GLP-1 receptor expression shows no causal link to altered bone mineral density, osteoporosis, fractures, or muscle function in Mendelian randomization study

Semaglutide, a glucagon-like peptide-1 receptor (GLP1R) agonist, is widely prescribed for type 2 diabetes and weight loss. While its efficacy in these areas is well-established, concerns have emerged regarding its potential long-term impact on musculoskeletal health. Significant weight loss, a common outcome of semaglutide use, can sometimes be associated with reduced bone mineral density and muscle mass. Therefore, understanding whether GLP1R activation itself, independent of weight changes, directly influences bone and muscle integrity is crucial for patient safety and treatment planning.

Researchers conducted a Summary-data-based Mendelian Randomization (SMR) analysis to assess the causal impact of GLP1R expression on bone and muscle traits. The exposure was defined as the blood expression level of the GLP1R gene, with the top expression quantitative trait locus (eQTL) rs9283907 serving as the instrumental variable. This was combined with genome-wide association studies (GWAS) data for various skeletal and muscular traits. Bone health was evaluated using total bone mineral density, osteoporosis, and fractures, while muscle quality was assessed via appendicular lean mass, grip strength, and walking speed. Type 2 diabetes and body mass index (BMI) served as positive controls to validate the eQTL instrument.

Positive control results confirmed the validity of the GLP1R eQTL instrument, showing that genetically predicted GLP1R expression was associated with reduced Type 2 diabetes risk and BMI. However, the SMR analysis revealed no significant causal impacts on any of the primary musculoskeletal endpoints. Specifically, there was no significant association with 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), or fracture risk (beta: 0.09, 95% CI: -0.10, 0.28, p=0.343). Muscle-related outcomes also showed no significant associations: 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), and grip strength (beta: -0.02, 95% CI: -0.06, 0.02, p=0.425) were unaffected.

The findings provide genetic evidence that GLP-1 receptor expression is not causally associated with altered musculoskeletal health, suggesting semaglutide is unlikely to adversely affect bone metabolism or muscle function regarding the outcomes measured.