Abstract
Introduction: The incidence and mortality of bone diseases are still gradually increasing, creating a significant financial burden for societies worldwide. The prevalence of osteopenia is projected to increase to 64.3 million Americans, and that of osteoporosis to 11.9 million by 2030. Melatonin, microRNAs, exosomes, and mesenchymal stem cells exert numerous physiological effects, including inducing anti-inflammatory and antioxidant functions, resetting circadian rhythms, and promoting wound healing and tissue regeneration, participating in the maintenance and regenerative processes of bones and cartilage. Objective: A systematic review was carried out to present the state of the art of melatonin regulation, mesenchymal stem cells, exosomes, microRNAs, and nutrients in the bone regeneration process. Methods: The systematic review rules (PRISMA) were followed. The search was carried out from March to May 2025 in the Scopus, PubMed, Science Direct, Scielo, databases, using scientific articles from 2016 to 2025. The quality of the studies was based on the GRADE instrument and the risk of bias was analyzed according to the Cochrane instrument. Results and discussion: A total of 126 studies were selected that were submitted to eligibility analysis, and then 80 that did not meet the criteria were excluded. The final sample consisted of 46 studies eligible for the present systematic review. Most studies showed homogeneity in their results, with X2=79.5%>50%. The symmetrical funnel plot does not suggest a risk of bias between small sample-size studies. Conclusion: Melatonin has important functions in regulating the regenerative activities of mesenchymal stem cells that modulate, together with nutrients, the activities of exosomes and microRNAs in the bone regeneration process.