Document Type : Review article
Authors
1
Trauma and Surgery Research Center, AJA University of Medical Sciences, Tehran, Iran.
2
Department of Internal Medicine, AJA University of Medical Sciences, Tehran, Iran.
3
PHARCO LTD, London, United Kingdom.
4
Business School, The Ingenuity Center Nottingham, Nottingham, University of Nottingham, United Kingdom.
5
School of Medicine, Tehran University of Medical Sciences, Tehran, Iran.
6
Toxicology Research Center, AJA University of Medical Sciences, Tehran, Iran.
7
Department of Orthopedic Surgery, AJA University of Medical Sciences, Tehran, Iran.
8
Orthopedic Research Center, Mazandaran University of Medical Science, Sari, Iran.
9
Department of Endocrinology and Metabolism, AJA University of Medical Sciences, Tehran, Iran.
Abstract
Background: Potent incretin-based therapies, particularly tirzepatide, can induce significant and sustained reductions in body weight and fat mass alongside broad cardiometabolic improvements, thereby forging a new link between metabolic and musculoskeletal medicine. This study reviews the studies on tirzepatide and dual incretin agonism in musculoskeletal medicine
Methods: This current concept review provides a focused conceptual synthesis of studies on tirzepatide, dual glucose-dependent insulinotropic polypeptide/glucagon-like peptide-1 (GIP/GLP-1) agonists, obesity, osteoarthritis (OA), cartilage biology, body composition, skeletal muscle, skeletal health, arthroplasty, perioperative management, and regenerative orthopedics. Particular emphasis is placed on randomized clinical trials (RCTs), systematic reviews, meta-analyses, and translational studies available up to September 2026. Finally, we presented a framework termed “metabolic optimization of the regenerative host.” This framework entails identifying and modifying systemic metabolic factors that may influence the environment surrounding joint preservation, arthroplasty, rehabilitation, tissue repair, and regenerative interventions.
Results: The orthopedic significance of these therapies cannot be inferred solely from weight loss. Evidence from RCTs supports symptomatic improvement with incretin-based obesity treatment in obesity-related knee OA; however, the strongest trial evidence regarding joint outcomes currently pertains specifically to semaglutide, not tirzepatide. Studies on tirzepatide have demonstrated substantial changes in fat mass, lean mass, and muscle composition, while emerging observations raise unresolved questions regarding skeletal health. Evidence concerning arthroplasty remains largely retrospective and heterogeneous, and preclinical signals of cartilage protection do not, in themselves, prove structural modification or human cartilage regeneration.
Conclusion: Tirzepatide is a relevant clinical model for profoundly altering host characteristics, rather than as a regenerative drug in its own right. The proposed framework is hypothesis-generating in nature and requires validation through prospective studies incorporating structural imaging, assessments of body composition and muscle function, skeletal health monitoring, metabolic and inflammatory biomarkers, and intervention-specific outcomes.
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