{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,2]],"date-time":"2026-10-02T00:04:55Z","timestamp":1790899495756,"version":"4.1.0"},"reference-count":101,"publisher":"MDPI AG","issue":"2","license":[{"start":{"date-parts":[[2022,1,12]],"date-time":"2022-01-12T00:00:00Z","timestamp":1641945600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Nutrients"],"abstract":"<jats:p>As a consequence of epidemiological studies showing significant associations of vitamin D deficiency with a variety of adverse extra-skeletal clinical outcomes including cardiovascular diseases, cancer, and mortality, large vitamin D randomized controlled trials (RCTs) have been designed and conducted over the last few years. The vast majority of these trials did not restrict their study populations to individuals with vitamin D deficiency, and some even allowed moderate vitamin D supplementation in the placebo groups. In these RCTs, there were no significant effects on the primary outcomes, including cancer, cardiovascular events, and mortality, but explorative outcome analyses and meta-analyses revealed indications for potential benefits such as reductions in cancer mortality or acute respiratory infections. Importantly, data from RCTs with relatively high doses of vitamin D supplementation did, by the vast majority, not show significant safety issues, except for trials in critically or severely ill patients or in those using very high intermittent vitamin D doses. The recent large vitamin D RCTs did not challenge the beneficial effects of vitamin D regarding rickets and osteomalacia, that therefore continue to provide the scientific basis for nutritional vitamin D guidelines and recommendations. There remains a great need to evaluate the effects of vitamin D treatment in populations with vitamin D deficiency or certain characteristics suggesting a high sensitivity to treatment. Outcomes and limitations of recently published large vitamin D RCTs must inform the design of future vitamin D or nutrition trials that should use more personalized approaches.<\/jats:p>","DOI":"10.3390\/nu14020303","type":"journal-article","created":{"date-parts":[[2022,1,12]],"date-time":"2022-01-12T09:10:36Z","timestamp":1641978636000},"page":"303","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":121,"title":["Critical Appraisal of Large Vitamin D Randomized Controlled Trials"],"prefix":"10.3390","volume":"14","author":[{"given":"Stefan","family":"Pilz","sequence":"first","affiliation":[{"name":"Division of Endocrinology and Diabetology, Department of Internal Medicine, Medical University of Graz, 8036 Graz, Austria"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christian","family":"Trummer","sequence":"additional","affiliation":[{"name":"Division of Endocrinology and Diabetology, Department of Internal Medicine, Medical University of Graz, 8036 Graz, Austria"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Verena","family":"Theiler-Schwetz","sequence":"additional","affiliation":[{"name":"Division of Endocrinology and Diabetology, Department of Internal Medicine, Medical University of Graz, 8036 Graz, Austria"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1761-2914","authenticated-orcid":false,"given":"Martin R.","family":"Gr\u00fcbler","sequence":"additional","affiliation":[{"name":"Division of Endocrinology and Diabetology, Department of Internal Medicine, Medical University of Graz, 8036 Graz, Austria"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nicolas D.","family":"Verheyen","sequence":"additional","affiliation":[{"name":"Division of Cardiology, Department of Internal Medicine, Medical University of Graz, 8036 Graz, Austria"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8176-5202","authenticated-orcid":false,"given":"Balazs","family":"Odler","sequence":"additional","affiliation":[{"name":"Division of Nephrology, Department of Internal Medicine, Medical University of Graz, 8036 Graz, Austria"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4225-2746","authenticated-orcid":false,"given":"Spyridon N.","family":"Karras","sequence":"additional","affiliation":[{"name":"National Scholarship Foundation, 55535 Thessaloniki, Greece"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6085-6554","authenticated-orcid":false,"given":"Armin","family":"Zittermann","sequence":"additional","affiliation":[{"name":"Clinic for Thoracic and Cardiovascular Surgery, Herz- und Diabeteszentrum Nordrhein-Westfalen (NRW), Ruhr University Bochum, 32545 Bad Oeynhausen, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Winfried","family":"M\u00e4rz","sequence":"additional","affiliation":[{"name":"Clinical Institute of Medical and Chemical Laboratory Diagnostics, Medical University of Graz, 8036 Graz, Austria"},{"name":"SYNLAB Academy, Synlab Holding Deutschland GmbH, 68159 Mannheim, Germany"},{"name":"V<sup>th<\/sup> Department of Medicine (Nephrology, Hypertensiology, Rheumatology, Endocrinology, Diabetology, Lipidology), Medical Faculty Mannheim, University of Heidelberg, 68167 Mannheim, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2022,1,12]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"R27","DOI":"10.1530\/EC-18-0432","article-title":"Vitamin D testing and treatment: A narrative review of current evidence","volume":"8","author":"Pilz","year":"2019","journal-title":"Endocr. 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