GLP-1 receptor agonists and the risk of fragility fractures in older adults with type 2 diabetes

Abstract Background GLP-1RAs are increasingly prescribed to older adults with type 2 diabetes for their metabolic and cardiovascular benefits, but their effects on bone health in this high-risk population are not well established. The aim of this study was to assess the risk of fragility fractures associated with glucagon-like peptide 1 receptor agonist (GLP-1RA) therapy compared to sodium-glucose cotransporter-2 inhibitors or dipeptidyl peptidase-4 inhibitors in older adults with type 2 diabetes. Methods We conducted a population-based retrospective new-user cohort study using the nationwide Clalit Health Services database. Participants included people with type 2 diabetes aged 65 years or older who initiated GLP-1RA therapy or comparator drugs during 2018–2022. The primary outcome was first fragility fracture. Follow-up continued until fracture occurrence, death, or 31 March 2024. An intention-to-treat approach was used. Baseline characteristics were balanced using inverse probability of treatment weighting based on propensity scores. Hazard ratios were estimated using multivariate survival analysis accounting for the competing risk of death. Results The study included 46,177 participants: 11,257 GLP-1RA users and 34,920 comparator drug users. During a median follow-up of 34.7 months, 4,086 (8.8%) individuals experienced a fragility fracture and 4,595 (10.0%) died. In the propensity score-weighted model adjusted for baseline characteristics and competing risk of death new users of GLP-1RAs had an 11% increased fracture risk compared to the comparator group (HR 1.11, 95% CI 1.01–1.21). Conclusion Initiating GLP-1RA therapy was associated with a modestly increased risk of fragility fractures in older adults with type 2 diabetes. These findings may inform clinical decisions by balancing clinical benefits against potential skeletal risks in this vulnerable population.