Abstract: nutrients Review A Narrative Review of the Evidence for Variations in Serum 25-Hydroxyvitamin D Concentration Thresholds for Optimal Health William B. Grant 1, * , Fatme Al Anouti 2 , Barbara J. Boucher 3 , Erdinç Dursun 4 , Duygu Gezen-Ak 4 , Edward B. Jude 5,6,7 , Tatiana Karonova 8 and Pawel Pludowski 9 1 2 3 4 5 6 7 8 9



 * Sunlight, Nutrition, and Health Research Center, P.O. Box 641603, San Francisco, CA 94164-1603, USA Department of Health Sciences, College of Natural and Health Sciences, Zayed University, Abu Dhabi 144534, United Arab Emirates; fatme.alanouti@zu.ac.ae The Blizard Institute, Barts & The London School of Medicine & Dentistry, Queen Mary University of London, London E12AT, UK; bboucher@doctors.org.uk Department of Neuroscience, Institute of Neurological Sciences, Istanbul University-Cerrahpasa, Istanbul 34098, Turkey; erdincdu@gmail.com (E.D.); duygugezenak@gmail.com (D.G.-A.) Tameside and Glossop Integrated Care NHS Foundation Trust, Fountain Street, Ashton-under-Lyne OL6 9RW, UK; Edward.jude@tgh.nhs.uk The University of Manchester, Oxford Road, Manchester M13 9PL, UK Manchester Metropolitan University, All Saints Building, Manchester M15 6BH, UK Clinical Endocrinology Laboratory, Department of Endocrinology, Almazov National Medical Research Centre, 194021 Saint-Petersburg, Russia; karonova@mail.ru Department of Biochemistry, Radioimmunology and Experimental Medicine, The Children’s Memorial Health Institute, 04730 Warsaw, Poland; p.pludowski@ipczd.pl Correspondence: wbgrant@infionline.net; Tel.: +1-415-409-1980 Citation: Grant, W.B.; Al Anouti, F.; Boucher, B.J.; Dursun, E.; Gezen-Ak, D.; Jude, E.B.; Karonova, T.; Pludowski, P. A Narrative Review of the Evidence for Variations in Serum 25-Hydroxyvitamin D Concentration Thresholds for Optimal Health. Nutrients 2022, 14, 639. https:// doi.org/10.3390/nu14030639 Academic Editors: Andrea Fabbri and Igor Sergeev Received: 7 January 2022 Accepted: 28 January 2022 Published: 2 February 2022 Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations. Copyright: © 2022 by the authors. Licensee MDPI, Basel, Switzerland. Abstract: Vitamin D3 has many important health benefits. Unfortunately, these benefits are not widely known among health care personnel and the general public. As a result, most of the world’s population has serum 25-hydroxyvitamin D (25(OH)D) concentrations far below optimal values. This narrative review examines the evidence for the major causes of death including cardiovascular disease, hypertension, cancer, type 2 diabetes mellitus, and COVID-19 with regard to sub-optimal 25(OH)D concentrations. Evidence for the beneficial effects comes from a variety of approaches including ecological and observational studies, studies of mechanisms, and Mendelian randomization studies. Although randomized controlled trials (RCTs) are generally considered the strongest form of evidence for pharmaceutical drugs, the study designs and the conduct of RCTs performed for vitamin D have mostly been flawed for the following reasons: they have been based on vitamin D dose rather than on baseline and achieved 25(OH)D concentrations; they have involved participants with 25(OH)D concentrations above the population mean; they have given low vitamin D doses; and they have permitted other sources of vitamin D. Thus, the strongest evidence generally comes from the other types of studies. The..