title: A randomized clinical trial of the effects of supplemental calcium and vitamin D3 on markers of their metabolism in normal mucosa of colorectal adenoma patients.
abstract: In cancer cell lines and rodent models, calcium and vitamin D favorably modulate cell proliferation, differentiation, and apoptosis in colonic epithelia. These effects may be modulated by local expression of the calcium receptor (CaR), the vitamin D receptor (VDR), and the P450 cytochromes, CYP27B1 and CYP24A1; however, they have yet to be investigated in humans. To address this gap, we conducted a randomized, double-blinded, placebo-controlled 2×2 factorial clinical trial. Patients with at least one pathology-confirmed colorectal adenoma were treated with 2 g/d elemental calcium and/or 800 IU/d vitamin D3 versus placebo over 6 months (n=92; 23 per group). CaR, VDR, CYP27B1, and CYP24A1 expression and distribution in biopsies of normal appearing rectal mucosa were detected by standardized, automated immunohistochemistry and quantified by image analysis. In the calcium-supplemented group, CaR expression increased 27% (P=0.03) and CYP24A1 expression decreased 21% (P=0.79). In the vitamin D3-supplemented group, CaR expression increased 39% (P=0.01) and CYP27B1 expression increased 159% (P=0.06). In patients supplemented with both calcium and vitamin D3, VDR expression increased 19% (P=0.13) and CaR expression increased 24% (P=0.05). These results provide mechanistic support for further investigation of calcium and vitamin D3 as chemopreventive agents against colorectal neoplasms, and CaR, VDR, CYP27B1, and CYP24A1 as modifiable, preneoplastic risk biomarkers for colorectal neoplasms.
authors.affiliation: Nutrition and Health Sciences Program, Graduate Division of Biological and Biomedical Sciences, Winship Cancer Institute, Emory University, Department of Epidemiology, Rollins School of Public Health, Atlanta, Georgia 30322, USA.
authors.forename: Thomas U
authors.initials: TU
authors.lastname: Ahearn
authors.forename: Marjorie L
authors.initials: ML
authors.lastname: McCullough
authors.forename: W Dana
authors.initials: WD
authors.lastname: Flanders
authors.forename: Qi
authors.initials: Q
authors.lastname: Long
authors.forename: Eduard
authors.initials: E
authors.lastname: Sidelnikov
authors.forename: Veronika
authors.initials: V
authors.lastname: Fedirko
authors.forename: Carrie R
authors.initials: CR
authors.lastname: Daniel
authors.forename: Robin E
authors.initials: RE
authors.lastname: Rutherford
authors.forename: Aasma
authors.initials: A
authors.lastname: Shaukat
authors.forename: Roberd M
authors.initials: RM
authors.lastname: Bostick
mesh_terms: D015090:25-Hydroxyvitamin D3 1-alpha-Hydroxylase / Q000096:biosynthesis; D000236:Adenoma / Q000097:blood / Q000188:drug therapy* / Q000378:metabolism; D014408:Biomarkers, Tumor / Q000378:metabolism*; D002118:Calcium / Q000008:administration & dosage* / Q000378:metabolism; D002762:Cholecalciferol / Q000008:administration & dosage*; D015179:Colorectal Neoplasms / Q000097:blood / Q000188:drug therapy / Q000378:metabolism / Q000517:prevention & control*; D004311:Double-Blind Method; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D007413:Intestinal Mucosa / Q000187:drug effects / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D010865:Pilot Projects; D011230:Precancerous Conditions / Q000097:blood / Q000188:drug therapy / Q000378:metabolism; D018167:Receptors, Calcitriol / Q000096:biosynthesis; D044169:Receptors, Calcium-Sensing / Q000096:biosynthesis; D013250:Steroid Hydroxylases / Q000096:biosynthesis; D014807:Vitamin D / Q000031:analogs & derivatives / Q000097:blood; D065668:Vitamin D3 24-Hydroxylase
chemical_list: D014408:Biomarkers, Tumor; D018167:Receptors, Calcitriol; D044169:Receptors, Calcium-Sensing; D014807:Vitamin D; D002762:Cholecalciferol; C097949:1,25-dihydroxyvitamin D; C104450:25-hydroxyvitamin D; D013250:Steroid Hydroxylases; C585549:CYP24A1 protein, human; D065668:Vitamin D3 24-Hydroxylase; D015090:25-Hydroxyvitamin D3 1-alpha-Hydroxylase; D002118:Calcium