GLP-1 Receptor Agonists May Reduce Fragility Fracture Risk: JAMA
Findings from a new study published in JAMA suggest that GLP-1 receptor agonists (GLP-1 RAs) may lower the risk of fragility fractures through mechanisms beyond their effects on weight loss and glycemic control. However, prospective studies are needed to establish a causal relationship and clarify their long-term effects on skeletal health. The study was conducted by Christopher D. and colleagues.
In order to assess the long-term risks of developing fractures due to low-energy trauma associated with GLP-1 RAs vs DPP-4i treatments, data have been retrieved from the TriNetX Research Network for the period ranging from January 1, 2015, to December 31, 2022. The database has been queried on January 26, 2026, to construct a line-level analysis database including adults ages between 50 and 90 with T2D who started treatment with either one of the two drugs.
Follow-up of patients was up to 3 years or until an event of fragility fracture, loss of follow-up, or death. Matching of cohorts based on propensity scores has been performed in order to control for demographic factors and clinical comorbidities at baseline. In addition, mediation analysis for time-varying exposures was performed to disentangle pharmacologic actions of GLP-1 RAs from those related to BMI and HbA1C reduction.
Key findings:
- In total, 133 606 patients were included (66 803 per group; GLP-1 RA vs DPP-4i; mean (SD) age was 63.2 (8.1) years compared with 63.8 (8.5) years; male, 35 195 [52.7%] vs 36 098 [54.0%]).
- Treatment initiation with a GLP-1 RA was associated with a significant reduction of the fragility fracture risk at 3 years by 21% compared to patients treated with DPP-4i (hazard ratio [HR] 0.79; 95% confidence interval [CI] 0.76-0.83; absolute risk reduction 0.79%; number needed to treat 126).
- The largest reduction was found for the vertebral fractures (HR 0.68; 95% CI 0.63-0.73) and fractures of the hip or femur (HR 0.70; 95% CI, 0.63-0.79).
- There was a significant reduction of the fracture risk in people with type 2 diabetes (T2D) (HR 0.91; 95% CI 0.88-0.95) whereas no reduction was found in people without T2D (HR 1.13; 95% CI 1.04-1.23; interaction P < .001).
- Mediation analysis confirmed that as adjusted for body mass index and changes in HbA1C, GLP-1 RA was producing an independent protective effect on bones (HR 0.81; 95% CI 0.76-0.86).
In summary, this emulation of a target trial among adults with T2D showed that a greater incidence of fragility fractures within 3 years was seen in patients initiating DPP-4i therapy than those initiating GLP-1 RA therapy, independently of fluctuations in body mass index and hemoglobin A1c. This provides evidence to support clinicians caring for elderly diabetic patients because GLP-1 RAs provide protection from osteoporotic fractures despite any weight reduction due to therapy.
Reference:
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
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