Tirzepatide Linked to Higher Osteoporosis and Fracture Risk Than Other GLP-1 Drugs | Research

The takeaway

Tirzepatide users had a 44% higher risk of osteoporosis or fragility fractures compared to users of other GLP-1 drugs in a study of nearly 460,000 patients.

44% higher fracture risk
Tirzepatide users had a significantly higher risk of osteoporosis or fragility fractures compared to other GLP-1 agonist users in a propensity-matched real-world study

What the researchers found

In a large real-world study of nearly 460,000 patients, tirzepatide was associated with a 44% higher risk of osteoporosis or fragility fractures compared to other GLP-1 receptor agonists (HR 1.44, 95% CI 1.22–1.69). Tirzepatide users were also 61% more likely to start osteoporosis therapy (HR 1.61, 95% CI 1.22–2.12).

Compared to non-users, tirzepatide showed a 48% higher risk of osteoporosis/fracture (HR 1.48, 95% CI 1.26–1.75), while other GLP-1 agonists showed no significant increase (HR 1.07, 95% CI 1.00–1.15).

This suggests the bone risk may be specific to tirzepatide — possibly related to its dual GLP-1/GIP mechanism or the more rapid and greater weight loss it produces — rather than a class effect shared by all GLP-1 drugs.

Why it matters

Tirzepatide (Mounjaro/Zepbound) produces the most weight loss of any approved GLP-1-class drug. But rapid, significant weight loss can reduce bone density because bone remodeling doesn't keep pace with fat and muscle loss. This study raises an important safety signal: tirzepatide may carry higher osteoporosis and fracture risk than other GLP-1 drugs, which could be particularly concerning for older patients and postmenopausal women.

The numbers in context

n=459,886 eligible · 66,329 matched per group · HR 1.44 vs other GLP-1 RAs · HR 1.48 vs nonusers · HR 1.61 for starting osteoporosis therapy · 14-month follow-up · June 2022–May 2024

How the study worked

Retrospective cohort study using the TriNetX federated research network. Identified 459,886 patients with type 2 diabetes or obesity who started tirzepatide or other GLP-1 agonists between June 2022 and May 2024. Used 1:1 propensity score matching (66,329 per group) to balance baseline characteristics. Primary outcome was composite of new-onset osteoporosis or fragility fracture over 14 months.

Who was studied

459,886 patients with type 2 diabetes or obesity who initiated tirzepatide or other GLP-1 RAs, propensity-matched to 66,329 per group

What this study cannot tell us

This is an observational study — it cannot prove tirzepatide directly causes bone loss, only that there's an association. Residual confounding is possible despite propensity score matching. Tirzepatide users may have higher BMI at baseline (since tirzepatide is often reserved for more severe obesity), which could influence fracture detection. The 14-month follow-up may be too short to capture the full fracture risk. The TriNetX database relies on diagnosis codes, which may have coding variability.

How to read the evidence

This is a large retrospective cohort study with propensity score matching from a major real-world database. The sample size is substantial and the methodology is rigorous for an observational study, though it cannot establish causation. Evidence strength is moderate-to-high.

When this study was published

Published in 2025 using data from June 2022–May 2024, this is one of the first large-scale studies to examine tirzepatide's bone safety. The finding is timely as tirzepatide prescriptions are rapidly increasing.

The bigger picture

As GLP-1 and dual-agonist drugs produce increasingly dramatic weight loss, the downstream effects on bone health are becoming a major concern. Bone density depends partly on mechanical loading from body weight, and rapid weight loss removes that stimulus. If tirzepatide's bone risk is confirmed in prospective studies, bone density monitoring and protective strategies (resistance exercise, calcium/vitamin D, possibly bone-sparing medications) may need to become standard alongside weight loss drug prescriptions.

Questions still open

Is tirzepatide's higher bone risk driven by its greater weight loss, its GIP receptor activity, or both?
Can resistance exercise and nutritional interventions mitigate the bone loss associated with tirzepatide?
Will retatrutide (a triple agonist producing even greater weight loss) show an even higher fracture risk?

Common questions

Does tirzepatide cause bone loss?

This study found an association between tirzepatide use and higher rates of osteoporosis and fractures compared to other GLP-1 drugs, but it cannot prove causation. The increased risk may be related to tirzepatide's greater weight loss effect — when you lose weight quickly, bones can lose density because they no longer carry as much load. Whether the GIP receptor component of tirzepatide plays a role is unknown.

Should I worry about my bones if I'm taking Mounjaro or Zepbound?

This is a signal worth discussing with your doctor, especially if you're at higher risk for osteoporosis (postmenopausal, family history, small frame). Practical steps include regular weight-bearing exercise, adequate calcium and vitamin D intake, and potentially a bone density scan. Don't stop your medication without consulting your doctor — the metabolic benefits may outweigh the bone risk, but monitoring is important.

Read the original research

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

View on PubMed ↗Publisher’s paper ↗

Citation

Hsu, Yung-Han; Liang, Yu-Cheng; Chan, Ka-Chon; Chou, Yu-Hsuan; Wu, Hung-Tsung; Ou, Horng-Yih. (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. https://doi.org/10.1016/j.diabres.2025.112995