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Systematic Review: Vitamin D and Calcium Supplementation in Prevention of Cardiovascular Events

Lu Wang, MD, PhD; JoAnn E. Manson, MD, DrPH; Yiqing Song, MD, ScD; and Howard D. Sesso, ScD
[+] Article and Author Information

From Brigham and Women's Hospital and Harvard School of Public Health, Boston, Massachusetts.


Grant Support: By a scientist development grant from the American Heart Association (grant 0735390N) and a research grant from the National Heart, Lung, and Blood Institute (grant HL075445).

Potential Conflicts of Interest: None disclosed.

Requests for Single Reprints: Lu Wang, MD, PhD, Division of Preventive Medicine, Brigham and Women's Hospital, 900 Commonwealth Avenue East, Boston, MA 02215; e-mail: luwang@rics.bwh.harvard.edu.

Current Author Addresses: Drs. Wang, Manson, Song, and Sesso: Division of Preventive Medicine, Brigham and Women's Hospital, 900 Commonwealth Avenue, Boston, MA 02215.

Author Contributions: Conception and design: L. Wang, J.E. Manson, H.D. Sesso.

Analysis and interpretation of the data: L. Wang, J.E. Manson, Y. Song, H.D. Sesso.

Drafting of the article: L. Wang.

Critical revision of the article for important intellectual content: L. Wang, J.E. Manson, Y. Song, H.D. Sesso.

Final approval of the article: L. Wang, J.E. Manson, Y. Song, H.D. Sesso.

Statistical expertise: L. Wang, Y. Song.

Obtaining of funding: L. Wang.

Administrative, technical, or logistic support: J.E. Manson, Y. Song, H.D. Sesso.

Collection and assembly of data: L. Wang, J.E. Manson, Y. Song, H.D. Sesso.


Ann Intern Med. 2010;152(5):315-323. doi:10.7326/0003-4819-152-5-201003020-00010
Text Size: A A A

Background: Vitamin D and calcium may affect the cardiovascular system independently and interactively.

Purpose: To assess whether vitamin D and calcium supplements reduce the risk for cardiovascular events in adults.

Data Sources: Studies published in English from 1966 to July 2009 in MEDLINE, EMBASE, and the Cochrane Central Register of Controlled Trials.

Study Selection: Two investigators independently selected 17 prospective studies and randomized trials that examined vitamin D supplementation, calcium supplementation, or both and subsequent cardiovascular events.

Data Extraction: Three investigators extracted and checked data about study designs, participants, exposures or interventions, outcomes, and data quality.

Data Synthesis: Five prospective studies of patients receiving dialysis and 1 study involving a general population showed consistent reductions in cardiovascular disease (CVD) mortality among adults who received vitamin D supplements. Four prospective studies of initially healthy persons found no differences in incidence of CVD between calcium supplement recipients and nonrecipients. Results of secondary analyses in 8 randomized trials showed a slight but statistically nonsignificant reduction in CVD risk (pooled relative risk, 0.90 [95% CI, 0.77 to 1.05]) with vitamin D supplementation at moderate to high doses (approximately 1000 IU/d) but not with calcium supplementation (pooled relative risk, 1.14 [CI, 0.92 to 1.41]), or a combination of vitamin D and calcium supplementation (pooled relative risk, 1.04 [CI, 0.92 to 1.18]) compared with placebo.

Limitations: Only articles published in English that reported cardiovascular event outcomes were included. The small number of studies, the lack of trials designed specifically to assess primary effects on cardiovascular outcomes, and important between-study heterogeneity preclude definitive conclusions.

Conclusion: Evidence from limited data suggests that vitamin D supplements at moderate to high doses may reduce CVD risk, whereas calcium supplements seem to have minimal cardiovascular effects. Further research is needed to elucidate the role of these supplements in CVD prevention.

Primary Funding Source: The American Heart Association and the National Heart, Lung, and Blood Institute.

Figures

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Figure 1.
Literature search and selection.

Search terms for vitamin D included vitamin D intake, vitamin D supplement, calcidiol, calcitriol, cholecalciferol, and ergocalciferol. Search terms for calcium included calcium intake, calcium supplement, calcium carbonate, and calcium citrate. Search terms for CVD included cardiovascular disease, ischemic heart disease, coronary artery disease, cardiovascular mortality, myocardial infarction, and stroke. The original search was further limited to articles published in English, human studies, and studies of adults aged ≥19 years. In each box, the sum of studies in all categories may exceed the total number of excluded or included studies because of overlapping classification. CVD = cardiovascular disease; RCT = randomized, controlled trial.

