Atypical Femoral Fractures: A Population-Based Study of Risk Factors and Relationship to Bisphosphonate Exposure and Discontinuation

 描述(由申请人提供)：骨折是骨质疏松症的一种常见且使人虚弱的后果，双膦酸盐(BPS)是世界范围内的一线药物治疗。不幸的是，从观察性研究中积累的证据表明，BP的使用与放射学上不同的非典型股骨骨折(AFF)的发展之间存在关系。尽管疑似或确诊AFF的总数相当少，但越来越多的患者和临床医生担心使用BPS应考虑AFF的风险。事实上，尽管人口老龄化，但自2007年以来，BP的使用量下降了三分之一，这可能反映了对感知到的风险与好处的不确定性。具体地说，关于AFF的总体发病率及其与BP使用的关系存在相互矛盾的证据，报告的相对风险存在巨大差异(从1到130以上)就是明证。既然已经建立了具体的病例定义和客观的放射学标准，未来的临床研究必须包括对疑似病例的专家放射学审查，以便只纳入确诊的AFF。不确定的关键领域包括与BP剂量和治疗持续时间的关系，以及重要的是BP治疗停止后风险的解决。其他内容 AFF的潜在危险因素，包括某些医疗条件和药物使用，无论是单独或与BP联合使用，都是很差的研究，但可能在临床上很重要，并允许更合理的治疗决定。因此，我们建议进行一项纵向研究，使用全面的丹麦国家医疗保健数据，包括自1995年以来的完整药房记录，以及收集和审查2010-14年间所有丹麦转子下和股骨干骨折的数字X光片。这项研究将填补我们对AFF知识的重大空白 目的：1)根据年龄、性别和双膦酸盐使用的不同阶层描述经放射检查确诊的AFF的人群发病率；2)根据使用时间和累积剂量确定双膦酸盐作为AFF风险因素的独立作用，并确定其他因素，如骨质疏松的严重程度、合并疾病和其他药物的使用等是否与AFF相关；3)确定双膦酸盐停药后AFF风险是否下降，并确定影响停药后AFF风险的患者和治疗特征。这项拟议的研究将为临床医生和患者提供有关AFF发生率和危险因素的重要信息，允许对风险和益处进行循证比较，并将对BPS在临床实践中的使用产生重大影响。

 DESCRIPTION (provided by applicant): Fractures are a common and debilitating consequence of osteoporosis, and bisphosphonates (BPs) are the first-line pharmacologic treatment worldwide. Unfortunately, accumulating evidence from observational studies points towards a relationship between BP use and the development of radiographically distinct atypical femoral fractures (AFF). Although the total number of suspected or confirmed AFFs is quite small, there is increasing patient and clinician concern that the use of BPs should account for AFF risk. In fact, despite the aging population the use of BPs since has declined by a third since 2007, likely reflecting uncertainty about the perceived risks vs. benefits. Specifically, there is conflicting evidence about the overall incidence of AFF and its relationship to BP use as evidenced by the huge variability in the reported relative risks (ranging from 1 to over 130). Now that a specific case definition and objective radiographic criteria have been established, future clinical studies must include expert radiograph review of suspected cases so that only confirmed AFF are included. Critical areas of uncertainty include relationships with BP dosing and duration of treatment, and importantly, resolution of risk after discontinuation of BP treatment. Additional potential risk factors for AFF, including certain medical conditions and medication use either alone or in combination with BPs, are poorly studies but might be clinically important and allow more rational treatment decisions. We therefore propose a longitudinal study using comprehensive Danish national health care data, including complete pharmacy records dating back to 1995, plus collection and review of digital radiographs of all Danish subtrochanteric and femoral shaft fractures from 2010-14. This study will fill significant gaps in our knowledge of AFF incidence and key risk factors by addressing 3 clinically important aims:1) To describe the population-based rates of radiographically confirmed AFF according to strata defined by age, gender and bisphosphonate use, 2) To determine the independent effect of bisphosphonate use as a risk factor for AFF by duration of use and cumulative dose, and to determine if other factors, such as severity of osteoporosis, co-morbid conditions and use of other medications, are associated with AFF, and 3) To determine if AFF risk declines after discontinuation of bisphosphonates, and to determine patient and treatment characteristics that influence AFF risk after discontinuation. The proposed study will provide clinicians and patients with important information about AFF incidence and risk factors, allowing an evidence-based comparison of both risks and benefits, and will have a substantial impact on the use of BPs in clinical practice.