“Long-Term Effect of Randomization to Calcium and Vitamin D Supplementation on Health in Older Women: Post-Intervention Follow-Up of a Randomized Clinical Trial”, Cynthia A. Thomson, Aaron K. Aragaki, Ross L. Prentice, Marcia L. Stefanick, JoAnn E. Manson, Jean Wactawski-Wende, Nelson B. Watts, Linda Van Horn, James M. Shikany, Thomas E. Rohan, Dorothy S. Lane, Robert A. Wild, Rogelio Robles-Morales, Aladdin H. Shadyab, Nazmus Saquib, Jane Cauley2024-03-12 (Vitamin D)⁠:

Background: Although calcium and vitamin D (CaD) supplementation may affect chronic disease in older women, evidence of long-term effects on health outcomes is limited.

Objective: To evaluate long-term health outcomes among postmenopausal women in the Women’s Health Initiative CaD trial.

Design: Post hoc analysis of long-term post-intervention follow-up of the 7-year randomized intervention trial of CaD. (ClinicalTrials.gov: NCT00000611)

Setting: A multicenter (n = 40) trial across the United States.

Participants: 36,282 postmenopausal women with no history of breast or colorectal cancer.

Intervention: Random 1:1 assignment to 1,000 mg of calcium carbonate (400 mg of elemental calcium) with 400 IU of vitamin D₃ daily or placebo.

Measurements: Incidence of colorectal, invasive breast, and total cancer; disease-specific and all-cause mortality; total cardiovascular disease (CVD); and hip fracture by randomization assignment (through December 2020). Analyses were stratified on personal supplement use.

Results: For women randomly assigned to CaD versus placebo, a 7% reduction in cancer mortality was observed after a median cumulative follow-up of 22.3 years (1,817 vs. 1,943 deaths; hazard ratio [HR], 0.93 [95% CI, 0.87–0.99]), along with a 6% increase in CVD mortality (2,621 vs. 2,420 deaths; HR, 1.06 [CI, 1.01–1.12]).

There was no overall effect on other measures, including all-cause mortality (7,834 vs. 7,748 deaths; HR, 1.00 [CI, 0.97–1.03]). [So they canceled out‽ Alarming (which one caused the CVD deaths?), but on the other hand, this was a rather small vitamin D dose, and the calcium may be to blame…]

Estimates for cancer incidence varied widely when stratified by whether participants reported supplement use before randomization, whereas estimates on mortality did not vary, except for CVD mortality.

Limitation: Hip fracture and CVD outcomes were available on only a subset of participants, and effects of calcium versus vitamin D versus joint supplementation could not be disentangled.

Conclusion: Calcium and vitamin D supplements seemed to reduce cancer mortality and increase CVD mortality after more than 20 years of follow-up among postmenopausal women, with no effect on all-cause mortality.