Skeletal effects of GLP-1 receptor agonist therapy in adults with overweight or obesity: a systematic review.

Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) are widely used for weight management, yet their skeletal effects remain unclear. This systematic review of eight randomized controlled trials (n = 493) evaluating dual-energy X-ray absorptiometry (DXA)-derived bone mineral density reports findings separately for each agent, without pooling, because the trials evaluated four pharmacologically distinct agents differing markedly in weight-lowering potency. The evidence is sparse for every agent and is insufficient to establish the skeletal effects of GLP-1 RA therapy in this population. PURPOSE: Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) are widely used for weight management, yet their skeletal effects remain uncertain. We systematically reviewed the randomized evidence on bone mineral density (BMD) and bone turnover markers in adults with overweight or obesity, reporting findings separately for each individual agent.

methodsThis PRISMA 2020-compliant systematic review (INPLASY202630076) searched PubMed, Embase, Cochrane CENTRAL, and Google Scholar (January 2015 to July 2026). Eligible randomized controlled trials (RCTs) enrolled adults aged ≥18 years with mean baseline body mass index (BMI) > 25 kg/m², compared a GLP-1 RA with placebo or another antidiabetic therapy for ≥12 weeks, and reported BMD assessed by dual-energy X-ray absorptiometry (DXA). Risk of bias was assessed using the Cochrane Risk of Bias 2 (RoB 2) tool and certainty of evidence using GRADE. Because the included trials evaluated pharmacologically distinct agents that differ substantially in weight-lowering potency, results were synthesized narratively and reported separately by agent; no meta-analysis was performed.

resultsEight RCTs (n = 493) were included. Three trials were at low risk of bias (Eriksson 2019; Hygum 2020; Hansen 2024) and five raised some concerns, principally regarding the randomization process and selective reporting; no agent is supported by more than one trial at low risk of bias. (Cai 2021 contributes two treatment arms assessed separately, giving nine comparisons in the risk-of-bias assessment.) Evidence was unevenly distributed across agents: semaglutide and dulaglutide were each evaluated in one trial, liraglutide in two, and exenatide in five. Five of the eight trials enrolled adults with type 2 diabetes, including all four that randomized an insulin comparator arm; three enrolled adults without diabetes, of which one was defined by obesity alone. By study-level mean baseline BMI, five trials lay in the obese range ( ≥ 30 kg/m²) and three in the overweight range (25 to <30 kg/m²). The single semaglutide trial (Hansen 2024; n = 64; low risk of bias), which produced the largest weight loss of any trial (estimated treatment difference [ETD] -6.8 kg vs placebo), reported reduced lumbar spine BMD (ETD - 0.018 g/cm², p = 0.007), reduced whole-body BMD (mean difference [MD] -0.02 g/cm²; 95% CI - 0.03 to -0.01), and increased C-terminal telopeptide (CTX; MD 166.50 pg/mL; 95% CI 66.60 to 266.40). Liraglutide was evaluated at two doses with divergent results. At the weight-management dose of 3.0 mg daily, in the only trial conducted in adults with obesity and without diabetes (Jensen 2024; ETD - 6.7 kg vs placebo), lumbar spine BMD (MD - 0.019 g/cm²; 95% CI - 0.034 to -0.004) and total hip BMD (MD - 0.013 g/cm²; 95% CI - 0.024 to -0.002) were reduced. At the diabetes dose of 1.8 mg daily (Hygum 2020; -3.8 kg), no site changed materially (lumbar spine MD 0.00 g/cm²; 95% CI - 0.01 to 0.01). Exenatide trials were inconsistent, ranging from 0.03 g/cm² (95% CI 0.02 to 0.03) at the lumbar spine (Renyuan 2015) to -0.04 g/cm² (95% CI - 0.15 to 0.07; Akyay 2023). Certainty of evidence was very low for every agent.

conclusionThe randomized evidence is too sparse and too clinically heterogeneous to determine the skeletal effects of GLP-1 RA therapy in adults with overweight or obesity. Each agent has been evaluated in at most five small trials, most conducted in adults with type 2 diabetes rather than in adults with obesity alone. The two trials producing the largest weight loss, one of semaglutide and one of liraglutide 3.0 mg, both reported reduced lumbar spine and total hip BMD at closely similar magnitudes of weight loss, and the semaglutide trial additionally reported increased bone resorption. This convergence warrants dedicated evaluation rather than extrapolation across the drug class. Adequately powered, agent-specific trials with fracture endpoints are required. PROTOCOL REGISTRATION: INPLASY202630076.