Departments of Obstetrics and Gynecology and Internal Medicine, Reading Hospital, and the Sidney Kimmel Medical College at Thomas Jefferson University, Philadelphia, Pennsylvania; the Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, Washington; Kaiser Permanente, Center for Health Research NW, Portland, Oregon; Department of Internal Medicine, Division of Cardiology, George Washington University School of Medicine and Health Sciences, Washington, DC; the Divisions of Preventive Medicine, Brigham and Women's Hospital/Harvard Medical School, Boston, Massachusetts, University of Alabama at Birmingham, School of Medicine, Birmingham, Alabama, and University of Tennessee Health Science Center, Memphis, Tennessee; the Department of Medicine, Stanford University School of Medicine, Stanford University, Stanford Prevention Research Center, Stanford, California; the Office of Research Development, Duke University School of Medicine, Durham, North Carolina; the University of Pittsburgh, Graduate School of Public Health, Pittsburgh, Pennsylvania; the Department of Epidemiology, MedStar Health Research Institute and Georgetown/Howard Universities Center for Clinical and Translational Science, Washington, DC; and UC Davis Medical Center, Sacramento, California.
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OBJECTIVE:To analyze the treatment effect of calcium+vitamin D supplementation, hormone therapy, both, and neither on cardiovascular disease risk factors.METHODS:We conducted a prospective, randomized, double-blind, placebo-controlled trial among Women's Health Initiative (WHI) participants. The predefined primary outcome was low-density lipoprotein cholesterol (LDL-C).RESULTS:Between September 1993 and October 1998, a total of 68,132 women aged 50–79 years were recruited and randomized to the WHI–Dietary Modification (n=48,835) and WHI–Hormone Therapy trials (n=27,347). Subsequently, 36,282 women from WHI–Hormone Therapy (16,089) and WHI–Dietary Modification (n=25,210) trials were randomized in the WHI–Calcium+Vitamin D trial to 1,000 mg elemental calcium carbonate plus 400 international units vitamin D3 daily or placebo. Our study group included 1,521 women who participated in both the hormone therapy and calcium+vitamin D trials and were in the 6% subsample of trial participants with blood sample collections at baseline and years 1, 3, and 6. The average treatment effect with 95% confidence interval, for LDL-C, compared with placebo, was −1.6, (95% confidence interval [CI] −5.5 to 2.2) mg/dL for calcium+vitamin D alone, −9.0 (95% CI −13.0 to −5.1) mg/dL for hormone therapy alone, and −13.8 (95% CI −17.8 to −9.8) mg/dL for the combination. There was no evidence of a synergistic effect of calcium+vitamin D+hormone therapy on LDL-C (P value for interaction=.26) except in those with low total intakes of vitamin D, for whom there was a significant synergistic effect on LDL (P value for interaction=.03).CONCLUSION:Reductions in LDL-C were greater among women randomized to both calcium+vitamin D and hormone therapy than for those randomized to either intervention alone or to placebo. The treatment effect observed in the calcium+vitamin D+hormone therapy combination group may be additive rather than synergistic. For clinicians and patients deciding to begin calcium+vitamin D supplementation, current use of hormone therapy should not influence that decision.CLINICAL TRIAL REGISTRATION:ClinicalTrials.gov, https://clinicaltrials.gov, NCT00000611.