Reviews
2 March 2010

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

Publication: Annals of Internal Medicine
Volume 152, Number 5

Abstract

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.

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References

1.
Holick MF. The vitamin D epidemic and its health consequences. J Nutr. 2005;135:2739S-48S. [PMID: 16251641]
2.
Fleming KHHeimbach JT. Consumption of calcium in the U.S.: food sources and intake levels. J Nutr. 1994;124:1426S-1430S. [PMID: 8064396]
3.
Food and Nutrition BoardInstitute of Medicine. Standing Committee on the Scientific Evaluation of Dietary Reference Intakes. Dietary reference intakes for calcium, phosphorus, magnesium, vitamin D, and fluoride. Washington, DC: National Academies Pr; 2003.
4.
Vieth R. Vitamin D supplementation, 25-hydroxyvitamin D concentrations, and safety. Am J Clin Nutr. 1999;69:842-56. [PMID: 10232622]
5.
Moyad MA. The potential benefits of dietary and/or supplemental calcium and vitamin D. Urol Oncol. 2003;21:384-91. [PMID: 14670550]
6.
Peterlik MCross HS. Vitamin D and calcium deficits predispose for multiple chronic diseases. Eur J Clin Invest. 2005;35:290-304. [PMID: 15860041]
7.
Zittermann A. Vitamin D and disease prevention with special reference to cardiovascular disease. Prog Biophys Mol Biol. 2006;92:39-48. [PMID: 16600341]
8.
Vaskonen T. Dietary minerals and modification of cardiovascular risk factors. J Nutr Biochem. 2003;14:492-506. [PMID: 14505811]
9.
Pittas AGLau JHu FBDawson-Hughes B. The role of vitamin D and calcium in type 2 diabetes. A systematic review and meta-analysis. J Clin Endocrinol Metab. 2007;92:2017-29. [PMID: 17389701]
10.
Bostick RMKushi LHWu YMeyer KASellers TAFolsom AR. Relation of calcium, vitamin D, and dairy food intake to ischemic heart disease mortality among postmenopausal women. Am J Epidemiol. 1999;149:151-61. [PMID: 9921960]
11.
Wang LManson JEBuring JELee IMSesso HD. Dietary intake of dairy products, calcium, and vitamin D and the risk of hypertension in middle-aged and older women. Hypertension. 2008;51:1073-9. [PMID: 18259007]
12.
Umesawa MIso HIshihara JSaito IKokubo YInoue Met alJPHC Study Group. Dietary calcium intake and risks of stroke, its subtypes, and coronary heart disease in Japanese: the JPHC Study Cohort I. Stroke. 2008;39:2449-56. [PMID: 18635855]
13.
Marniemi JAlanen EImpivaara OSeppänen RHakala PRajala Tet al. Dietary and serum vitamins and minerals as predictors of myocardial infarction and stroke in elderly subjects. Nutr Metab Cardiovasc Dis. 2005;15:188-97. [PMID: 15955467]
14.
Ascherio ARimm EBHernán MAGiovannucci ELKawachi IStampfer MJet al. Intake of potassium, magnesium, calcium, and fiber and risk of stroke among US men. Circulation. 1998;98:1198-204.
15.
Larsson SCVirtanen MJMars MMännistö SPietinen PAlbanes Det al. Magnesium, calcium, potassium, and sodium intakes and risk of stroke in male smokers. Arch Intern Med. 2008;168:459-65.
16.
Van der Vijver LPvan der Waal MAWeterings KGDekker JMSchouten EGKok FJ. Calcium intake and 28-year cardiovascular and coronary heart disease mortality in Dutch civil servants. Int J Epidemiol. 1992;21:36-9.
17.
Reid IRBolland MJGrey A. Effect of calcium supplementation on hip fractures. Osteoporos Int. 2008;19:1119-23.
18.
Bischoff-Ferrari HAWillett WCWong JBStuck AEStaehelin HBOrav EJet al. Prevention of nonvertebral fractures with oral vitamin D and dose dependency: a meta-analysis of randomized controlled trials. Arch Intern Med. 2009;169:551-61.