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Figure 2.
Meta-analysis of the relative risk for cardiovascular events with vitamin D supplementation, calcium supplementation, or combination treatment versus placebo in randomized, controlled trials.
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Vitamin D Systematic Reviews
Posted on March 8, 2010
Robert P. Heaney
Creighton University
Conflict of Interest: None Declared

Editor: It is exceedingly disappointing to find, in the world's leading journal of internal medicine, two poorly conceived systematic reviews of vitamin D effects on the cardiovascular system (1, 2), accompanied by a largely supportive editorial (3), all three of which exhibit a limited awareness of current vitamin D physiology. For example, the review by Wang et al. (1) identifies a group of six prospective studies, only one of which used actual vitamin D (cholecalciferol). The others all used various 1- hydroxylated derivatives. Nor did the editorial, citing those six, pick up this critical distinction. Presumably the authors of the studies included were operating on the premise that, since calcitriol [1,25(OH)2D] is the ultimate, active form of the vitamin, it made sense to use that compound in their studies. That use, in hindsight, is understandable, even if now recognized to be inappropriate. The authors of the systematic reviews, however, should have been aware of current biology and therefore excluded them. The fact that the authors of the papers concerned used the term "vitamin D as a key word, or explicitly in their titles, simply highlights why individuals doing systematic reviews need to have up-to-date content knowledge of the subject they are reviewing. A very large body of literature, published over the past 10 years, makes clear that the non-calcium effects of vitamin D are autocrine (4), not endocrine, and that the 1- hydroxylated form of the vitamin is synthesized intracellularly by the target tissues concerned and is not derived from circulating calcitriol (5). Available evidence indicates that the concentration of calcitriol required to produce these non-calcium effects is higher than can safely be achieved through the mediation of serum calcitriol (5). Rather, serum 25(OH)D, present in thousand-fold greater concentration than calcitriol, provides the substrate for cells to manufacture as much calcitriol as they need, confined to the tissues concerned. But that works only so long as serum 25(OH)D levels are themselves adequate. Hence the critical importance of sufficient cholecalciferol input. One review hedges its conclusions with the qualifier "the dosages used which, as it turns out, were small. Both the editorial and Wang et al. speak of doses of 700-1000 IU/d as high. True, 700-800 IU is above the 1997 AI for vitamin D, but more than 95% of what is currently known about vitamin D has been published since those 1997 recommendations. It is now clear that outdoor summer workers commonly have serum 25(OH)D values between 120 and 200 nmol/L and that this may well be the primitive human level, as judged by values found in agricultural workers in the tropics (6). Both controlled dosing studies and extensive experience in recent years have established that serum 25(OH)D rises by about 0.6-1.0 nmol/L/ (or 1.5-2.5 nmol/L/100 IU/d) (7). Thus serum levels of 80 nmol/L require continuous inputs from all sources on the order of 4000 IU/d, and 100 nmol/L, 5000 IU/d, etc. Such doses are not only not high but physiological, as they occur in normal individuals under conditions approximating those experienced by our ancestors. Finally, the editorial raises a note of caution by way of comparison with trials of e.g, -carotene. While moving subjects from normal to high vitamin A levels may well produce harm, that is quite different from moving subjects from low to physiological levels of vitamin D. In brief, the systematic reviews were largely non-informative and the cautionary note struck by the editorial has essentially no basis in the evidence.

References

1. Wang L, Manson JE, Song Y, Sesso HD. Systematic review: Vitamin D and calcium supplementation in prevention of cardiovascular events. Ann Intern Med 2010;152:315-323.

2. Pittas AG, Chung M, Trikalinos T, Mitri J, Brendel M, Patel K, et al. Systematic review: Vitamin D and cardiometabolic outcomes. Ann Intern Med 2010;152:307-314.

3. Guallar E, Miller ER III, Ordovas JM, Stranges S. Vitamin D supplementation in the age of lost innocence. Ann Intern Med 2010;152:327- 329.

4. Holick MF. The vitamin D deficiency pandemic and consequences for nonskeletal health: mechanisms of action. Mol Aspects Med 2008;29:361-368.

5. Liu PT, Stenger S, Li H, Wenzel L, Tan BH, Krutzik S, et al. Toll-like receptor triggering of a vitamin D-mediated human antimicrobial response. Science 2006;311:1770-1773.

6. Vieth R. Vitamin D supplementation, 25-hydroxyvitamin D levels, and safety. Am J Clin Nutr 1999;69:842-856.

7. Heaney RP, Davies KM, Chen TC, Holick MF, Barger-Lux MJ. Human serum 25 -hydroxy-cholecalciferol response to extended oral dosing with cholecalciferol. Am J Clin Nutr 2003;77:204-210.

Conflict of Interest:

None declared

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