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Epidemiology:
doi: 10.1097/EDE.0b013e31824deb09
Letters

Calcium, Magnesium, and Colorectal Cancer

Dai, Qi; Sandler, Robert; Barry, Elizabeth; Summers, Robert; Grau, Maria; Baron, John

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Department of Medicine Vanderbilt Epidemiology Center Vanderbilt-Ingram Cancer Center Vanderbilt School of Medicine Nashville, TN Qi.Dai@vanderbilt.edu (Dai)

Department of Medicine University of North Carolina School of Medicine Chapel Hill, NC (Sandler)

Department of Community and Family Medicine Dartmouth Medical School Hanover, NH (Barry)

Department of Medicine University of Iowa Carver College of Medicine Iowa City, IA (Summers)

Department of Community and Family Medicine Dartmouth Medical School Hanover, NH (Grau)

Department of Medicine University of North Carolina School of Medicine Chapel Hill, NC Departments of Community and Family Medicine and of Medicine Dartmouth Medical School Hanover, NH (Baron)

John Baron and Dartmouth College hold a use patent for the chemopreventive use of calcium supplementation, currently licensed to Pfizer. Proceeds are used to support the research of the Polyp Prevention Study Group.

The Calcium Polyp Prevention Study was supported by grants U01 CA46927 and R01 CA98286 from the National Institutes of Health (to J.A.B.). Calcium and placebo tablets were provided by Lederle (subsequently Wyeth and currently Pfizer), Pearl River, NY. Dr. Dai's effort on the study has been supported by R01 AT004660 from the National Center for Complementary & Alternative Medicine, R01 CA149633 from National Cancer Institute, Department of Health and Human Services and AICR 08A074-REV from the American Institute for Cancer Research. Dr. Baron's effort on this work was supported by RO1 CA098286. The authors reported no other financial interests related to this research.

Supplemental digital content is available through direct URL citations in the HTML and PDF versions of this article (www.epidem.com). This content is not peer-reviewed or copy-edited; it is the sole responsibility of the author.

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To the Editor:

High calcium consumption may confer a reduced risk of colorectal cancer.1,2 Dai and colleagues3 recently reported in a case-control study that intake of calcium may be associated with a decreased risk of colorectal adenoma only when the dietary calcium:magnesium intake ratio is low. This finding provides one possible interpretation for inconsistencies in previous studies of the association of calcium intake with risk of colorectal neoplasia.4

Belonging to the same family in the periodic table, calcium (Ca2+) and magnesium (Mg2+) share the same homeostatic control system and have the potential to antagonize each other physiologically.5 A high calcium intake reduces absorption of both magnesium and calcium,6 whereas moderate magnesium deprivation results in negative magnesium balance but increased calcium retention.7 Because of the potential competition between magnesium and calcium, we hypothesized that the dietary calcium:magnesium ratio may modify the effects of calcium supplementation on colorectal carcinogenesis.

We sought to test this hypothesis using data from a randomized clinical trial of calcium supplementation (1200 mg/day), to prevent adenoma recurrence for a 4-year period. The outcome measure in this analysis was the recurrence of adenomas during the prespecified main risk period (ie, after a year-1 colonoscopy up to and including a year-4 examination).2 A validated semi-quantitative food frequency questionnaire (FFQ) was given at study entry to assess the usual diet.

Consistent with our hypothesis,3 we found suggestions that the baseline dietary calcium:magnesium intake ratio modified the effect of calcium treatment on adenoma recurrence. Among subjects with the intake ratio above the median, calcium supplementation had no effect on the risk of one or more recurrent adenomas (relative risk [RR] = 0.98 [95% confidence interval (CI) = 0.75–1.28]) (Table). In contrast, among those with the baseline ratio less than or equal to the median, calcium treatment was associated with reduced risk (RR = 0.68 [95% CI = 0.52–0.90]; test for interaction, P = 0.075).

