Osteoporosis and fragility fractures remain major complications in patients with diabetes and obesity, and against the backdrop of a rapid rise in tirzepatide prescriptions globally, the long-term musculoskeletal effects of the medication have become clinically important.
In this large retrospective cohort, the TriNetX network provided data on 459,886 eligible patients with type 2 diabetes or obesity who initiated tirzepatide or other GLP-1 RAs between June 2022 and May 2024. To reduce baseline differences, the researchers conducted 1:1 propensity score matching, yielding 66,329 participants per group.
The primary outcome was a composite of new-onset osteoporosis or fragility fractures within 14 months of treatment initiation. Secondary outcomes included the initiation of osteoporosis therapy. Comparative analyses were performed between tirzepatide users, users of other GLP-1 RAs, and nonusers.
Results
After matching, users of tirzepatide had a significantly higher risk for the primary composite outcome versus users of other GLP-1 RAs, with a hazard ratio of 1.44 (95% CI: 1.22–1.69).
The risk of the initiation of osteoporosis treatment was also higher in the group treated with tirzepatide, with an HR of 1.61 (95% CI: 1.22–2.12).
Compared with nonusers, users of tirzepatide had an even stronger association, at an HR of 1.48 (95% CI: 1.26–1.75) for developing osteoporosis or fragility fractures.
Comparing the other GLP-1 RAs to nonusers, however, revealed a very minimal increased risk overall: HR 1.07; 95% CI: 1.00–1.15, thereby suggesting that the associated bone risk appears more specific to tirzepatide rather than the entire drug class.
In this large, real-world cohort study, initiation of tirzepatide was associated with a significantly higher risk of osteoporosis or fragility fractures compared with other GLP-1 receptor agonists. These results strengthen the evidence that tirzepatide, despite its metabolic benefits, may require additional safety surveillance focused on skeletal outcomes.
Reference:
Hsu, Y.-H., Liang, Y.-C., Chan, K.-C., Chou, Y.-H., Wu, H.-T., & Ou, H.-Y. (2025). Association of tirzepatide use with risk of osteoporosis compared with other GLP-1 receptor agonists: A retrospective cohort study using the TriNetX database. Diabetes Research and Clinical Practice, 230(112995), 112995.
https://doi.org/10.1016/j.diabres.2025.112995
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