Response to Letters Regarding Article, “Calcium/Vitamin D Supplementation and Cardiovascular Events”
We appreciate the comments of Drs Zittermann and Wallis and their colleagues with regard to vitamin D. The Women’s Health Initiative Calcium/Vitamin D trial was designed in the early 1990s to assess whether calcium/vitamin D supplementation reduced hip fracture1; cardiovascular events were secondary, albeit prespecified, outcomes. The trial chose the vitamin D3 supplement dose of 200 IU twice daily because it was the recommended daily allowance at that time, had low risk of toxicity, raised 25-hydroxy vitamin D3 concentrations to acceptable levels,2 and slowed bone loss.3 In 1999, the Institute of Medicine confirmed 400 IU daily as an adequate intake of vitamin D for healthy older women to maintain bone health and normal calcium metabolism.4
In our trial, vitamin D intake (supplements and diet) at baseline was ≈365 IU daily; women randomized to active supplements thus consumed ≈765 IU daily, well above the recommended adequate intake, and a dose sufficient to favorably affect hip bone mineral density.5 Although calcitriol was not measured, baseline serum 25-hydroxy vitamin D levels (Liaison chemiluminescent immunoassay; DiaSorin Inc., Stillwater, Minn.) were <30 ng/mL in 87% of a subsample of hip fracture cases (n=1818) and 85% of matched controls (n=1813). Thus, a higher dose of vitamin D supplementation may well be needed to achieve optimal effects on bone metabolism and to demonstrate any potential impact on cardiovascular events.
Nonetheless, we have demonstrated that supplementation with currently recommended quantities of vitamin D does not modulate risk of coronary events or stroke. The safety of higher doses of supplements would need to be evaluated, bearing in mind the increased incidence of kidney stones in our trial among women assigned to active calcium/vitamin D supplements (449 versus 381 among women assigned to placebo; hazard ratio, 1.17; 95% confidence interval, 1.02 to 1.34).5
Dr Hsia received a research grant from GlaxoSmithKline. The other authors report no disclosures.
Webb A, Pilbeam C, Hanofin N, Holick MF. An evaluation of the relative contributions of exposure to sunlight and of diet to the circulating concentrations of 25-hydroxyvitamin D in an elderly nursing home population in Boston. Am J Clin Nutr. 1990; 51: 1075–1081.
Institute of Medicine, Food and Nutrition Board. Dietary Reference Intakes: Calcium, Phosphorus, Magnesium, Vitamin D and Fluoride. National Academy Press, Washington, DC, 1999.
Jackson RD, LaCroix AZ, Gass M, Wallace RB, Robbins J, Lewis CE, Bassford T, Beresford SAA, Black HR, Blanchette P, Bonds DE, Brunner RL, Brzyski RG, Caan B, Cauley JA, Chlebowski RT, Cummings SR, Granek I, Hays J, Heiss G, Hendrix SL, Howard BV, Hsia J, Hubbell FA, Johnson KC, Judd H, Kotchen JM, Kuller LH, Langer RD, Lasser NL, Limacher MC, Ludlam S, Manson JE, Margolis KL, McGowan J, Ockene JK, O’Sullivan MJ, Phillips L, Prentice RL, Sarto GE, Anderson GL, Assaf AR, Barad D; for the Women’s Health Initiative investigators. Calcium plus vitamin D: supplementation and the risk of fractures. N Engl J Med. 2006; 354: 669–683.