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Effects of Calcium, Vitamin D, and Hormone Therapy on Cardiovascular Disease Risk Factors in the Women's Health Initiative: A Randomized Controlled Trial

Schnatz, Peter F. DO; Jiang, Xuezhi MD, PhD; Aragaki, Aaron K. MS; Nudy, Matthew MD; O'Sullivan, David M. PhD; Williams, Mark MD; LeBlanc, Erin S. MD, MPH; Martin, Lisa W. MD; Manson, JoAnn E. MD, DrPH; Shikany, James M. DrPH; Johnson, Karen C. MD, MPH; Stefanick, Marcia L. PhD; Payne, Martha E. RD, PhD; Cauley, Jane A. DrPH; Howard, Barbara V. PhD; Robbins, John MD

doi: 10.1097/AOG.0000000000001774
Contents: Original Research

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.


Supplemental Digital Content is Available in the Text.Additive effects (both positive and some negative) on multiple cardiovascular disease risk factors were observed when menopausal women were randomized to both calcium and vitamin D and hormone therapy.

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.

Corresponding author: Peter F. Schnatz, DO, Departments of OB/GYN & Internal Medicine, Sidney Kimmel Medical College of Thomas Jefferson University, Associate Chair & Residency Program Director, The Reading Hospital, Department of OB/GYN—R1, PO Box 16052, Reading, PA 19612-6052; email:

The study sponsors had no role in the design of the study; the collection, analysis, and interpretation of the data; the writing of the manuscript; or the decision to submit the manuscript for publication. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Heart, Lung, and Blood Institute or the National Institutes of Health.

Financial Disclosure Dr. LeBlanc has received grants from Amgen Inc, Bristol Meyers Squibb, Merck, and AstraZeneca (unrelated to the current research). Dr. Payne's effort was supported by a National Institutes of Health Building Interdisciplinary Research Careers in Women's Health (BIRCWH) K12 grant (HD043446). The other authors did not report any potential conflicts of interest.

Presented as a poster at the 26th Annual Scientific Meeting of the North American Menopause Society, September 30–October 3, 2015, Las Vegas, Nevada.

The research reported in this article was supported by the research budget of the Reading Health System. The research on which this publication is based was supported by R01 HL083326 (to Dr Mackey) from the National Heart, Lung, and Blood Institute. The Women's Health Initiative (WHI) program is funded by the National Heart, Lung, and Blood Institute, National Institutes of Health, U.S. Department of Health and Human Services through contracts HHSN268201100046C, HHSN268201100001C, HHSN268201100002C, HHSN268201100003C, HHSN268201100004C, and HHSN271201100004C. Information about the WHI investigators, their academic centers, the program office, and the clinical coordinating center can be found online at:

For a list of names associated with this study, please see Appendix 1 online at

Each author has indicated that he or she has met the journal's requirements for authorship.

© 2017 by The American College of Obstetricians and Gynecologists. Published by Wolters Kluwer Health, Inc. All rights reserved.