Advertisement

Osteoporosis International

, Volume 22, Issue 6, pp 1649–1658 | Cite as

Cardiovascular effects of calcium supplementation

  • I. R. ReidEmail author
  • M. J. Bolland
  • A. Avenell
  • A. Grey
Review

Abstract

Trials in normal older women and in patients with renal impairment suggest that calcium supplements increase the risk of cardiovascular disease. To further assess their safety, we recently conducted a meta-analysis of trials of calcium supplements, and found a 27–31% increase in risk of myocardial infarction and a 12–20% increase in risk of stroke. These findings are robust because they are based on pre-specified analyses of randomized, placebo-controlled trials and show consistent risk across the trials. The fact that cardiovascular events were not primary endpoints of any of these studies will introduce noise but not bias into the data. A recent re-analysis of the Women's Health Initiative suggests that co-administration of vitamin D with calcium does not lessen these adverse effects. The increased cardiovascular risk with calcium supplements is consistent with epidemiological data relating higher circulating calcium concentrations to cardiovascular disease in normal populations. There are several possible pathophysiological mechanisms for these effects, including effects on vascular calcification, on the function of vascular cells, and on blood coagulation. Calcium-sensing receptors might mediate some of these effects. Because calcium supplements produce small reductions in fracture risk and a small increase in cardiovascular risk, there may be no net benefit from their use. Food sources of calcium appear to produce similar benefits on bone density, although their effects on fracture are unclear. Since food sources have not been associated with adverse cardiovascular effects, they may be preferable. Available evidence suggests that other osteoporosis treatments are still effective without calcium co-administration.

Keywords

Mineral supplements Nutrition Osteoporosis 

Notes

Acknowledgments

The authors are grateful to Dwight A. Towler for valuable discussions of the pathogenesis of vascular disease, and to Sarah Bristow for help in writing this manuscript. This work was supported by the Health Research Council of New Zealand. AA was funded by a Career Scientist award of the Chief Scientist Office of the Scottish Government Health Directorates. The Health Services Research Unit is funded by the Chief Scientist Office of the Scottish Government Health Directorates.

Conflicts of interest

Ian R. Reid has received funding from Fonterra and Mission Pharmacal. There are no disclosures from the other authors.

