A prospective cohort study observed that higher energy-adjusted folate intake in the form of multivitamins containing folic acid was related to a lower risk for colon cancer (RR = 0.69; 95% CI, 0.52-0.93) for intake of more than 400 �g/day compared with intake of 200 �g/day or less after controlling for age, family history of CRC, ASA use, smoking, body mass, physical activity, and intakes of red meat, alcohol, methionine, and fiber. In a double-blind, placebo-controlled, two-factor, phase III randomized clinical trial (ASA/Folate Polyp Prevention Study) involving 1,021 men and women with a recent history of colorectal adenoma, folic acid (1 mg/day) was associated with higher risks of developing at least one advanced adenoma (11.6% for folic acid [n = 35]); 6.9% for placebo [n = 21]; unadjusted RR = 1.67; 95% CI, 1.00-2.80; P = .05). Folic acid ingestion was associated with higher risks of having three or more adenomas and of non-CRCs. There was no effect modification by sex, age, smoking, alcohol use, BMI, baseline plasma folate, or ASA use. There was no apparent effect on overall adenoma incidence (44.1% for folic acid [n = 221]); 42.4% for placebo [n = 206]; unadjusted use ratio 1.04; 95% CI, 0.9-1.20; P = .58).
It has been hypothesized that orally ingested calcium lowers colon cancer risk by binding bile acids and fatty acids, thereby reducing exposure to toxic intraluminal compounds. Indirect effects on bile acid metabolism and a direct effect on colonic epithelial cells are also possible.
Several [127,128,129,130] but not all [100,131] epidemiologic studies have observed an inverse relationship between calcium intake and cancer risk. Interpretation of these studies can be quite complex. In Utah, an inverse relationship between colon cancer and calcium was observed in a study that compared members of the Church of Jesus Christ of Latter-Day Saints (Mormons) and Seventh Day Adventists with a group from the U.S. population at large. Both study groups have higher calcium intakes, mainly milk and dairy products, than the national average. Unlike the Seventh Day Adventists, however, the Mormon group had a consumption of meats and fat similar to that of the general population.
Experimental studies in rodents  and some but not all human studies [133,134,135,136] have described a decrease in colonic epithelial cell proliferation after the administration of calcium citrate. Human studies using the labeling index are dependent on a complex methodology. A randomized placebo-controlled trial tested the effect of calcium supplementation (3 g calcium carbonate daily [1,200 mg elemental calcium]) on the risk of recurrent adenoma. The primary endpoint was the proportion of patients (72% of whom were male) in whom at least one adenoma was detected following a first and/or second follow-up endoscopy. A modest decrease in risk was found for both developing at least one recurrent adenoma (adjusted risk ratio [ARR] = 0.81; 95% CI, 0.67-0.99) and in the average number of adenomas (ARR = 0.76; 95% CI, 0.60-0.96). The investigators found the effect of calcium was similar across age, sex, and baseline dietary intake categories of calcium, fat, or fiber. The study was limited to individuals with a recent history of colorectal adenomas and could not determine the effect of calcium on risk of the first adenoma, nor was it large enough or of sufficient duration to examine the risk of invasive CRC. After calcium supplementation is stopped, the lower risk may persist up to 5 years. The results of other ongoing adenoma recurrence studies are awaited with interest. It is important to note that the dose of calcium salt administered may be important; the usual daily doses in trials have ranged from 1,250 to 2,000 mg of calcium.