European Journal of Epidemiology

, Volume 27, Issue 8, pp 581–591 | Cite as

Circulating vitamin D, calcium and risk of cerebrovascular disease: a systematic review and meta-analysis

  • Rajiv Chowdhury
  • Sarah Stevens
  • Heather Ward
  • Susmita Chowdhury
  • Ayesha Sajjad
  • Oscar H. Franco


Available literature suggests that both vitamin D and calcium may be associated with a wide range of non-skeletal outcomes. However, epidemiological evidence supporting their individual associations with incident cerebrovascular disease is scarce. We conducted a systematic review and meta-analysis of prospective cohort studies, published before February 2012 and sought from MEDLINE, EMBASE, BIOSIS and the Science Citation Index databases, and reported cerebrovascular disease (defined as any fatal or non-fatal ischemic stroke, hemorrhagic stroke, cerebrovascular accident or transient ischemic attack) by circulating vitamin D (25-hydroxy vitamin D [25(OH)D] as active metabolite) and calcium levels. Two independent investigators abstracted information on 25(OH)D and calcium, cerebrovascular outcomes and other characteristics from selected studies. Relative risks (RRs) were pooled by both random and fixed effects meta-analyses and were further examined under different study-level characteristics. Publication bias was assessed with funnel plots and Egger’s asymmetry test. From 5,778 initial references, nine unique prospective cohort studies met our inclusion criteria. Seven studies (involving 47,809 participants and 926 cerebrovascular events) focused on circulating 25(OH)D and 3 reported on circulating calcium (22,577 participants and 727 events). For 25(OH)D, in a comparison of individuals in the top third versus those in the bottom third at baseline, the combined RR for cerebrovascular disease, adjusted for several conventional risk factors, was 0.60 (95 % CI 0.48, 0.72). The corresponding RR in the prospective studies that reported on baseline circulating calcium levels for cerebrovascular disease was 1.40 (95 % CI 1.19, 1.64). There was no apparent evidence of heterogeneity or publication bias among included studies. Available data indicate that higher circulating level of vitamin D is associated with a decreased risk of cerebrovascular disease. Conversely, higher circulating calcium concentration is associated with an increased risk of cerebrovascular disease.


Vitamin D Calcium Cerebrovascular disease Meta-analysis 



Dr Chowdhury has been a recipient of the Gates Cambridge Ph.D. scholarship; and Prof. Franco is the recipient of a grant from Pfizer Nutrition to establish a new center on ageing research focused on nutrition and lifestyle, ErasmusAGE. Dr Sajjad works within ErasmusAGE.

Supplementary material

10654_2012_9729_MOESM1_ESM.docx (24 kb)
Supplementary material 1 (DOC 25 kb)


