JAAOS - 2026-06-15 - Journal Article
The Impact of Glucagon-Like Peptide-1 Receptor Agonists on Fracture Risk in Overweight or Obese, Nondiabetic Patients.
Constantine E, Enthoven L, Kahan R, Pflug EM, Lauder A
Topics
Key Takeaway
GLP-1RA use in nondiabetic overweight/obese patients was associated with a 19% increased odds of fracture within 1 year (OR 1.19, NNH=227), with dramatically higher risk in patients aged 78–88 years (OR 4.99, NNH=24).
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Summary
This retrospective case-control study used the TriNetX database (2015–2022) to assess fracture risk in nondiabetic overweight/obese patients prescribed GLP-1RAs versus matched controls. After propensity matching, GLP-1RA users had a significantly higher fracture rate (3.05% vs. 2.61%, OR 1.19). Subgroup analysis identified the highest risk in patients aged 78–88 years (OR 4.99, NNH=24) and those with BMI ≥40 (OR 1.26, NNH=81).
Key Limitation
The database design precludes differentiation between fragility and traumatic fractures, making it impossible to determine whether the signal reflects bone quality deterioration, increased falls from rapid weight loss, or both.
Original Abstract
INTRODUCTION
Glucagon-like peptide-1 receptor agonists (GLP-1RA) are prescribed for glycemic control and weight reduction. Little is known regarding the impact of GLP-1RAs on bone health in patients without diabetes.
METHODS
This retrospective case-control study was conducted using data from TriNetX database between 2015 and 2022. The primary objective was to assess fracture risk in overweight and obese patients without diabetes following GLP-1RA use. Patients with an ICD-10 diagnosis of overweight or obesity were included. Patients with diabetes or an increased risk of fragility fractures were excluded. An initial query resulted in 1,155,496 patients with 606,364 available for analysis. This cohort was divided into (1) those with GLP-1RA prescriptions (n = 33,220) and (2) those without GLP-1RA prescriptions (n = 593,748). Propensity matching was done for these groups (n = 33,210 each) at the time of prescription. The primary outcome was fracture diagnosis within 1 year of GLP-1RA prescription. Risk and odds ratio (OR) with 95% confidence intervals (CIs) were estimated using multiple logistic regression.
RESULTS
Fracture risk was significantly increased in overweight and obese patients without diabetes who were prescribed a GLP-1RA compared with patients who were not (3.05% vs. 2.61%, number needed to harm [NNH] = 227, OR 1.19, CI [1.09 to 1.31]; risk ratio 1.09 CI [1.04 to 1.14]). Subanalyses based on body mass index (BMI) and age group demonstrated increased fracture risk in the GLP-1RA group in patients with a BMI ≥40 (3.15% vs. 1.91%, NNH = 81, OR 1.26, CI [1.04 to 1.52]) and those older than 67 years, including those aged 68 to 77 years (5.61% vs. 3.65%, NNH = 51, OR 2.25, CI [1.62 to 3.13]) and 78 to 88 years (9.28% vs. 5.10%, NNH = 24, OR 4.99, CI [2.68 to 9.26]).
CONCLUSION
GLP-1RA use was associated with increased fracture risk in nondiabetic patients who were overweight or obese. Subgroup analysis demonstrated that only those with BMI ≥40 and age ≥68 years were found to have a significant increase in fracture risk. Further research is necessary to guide GLP-1RA prescriptions.