Therapeutic Potential of Melatonin in Osteoarticular Diseases and Musculoskeletal Medicine: A Narrative Review

1. Introduction

Melatonin, or N-acetyl-5-methoxytryptamine, is an evolutionarily conserved indoleamine best known for its role in circadian regulation and synchronization of biological rhythms. In recent decades, however, the molecule has attracted increasing interest beyond sleep medicine because it also acts as a regulator of redox balance, mitochondrial stability, inflammatory signaling and immune responses [1,2,3,4,5,6,7]. These actions are of particular interest in tissues exposed to chronic mechanical loading, relative hypoxia, senescence, metabolic stress and repeated inflammatory stimulation, including bone, articular cartilage, skeletal muscle, tendon, ligament and the intervertebral disc.

Although pineal secretion remains the most recognized source of circulating melatonin, extrapineal synthesis has been described in several tissues, including the gastrointestinal tract, retina, immune cells and bone marrow. This widespread distribution supports the concept that melatonin may act not only as an endocrine hormone but also as a paracrine, autocrine and intracellular protective signal [6,7,8,9,10,11,12,13,14,15,16]. In musculoskeletal tissues, such local and systemic actions may intersect with mechanisms that are central to degeneration and repair, including mitochondrial dysfunction, oxidative damage, nuclear factor kappa B (NF-kB) activation, altered autophagy, impaired matrix turnover and cellular senescence [17,18,19,20,21].

The burden of osteoarticular disorders continues to increase with population aging. Osteoarthritis, osteoporosis, sarcopenia, tendinopathy and degenerative spine disease share several biological denominators: persistent low-grade inflammation, excessive reactive oxygen species production, impaired tissue repair, reduced anabolic signaling and disruption of the circadian and endocrine environment. The age-related decline in nocturnal melatonin secretion has therefore been proposed as one of several factors potentially associated with the increased vulnerability of musculoskeletal tissues in older adults, although a direct causal relationship has not been definitively established [17,18,19,20].

From a clinical perspective, current conservative treatments for chronic osteoarticular disease are often effective for symptom control but less effective in modifying the biological pathways that sustain tissue deterioration. This has encouraged research into agents that may act simultaneously on oxidative stress, inflammation and repair. Melatonin is of interest in this context because it is not a single-target anti-inflammatory drug. Rather, it behaves as a multi-pathway modulator capable of influencing mitochondrial function, antioxidant defenses, cell survival, matrix metabolism and circadian homeostasis [21,22,23,24,25,26,27,28,29,30,31,32,33,34,35].

The purpose of this narrative review is to summarize and critically discuss the biological rationale and translational evidence supporting the potential use of melatonin in musculoskeletal medicine. The review focuses on bone metabolism and fracture healing, cartilage and osteoarthritis, skeletal muscle and soft-tissue repair, spinal cord injury, intervertebral disc degeneration, sports medicine and pharmaceutical delivery systems. Particular attention is given to the distinction between robust preclinical evidence and the still limited clinical data available for routine orthopedic practice.

2. Materials and Methods: Literature Search Strategy

A narrative review of the literature was performed using PubMed/MEDLINE, Scopus and Web of Science. Search terms included “melatonin”, “N-acetyl-5-methoxytryptamine”, “bone”, “osteoporosis”, “fracture healing”, “cartilage”, “osteoarthritis”, “chondrocyte”, “muscle”, “tendon”, “ligament”, “spinal cord injury”, “intervertebral disc degeneration”, “sports medicine”, “oxidative stress”, “inflammation”, “mitochondria”, “ferroptosis”, “nanoparticles” and “hydrogel”. Boolean operators were used to combine melatonin-related terms with musculoskeletal keywords.

Preclinical in vitro and in vivo studies, clinical trials, systematic reviews, meta-analyses and translational articles were considered when they provided mechanistic or clinically relevant information. Priority was given to peer-reviewed papers directly addressing musculoskeletal tissues or pathways of clear orthopedic relevance. Because of the heterogeneity of experimental models, doses, timing, routes of administration and outcome measures, a formal meta-analysis was not appropriate. For the same reason, the manuscript was structured as a narrative review rather than as a systematic review according to Preferred Reporting Items for Systematic Reviews and Meta-Analyses methodology.

