The effect of glucagon-like peptide-1 receptor agonists on bone metabolism: A systematic review and meta-analysis of randomized placebo-controlled trials of predominantly first-generation agents
- Design
- Meta-analysis
- Drugs
- Semaglutide, Liraglutide, Dulaglutide, Exenatide, Tirzepatide
- Assessment
- Not yet reviewed by a person · added Nov 8, 2026
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Abstract
[BACKGROUND] Glucagon-like peptide-1 receptor agonists (GLP-1RAs) improve cardiometabolic outcomes, but their isolated effects on human bone remodeling remain uncertain because prior syntheses pooled heterogeneous study designs and active antidiabetic comparators. This systematic review and meta-analysis quantified the effects of GLP-1RAs versus placebo on densitometric, biochemical, and inflammatory markers of bone metabolism in randomized controlled trials (RCTs). [METHODS] Scopus, Web of Science, Embase, and PubMed/MEDLINE were searched from inception through May 12, 2026 for randomized placebo-controlled trials of GLP-1RAs or dual incretin agonists administered for 12 to 52 weeks. Eleven trials provided compatible data for random-effects meta-analysis and one additional trial was synthesized narratively, comprising 11 trials of first-generation agents (exenatide, dulaglutide, liraglutide) and one trial of second-generation semaglutide (1.0 mg/week), with zero eligible placebo-controlled trials identified for semaglutide 2.4 mg/week or tirzepatide. Weighted mean differences (WMDs) with 95% confidence intervals (CIs) were calculated for dual-energy X-ray absorptiometry (DXA) bone mineral density (BMD), bone turnover markers, and high-sensitivity C-reactive protein (hs-CRP), and evidence certainty was rated using GRADE. [RESULTS] Compared with placebo, GLP-1RA treatment reduced lumbar spine BMD (WMD: -0.02 g/cm2, 95% CI: -0.03 to -0.00, I2 = 0.0%; 3 trials, N = 222; Moderate certainty) and increased the bone resorption marker C-terminal telopeptide (CTX) (WMD: 0.05 μg/L, 95% CI: 0.01 to 0.08, I2 = 72.5%; 6 trials, N = 439; Low certainty), while reducing serum hs-CRP (WMD: -0.49 mg/L, 95% CI: -0.97 to -0.00, I2 = 0.0%; 4 trials [5 arms], N = 340; Low certainty). No significant differences were observed for femoral neck BMD (WMD: 0.01 g/cm2, 95% CI: -0.02 to 0.04, I2 = 68.9%; 5 trials [6 arms], N = 323; Very Low certainty), total hip BMD (WMD: 0.00 g/cm2, 95% CI: -0.02 to 0.03, I2 = 70.8%; 5 trials [6 arms], N = 382; Low certainty), or procollagen type 1 N-terminal propeptide (P1NP) (WMD: -1.24 μg/L, 95% CI: -3.61 to 1.13, I2 = 0.0%; 5 trials, N = 399; Moderate certainty), and leave-one-out exclusion of the single semaglutide trial did not alter the direction or significance of any pooled estimate. [CONCLUSIONS] Treatment with predominantly first-generation GLP-1RAs over 12 to 52 weeks increases osteoclastic bone resorption and induces a small, borderline reduction in lumbar spine BMD while preserving hip BMD and lowering systemic inflammation. Because existing placebo-controlled RCTs largely reflect earlier-generation agents with moderate weight loss, these findings cannot be extrapolated to higher-potency anti-obesity therapies such as semaglutide 2.4 mg/week or tirzepatide, which require dedicated long-term skeletal safety trials.