19.
Lanham-New SA. Importance of calcium, vitamin D and vitamin K for osteoporosis prevention and treatment. Proc Nutr Soc. 2008;67:163-76.
20.
Subar AFBlock G. Use of vitamin and mineral supplements: demographics and amounts of nutrients consumed. The 1987 Health Interview Survey. Am J Epidemiol. 1990;132:1091-101.
21.
Balk EChung MLichtenstein AChew PKupelnick BLawrence Aet al. Effects of omega-3 fatty acids on cardiovascular risk factors and intermediate markers of cardiovascular disease. Evid Rep Technol Assess (Summ). 2004;:1-6.
22.
National Kidney Foundation. K/DOQI clinical practice guidelines for chronic kidney disease: evaluation, classification, and stratification. Am J Kidney Dis. 2002;39:S1-266.
23.
DerSimonian RLaird N. Meta-analysis in clinical trials. Control Clin Trials. 1986;7:177-88.
24.
Begg CBMazumdar M. Operating characteristics of a rank correlation test for publication bias. Biometrics. 1994;50:1088-101.
25.
Marco MPCraver LBetriu ABelart MFibla JFernández E. Higher impact of mineral metabolism on cardiovascular mortality in a European hemodialysis population. Kidney Int Suppl. 2003;:S111-4. [PMID: 12753279]
26.
Shoji TShinohara KKimoto EEmoto MTahara HKoyama Het al. Lower risk for cardiovascular mortality in oral 1alpha-hydroxy vitamin D3 users in a haemodialysis population. Nephrol Dial Transplant. 2004;19:179-84.
27.
Teng MWolf MOfsthun MNLazarus JMHernán MACamargo CA Jret al. Activated injectable vitamin D and hemodialysis survival: a historical cohort study. J Am Soc Nephrol. 2005;16:1115-25.
28.
Wolf MShah AGutierrez OAnkers EMonroy MTamez Het al. Vitamin D levels and early mortality among incident hemodialysis patients. Kidney Int. 2007;72:1004-13.
29.
Naves-Díaz MAlvarez-Hernández DPasslick-Deetjen JGuinsburg AMarelli CRodriguez-Puyol Det al. Oral active vitamin D is associated with improved survival in hemodialysis patients. Kidney Int. 2008;74:1070-8.
30.
Al-Delaimy WKRimm EWillett WCStampfer MJHu FB. A prospective study of calcium intake from diet and supplements and risk of ischemic heart disease among men. Am J Clin Nutr. 2003;77:814-8.
31.
Iso HStampfer MJManson JERexrode KHennekens CHColditz GAet al. Prospective study of calcium, potassium, and magnesium intake and risk of stroke in women. Stroke. 1999;30:1772-9.
32.
Trivedi DPDoll RKhaw KT. Effect of four monthly oral vitamin D3 (cholecalciferol) supplementation on fractures and mortality in men and women living in the community: randomised double blind controlled trial. BMJ. 2003;326:469. [PMID: 12609940]
33.
Bolland MJBarber PADoughty RNMason BHorne AAmes Ret al. Vascular events in healthy older women receiving calcium supplementation: randomised controlled trial. BMJ. 2008;336:262-6.
34.
Hsia JHeiss GRen HAllison MDolan NCGreenland Pet alWomen's Health Initiative Investigators. Calcium/vitamin D supplementation and cardiovascular events. Circulation. 2007;115:846-54.
35.
Prince RLAustin NDevine ADick IMBruce DZhu K. Effects of ergocalciferol added to calcium on the risk of falls in elderly high-risk women. Arch Intern Med. 2008;168:103-8.
36.
Baron JABeach MMandel JSvanStolk RUHaile RWSandler RSet al. Calcium supplements for the prevention of colorectal adenomas. Calcium Polyp Prevention Study Group. N Engl J Med. 1999;340:101-7.
37.
Prince RLDevine ADhaliwal SSDick IM. Effects of calcium supplementation on clinical fracture and bone structure: results of a 5-year, double-blind, placebo-controlled trial in elderly women. Arch Intern Med. 2006;166:869-75.
