1.
Calcium intake and colorectal adenoma risk: dose-response meta-analysis of prospective observational studies.
Keum, N, Lee, DH, Greenwood, DC, Zhang, X, Giovannucci, EL
International journal of cancer. 2015;(7):1680-7
-
-
Free full text
-
Abstract
Evidence from randomized controlled trials suggests that calcium may protect against recurrence of colorectal adenomas, which could lead to the subsequent prevention of cancer. Yet the trials used only a large single dose and were of small sizes, and thus, knowledge of the dose-response relationship and influence on high-risk adenomas is limited. To address these issues, we conducted linear and nonlinear dose-response meta-analyses primarily based on prospective observational studies published up to July 2014 identified from PubMed and Embase. Summary relative risks (RRs) and 95% confidence intervals (CIs) were calculated for total and supplemental calcium intake, respectively, using a random-effects model. For total calcium intake, summary RR for each 300 mg/day increase was 0.95 (95% CI = 0.92-0.98; I(2) = 45%; eight studies with 11,005 cases; range of intake = 333-2,229 mg/day). Evidence of nonlinearity was indicated: approximately, compared to 550 mg/day of total calcium intake, the summary RR was 0.92 (95% CI = 0.89-0.94) at 1,000 mg/day and 0.87 (95% CI = 0.84-0.90) at 1,450 mg/day (pnonlinearity < 0.01). Associations were stronger for high-risk adenomas (≥1 cm in diameter, (tubulo)villous histology, dysplasia, or multiplicity): approximately, compared to 550 mg/day of total calcium intake, the summary RR was 0.77 (95% CI = 0.74-0.81) at 1,000 mg/day and reduced to 0.69 (95% CI = 0.66-0.73) at 1,450 mg/da (pnonlinearity < 0.01). For supplemental calcium intake, summary RR of total adenoma risk for each 300 mg/day increase was 0.96 (95% CI = 0.93-0.99; I(2) = 0%; three studies with 4,548 cases; range of supplementation = 0-1,366 mg/day). In conclusion, calcium intake may continue to decrease the risk of adenomas, particularly high-risk adenomas, over a wide range of calcium intake.
2.
Calcium intake and colorectal cancer risk: dose-response meta-analysis of prospective observational studies.
Keum, N, Aune, D, Greenwood, DC, Ju, W, Giovannucci, EL
International journal of cancer. 2014;(8):1940-8
-
-
Free full text
-
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.
3.
Interaction of estrogen therapy with calcium and vitamin D supplementation on colorectal cancer risk: reanalysis of Women's Health Initiative randomized trial.
Ding, EL, Mehta, S, Fawzi, WW, Giovannucci, EL
International journal of cancer. 2008;(8):1690-4
-
-
Free full text
-
Abstract
Although calcium and vitamin-D intake were consistently shown to be inversely associated with colorectal cancer risk in several large prospective studies and protective against adenoma and cancer in multiple randomized trials, the Women's Health Initiative (WHI) of calcium and low-dose vitamin-D supplementation trial found no overall effects on colorectal cancer. However, the previous report did not recognize an important biologic interaction with estrogen therapy. We investigated the treatment interaction of estrogen with calcium and vitamin-D on risk of colorectal cancer via a reanalysis of primary data results from the WHI calcium and vitamin-D supplementation trial (1,000 mg elemental calcium, 400 IU of vitamin-D3, or placebo), reanalyzing results from women concurrently randomized to estrogen interventions and placebo. Results indicate that concurrent estrogen therapy was a strong effect modifier of calcium and vitamin-D supplementation on colorectal cancer risk. While calcium plus vitamin-D supplementation among women concurrently assigned to estrogen therapies suggested increased risk (Hazard Ratio = 1.50, 95% CI: 0.96-2.33), among women concurrently assigned to placebos arms of the estrogen trials, calcium plus vitamin-D indicated suggestive benefits (HR = 0.71, 95% CI: 0.46-1.09) (p-for-estrogen-interaction = 0.018). Consistent interaction was also found by reported estrogen use (p interaction = 0.037). Results indicate contrasting effects of calcium and vitamin-D by concurrent estrogen therapy on colorectal cancer risk. Although further clinical and mechanistic studies are warranted, the potential clinical implications of the apparent interaction of estrogen therapy with calcium and vitamin-D supplementation should be recognized. Important biological mechanisms related to the key membrane receptor megalin and estrogen-dependent protein calbindin are discussed.