Large analysis links GLP-1 drugs to lean mass loss but finds no bone effect

A systematic review and meta-analysis published in the journal Drugs found that GLP-1 receptor agonists did not affect bone mineral density, fractures or osteoarthritis measures, but were consistently associated with a loss of lean body mass and fat-free mass ^[1].

The analysis combined 60 studies — 46 randomized controlled trials, 13 real-world evidence studies and one pharmacovigilance study — covering 1,250,717 individuals ^[1]. The authors searched MEDLINE, the Cochrane Central Register of Controlled Trials and Embase from inception through March 2025, and registered their protocol with PROSPERO (record CRD420251024082) ^[1].

What the review found

For bone, the review reported no effect on bone mineral density at any site or on fractures at any site when the statistical models used the most adjusted effect estimate ^[1]. For joints, the models showed no significant change in the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) scores for pain, physical function or stiffness ^[1].

For muscle, the picture was different. Pooled across 28 studies, the standardized mean difference for lean body mass or fat-free mass was 0.52, with a 95% confidence interval of −0.8 to −0.23 and high heterogeneity (I2 = 88%, p < 0.0001 for heterogeneity) ^[1]. The authors said the finding held up in all sensitivity analyses, and that no publication bias was found ^[1].

Subgroup analyses showed the lean mass effect was mainly driven by liraglutide and semaglutide, and that the decrease appeared when GLP-1 receptor agonists were compared with placebo ^[1]. The studies covered several drugs in the class, including semaglutide (sold as Ozempic, Wegovy and Rybelsus), liraglutide, exenatide, dulaglutide and tirzepatide (Mounjaro and Zepbound), which is a dual GIP/GLP-1 agonist ^[1].

The authors rated the certainty of the evidence on lean mass as low, and said the changes appeared largely related to weight loss ^[1]. They wrote that whether these changes translate into clinically meaningful impairments in muscle function or physical performance remains uncertain ^[1].

The review did not report results for muscle strength, muscle function or physical performance. The authors listed those as areas needing further study ^[1].

Why it matters for patients

The bone and joint findings are the reassuring half of the result. Across more than 1.25 million people, the analysis did not turn up a signal that these drugs thin bone or raise fracture risk, and it did not find a change in osteoarthritis pain, stiffness or physical function scores ^[1].

The muscle finding is the part that remains open. Loss of lean body mass is a known feature of weight loss in general, including weight loss from diet, and the authors say the reductions they saw appeared largely tied to losing weight ^[1]. What is not established is whether that loss leaves people weaker, slower or less able to do daily tasks. The review did not measure strength or physical performance, and the authors state that the link to meaningful impairment is still uncertain ^[1].

That leaves a practical gap: patients and clinicians can see a drop in lean mass on a body composition scan, but the review does not answer whether it matters for how someone feels or functions. The certainty rating of low also means the underlying studies varied widely and the pooled estimate should be read with caution ^[1].

It is also worth noting what the analysis covered. It examined people taking GLP-1 receptor agonists for type 2 diabetes and obesity, and it included tirzepatide even though that drug works on two hormone pathways rather than one ^[1]. How the results apply to any single drug, dose or duration of treatment has not been reported.

What happens next

The authors call for further studies on muscle function, strength and physical performance, using models that account for confounding factors, to strengthen the evidence ^[1]. No timeline for such studies has been disclosed.

The review's materials, including its protocol, are publicly available in an Open Science Framework deposit ^[1]. Two of the authors disclosed outside interests: one reported personal speaker fees from Nutricia, and another is president of a nonprofit musculoskeletal research organization and serves on the editorial board of Drugs ^[1].