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

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 5 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 5 0.71, 95% CI: 0.46-1.09) (p-for-estrogen-interaction 5 0.018). Consistent interaction was also found by reported estrogen use (p interaction 5 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.Key words: vitamin D; calcium; estrogen; colorectal cancer; randomized trial; epidemiology; women; calcitriol; cholecalciferol; megalin In 1980, vitamin D was first proposed to have benefit against colorectal cancer based on ecological studies of colorectal cancer incidence and low sunlight exposure. 1 Vitamin D has been documented to possess a variety of anti-cancer properties, 2 including inhibit growth and induce differentiation and apoptosis of colon tumor cells, 3 as well as shown to be associated with lower risk of colorectal cancer and adenoma in prospective studies. [4][5][6][7] In addition to a meta-analysis of observational studies supporting the relation of vitamin D and lower colorectal cancer risk, 8 a recent meta-analysis of randomized trials indicates vitamin D supplementation likely decreases risk of all-cause mortality, with benefits for cancer thought to be a major explanatory factor. 9 Consistent with a 5 year vitamin D trial that suggested benefits against colorectal cancer mortality, 10 a large randomized trial indeed demonstrated that moderate dose 1,000 IU vitamin D and calcium supplementation substan...

Reply to Comment on: Interaction of hormone replacement therapy with calcium and Vitamin D supplementation on colorectal cancer risk

“…Notably, the P for effect modification by estrogen remained significant -with the reanalysis still consistently indicating an interaction where concurrent estrogen use attenuated the benefits of vitamin D and calcium supplementation on colorectal cancer risk. It is worthy of note that a consistent estrogen interaction was also found by participantreported estrogen use (p interaction 5 0.04), 3 further corroborating the findings by WHI randomized estrogen treatment assignments.…”

How strong is the evidence that solar ultraviolet B and vitamin D reduce the risk of cancer? An examination using Hill’s criteria for causality

“…21 However, there was a positive finding for colorectal cancer when estrogen therapy was also considered. 105 Some evidence now exists that the vitamin D dose-cancer response relation for breast cancer is nonlinear, with a threshold effect at about 20 ng/mL. 57 This finding may help explain why 400 IU/ day seemingly has no effect on cancer rates.…”

“…105 Another line of experimental verification is to study the role of vitamin D on cancer by using animal models. [114][115][116] For example, in a colon cancer xenograft experiment, vitamin D metabolites slowed tumor growth.…”

Vitamin D and Colorectal Cancer Prevention: A Review of Epidemiologic Studies

“…Low benefit of vitamin D among those who used estrogen therapy also has been suggested [52]. A reanalysis of the Women's Health Initiative trial of vitamin D and calcium supplementation showed a nonsignificant higher risk of colorectal cancer among those who received vitamin D and calcium supplementation and were concurrently assigned to estrogen therapy, but a nonsignificant lower risk of colorectal cancer among those who received vitamin D and calcium supplementation and were concurrently assigned to the placebo group of the estrogen trial [52]. This apparent interaction of estrogen therapy with calcium and vitamin D supplementation warrants further investigation.…”