The interpretation of evidence was clinically oriented. Preclinical findings were considered hypothesis-generating unless supported by clinical data. Statements regarding therapeutic use in patients were therefore formulated cautiously, emphasizing the need for randomized, controlled and adequately powered trials before routine adoption in orthopedic and rehabilitation protocols.

3. Biological Rationale and Molecular Mechanisms

Melatonin exerts its biological effects through receptor-dependent and receptor-independent pathways. The membrane receptors MT1 and MT2 are G protein-coupled receptors expressed in peripheral tissues, including tissues relevant to the musculoskeletal system. Receptor activation may influence cyclic adenosine monophosphate signaling, intracellular calcium handling, inflammatory transcription factors and differentiation pathways. In bone, activation of melatonin signaling has been associated with enhanced osteoblastic differentiation and modulation of osteoclast formation, particularly through pathways involving bone morphogenetic proteins, receptor activator of nuclear factor kappa B ligand (RANKL), osteoprotegerin and NF-kB [21,22,23,24,25,26,27,28,29,30,31,32,33,34,35,36,37,38,39,40].

Independent of membrane receptors, melatonin is a direct scavenger of reactive oxygen and nitrogen species. Its amphiphilic structure allows distribution across cellular compartments, including mitochondria, where it can reduce lipid peroxidation and stabilize the electron transport chain. In addition, metabolites of melatonin may contribute to a cascade of antioxidant protection, extending its redox effects beyond the parent molecule [22,23,24,25,26,27,28]. The activation of nuclear factor erythroid 2-related factor 2 (Nrf2) signaling is another important mechanism, because Nrf2 regulates endogenous antioxidant enzymes such as superoxide dismutase, catalase, heme oxygenase-1 and glutathione peroxidase [24,25,26,27,28,29,30,31].

Mitochondrial protection is particularly relevant to musculoskeletal tissues because chondrocytes, osteoblasts, myocytes and nucleus pulposus cells are vulnerable to energetic failure and oxidative injury. Melatonin has been reported to stabilize mitochondrial membranes, limit cytochrome c release, reduce apoptosis and influence mitophagy. In degenerative diseases, these effects may be relevant to cell survival and extracellular matrix preservation. At the same time, melatonin may regulate inflammatory responses through inhibition of NF-kB and downstream cytokines such as tumor necrosis factor alpha, interleukin 1 beta and interleukin 6 [28,29,30,31,32,33,34,35].

Emerging work has also explored the relationship between melatonin and ferroptosis, a form of regulated cell death driven by iron-dependent lipid peroxidation. Ferroptosis has been implicated in bone loss, diabetic osteoporosis and intervertebral disc degeneration. By limiting oxidative overload and activating protective pathways such as Nrf2/heme oxygenase-1, melatonin may attenuate ferroptotic injury in selected experimental models [29,30,31,32,33,34,35]. The main mechanisms relevant to musculoskeletal medicine are summarized in Table 1.

4. Bone Metabolism, Osteoporosis and Fracture Healing

Bone remodeling depends on the balance between osteoblast-mediated bone formation and osteoclast-mediated bone resorption. Disturbance of this balance contributes to osteoporosis, delayed union and impaired skeletal repair. Experimental studies suggest that melatonin can shift bone metabolism toward an anabolic phenotype by promoting the osteogenic differentiation of bone marrow mesenchymal stem cells and by suppressing osteoclastogenesis [36,37,38,39,40,41]. These actions have been linked to upregulation of osteogenic markers, modulation of bone morphogenetic proteins and inhibition of RANKL-mediated osteoclast differentiation.

In animal models, melatonin has been associated with improvements in trabecular architecture, bone mineral density and parameters of callus formation. Studies in ovariectomized models, commonly used to simulate postmenopausal osteoporosis, have reported attenuation of bone loss and improvement in bone microstructure after melatonin administration [42,43,44,45,46,47]. These effects appear to be mediated by both antioxidant and anti-inflammatory mechanisms, as well as by direct regulation of osteoblast and osteoclast activity.

Clinical evidence is less definitive but clinically relevant. In postmenopausal women, combined supplementation strategies including melatonin and micronutrients have been investigated for effects on bone density, bone turnover markers and quality of life [46]. Observational data also suggest a relationship between circadian disruption, night-shift work and fracture risk, supporting a possible link between circadian biology and skeletal health [49]. Nevertheless, existing human studies do not yet allow firm conclusions regarding melatonin as a stand-alone treatment for osteoporosis or fracture healing.