References

  1. 1.
    Yacowitz H, Fleischman AI, Bierenbaum ML (1965) Effects of oral calcium on serum lipids in man. BMJ 1:1352–1354PubMedCrossRefGoogle Scholar
  2. 2.
    Govers MJAP, Vandermeer R (1993) Effects of dietary calcium and phosphate on the intestinal interactions between calcium, phosphate, fatty acids, and bile acids. Gut 34:365–370PubMedCrossRefGoogle Scholar
  3. 3.
    Denke MA, Fox MM, Schulte MC (1993) Short-term dietary calcium fortification increases fecal saturated fat content and reduces serum lipids in men. J Nutr 123:1047–1053PubMedGoogle Scholar
  4. 4.
    Christensen R, Lorenzen JK, Svith CR, Bartels EM, Melanson EL, Saris WH, Tremblay A, Astrup A (2009) Effect of calcium from dairy and dietary supplements on faecal fat excretion: a meta-analysis of randomized controlled trials. Obes Rev 10:475–486PubMedCrossRefGoogle Scholar
  5. 5.
    Zemel MB, Sun X (2008) Calcitriol and energy metabolism. Nutr Rev 66:S139–S146PubMedCrossRefGoogle Scholar
  6. 6.
    Reid IR, Mason B, Horne A, Ames R, Clearwater J, Bava U, Orr-Walker B, Wu F, Evans MC, Gamble GD (2002) Effects of calcium supplementation on serum lipid concentrations in normal older women: a randomized controlled trial. Am J Med 112:343–347PubMedCrossRefGoogle Scholar
  7. 7.
    Bostick RM, Fosdick L, Grandits GA, Grambsch P, Gross M, Louis TA (2000) Effect of calcium supplementation on serum cholesterol and blood pressure—a randomized, double-blind, placebo-controlled, clinical trial. Arch Fam Med 9:31–38PubMedCrossRefGoogle Scholar
  8. 8.
    Reid IR, Ames R, Mason B, Bolland MJ, Bacon CJ, Reid HE, Kyle C, Gamble GD, Grey A, Horne A (2010) Effects of calcium supplementation on lipids, blood pressure, and body composition in healthy older men: a randomized controlled trial. Am J Clin Nutr 91:131–139PubMedCrossRefGoogle Scholar
  9. 9.
    Griffith LE, Guyatt GH, Cook RJ, Bucher HC, Cook DJ (1999) The influence of dietary and nondietary calcium supplementation on blood pressure—an updated metaanalysis of randomized controlled trials. Am J Hypertens 12:84–92PubMedCrossRefGoogle Scholar
  10. 10.
    Reid IR, Horne A, Mason B, Ames R, Bava U, Gamble GD (2005) Effects of calcium supplementation on body weight and blood pressure in normal older women: a randomized controlled trial. J Clin Endocrinol Metabol 90:3824–3829CrossRefGoogle Scholar
  11. 11.
    van Mierlo LAJ, Arends LR, Streppel MT, Zeegers MPA, Kok FJ, Grobbee DE, Geleijnse JM (2006) Blood pressure response to calcium supplementation: a meta-analysis of randomized controlled trials. J Hum Hypertens 20:571–580PubMedCrossRefGoogle Scholar
  12. 12.
    Lanou AJ, Barnard ND (2008) Dairy and weight loss hypothesis: an evaluation of the clinical trials. Nutr Rev 66:272–279PubMedCrossRefGoogle Scholar
  13. 13.
    Russo D, Miranda I, Ruocco C, Battaglia Y, Buonanno E, Manzi S, Russo L, Scafarto A, Andreucci VE (2007) The progression of coronary artery calcification in predialysis patients on calcium carbonate or sevelamer. Kidney Int 72:1255–1261PubMedCrossRefGoogle Scholar
  14. 14.
    Block GA, Raggi P, Bellasi A, Kooienga L, Spiegel DM (2007) Mortality effect of coronary calcification and phosphate binder choice in incident hemodialysis patients. Kidney Int 71:438–441PubMedCrossRefGoogle Scholar
  15. 15.
    Bolland MJ, Barber PA, Doughty RN, Mason B, Horne A, Ames R, Gamble GD, Grey A, Reid IR (2008) Vascular events in healthy older women receiving calcium supplementation: randomised controlled trial. BMJ. doi: 10.1136/bmj.39440.525752.BE: PubMedGoogle Scholar
  16. 16.
    Bolland MJ, Avenell A, Baron JA, Grey A, MacLennan GS, Gamble GD, Reid IR (2010) Effect of calcium supplements on risk of myocardial infarction and cardiovascular events: meta-analysis—art. no. c3691. Br Med J 341:C3691CrossRefGoogle Scholar
  17. 17.
    Reid IR, Ames R, Mason B, Reid HE, Bacon CJ, Bolland MJ, Gamble GD, Grey A, Horne A (2008) Randomized controlled trial of calcium supplementation in healthy, nonosteoporotic, older men. Arch Intern Med 168:2276–2282PubMedCrossRefGoogle Scholar
