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Calcium, vitamin D and colorectal cancer chemoprevention
Best Practice & Research Clinical Gastroenterology 25 (2011) 485–494
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Best Practice & Research Clinical Gastroenterology
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Calcium, vitamin D and colorectal cancer chemoprevention Xuehong Zhang, MD, MSc, ScD, Post-doctoral Research Fellow a,1, Edward Giovannucci, MD, ScD, Professor of Nutrition and Epidemiology a, b, c, * a
Channing Laboratory at Landmark Center (West Wing), Department of Medicine, Brigham and Women’s Hospital and Harvard Medical School, 401 Park Drive, Boston, MA 02115, USA b Department of Nutrition, Harvard School of Public Health, Boston, MA, USA c Department of Epidemiology, Harvard School of Public Health, Boston, MA, USA
Keywords: Calcium vitamin D Milk Dairy products Colorectal cancer Adenomas Chemoprevention Incidence Mortality Survival Case–control study Cohort study Randomized control trial Epidemiology
Identifying modifiable risk factors, particularly dietary factors, which have been hypothesized to play an important role in colorectal carcinogenesis, remains crucial in developing primary prevention strategies. Calcium and vitamin D have been shown consistently in experimental studies to have anti-cancerous properties including but not limited to stimulating differentiation, reducing proliferation, and inducing apoptosis. The majority of epidemiologic studies consistently support an approximately 20–30% reduction in risk of colorectal cancer and adenomas comparing high to low intake categories of both calcium and vitamin D, although independent effects may not be adequately separated. Less consistency exists on the dose– response relation for both nutrients. Intake of calcium of not more than 1000 mg/d and intake of vitamin D of 1000–2000 IU/d, achieving a level of at least 30 ng/mL, appear important for colorectal cancer prevention. More study is warranted to determine the optimal intake levels and duration to reduce the colorectal cancer risk. Ó 2011 Elsevier Ltd. All rights reserved.
Introduction Colorectal cancer is the third most common type of cancer in both men and women worldwide. Higher incidence rates are observed in high-income countries compared to middle- and low-income countries, though incidence rates are increasing rapidly in low to middle-income areas [1]. Around
* Corresponding author. Harvard School of Public Health, 665 Huntington Avenue, Boston, MA 02115, USA. Tel.: þ1 617 432 4648; fax: þ1 617 432 2435. E-mail addresses: [email protected] (X. Zhang), [email protected] (E. Giovannucci). 1 Tel.: þ1 617 519 3550; fax: þ1 617 432 2435. 1521-6918/$ – see front matter Ó 2011 Elsevier Ltd. All rights reserved. doi:10.1016/j.bpg.2011.10.001
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the world, age-adjusted incidence rates range from 30 or more per 100,000 people in North America, parts of Europe, Australia, New Zealand, and Japan to less than 5 per 100,000 in much of Africa and parts of Asia [2]. The substantial difference in incidence rates across geographic regions suggests the importance of environmental influences on colorectal carcinogenesis. Substantial research conducted in past decades has advanced our understanding of colorectal cancer aetiology. As summarized in a 2010 review, [3] some lifestyle, nutritional, and medication factors have been identified to be associated with colorectal cancer risk. With respect to dietary factors however, the effect on colorectal cancer remains largely uncertain [1,4]. Among these factors, calcium and vitamin D appear to show great potential for colorectal cancer prevention. This review aims to provide a brief review of a few human clinical trials and epidemiologic studies on calcium and vitamin D on sporadic colorectal adenoma and cancer risk. Although effects of these nutrients may be mediated by genetic variants of the vitamin D receptor (VDR) and the calcium sensing receptor (CASR), relatively limited data are available to date [5–7] and these data were not reviewed here. Calcium and colorectal cancer Calcium is an essential nutrient and plays an important role in muscular contraction, cellular growth, cell adhesion, and bone formation. The calcium-colorectal cancer hypothesis has evolved over time. In 1980, Garland and Garland proposed that vitamin D was a protective factor for colon cancer based on ecologic data showing variation of colon cancer mortality rates by latitudes [8]. One of the mechanisms to explain this potential effect of vitamin D was through enhanced calcium absorption. They hypothesized that calcium may reduce the inflammatory response of lumen epithelial cells to bacteria flora and other agents [9]. In 1984, Newmark et al [10] further hypothesized that calcium ions neutralize the toxic effects of free ionized fatty acids and bile acids by forming insoluble mineral–fat complexes or soaps in the large bowel. Subsequent experimental studies showed calcium administration reduces the occurrence of chemically induced tumours in animals [11] and the proliferation of colonic epithelial cells in humans [12]. Other data including in vitro studies also suggested that calcium may act directly on colonic epithelial cells by regulating the cell cycle and inducing terminal differentiation [13–17]. Numerous case–control and cohort studies have examined the relation between calcium intake and colorectal cancer risk. Epidemiologic studies conducted through middle 1990s tend to report a modest, non-significant, association. For example, a quantitative review published in 1996 by Bergsma-Kadijk et al [18] summarized twenty-one articles (seven cohort and fourteen case–control studies) published from 1980 to 1994 and the results did not indicate substantial protection by calcium. The summary multivariable relative risks (RR) were 0.90 (95% CI: 0.78–1.05) for cohort studies and 0.88 (95% CI: 0.73– 1.04) for case–control studies. Subsequently, results from the observational studies, as summarized in 2007 and 2011 World Cancer Research Foundation and American Institute for Cancer Research (WCRF/ AICR) reports [1,4], tend to support a fairly consistent stronger inverse association with approximate 20–30% risk reductions for the highest vs. the lowest intake categories. For example, results from the Multiethnic Cohort showed that total calcium intake (from foods and supplements) was inversely associated with colorectal cancer risk in both men (highest vs. lowest quintile, RR ¼ 0.70, 95% CI: 0.52– 0.93) and women (RR ¼ 0.64, 95% CI: 0.50–0.83) [19]. Higher calcium intake (highest quintile vs. lowest) was associated with a lower risk of colorectal cancer in cohorts conducted in France (RR ¼ 0.72, 95% CI: 0.47–1.10) [20] and in China (RR ¼ 0.6, 95% CI: 0.3–1.0) [21]. Similar magnitudes of inverse associations were also observed in the Cohort of Swedish Men (highest vs. lowest quartile, RR ¼ 0.68, 95% CI: 0.51–0.91) [22], in the Japan Public Health Center-based Prospective Study (highest vs. lowest quintile, RR ¼ 0.71, 95% CI: 0.52–0.98; men only) [23], and in the Cancer Prevention Study II Nutrition Cohort [24] of both men and women (highest vs. lowest quintiles, RR ¼ 0.87, 95% CI: 0.67–1.12). In addition to cohort studies, case–control studies [25–29] generally showed inverse associations with calcium intake and colorectal cancer risk. The magnitude of the inverse association was comparable to that observed in cohort studies. For example, a large case–control study of 1993 incident colon cancer cases and 2410 population-based controls conducted in the US showed that dietary calcium was inversely associated with colon cancer risk in men (highest vs. lowest quintile, OR ¼ 0.6, 95% CI: 0.5–0.9) and women (OR ¼ 0.6, 95% CI: 0.4–0.9) [26]. A case–control study of 1,953 colorectal