A balanced interpretation is essential. Not all experimental data are uniformly positive; some models have suggested that melatonin may impair aspects of fracture remodeling under specific conditions, possibly by suppressing RANKL-mediated remodeling too strongly [48]. This reinforces the concept that timing, dose, local biology and stage of healing may be decisive. Melatonin may have different effects during inflammatory, reparative and remodeling phases of fracture healing, and these differences must be clarified before clinical protocols can be proposed.

5. Articular Cartilage and Osteoarthritis

Osteoarthritis is characterized by progressive cartilage degradation, subchondral bone remodeling, synovial inflammation and pain. At the cellular level, oxidative stress and inflammatory cytokines promote chondrocyte apoptosis, extracellular matrix degradation and altered expression of matrix metalloproteinases. Melatonin has been studied as a potential disease-modifying adjunct because it targets several pathways implicated in osteoarthritis progression [50,51,52,53,54,55,56,57,58,59].

In chondrocytes, melatonin may reduce oxidative injury, inhibit apoptosis and support autophagy. Experimental models have demonstrated modulation of AMP-activated protein kinase, forkhead box O3, SIRT1, NF-kB, Nrf2 and transforming growth factor beta/bone morphogenetic protein pathways. These mechanisms can decrease inflammatory cytokine production and protect cartilage matrix components such as type II collagen and aggrecan [51,52,53,54,55,56].

Non-coding ribonucleic acids have also emerged as mediators of melatonin activity in osteoarthritis. MicroRNAs, long non-coding RNAs and circular RNAs are involved in chondrocyte survival, extracellular matrix metabolism and inflammatory activation. In particular, regulation of microRNA-140 and related pathways may contribute to reduced cartilage degradation in experimental osteoarthritis [54,55,56]. This field is still largely preclinical, but it provides a biologically coherent explanation for the multi-layered actions of melatonin on cartilage homeostasis.

A key translational challenge is delivery. Oral melatonin has variable bioavailability and a short plasma half-life, which may limit sustained intra-articular exposure. For this reason, recent research has explored local delivery through nanoparticles, polymeric scaffolds and sustained-release systems. Melatonin-loaded nanoparticles and scaffolds have shown potential to prolong local activity and improve chondroprotective effects in experimental models [56,57,58,59]. If confirmed clinically, such strategies could be most relevant in early or moderate osteoarthritis, where viable chondrocytes and residual matrix remain biologically responsive.

At present, however, melatonin should not be considered an established alternative to evidence-based conservative treatments for osteoarthritis. Its role is better conceptualized as a potential biological adjunct, particularly in multimodal strategies that include weight control, exercise therapy, correction of metabolic risk factors, intra-articular treatments where indicated and optimization of sleep and recovery.

6. Muscle, Tendons, Ligaments and Rehabilitation

Skeletal muscle and connective tissues are highly sensitive to oxidative stress and inflammatory signaling during trauma, surgery, immobilization and intensive exercise. Reactive oxygen species are not exclusively harmful; they also participate in adaptive signaling. However, excessive oxidative stress can impair repair, promote apoptosis and delay functional recovery [60,61,62]. Melatonin may help restore a more favorable redox balance, particularly when oxidative and inflammatory responses are disproportionate.

Experimental studies have reported protective effects of melatonin in muscular trauma and sepsis-induced muscle atrophy. These effects include attenuation of inflammatory signaling, reduction of oxidative markers, preservation of mitochondrial function and modulation of the phosphoinositide 3-kinase/protein kinase B pathway [62,63,64]. In athletes and trained individuals, melatonin supplementation has been associated in some studies with reductions in biomarkers of oxidative stress, inflammatory cytokines and cellular damage after strenuous exercise [64,65,66,67,68,69,70].

The interpretation of sports-related evidence must be cautious. Improvements in biochemical recovery do not always translate into measurable gains in strength, speed or sport performance. The most plausible benefits may be indirect, mediated by improved sleep quality, circadian alignment, reduction of oxidative overload and enhanced recovery capacity. These mechanisms may be relevant in periods of heavy training, travel, jet lag, evening competition schedules or overreaching [68,69,70,71].

