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

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      Author(s): 1 , 2 , 2 , 2 , 3 , 4 , 2 , 4 , 4 , 5 , 6 , 7 , 5 , 8 , 9 , 10 , 11 , 1 , 9 , 12 , 13 , 13 , 14 , 15 , 13 , 16 , 13 , 16 , 17 , 17 , 18 , 17 , 17 , 17 , 19 , 19 , 20 , 20 , 20 , 20 , 17 , 21 , 22 , 17 , 23 , 24 , 25 , 25 , 25 , 26 , 25 , 27 , 1 , 17 , *
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      Publication date (Electronic):
      Journal: PLoS ONE
      Publisher: Public Library of Science

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          Abstract

          Background

          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.

          Methods

          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 ClinicalTrials.gov, number NCT02438488.

          Findings

          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.

          Interpretation

          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.

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          Vitamin D and mortality: meta-analysis of individual participant data from a large consortium of cohort studies from Europe and the United States

          Ben Schöttker, Rolf Jorde, Anne Peasey … (2014)
          Objective To investigate the association between serum 25-hydroxyvitamin D concentrations (25(OH)D) and mortality in a large consortium of cohort studies paying particular attention to potential age, sex, season, and country differences. Design Meta-analysis of individual participant data of eight prospective cohort studies from Europe and the US. Setting General population. Participants 26 018 men and women aged 50-79 years Main outcome measures All-cause, cardiovascular, and cancer mortality. Results 25(OH)D concentrations varied strongly by season (higher in summer), country (higher in US and northern Europe) and sex (higher in men), but no consistent trend with age was observed. During follow-up, 6695 study participants died, among whom 2624 died of cardiovascular diseases and 2227 died of cancer. For each cohort and analysis, 25(OH)D quintiles were defined with cohort and subgroup specific cut-off values. Comparing bottom versus top quintiles resulted in a pooled risk ratio of 1.57 (95% CI 1.36 to 1.81) for all-cause mortality. Risk ratios for cardiovascular mortality were similar in magnitude to that for all-cause mortality in subjects both with and without a history of cardiovascular disease at baseline. With respect to cancer mortality, an association was only observed among subjects with a history of cancer (risk ratio, 1.70 (1.00 to 2.88)). Analyses using all quintiles suggest curvilinear, inverse, dose-response curves for the aforementioned relationships. No strong age, sex, season, or country specific differences were detected. Heterogeneity was low in most meta-analyses. Conclusions Despite levels of 25(OH)D strongly varying with country, sex, and season, the association between 25(OH)D level and all-cause and cause-specific mortality was remarkably consistent. Results from a long term randomised controlled trial addressing longevity are being awaited before vitamin D supplementation can be recommended in most individuals with low 25(OH)D levels.
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            The effect of vitamin D supplementation on skeletal, vascular, or cancer outcomes: a trial sequential meta-analysis.

            Mark J Bolland, Andrew Grey, Greg D Gamble … (2014)
            Vitamin D insufficiency is associated with many disorders, leading to calls for widespread supplementation. Some investigators suggest that more clinical trials to test the effect of vitamin D on disorders are needed. We did a trial sequential meta-analysis of existing randomised controlled trials of vitamin D supplements, with or without calcium, to investigate the possible effect of future trials on current knowledge. We estimated the effects of vitamin D supplementation on myocardial infarction or ischaemic heart disease, stroke or cerebrovascular disease, cancer, total fracture, hip fracture, and mortality in trial sequential analyses using a risk reduction threshold of 5% for mortality and 15% for other endpoints. The effect estimate for vitamin D supplementation with or without calcium for myocardial infarction or ischaemic heart disease (nine trials, 48 647 patients), stroke or cerebrovascular disease (eight trials 46 431 patients), cancer (seven trials, 48 167 patients), and total fracture (22 trials, 76 497 patients) lay within the futility boundary, indicating that vitamin D supplementation does not alter the relative risk of any of these endpoints by 15% or more. Vitamin D supplementation alone did not reduce hip fracture by 15% or more (12 trials, 27 834 patients). Vitamin D co-administered with calcium reduced hip fracture in institutionalised individuals (two trials, 3853 patients) but did not alter the relative risk of hip fracture by 15% or more in community-dwelling individuals (seven trials, 46 237 patients). There is uncertainty as to whether vitamin D with or without calcium reduces the risk of death (38 trials, 81 173). Our findings suggest that vitamin D supplementation with or without calcium does not reduce skeletal or non-skeletal outcomes in unselected community-dwelling individuals by more than 15%. Future trials with similar designs are unlikely to alter these conclusions. Health Research Council of New Zealand. Copyright © 2014 Elsevier Ltd. All rights reserved.
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              Flexible meta-regression functions for modeling aggregate dose-response data, with an application to alcohol and mortality.