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cancer cases conducted in Italy also observed inverse association with calcium intake (1495 vs. <1013 mg/d, OR ¼ 0.72, 95% CI: 0.6–0.9) [25]. The potential beneficial effect of calcium on colorectal cancer observed in animal, mechanistic and epidemiologic evidence has also been tested in randomized control trials of adenomas, precursors of colorectal cancer. The randomized trial is considered as ‘gold standard’ in establishing a cause–effect relation, mainly because theoretically known or unknown confounding factors can be balanced between randomized groups. However, selection of the appropriate dose, compliance, unknown lag time between start of the intervention and disease onset pose challenges on the trial and results from trials need to be interpreted with caution. Nonetheless, results from the trials offer complementary data to test the calcium-colorectal cancer hypothesis. At least three trials have been conducted. A first small trial of daily mixture of antioxidative vitamins and calcium showed a significant reduction in adenoma recurrence, but a separate calcium effect could not be disentangled because of the combined intervention [30]. Results from the European Cancer Prevention trial of 2 g elemental calcium daily vs. placebo found a modest non-significant reduction in the risk of adenoma recurrence (RR ¼ 0.66, 95% CI: 0.38–1.17) in this relatively small study [31]. To date, the largest study is the Calcium Polyp Prevention Study, 913 subjects with a recent history of colorectal adenomas were to receive either calcium carbonate (1200 mg of elemental calcium daily) or placebo. A modest yet statistically significant reduction in the risk of recurrent colorectal adenomas was observed in the calcium group (RR ¼ 0.76, 95% CI: 0.60–0.96) [32]. Subsequent analysis of this trial showed a stronger effect of calcium on advanced adenomas (RR ¼ 0.65, 95% CI: 0.46–0.93) [33]. In addition, a prolonged effect of calcium supplementation was observed because participants in the calcium group had a significantly lower risk of any adenoma than those in the placebo group (RR ¼ 0.63, 95% CI: 0.46–0.87) during the first 5 years after randomization ended [34]. A recent meta-analysis of these trials also supported a statistically significant reduction in the RR for adenoma recurrence (RR ¼ 0.80, 95% CI: 0.69–0.94) for those receiving calcium 1200–2000 mg/d [35]. The magnitude of adenoma recurrence reduction in these trials is generally in line with the magnitude of the inverse associations seen in observational epidemiologic studies [9]. The potential beneficial effect of calcium on colorectal cancer seems not dependent on sources of calcium. Although relatively limited studies have been conducted on calcium from dairy sources and calcium from non-dietary sources, [4] both total calcium and dietary calcium were modestly associated with colorectal cancer risk as shown in a pooled analysis [36]. Cho et al performed a pooled analysis of ten cohort studies on the association of dietary calcium intake and risk of colorectal cancer incidence in the Pooling Project of Prospective Studies of Diet and Cancer [36]. After 6–16 years of follow-up of 534,536 individuals, 4,992 colorectal cancer cases were ascertained. For the highest vs. the lowest quintile of dietary calcium intake, the multivariate adjusted RR was 0.86 (95% CI: 0.78–0.95) [36]. For the highest vs. the lowest quintile of total calcium intake, the RR was 0.78 (95% CI: 0.69–0.88) [36]. In addition, calcium-rich foods such as milk and dairy products appear to be associated with a lower risk of colorectal cancer, as shown in WCRF/AICR reports [1,4] and several meta-analyses [36–38]. In the 2011 most recent WCRF/AICR report, [4] the summary RR per 200 g/d of total milk intake was 0.91 (95% CI: 0.86–0.97, p value for heterogeneity ¼ 0.87, 7 studies) and the RR per 400 grams per day of total dairy intake was 0.85 (95% CI: 0.81–0.90, p value for heterogeneity ¼ 0.57, 9 studies) for colorectal cancer. In contrast to the inverse association observed in the majority of epidemiologic studies, results from some studies provide little support for reduction in risk with increasing calcium intake. For example, the Women’s Health Study [39] found that intakes of total calcium were not associated with risk of colorectal cancer (highest vs. lowest quintile, RR ¼ 1.20, 95% CI: 0.79–1.85). Results from the Netherlands Cohort Study showed null associations with calcium intake (highest vs. lowest quintile, RR ¼ 0.92; 95% CI: 0.64–1.34), possibility due to short follow-up (e.g., 3.3 years) [40]. The potential beneficial effect of calcium (with vitamin D) on colorectal cancer has also been tested in the Women’s Health Initiative (WHI) [41]. The WHI is a randomized placebo-controlled trial of 36,282 postmenopausal women given 400 IU vitamin D plus 1000 mg/d of elemental calcium or placebo. During approximately 7 years of follow-up, the incidence of colorectal cancer did not differ between women assigned to calcium plus vitamin D and those in placebo group (Hazard Ratio ¼ 1.08, 95% CI: 0.86–1.34) [41]. Inverse associations observed in observational studies and secondary prevention of calcium on adenomas shown in the trials seemed not to translate into a reduction in colorectal cancer. However, the results need to be interpreted
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with caution because of several important limitations of this study. First, the relatively high background intakes of calcium might have limited the ability to influence the rates of colorectal cancer further because in addition to 1000 mg/d study assigned amount, participants have mean total calcium intake of 1151 mg/d at enrolment (which increased further during the study) [41]. As shown in a pooled analysis of 10 cohort studies conducted in five countries, no further benefit of calcium on colorectal cancer was observed for calcium intake beyond 1000 mg/d [36]. Of note, calcium plus vitamin D supplementation was not protective among women with baseline calcium intake below 800 mg/d [41], which did not support this explanation, though power may have been limited. Moreover, the WHI trial may have been of insufficient duration because the epidemiological data on duration, although limited, indicates at least 10 years to see the effects of calcium and vitamin D [42]. When considering the whole body of literature on this subject, relatively consistent evidence supports a possible role for calcium in modestly reducing colon cancer risk, as supported by a 2009 meta-analysis of 26,335 colorectal cancer cases from 60 epidemiologic studies [37]. The summary RR for the highest vs. lowest intake of calcium was 0.76 (95% CI: 0.69–0.84, p value for heterogeneity ¼ 0.70, 10 cohort studies) for colon and 0.72 (95% CI: 0.60–0.86, p value for heterogeneity ¼ 0.92, 7 cohort studies) for rectum [37]. In summary, although confounding remains a possibility in the observation data, case–control studies and cohort studies had relatively consistent results compatible with decreased adenoma or colorectal cancer risk with increasing calcium intakes. In general, similar inverse associations were observed for both men and women. Future research is needed because less consistency remains regarding the sub-site differences (colon vs. rectum; proximal vs. distal colon), potential interaction with other nutrients such as phosphorous, magnesium, fat, fibre, and vitamin D intake, the optimal duration, and the dose–response relation. First, although sub-site differences between colon and rectum were observed in some studies [43,44], as mentioned in another brief review [45], the difference in risk with calcium intake was very slight between the colon and rectum. With respect to colon sub-site, a study of 87,998 women in the Nurses’ Health Study and 47,344 men in the Health Professionals Follow-up Study found an inverse association between higher total calcium intake (>1250 mg/day vs. 500 mg/day) and distal colon cancer (pooled RR ¼ 0.65, 95% CI: 0.43–0.98), but for proximal colon cancer (RR ¼ 1.14, 95% CI: 0.72– 1.81) [46]. Similarly, a pooled analysis of 10 cohort studies found that milk consumption (250 vs. <70 g/d) was associated with a lower risk of distal colon cancer (RR ¼ 0.73, 95% CI: 0.62–0.87) and rectal cancer (RR ¼ 0.80, 95% CI: 0.66–0.96) but not with proximal colon cancer (RR ¼ 0.99, 95% CI: 0.85–1.15) [36]. In contrast, total calcium was suggestively associated with a lower risk of proximal colon cancer (RR ¼ 0.57, 95% CI: 0.28–1.13) but not with distal colon cancer (RR ¼ 1.00, 95% CI: 0.47– 2.13) in the Cancer Prevention Study II Nutrition Cohort [24]. Interestingly, results from the Breast Cancer Detection Demonstration Project found similar non-significant inverse associations with proximal (>1270 vs. <472 mg/d, RR ¼ 0.68, 95% CI: 0.42–1.08) and distal colon cancer (RR ¼ 0.71, 95% CI: 0.46–1.26) [47]. Future research needs to clarify the potential difference in colon cancer sub-sites. Several dietary factors may potentially modify the calcium-colorectal cancer association. Experimental studies have indicated that the potential effect of calcium on colorectal cancer risk may be confined to animals fed with relatively high-fat diets [48,49]. Intakes of phosphorous and fibre might influence the absorption of calcium in the gut [50]. In addition, a recent case–control study indicated a possible interaction between calcium and magnesium intake in relation to risk of colorectal adenoma and hyperplastic polyps [51]. More importantly, calcium might interact with vitamin D because the absorption of calcium relies on adequate vitamin D. However, to separate the independent effect of each nutrient is challenging because they are generally correlated. In addition, relatively limited studies have examined the interaction between calcium with these dietary factors [28,50]. The potential interaction may not change the overall conclusion, that is, calcium may protect against colorectal cancer, but can help identify subgroups to maximize the beneficial effect of calcium. Lastly, in contrast to inverse association observed across the entire range of intake categories in many studies, a pooled analysis of 10 cohort studies conducted in five countries found that most of the risk reduction was achieved by attaining intakes of not more than 1000 mg/day [36], which suggests a threshold level above which further calcium may not be beneficial. More research to address the above-mentioned issues including determining the optimal dose and duration is warranted.