Table. Effect of Cal...
Table. Effect of Cal...
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The effect of calcium treatment did not differ by magnesium intake at baseline (test for interactions, P = 0.68). Previously, the study had shown that the effects of calcium supplementation on adenoma recurrence did not differ by baseline dietary intakes of calcium. We found no material change after adjustment for baseline dietary calcium intake. Thus, the suggestion of effect modification by the calcium:magnesium ratio cannot be attributed solely to the baseline dietary intake of either calcium or magnesium. Point estimates suggest that calcium reduces the risk of advanced adenoma regardless of the calcium:magnesium intake ratio level, a null finding that could be due to lack of statistical power. The effect of calcium on the risk of hyperplastic polyps did not differ by baseline calcium:magnesium intake ratio, but a protective effect of calcium on hyperplastic polyps was observed when baseline magnesium intake was below the median (test for interaction, P = 0.05) (eTable1, http://links.lww.com/EDE/A577).

Although not entirely consistent, prospective studies conducted in Western societies have suggested that high intake of magnesium was associated with a reduced risk of colorectal cancer.8 Also, in a previous case-control study,3 polyp-free controls consumed substantially higher levels of magnesium than patients diagnosed with an initial colorectal adenoma. There are several possible reasons for the null magnesium finding in this study. It is possible that the association between magnesium intake and adenoma recurrence differs from that of an initial adenoma diagnosis. Also, baseline adenomas in participants with high dietary magnesium at entry may have occurred despite that intake, and so might develop adenoma recurrence along pathways unaffected by magnesium at that level. Future studies are needed to investigate the possibility that magnesium treatment among those with a high calcium:magnesium ratio at baseline could reduce the calcium:magnesium ratio and, in turn, reduce colorectal cancer risk.

Qi Dai

Department of Medicine

Vanderbilt Epidemiology Center

Vanderbilt-Ingram Cancer Center

Vanderbilt School of Medicine

Nashville, TN

Qi.Dai@vanderbilt.edu

Robert Sandler

Department of Medicine

University of North Carolina School of

Medicine

Chapel Hill, NC

Elizabeth Barry

Department of Community and Family

Medicine

Dartmouth Medical School

Hanover, NH

Robert Summers

Department of Medicine

University of Iowa Carver College of

Medicine

Iowa City, IA

Maria Grau

Department of Community and Family

Medicine

Dartmouth Medical School

Hanover, NH

John Baron

Department of Medicine

University of North Carolina School of

Medicine

Chapel Hill, NC

Departments of Community and Family

Medicine and of Medicine

Dartmouth Medical School

Hanover, NH

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REFERENCES

1. Cho E, Smith-Warner SA, Spiegelman D, et al.. Dairy foods, calcium, and colorectal cancer: a pooled analysis of 10 cohort studies. J Natl Cancer Inst. 2004;96: 1015–1022.

2. Baron JA, Beach M, Mandel JS, et al.. Calcium supplements for the prevention of colorectal adenomas. Calcium Polyp Prevention Study Group. N Engl J Med. 1999;340: 101–107.

3. Dai Q, Shrubsole MJ, Ness RM, et al.. The relation of magnesium and calcium intakes and a genetic polymorphism in the magnesium transporter to colorectal neoplasia risk. Am J Clin Nutr. 2007;86: 743–751.

4. Wactawski-Wende J, Kotchen JM, Anderson GL, et al.. Calcium plus vitamin D supplementation and the risk of colorectal cancer. N Engl J Med. 2006;354: 684–696.

5. Iseri LT, French JH. Magnesium: nature's physiologic calcium blocker. Am Heart J.1984; 108: 188–193.

6. Norman DA, Fordtran JS, Brinkley LJ, et al.. Jejunal and ileal adaptation to alterations in dietary calcium: changes in calcium and magnesium absorption and pathogenetic role of parathyroid hormone and 1,25-dihydroxyvitamin D. J Clin Invest. 1981;67: 1599–1603.

7. Nielsen FH, Milne DB, Gallagher S, Johnson L, Hoverson B. Moderate magnesium deprivation results in calcium retention and altered potassium and phosphorus excretion by postmenopausal women. Magnes Res. 2007;20: 19–31.

8. Larsson SC, Bergkvist L, Wolk A. Magnesium intake in relation to risk of colorectal cancer in women. JAMA.2005; 293: 86–89.

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ACKNOWLEDGMENTS

We are indebted to the study subjects and their physicians for their cooperation and enthusiasm, to the study coordinators at the clinical sites, and to the many investigators who supported the research.

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© 2012 Lippincott Williams & Wilkins, Inc.

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