Calcium plus vitamin D supplementation and health outcomes five years after active intervention ended: the Women's Health Initiative

Abstract

Background: Clinical outcomes of the Women's Health Initiative (WHI) calcium plus vitamin D supplementation trial have been reported during 7.0 years of active intervention. We now report outcomes 4.9 years after the intervention stopped and cumulative findings.

Methods: Postmenopausal women (N=36,282) were randomized; postintervention follow-up continued among 29,862 (86%) of surviving participants. Primary outcomes were hip fracture and colorectal cancer. Breast cancer, all cancers, cardiovascular disease (CVD), and total mortality were predetermined major study outcomes.

Results: Hip fracture incidence was comparable in the supplement and the placebo groups, postintervention hazard ratio (HR)=0.95, 95% confidence interval (95% CI: 0.78, 1.15) and overall HR=0.91 (95% CI: 0.79, 1.05). Overall, colorectal cancer incidence did not differ between randomization groups, HR=0.95 (95% CI: 0.80, 1.13). Throughout, there also was no difference in invasive breast cancer, CVD, and all-cause mortality between groups. In subgroup analyses, the invasive breast cancer effect varied by baseline vitamin D intake (p=0.03 for interaction). Women with vitamin D intakes >600 IU/d, had an increased risk of invasive breast cancer, HR=1.28 (95% CI; 1.03, 1.60). Over the entire study period, in post hoc analyses, the incidence of vertebral fractures, HR=0.87 (95% CI: 0.76, 0.98) and in situ breast cancers, HR=0.82 (95% CI: 0.68, 0.99) were lower among women randomized to supplementation.

Conclusion: After an average of 11 years, calcium and vitamin D supplementation did not decrease hip fracture or colorectal cancer incidence. Exploratory analyses found lower vertebral fracture and in situ breast cancer incidence in the supplement users. There was no effect on CVD or all-cause mortality.

FIG. 1.

Incident clinical events by randomization assignment and corresponding hazard ratios (HRs) for the intervention, postintervention, and overall follow-up period. The HR and 95% confidence interval (CI) for intervention period events are derived from a proportional hazards model stratified on age, prevalent condition (where appropriate), and randomization arm in the hormone therapy (HT) and diet modification (DM) trials, where time to event equals 0 on date of randomization. The HR and CI for postintervention period events are derived from a Cox proportional hazards model stratified on age, prevalent condition (where appropriate), and randomization arm in the HT and DM trials, where time to event equals 0 on calcium and vitamin D (CaD) trial close-out date. The HR and CI for the overall combined period events are derived from a proportional hazards model stratified by prevalent condition (where appropriate), age, HT and DM randomization arm, and trial phase (time-dependent), where time to event equals 0 on date of randomization. P-values for the difference between the intervention and postintervention periods are derived from a Cox proportional hazards models stratified by prevalent condition (where appropriate), age, HT and DM randomization arm, and trial phase (time-dependent), where time to event equals 0 on date of randomization. The p-value tests whether the HR for the intervention period equals the HR for the postintervention period. All nonhip fractures use adjudicated data during the clinical trial and self-reported data thereafter.

FIG. 2.

Risks and benefits by randomization assignment to calcium plus vitamin D supplementation or placebo before or after termination of the intervention. Kaplan Meier cumulative hazards for clinical outcomes, by time in the trial and time after termination of the intervention. Dotted vertical lines represent quintiles of duration of the intervention in the study population (elapsed time from randomization until the main study close-out). Overall curves include events from randomization to September 30, 2010. Postintervention curves include events from CaD study close-out to September 30, 2010. CHD, coronary heart disease.

Appendix Figure A1.

Women's Health Initiative calcium and vitamin D (CaD) trial through extended follow-up.