              Vincenzo Bagnardi, Piero Quatto, Antonella Zambon … (2004)
              In this paper, the authors describe fractional polynomials and cubic splines with which to represent smooth dose-response relations in summarizing meta-analytical aggregate data. Use of these two curve-fitting families can help prevent the problems arising from inappropriate linearity assumptions. These methods are illustrated in the problem of estimating the shape of the dose-response curve between alcohol consumption and all-cause mortality risk. The authors considered aggregate data from 29 cohort studies investigating this issue (1966-2000). J-shaped curves with a nadir at approximately 5-7 g/day of alcohol consumption and a last protective dose of 47-60 g/day were consistently obtained from fractional polynomials and cubic splines. The authors conclude that both of the curve-fitting families are useful tools with which to explore dose-response epidemiologic questions by means of meta-analytical approaches, especially when important nonlinearity is anticipated.
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                Author and article information

                Contributors
                Michal Zmijewski: Role: Editor
                Journal
                Journal ID (nlm-ta): PLoS One
                Journal ID (iso-abbrev): PLoS ONE
                Journal ID (publisher-id): plos
                Journal ID (pmc): plosone
                Title: PLoS ONE
                Publisher: Public Library of Science (San Francisco, CA USA )
                ISSN (Electronic): 1932-6203
                Publication date (Electronic): 16 February 2017
                Publication date Collection: 2017
                Volume: 12
                Issue: 2
                Electronic Location Identifier: e0170791
                Affiliations
                [1 ]Department of Internal Medicine, Division of Endocrinology and Diabetology, Medical University of Graz, Graz, Austria
                [2 ]Tromsø Endocrine Research Group, Department of Clinical Medicine, University of Tromsø, Tromsø, Norway
                [3 ]Tromsø Cardiovascular Research Group UNN, Department of Clinical Medicine, UiT The Arctic University of Norway, Tromsø, Norway
                [4 ]Department of Community Medicine, UiT The Arctic University of Norway, Tromsø, Norway
                [5 ]Mannheim Institute of Public Health, Social and Preventive Medicine, Mannheim Medical Faculty, University of Heidelberg, Mannheim, Germany
                [6 ]Synlab Academy, Mannheim, Germany
                [7 ]Clinical Institute of Medical and Chemical Laboratory Diagnostics, Medical University of Graz, Graz, Austria
                [8 ]Department of Internal Medicine II - Cardiology, University of Ulm Medical Centre, Ulm, Germany
                [9 ]Department of Cardiology, Medical University of Graz, Graz, Austria
                [10 ]Specialist Clinic for Rehabilitation Bad Aussee, Bad Aussee, Austria
                [11 ]Department of Internal Medicine - Cardiology, Charité University Hospital Berlin, Campus Virchow Klinikum, Berlin, Germany
                [12 ]Swiss Cardiovascular Center Bern, Department of Cardiology, Bern University Hospital, Bern, Switzerland
                [13 ]Icelandic Heart Association, Kopavogur, Iceland
                [14 ]National Institute on Aging, Laboratory of Epidemiology, and Population Sciences, Bethesda, Maryland, United States of America
                [15 ]Division of Epidemiology and Clinical Applications, National Eye Institute, Bethesda, Maryland, United States of America
                [16 ]Faculty of Medicine, School of Health Sciences, University of Iceland, Reykjavik, Iceland
                [17 ]Department of Epidemiology and Biostatistics and EMGO+ Institute for Health and Care Research, VU University Medical Centre, Amsterdam, the Netherlands
                [18 ]Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht, Utrecht, The Netherlands
                [19 ]Department of Endocrinology and Internal Medicine, Aarhus University Hospital, Aarhus, Denmark
                [20 ]Department of Epidemiology and Health Monitoring, Robert Koch Institute, Berlin, Germany
                [21 ]Department of Health Sciences and the EMGO Institute for Health and Care Research, Faculty of Earth and Life Sciences, VU University Amsterdam, Amsterdam, The Netherlands
                [22 ]Department of Internal Medicine, Endocrine Section, VU University medical center, Amsterdam, the Netherlands
                [23 ]National Institute of Health Office of Dietary Supplements, Bethesda, Maryland, United States of America
                [24 ]Department of Preventive Medicine and Epidemiology, Loyola University Medical Center, Maywood, Illinois, United States of America
                [25 ]Cork Centre for Vitamin D and Nutrition Research, School of Food and Nutritional Sciences, University College Cork, Cork, Ireland
                [26 ]Department of Medicine, University College Cork, Cork, Ireland
                [27 ]Irish Centre for Fetal and Neonatal Translational Research [INFANT], University College Cork, Cork, Ireland
                Medical University of Gdańsk, POLAND
                Author notes

                Competing Interests: The authors have declared that no competing interests exist.

