GLP-1 Receptor Agonists and Musculoskeletal Outcomes: A Systematic Literature Review and Meta-Analysis

Funding and conflicts

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not reported in abstract

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Author conflicts

Declarations. Conflict of Interest: D.S-R. reports personal speaker fees from Nutricia outside the submitted work. J-Y.R. is President of the European Society for Clinical and Economic Aspects of Osteoporosis, Osteoarthritis and Musculoskeletal Diseases (ESCEO), a not-for-profit organisation receiving Unrestricted Educational Grands from corporate partners. J-Y.R. is an Editorial Board member of Drugs. J-Y.R. was not involved in the selection of peer reviewers for the manuscript nor any of the subsequent editorial decisions. Other authors did not report any conflicts of interest in relation to this work. Disclaimer: The authors alone are responsible for the views expressed in this article, and they do not necessarily represent the views, decisions, or policies of the institutions with which they are affiliated. Ethics Approval: Not applicable. Consent to Participate: Not applicable. Consent for Publication: Not applicable. Code Availability: All materials related to this work are freely available on the Open Science Framework deposit – https://osf.io/zbhwc/ Availability of Data and Material: All materials related to this work are freely available on the Open Science Framework deposit – https://osf.io/zbhwc/ Authors’ Contribution: J-Y.R. and J.A.T. are at the initiative of the research question. C.B. and Y.M. are the main investigators of the present research. C.B. drafted the protocol, which was reviewed by A.S. and J-Y.R. C.B. developed the search strategies and identified p

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Abstract

[INTRODUCTION] Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) are increasingly used for the treatment of type 2 diabetes and obesity, but their effects on musculoskeletal health remain completely misunderstood. [OBJECTIVE] This systematic review/meta-analysis aims to synthesise clinical data on the effects of GLP-1 RAs on key relevant bone, muscle, and joint outcomes. [METHODS] MEDLINE, Cochrane Central Register of Controlled Trials (CENTRAL) (both via Ovid® platform) and Embase were searched from inception to March 2025 to identify relevant randomised controlled trials (RCTs) or real-world evidence (RWE) studies to be included. This bibliographic search was completed manually. A random-effect model meta-analysis was performed for any outcome reported in at least 2 studies. Subgroup analyses were performed on the type of GLP-1 RAs, type of comparator used and study design. Sensitivity analyses (i.e., leave-out sensitivity analyses and analyses restricted to the most adjusted effect estimate) were performed to test the robustness of the data. The strength of evidence was assessed using GRADE. This work has been performed in adherence with PRISMA statement. (PROSPERO Record ID: CRD420251024082). [RESULTS] From 1148 potentially relevant references, 60 articles (46 RCTs, 13 RWE studies and 1 pharmacovigilance study, comprising 1,250,717 individuals) met our inclusion criteria. Different GLP-1 RAs were represented across the panel of studies, i.e., semaglutide, liraglutide, exenatide, dulaglutide, tirzepatide (dual agonist gastric inhibitory polypeptide [GIP]/GLP-1) and others. No effect on bone outcomes (i.e., bone mineral density [all sites] and fractures [all sites]) were observed when the meta-analytical models included the most adjusted effect size. Regarding muscle outcomes, a significant decrease of lean body mass/fat-free mass was consistently observed with GLP-1 RAs in the global model (k = 28, standardised mean difference [SMD] 0.52, 95% confidence interval [CI] -0.8; -0.23, I2 88%, p-value for heterogeneity <0.0001), which remained robust in all sensitivity analyses. Subgroup analyses showed that the effect was mainly driven by liraglutide and semaglutide, with a decrease in lean body mass/fat-free mass observed when GLP-1 RAs were compared with placebo. No publication bias was found. Regarding joint outcome, models revealed no significant change in The Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) pain, physical function and stiffness. [CONCLUSIONS] This meta-analysis is the first to investigate the effects of GLP-1 RAs on a large panel of musculoskeletal health outcomes. While no significant effects were observed on bone- or joint-related outcomes, GLP-1 RAs were associated with reductions in lean body mass/fat-free mass, although the certainty of evidence was low and these changes appeared largely related to weight loss. Whether these changes translate into clinically meaningful impairments in muscle function or physical performance remains uncertain. Further studies in this field, including those looking at muscle function, strength or performance and using multivariate models considering confounding are needed to better reinforce the models and final findings.

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