  18. 18.
    Writing Group for the Women's Health Initiative Investigators (2002) Risks and benefits of estrogen plus progestin in healthy postmenopausal women. JAMA 288:321–333CrossRefGoogle Scholar
  19. 19.
    Nissen SE, Wolski K (2010) Rosiglitazone revisited. Arch Intern Med 170:1191–1201CrossRefGoogle Scholar
  20. 20.
    Autier P, Gandini S (2007) Vitamin D supplementation and total mortality: a meta-analysis of randomized controlled trials. Arch Intern Med 167:1730–1737PubMedCrossRefGoogle Scholar
  21. 21.
    Melamed ML, Michos ED, Post W, Astor B (2008) 25-hydroxyvitamin D levels and the risk of mortality in the general population. Arch Intern Med 168:1629–1637PubMedCrossRefGoogle Scholar
  22. 22.
    Grant AM, Avenell A, Campbell MK et al (2005) Oral vitamin D3 and calcium for secondary prevention of low-trauma fractures in elderly people (Randomised Evaluation of Calcium Or vitamin D, RECORD): a randomised placebo-controlled trial. Lancet 365:1621–1628PubMedCrossRefGoogle Scholar
  23. 23.
    Hsia J, Heiss G, Ren H et al (2007) Calcium/vitamin D supplementation and cardiovascular events. Circulation 115:846–854PubMedCrossRefGoogle Scholar
  24. 24.
    Bolland MJ, Grey A, Gamble GD, Reid IR (2010) Risk of cardiovascular events with calcium/vitamin D—a re-analysis of the Women's Health Initiative. J Bone Miner Res 25(Suppl 1):S50Google Scholar
  25. 25.
    Lappe JM, Travers-Gustafson D, Davies KM, Recker RR, Heaney RP (2007) Vitamin D and calcium supplementation reduces cancer risk: results of a randomized trial. Am J Clin Nutr 85:1586–1591PubMedGoogle Scholar
  26. 26.
    Bischoff-Ferrari HA, Dawson-Hughes B, Baron JA et al (2007) Calcium intake and hip fracture risk in men and women: a meta-analysis of prospective cohort studies and randomized controlled trials. Am J Clin Nutr 86:1780–1790PubMedGoogle Scholar
  27. 27.
    Tang BM, Eslick GD, Nowson C, Smith C, Bensoussan A (2007) Use of calcium or calcium in combination with vitamin D supplementation to prevent fractures and bone loss in people aged 50 years and older: a meta-analysis. Lancet 370:657–666PubMedCrossRefGoogle Scholar
  28. 28.
    Wang L, Manson JE, Song Y, Sesso HD (2010) Systematic review: vitamin D and calcium supplementation in prevention of cardiovascular events. Ann Intern Med 152:315–323PubMedGoogle Scholar
  29. 29.
    Prince RL, Devine A, Dhaliwal SS, Dick IM (2006) 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 166:869–875PubMedCrossRefGoogle Scholar
  30. 30.
    Lewis JR, Calver J, Zhu K, Flicker L, Prince RL (2011) Calcium supplementation and the risks of atherosclerotic vascular disease in older women: results of a 5-year RCT and a 4.5-year follow-up. J Bone Miner Res 26:35–41PubMedCrossRefGoogle Scholar
  31. 31.
    Montori VM, Permanyer-Miralda G, Ferreira-Gonzalez I et al (2005) Validity of composite end points in clinical trials. BMJ 330:594–596PubMedCrossRefGoogle Scholar
  32. 32.
    Lewis JR, Zhu K, Prince RL (2010) Errors in self-reported myocardial infarction in calcium intervention studies. Proceedings of the Australian & New Zealand Bone & Mineral Society Annual Scientific Meeting P17Google Scholar
  33. 33.
    Bonnick S, Broy S, Kaiser F, Teutsch C, Rosenberg E, DeLucca P, Melton M (2007) Treatment with alendronate plus calcium, alendronate alone, or calcium alone for postmenopausal low bone mineral density. Curr Med Res Opin 23:1341–1349PubMedCrossRefGoogle Scholar
  34. 34.
    Grey A, Bolland MJ, Wattie D, Horne A, Gamble G, Reid IR (2009) The antiresorptive effects of a single dose of zoledronate persist for 2 years: a randomized, placebo-controlled trial in osteopenic postmenopausal women. J Clin Endocrinol Metabol 94:538–544CrossRefGoogle Scholar
  35. 35.
    Black DM, Delmas PD, Eastell R et al (2007) Once-yearly zoledronic acid for treatment of postmenopausal osteoporosis. N Engl J Med 356:1809–1822PubMedCrossRefGoogle Scholar
  36. 36.
