Abstract and Introduction
Abstract
Objective. This study aims to test the added value of calcium and vitamin D (CaD) in fracture prevention among women taking postmenopausal hormone therapy (HT).
Methods. This is a prospective, partial-factorial, randomized, controlled, double-blind trial among Women’s Health Initiative postmenopausal participants aged 50 to 79 years at 40 centers in the United States with a mean follow-up of 7.2 years. A total of 27,347 women were randomized to HT (0.625 mg of conjugated estrogens alone, or 0.625 mg of conjugated equine estrogens plus 2.5 mg of medroxyprogesterone acetate daily), and 36,282 women were randomized to 1,000 mg of elemental calcium (carbonate) plus 400 IU of vitamin D3 daily, each compared with placebo. A total of 16,089 women participated in both arms. The predefined outcomes were adjudicated hip fractures and measured bone mineral density.
Results. Interaction between HT and CaD on hip fracture (P interaction = 0.01) was shown. The effect of CaD was stronger among women assigned to HT (hazard ratio [HR], 0.59; 95% CI, 0.38-0.93) than among women assigned to placebo (HR, 1.20; 95% CI, 0.85-1.69). The effect of HT on hip fracture was stronger among women assigned to active CaD (HR, 0.43; 95% CI, 0.28-0.66) than among women assigned to placebo (HR, 0.87; 95% CI, 0.60-1.26). CaD supplementation enhanced the antifracture effect of HT at all levels of personal calcium intake. There was no interaction between HT and CaD on change in hip or spine bone mineral density.
Conclusions. Postmenopausal women at normal risk for hip fracture who are on CaD supplementation experience significantly reduced incident hip fractures beyond HT alone at all levels of personal baseline total calcium intake.
Introduction
Controversy surrounds the use of supplemental calcium and vitamin D (CaD). The literature is full of conflicting reports and strong opinions. Major authorities have questioned the health benefits/risks of widespread supplementation. The US Preventive Services Task Force recently published recommendations advising against routine supplementation with CaD.
In practice, most trials of osteoporosis medications have included CaD supplementation for both active and placebo groups. Little data support this practice. Conflicting results have been published from prior trials. One publication looking at response to bisphosphonates showed improved response in bone mineral density (BMD) and turnover markers with higher vitamin D serum levels. Using data from the Fracture Intervention Trial of alendronate, Antoniucci et al showed that baseline vitamin D levels did not change outcomes. Looking at a relatively small number of participants in zolentonate trials, an Australian group was unable to show a statistically significant effect of either dietary CaD or vitamin D levels on BMD or turnover makers. Another recent publication only showed a response among those with initially low vitamin D levels.
The use of postmenopausal hormones is also controversial. Some groups support the use of estrogen therapy for the treatment of osteoporosis, although it may not be considered the standard of care.
Women’s Health Initiative (WHI) clinical trials that did not select women based on low bone density or osteoporosis demonstrated that estrogen therapy, with or without progestin, increased bone density and reduced fracture risk similarly. In this article, we address two major research questions: (1) Does CaD supplementation increase bone health benefits in postmenopausal women on estrogen therapy? (2) Does estrogen therapy increase bone health benefits in women taking CaD supplementation?
The WHI offers a unique opportunity to address these questions through secondary analyses of data from prospective, partial-factorial, randomized trials. The WHI used a partial factorial design for two hormonal trials (conjugated equine estrogens [CEE] alone and CEE + medroxyprogesterone acetate [MPA]) and for a trial of CaD supplementation. This permits the exploration of the effects of CaD on hip fractures in women receiving hormonal supplementation in a double-blind prospective study, and vice versa.
Women were randomized to either, both, or neither of the hormonal and CaD trials. After the hormone therapy (HT) intervention ended, only a small percentage of participants reported using HT; less than 5% of women in the active arms and less than 3% of women in the placebo arms of either WHI HT trial continued to take hormones. Incident hip fracture outcomes were assessed and adjudicated by investigators blinded to treatment assignments. Four clinical sites assessed BMD in a subsample of women, using dual-energy x-ray absorptiometry (DXA), at baseline and on years 1, 3, and 6 after HT randomization.