Research Article: Vitamin D and mortality: Individual participant data meta-analysis of standardized 25-hydroxyvitamin D in 26916 individuals from a European consortium

Date Published: February 16, 2017

Publisher: Public Library of Science

Author(s): Martin Gaksch, Rolf Jorde, Guri Grimnes, Ragnar Joakimsen, Henrik Schirmer, Tom Wilsgaard, Ellisiv B. Mathiesen, Inger Njølstad, Maja-Lisa Løchen, Winfried März, Marcus E. Kleber, Andreas Tomaschitz, Martin Grübler, Gudny Eiriksdottir, Elias F. Gudmundsson, Tamara B. Harris, Mary F. Cotch, Thor Aspelund, Vilmundur Gudnason, Femke Rutters, Joline W. J. Beulens, Esther van ‘t Riet, Giel Nijpels, Jacqueline M. Dekker, Diana Grove-Laugesen, Lars Rejnmark, Markus A. Busch, Gert B. M. Mensink, Christa Scheidt-Nave, Michael Thamm, Karin M. A. Swart, Ingeborg A. Brouwer, Paul Lips, Natasja M. van Schoor, Christopher T. Sempos, Ramón A. Durazo-Arvizu, Zuzana Škrabáková, Kirsten G. Dowling, Kevin D. Cashman, Mairead Kiely, Stefan Pilz, Michal Zmijewski.


Vitamin D deficiency may be a risk factor for mortality but previous meta-analyses lacked standardization of laboratory methods for 25-hydroxyvitamin D (25[OH]D) concentrations and used aggregate data instead of individual participant data (IPD). We therefore performed an IPD meta-analysis on the association between standardized serum 25(OH)D and mortality.

In a European consortium of eight prospective studies, including seven general population cohorts, we used the Vitamin D Standardization Program (VDSP) protocols to standardize 25(OH)D data. Meta-analyses using a one step procedure on IPD were performed to study associations of 25(OH)D with all-cause mortality as the primary outcome, and with cardiovascular and cancer mortality as secondary outcomes. This meta-analysis is registered at, number NCT02438488.

We analysed 26916 study participants (median age 61.6 years, 58% females) with a median 25(OH)D concentration of 53.8 nmol/L. During a median follow-up time of 10.5 years, 6802 persons died. Compared to participants with 25(OH)D concentrations of 75 to 99.99 nmol/L, the adjusted hazard ratios (with 95% confidence interval) for mortality in the 25(OH)D groups with 40 to 49.99, 30 to 39.99, and <30 nmol/L were 1.15 (1.00–1.29), 1.33 (1.16–1.51), and 1.67 (1.44–1.89), respectively. We observed similar results for cardiovascular mortality, but there was no significant linear association between 25(OH)D and cancer mortality. There was also no significantly increased mortality risk at high 25(OH)D levels up to 125 nmol/L. In the first IPD meta-analysis using standardized measurements of 25(OH)D we observed an association between low 25(OH)D and increased risk of all-cause mortality. It is of public health interest to evaluate whether treatment of vitamin D deficiency prevents premature deaths.

Partial Text

Vitamin D is involved in the regulation of calcium homeostasis and exerts beneficial effects on skeletal health.[1] Serum concentrations of 25-hydroxyvitamin D (25[OH]D) are measured to assess vitamin D status, which is mainly determined by sunlight (ultraviolet-B [UV-B]) induced vitamin D production in the skin and, to a lesser extent, by dietary or supplemental vitamin D intake.[1] Low 25(OH)D status has emerged as a risk factor for various adverse health outcomes including mortality,[2] but there is controversy on the classification of 25(OH)D status and the shape of the association between 25(OH)D concentrations and mortality.[1–10]

Baseline characteristics of the entire study population and of all eight individual cohort studies comprising 26916 participants are shown in Table 1.

In this IPD meta-analysis of a Northern European consortium, we have shown that low standardized 25(OH)D concentrations are associated with an increased risk of all-cause and cardiovascular mortality, but not with cancer mortality.




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