Tendon and ligament healing are also influenced by oxidative stress, local inflammation, collagen synthesis and mechanical loading. In preclinical models, melatonin has been investigated in supraspinatus overuse tendinopathy, diabetic ligament changes, Achilles tendon injury and tendon-derived stem cell differentiation [72,73,74,75,76,77]. Reported effects include modulation of tenocyte activity, anti-inflammatory actions and improved extracellular matrix organization. Nevertheless, translation to clinical practice is still premature. Tendon healing is strongly load-dependent, and any pharmacological adjunct must be integrated with appropriate surgical repair, progressive rehabilitation and mechanical stimulation.

In postoperative orthopedic rehabilitation, melatonin could theoretically support recovery by improving sleep continuity, reducing oxidative stress and influencing pain perception. These possibilities are clinically attractive after major procedures such as hip and knee arthroplasty, ligament reconstruction or fracture fixation. However, specific randomized trials in postoperative orthopedic populations remain necessary before routine perioperative protocols can be recommended.

7. Spine, Spinal Cord Injury and Intervertebral Disc Degeneration

Spinal disorders represent another area in which melatonin has been investigated. In spinal cord injury, secondary damage is driven by oxidative stress, mitochondrial dysfunction, inflammation, blood-spinal cord barrier disruption, apoptosis and impaired axonal regeneration. Experimental evidence suggests that melatonin may reduce secondary injury through antioxidant and anti-inflammatory mechanisms, preservation of mitochondrial homeostasis and modulation of neuroprotective pathways [78,79,80,81,82,83,84,85,86,87,88,89,90,91].

Several animal studies have reported improved neuronal survival, reduced apoptosis and enhanced functional recovery after melatonin administration in models of spinal cord injury. Mechanisms include activation of Nrf2/Keap1 signaling, regulation of SIRT1/Drp1-mediated mitochondrial dynamics, reduction of inflammatory activation and promotion of neuroplasticity [80,81,82,83,84,85,86,87,88,89,90,91]. These findings are biologically compelling, but robust clinical evidence in human spinal cord injury remains lacking.

Intervertebral disc degeneration is characterized by extracellular matrix breakdown, nucleus pulposus cell senescence, mitochondrial dysfunction, inflammation and altered mechanical loading. Melatonin has been shown in experimental studies to protect nucleus pulposus and annulus fibrosus cells from inflammatory and oxidative injury, to reduce apoptosis and to preserve matrix integrity [32,35,81,85,92,93,94,95]. The ability to influence ferroptosis may be particularly relevant in the harsh microenvironment of the degenerating disc, where low oxygen tension, acidosis and oxidative stress coexist.

Compared with established interventional strategies for discogenic pain, such as rehabilitation, injections or selected surgical procedures, melatonin remains an investigational biological approach. Its potential role could be adjunctive, aiming to modify cellular stress and degeneration rather than to provide immediate mechanical decompression or analgesia. Future research should clarify whether local delivery, combination with regenerative approaches or integration with physical therapy can produce clinically meaningful improvements in pain, function or structural progression [96,97].

8. Sports Medicine and Recovery

In sports medicine, melatonin has been investigated mainly as an antioxidant and chronobiotic compound. Strenuous exercise increases reactive oxygen species production, muscle membrane stress and inflammatory mediators. A physiological amount of oxidative stress is necessary for training adaptation, but excessive or prolonged oxidative injury may contribute to delayed recovery, fatigue and tissue damage [64,65,66,67,68,69,70,98].

Randomized and controlled studies in trained athletes have reported that melatonin supplementation can reduce markers of oxidative stress and inflammation after intense exercise, including tumor necrosis factor alpha and interleukin 6, while supporting antioxidant capacity and anti-inflammatory responses [64,65,66,67,68,69,70,98]. Some studies have also examined physical performance and next-day recovery, but results are not uniform. The most consistent rationale is therefore not that melatonin is a direct ergogenic agent, but that it may support recovery conditions through sleep improvement, circadian synchronization and reduction of excessive oxidative load.

This distinction is important for clinical communication. In athletes, melatonin should not be promoted as a performance-enhancing drug. Rather, it may be considered, when appropriate and permitted, as part of a recovery-oriented strategy that includes sleep hygiene, nutritional adequacy, training load management, rehabilitation and monitoring of symptoms. The dose, timing and duration of supplementation should be individualized, and clinicians should consider possible daytime sleepiness, interaction with sedative drugs and regulatory issues in professional sports settings.

