Keum N, Aune D, Greenwood DC, Ju W, Giovannucci EL. - 45355 N - Int J Cancer 2014 ; in press.
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 300mg/day increase was associated with an approximately 8% reduced risk of CRC (summary RR=0.92, 95% CI=0.89-0.95, I2 =47%, 15 studies with 12,305 cases, intake=250-1900 mg/day, follow-up=3.3-16 years). While the risk decreased less steeply in higher range of total calcium intake (Pnon -linearity =0.04), the degree of curvature was mild and statistical significance of non-linearity was sensitive to one study. For supplementary calcium, each 300mg/day increase was associated with an approximately 9% reduced risk of CRC (summary RR=0.91, 95% CI=0.86-0.98, I2 =67%, six studies with 8,839 cases, intake=0-1150 mg/day, follow-up=5-10 years). The test for non-linearity was not statistically significant (Pnon -linearity =0.11). In conclusion, both dietary and supplementary calcium intake may continue to decrease CRC risk beyond 1000mg/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.