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Vitamin D and colorectal cancer As an essential nutrient, in addition to an important role in bone health and maintenance of calcium balance, vitamin D exerts various physiological functions. Experimental studies showed that many cell types including colorectal cells express vitamin D receptors and 1-a-hydroxylase, and are therefore capable to convert 25-hydroxyvitamin D (25(OH)D) into 1,25(OH)2 vitamin D, the most active metabolite of vitamin D [52]. Activation of these receptors by 1,25(OH)2D has anti-cancerous properties including increasing differentiation, apoptosis and inhibiting proliferation, invasiveness, angiogenesis, and metastatic potential [14,53,54]. A relationship between vitamin D and colorectal cancer was first hypothesized by Garland and Garland in 1980 based on the inverse association observed between UV-B radiation exposure and colon cancer risk [8]. At that time, little was known regarding the biology of vitamin D beyond effects on calcium absorption, and epidemiologic studies were sparse. Motivated largely by this study, substantial research has been conducted during the past three decades to assess the biological basis for this hypothesis and to investigate the potential effect of vitamin D status on subsequent risk of colorectal cancer or adenomas. These studies used various approaches to evaluate the vitamin D status, including using UV-B radiation as a proxy, direct measures of circulating 25(OH)D levels, dietary or supplemental intake, and predicted 25(OH)D score [55]. The evidence from these approaches used in the observational studies is summarized below. Ecological data using UV-B radiation as a surrogate UV-B radiation exposure has been the major source of vitamin D, probably accounting for the majority of vitamin D for most human populations. The UV-B abundance decreases substantially with increasing latitude. Thus, geographic location can be used as a surrogate for sun exposure. In 1980, Garland and Garland reported that the mortality from colon cancer was highest in states of the USA that had the lowest levels of solar radiation and hypothesized that the association could be due to vitamin D [8]. As summarized in the 2008 IARC report [56], many ecological studies found associations between increasing latitude and increasing colorectal cancer incidence or mortality. Despite the usefulness of ecologic data in generating hypothesis, causal inference from these ecological studies should be interpreted with caution because these studies cannot adequately control for confounding factors, which may also vary with latitude (e.g., physical activity or dietary habits). In addition, people’s exposure to UV-B radiation is influenced by the time spending outdoors, clothing habits and use of sunscreen. Vitamin D intakes in relation to colorectal cancer Numerous case–control and cohort studies have examined vitamin D intake (total, dietary, supplemental) in relation to risk of colorectal cancer or adenoma. These studies have been reviewed in detail [4,53,56–60] and have generally shown an inverse association between vitamin D intake and risk of colorectal cancer or adenoma. Many of the studies controlled for known or suspected risk factors for colorectal cancer, although the independent effects of vitamin D and calcium intakes might be difficult to separate entirely. A quantitative review by Gorham et al found that intake of 1000 IU/day of vitamin D, compared to <100 IU/day vitamin D, was associated with 50% lower risk [58]. A 2008 meta-analysis of 12 observational studies on vitamin D intake found an 11% marginally decreased risk of colorectal adenomas (highest vs. lowest quintile, RR ¼ 0.89; 95% CI: 0.78–1.02). The inverse associations appeared stronger for advanced adenoma (RR ¼ 0.77; 95% CI: 0.63–0.95), but the number of studies was small [59]. Results for the randomized control trials provide more definitive causal association, but the current data are sparse. To date, the largest study on this topic is the Women’s Health Initiative (WHI) [41]. As noted earlier, results from the WHI trial did not support a strong effect of calcium and vitamin D on colorectal cancer during 7 years of follow-up [41]. However, the results need to be interpreted with caution because of several important limitations of this study, as discussed earlier [61,62]. In brief, the dose of vitamin D supplement was relatively low because the expected increase of 25(OH)D for an increment of 400 IU/d would be w3 ng/mL. In the observational studies of 25(OH)D showing
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significant associations, the difference between high and low quintiles was generally 20 ng/mL or higher. Secondly, the compliance was suboptimal because only 50–60% of women took 80% of the scheduled supplementation. Moreover, some interactions may have been missed in the original analysis. Re-analysis of WHI trial showed that calcium plus vitamin D supplementation among women concurrently assigned to oestrogen therapies were associated an increased risk (Hazard Ratio ¼ 1.50, 95% CI: 0.96–2.33). Among women concurrently assigned to placebos arms of the oestrogen trials, calcium plus vitamin D indicated suggested benefits (Hazard Ratio ¼ 0.71, 95% CI: 0.46–1.09) (p for interaction ¼ 0.018) [63]. Thus, the WHI trial was probably inadequate in testing the vitamin D and colorectal cancer hypothesis. It is also possible that vitamin D supplement could have more impact on cancer mortality than on cancer incidence. A meta-analysis of 18 randomized trials including 57,311 participants on intakes of vitamin D and calcium supplements found that intake of ordinary doses of vitamin D, but not calcium, supplements (trial size-adjusted mean daily vitamin D dose was 528 IU, comparable with the dose in WHI) seems to be associated with reduction in total mortality rates. The summary relative risk for all-cause mortality was 0.93 (95% CI: 0.87–0.99) [64]. Pre-diagnostic serum levels of 25(OH)D in relation to colorectal cancer UV-B converts 7-dehydrocholesterol into vitamin D in the skin and then hydroxylated in the liver to produce 25(OH)D, which can be converted by 1-a-hydroxylase into 1,25(OH)2D [53]. Circulating 1, 25(OH)2D is tightly regulated largely by renal 1-a-hydroxylase activity and does not typically reflect the vitamin D status, except at extreme deficiency [53]. In contrast, 25(OH)D is less tightly controlled and accounts not only for skin exposure to UV-B radiation, but also for total vitamin D intake and for factors such as skin pigmentation, physical activity and adiposity [53]. In addition, 25(OH)D has about 2–3 weeks of half-life (t1/2) in the circulatory system, and thus can provide a fairly good indicator of longterm vitamin D status. Studies that have examined 25(OH)D levels prospectively in relation to subsequent risk of colorectal cancer or adenoma have generally supported an inverse association. Among the largest studies are the Nurses’ Health Study (NHS) [65] and the European Prospective Investigation into Cancer (EPIC) study [66]. The NHS study, based on 193 incident colorectal cancer cases and with adjustment for established or potential confounding factors including physical activity and obesity, found a monotonic reduction in risk across quintiles of 25(OH)D concentration, with an RR of 0.53 (95% CI: 0.27–1.04) for highest vs. lowest quintile [65]. In the EPIC study, 1,248 colorectal cancer cases were identified and matched to 1248 control subjects by age, gender, study center, follow-up time, fasting status, and time of day of blood donation [66]. Compared to a serum 25(OH)D concentration of 20–29 ng/mL, lower levels of a 25(OH)D concentration were associated with an increase in colorectal cancer risk (<10 ng/mL: OR ¼ 1.32, 95% CI: 0.87–2.01; 10–19 ng/mL: OR ¼ 1.28, 95% CI: 1.05– 1.56), whereas higher concentrations were associated with a decreased risk of colorectal cancer (30– 39 ng/mL: OR ¼ 0.88, 95% CI: 0.68–1.13; 40 ng/mL: RR ¼ 0.77, 95% CI: 0.56–1.06) [66]. Pooled analyses of studies on 25(OH)D levels confirm a significant inverse association [58,67,68]. As shown in the most recent 2010 meta-analysis of all current studies, based on 1,822 colon and 868 rectal cancers, increasing circulating 25(OH)D levels was associated with a significant reduction in colorectal cancer (top vs. bottom quantiles, OR ¼ 0.66, 95% CI: 0.54–0.81) [67]. The inverse association was stronger for rectal cancer (OR ¼ 0.50, 95% CI: 0.28–0.88) than colon cancer (OR ¼ 0.77, 95% CI: 0.56– 1.07) but no significant difference was noted (p value for difference between colon and rectal cancer ¼ 0.20) [67]. This association is further supported by a decrease in colonic adenomas, precursors to colorectal cancer, with higher serum 25(OH)D. A meta-analysis published in 2008 showed that 25(OH)D was inversely associated with risk of colorectal adenomas (high vs. low circulating levels, RR ¼ 0.70, 95% CI: 0.56–0.87) [59]. The inverse associations appeared stronger for advanced adenoma (RR ¼ 0.64, 95% CI: 0.45–0.90), but the number of studies was small [59]. Taken together, observational studies provide evidence of a decreased risk of colorectal cancer or adenoma associated with higher serum 25(OH)D and controlling for multiple covariates had little influence on the findings. Although optimal 25(OH)D levels to reduce colorectal cancer risk needs to be established in future studies, the dose–response appears linear up to a 25(OH)D level of at least 30 ng/ mL. The results are somewhat inconsistent in determining whether the association is stronger for colon cancer or for rectal cancer, possibly due to small numbers.