                • Conceptualization: SP R. Jorde R. Joakimsen GE VG LR NMS PL KDC MK.

                • Data curation: M. Gaksch SP AB GBMM CTS RADA.

                • Formal analysis: M. Gaksch SP.

                • Funding acquisition: KDC MK.

                • Investigation: M. Gaksch SP R. Jorde GG R. Joakimsen EBM TW IN MLL MEK WM GE EFG VG TA TBH MFC FR JWJB EVR GN JMD DGL LR MAB GBMM CSN KMAS NMS IAB PL ZS KGD KDC MK.

                • Methodology: SP M. Gaksch.

                • Project administration: SP R. Jorde KDC MK.

                • Resources: M. Gaksch SP R. Jorde GG R. Joakimsen EBM TW IN MLL MEK WM GE EFG VG TA TBH MFC FR JWJB EVR GN JMD DGL LR MAB GBMM CSN KMAS NMS IAB PL ZS KGD KDC MK.

                • Software: M. Gaksch SP AB GBMM CTS RADA.

                • Supervision: SP R. Jorde.

                • Validation: M. Gaksch SP AB GBMM CTS RADA.

                • Visualization: M. Gaksch.

                • Writing – original draft: SP.

                • Writing – review & editing: M. Grübler SP R. Jorde R. Joakimsen EBM GE EFG TBH MFC FR JWJB EVR MAB GBMM CSN KMAS NMS IAB PL CTS KGD KDC MK.

                Article
                Publisher ID: PONE-D-16-36649
                DOI: 10.1371/journal.pone.0170791
                PMC ID: 5312926
                PubMed ID: 28207791
                SO-VID: 6d716461-9a06-4fd8-bbdc-b3f26a501447
                License:

                This is an open access article, free of all copyright, and may be freely reproduced, distributed, transmitted, modified, built upon, or otherwise used by anyone for any lawful purpose. The work is made available under the Creative Commons CC0 public domain dedication.

                History
                Date received : 3 October 2016
                Date accepted : 16 December 2016
                Page count
                Figures: 1, Tables: 4, Pages: 15
                Funding
                Funded by: funder-id http://dx.doi.org/10.13039/501100004963, Seventh Framework Programme;
                Award ID: 613977
                Award Recipient :
                This project has received funding from the European Community’s Seventh Framework Programme (FP7/2007-2013) under Grant Agreement 613977 for the ODIN Integrated Project [Food-based solutions for optimal vitamin D nutrition and health through the life cycle http://www.odin-vitd.eu/]. Funding for the individual studies contributing data to this effort can be found in Appendix (S1 File), section 11.
                Categories
                Subject: Research Article
                Subject: Physical sciences
                Subject: Chemistry
                Subject: Chemical compounds
                Subject: Organic compounds
                Subject: Vitamins
                Subject: Vitamin D
                Subject: Physical sciences
                Subject: Chemistry
                Subject: Organic chemistry
                Subject: Organic compounds
                Subject: Vitamins
                Subject: Vitamin D
                Subject: Research and Analysis Methods
                Subject: Mathematical and Statistical Techniques
                Subject: Statistical Methods
                Subject: Meta-Analysis
                Subject: Physical Sciences
                Subject: Mathematics
                Subject: Statistics (Mathematics)
                Subject: Statistical Methods
                Subject: Meta-Analysis
                Subject: Medicine and Health Sciences
                Subject: Cardiovascular Medicine
                Subject: Cardiovascular Diseases
                Subject: People and Places
                Subject: Demography
                Subject: Death Rates
                Subject: Research and Analysis Methods
                Subject: Research Design
                Subject: Cohort Studies
                Subject: Biology and life sciences
                Subject: Nutrition
                Subject: Nutritional deficiencies
                Subject: Vitamin D deficiency
                Subject: Medicine and health sciences
                Subject: Nutrition
                Subject: Nutritional deficiencies
                Subject: Vitamin D deficiency
                Subject: Medicine and Health Sciences
                Subject: Vascular Medicine
                Subject: Blood Pressure
                Subject: Hypertension
                Subject: Medicine and Health Sciences
                Subject: Endocrinology
                Subject: Endocrine Disorders
                Subject: Diabetes Mellitus
                Subject: Medicine and Health Sciences
                Subject: Metabolic Disorders
                Subject: Diabetes Mellitus
                Custom metadata
                Data Availability All relevant data are within the paper and its Supporting Information files.

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