Semaglutide and Musculoskeletal Health: A Mendelian Randomization Study Based on GLP-1 Receptor Expression

Semaglutide, a glucagon-like peptide-1 receptor (GLP1R) agonist, is clinically used for glycemic control and weight loss. However, it is still unclear whether it has any impact on bones and muscles. Does semaglutide have any impact on the musculoskeletal system of patients during its use, or does it have any negative effects on them? This study aims to assess the impact of GLP1R on bone and muscle using Mendelian Randomization.

We employed expression quantitative trait loci (eQTL) data for the GLP1R gene and combined it with genome-wide association studies (GWAS) data for skeletal and muscular traits to conduct Summary-data-based Mendelian Randomization (SMR) analysis. The exposure was defined as the blood expression level of the GLP1R gene, with the eQTL serving as the instrumental variable. Total bone mineral density, osteoporosis, and fractures were used to evaluate bone health, while appendicular lean mass, grip strength, and walking speed assessed muscle quality. Type 2 diabetes and body mass index (BMI) served as positive controls.

The top eQTL rs9283907 was used to predict GLP1R expression. Positive control results confirmed that GLP1R agonists are effective diabetes treatments and can reduce BMI. There were no significant impacts on osteoporosis (beta: 0.00, 95% CI: -0.01, 0.01, p=0.416), total bone mineral density (beta: -0.03, 95% CI: -0.19, 0.13, p=0.702), fracture (beta: 0.09, 95% CI: -0.10, 0.28, p=0.343), walking pace (beta: 0.00, 95% CI: -0.01, 0.06, p=0.216), appendicular lean mass (beta: -0.01, 95% CI: -0.08, 0.06, p=0.676), or grip strength (beta: -0.02, 95% CI: -0.06, 0.02, p=0.425).

This Mendelian randomization study provides genetic evidence that GLP-1 receptor expression is not causally associated with altered musculoskeletal health. The findings suggest that semaglutide is unlikely to adversely affect bone metabolism or muscle function regarding the outcomes measured. These results support the musculoskeletal safety profile of semaglutide; however, as genetic associations do not fully capture the clinical pharmacology of the drug, further validation through long-term randomized controlled trials is warranted.

According to our results, high expression of glucagon-like peptide-1 receptor does not lead to bone and muscle loss, which indicates that semaglutide may be safe for the musculoskeletal system.