Vitamin D with Calcium Reduces Mortality: Patient Level Pooled Analysis of 70,528 Patients from Eight Major Vitamin D Trials

The Journal of Clinical Endocrinology & Metabolism May 17, 2012 jc.2011-3328
Lars Rejnmark, Alison Avenell, Tahir Masud, Frazer Anderson, Haakon E. Meyer, Kerrie M. Sanders, Kari Salovaara, Cyrus Cooper, Helen E. Smith, Elizabeth. T. Jacobs, David Torgerson, Rebecca D. Jackson, JoAnn E. Manson, Kim Brixen, Leif Mosekilde, John A. Robbins, Roger M. Francis and Bo Abrahamsen
Department of Endocrinology and Internal Medicine (L.R., L.M.), Aarhus University Hospital, 8000 Aarhus, Denmark; Health Services Research Unit (A.A.), University of Aberdeen, Aberdeen AB24 2TZ, United Kingdom; Geriatric Medicine (T.M.), Nottingham University Hospitals, Nottingham NG1 5DU, United Kingdom; Institute of Clinical Research (T.M., K.B., B.A.), University of Southern Denmark, 5000 Odense, Denmark; Geriatric Medicine (F.A.), Developmental Origins of Health and Disease Research Division, University of Southampton School of Medicine, Southampton SO17 1BJ, United Kingdom; Division of Epidemiology (H.E.M.), Norwegian Institute of Public Health, 0456 Oslo, Norway; Department of Community Medicine (H.E.M.), University of Oslo, 0316 Oslo, Norway; NorthWest Academic Centre (K.M.S.), Department of Medicine, University of Melbourne and Western Health, Victoria 3052, Australia; Bone and Cartilage Research Unit (K.S.), University of Eastern Finland, 70210 Kuopio, Finland; Department of Orthopedics, Traumatology, and Handsurgery (K.S.), Kuopio University Hospital, 70211 Kuopio, Finland; Medical Research Council Lifecourse Epidemiology Unit (C.C.), University of Southampton and National Institute for Health Research Biomedical Research Unit in Musculoskeletal Science, University of Oxford, Oxford OX1 2JD, United Kingdom; Primary Care and Public Health (H.E.S.), Brighton and Sussex Medical School, Brighton BN19PH, United Kingdom; Mel and Enid Zuckerman College of Public Health and the Arizona Cancer Center (E.T.J.), University of Arizona, Tucson Arizona 85721; York Trials Unit (D.T.), University of York, York YO1 05DD, United Kingdom; Division of Endocrinology, Diabetes, and Metabolism (R.D.J.), College of Medicine, The Ohio State University, Columbus, Ohio 43210; Department of Medicine (J.E.M.), Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts 02115; Endocrinology (K.B.), Odense University Hospital, DK-5000 Odense, Denmark; Internal Medicine (J.A.R.), University of California Davis, Sacramento, California 95817; Institute for Ageing and Health (R.M.F.), Newcastle University, Campus for Ageing and Vitality, Newcastle upon Tyne NE4 5PL, United Kingdom; and Department of Medicine F (B.A.), Copenhagen University Hospital Gentofte, DK-2900 Hellerup, Denmark
Address all correspondence and requests for reprints to: Lars Rejnmark, M.D., Ph.D., Dr.Med.Sc., Associate Professor of Endocrinology, Aarhus University, Department of Endocrinology and Internal Medicine, Aarhus Sygehus, Aarhus University Hospital, Tage-Hansens gade 2, DK 8000 Aarhus C, Denmark. E-mail: rejnmark at post6.tele.dk.

Introduction: Vitamin D may affect multiple health outcomes. If so, an effect on mortality is to be expected. Using pooled data from randomized controlled trials, we performed individual patient data (IPD) and trial level meta-analyses to assess mortality among participants randomized to either vitamin D alone or vitamin D with calcium.

Subjects and Methods: Through a systematic literature search, we identified 24 randomized controlled trials reporting data on mortality in which vitamin D was given either alone or with calcium. From a total of 13 trials with more than 1000 participants each, eight trials were included in our IPD analysis. Using a stratified Cox regression model, we calculated risk of death during 3 yr of treatment in an intention-to-treat analysis. Also, we performed a trial level meta-analysis including data from all studies.

Results: The IPD analysis yielded data on 70,528 randomized participants (86.8% females) with a median age of 70 (interquartile range, 62–77) yr. Vitamin D with or without calcium reduced mortality by 7% [hazard ratio, 0.93; 95% confidence interval (CI), 0.88–0.99]. However, vitamin D alone did not affect mortality, but risk of death was reduced if vitamin D was given with calcium (hazard ratio, 0.91; 95% CI, 0.84–0.98). The number needed to treat with vitamin D plus calcium for 3 yr to prevent one death was 151. Trial level meta-analysis (24 trials with 88,097 participants) showed similar results, i.e. mortality was reduced with vitamin D plus calcium (odds ratio, 0.94; 95% CI, 0.88–0.99), but not with vitamin D alone (odds ratio, 0.98; 95% CI, 0.91–1.06).

Conclusion: Vitamin D with calcium reduces mortality in the elderly, whereas available data do not support an effect of vitamin D alone.
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Letter to Editor with reply

Vitamin D trials have many problems

Willia B. Grant, Director
Sunlight, Nutrition and Health Research Center
The pooled analysis of patient-level mortality rates from vitamin D and vitamin D plus calcium randomized controlled trials (RCTs) found a 9% reduction [odds ratio (OR) = 0.91 (95% CI, 0.84-0.98)] for vitamin D plus calcium but no effect with vitamin D alone [OR = 0.98 (95% CI, 0.91-1.06)] (1). The finding regarding vitamin D alone is puzzling and disagrees with an earlier meta-analysis of vitamin D trials with a mean daily supplementation of 528 IU (13.2 ?g) ref. 4 in (1) and a meta-analysis of observational studies of mortality rate with respect to 25-hydroxyvitamin D 25(OH)D concentrations (2).