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A strength of using 25(OH)D levels includes examining prior to diagnosis the best single indicator of vitamin D status with subsequent risk, which minimizes potential reverse causation. Confounding can be reasonably controlled in the multivariable models through adjusting factors such as body mass index and physical activity. A limitation is that, although the t1/2 in the circulation of w2–3 week is fairly reasonable, the correlation with long-term vitamin D status is unclear. Some of the variability picked up by 25(OH)D levels might be due to relatively recent exposures, and may not reflect long-term status. Predicted 25(OH)D score in relation to colorectal cancer As noted earlier, circulating 25(OH)D can be influenced by several factors. Thus, using known predictors of 25(OH)D level can derive a predicted 25(OH)D score. This approach has been used in the Health Professionals Follow-up Study [69]. With a sample of 1095 men in this cohort who had circulating 25(OH)D levels measured, the authors first used a multiple linear regression to develop a predicted 25(OH)D score based on geographical region, skin pigmentation, dietary intake, supplement intake, body mass index, and leisure time physical activity (a surrogate of potential exposure to sunlight UV-B). The score was then calculated for each of the approximately 47,000 cohort members and was examined prospectively in relation to subsequent risk of cancer incidence and mortality. For colorectal cancer, based on 691 cases diagnosed from 1986 to 2000, a predicted 10 ng/mL increment in 25(OH)D was associated with a reduced risk (RR ¼ 0.63, 95% CI: 0.48–0.83). This association persisted when controlled for body mass index or physical activity. Summary Overall, the current epidemiologic evidence supports a beneficial role of calcium and vitamin D in colorectal carcinogenesis [4,56,60]. Because of the limitations of observational studies [70], these data do not prove a cause–effect relation, but they are strongly suggestive of such an effect. Confounding seem unlikely entirely account for all these associations. In addition, these associations were supported by numerous in vitro, animal and clinical studies that indicate that calcium and vitamin D may have anti-cancerous benefits against colorectal cancer and possibly other cancers. The optimal dose and duration of calcium on colorectal cancer remains to be established. Similarly for vitamin D, in the US, the current recommended daily vitamin D intake (e.g., 600–800 depending on age) [71] may not meet the optimal requirement [72,73], especially of certain groups of people at higher risk of vitamin D deficiency. These people include individuals who live in regions with low sunlight intensity, who avoid sunlight or thoroughly use sunscreen, who have darker skin, who are old, who live in a nursing home, and who are overweight or obese [60]. Given that few foods contain vitamin D, supplements are the simplest, safest way to get vitamin D. For most people, solar UV-B exposure remains the major source of vitamin D. However, unprotected sun exposure is commonly discouraged because of the concerns of skin damage and cancer. Given the potential benefits from these nutrients against colorectal cancer, optimal dose and duration needs to be considered in formulating recommendations and guidelines.
Practice points Although cause–effect is not definitely proven, the current overall epidemiologic evidence supports significant inverse associations between calcium and vitamin D and colorectal cancer risk. Although more research on optimal dose for both calcium and vitamin D is warranted, intake of calcium of not more than 1000 mg/d and vitamin D of 1000–2000 IU/d, achieving a level of at least 30 ng/mL, appears important for colorectal cancer prevention.
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Research agenda The optimal dose and duration of the calcium and vitamin D on colorectal cancer needs to be elucidated; in particular, future randomized control trials of higher doses of calcium and vitamin D with longer duration might provide more insights of these nutrients on colorectal cancer prevention. The potential interaction of calcium with phosphorous, magnesium, fat, retinol, vitamin D and hormone replace therapy (HRT) merits attention. Whether the effect of calcium on colorectal cancer differs by sub-sites (e.g., colon vs. rectum, proximal colon vs. distal colon) needs to be clarified. The potential interaction of vitamin D status with intakes of calcium and retinol needs to be established. Research of vitamin D and colorectal cancer risk in ethnic groups other than whites are warranted. The effect of calcium and vitamin D on colorectal cancer survival and mortality requires more research.
Conflict of interest None. References [1] World Cancer Research Fund, American Institute for Cancer Research Expert Panel. Food, nutrition and the prevention of cancer: a global perspective. Wash (DC) Am Inst for Cancer Res; 2007. [2] Ferlay J, Shin HR, Bray F, Forman D, Mathers C, Parkin DM. Estimates of worldwide burden of cancer in 2008: GLOBOCAN 2008. Int J Cancer 2010;127:2893–917. [3] Chan AT, Giovannucci EL. Primary prevention of colorectal cancer. Gastroenterology 2010;138:2029–43. *[4] World Cancer Research Fund. American Institute for Cancer Research. Continuous Update Project Report Summary. Food, Nutrition, Physical Activity, and the Prevention of Colorectal Cancer. 2011. This 2011 report, together with the 2007 report, summarized the most recent data on nutritional factors including calcium and colorectal cancer risk. [5] Jenab M, McKay J, Bueno-de-Mesquita HB, van Duijnhoven FJ, Ferrari P, Slimani N, et al. Vitamin D receptor and calcium sensing receptor polymorphisms and the risk of colorectal cancer in European populations. Cancer Epidemiol Biomark Prev 2009;18:2485–91. [6] Slattery ML, Neuhausen SL, Hoffman M, Caan B, Curtin K, Ma KN, et al. Dietary calcium, vitamin D, VDR genotypes and colorectal cancer. Int J Cancer 2004;111:750–6. [7] Slattery ML, Murtaugh M, Caan B, Ma KN, Wolff R, Samowitz W. Associations between BMI, energy intake, energy expenditure, VDR genotype and colon and rectal cancers (United States). Cancer Causes Control 2004;15:863–72. *[8] Garland CF, Garland FC. Do sunlight and vitamin D reduce the likelihood of colon cancer? Int J Epidemiol 1980;9:227–31. This study first proposed the vitamin D and colorectal cancer hypothesis. [9] Schatzkin A, Peters U. Advancing the calcium-colorectal cancer hypothesis. J Natl Cancer Inst 2004;96:893–4. *[10] Newmark HL, Wargovich MJ, Bruce WR. Colon cancer and dietary fat, phosphate, and calcium: a hypothesis. J Natl Cancer Inst 1984;72:1323–5. This study proposed several important mechanisms whereby calcium may protect against colorectal cancer. [11] Wargovich MJ, Lynch PM, Levin B. Modulating effects of calcium in animal models of colon carcinogenesis and short-term studies in subjects at increased risk for colon cancer. Am J Clin Nutr 1991;54:202S–5S. [12] Lipkin M, Newmark H. Effect of added dietary calcium on colonic epithelial-cell proliferation in subjects at high risk for familial colonic cancer. N Engl J Med 1985;313:1381–4. [13] Lipkin M, Newmark H. Calcium and the prevention of colon cancer. J Cell Biochem Suppl 1995;22:65–73. [14] Lamprecht SA, Lipkin M. Cellular mechanisms of calcium and vitamin D in the inhibition of colorectal carcinogenesis. Ann N Y Acad Sci 2001;952:73–87. [15] Newmark HL, Lipkin M. Calcium, vitamin D, and colon cancer. Cancer Res 1992;52:2067s–70s. [16] Lipkin M. Update of preclinical and human studies of calcium and colon cancer prevention. World J Gastroenterol 1999;5: 461–4. [17] Lamprecht SA, Lipkin M. Chemoprevention of colon cancer by calcium, vitamin D and folate: molecular mechanisms. Nat Rev Cancer 2003;3:601–14. [18] Bergsma-Kadijk JA, van ’t Veer P, Kampman E, Burema J. Calcium does not protect against colorectal neoplasia. Epidemiology 1996;7:590–7. [19] Park SY, Murphy SP, Wilkens LR, Nomura AM, Henderson BE, Kolonel LN. Calcium and vitamin D intake and risk of colorectal cancer: the multiethnic cohort study. Am J Epidemiol 2007;165:784–93.
