Interaction of estrogen therapy with calcium and vitamin D supplementation on colorectal cancer risk: Reanalysis of Women's Health Initiative randomized trial

Authors

  • Eric L. Ding,

    Corresponding author
    1. Department of Nutrition, Harvard School of Public Health, Boston, MA
    2. Department of Epidemiology, Harvard School of Public Health, Boston, MA
    3. Division of Preventive Medicine, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA
    • Harvard School of Public Health, 655 Huntington Ave, Boston, MA 02115, USA
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    • The first two authors contributed equally to this paper.

  • Saurabh Mehta,

    1. Department of Nutrition, Harvard School of Public Health, Boston, MA
    2. Department of Epidemiology, Harvard School of Public Health, Boston, MA
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    • The first two authors contributed equally to this paper.

  • Wafaie W. Fawzi,

    1. Department of Nutrition, Harvard School of Public Health, Boston, MA
    2. Department of Epidemiology, Harvard School of Public Health, Boston, MA
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  • Edward L. Giovannucci

    1. Department of Nutrition, Harvard School of Public Health, Boston, MA
    2. Department of Epidemiology, Harvard School of Public Health, Boston, MA
    3. Channing Laboratory, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA
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Abstract

Although calcium and vitamin-D intake were consistently shown to be inversely associated with colorectal cancer risk in several large prospective studies and protective against adenoma and cancer in multiple randomized trials, the Women's Health Initiative (WHI) of calcium and low-dose vitamin-D supplementation trial found no overall effects on colorectal cancer. However, the previous report did not recognize an important biologic interaction with estrogen therapy. We investigated the treatment interaction of estrogen with calcium and vitamin-D on risk of colorectal cancer via a reanalysis of primary data results from the WHI calcium and vitamin-D supplementation trial (1,000 mg elemental calcium, 400 IU of vitamin-D3, or placebo), reanalyzing results from women concurrently randomized to estrogen interventions and placebo. Results indicate that concurrent estrogen therapy was a strong effect modifier of calcium and vitamin-D supplementation on colorectal cancer risk. While calcium plus vitamin-D supplementation among women concurrently assigned to estrogen therapies suggested increased risk (Hazard Ratio = 1.50, 95% CI: 0.96–2.33), among women concurrently assigned to placebos arms of the estrogen trials, calcium plus vitamin-D indicated suggestive benefits (HR = 0.71, 95% CI: 0.46–1.09) (p-for-estrogen-interaction = 0.018). Consistent interaction was also found by reported estrogen use (p interaction = 0.037). Results indicate contrasting effects of calcium and vitamin-D by concurrent estrogen therapy on colorectal cancer risk. Although further clinical and mechanistic studies are warranted, the potential clinical implications of the apparent interaction of estrogen therapy with calcium and vitamin-D supplementation should be recognized. Important biological mechanisms related to the key membrane receptor megalin and estrogen-dependent protein calbindin are discussed. © 2007 Wiley-Liss, Inc.

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