Abstract
Objective To describe the protocol for a systematic review and meta-analysis that will evaluate the association between bisphosphonate use and the risk of atypical femoral fractures (AFFs), as well as estimate the incidence of AFFs among adults with osteoporosis. Methods This protocol will follow the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines and the Cochrane Handbook recommendations. Electronic searches will be conducted in PubMed, Embase, and Scopus from database inception to the final search date. Cohort and case-control studies evaluating oral or intravenous bisphosphonates in adults with osteoporosis will be included. Risk of bias will be assessed using the ROBINS-I tool. When appropriate, random-effects meta-analyses will be performed to estimate pooled risk ratios or incidence rate ratios, and single-arm meta-analyses will be used to estimate the incidence of AFFs per 100,000 person-years. Subgroup, sensitivity, and meta-regression analyses will be conducted when feasible. Results This review is expected to provide updated and methodologically robust evidence regarding the risk and incidence of atypical femoral fractures associated with bisphosphonate therapy, while exploring potential sources of heterogeneity across studies. The findings of this systematic review and meta-analysis are expected to support evidence-based clinical decision-making regarding the long-term use of bisphosphonates for osteoporosis and contribute to optimizing the balance between treatment benefits and potential risks.