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[30] Hofstad B, Almendingen K, Vatn M, Andersen SN, Owen RW, Larsen S, et al. Growth and recurrence of colorectal polyps: a double-blind 3-year intervention with calcium and antioxidants. Digestion 1998;59:148–56. [31] Bonithon-Kopp C, Kronborg O, Giacosa A, Rath U, Faivre J. Calcium and fibre supplementation in prevention of colorectal adenoma recurrence: a randomised intervention trial. European Cancer Prevention Organisation Study Group. Lancet 2000;356:1300–6. *[32] Baron JA, Beach M, Mandel JS, van Stolk RU, Haile RW, Sandler RS, et al. Calcium supplements for the prevention of colorectal adenomas. calcium polyp prevention study group. N Engl J Med 1999;340:101–7. The largest randomized controlled trial to date showed calcium supplementation was associated with a significant reduction in the risk of recurrent colorectal adenomas. [33] Wallace K, Baron JA, Cole BF, Sandler RS, Karagas MR, Beach MA, et al. Effect of calcium supplementation on the risk of large bowel polyps. J Natl Cancer Inst 2004;96:921–5. [34] Grau MV, Baron JA, Sandler RS, Wallace K, Haile RW, Church TR, et al. Prolonged effect of calcium supplementation on risk of colorectal adenomas in a randomized trial. J Natl Cancer Inst 2007;99:129–36. [35] Carroll C, Cooper K, Papaioannou D, Hind D, Pilgrim H, Tappenden P. Supplemental calcium in the chemoprevention of colorectal cancer: a systematic review and meta-analysis. Clin Ther 2010;32:789–803. *[36] Cho E, Smith-Warner SA, Spiegelman D, Beeson WL, van den Brandt PA, Colditz GA, et al. Dairy foods, calcium, and colorectal cancer: a pooled analysis of 10 cohort studies. J Natl Cancer Inst 2004;96:1015–22. This pooled analysis of 10 cohort studies conducted in five countries showed that higher consumption of calcium and milk was associated with a lower risk of colorectal cancer. [37] Huncharek M, Muscat J, Kupelnick B. Colorectal cancer risk and dietary intake of calcium, vitamin D, and dairy products: a meta-analysis of 26,335 cases from 60 observational studies. Nutr Cancer 2009;61:47–69. [38] Jarvinen R, Knekt P, Hakulinen T, Aromaa A. Prospective study on milk products, calcium and cancers of the colon and rectum. Eur J Clin Nutr 2001;55:1000–7. [39] Lin J, Zhang SM, Cook NR, Manson JE, Lee IM, Buring JE. Intakes of calcium and vitamin D and risk of colorectal cancer in women. Am J Epidemiol 2005;161:755–64. [40] Kampman E, Goldbohm RA, van den Brandt PA, van ’t Veer P. Fermented dairy products, calcium, and colorectal cancer in The Netherlands Cohort Study. Cancer Res 1994;54:3186–90. *[41] Wactawski-Wende J, Kotchen JM, Anderson GL, Assaf AR, Brunner RL, O’Sullivan MJ, et al. Calcium plus vitamin D supplementation and the risk of colorectal cancer. N Engl J Med 2006;354:684–96. The current largest randomized controlled trial showed that daily supplementation of calcium plus vitamin D for seven years had no effect on the incidence of colorectal cancer among postmenopausal women. [42] Martinez ME, Giovannucci EL, Colditz GA, Stampfer MJ, Hunter DJ, Speizer FE, et al. Calcium, vitamin D, and the occurrence of colorectal cancer among women. J Natl Cancer Inst 1996;88:1375–82. [43] Bostick RM, Potter JD, Sellers TA, McKenzie DR, Kushi LH, Folsom AR. Relation of calcium, vitamin D, and dairy food intake to incidence of colon cancer among older women. The Iowa Women’s Health Study. Am J Epidemiol 1993;137:1302–17. [44] Zheng W, Anderson KE, Kushi LH, Sellers TA, Greenstein J, Hong CP, et al. A prospective cohort study of intake of calcium, vitamin D, and other micronutrients in relation to incidence of rectal cancer among postmenopausal women. Cancer Epidemiol Biomark Prev 1998;7:221–5. [45] Chia V, Newcomb PA. Calcium and colorectal cancer: some questions remain. Nutr Rev 2004;62:115–20. [46] Wu K, Willett WC, Fuchs CS, Colditz GA, Giovannucci EL. Calcium intake and risk of colon cancer in women and men. J Natl Cancer Inst 2002;94:437–46. [47] Flood A, Peters U, Chatterjee N, Lacey Jr JV, Schairer C, Schatzkin A. Calcium from diet and supplements is associated with reduced risk of colorectal cancer in a prospective cohort of women. Cancer Epidemiol Biomark Prev 2005;14:126–32. [48] Pence BC, Buddingh F. Inhibition of dietary fat-promoted colon carcinogenesis in rats by supplemental calcium or vitamin D3. Carcinogenesis 1988;9:187–90. [49] Pence BC. Role of calcium in colon cancer prevention: experimental and clinical studies. Mutat Res 1993;290:87–95. [50] Chan JM, Giovannucci E, Andersson SO, Yuen J, Adami HO, Wolk A. Dairy products, calcium, phosphorous, vitamin D, and risk of prostate cancer (Sweden). Cancer Causes Control 1998;9:559–66.
