In this large randomized trial of women aged 50–79, CaD supplementation for an average of 7 years was associated with a nonsignificant reduction in the risk of death (9% with 95% CI, 17% reduction to a 1% increase in risk). The evidence was most consistent for a decrease in cancer mortality.
Among the 23 interactions tested, none was statistically significant. Age, as the strongest predictor of mortality in the general population, was of particular interest. Among the women younger than 70 years, CaD supplementation appeared to reduce risks of total, CVD, and cancer death. In older women, only cancer mortality appeared to be reduced. The interaction between CaD supplementation and age was not statistically significant for total mortality overall but was so among adherent women (p
Because the majority of statistical tests reported herein are not significant at the .05 level, a viable explanation for these results is chance alone. Among the younger women, there was a difference favoring intervention for reduced mortality within the first year, which is difficult to attribute to intervention. A trial designed to confirm this association would require more than 90,000 women aged 50 and older followed for 5 or more years to detect a statistically significant reduction in mortality rates of 9%–10%.
Nonetheless, previous randomized controlled trials, most of which enrolled only older women, have also shown nonsignificant reductions in total mortality. A recent meta-analysis of nine trials testing vitamin D supplementation reported an overall HR of 0.93 (95% CI, 0.87–0.99); however, this point estimate largely reflects the contribution of WHI women who contributed a majority of the person-time. Six of the remaining eight smaller trials showed nonsignificant reductions in total mortality (4
). Cause-specific mortality was examined in only one previous trial and showed nonsignificant reductions in cardiovascular, total cancer, and colorectal cancer mortality with very wide CIs (3
If the results did not occur by chance, multiple pathways could be involved including any elements of the supplements tested: calcium, vitamin D3
, or carbonate, or all. Calcium supplementation has been shown in small experimental studies to lower blood pressure (10
) and reduce cholesterol levels (11
). Observational epidemiological studies have shown an association of calcium intake with reduced stroke incidence and mortality (14
) and inconsistent associations with reduced risk of coronary disease (16
). Lower bone density has been associated with increased mortality risks (18
). In the WHI CaD trial, the intervention group had statistically significant but small reductions in low-density lipoprotein, weight, and waist circumference, whereas blood pressure change was slightly increased compared with placebo (20
). Although the intervention improved hipbone density by about 1%, it produced no significant differences in CHD or stroke incidence.
Vitamin D insufficiency has now been linked to a broad spectrum of human diseases from cancer to cardiovascular to autoimmune conditions (21
). A recent ecological study showed consistently elevated death rates from cancer sites among U.S. women with less solar ultraviolet-B exposure (22
). Vitamin D receptors are present in many cell types and 1,25-dihydroxyvitamin D has been shown to favor cell differentiation over proliferation and to inhibit potential for metastasis and invasiveness (23
). Serum vitamin D levels were inversely associated with colon cancer risk in the Nurses' Health Study (24
), in the WHI CaD trial (6
), and with colon cancer mortality in National Health and Nutrition Examination Survey
). Supplementation with 1,100 IU of vitamin D3
reduced the risk of cancer in a recent small trial of healthy postmenopausal women (26
). Two recent prospective studies link levels of serum 25-hydroxyvitamin D below 44.4 nmol/L (27
) or 25.2 nmol/L (28
) to increased risk of total mortality.
The emerging optimism over vitamin D supplementation for the prevention of cancer (29
) is occurring in the absence of confirmation from large prevention trials that can determine the benefits and any currently unknown risks. Proponents argue that the necessary levels of vitamin D supplementation to exert anticancer effects might be 1,500–2,000 IU/d based on selective findings from observational studies (30
). The optimum dose of vitamin D for reducing cancer or mortality is unknown and, if it exists, can only be determined from future large randomized trials.
The trends toward reductions in risks of both cardiovascular and cancer mortality in this trial, if real, suggest mechanisms that may have broad physiological effects. Vitamin D supplementation has been shown experimentally to increase levels of the anti-inflammatory cytokine interleukin-10, while preventing increases in tumor necrosis factor alpha (32
). Calcium and vitamin D supplementation both lower parathyroid hormone levels (PTH), and PTH levels have been associated with an increased risk of mortality in a vitamin D–deficient cohort of the very old age (33
). Chronic metabolic acidosis increases with age and declining kidney function even when plasma measures of acid–base balance are normal. Administration of bicarbonate has been shown to reverse acidosis (34
). Beneficial effects of CaD supplementation on cytokine profiles, PTH, or acidosis might be expected to produce greater benefits in older women, whereas the opposite trend was observed in this trial. However, it is also possible that mortality could be delayed by improvements in these parameters and eventually benefits diminish with disease progression in later life.
Strengths of this trial include its large size, diversity, long duration, excellent retention, and reasonably good adherence for an average of 7 years of follow-up. This study is limited by lack of statistical power for detecting intervention effects on mortality, as it was not designed for this purpose. We did not collect postintervention serum specimens for exploring potential intermediate effects of the intervention that might have influenced mortality. We cannot distinguish between effects of calcium, vitamin D, or carbonate because the intervention combined these ingredients. We do not know whether higher supplement doses of vitamin D would have produced different results.
In conclusion, the WHI CaD trial supports the hypothesis that CaD supplementation provides a modest reduction in rates of total and categories of cause-specific mortality, but the results are too imprecise to be definitive. Moreover, these data can neither support nor refute recommendations for higher dose vitamin D supplementation to reduce cancer or total mortality. This hypothesis merits further consideration by testing alternative underlying mechanisms and possibly by testing higher dose supplements in even larger randomized trials.
Cumulative mortality Kaplan–Meier curves by age group.