GLP-1 Receptor Agonists Linked to Lower Fracture Risk in T2D

Initiation of a glucagon-like peptide-1 receptor agonist (GLP-1 RA) was associated with a significantly lower 3-year risk of fragility fracture compared with initiation of a dipeptidyl peptidase-4 inhibitor (DPP-4i) among adults with type 2 diabetes (T2D), according to a comparative effectiveness study published in JAMA Network Open.¹ The findings, drawn from a target trial emulation of the TriNetX Research Network, add to growing evidence that GLP-1 RAs may have favorable effects on bone health, although prior studies have reported mixed findings. The results also suggest a potential skeletal benefit that may be independent of changes in body weight or glycemic control.

“Importantly, to our knowledge, this study used the largest dataset to date to evaluate GLP-1 RAs and fracture risk,” wrote the researchers of the study. “As GLP-1 RA use expands, the favorable skeletal associations observed here warrant further investigation, including in patients with osteopenia or early osteoporosis.”

Researchers analyzed deidentified electronic health record data from January 2015 through December 2022, identifying adults aged 50 to 90 years with T2D who newly initiated either a GLP-1 RA or a DPP-4i, chosen as an active comparator because it is commonly used as a second-line glucose-lowering therapy. After propensity score matching on 40 baseline covariates, the analytic cohort included 133,606 patients (66,803 per group; mean age, 63.2 vs 63.8 years). Patients with osteoporosis, osteopenia, vitamin D deficiency, advanced chronic kidney disease, and prior fragility fracture were excluded, and the matched cohorts were well balanced across demographic and clinical characteristics.

Fracture Risk Findings

Over 3 years of follow-up, GLP-1 RA initiation was associated with a lower risk of fragility fracture compared with DPP-4i initiation (HR, 0.79; 95% CI, 0.76-0.83), corresponding to an absolute risk reduction of 0.79% (95% CI, 0.60%-0.99%) and a number needed to treat of 126 (95% CI, 101-168). The strongest associations were observed for vertebral (HR, 0.68; 95% CI, 0.63-0.73) and hip or femur (HR, 0.70; 95% CI, 0.63-0.79) fractures, while no significant association was observed for distal radius, ulna, or proximal humerus fractures.

Subgroup findings were generally consistent across age, sex, and frailty strata. However, the association appeared to weaken over time, with no statistically significant difference observed during the third year of follow-up (HR, 0.94; 95% CI, 0.86-1.02).

In an additional analysis that included GLP-1 RA users without T2D, the inverse association with fragility fracture was observed only among individuals with T2D (HR, 0.91; 95% CI, 0.88-0.95), whereas GLP-1 RA use among those without T2D was associated with a modestly higher fracture risk (HR, 1.13; interaction P < .001). Mediation analyses further indicated that the observed association was not fully explained by changes in body mass index or hemoglobin A_1C.

However, the researchers noted limitations. Because this was a retrospective observational target trial emulation using electronic health record data, residual confounding and outcome misclassification were possible despite extensive propensity score matching. They call for larger prospective and mechanistic studies to clarify the durability and biological basis of the observed association.

“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_1C,” wrote the researchers. “Prospective studies are needed to establish causality and define long-term skeletal effects.”

Managed Care Implications

For managed care organizations, these findings add a new dimension to formulary and utilization management discussions around GLP-1 RAs. If confirmed in prospective trials, a fracture-risk benefit could offset downstream costs associated with hip and vertebral fractures, which carry substantial morbidity, mortality, and post–acute care spending. However, payers should note that the protective signal was specific to patients with T2D and did not extend to GLP-1 RA use for other indications, underscoring the importance of indication-specific utilization criteria and continued monitoring as evidence on long-term skeletal effects matures.

A recent narrative review of GLP-1 RAs and bone health similarly concluded that the overall evidence remains inconclusive, particularly in people using these agents.² Although preclinical studies suggest GLP-1 RAs may promote bone formation, clinical studies have generally shown neutral or only modest effects on bone mineral density and bone turnover markers, with fracture risk not appearing to increase at approved doses.

References

1. Hamad CD, Wiener J, Golzar A, et al. Glucagon-like peptide-1 receptor agonists and fragility fracture risk in type 2 diabetes. JAMA Netw Open. 2026;9(7):e2625141. doi:10.1001/jamanetworkopen.2026.25141
2. Karam L, Mabilleau G, Paccou J. Effects of glucagon-like peptide-1 receptor agonists on bone health in people living with obesity. Osteoporos Int. 2025;36(11):2115-2126. doi:10.1007/s00198-025-07664-1