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[51] Dai Q, Shrubsole MJ, Ness RM, Schlundt D, Cai Q, Smalley WE, et al. The relation of magnesium and calcium intakes and a genetic polymorphism in the magnesium transporter to colorectal neoplasia risk. Am J Clin Nutr 2007;86:743–51. [52] Peterlik M, Cross HS. Vitamin D and calcium deficits predispose for multiple chronic diseases. Eur J Clin Invest 2005;35: 290–304. [53] Giovannucci E. The epidemiology of vitamin D and cancer incidence and mortality: a review (United States). Cancer Causes Control 2005;16:83–95. [54] Iseki K, Tatsuta M, Uehara H, Iishi H, Yano H, Sakai N, et al. Inhibition of angiogenesis as a mechanism for inhibition by 1alpha-hydroxyvitamin D3 and 1,25-dihydroxyvitamin D3 of colon carcinogenesis induced by azoxymethane in Wistar rats. Int J Cancer 1999;81:730–3. [55] Giovannucci E. Epidemiological evidence for vitamin D and colorectal cancer. J Bone Miner Res 2007;22(Suppl. 2):V81–5. *[56] IARC. Vitamin D and cancer. In: IARC Working Group Reports, vol. 5. Lyon: International Agency for research on Cancer; 25 November 2008. This report comprehensively summarized the associations between vitamin D status and risk of cancer including colorectal cancer, breast cancer, and prostate cancer. [57] Grant WB, Garland CF. A critical review of studies on vitamin D in relation to colorectal cancer. Nutr Cancer 2004;48:115– 23. [58] Gorham ED, Garland CF, Garland FC, Grant WB, Mohr SB, Lipkin M, et al. Vitamin D and prevention of colorectal cancer. J Steroid Biochem Mol Biol 2005;97:179–94. [59] Wei MY, Garland CF, Gorham ED, Mohr SB, Giovannucci E. Vitamin D and prevention of colorectal adenoma: a metaanalysis. Cancer Epidemiol Biomark Prev 2008;17:2958–69. [60] Giovannucci E. Epidemiology of vitamin D and colorectal cancer: casual or causal link? J Steroid Biochem Mol Biol 2010; 121:349–54. [61] Holick MF. Calcium plus vitamin D and the risk of colorectal cancer. N Engl J Med 2006;354:2287–8. author reply 2287– 2288. [62] Giovannucci E. Calcium plus vitamin D and the risk of colorectal cancer. N Engl J Med 2006;354:2287–8. author reply 2287–2288. [63] Ding EL, Mehta S, Fawzi WW, Giovannucci EL. Interaction of estrogen therapy with calcium and vitamin D supplementation on colorectal cancer risk: reanalysis of Women’s Health Initiative randomized trial. Int J Cancer 2008;122: 1690–4. [64] Autier P, Gandini S. Vitamin D supplementation and total mortality: a meta-analysis of randomized controlled trials. Arch Intern Med 2007;167:1730–7. [65] Feskanich D, Ma J, Fuchs CS, Kirkner GJ, Hankinson SE, Hollis BW, et al. Plasma vitamin D metabolites and risk of colorectal cancer in women. Cancer Epidemiol Biomark Prev 2004;13:1502–8. [66] Jenab M, Bueno-de-Mesquita HB, Ferrari P, van Duijnhoven FJ, Norat T, Pischon T, et al. Association between prediagnostic circulating vitamin D concentration and risk of colorectal cancer in European populations:a nested case– control study. BMJ 2010;340:b5500. [67] Lee JE, Li H, Chan AT, Hollis BW, Lee IM, Stampfer MJ, et al. Circulating levels of vitamin D and colon and rectal cancer: the Physicians’ Health Study and a meta-analysis of prospective studies. Cancer Prev Res (Phila) 2011;4:735–43. [68] Yin L, Grandi N, Raum E, Haug U, Arndt V, Brenner H. Meta-analysis: longitudinal studies of serum vitamin D and colorectal cancer risk. Aliment Pharmacol Ther 2009;30:113–25. [69] Giovannucci E, Liu Y, Rimm EB, Hollis BW, Fuchs CS, Stampfer MJ, et al. Prospective study of predictors of vitamin D status and cancer incidence and mortality in men. J Natl Cancer Inst 2006;98:451–9. [70] Giovannucci E. Strengths and limitations of current epidemiologic studies: vitamin D as a modifier of colon and prostate cancer risk. Nutr Rev 2007;65:S77–9. [71] Institute of Medicine. Dietary reference intakes for calcium and vitamin D. Washington, D.C: National Academies Press; 2010. [72] Bischoff-Ferrari HA, Shao A, Dawson-Hughes B, Hathcock J, Giovannucci E, Willett WC. Benefit-risk assessment of vitamin D supplementation. Osteoporos Int 2010;21:1121–32. [73] Giovannucci E. Vitamin D, how much is enough and how much is too much? Public Health Nutr 2011;14:740–1.
Contents lists available at SciVerse ScienceDirect
Best Practice & Research Clinical Gastroenterology
4
Calcium, vitamin D and colorectal cancer chemoprevention Xuehong Zhang, MD, MSc, ScD, Post-doctoral Research Fellow a,1, Edward Giovannucci, MD, ScD, Professor of Nutrition and Epidemiology a, b, c, * a
Channing Laboratory at Landmark Center (West Wing), Department of Medicine, Brigham and Women’s Hospital and Harvard Medical School, 401 Park Drive, Boston, MA 02115, USA b Department of Nutrition, Harvard School of Public Health, Boston, MA, USA c Department of Epidemiology, Harvard School of Public Health, Boston, MA, USA
Keywords: Calcium vitamin D Milk Dairy products Colorectal cancer Adenomas Chemoprevention Incidence Mortality Survival Case–control study Cohort study Randomized control trial Epidemiology
Identifying modifiable risk factors, particularly dietary factors, which have been hypothesized to play an important role in colorectal carcinogenesis, remains crucial in developing primary prevention strategies. Calcium and vitamin D have been shown consistently in experimental studies to have anti-cancerous properties including but not limited to stimulating differentiation, reducing proliferation, and inducing apoptosis. The majority of epidemiologic studies consistently support an approximately 20–30% reduction in risk of colorectal cancer and adenomas comparing high to low intake categories of both calcium and vitamin D, although independent effects may not be adequately separated. Less consistency exists on the dose– response relation for both nutrients. Intake of calcium of not more than 1000 mg/d and intake of vitamin D of 1000–2000 IU/d, achieving a level of at least 30 ng/mL, appear important for colorectal cancer prevention. More study is warranted to determine the optimal intake levels and duration to reduce the colorectal cancer risk. Ó 2011 Elsevier Ltd. All rights reserved.
