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 Recom...