractures, but only zoledronic acid and risedronate significantly reduce non-vertebral fracture risk in pivotal trials. Moreover, reduction in hip fracture risk has only been established for alendronate, risedronate and zoledronic acid. Current data suggest that ibandronate and zoledronic acid have the most persistent antifracture effect. Bisphosphonates have been associated with a number of side effects, the evidence for which is summarized in this review. The most pertinent of these when choosing a bisphosphonate for a particular patient are the well-documented associations between gastrointestinal adverse events and oral administration, and between acute phase reactions and intravenous administration. Ultimately, selection of a specific bisphosphonate for treatment of PMO should be based on efficacy, risk profile, cost-effectiveness and patient preference.

Improvement in spine bone density and reduction in risk of vertebral fractures during treatment with antiresorptive drugs

Keywords Raloxifene Alkaline Phosphatase Quantitative Ultrasound Speed of Sound Chronic Kidney Disease