38.
Reid IRAmes RMason BReid HEBacon CJBolland MJet al. Randomized controlled trial of calcium supplementation in healthy, nonosteoporotic, older men. Arch Intern Med. 2008;168:2276-82.
39.
Brazier MGrados FKamel SMathieu MMorel AMaamer Met al. Clinical and laboratory safety of one year's use of a combination calcium + vitamin D tablet in ambulatory elderly women with vitamin D insufficiency: results of a multicenter, randomized, double-blind, placebo-controlled study. Clin Ther. 2005;27:1885-93.
40.
Rammos GTseke PZiakka S. Vitamin D, the renin-angiotensin system, and insulin resistance. Int Urol Nephrol. 2008;40:419-26.
41.
Li YC, Qiao G, Uskokovic M, Xiang W, Zheng W, Kong J. Vitamin D: a negative endocrine regulator of the renin-angiotensin system and blood pressure. J Steroid Biochem Mol Biol. 2004;89-90:387-92. [ 15225806]
42.
Chiu KCChu AGo VLSaad MF. Hypovitaminosis D is associated with insulin resistance and beta cell dysfunction. Am J Clin Nutr. 2004;79:820-5.
43.
Maestro BCampión JDávila NCalle C. Stimulation by 1,25-dihydroxyvitamin D3 of insulin receptor expression and insulin responsiveness for glucose transport in U-937 human promonocytic cells. Endocr J. 2000;47:383-91.
44.
Carthy EPYamashita WHsu AOoi BS. 1,25-Dihydroxyvitamin D3 and rat vascular smooth muscle cell growth. Hypertension. 1989;13:954-9.
45.
Levin ALi YC. Vitamin D and its analogues: do they protect against cardiovascular disease in patients with kidney disease? Kidney Int. 2005;68:1973-81.
46.
Deluca HFCantorna MT. Vitamin D: its role and uses in immunology. FASEB J. 2001;15:2579-85.
47.
Gysemans CACardozo AKCallewaert HGiulietti AHulshagen LBouillon Ret al. 1,25-Dihydroxyvitamin D3 modulates expression of chemokines and cytokines in pancreatic islets: implications for prevention of diabetes in nonobese diabetic mice. Endocrinology. 2005;146:1956-64.
48.
Wang TJPencina MJBooth SLJacques PFIngelsson ELanier Ket al. Vitamin D deficiency and risk of cardiovascular disease. Circulation. 2008;117:503-11.
49.
Giovannucci ELiu YHollis BWRimm EB. 25-hydroxyvitamin D and risk of myocardial infarction in men: a prospective study. Arch Intern Med. 2008;168:1174-80.
50.
Wang AYLam CWSanderson JEWang MChan IHLui SFet al. Serum 25-hydroxyvitamin D status and cardiovascular outcomes in chronic peritoneal dialysis patients: a 3-y prospective cohort study. Am J Clin Nutr. 2008;87:1631-8.
51.
Dobnig HPilz SScharnagl HRenner WSeelhorst UWellnitz Bet al. Independent association of low serum 25-hydroxyvitamin D and 1,25-dihydroxyvitamin D levels with all-cause and cardiovascular mortality. Arch Intern Med. 2008;168:1340-9.
52.
Pilz SDobnig HFischer JEWellnitz BSeelhorst UBoehm BOet al. Low vitamin D levels predict stroke in patients referred to coronary angiography. Stroke. 2008;39:2611-3.
53.
Melamed MLMichos EDPost WAstor B. 25-hydroxyvitamin D levels and the risk of mortality in the general population. Arch Intern Med. 2008;168:1629-37.
54.
Zemel MB. Calcium modulation of hypertension and obesity: mechanisms and implications. J Am Coll Nutr. 2001;20:428S-435S; discussion 440S-442S. [ 11603653]
55.
Milner RDHales CN. The role of calcium and magnesium in insulin secretion from rabbit pancreas studied in vitro. Diabetologia. 1967;3:47-9.
56.
Wright DCHucker KAHolloszy JOHan DH. Ca2+ and AMPK both mediate stimulation of glucose transport by muscle contractions. Diabetes. 2004;53:330-5.
