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Dermatoendocrinol. 2016 May 16;8(1):e1187349. doi: 10.1080/19381980.2016.1187349. eCollection 2016 Jan-Dec.

Do studies reporting 'U'-shaped serum 25-hydroxyvitamin D-health outcome relationships reflect adverse effects?

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Sunlight, Nutrition, and Health Research Center San Francisco , CA, USA.
Unit of Reproductive Endocrinology, First Department of Obstetrics and Gynecology, Medical School, Aristotle University of Thessaloniki , Thessaloniki, Greece.
Department of Geriatrics, University Hospital Zurich, Switzerland Centre on Aging and Mobility, University of Zurich , Switzerland.
Department of Neuroscience, Division of Geriatric Medicine, Angers University Hospital, University Memory Clinic of Angers, UPRES EA 4638, University of Angers , France.
Honorary Professor, Blizard Institute, Barts & The London School of Medicine & Dentistry, Queen Mary University of London , London UK.
Oslo University Hospital, The Norwegian Radium Hospital, Institute for Cancer Research, Department of Radiation Biology , Montebello, Oslo, Norway.
Department of Family Medicine and Public Health, University of California San Diego , La Jolla, CA USA.
Section of Endocrinology, Diabetes and Nutrition, Department of Medicine, Boston University Medical Center , Boston, MA, USA.


Several reports describe U-shaped 25-hydroxyvitamin D [25(OH)D] concentration-health outcomes, including musculo-skeletal disorders such as falls and fractures, several cancers, cardiovascular disease (CVD), cognitive function, all-cause mortality rates, birth outcomes, allergic reactions, frailty, and some other disorders. This paper reviews reports of U-shaped outcome associations with vitamin D status for evidence of underlying pathophysiological processes, or of confounding, finding that some U-shaped associations appear to be biologically meaningful, but that many could well reflect confounding by factors such as lifestyle, or hypovitaminosis D-related disease onset being masked by self-supplementation that was begun too late to correct developing health problems but before baseline vitamin D status assessment. However, the various U-shaped associations for allergic reactions may be due to vitamin D modulation of the phenotype of the immune response, shifting the Th1-Th2 balance toward Th2 formation. For prostate cancer, there seems to be little effect of 25(OH)D concentration on incidence; however, there is an inverse correlation between 25(OH)D concentration and mortality rates. Future observational studies, and randomized controlled trial data analyses, should include adjustment for data collected on prior long-term vitamin D supplementation and solar UVB exposure, as well as other potential confounders.


0mortality rate; 25-hydroxyvitamin D; U-shaped; Vitamin D; allergic reactions; cancer; cardiovascular disease; falls; fractures; pancreas; prostate

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