Calcium plus vitamin D supplementation and the risk of fractures.

Randomized, placebo-controlled trial in healthy postmenopausal women aged 50 to 79 years enrolled at 40 Women's Health Initiative clinical centers in the United States. Participants were followed in the community setting for a mean of 7.0 years, with baseline characteristics including mean age 62.4 years and mean BMI 29.

The active regimen was oral calcium carbonate plus vitamin D3: each tablet contained 500 mg elemental calcium and 200 IU vitamin D3, taken as two tablets per day in divided doses with meals. The comparator was placebo, and tablets were chewable or swallowable after July 1997.

Calcium plus vitamin D did not significantly reduce hip fracture or total fractures, although it produced a small improvement in hip bone density. Hip fracture occurred in 175 women in the calcium plus vitamin D group versus 199 in placebo (hazard ratio 0.88, 95% CI 0.72-1.08), and total fractures occurred in 2102 versus 2158 (hazard ratio 0.96, 95% CI 0.91-1.02). Hip bone density was 1.06 percent higher in the calcium plus vitamin D group (P<0.01), and the adherence-adjusted hip fracture hazard ratio was 0.71 (0.52-0.97). The regimen increased renal calculi risk (hazard ratio 1.17, 95% CI 1.02-1.34) and raised 25-hydroxyvitamin D levels by 28 percent, but there was no clear interaction with baseline vitamin D status.

Fracture outcomes were not significantly improved in the intention-to-treat analysis despite a bone density benefit, and adherence influenced the apparent hip-fracture reduction. The population was healthy postmenopausal women with relatively high baseline calcium intake, which may limit generalizability and reduce the ability to detect benefit. Concomitant use of bisphosphonates and calcitonin was permitted, and kidney stone risk increased.