Therapeutic potential of melatonin in musculoskeletal medicine

Melatonin, traditionally recognised for regulating circadian rhythms, has gained increasing attention in pharmaceutical science due to its pleiotropic actions extending beyond sleep physiology. Evidence from PubMed-indexed studies demonstrates that melatonin exerts receptor-dependent and receptor-independent effects relevant to musculoskeletal health, including antioxidant, anti-inflammatory, mitochondrial, and epigenetic regulation. In bone, it promotes osteoblast differentiation, suppresses osteoclastogenesis, and preserves microarchitecture, with promising applications in the treatment of osteoporosis and fracture healing. In cartilage, melatonin protects chondrocytes from oxidative stress and apoptosis, modulates non-coding RNAs, and shows enhanced efficacy when delivered through intra-articular sustained-release systems, making it a potential adjunct in osteoarthritis therapy. In muscle and tendon, it limits exercise-induced damage, prevents sepsis-related myopathy, and promotes collagen synthesis and organised matrix remodelling. In spinal cord injury, melatonin reduces oxidative stress, preserves neuronal integrity, and enhances neuroregeneration. In intervertebral disc degeneration, it counteracts apoptosis, inflammation, and ferroptosis. Sports medicine applications include attenuation of oxidative stress and inflammatory markers in highly trained athletes, with indirect benefits on recovery and adaptation, although direct improvements in performance remain uncertain. Oncological studies have highlighted the anti-proliferative, pro-apoptotic, and anti-metastatic effects of osteosarcoma, with synergy observed when these effects are combined with chemotherapy. Novel pharmaceutical formulations such as nanoparticles and hydrogels further expand therapeutic potential, supported by a favourable safety profile. Despite robust preclinical evidence, translation into clinical practice requires large, well-designed trials. Melatonin should therefore be considered a promising adjunct in orthopaedics, rehabilitation, sports medicine, and trauma care, with future research aimed at optimising delivery and validating efficacy.