Dairy Foods, Calcium, and Colorectal Cancer: A Pooled Analysis of 10 Cohort Studies

Cho, Eunyoung; Smith‐Warner, Stephanie A.; Spiegelman, Donna; Beeson, W. Lawrence; Brandt, Piet A. van den; Colditz, Graham A.; Folsom, Aaron R.; Fraser, Gary E.; Freudenheim, Jo L.; Giovannucci, Edward; Goldbohm, R. Alexandra; Graham, Saxon; Miller, Anthony B.; Pietinen, Pirjo; Potter, John D.; Rohan, Thomas E.; Terry, Paul; Toniolo, Paolo; Virtanen, Mikko; Willett, Walter C.; Wolk, Alicja; Wu, Kana; Yaun, Shiaw-Shyuan; Zeleniuch‐Jacquotte, Anne; Hunter, David J.

doi:10.1093/jnci/djh185

Cited by 473 publications

(362 citation statements)

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“…22,54 Data from both a pooled analysis of CRC cohort studies and a randomized trial of calcium supplementation for CRA recurrence prevention indicate that the protective effects of high calcium intake are seen only in individuals who also have a high intake or high circulating levels of vitamin D. 22,53 Conversely, the benefits of high vitamin D levels are restricted to individuals with high calcium intake. In the United States, dairy products are an important source of both calcium and vitamin D, and may therefore exert a greater influence than micronutrient considered in isolation.…”

Section: Discussionmentioning

confidence: 99%

“…Calcium in milk is highly bioavailable, which may make milk appear to be associated with CRC risk independent of total calcium intake. 53 Alternatively, the protective effects of dairy products may be due to other components, such as conjugated linoleic acid and lactoferrin, which inhibit colonic carcinogenesis in animal models, 55,56 or the milk protein casein, which has been reported to have antimutagenic activity on the digestive tract. 57 Randomized trials of calcium supplementation indicate a modest but significant protective effect against CRA recurrence (pooled RR from 3 trials combined 0.80, 95%CI: 0.68-0.93).…”

Section: Discussionmentioning

confidence: 99%

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Dairy products, polymorphisms in the vitamin D receptor gene and colorectal adenoma recurrence

Muir

Liu

Logan

et al. 2008

Intl Journal of Cancer

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Vitamin D receptor (VDR) activation inhibits proliferation and angiogenesis in the colorectal epithelium, and inhibits metastasis of colorectal tumors. Polymorphisms in the VDR gene alter receptor cellular levels and functioning, and may confer altered susceptibility to colorectal neoplasia. We aimed to investigate the influence of VDR polymorphisms and dietary factors impacting on vitamin D metabolism on colorectal adenoma (CRA) recurrence. Data on dietary intakes of calcium, vitamin D and dairy products were collected from 853 participants in the United Kingdom Colorectal Adenoma Prevention trial, a randomized trial of aspirin and folate for CRA recurrence prevention. The VDR Cdx2, FokI, BsmI, ApaI and TaqI polymorphisms were genotyped in 546 participants with available DNA, and gene-diet interaction analyses performed in 480. Dairy product intake was inversely related to CRA recurrence risk independent of calcium and vitamin D [relative risk (RR) 5 0.64; 95% confidence intervals (CIs): 0.47-0.88, for subjects in the highest compared to lowest intake tertile, p trend 5 0.005]. Milk accounted for 60% of dairy product intake, and on analysis of milk and nonmilk dairy products separately recurrence risk in individuals in the highest tertile of milk intake was half that of lowest tertile individuals (RR 5 0.52; 95% CI: 0.38-0.72, p trend 5 3.2 3 10 25 ), whereas nonmilk dairy products did not influence recurrence. VDR polymorphism genotypes and haplotypes did not directly alter recurrence risk, but the reduction in risk associated with high dairy product intake was confined to individuals with ApaI aA/AA genotype (p interaction 5 0.02). These findings indicate dairy products, and in particular milk, have chemopreventive activity against CRA recurrence. ' 2008 Wiley-Liss, Inc.Key words: colorectal adenoma recurrence; dairy products; VDR; polymorphism Colorectal cancer (CRC) is the third commonest cancer worldwide after lung and breast cancer, and two-thirds of CRC occurs in developed countries. 1 Up to 90% of CRCs develop from colorectal adenomas (CRAs) and colonoscopic removal of CRA reduces the incidence of CRC. 2,3 In some individuals, the recurrence rate for CRA is as high as 40-50% after 3 years, 4 CRA recurrence is a surrogate marker for CRC risk and prevention of CRA recurrence is a useful endpoint for evaluating chemopreventive agents. 5 Activation of vitamin D receptors (VDRs) present in many cell types, including colorectal epithelial cells, can inhibit proliferation, angiogenesis and invasiveness, and studies in animal models indicate that vitamin D supplementation can lower the incidence and metastatic potential of intestinal tumors. 6-9 Ecological studies correlating sunlight exposure with cancer incidence provided the first evidence that vitamin D levels are inversely related to CRC development in humans. 10 Subsequent epidemiological studies have reported lower risks of CRA and CRC in individuals with high intakes and circulating levels of vitamin D. 11-14 Vitamin D plays a crucial role in calcium me...

