Table 1 lists the characteristics of the study participants by categories of calcium intake. The average total cumulative calcium intake in the lowest category was 572 mg/day and in the highest was 2137 mg/day. With increasing categories of energy standardised calcium intake, the reported intake for most other nutrients also increased, although alcohol intake tended to decrease. There were small differences in calcium supplement use, comorbidity, educational level, smoking status, and physical activity level between categories of calcium intake.
Table 1 Characteristics of participants by categories of average cumulative total intake of calcium. Values are numbers (percentages) unless stated otherwise
During a median of 19 years of follow-up and 1
880 person years at risk, 11
944 women (17%) died; of these women, the underlying cause of death was cardiovascular disease in 3862, ischaemic heart disease in 1932, and stroke in 1100.
The highest rates of death from all causes, cardiovascular disease, and ischaemic heart disease but not stroke were observed among those with a dietary calcium intake higher than 1400 mg/day (table 2). These intakes, compared with dietary intakes between 600 and 1000 mg/day, conferred hazard ratios of 1.40 (95% confidence interval 1.17 to 1.67) for all cause mortality, 1.49 (1.09 to 2.02) for cardiovascular disease mortality, and 2.14 (1.48 to 3.09) for ischaemic heart disease mortality.
Table 2 Absolute rates and age and multivariable adjusted hazard ratios of all cause and cardiovascular mortality by categories of average cumulative intake of total and dietary calcium
After multivariable adjustment, a high total calcium intake was also associated with a higher mortality risk (table 2). The shift from a lower to a higher risk with the multivariable model was mainly the consequence of the adjustment for use of calcium containing supplements (see supplementary table 1). In addition, mortality rates were higher among women with an intake below 600 mg/day (table 2). The tendency of a U-shaped association between both dietary and total calcium intake with deaths from all causes, cardiovascular disease, and ischaemic heart disease is also visualised by the pattern of the spline curves in figure 2, a pattern that was not apparent for stroke mortality. However, to deal further with possible bias introduced by using time updated information in the models, sensitivity analyses were carried out. Firstly, only baseline data were included, without updating with information from the second questionnaire (see supplementary table 2). This analysis indicated a higher risk of death with high dietary calcium intakes but not with low intakes. Secondly, a causal inference analytical model was used. Although hampered by a lower precision (see supplementary table 3), the results for the high dietary calcium intake level are essentially similar to those obtained by ordinary Cox’s regression analysis (table 2 and supplementary table 2) but the estimates for women with low dietary calcium intakes were attenuated. Moreover, mortality estimates for women with both low and high total calcium intakes were attenuated compared with the time dependent Cox regression model.
Fig 2 Multivariable adjusted spline curves for relation between cumulative average of dietary and total calcium intake with time to death from all causes, cardiovascular disease, ischaemic heart disease, and stroke. *Adjusted for age, total energy and (more ...)
Calcium containing supplements were used by one fourth (10
984) of the study population in 1997. The largest source of supplemented calcium was from multivitamins with minerals (120 mg per tablet; 74% of supplement users). Most women taking calcium tablets were also regular users of multivitamins. The average dietary intake of calcium was similar in calcium supplement users, both at baseline (users reported 6 mg lower dietary calcium intake; 95% confidence interval −2 to 13 mg) and at the second investigation in 1997 (users reported 6 mg lower intake; 0 to 13 mg). Use of calcium containing supplements in 1997 was not associated with death from cardiovascular disease or ischaemic heart disease (see supplementary table 4).
Women who had a high dietary intake of calcium exceeding 1400 mg/day and additionally used calcium supplements had a higher mortality rate than women with a similarly high intake of calcium but without taking supplements (table 3). Thus, among calcium tablet users (500 mg calcium per tablet), a high dietary calcium intake (>1400 mg/day) conferred a multivariable adjusted hazard ratio of 2.57 (95% confidence interval 1.19 to 5.55) for all cause mortality compared with a dietary calcium intake of between 600 and 999 mg/day. The same comparison among women with use of any type of calcium containing supplement, yielded a multivariable adjusted hazard ratio of 1.51 (0.91 to 2.50), whereas the hazard ratio among non-users of calcium containing supplements was 1.17 (0.97 to 1.41). Thus, among women with a high dietary intake of calcium, the addition of calcium supplements increased the risk of death in a dose dependent fashion. The synergy index for the interaction between a high dietary calcium intake and calcium tablet use was 4.87 (95% confidence interval 1.11 to 21.32).
Table 3 Absolute rates and age and multivariable adjusted hazard ratios of all cause mortality by categories of average cumulative intake of dietary calcium by calcium supplement use
Vitamin D intake did not significantly modify the associations between calcium intake and the rate of deaths from all causes, cardiovascular disease, or ischaemic heart disease (results not shown).