Calcium plus vitamin D supplementation and the risk of breast cancer

Abstract

Background: Although some observational studies have associated higher calcium intake and especially higher vitamin D intake and 25-hydroxyvitamin D levels with lower breast cancer risk, no randomized trial has evaluated these relationships.

Methods: Postmenopausal women (N = 36 282) who were enrolled in a Women's Health Initiative clinical trial were randomly assigned to 1000 mg of elemental calcium with 400 IU of vitamin D(3) daily or placebo for a mean of 7.0 years to determine the effects of supplement use on incidence of hip fracture. Mammograms and breast exams were serially conducted. Invasive breast cancer was a secondary outcome. Baseline serum 25-hydroxyvitamin D levels were assessed in a nested case-control study of 1067 case patients and 1067 control subjects. A Cox proportional hazards model was used to estimate the risk of breast cancer associated with random assignment to calcium with vitamin D(3). Associations between 25-hydroxyvitamin D serum levels and total vitamin D intake, body mass index (BMI), recreational physical activity, and breast cancer risks were evaluated using logistic regression models. Statistical tests were two-sided.

Results: Invasive breast cancer incidence was similar in the two groups (528 supplement vs 546 placebo; hazard ratio = 0.96; 95% confidence interval = 0.85 to 1.09). In the nested case-control study, no effect of supplement group assignment on breast cancer risk was seen. Baseline 25-hydroxyvitamin D levels were modestly correlated with total vitamin D intake (diet and supplements) (r = 0.19, P < .001) and were higher among women with lower BMI and higher recreational physical activity (both P < .001). Baseline 25-hydroxyvitamin D levels were not associated with breast cancer risk in analyses that were adjusted for BMI and physical activity (P(trend) = .20).

Conclusions: Calcium and vitamin D supplementation did not reduce invasive breast cancer incidence in postmenopausal women. In addition, 25-hydroxyvitamin D levels were not associated with subsequent breast cancer risk. These findings do not support a relationship between total vitamin D intake and 25-hydroxyvitamin D levels with breast cancer risk.

Figure 1

CONSORT diagram of the Women's Health Initiative randomized trial of calcium and vitamin D. Permission for reproduction was granted from The Publishing Division of the Massachusetts Medical Society (12).

Figure 2

Kaplan–Meier estimates of the cumulative hazard ratio for invasive breast cancer with supplemental calcium plus vitamin D (Ca/D) as compared with placebo. HR, hazard ratio; CI, confidence interval. Error bars represent 95% CIs of the estimates at each year, using solid and dashed lines for the Ca/D and placebo groups, respectively.

Figure 3

Estimated effects of supplemental calcium with vitamin D (CaD) on the risk of invasive breast cancer, according to selected baseline characteristics. Modeling for interaction testing used the continuous form of the following variables: age at screening, body mass index (BMI), Gail risk score, and baseline total calcium and vitamin D intake. Data were missing for some variables. HT = hormone therapy; E = estrogen; P = progestin; DM = dietary modification. All models were stratified by age (50–54, 55–59, 60–69, 70–79 years), prevalent disease, and randomization in the dietary modification and HT trials. *Women not randomized in the HT trials are excluded. †Adjusted for age (linear), weight, and baseline percentage of energy from total fat. Women not randomized in the DM trial are excluded. P values are two-sided.

Figure 4

Self-reported individual vitamin D intake (diet plus supplementation) and serum 25-hydroxyvitamin D levels at baseline. Serum 25-hydroxyvitamin D levels were obtained at baseline entry into the calcium plus vitamin D clinical trial. Results from the 1067 women identified as control subjects from the nested case–control study are shown. Daily intakes of dietary and supplemental vitamin D were determined from self-report. The range of vitamin D intakes substantially overlap in each 25-hydroxyvitamin D quintile, and an average vitamin D intake difference of only 238 IU/day separates women in the low vs high 25-hydroxyvitamin D quintiles. Line segments connect the mean vitamin D intake level in each quintile.