Do glucagon-like peptide-1 receptor agonists affect risk of fragility fractures?

Obesity, type 2 diabetes and weight loss are associated with increased fragility fracture risk. Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) are a widely prescribed class of drugs, but their effects on skeletal outcomes remain uncertain.To examine this issue, US researchers evaluated the association between initiation of GLP-1 RA versus dipeptidyl peptidase-4 inhibitor (DPP-4i) therapy and fragility fracture risk at three years among adults with type 2 diabetes. GLP-1 RAs in the study included semaglutide, dulaglutide, tirzepatide, liraglutide, exenatide and lixisenatide, while DPP-4 inhibitors in the active comparator group included sitagliptin, linagliptin, saxagliptin and alogliptin.The comparative effectiveness study, using retrospective target trial emulation, examined data from a multicentre US electronic health record database (TriNetX Research Network) from 2015–2022. Adults 50–90 years of age with type 2 diabetes who were newly started on a GLP-1 RA or DPP-4i were followed for up to three years. A separate cohort stratified by type 2 diabetes status was also analyzed. The primary outcome was incident fragility fracture, defined as a fracture after low-energy trauma (e.g., fall from standing height). Cohorts were propensity score matched. Baseline use of other glucose-lowering agents (metformin, sodium-glucose cotransporter 2 inhibitors, thiazolidinediones, insulin, sulfonylureas) were adjusted for in propensity score models. Time-varying mediation analyses were used to evaluate the contribution of changes in body mass index and glycated hemoglobin (A1C).Key results:After matching, 133,606 patients (66,803 per group) were included. Initiation of GLP-1 RA was associated with lower fragility fracture risk compared with DPP-4i initiation (hazard ratio [HR], 0.79 [95%CI, 0.76–0.83]; absolute risk reduction, 0.79% [95%CI, 0.60%–0.99%]; number needed to treat, 126 [95%CI, 101–168]). The largest risk reductions were observed with vertebral fractures (HR, 0.68 [95%CI, 0.63–0.73]) and hip or femur fractures (HR, 0.70 [95%CI, 0.63–0.79]). In a sensitivity analysis stratified by diabetes status, fracture risk reduction was observed among patients with type 2 diabetes (HR, 0.91 [95%CI, 0.88–0.95]), but not among those without type 2 diabetes (HR, 1.13 [95%CI, 1.04–1.23]; interaction P < .001). Mediation analyses showed that the direct association between GLP-1 RA use and lower fracture risk persisted at three years (HR, 0.81 [95%CI, 0.76–0.86]).This target trial emulation study of adults with type 2 diabetes found that starting a GLP-1 RA was associated with a statistically significant 21% lower three-year risk of fragility fracture compared with initiation of a DPP-4i. Results were independent of changes in body mass index and A1C, which the authors comment is consistent with a potential direct skeletal effect of GLP-1 RA therapy. The authors note that although the absolute risk reduction at three years was modest (0.79%), this magnitude is clinically relevant given the substantial morbidity and mortality associated with hip and vertebral fractures. Even small absolute reductions may translate into meaningful population level fracture prevention. The investigators recommend prospective studies to establish causality and define long-term skeletal effects of GLP-1 RAs. Reference:Hamad CD, Wiener J, Golzar A, et al. Glucagon-like peptide-1 receptor agonists and fragility fracture risk in type 2 diabetes. JAMA Network Open 2026;9(7):e2625141. (accessed July 28, 2026).

Do glucagon-like peptide-1 receptor agonists affect risk of fragility fractures?

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