    McCloskey EV, Beneton M, Charlesworth D et al (2007) Clodronate reduces the incidence of fractures in community-dwelling elderly women unselected for osteoporosis: results of a double-blind, placebo-controlled randomized study. J Bone Miner Res 22:135–141PubMedCrossRefGoogle Scholar
  37. 37.
    Cummings SR, San Martin J, McClung MR et al (2009) Denosumab for prevention of fractures in postmenopausal women with osteoporosis. N Engl J Med 361:756–765PubMedCrossRefGoogle Scholar
  38. 38.
    Lindsay R, Hart DM, Forrest C, Baird C (1980) Prevention of spinal osteoporosis in oophorectomised women. Lancet ii:1151–1153CrossRefGoogle Scholar
  39. 39.
    Bostick RM, Kushi LH, Wu Y, Meyer KA, Sellers TA, Folsom AR (1999) Relation of calcium, vitamin D, and dairy food intake to ischemic heart disease mortality among postmenopausal women. Am J Epidemiol 149:151–161PubMedGoogle Scholar
  40. 40.
    Knox EG (1973) Ischaemic-heart-disease mortality and dietary intake of calcium. Lancet ii:1465–1467CrossRefGoogle Scholar
  41. 41.
    Gibson RA, Makrides M, Smithers LG, Voevodin M, Sinclair AJ (2009) The effect of dairy foods on CHD: a systematic review of prospective cohort studies. Br J Nutr 102:1267–1275PubMedCrossRefGoogle Scholar
  42. 42.
    Reid IR, Schooler BA, Hannon S, Ibbertson HK (1986) The acute biochemical effects of four proprietary calcium supplements. Aust NZ J Med 16:193–197Google Scholar
  43. 43.
    Karp HJ, Ketola ME, Lamberg-Allardt CJE (2009) Acute effects of calcium carbonate, calcium citrate and potassium citrate on markers of calcium and bone metabolism in young women. Br J Nutr 102:1341–1347PubMedCrossRefGoogle Scholar
  44. 44.
    Heller HJ, Stewart A, Haynes S, Pak CYC (1999) Pharmacokinetics of calcium absorption from two commercial calcium supplements. J Clin Pharmacol 39:1151–1154PubMedGoogle Scholar
  45. 45.
    Heller HJ, Greer LG, Haynes SD, Poindexter JR, Pak CYC (2000) Pharmacokinetic and pharmacodynamic comparison of two calcium supplements in postmenopausal women. J Clin Pharmacol 40:1237–1244PubMedGoogle Scholar
  46. 46.
    Green JH, Booth C, Bunning R (2003) Postprandial metabolic responses to milk enriched with milk calcium are different from responses to milk enriched with calcium carbonate. Asia Pac J Clin Nutr 12:109–119PubMedGoogle Scholar
  47. 47.
    Rubin MR, Rundek T, McMahon DJ, Lee H-S, Sacco RL, Silverberg SJ (2007) Carotid artery plaque thickness is associated with increased serum calcium levels: the Northern Manhattan study. Atherosclerosis 194:426–432PubMedCrossRefGoogle Scholar
  48. 48.
    Bolland MJ, Wang TKM, van Pelt NC, Horne AM, Mason BH, Ames RW, Grey AB, Ruygrok PN, Gamble GD, Reid IR (2010) Abdominal aortic calcification on vertebral morphometry images predicts incident myocardial infarction. J Bone Miner Res 25:505–512PubMedCrossRefGoogle Scholar
  49. 49.
    Slinin Y, Blackwell T, Ishani A, Cummings SR, Ensrud KE (2010) Serum calcium, phosphorus and cardiovascular events in post-menopausal women. Int J Cardiol (in press)Google Scholar
  50. 50.
    Lind L, Skarfors E, Berglund L, Lithell H, Ljunghall S (1997) Serum calcium: a new, independent, prospective risk factor for myocardial infarction in middle-aged men followed for 18 years. J Clin Epidemiol 50:967–973PubMedCrossRefGoogle Scholar
  51. 51.
    Foley RN, Collins AJ, Ishani A, Kalra PA (2008) Calcium-phosphate levels and cardiovascular disease in community-dwelling adults: the Atherosclerosis Risk in Communities (ARIC) Study. Am Heart J 156:556–563PubMedCrossRefGoogle Scholar
  52. 52.
    Jorde R, Sundsfjord J, Fitzgerald P, Bonaa KH (1999) Serum calcium and cardiovascular risk factors and diseases: the Tromso study. Hypertension 34:484–490PubMedGoogle Scholar
  53. 53.
    Leifsson BG, Ahren B (1996) Serum calcium and survival in a large health screening program. J Clin Endocrinol Metabol 81:2149–2153CrossRefGoogle Scholar
  54. 54.
