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Long term calcium intake and rates of all cause and cardiovascular mortality: community based prospective longitudinal cohort study

BMJ 2013; 346 doi: (Published 13 February 2013) Cite this as: BMJ 2013;346:f228

Re: Long term calcium intake and rates of all cause and cardiovascular mortality: community based prospective longitudinal cohort study

The paper by Michaëlsson and colleagues reported that community dwelling women in Sweden who had greater than 1400 mg/d calcium intake had significantly increased hazard ratios for all-cause, cardiovascular disease (CVD), and ischaemic heart disease mortality rates during a 19-year follow-up study of 61,433 women [1]. Possible explanations were given for the findings. However, given what is known about the role of calcium in human health, there is the question of whether the finding is really related to long-term calcium intake as indicated in the title.

A review of calcium supplementation and risk of CVD by Heaney and colleagues found no evidence that calcium intake is a risk factor for CVD [2]. This paper was published in November 2012, which is prior to the acceptance date of Ref. 1 [28 December 2012], so should have been known to the authors, reviewers, and editors. The review examined some of the studies references in Ref. 1 as showing support for the hypothesis that higher calcium intake increases the risk of CVD [3,4]. The review pointed out that the meta-analysis in Ref. 3 appeared to have some shortcomings, and that bias and confounding could not be ruled out as an explanation for their findings. The review also examined the calcium-CVD hypothesis with respect to four of A. Bradford Hill’s criteria for causality in a biological system: strength of association; consistency; dose-response; and biological plausibility [5]. It found that the meta-analysis [3] failed in all four criteria. They also presented the findings from four randomized controlled trials and eight observational studies not included in the meta-analysis. While most of the studies included in the review were based on less than 1400 mg/d, one randomized controlled trial used 1450 mg/d calcium along with 1100 IU/d vitamin D3 on postmenopausal women for a year and found 4.76 CVD events/1000 person years in the calcium treatment group compared to 6.94 CVD events/1000 person years in the placebo group [6].

The finding in Ref. 1 is similar to the finding by the same group for all-cause and cancer mortality rates but not cardiovascular mortality rates as a function of serum 25-hydroxyvitamin D [25(OH)D] concentrations [7]. Their finding of a non-significant increased hazard ratio for all-cause mortality rate is in general disagreement with ten other observational studies included in a recent meta-analysis of all-cause mortality rate [8].

An alternate explanation for their findings is that those participants with higher calcium intake or 25(OH)D concentrations started taking calcium or vitamin D supplements late in life due to a diagnosis of a vitamin D- or calcium-deficiency disease such as osteoporosis. Support for this explanation is provided in two studies of the association of frailty with serum 25(OH)D concentrations in the United States: older women had a U-shaped relation between 25(OH)D concentration and frailty status [9], while men had a linear inverse relation [10]. In the United States, women are much more likely to be diagnosed with low bone mass density and advised to take extra vitamin D and calcium supplementation. These two papers suggest that taking vitamin D late in life cannot overcome the adverse health effects of low 25(OH)D concentrations earlier in life.

A way to investigate this explanation is to review the medical records of some of the 1241 participants in the study to see what their health status was prior to the time they were identified as taking more than 1400 mg/d calcium and whether such status may have resulted in increased supplement use.

1.Michaëlsson K, Melhus H, Lemming EW, Wolk A, Byberg L. Long term calcium intake and rates of all cause and cardiovascular mortality: community based prospective longitudinal cohort study. BMJ. 2013;346:1228.

2. Heaney RP, Kopecky S, Maki KC, Hathcock J, Mackay D, Wallace TC. A review of calcium supplements and cardiovascular disease risk. Adv Nutr. 2012;3:763-71.

3. Bolland MJ, Avenell A, Baron JA, Grey A, MacLennan GS, Gamble GD, et al. Effect of calcium supplements on risk of myocardial infarction and cardiovascular events: meta-analysis. BMJ. 2010;341:c3691.

4. 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;342:d2040.

5. Hill AB. The environment and disease: Association or causation? Proc R Soc Med. 1965;58:295-300.

6. Lappe JM, Travers-Gustafson D, Davies KM, Recker RR, Heaney RP. Vitamin D and calcium supplementation reduces cancer risk: results of a randomized trial. Am J Clin Nutr. 2007;85:1586-91.

7. Michaëlsson K, Baron JA, Snellman G, Gedeborg R, Byberg L, Sundström J, et al. Plasma vitamin D and mortality in older men: a community-based prospective cohort study. Am J Clin Nutr. 2010;92:841-8.

8. Zittermann A, Iodice S, Pilz S, Grant WB, Bagnardi V, Gandini S. Vitamin D deficiency and mortality risk in the general population: A meta-analysis of prospective cohort studies. Am J Clin Nutr. 2012;95:91-100.

9. Ensrud KE, Ewing SK, Fredman L, Hochberg MC, Cauley JA, Hillier TA, et al. Circulating 25-hydroxyvitamin D levels and frailty status in older women. J Clin Endocrinol Metab. 2010;95:5266-73.

10. Ensrud KE, Blackwell TL, Cauley JA, Cummings SR, Barrett-Connor E, Dam TT, et al. Circulating 25-hydroxyvitamin D levels and frailty in older men: the osteoporotic fractures in men study. J Am Geriatr Soc. 2011;59:101-6.

Competing interests: I receive funding from Bio-Tech Pharmacal (Fayetteville, AR), and the Sunlight Research Forum (Veldhoven) and have received funding from the UV Foundation (McLean, VA), the Vitamin D Council (San Luis Obispo, CA), and the Vitamin D Society (Canada).

14 February 2013
William B. Grant
Sunlight, Nutrition and Health Research Cencer
PO Box 641603