  1. 1.
    Committee to Review Dietary Reference Intakes for Vitamin D and Calcium FaNB, Institute of Medicine. Dietary Reference Intakes for Calcium and Vitamin D. Washington: National Academy Press; 2010.Google Scholar
  2. 2.
    Ma YZP, Wang F, Yang J, Liu Z, Qin H. Association between vitamin D and risk of colorectal cancer: a systematic review of prospective studies. J Clin Oncol. 2011;29(28):3775–82.PubMedCrossRefGoogle Scholar
  3. 3.
    Gilbert R, Martin RM, Beynon R, Beynon R, Harris R, Savovic J, Zuccolo L, Bekkering GE, Fraser WD, Sterne JA, Metcalfe C. Associations of circulating and dietary vitamin D with prostate cancer risk: a systematic review and dose-response meta-analysis. Cancer Causes Control. 2011;22(3):319–40.PubMedCrossRefGoogle Scholar
  4. 4.
    Parker J, Hashmi O, Dutton D, Mavrodaris A, Stranges S, Kandala NB, Clarke A, Franco OH. Levels of vitamin D and cardiometabolic disorders: systematic review and meta-analysis. Maturitas. 2010; 65(3):225–36. Epub 2009 Dec 23.Google Scholar
  5. 5.
    Chen P, Hu P, Xie D. Meta-analysis of vitamin D, calcium and the prevention of breast cancer. Breast Cancer Res Treat. 2010;121(2):469–77.PubMedCrossRefGoogle Scholar
  6. 6.
    Bolland MJ, Grey A, Avenell A, Gamble GD, Reid IR. Calcium supplements with or without vitamin D and risk of cardiovascular events: reanalysis of the women’s health initiative limited access dataset and meta-analysis. BMJ. 2011;19:342.Google Scholar
  7. 7.
    Grandi NC, Breitling LP, Brenner H. Vitamin D and cardiovascular disease: systematic review and meta-analysis of prospective studies. Prev Med. 2010;51(3–4):228–33.PubMedCrossRefGoogle Scholar
  8. 8.
    Pittas A, Lau J, Hu FB, Dawson-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.PubMedCrossRefGoogle Scholar
  9. 9.
    Autier P, Gandini S. Vitamin D supplementation and total mortality: a meta-analysis of randomized controlled trials. Arch Intern Med. 2007;167(16):1730–7.PubMedCrossRefGoogle Scholar
  10. 10.
    Holick MF. Vitamin D deficiency. N Engl J Med. 2007;357:266–81.PubMedCrossRefGoogle Scholar
  11. 11.
    Ginde AA, Liu MC, Camargo CA Jr. Demographic differences and trends of vitamin D insufficiency in the US population, 1988–2004. Arch Intern Med. 2009;169(6):626–32.PubMedCrossRefGoogle Scholar
  12. 12.
    Lips P, Vitamin D. status and nutrition in Europe and Asia. J Steroid Biochem Mol Biol. 2007;103(3–5):620–5.PubMedCrossRefGoogle Scholar
  13. 13.
    Camargo C. Vitamin D and cardiovascular disease: time for large randomized trials. J Am Coll Cardiol. 2011;58(14):1442–4.PubMedCrossRefGoogle Scholar
  14. 14.
    Willett W. Nutritional epidemiology. 2nd ed. New York: Oxford University Press; 1998.CrossRefGoogle Scholar
  15. 15.
    Holick MF. Vitamin D status: measurement, interpretation, and clinical application. Ann Epidemiol. 2009;19(2):73–8.PubMedCrossRefGoogle Scholar
  16. 16.
    Riboli E, Ronnholm H, Saracci R. Biological markers of diet. Cancer Surv. 1987;6:685–718.PubMedGoogle Scholar
  17. 17.
    Stroup DF, Berlin JA, Morton SC, Olkin I, Williamson GD, Rennie D, Moher D, Becker BJ, Sipe TA, Thacker SB. Meta-analysis of observational studies in epidemiology: a proposal for reporting. Meta-analysis of observational studies in epidemiology (MOOSE) group. JAMA. 2000;283(15):2008–12.PubMedCrossRefGoogle Scholar
  18. 18.