57.
Draznin BSussman KKao MLewis DSherman N. The existence of an optimal range of cytosolic free calcium for insulin-stimulated glucose transport in rat adipocytes. J Biol Chem. 1987;262:14385-8.
58.
Zemel MB. Nutritional and endocrine modulation of intracellular calcium: implications in obesity, insulin resistance and hypertension. Mol Cell Biochem. 1998;188:129-36.
59.
Draznin BSussman KEEckel RHKao MYost TSherman . Possible role of cytosolic free calcium concentrations in mediating insulin resistance of obesity and hyperinsulinemia. J Clin Invest. 1988;82:1848-52.
60.
Pörsti IWuorela HArvola PSäynävälammi PNurmi AKHuhtala Het al. Effects of calcium and deoxycorticosterone on blood pressure, plasma renin activity and vascular reactivity in spontaneously hypertensive rats. Clin Exp Hypertens A. 1990;12:1159-74.
61.
Bohr DF. Vascular smooth muscle: dual effect of calcium. Science. 1963;139:597-599.
62.
Mäkynen HKähönen MWu XArvola PPörsti I. Endothelial function in deoxycorticosterone-NaCl hypertension: effect of calcium supplementation. Circulation. 1996;93:1000-8.
63.
Jolma PKalliovalkama JTolvanen JPKööbi PKähönen MHutri-Kähönen Net al. High-calcium diet enhances vasorelaxation in nitric oxide-deficient hypertension. Am J Physiol Heart Circ Physiol. 2000;279:H1036-43.
64.
Umesawa MIso HDate CYamamoto AToyoshima HWatanabe Yet al. Dietary intake of calcium in relation to mortality from cardiovascular disease: the JACC Study. Stroke. 2006;37:20-6.
65.
Abbott RDCurb JDRodriguez BLSharp DSBurchfiel CMYano K. Effect of dietary calcium and milk consumption on risk of thromboembolic stroke in older middle-aged men. The Honolulu Heart Program. Stroke. 1996;27:813-8.
66.
Wactawski-Wende JKotchen JMAnderson GLAssaf ARBrunner RLO'Sullivan MJet alWomen's Health Initiative Investigators. Calcium plus vitamin D supplementation and the risk of colorectal cancer. N Engl J Med. 2006;354:684-96.
67.
Bischoff-Ferrari HAGiovannucci EWillett WCDietrich TDawson-Hughes B. Estimation of optimal serum concentrations of 25-hydroxyvitamin D for multiple health outcomes. Am J Clin Nutr. 2006;84:18-28.

Information & Authors

Information

Published In

cover image Annals of Internal Medicine
Annals of Internal Medicine
Volume 152Number 52 March 2010
Pages: 315 - 323

History

Published online: 2 March 2010
Published in issue: 2 March 2010

Keywords

Authors

Affiliations

Lu Wang, MD, PhD
From Brigham and Women's Hospital and Harvard School of Public Health, Boston, Massachusetts.
JoAnn E. Manson, MD, DrPH
From Brigham and Women's Hospital and Harvard School of Public Health, Boston, Massachusetts.
Yiqing Song, MD, ScD
From Brigham and Women's Hospital and Harvard School of Public Health, Boston, Massachusetts.
Howard D. Sesso, ScD
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).
Disclosures: None disclosed.
Corresponding Author: Lu Wang, MD, PhD, Division of Preventive Medicine, Brigham and Women's Hospital, 900 Commonwealth Avenue East, Boston, MA 02215; e-mail: [email protected].
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.

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Lu Wang, JoAnn E. Manson, Yiqing Song, et al. Systematic Review: Vitamin D and Calcium Supplementation in Prevention of Cardiovascular Events. Ann Intern Med.2010;152:315-323. [Epub 2 March 2010]. doi:10.7326/0003-4819-152-5-201003020-00010

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