Analysis of 43 randomized controlled trials encompassing 100,488 participants found no significant association between GLP-1 receptor agonists and musculoskeletal adverse events, including gouty arthritis, rheumatoid arthritis, osteoarthritis, osteoporotic fractures, synovitis, or disc protrusion. Notably, male participants showed fewer osteoarthritis reports when using these medications. This finding addresses a critical safety question as GLP-1 drugs like semaglutide and tirzepatide become widely prescribed for weight management. The musculoskeletal safety profile matters particularly because rapid weight loss can theoretically stress joints and bones through multiple mechanisms—altered biomechanics, nutritional changes, and hormonal shifts. However, the neutral safety signal suggests these drugs' anti-inflammatory properties and metabolic benefits may offset any mechanical stress from weight loss. The male-specific osteoarthritis reduction hints at sex-specific protective mechanisms, possibly related to testosterone interactions or different inflammatory responses. While reassuring for current users, this meta-analysis relies on spontaneous adverse event reporting, which may underestimate subtle or delayed musculoskeletal effects. Long-term prospective studies tracking bone density and joint imaging would provide more definitive evidence about skeletal health during prolonged GLP-1 therapy.