Relationship between low vitamin D status and extra-skeletal diseases: a systematic review on effects of prophylaxis with vitamin D Lorella Magnani Clinical Trials in Degenerative Diseases 2019 4(2):56-63 Background and objective: A recent body of observational evidence has suggested that the low vitamin D status is related to various diseases, both skeletal and extra-skeletal muscle, including cardiovascular disease, chronic obstructive pulmonary disease and cystic fibrosis, inflammatory bowel disease, cancer, diabetes, immune system diseases (allergies), generating a growing use of supplementation, and at high doses. We conducted this systematic review with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA)statement, to summarize the scientific literature concerning the role of low-level vitamin D in the extra-skeletal outcomes and the effects of supplementation. Materials and methods: Articles from PubMed, MEDLINE,and Cochrane Library were searched. Finally, 18 systematic reviews/meta-analyses, 11 documents of scientific societies/guidelines/editorials/books, and 19 interventions and observational studies (of which 5 randomized controlled trials) were included. Results: It has been found that, despite there is a large amount of observational cohort studies and anecdotal evidence of the benefits of vitamin D supplementation both on skeletal and extra-skeletal outcomes, more research is needed to verify the causality (and not only correlation) of low vitamin D status on extra-skeletal outcomes, considering that solid evidence from randomized controlled trials or other intervention studies are few, that the results of different randomized controlled trials cancel each other coming to opposite conclusions and that pervasive methodological defects make the evidence unreliable. Conclusion: Vitamin D supplementation for extra-skeletal outcomes does not seem justified, if not in clinically documented deficiencies or in specially designed clinical trials.