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

Dong Li¹, Xinyu Liang¹, Zhijun Li¹

¹Department of Orthopedics, Tianjin Medical University General Hospital, Tianjin, China.

Endocrine, Metabolic & Immune Disorders Drug Targets

|July 6, 2026

Summary

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Glucagon-like Receptor Agonists

Glucagon-like Receptor Agonists

Incretins include glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP), which stimulate insulin secretion post-meals. In type 2 diabetes, GIP's efficacy is reduced, making GLP-1 a viable drug target. GIP originates from preproGIP.
GLP-1, when administered in high doses intravenously, triggers insulin secretion, inhibits glucagon release, slows gastric emptying, reduces food intake, and restores normal insulin secretion. However, its rapid inactivation by the...

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Semaglutide, a GLP1R agonist, does not appear to negatively impact bone or muscle health. This genetic study suggests semaglutide is safe for the musculoskeletal system, though further clinical trials are recommended.

Area of Science:

Endocrinology
Genetics
Pharmacology

Background:

Semaglutide, a glucagon-like peptide-1 receptor (GLP1R) agonist, is widely used for glycemic control and weight management.
The potential effects of semaglutide on the musculoskeletal system, specifically bone and muscle health, remain unclear.
Understanding these effects is crucial for comprehensive patient care.

Purpose of the Study:

To investigate the causal relationship between GLP1R expression and musculoskeletal health using Mendelian Randomization (MR).
To assess the impact of GLP1R on bone mineral density, osteoporosis, fractures, lean mass, grip strength, and walking speed.
To provide genetic evidence regarding the safety of semaglutide for bone and muscle.

Main Methods:

Summary-data-based Mendelian Randomization (SMR) analysis was performed.

Keywords:

GLP1R bone diabetes muscle obesity

Related Experiment Videos

Expression quantitative trait loci (eQTL) data for GLP1R was combined with genome-wide association study (GWAS) data for skeletal and muscular traits.

Bone health was assessed via total bone mineral density, osteoporosis, and fractures; muscle quality via appendicular lean mass, grip strength, and walking speed.

Main Results:

Positive controls confirmed semaglutide's efficacy in treating type 2 diabetes and reducing BMI.
No significant causal associations were found between GLP1R expression and osteoporosis, total bone mineral density, or fracture risk.
No significant impacts were observed on appendicular lean mass, grip strength, or walking speed.

Conclusions:

Genetic evidence indicates that GLP-1 receptor expression is not causally linked to adverse musculoskeletal outcomes.
The findings suggest semaglutide is unlikely to negatively affect bone metabolism or muscle function.
While supporting the musculoskeletal safety of semaglutide, further long-term randomized controlled trials are warranted for complete clinical validation.