    Nilsson IL, Yin L, Lundgren E, Rastad J, Ekbom A (2002) Clinical presentation of primary hyperparathyroidism in Europe -Nationwide cohort analysis on mortality from nonmalignant causes. J Bone Miner Res 17:N68–N74PubMedGoogle Scholar
  55. 55.
    Persy V, D'Haese P (2009) Vascular calcification and bone disease: the calcification paradox. Trends Mol Med 15:405–416PubMedCrossRefGoogle Scholar
  56. 56.
    Reid IR, Bolland MJ, Grey A (2010) Does calcium supplementation increase cardiovascular risk? Clin Endocrinol 73:689–695CrossRefGoogle Scholar
  57. 57.
    Reynolds JL, Joannides AJ, Skepper JN, Mcnair R, Schurgers LJ, Proudfoot D, Jahnen-Dechent W, Weissberg PL, Shanahan CM (2004) Human vascular smooth muscle cells undergo vesicle-mediated calcification in response to changes in extracellular calcium and phosphate concentrations: a potential mechanism for accelerated vascular calcification in ESRD. J Am Soc Nephrol 15:2857–2867PubMedCrossRefGoogle Scholar
  58. 58.
    Marz W, Seelhorst U, Wellnitz B, Tiran B, Obermayer-Pietsch B, Renner W, Boehm BO, Ritz E, Hoffmann MM (2007) Alanine to serine polymorphism at position 986 of the calcium-sensing receptor associated with coronary heart disease, myocardial infarction, all-cause, and cardiovascular mortality. J Clin Endocrinol Metabol 92:2363–2369CrossRefGoogle Scholar
  59. 59.
    Cheng SL, Shao JS, Halstead LR, Distelhorst K, Sierra O, Towler DA (2010) Activation of vascular smooth muscle parathyroid hormone receptor inhibits Wnt/beta-catenin signaling and aortic fibrosis in diabetic arteriosclerosis. Circ Res 107:271–282PubMedCrossRefGoogle Scholar
  60. 60.
    Hilgard P (1973) Experimental hypercalcaemia and whole blood clotting. J Clin Pathol 28:616–619CrossRefGoogle Scholar
  61. 61.
    James MFM, Roche AM (2004) Dose–response relationship between plasma ionized calcium concentration and thrombelastography. J Cardiothorac Vasc Anesth 18:581–586PubMedCrossRefGoogle Scholar
  62. 62.
    Neunteufl T, Katzenschlager R, Abela C, Kostner K, Niederle B, Weidinger F, Stefenelli T (1998) Impairment of endothelium-independent vasodilation in patients with hypercalcemia. Cardiovasc Res 40:396–401PubMedCrossRefGoogle Scholar
  63. 63.
    Baykan M, Erem C, Erdogan T, Hacihasanoglu A, Gedikli O, Kiris A, Kucukosmanoglu M, Ersoz HO, Celik S (2007) Impairment of flow mediated vasodilatation of brachial artery in patients with primary hyperparathyroidism. Int J Cardiovasc Imag 23:323–328CrossRefGoogle Scholar
  64. 64.
    Kyriazis J, Katsipi I, Stylianou K, Jenakis N, Karida A, Daphnis E (2007) Arterial stiffness alterations during hemodialysis: the role of dialysate calcium. Nephron Clin Pract 106:C34–C42PubMedCrossRefGoogle Scholar
  65. 65.
    Nilsson IL, Rastad J, Johansson K, Lind L (2001) Endothelial vasodilatory function and blood pressure response to local and systemic hypercalcemia. Surgery 130:986–990PubMedCrossRefGoogle Scholar
  66. 66.
    Lau EMC, Woo J, Lam V, Hong A (2001) Milk supplementation of the diet of postmenopausal Chinese women on a low calcium intake retards bone loss. J Bone Miner Res 16:1704–1709PubMedCrossRefGoogle Scholar
  67. 67.
    Cadogan J, Eastell R, Jones N, Barker ME (1997) Milk intake and bone mineral acquisition in adolescent girls—randomised, controlled intervention trial. BMJ 315:1255–1260PubMedGoogle Scholar
  68. 68.
    Committee to Review Dietary Reference Intakes for Vitamin D and Calcium (2010) Dietary reference intakes for calcium and vitamin D. Institute of Medicine, WashingtonGoogle Scholar

Copyright information

© International Osteoporosis Foundation and National Osteoporosis Foundation 2011

Authors and Affiliations

  • I. R. Reid
    • 1
    • 3
    Email author
  • M. J. Bolland
    • 1
  • A. Avenell
    • 2
  • A. Grey
    • 1
  1. 1.Department of Medicine, Faculty of Medical and Health SciencesUniversity of AucklandAucklandNew Zealand
  2. 2.Health Services Research UnitUniversity of AberdeenAberdeenUK
  3. 3.Faculty of Medical and Health SciencesUniversity of AucklandAucklandNew Zealand

Personalised recommendations