{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,30]],"date-time":"2026-10-30T15:16:58Z","timestamp":1793373418368,"version":"4.5.0"},"reference-count":50,"publisher":"American Medical Association (AMA)","issue":"7","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["JAMA Netw Open"],"abstract":"\n Importance<\/jats:title>\n Obesity, type 2 diabetes (T2D), and weight loss are associated with increased fragility fracture risk. Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) are widely prescribed, yet their effects on skeletal outcomes remain uncertain.<\/jats:p>\n <\/jats:sec>\n \n Objective<\/jats:title>\n To evaluate the association between GLP-1 RA initiation and 3-year fragility fracture risk compared with dipeptidyl peptidase-4 inhibitor (DPP-4i) initiation among adults with T2D.<\/jats:p>\n <\/jats:sec>\n \n Design, Setting, and Participants<\/jats:title>\n This comparative effectiveness study using retrospective target trial emulation examined data from the TriNetX Research Network (January 1, 2015, to December 31, 2022), a multicenter US electronic health record database. Adults aged 50 to 90 years with T2D who newly initiated a GLP-1 RA or DPP-4i were followed up for up to 3 years. A separate cohort stratified by T2D status was also analyzed. The database was queried on January 26, 2026, to generate a line-level analytic dataset.<\/jats:p>\n <\/jats:sec>\n \n Exposures<\/jats:title>\n Initiation of GLP-1 RAs vs DPP-4is.<\/jats:p>\n <\/jats:sec>\n \n Main Outcomes and Measures<\/jats:title>\n \n The primary outcome was incident fragility fracture, defined as fractures after low-energy trauma (eg, fall from standing height). Cohorts were propensity score matched. Time-varying mediation analyses were used to evaluate the contribution of changes in body mass index and hemoglobin A\n 1c<\/jats:sub>\n .\n <\/jats:p>\n <\/jats:sec>\n \n Results<\/jats:title>\n \n After matching, 133\u202f606 patients (66\u202f803 per group; GLP-1 RA vs DPP-4i: mean [SD] age 63.2 [8.1] vs 63.8 [8.5] years; 35 195 [52.7%] vs 36 098 [54.0%] male) 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 (HR, 0.68 [95% CI, 0.63-0.73]) and hip or femur (HR, 0.70 [95% CI, 0.63-0.79]) fractures. In a sensitivity analysis stratified by diabetes status, fracture risk reduction was observed among patients with T2D (HR, 0.91 [95% CI, 0.88-0.95]) but not among those without T2D (HR, 1.13 [95% CI, 1.04-1.23]; interaction\n P<\/jats:italic>\n \u2009&amp;lt;\u2009.001). Mediation analyses showed that the direct association between GLP-1 RA use and lower fracture risk persisted (HR, 0.81 [95% CI, 0.76-0.86]).\n <\/jats:p>\n <\/jats:sec>\n \n Conclusions and Relevance<\/jats:title>\n \n This target trial emulation study of adults with T2D found that initiation of a GLP-1 RA was associated with lower 3-year fragility fracture risk compared with initiation of a DPP-4i, independent of changes in body mass index and hemoglobin A\n 1c<\/jats:sub>\n . Prospective studies are needed to establish causality and define long-term skeletal effects.\n <\/jats:p>\n <\/jats:sec>","DOI":"10.1001\/jamanetworkopen.2026.25141","type":"journal-article","created":{"date-parts":[[2026,7,24]],"date-time":"2026-07-24T15:30:17Z","timestamp":1784907017000},"page":"e2625141","source":"Crossref","is-referenced-by-count":4,"title":["Glucagon-Like Peptide-1 Receptor Agonists and Fragility Fracture Risk in Type 2 Diabetes"],"prefix":"10.1001","volume":"9","author":[{"given":"Christopher D.","family":"Hamad","sequence":"first","affiliation":[{"name":"Department of Orthopaedic Surgery, University of California, Los Angeles"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Joshua","family":"Wiener","sequence":"additional","affiliation":[{"name":"Department of Orthopaedic Surgery, University of California, Los Angeles"},{"name":"Case Western Reserve University School of Medicine, Cleveland, Ohio"},{"name":"Department of Population and 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