Abstract
Calcitonin gene-related peptide (CGRP) is a sensory neuropeptide with established roles in vasodilation and nociception and increasing relevance to musculoskeletal biology. While CGRP-targeted therapies are widely used for migraine prevention, emerging experimental evidence suggests that CGRP also plays important roles in bone remodeling, fracture healing, angiogenesis, and musculoskeletal pain, raising questions about the skeletal implications of modulating the CGRP pathway. This scoping review aimed to systematically map the existing evidence on CGRP signaling in orthopaedic and musculoskeletal contexts, focusing on bone repair, cartilage and tendon biology, pain modulation, and potential clinical implications of CGRP-targeted therapies. The review was conducted in accordance with the PRISMA-ScR guidelines. PubMed, Embase, and Scopus were searched from inception to December 2025 for in vitro, animal, and human studies evaluating CGRP signaling in musculoskeletal conditions. Data were charted and synthesized descriptively across musculoskeletal surgery domains. Preclinical studies consistently demonstrate that CGRP promotes osteogenesis, inhibits osteoclast activity, enhances angiogenesis, and supports fracture healing. In contrast, genetic or pharmacological inhibition of CGRP signaling impairs callus formation and biomechanical recovery. CGRP also contributes to peripheral nociceptive sensitization in osteoarthritis and tendinopathy, highlighting a pain-repair paradox. In cartilage, effects are context-dependent: CGRP is anabolic in healthy chondrocytes but pro-apoptotic and pro-senescent in osteoarthritic chondrocytes, and antagonism of the CGRP receptor attenuated cartilage degeneration in a murine osteoarthritis model. A randomized clinical trial of the anti-CGRP antibody galcanezumab did not reduce signs or symptoms of knee osteoarthritis. Human evidence remains limited to short-term biomarker studies, rare case reports, and ongoing clinical trials, with no definitive data on fracture healing, osseointegration, or long-term bone outcomes. CGRP plays a biologically significant role in musculoskeletal repair and pain modulation. While routine modification of anti-CGRP therapy in musculoskeletal patients is not currently supported by clinical evidence, important translational gaps remain. Prospective studies evaluating orthopaedic outcomes are urgently needed.