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). 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).
Discussion
In this study of women in the Swedish mammography cohort, a high calcium intake (>1400 mg/day) was associated with an increased rate of mortality, including death from cardiovascular disease. The increase was moderate with a high dietary calcium intake without supplement use, but the combination of a high dietary calcium intake and calcium tablet use resulted in a more pronounced increase in mortality. For most women with lower intakes we observed only modest differences in risk.
Strengths and weaknesses of the study
Strengths of our study include the population based prospective design, study size, and repeated measurements of calcium intake, as well as a large number of potential covariates. Date and cause of death were traced through national healthcare registries and deterministic record linkage, permitting complete ascertainment of the outcomes. The accuracy of classification of causes of death in the cause of death registry and diagnoses in the national patient registry are high.43 Furthermore, we adjusted for several important covariates (for example, smoking, socioeconomic status, physical activity, nutrients other than calcium, educational level, and comorbidity), but residual confounding remains a possible limitation. The lower age adjusted rates of death from all causes and cardiovascular disease among women with a high total calcium intake were largely explained by their use of dietary supplements (table 2), a variable considered in the multivariable models. Other health related covariates, including a healthy diet and level of physical activity contributed to a lesser degree. People who use dietary supplements have, on average, a healthier lifestyle and a lower risk factor profile for
cardiovascular disease44 and not considering this might distort the risk estimates. Moreover, the low proportion of women who took prescription calcium tablets (6%), containing a four times higher dose of calcium than in regular multivitamin dietary supplements, made it difficult to detect modestly strong associations with calcium tablet use specifically. Dietary
assessment methods are prone to several limitations, affecting both the precision and accuracy of the measurement. In larger studies, a food frequency questionnaire is used to assess the habitual intake of diet, and a recent review concluded that it was a valid method for assessing dietary mineral intake, particularly for calcium.45 The food frequency questionnaire may, to some extent, overestimate calcium intake,25 which was also indicated by our validation. A further limitation in our study is the use of age standardised portion sizes and not actual individual portion sizes. By use of our calibrated analysis of calcium intake, we none the less tried to avoid some misclassification of study participants. By using repeated measurements on dietary intake we increased the accuracy of the measurement but may also have introduced bias using time dependent Cox regression models. Indeed, after using only baseline data and also after performing the marginal structural model analyses, we no longer observed an increased mortality for women with low calcium intakes or a high total calcium intake. Without being causally linked to death, a low calcium intake could therefore be viewed as a marker of frailty or a less healthy behaviour associated with a higher mortality. There are, however, also theoretical drawbacks of our causal inference model. It is sensitive to correct model specifications and indeed renders estimates with lower precision than ordinary Cox’s regression.46 47 It is worth emphasising that traditionally obtained estimates, such as those from Cox’s regression, would not generally agree with estimates from marginal structural models even when there is no confounding.48 Irrespective of analytical approach, the observational study design precludes conclusions
about causality, and cautious interpretations of the results are therefore recommended.