Introduction Colorectal cancer is the third most common type of cancer in both men and women worldwide. Higher incidence rates are observed in high-income countries compared to middle- and low-income countries, though incidence rates are increasing rapidly in low to middle-income areas [1]. Around
* Corresponding author. Harvard School of Public Health, 665 Huntington Avenue, Boston, MA 02115, USA. Tel.: þ1 617 432 4648; fax: þ1 617 432 2435. E-mail addresses: [email protected] (X. Zhang), [email protected] (E. Giovannucci). 1 Tel.: þ1 617 519 3550; fax: þ1 617 432 2435. 1521-6918/$ – see front matter Ó 2011 Elsevier Ltd. All rights reserved. doi:10.1016/j.bpg.2011.10.001
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the world, age-adjusted incidence rates range from 30 or more per 100,000 people in North America, parts of Europe, Australia, New Zealand, and Japan to less than 5 per 100,000 in much of Africa and parts of Asia [2]. The substantial difference in incidence rates across geographic regions suggests the importance of environmental influences on colorectal carcinogenesis. Substantial research conducted in past decades has advanced our understanding of colorectal cancer aetiology. As summarized in a 2010 review, [3] some lifestyle, nutritional, and medication factors have been identified to be associated with colorectal cancer risk. With respect to dietary factors however, the effect on colorectal cancer remains largely uncertain [1,4]. Among these factors, calcium and vitamin D appear to show great potential for colorectal cancer prevention. This review aims to provide a brief review of a few human clinical trials and epidemiologic studies on calcium and vitamin D on sporadic colorectal adenoma and cancer risk. Although effects of these nutrients may be mediated by genetic variants of the vitamin D receptor (VDR) and the calcium sensing receptor (CASR), relatively limited data are available to date [5–7] and these data were not reviewed here. Calcium and colorectal cancer Calcium is an essential nutrient and plays an important role in muscular contraction, cellular growth, cell adhesion, and bone formation. The calcium-colorectal cancer hypothesis has evolved over time. In 1980, Garland and Garland proposed that vitamin D was a protective factor for colon cancer based on ecologic data showing variation of colon cancer mortality rates by latitudes [8]. One of the mechanisms to explain this potential effect of vitamin D was through enhanced calcium absorption. They hypothesized that calcium may reduce the inflammatory response of lumen epithelial cells to bacteria flora and other agents [9]. In 1984, Newmark et al [10] further hypothesized that calcium ions neutralize the toxic effects of free ionized fatty acids and bile acids by forming insoluble mineral–fat complexes or soaps in the large bowel. Subsequent experimental studies showed calcium administration reduces the occurrence of chemically induced tumours in animals [11] and the proliferation of colonic epithelial cells in humans [12]. Other data including in vitro studies also suggested that calcium may act directly on colonic epithelial cells by regulating the cell cycle and inducing terminal differentiation [13–17]. Numerous case–control and cohort studies have examined the relation between calcium intake and colorectal cancer risk. Epidemiologic studies conducted through middle 1990s tend to report a modest, non-significant, association. For example, a quantitative review published in 1996 by Bergsma-Kadijk et al [18] summarized twenty-one articles (seven cohort and fourteen case–control studies) published from 1980 to 1994 and the results did not indicate substantial protection by calcium. The summary multivariable relative risks (RR) were 0.90 (95% CI: 0.78–1.05) for cohort studies and 0.88 (95% CI: 0.73– 1.04) for case–control studies. Subsequently, results from the observational studies, as summarized in 2007 and 2011 World Cancer Research Foundation and American Institute for Cancer Research (WCRF/ AICR) reports [1,4], tend to support a fairly consistent stronger inverse association with approximate 20–30% risk reductions for the highest vs. the lowest intake categories. For example, results from the Multiethnic Cohort showed that total calcium intake (from foods and supplements) was inversely associated with colorectal cancer risk in both men (highest vs. lowest quintile, RR ¼ 0.70, 95% CI: 0.52– 0.93) and women (RR ¼ 0.64, 95% CI: 0.50–0.83) [19]. Higher calcium intake (highest quintile vs. lowest) was associated with a lower risk of colorectal cancer in cohorts conducted in France (RR ¼ 0.72, 95% CI: 0.47–1.10) [20] and in China (RR ¼ 0.6, 95% CI: 0.3–1.0) [21]. Similar magnitudes of inverse associations were also observed in the Cohort of Swedish Men (highest vs. lowest quartile, RR ¼ 0.68, 95% CI: 0.51–0.91) [22], in the Japan Public Health Center-based Prospective Study (highest vs. lowest quintile, RR ¼ 0.71, 95% CI: 0.52–0.98; men only) [23], and in the Cancer Prevention Study II Nutrition Cohort [24] of both men and women (highest vs. lowest quintiles, RR ¼ 0.87, 95% CI: 0.67–1.12). In addition to cohort studies, case–control studies [25–29] generally showed inverse associations with calcium intake and colorectal cancer risk. The magnitude of the inverse association was comparable to that observed in cohort studies. For example, a large case–control study of 1993 incident colon cancer cases and 2410 population-based controls conducted in the US showed that dietary calcium was inversely associated with colon cancer risk in men (highest vs. lowest quintile, OR ¼ 0.6, 95% CI: 0.5–0.9) and women (OR ¼ 0.6, 95% CI: 0.4–0.9) [26]. A case–control study of 1,953 colorectal
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cancer cases conducted in Italy also observed inverse association with calcium intake (1495 vs. <1013 mg/d, OR ¼ 0.72, 95% CI: 0.6–0.9) [25]. The potential beneficial effect of calcium on colorectal cancer observed in animal, mechanistic and epidemiologic evidence has also been tested in randomized control trials of adenomas, precursors of colorectal cancer. The randomized trial is considered as ‘gold standard’ in establishing a cause–effect relation, mainly because theoretically known or unknown confounding factors can be balanced between randomized groups. However, selection of the appropriate dose, compliance, unknown lag time between start of the intervention and disease onset pose challenges on the trial and results from trials need to be interpreted with caution. Nonetheless, results from the trials offer complementary data to test the calcium-colorectal cancer hypothesis. At least three trials have been conducted. A first small trial of daily mixture of antioxidative vitamins and calcium showed a significant reduction in adenoma recurrence, but a separate calcium effect could not be disentangled because of the combined intervention [30]. Results from the European Cancer Prevention trial of 2 g elemental calcium daily vs. placebo found a modest non-significant reduction in the risk of adenoma recurrence (RR ¼ 0.66, 95% CI: 0.38–1.17) in this relatively small study [31]. To date, the largest study is the Calcium Polyp Prevention Study, 913 subjects with a recent history of colorectal adenomas were to receive either calcium carbonate (1200 mg of elemental calcium daily) or placebo. A modest yet statistically significant reduction in the risk of recurrent colorectal adenomas was observed in the calcium group (RR ¼ 0.76, 95% CI: 0.60–0.96) [32]. Subsequent analysis of this trial showed a stronger effect of calcium on advanced adenomas (RR ¼ 0.65, 95% CI: 0.46–0.93) [33]. In addition, a prolonged effect of calcium supplementation was observed because participants in the calcium group had a significantly lower risk of any adenoma than those in the placebo group (RR ¼ 0.63, 95% CI: 0.46–0.87) during the first 5 years after randomization ended [34]. A recent meta-analysis of these trials also supported a statistically significant reduction in the RR for adenoma recurrence (RR ¼ 0.80, 95% CI: 0.69–0.94) for those receiving calcium 1200–2000 mg/d [35]. The magnitude of adenoma recurrence reduction in these trials is generally in line with the magnitude of the inverse associations seen in observational epidemiologic studies [9]. The potential beneficial effect of calcium on colorectal cancer seems not dependent on sources of calcium. Although relatively limited studies have been conducted on calcium from dairy sources and calcium from non-dietary sources, [4] both total calcium and dietary calcium were modestly associated with colorectal cancer risk as shown in a pooled analysis [36]. Cho et al performed a pooled analysis of ten cohort studies on the association of dietary calcium intake and risk of colorectal cancer incidence in the Pooling Project of Prospective Studies of Diet and Cancer [36]. After 6–16 years of follow-up of 534,536 individuals, 4,992 colorectal cancer cases were ascertained. For the highest vs. the lowest quintile of dietary calcium intake, the multivariate adjusted RR was 0.86 (95% CI: 0.78–0.95) [36]. For the highest vs. the lowest quintile of total calcium intake, the RR was 0.78 (95% CI: 0.69–0.88) [36]. In addition, calcium-rich foods such as milk and dairy products appear to be associated with a lower risk of colorectal cancer, as shown in WCRF/AICR reports [1,4] and several meta-analyses [36–38]. In the 2011 most recent WCRF/AICR report, [4] the summary RR per 200 g/d of total milk intake was 0.91 (95% CI: 0.86–0.97, p value for heterogeneity ¼ 0.87, 7 studies) and the RR per 400 grams per day of total dairy intake was 0.85 (95% CI: 0.81–0.90, p value for heterogeneity ¼ 0.57, 9 studies) for colorectal cancer. In contrast to the inverse association observed in the majority of epidemiologic studies, results from some studies provide little support for reduction in risk with increasing calcium intake. For example, the Women’s Health Study [39] found that intakes of total calcium were not associated with risk of colorectal cancer (highest vs. lowest quintile, RR ¼ 1.20, 95% CI: 0.79–1.85). Results from the Netherlands Cohort Study showed null associations with calcium intake (highest vs. lowest quintile, RR ¼ 0.92; 95% CI: 0.64–1.34), possibility due to short follow-up (e.g., 3.3 years) [40]. The potential beneficial effect of calcium (with vitamin D) on colorectal cancer has also been tested in the Women’s Health Initiative (WHI) [41]. The WHI is a randomized placebo-controlled trial of 36,282 postmenopausal women given 400 IU vitamin D plus 1000 mg/d of elemental calcium or placebo. During approximately 7 years of follow-up, the incidence of colorectal cancer did not differ between women assigned to calcium plus vitamin D and those in placebo group (Hazard Ratio ¼ 1.08, 95% CI: 0.86–1.34) [41]. Inverse associations observed in observational studies and secondary prevention of calcium on adenomas shown in the trials seemed not to translate into a reduction in colorectal cancer. However, the results need to be interpreted
