Project Summary Use of bisphosphonate (BP) medications for the prevention of fractures is declining, partially due to patient and provider fears about the occurrence of atypical femur fractures (AFF), which are clearly associated with long- term bisphosphonate use. Many individuals are choosing to not use these medications at all rather than risk having this rare outcome. This decision may leave individuals at high risk of morbidity and mortality. Balancing the risk of typical osteoporosis-related fractures, such as hip or vertebral fractures, with the risk of the much rarer AFF, is an important component of decision-making by physicians and patients about medication use. Thus, the RFA issued by NIA and NIAMS solicited applications for secondary analyses of existing datasets to provide evidence about appropriate strategies for long-term osteoporosis therapies, including drug holidays, and to better understand their risks and benefits (RFA-AG-22-018). Our parent grant will address these issues by combining individual-level data from three large, population-based cohort studies with radiographically verified AFFs, comprehensive longitudinal medication exposure, data harmonized definitions of other covariables, and centrally coordinated statistical programming; this project focuses on 1) examining the risks of long-term use of BP for the prevention of AFF by determining the independent effects of BP treatment and drug holidays on AFF risk, including the potential interplay between pre-holiday duration of treatment and duration of holiday and 2) developing and validating predictive models incorporating patterns of long-term BP treatment, drug holidays and clinical risk factors, to comprehensively model the expected fracture protection and potential harms for individual patients and evaluate the group-level balance between AFF risk and osteoporosis-related fracture prevention. Three other projects with diverse sets of aims and methodologies using combinations of claims and electronic health records data were also funded to advance the research program. This administrative supplement is aimed to support the coordination and collaboration of a consortium consisting of the four R01-funded projects that are leveraging existing large databases and cohorts to better understand the risks and benefits of long-term osteoporosis therapy and drug holiday.