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Dairy products, polymorphisms in the vitamin D receptor gene and colorectal adenoma recurrence

Muir

Liu

Logan

et al. 2008

Intl Journal of Cancer

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“…[4][5][6][7] In addition to a meta-analysis of observational studies supporting the relation of vitamin D and lower colorectal cancer risk, 8 a recent meta-analysis of randomized trials indicates vitamin D supplementation likely decreases risk of all-cause mortality, with benefits for cancer thought to be a major explanatory factor. 9 Consistent with a 5 year vitamin D trial that suggested benefits against colorectal cancer mortality, 10 a large randomized trial indeed demonstrated that moderate dose 1,000 IU vitamin D and calcium supplementation substantially reduces all-cancer risk after 1-4 years follow-up RR 5 0.23 (95% CI: 0.09-0.60), 11 where vitamin D significantly contributed benefit beyond calcium supplementation alone.Similarly, however, calcium may also impede colonic carcinogenesis via a variety of mechanisms, 3 as calcium has been inversely associated with colorectal cancer risk in prospective studies, 12,13 and also been demonstrated to be protective against colorectal carcinogenesis and adenomas in multiple randomized trials. [14][15][16][17] Furthermore, a large pooled analysis of 10 international prospective cohorts found that milk and calcium intakes were both associated with significantly lower risk of colorectal cancer, with the relative risks, comparing highest vs. lowest categories of intake, of 0.85 (95% CI: 0.78, 0.94) for milk and 0.78 (95% CI: 0.69, 0.88) for calcium.…”

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confidence: 99%

Interaction of estrogen therapy with calcium and vitamin D supplementation on colorectal cancer risk: Reanalysis of Women's Health Initiative randomized trial

Ding

Mehta

Fawzi

et al. 2007

Intl Journal of Cancer

103

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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 5 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 5 0.71, 95% CI: 0.46-1.09) (p-for-estrogen-interaction 5 0.018). Consistent interaction was also found by reported estrogen use (p interaction 5 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. ' 2007 Wiley-Liss, Inc.Key words: vitamin D; calcium; estrogen; colorectal cancer; randomized trial; epidemiology; women; calcitriol; cholecalciferol; megalin In 1980, vitamin D was first proposed to have benefit against colorectal cancer based on ecological studies of colorectal cancer incidence and low sunlight exposure. 1 Vitamin D has been documented to possess a variety of anti-cancer properties, 2 including inhibit growth and induce differentiation and apoptosis of colon tumor cells, 3 as well as shown to be associated with lower risk of colorectal cancer and adenoma in prospective studies. [4][5][6][7] In addition to a meta-analysis of observational studies supporting the relation of vitamin D and lower colorectal cancer risk, 8 a recent meta-analysis of randomized trials indicates vitamin D supplementation likely decreases risk of all-cause mortality, with benefits for cancer thought to be a major explanatory factor. 9 Consistent with a 5 year vitamin D trial that suggested benefits against colorectal cancer mortality, 10 a large randomized trial indeed demonstrated that moderate dose 1,000 IU vitamin D and calcium supplementation substan...