9. Translational Perspectives, Delivery Systems and Safety

One of the main pharmacokinetic limitations of oral melatonin is its variable bioavailability and relatively short half-life, partly related to first-pass hepatic metabolism. This limitation has stimulated the development of advanced delivery systems, including nanocarriers, polymeric scaffolds, injectable hydrogels and sustained-release platforms [99,100,101,102,103]. In musculoskeletal medicine, local delivery may be particularly attractive because it could increase tissue exposure while reducing systemic variability.

In osteoarthritis, experimental delivery systems aim to prolong intra-articular residence time and maintain biologically active concentrations in the synovial environment. In bone and soft-tissue engineering, melatonin-containing scaffolds and hydrogels may theoretically combine structural support with antioxidant and pro-regenerative signaling [101,102,103]. These approaches remain largely preclinical, but they are consistent with the broader direction of orthopedic regenerative medicine, which increasingly seeks localized and controlled biological modulation rather than systemic pharmacological exposure.

The distinction between synthetic melatonin and phytomelatonin has also received attention. From a chemical and receptor-binding perspective, the active molecule is the same. Phytomelatonin preparations may contain additional plant-derived compounds with antioxidant properties, but clinical superiority over purified synthetic melatonin has not been established [104,105,106]. For scientific manuscripts and clinical prescriptions, the generic drug name should be used, and any commercial product or supplement should be described only when relevant to the study design.

Overall, melatonin has a favorable safety profile in adults, and adverse events reported with oral administration are usually mild and reversible, including sleepiness, dizziness, headache or changes in sleep timing [107,108,109]. Nevertheless, safety should not be oversimplified. Dose, age, comorbidities, pregnancy status, hepatic metabolism, concomitant medications and pediatric use require careful consideration [109,110,111]. For orthopedic applications, additional safety questions are specific to local delivery systems, including biomaterial tolerability, sterility, release kinetics, intra-articular inflammation and interaction with tissue healing.

10. Discussion and Future Directions

The main limitation of the current evidence is the gap between strong mechanistic plausibility and limited clinical validation. Many studies are preclinical, use different animal models, employ heterogeneous doses and routes of administration and evaluate surrogate outcomes rather than patient-centered endpoints. In osteoarthritis, for example, improvements in histological cartilage scores or inflammatory markers do not necessarily translate into meaningful pain relief, functional improvement or delayed arthroplasty. Similarly, enhanced fracture callus parameters in animals cannot be directly extrapolated to elderly patients with multimorbidity, diabetes, osteoporosis or polypharmacy.

Another limitation is the heterogeneity of melatonin pharmacology. Oral, topical, intra-articular, scaffold-based and nanoparticle-mediated delivery may produce very different tissue concentrations. Timing may also be critical: the biological requirements of acute inflammation, tissue proliferation and remodeling are not identical. A compound that reduces excessive inflammation may be beneficial in one phase but less useful, or potentially harmful, in another if it suppresses necessary remodeling signals.

Future clinical studies should therefore define the target condition precisely, use standardized formulations, report pharmacokinetic considerations, include clinically meaningful outcome measures and stratify patients according to age, metabolic status, sleep quality and disease stage. Randomized controlled trials in early osteoarthritis, postoperative recovery, fracture healing and tendinopathy could be particularly informative if designed with adequate follow-up and appropriate functional endpoints.

11. Conclusions

Melatonin is a pleiotropic molecule with a coherent biological rationale in musculoskeletal medicine. Its actions on oxidative stress, inflammation, mitochondrial homeostasis, autophagy, ferroptosis and circadian regulation intersect with pathways involved in bone loss, cartilage degeneration, muscle injury, tendon remodeling, spinal cord injury and intervertebral disc degeneration. Preclinical evidence is substantial and supports continued investigation.

At present, however, melatonin should be regarded as a promising adjunct rather than an established disease-modifying treatment for osteoarticular disorders. Its favorable safety profile, low cost and broad biological activity make it attractive, but routine clinical use in orthopedic indications requires stronger human evidence. The next step should be the design of multicenter, randomized, placebo-controlled trials able to define dose, timing, route of administration and patient groups most likely to benefit. Until such evidence is available, melatonin remains an important translational candidate in regenerative and conservative musculoskeletal medicine.