    von Elm E, Altman DG, Egger M, Pocock SJ, Gotzsche PC, Vandenbroucke JP. The strengthening the reporting of observational studies in epidemiology (STROBE) statement: guidelines for reporting observational studies. J Clin Epidemiol. 2008;61(4):344–9.CrossRefGoogle Scholar
  19. 19.
    Wong WC, Cheung CS, Hart GJ. Development of a quality assessment tool for systematic reviews of observational studies (QATSO) of HIV prevalence in men having sex with men and associated risk behaviours. Emerg Themes Epidemiol. 2008;5:23.PubMedCrossRefGoogle Scholar
  20. 20.
    Danesh J, Collins R, Appleby P, Peto R. Association of fibrinogen, C-reactive protein, albumin, or leukocyte count with coronary heart disease: meta-analyses of prospective studies. JAMA. 1998;279:1477–82.PubMedCrossRefGoogle Scholar
  21. 21.
    Higgins JP, Thompson SG, Deeks JJ, Altman DG. Measuring inconsistency in meta-analyses. BMJ. 2003;327:557–60.PubMedCrossRefGoogle Scholar
  22. 22.
    Egger M, Davey Smith G, Schneider M, Minder C. Bias in meta-analysis detected by a simple, graphical test. BMJ. 1997;315:629–34.PubMedCrossRefGoogle Scholar
  23. 23.
    Marniemi J, Alanen E, Impivaara O, Seppänen R, Hakala P, Rajala T, Rönnemaa T. Dietary and serum vitamins and minerals as predictors of myocardial infarction and stroke in elderly subjects. Nutr Metab Cardiovasc Dis. 2005;15:188–97.PubMedCrossRefGoogle Scholar
  24. 24.
    Anderson JL, May HT, Horne BD, Bair TL, Hall NL, Carlquist JF, Lappe DL. Intermountain heart collaborative (IHC) Study group. relation of vitamin D deficiency to cardiovascular risk factors, disease status, and incident events in a general healthcare population. Am J Cardiol. 2010;106(7):963–8.PubMedCrossRefGoogle Scholar
  25. 25.
    Drechsler C, Pilz S, Obermayer-Pietsch B, Verduijn M, Tomaschitz A, Krane V, Espe K, Dekker F, Brandenburg V, Marz W, Ritz E, Wanner C. Vitamin D deficiency is associated with sudden cardiac death, combined cardiovascular events, and mortality in haemodialysis patients. Eur Heart J. 2010;31(18):2253–61.PubMedCrossRefGoogle Scholar
  26. 26.
    Foley RN, Collins AJ, Ishani A, Kalra PA. Calcium-phosphate levels and cardiovascular disease in community-dwelling adults: the atherosclerosis risk in communities (ARIC) Study. Am Heart J. 2008;156(3):556–63.PubMedCrossRefGoogle Scholar
  27. 27.
    Kilkkinen A, Knekt P, Aro A, Rissanen H, Marniemi J, Heliovaara M, Impivaara O, Reunanen A. Vitamin D status and the risk of cardiovascular disease death. Am J Epidemiol. 2009;170(8):1032–9.PubMedCrossRefGoogle Scholar
  28. 28.
    Pilz S, Dobnig H, Fischer JE, Wellnitz B, Seelhorst U, Boehm BO, März W. Low vitamin d levels predict stroke in patients referred to coronary angiography. Stroke. 2008;39(9):2611–3.PubMedCrossRefGoogle Scholar
  29. 29.
    Michos ED, Reiss JP, Post WS, Lutsey PL, Gottesman RF, Mosley TH, Sharrett AR, Melamed ML. 25-Hydroxyvitamin D deficiency is associated with fatal stroke among whites but not blacks: The NHANES-III linked mortality files. Nutrition 2012;1–5.Google Scholar
  30. 30.
    Bolland MJ, Bacon CJ, Horne AM, Mason BH, Ames RW, Wang TK, et al. Vitamin D insufficiency and health outcomes over 5 years in older women. Am J Clin Nutr. 2010;91(1):82–9.Google Scholar
  31. 31.
    Slinin Y, Blackwell T, Ishani A, Cummings SR, Ensrud KE. Serum calcium, phosphorus and cardiovascular events in post-menopausal women. Int J Cardiol. 2011;149(3):335–40.Google Scholar
