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Effects of Vitamin D and Calcium Supplementation on Markers of Apoptosis in Normal Colon Mucosa: A Randomized, Double-Blind, Placebo-Controlled Clinical Trial

Authors' Affiliations: Departments of ¹ Epidemiology and ² Biostatistics and Bioinformatics, Rollins School of Public Health, ³ Winship Cancer Institute, and ⁴ Nutrition and Health Sciences Program, Graduate Division of Biological and Biomedical Sciences, Emory University; ⁵ Division of Digestive Diseases, Emory University School of Medicine, Atlanta, Georgia and ⁶ Department of Medicine, GI Division University of Minnesota, Minneapolis, Minnesota

Requests for reprints: Roberd M. Bostick, Department of Epidemiology, Rollins School of Public Health, Emory University, 1518 Clifton Road Northeast, Atlanta, GA 30322. Phone: 404-727-2671; Fax: 404-727-8737; E-mail: rmbosti{at}sph.emory.edu.

To further clarify and/or develop calcium and vitamin D as chemopreventive agents against colorectal cancer in humans, understand the mechanisms by which these agents reduce risk for the disease, and develop "treatable" biomarkers of risk for colorectal cancer, we conducted a pilot, randomized, double-blind, placebo-controlled, 2 x 2 factorial clinical trial to test the effects of calcium and vitamin D₃, alone and in combination on markers of apoptosis, in the normal colorectal mucosa. Ninety-two men and women with at least one pathology-confirmed colorectal adenoma were treated with 2.0 g/d calcium or 800 IU/d vitamin D₃, alone or in combination, versus placebo over 6 months. Overall expression and colorectal crypt distributions of Bcl-2 (an apoptosis inhibitor) and Bax (an apoptosis promoter) in biopsies of normal-appearing rectal mucosa were detected by automated immunohistochemistry and quantified by image analysis. After 6 months of treatment, Bax expression along the full lengths of crypts increased 56% (P = 0.02) in the vitamin D group and 33% in both the calcium (P = 0.31) and calcium plus vitamin D (P = 0.36) groups relative to the placebo group. The vitamin D treatment effect was more pronounced in the upper 40%, or differentiation zone, of crypts (80%; P = 0.01). There were no statistically significant treatment effects on Bcl-2 expression. Overall, these preliminary results suggest that calcium and vitamin D, individually or together, may enhance apoptosis in the normal human colorectal epithelium, and the strongest treatment effects may be vitamin D related and in the upper sections of the colorectal crypts.

Key Words: vitamin D • calcium • apoptosis • randomized controlled trial • normal colorectal mucosa

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