Calcium supplementation reduces sporadic colorectal adenoma recurrence, and higher serum vitamin D levels are associated with reduced risk for colorectal cancer, the second leading cause of cancer deaths in the US. Despite strong biological plausibility and supportive observational data, the independent and, especially, synergistic anti-neoplastic effects of calcium and vitamin D in humans are not clear. Proposed mechanisms have included protection of the colonic epithelium against bile acids, direct effects on the cell cycle, and modulation of growth factor signaling, inflammation, and immune function. Based on basic science and limited human evidence, we hypothesize that calcium and vitamin D supplementation decrease blood levels of biomarkers of inflammation and colonic permeability in humans. We will investigate this in an adjunct study to an ongoing multi-center, randomized, double-blind, placebo-controlled, 2 x 2 factorial chemoprevention clinical trial (n = 2,259) of supplemental calcium (1,200 mg elemental calcium daily as calcium carbonate) and vitamin D3 (1,000 IU daily), alone and in combination vs. placebo over 3 - 5 years (the 'parent study'). A sub-set of participants (n = 460) with end-of-treatment biopsies of normal-appearing rectal mucosa taken at 3- or 5-year follow-up colonoscopies is selected for this adjunct study.
The aims of the proposed study are to 1) test the separate and joint effects of calcium and vitamin D supplementation on a custom panel of biomarkers of inflammation/immunomodulation (GM-CSF, IFN?, TNF?, IL-6, IL-1?, IL-4, IL-8, IL-10, IL-12p40, and IL-17) representing different classes of inflammatory responses in patients with previous sporadic colorectal adenomas (n = 460);2) obtain preliminary data on the effects of supplementation with calcium and vitamin D alone or in combination on biomarkers of colonic permeability (specific IgG and IgA to lipopolysaccharide [LPS] and flagellin) (n = 120);and 3) obtain preliminary data on whether changes in the biomarker levels are associated with decreased sporadic colorectal adenoma recurrence. The proposed scope of work is limited to laboratory and statistical analyses using biological samples and questionnaire data from the 'parent study'. This adjunct study offers a unique, cost-effective opportunity in a large, ongoing trial in humans to 1) confirm anti-inflammatory effects of calcium and vitamin D in humans;2) explore a novel hypothesis that calcium and vitamin D beneficially modulate colonic permeability;3) elucidate the combined effects of calcium and vitamin D on biomarkers of inflammation;and 4) as a secondary objective, obtain preliminary data on whether modulation of these biomarkers predicts preventing sporadic colorectal adenoma recurrence. Elucidation of vitamin D and calcium anti-inflammatory effects is of great importance, not only to colorectal cancer chemoprevention, but also to the prevention of other inflammation-mediated chronic diseases.
We will test in humans at increased risk for colorectal cancer whether calcium and vitamin D can reduce inflammation and increase colorectal barriers against bacteria, and lead to lower risk for colorectal tumors. To do this we will use blood samples and data from a large clinical trial of supplemental vitamin D and calcium in persons who have had pre-cancerous colon polyps. If our ideas are correct, it would be like proving that blood cholesterol and pressure can be treated with simple dietary changes and lead to preventing heart disease.