title: Do studies reporting 'U'-shaped serum 25-hydroxyvitamin D-health outcome relationships reflect adverse effects?
abstract: 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.
authors.affiliation: Sunlight, Nutrition, and Health Research Center San Francisco , CA, USA.
authors.forename: William B
authors.initials: WB
authors.lastname: Grant
authors.affiliation: Unit of Reproductive Endocrinology, First Department of Obstetrics and Gynecology, Medical School, Aristotle University of Thessaloniki , Thessaloniki, Greece.
authors.forename: Spyridon N
authors.initials: SN
authors.lastname: Karras
authors.affiliation: Department of Geriatrics, University Hospital Zurich, Switzerland Centre on Aging and Mobility, University of Zurich , Switzerland.
authors.forename: Heike A
authors.initials: HA
authors.lastname: Bischoff-Ferrari
authors.affiliation: Department of Neuroscience, Division of Geriatric Medicine, Angers University Hospital, University Memory Clinic of Angers, UPRES EA 4638, University of Angers , France.
authors.forename: Cedric
authors.initials: C
authors.lastname: Annweiler
authors.affiliation: Honorary Professor, Blizard Institute, Barts & The London School of Medicine & Dentistry, Queen Mary University of London , London UK.
authors.forename: Barbara J
authors.initials: BJ
authors.lastname: Boucher
authors.affiliation: Oslo University Hospital, The Norwegian Radium Hospital, Institute for Cancer Research, Department of Radiation Biology , Montebello, Oslo, Norway.
authors.forename: Asta
authors.initials: A
authors.lastname: Juzeniene
authors.affiliation: Department of Family Medicine and Public Health, University of California San Diego , La Jolla, CA USA.
authors.forename: Cedric F
authors.initials: CF
authors.lastname: Garland
authors.affiliation: Section of Endocrinology, Diabetes and Nutrition, Department of Medicine, Boston University Medical Center , Boston, MA, USA.
authors.forename: Michael F
authors.initials: MF
authors.lastname: Holick
keywords: 0mortality rate; 25-hydroxyvitamin D; U-shaped; Vitamin D; allergic reactions; cancer; cardiovascular disease; falls; fractures; pancreas; prostate