Benefits and Harms of Long-term Osteoporosis Pharmacotherapy: Impact of Treatment Length, Type, Switching, and Holidays

项目摘要 60%的老年人开始骨质疏松症药物治疗（ODT）与口服双膦酸盐（BP）， 长期暴露（3年或以上，依从性≥ 80%）。虽然至少有6到12个月的 需要BP治疗来降低骨折风险，BP延长了半衰期，可以长期提供益处 停药后。临床试验已经发现，停止服用避孕药的女性骨折风险几乎没有差异。 与3到5年后的持续BP相比。此外，长期使用BP与不良事件有关， 非典型股骨骨折（AFF）。因此，指南建议对大多数人来说， 使用BP 3 - 5年后的患者。骨折风险高的患者建议继续BP或转换 另一种ODT，如狄诺塞单抗、特立帕罗、阿巴帕林或雷洛昔芬。知识方面的几个关键空白 存在长期BP使用的风险和益处，药物假期，ODT切换临床结果， 不良事件，特别是在试验中代表性有限的人群中，如男性和疗养院（NH） 居民该提案有三个具体目标：（1）在至少有3岁的社区居住老年人中， 年的BP使用，检查BP药物假期和ODT转换对骨折，骨折后遗症的影响 (e.g.,死亡，进入NH）和AFF。(2)在至少有3年ODT的NH居民中，比较 中断与继续ODT对骨折/后遗症和以患者为中心的结局的影响（例如， 功能，疼痛）;和（3）开发和验证临床预测算法，为骨质疏松性骨折和AFF 指导临床医生决定是否启动休药期。我们的中心假设是， 长期ODT策略的效果将取决于治疗长度、类型和患者特征。 我们提出的严格研究将使用跨国关联的管理和临床数据集。研究 人口将包括美国和加拿大安大略66岁或以上的老年人，他们至少有 3年的长期ODT。本研究的数据将来自1）关联的全民医疗保健和药物 安大略所有年龄≥65岁的人（社区居民和NH）的索赔数据; 2）美国医疗保险索赔 社区居住的老年人;以及3）多达10，000个NHS的电子健康记录（EHR）数据 医疗保险索赔。我们将为骨质疏松症药物索赔实施经过验证的数据清理算法 以及新颖的滚动窗口方法来捕获长期ODT。时变倾向评分方法， 新的因果推理方法，如目标试验仿真将被采用。这个项目将产生关键的， 在老年人中指导长期ODT、预防骨折和尽量减少AFF的可推广证据。这 研究将直接解决RFA-AG-22-018，骨质疏松症药物治疗的适当使用 预防骨折的途径讲习班小组建议1和4以及战略目标 国家老龄化研究所的C。此外，该项目将建立国际数据伙伴关系， 利用EHR和通用医疗保健数据回答有关ODT的新兴研究问题。

Project Summary Sixty percent of older adults who start osteoporosis drug therapy (ODT) with an oral bisphosphonate (BP) have long-term exposure (3 or more years with 80% or higher adherence). Although a minimum of 6 to 12 months of BP treatment is required to reduce fracture risk, BPs have extended half-lives and can provide benefits long after discontinuation. Clinical trials have identified little difference in fracture risk for women who stopped versus continued BP after 3 to 5 years. Further, prolonged BP use has been linked to adverse events like atypical femoral fracture (AFF). Thus, guidelines recommend a drug holiday (pause in therapy) for most patients after 3 to 5 years of BP use. Patients at high fracture risk are recommended to continue BP or switch to another ODT, like denosumab, teriparatide, abaloparatide, or raloxifene. Several critical gaps in knowledge exist about the risks and benefits of long-term BP use, drug holidays, ODT switching on clinical outcomes and adverse events, particularly in groups with limited representation in trials like men and nursing home (NH) residents. This proposal has three specific aims: (1) Among community-dwelling older adults with at least 3 years of BP use, examine the effects of BP drug holidays and ODT switching on fractures, fracture sequelae (e.g., death, entry into NH), and AFF. (2) Among NH residents with at least 3 years of ODT, compare the effects of discontinuing versus continuing ODT on fractures/sequelae and patient-centered outcomes (e.g., functioning, pain); and (3) Develop and validate clinical prediction algorithms for osteoporotic fracture and AFF to guide clinicians making decisions on whether to initiate a drug holiday. Our central hypothesis is that the effects of long-term ODT strategies will be dependent on treatment length, type, and patient characteristics. The rigorous studies we propose will use multinational linked administrative and clinical datasets. The study population will comprise older adults aged 66 years or older in the US and Ontario, Canada who have at least 3 years of long-term ODT. Data for this study will come from 1) Linked, universal healthcare and medication claims data for all people (community-dwelling and NH) aged ≥65 years in Ontario; 2) U.S. Medicare claims on community-dwelling older adults; and 3) Electronic health record (EHR) data for up to 10,000 NHs linked to Medicare claims. We will implement a validated data cleaning algorithm for osteoporosis medication claims and novel rolling window method to capture long-term ODT. Time-varying propensity score approaches and novel causal inference methods like target trial emulation will be employed. This project will generate critical, generalizable evidence to guide long-term ODT, prevent fractures, and minimize AFF among older adults. This research will directly address RFA-AG-22-018, the Appropriate Use of Drug Therapies for Osteoporotic Fracture Prevention Pathways to Prevention Workshop Panel Recommendations 1 and 4, and Strategic Goal C of the National Institute on Aging. Additionally, the project will create an international data partnership to leverage EHR and universal healthcare data to answer emerging research questions on ODT.