Inspection of the details of the eight studies provides some reasons why the vitamin D without calcium studies may not have found beneficial results. First, two of the studies used bolus doses (300,000 or 500,000 IU) once a year. This is not a physiological dose and has not been shown to be equivalent to taking the same total amount divided into equal daily doses. In fact, the high dose was associated with greater risk of falls and fractures, especially in the first three months after dosing [ref. 20 in (1)].

Second, three of the studies were based on those with impaired health, either living in a nursing home or having risk factors for fractures or having suffered previous osteoporotic fracture. Such conditions and diseases as autoimmune diseases, calcified arteries, undiagnosed cancer, cognitive impairment, and diabetes mellitus can arise from low serum 25(OH)D concentrations, and once developed the severity can be moderated with vitamin D supplements but are unlikely to be reversed.

Third, and most important, none of the eight studies seems to have included an analysis of initial serum 25(OH)D concentrations and desirable 25(OH)D concentrations after dosing in the design of the study or selection of participants. The importance of doing so is highlighted in a recent paper, showing that the physiological effect of increasing nutrient intake or status varies as a function of the nutrient status (3). The serum 25(OH)D concentration-cancer and cardiovascular disease incidence relations change rapidly for low initial 25(OH)D concentrations, then very slowly above 75-100 nmol/liter (4). Another recent paper reported that there is considerable individual variation in 25(OH)D concentrations for and given oral intake (5). Evidently RCTs involving vitamin D are largely based on the protocols for pharmaceutical drugs, which generally exhibit linear dose-response relations and are not being obtained from other sources.

Hopefully vitamin D RCTs reported in the future will address the problems noted and, as a result, more readily confirm the findings of numerous ecological and observational studies (4). Ecological and observational studies appear to be more appropriate for studying the health effects of solar ultraviolet-B (UVB) irradiance and vitamin D since solar UVB is the primary source of vitamin D for most people and since long-term studies are preferable to short-term studies.

References

1. Rejnmark L, Avenell A, Masud T, Anderson F, Meyer HE, Sanders KM, Salovaara K, Cooper C, Smith HE, Jacobs ET, Torgerson D, Jackson RD, Manson JE, Brixen K, Mosekilde L, Robbins JA, Francis RM, Abrahamsen B. (2011) Vitamin D with calcium reduces mortality: Patient level pooled analysis of 70,528 patients from eight major vitamin D trials. J Clin Endocrinol Metab May 17.
2. Schottker B, Ball D, Gellert C, Brenner H. (2012) Serum 25-hydroxyvitamin D levels and overall mortality. A systematic review and meta-analysis of prospective cohort studies. Ageing Res Rev Feb 16.
3. Lappe JM, Heaney RP. (2012) Why randomized controlled trials of calcium and vitamin D sometimes fail. Dermatoendocrin 4(2) epub http://www.landesbioscience.com/journals/dermatoendocrinology/article/19833/
4. Grant WB. (2011) An estimate of the global reduction in mortality rates through doubling vitamin D levels. Eur J Clin Nutr 65:1016-1026.
5. Garland CF, French CB, Baggerly LL, Heaney RP. (2011) Vitamin D supplement doses and serum 25-hydroxyvitamin D in the range associated with cancer prevention. Anticancer Res 31:617-622.

Conflict of Interest: I receive funding from the UV Foundation (McLean, VA), Bio-Tech Pharmacal (Fayetteville, AR), the Vitamin D Council (San Luis Obispo, CA), and the Vitamin D Society (Canada).

Reply

Lars Rejnmark for the authors of the paper
Aarhus University Hospital, Aarhus, Denmark
We appreciate the thoughtful comments from Dr. Grant regarding effects of vitamin D alone on mortality. As clearly stated in our paper, major differences exist between trials on vitamin D alone supplements and trials on effects of vitamin D in combination with calcium (CaD). As outlined by Dr. Grant, two of the vitamin D alone trials studied effects of intermittent treatment with vitamin D in high doses, and the participants included in the vitamin D alone trials were, in general, older and more frail than participants included in the CaD trials. Although this may suggest an explanation for the apparently differential effect on mortality in response to supplementation with CaD compared with vitamin D alone, we would like to underline that such explanations should only be interpreted as a possible hypothesis that needs to be verified in further trials.

Moreover, we would like to underline that we do find it of importance to aim at establishing whether vitamin D alone is causally related to different health outcomes. Dr. Grant suggests that non-randomized trials may be most appropriate to study effects of vitamin D. Our findings of a significantly reduced mortality in response to CaD supplements show that use of gold standard methodology for establishing cause-effect relationships is possible and calls for further well designed randomized controlled trials. As suggested by Dr. Grant, such trials should, of course, include measurements of 25-hydroxyvitamin D levels. If beneficial effects are documented in randomized controlled trials, extrapolation to health effects from solar ultraviolet-B (UVB) irradiance and dietary vitamin D intake will be more reliable than conclusions based on solely observational studies.
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Comment by VitaminDWiki

7% reduction in death rate
Many meta-analysis like this do not even consider the amount of vitamin D used in each trial

See also VitaminDWiki

• Mortality reduced 1 percent for every 1 nanogram increase in vitamin D – Feb 2012
• All items in category Mortality and Vitamin D 312 items
• All items in category Meta-analysis and Vitamin D 641 items
• 40 ng Vitamin D perhaps optimal for reduced mortality – Meta-analysis Jan 2012
• Dr. Grant on vitamin D and mortality in VitaminDWiki