  32. 32.
    McCullough ML, Bowstick RM, Mayo TL. Vitamin D gene pathway polymorphisms and risk of colorectal, breast, and prostate cancer. Annu Rev Nutr. 2009;29:111–32.PubMedCrossRefGoogle Scholar
  33. 33.
    Lee JH, O’Keefe JH, Bell D, Hensrud DD, Holick MF. Vitamin D deficiency an important, common, and easily treatable cardiovascular risk factor? J Am Coll Cardiol. 2008;52(24):1949–56.PubMedCrossRefGoogle Scholar
  34. 34.
    Takiishi T, Gysemans C, Bouillon R, Mathieu C. Vitamin D and diabetes. Endocrinol Metab Clin North Am. 2010;39(2):419–46.PubMedCrossRefGoogle Scholar
  35. 35.
    Pilz S, Tomaschitz A, Ritz E, Pieber TR. Vitamin D status and arterial hypertension: a systematic review. Nat Rev Cardiol. 2009;6:621–30.PubMedCrossRefGoogle Scholar
  36. 36.
    Guillot X, Semerano L, Saidenberg-Kermanac’h N, Falgarone G, Boissier MC. Vitamin D and inflammation. Jt Bone Spine. 2010;77(6):552–7.CrossRefGoogle Scholar
  37. 37.
    Aihara K, Azuma H, Akaike M, Ikeda Y, Yamashita M, Sudo T, Hayashi H, Yamada Y, Endoh F, Fujimura M, Yoshida T, Yamaguchi H, Hashizume S, Kato M, Yoshimura K, Yamamoto Y, Kato S, Matsumoto T. Disruption of nuclear vitamin D receptor gene causes enhanced thrombogenicity in mice. J Biol Chem. 2004;279:35798–802.PubMedCrossRefGoogle Scholar
  38. 38.
    Kiraly SJ, Kiraly MA, Hawe RD, Makhani N. Vitamin D as a neuroactive substance: review. Sci World J. 2006;6:125–39.CrossRefGoogle Scholar
  39. 39.
    Lind L, Jakobsson S, Lithell H, Wengle B, Ljunghall S. Relation of serum calcium concentration to metabolic risk factors for cardiovascular disease. BMJ. 1988;297(6654):960–3.PubMedCrossRefGoogle Scholar
  40. 40.
    Goodman WG, Goldin J, Kuizon BD, Yoon C, Gales B, Sider D, Wang Y, Chung J, Emerick A, Greaser L, Elashoff RM, Salusky IB. Coronary-artery calcification in young adults with end-stage renal disease who are undergoing dialysis. N Engl J Med. 2000;342(20):1478–83.PubMedCrossRefGoogle Scholar
  41. 41.
    Block GA, Spiegel DM, Ehrlich J, Mehta R, Lindbergh J, Dreisbach A, Raggi P. Effects of sevelamer and calcium on coronary artery calcification in patients new to hemodialysis. Kidney Int. 2005;68:1815–24.PubMedCrossRefGoogle Scholar
  42. 42.
    Bolland MJ, Avenell A, Baron JA, Grey A, MacLennan GS, Gamble GD, Reid IR. Effect of calcium supplements on risk of myocardial infarction and cardiovascular events: meta-analysis. BMJ. 2010;341:c3691.PubMedCrossRefGoogle Scholar
  43. 43.
    Fibrinogen Studies Collaboration, Wood AM, White I, Thompson SG, Lewington S, Danesh J. Regression dilution methods for metaanalysis: assessing long-term variability in plasma fibrinogen among 27247 adults in 15 prospective studies. Int J Epidemiol. 2006;35:1570–8.PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media B.V. 2012

Authors and Affiliations

  • Rajiv Chowdhury
    • 1
  • Sarah Stevens
    • 2
  • Heather Ward
    • 3
  • Susmita Chowdhury
    • 4
  • Ayesha Sajjad
    • 5
  • Oscar H. Franco
    • 1
    • 5
  1. 1.Department of Public Health and Primary CareUniversity of CambridgeCambridgeUK
  2. 2.NHS Midlands and EastCambridgeUK
  3. 3.Department of Epidemiology School of Public HealthImperial College LondonLondonUK
  4. 4.Foundation for Genomics and Population HealthCambridgeUK
  5. 5.Department of Epidemiology, Erasmus MCUniversity Medical Center RotterdamRotterdamThe Netherlands

Personalised recommendations