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“…6 Although a meta-analysis 8 concluded that calcium had no protective effect on colorectal tumours, prospective studies and large case-control studies subsequently found a modestly beneficial effect. [9][10][11] Recently the Pooling Project, a pooled analysis of 10 prospective studies, 12 showed a significant protective effect of calcium and milk on colorectal cancer risk.…”

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confidence: 99%

Dietary calcium, phosphorus, vitamin D, dairy products and the risk of colorectal adenoma and cancer among French women of the E3N-EPIC prospective study

et al. 2005

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A protective effect of calcium and/or dairy products on colorectal cancer has been reported in epidemiological studies but the findings are considered inconsistent. In particular, it is unclear whether they act at a particular step of the adenoma-carcinoma sequence. To investigate the effect of dairy product consumption and dietary calcium, vitamin D and phosphorus intake on the adenoma-carcinoma sequence in the French E3N-EPIC prospective study. The population for the study of risk factors for adenomas was composed of 516 adenoma cases, including 175 high-risk adenomas, and of 4,804 polyp-free subjects confirmed by colonoscopy. The population for the colorectal cancer study was composed of 172 cases and 67,312 cancer-free subjects. Diet was assessed using a self-administered questionnaire completed at baseline. There was a trend of decreasing risk of both adenoma (p trend 5 0.04) and cancer (p trend 50.08) with increasing calcium intake, with RRs for adenoma and cancer of 0.80 (IC 95%50.62-1.03) and 0.72 (95% CI50.47-1.10), respectively, in the fourth quartile compared to the first. A protective effect of dairy products on adenoma (RR Q4 vs. Q1 5 0.80, 95% CI50.62-1.05, p trend 5 0.04) was observed and of milk consumption on colorectal cancer (RR Q4vs. Q1 5 0.54, 95% CI50.33-0.89, p trend 5 0.09), although the latter did not reach significance. Phosphorus intake also decreased the risk of adenoma (RR Q4 vs. Q1 50.70, 95% CI50.54-0.90, p trend 5 0.005). No vitamin D effect was identified. Our data support the hypothesis that calcium, dairy products and phosphorus exert a protective effect at certain steps of the adenoma-carcinoma sequence. ' 2005 Wiley-Liss, Inc.Key words: colorectal cancer; colorectal adenoma; calcium; vitamin D; phosphorus; dairy productThe idea that an intake of calcium and vitamin D might protect against colorectal cancer was first suggested by Newmark et al. 1 In experimental studies, low calcium diets have consistently been associated with increased cell proliferation and low cell differentiation. 2 It has therefore been suggested that calcium acts directly on epithelial cell proliferation and differentiation, as well as indirectly by forming insoluble soaps with secondary bile acids, although this point has never been formally demonstrated. 2,3 Vitamin D plays a major role in the homeostasis of calcium and 2 studies have also suggested that it reduces epithelial cell proliferation and promotes differentiation. 2,4 It has been further suggested that polymorphisms of the vitamin D receptor (VDR) might modulate this effect. 5 However, findings from epidemiological studies on the relationship between calcium or dairy product intake and risk of colorectal adenoma or/and of cancer were judged inconsistent in 2 reviews, 6,7 except for a steady protective effect of dairy product reported in cohort studies. 6 Although a meta-analysis 8 concluded that calcium had no protective effect on colorectal tumours, prospective studies and large case-control studies subsequently found a modestly beneficial ...

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Dairy Foods, Calcium, and Colorectal Cancer: A Pooled Analysis of 10 Cohort Studies

Abstract: Higher consumption of milk and calcium is associated with a lower risk of colorectal cancer.

Cited by 473 publications

References 54 publications

Dairy products, polymorphisms in the vitamin D receptor gene and colorectal adenoma recurrence

Dairy products, polymorphisms in the vitamin D receptor gene and colorectal adenoma recurrence

Interaction of estrogen therapy with calcium and vitamin D supplementation on colorectal cancer risk: Reanalysis of Women's Health Initiative randomized trial

Dietary calcium, phosphorus, vitamin D, dairy products and the risk of colorectal adenoma and cancer among French women of the E3N-EPIC prospective study

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