Antiresorptive therapies reduce fracture risk; however, long-term bone turnover inhibition may raise concerns about rare, but serious, skeletal adverse events-atypical femoral fracture (AFF) and osteonecrosis of the jaw (ONJ). Denosumab, a fully human monoclonal antibody against RANKL, has demonstrated sustained low vertebral and nonvertebral fracture rates with low skeletal adverse event rates in the 3-year FREEDOM trial and its 7-year Extension (in which all subjects received open-label denosumab). In this analysis, we aimed to estimate fractures prevented relative to skeletal adverse events observed with 10 years of denosumab therapy. We modeled a hypothetical placebo group using the virtual-twin method, thereby allowing calculation of fractures prevented with denosumab treatment (relative to the virtual-placebo group) in the context of AFF or ONJ events observed in the long-term denosumab group. Estimated virtual-placebo and observed long-term denosumab exposure-adjusted fracture rates per 100,000 subject-years were calculated for fractures classified as clinical (3180 and 1777, respectively), major osteoporotic (2699 and 1525), vertebral (1879 and 901), and nonvertebral (2924 and 1528), and compared with observed AFF and ONJ in the long-term denosumab group (5 and 35 per 100,000 subject-years, respectively). The skeletal benefit/risk ratio (fractures prevented per adverse event observed) for clinical fractures was 281 (AFF) and 40 (ONJ). Based on this model, denosumab treatment for up to 10 years has a favorable skeletal benefit/risk profile when comparing fractures prevented per skeletal adverse event observed. Clinical trial registration: NCT00089791.

中文翻译：

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长期狄诺塞麦治疗的有利骨骼益处/风险：相对于观察到的骨骼安全事件预防骨折的虚拟孪生分析

抗吸收疗法降低骨折风险；然而，长期的骨转换抑制可能会引起人们对罕见但严重的骨骼不良事件——非典型股骨骨折 (AFF) 和颌骨坏死 (ONJ) 的担忧。狄诺塞麦是一种针对 RANKL 的全人源单克隆抗体，在 3 年 FREEDOM 试验及其 7 年扩展试验（其中所有受试者接受开放标签狄诺塞麦）中显示出持续的低椎体和非椎体骨折率和低骨骼不良事件发生率。在这项分析中，我们旨在评估相对于 10 年狄诺塞麦治疗观察到的骨骼不良事件预防的骨折。我们使用虚拟双胞胎方法模拟了一个假设的安慰剂组，从而允许在长期狄诺塞麦组中观察到的 AFF 或 ONJ 事件的背景下计算狄诺塞麦治疗预防的骨折（相对于虚拟安慰剂组）。对于分类为临床骨折（分别为 3180 和 1777）、严重骨质疏松（2699 和 1525）、椎体骨折（1879 和 901），计算了每 100,000 个受试者年的估计虚拟安慰剂和观察到的长期狄诺塞麦暴露调整骨折率，和非椎体（2924 和 1528），并与长期狄诺塞麦组中观察到的 AFF 和 ONJ 进行比较（分别为每 100,000 个受试者年 5 和 35）。临床骨折的骨骼获益/风险比（根据观察到的不良事件预防的骨折）为 281 (AFF) 和 40 (ONJ)。基于这个模型，在比较每个观察到的骨骼不良事件预防的骨折时，狄诺塞麦治疗长达 10 年具有有利的骨骼益处/风险特征。临床试验注册：NCT00089791。