Effects of vitamin d and calcium on proliferation and differentiation in normal colon mucosa: a randomized clinical trial

Cancer Epidemiol Biomarkers Prev. 2009 Nov;18(11):2933-41. doi: 10.1158/1055-9965.EPI-09-0239. Epub 2009 Oct 27.


To investigate the potential efficacy of calcium and vitamin D in reducing risk for colorectal neoplasms and to develop "treatable" phenotypic biomarkers of risk for colorectal neoplasms, we conducted a pilot, randomized, double-blind, placebo-controlled, 2 x 2 factorial clinical trial to test the effects of these agents on cell cycle markers in the normal colorectal mucosa. Ninety-two men and women with at least one pathology-confirmed colorectal adenoma were treated with 2 g/day calcium and/or 800 IU/day vitamin D(3) versus placebo over 6 months. Overall expression and distributions of p21(waf1/cip1) (marker of differentiation), MIB-1 (marker of short-term proliferation), and hTERT (marker of long-term proliferation) in colorectal crypts in the normal-appearing rectal mucosa were detected by automated immunohistochemistry and quantified by image analysis. In the calcium, vitamin D, and calcium plus vitamin D groups relative to the placebo, p21 expression increased by 201% (P = 0.03), 242% (P = 0.005), and 25% (P = 0.47), respectively, along the full lengths of colorectal crypts after 6 months of treatment. There were no statistically significant changes in the expression of either MIB-1 or hTERT in the crypts overall; however, the proportion of hTERT, but not MIB-1, expression that extended into the upper 40% of the crypts was reduced by 15% (P = 0.02) in the vitamin D plus calcium group relative to the placebo. These results indicate that calcium and vitamin D promote colorectal epithelial cell differentiation and may "normalize" the colorectal crypt proliferative zone in sporadic adenoma patients, and support further investigation of calcium and vitamin D as chemopreventive agents against colorectal neoplasms.

Publication types

  • Randomized Controlled Trial
  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Aged
  • Calcium / pharmacology*
  • Cell Differentiation / drug effects*
  • Cell Proliferation / drug effects*
  • Cholecalciferol / pharmacology*
  • Colon / cytology*
  • Colon / metabolism
  • Colorectal Neoplasms / prevention & control
  • Cyclin-Dependent Kinase Inhibitor p21 / metabolism
  • Double-Blind Method
  • Drug Combinations
  • Female
  • Humans
  • Intestinal Mucosa / cytology*
  • Intestinal Mucosa / metabolism
  • Male
  • Middle Aged
  • Pilot Projects
  • Placebos
  • Prognosis
  • Telomerase / metabolism
  • Ubiquitin-Protein Ligases / metabolism


  • CDKN1A protein, human
  • Cyclin-Dependent Kinase Inhibitor p21
  • Drug Combinations
  • Placebos
  • Cholecalciferol
  • MIB1 ligase, human
  • Ubiquitin-Protein Ligases
  • TERT protein, human
  • Telomerase
  • Calcium