title: Calcium intake and colorectal cancer risk: dose-response meta-analysis of prospective observational studies.
abstract: Mechanistic and epidemiologic studies provide considerable evidence for a protective association between calcium intake and incident colorectal cancer (CRC). While the relationship has not been substantiated by short-duration randomized controlled trials (RCTs) of CRC, trials do show a benefit on adenomas, a precursor to CRC. To address some of this inconsistency, we conducted dose-response meta-analyses by sources of calcium intake, based on prospective observational studies published up to December 2013 identified from PubMed, Embase, and BIOSIS. Summary relative risks (RRs) and 95% confidence intervals (CIs) were calculated using a random-effects model. For total calcium intake, each 300 mg/day increase was associated with an approximately 8% reduced risk of CRC (summary RR = 0.92, 95% CI = 0.89-0.95, I(2)  = 47%, 15 studies with 12,305 cases, intake = 250-1,900 mg/day, follow-up = 3.3-16 years). While the risk decreased less steeply in higher range of total calcium intake (P(non-linearity)  = 0.04), the degree of curvature was mild and statistical significance of non-linearity was sensitive to one study. For supplementary calcium, each 300 mg/day increase was associated with an approximately 9% reduced risk of CRC (summary RR = 0.91, 95% CI = 0.86-0.98, I(2)  = 67%, six studies with 8,839 cases, intake = 0-1,150 mg/day, follow-up = 5-10 years). The test for non-linearity was not statistically significant (P(non-linearity)  = 0.11). In conclusion, both dietary and supplementary calcium intake may continue to decrease CRC risk beyond 1,000 mg/day. Calcium supplements and non-dairy products fortified with calcium may serve as additional targets in the prevention of CRC. RCTs of calcium supplements with at least 10 years of follow-up are warranted to confirm a benefit of calcium supplements on CRC risk.
authors.affiliation: Department of Nutrition, Harvard School of Public Health, Boston, MA; Department of Epidemiology, Harvard School of Public Health, Boston, MA.
authors.forename: NaNa
authors.initials: N
authors.lastname: Keum
authors.forename: Dagfinn
authors.initials: D
authors.lastname: Aune
authors.forename: Darren C
authors.initials: DC
authors.lastname: Greenwood
authors.forename: Woong
authors.initials: W
authors.lastname: Ju
authors.forename: Edward L
authors.initials: EL
authors.lastname: Giovannucci
mesh_terms: D016588:Anticarcinogenic Agents / Q000008:administration & dosage*; D002118:Calcium / Q000008:administration & dosage*; D015179:Colorectal Neoplasms / Q000517:prevention & control*; D019587:Dietary Supplements; D004305:Dose-Response Relationship, Drug; D006801:Humans; D064887:Observational Studies as Topic; D011446:Prospective Studies; D012306:Risk
chemical_list: D016588:Anticarcinogenic Agents; D002118:Calcium
keywords: calcium supplements; colorectal cancer; dietary calcium; dose-response; meta-analysis