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with caution because of several important limitations of this study. First, the relatively high background intakes of calcium might have limited the ability to influence the rates of colorectal cancer further because in addition to 1000 mg/d study assigned amount, participants have mean total calcium intake of 1151 mg/d at enrolment (which increased further during the study) [41]. As shown in a pooled analysis of 10 cohort studies conducted in five countries, no further benefit of calcium on colorectal cancer was observed for calcium intake beyond 1000 mg/d [36]. Of note, calcium plus vitamin D supplementation was not protective among women with baseline calcium intake below 800 mg/d [41], which did not support this explanation, though power may have been limited. Moreover, the WHI trial may have been of insufficient duration because the epidemiological data on duration, although limited, indicates at least 10 years to see the effects of calcium and vitamin D [42]. When considering the whole body of literature on this subject, relatively consistent evidence supports a possible role for calcium in modestly reducing colon cancer risk, as supported by a 2009 meta-analysis of 26,335 colorectal cancer cases from 60 epidemiologic studies [37]. The summary RR for the highest vs. lowest intake of calcium was 0.76 (95% CI: 0.69–0.84, p value for heterogeneity ¼ 0.70, 10 cohort studies) for colon and 0.72 (95% CI: 0.60–0.86, p value for heterogeneity ¼ 0.92, 7 cohort studies) for rectum [37]. In summary, although confounding remains a possibility in the observation data, case–control studies and cohort studies had relatively consistent results compatible with decreased adenoma or colorectal cancer risk with increasing calcium intakes. In general, similar inverse associations were observed for both men and women. Future research is needed because less consistency remains regarding the sub-site differences (colon vs. rectum; proximal vs. distal colon), potential interaction with other nutrients such as phosphorous, magnesium, fat, fibre, and vitamin D intake, the optimal duration, and the dose–response relation. First, although sub-site differences between colon and rectum were observed in some studies [43,44], as mentioned in another brief review [45], the difference in risk with calcium intake was very slight between the colon and rectum. With respect to colon sub-site, a study of 87,998 women in the Nurses’ Health Study and 47,344 men in the Health Professionals Follow-up Study found an inverse association between higher total calcium intake (>1250 mg/day vs. 500 mg/day) and distal colon cancer (pooled RR ¼ 0.65, 95% CI: 0.43–0.98), but for proximal colon cancer (RR ¼ 1.14, 95% CI: 0.72– 1.81) [46]. Similarly, a pooled analysis of 10 cohort studies found that milk consumption (250 vs. <70 g/d) was associated with a lower risk of distal colon cancer (RR ¼ 0.73, 95% CI: 0.62–0.87) and rectal cancer (RR ¼ 0.80, 95% CI: 0.66–0.96) but not with proximal colon cancer (RR ¼ 0.99, 95% CI: 0.85–1.15) [36]. In contrast, total calcium was suggestively associated with a lower risk of proximal colon cancer (RR ¼ 0.57, 95% CI: 0.28–1.13) but not with distal colon cancer (RR ¼ 1.00, 95% CI: 0.47– 2.13) in the Cancer Prevention Study II Nutrition Cohort [24]. Interestingly, results from the Breast Cancer Detection Demonstration Project found similar non-significant inverse associations with proximal (>1270 vs. <472 mg/d, RR ¼ 0.68, 95% CI: 0.42–1.08) and distal colon cancer (RR ¼ 0.71, 95% CI: 0.46–1.26) [47]. Future research needs to clarify the potential difference in colon cancer sub-sites. Several dietary factors may potentially modify the calcium-colorectal cancer association. Experimental studies have indicated that the potential effect of calcium on colorectal cancer risk may be confined to animals fed with relatively high-fat diets [48,49]. Intakes of phosphorous and fibre might influence the absorption of calcium in the gut [50]. In addition, a recent case–control study indicated a possible interaction between calcium and magnesium intake in relation to risk of colorectal adenoma and hyperplastic polyps [51]. More importantly, calcium might interact with vitamin D because the absorption of calcium relies on adequate vitamin D. However, to separate the independent effect of each nutrient is challenging because they are generally correlated. In addition, relatively limited studies have examined the interaction between calcium with these dietary factors [28,50]. The potential interaction may not change the overall conclusion, that is, calcium may protect against colorectal cancer, but can help identify subgroups to maximize the beneficial effect of calcium. Lastly, in contrast to inverse association observed across the entire range of intake categories in many studies, a pooled analysis of 10 cohort studies conducted in five countries found that most of the risk reduction was achieved by attaining intakes of not more than 1000 mg/day [36], which suggests a threshold level above which further calcium may not be beneficial. More research to address the above-mentioned issues including determining the optimal dose and duration is warranted.
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Vitamin D and colorectal cancer As an essential nutrient, in addition to an important role in bone health and maintenance of calcium balance, vitamin D exerts various physiological functions. Experimental studies showed that many cell types including colorectal cells express vitamin D receptors and 1-a-hydroxylase, and are therefore capable to convert 25-hydroxyvitamin D (25(OH)D) into 1,25(OH)2 vitamin D, the most active metabolite of vitamin D [52]. Activation of these receptors by 1,25(OH)2D has anti-cancerous properties including increasing differentiation, apoptosis and inhibiting proliferation, invasiveness, angiogenesis, and metastatic potential [14,53,54]. A relationship between vitamin D and colorectal cancer was first hypothesized by Garland and Garland in 1980 based on the inverse association observed between UV-B radiation exposure and colon cancer risk [8]. At that time, little was known regarding the biology of vitamin D beyond effects on calcium absorption, and epidemiologic studies were sparse. Motivated largely by this study, substantial research has been conducted during the past three decades to assess the biological basis for this hypothesis and to investigate the potential effect of vitamin D status on subsequent risk of colorectal cancer or adenomas. These studies used various approaches to evaluate the vitamin D status, including using UV-B radiation as a proxy, direct measures of circulating 25(OH)D levels, dietary or supplemental intake, and predicted 25(OH)D score [55]. The evidence from these approaches used in the observational studies is summarized below. Ecological data using UV-B radiation as a surrogate UV-B radiation exposure has been the major source of vitamin D, probably accounting for the majority of vitamin D for most human populations. The UV-B abundance decreases substantially with increasing latitude. Thus, geographic location can be used as a surrogate for sun exposure. In 1980, Garland and Garland reported that the mortality from colon cancer was highest in states of the USA that had the lowest levels of solar radiation and hypothesized that the association could be due to vitamin D [8]. As summarized in the 2008 IARC report [56], many ecological studies found associations between increasing latitude and increasing colorectal cancer incidence or mortality. Despite the usefulness of ecologic data in generating hypothesis, causal inference from these ecological studies should be interpreted with caution because these studies cannot adequately control for confounding factors, which may also vary with latitude (e.g., physical activity or dietary habits). In addition, people’s exposure to UV-B radiation is influenced by the time spending outdoors, clothing habits and use of sunscreen. Vitamin D intakes in relation to colorectal cancer Numerous case–control and cohort studies have examined vitamin D intake (total, dietary, supplemental) in relation to risk of colorectal cancer or adenoma. These studies have been reviewed in detail [4,53,56–60] and have generally shown an inverse association between vitamin D intake and risk of colorectal cancer or adenoma. Many of the studies controlled for known or suspected risk factors for colorectal cancer, although the independent effects of vitamin D and calcium intakes might be difficult to separate entirely. A quantitative review by Gorham et al found that intake of 1000 IU/day of vitamin D, compared to <100 IU/day vitamin D, was associated with 50% lower risk [58]. A 2008 meta-analysis of 12 observational studies on vitamin D intake found an 11% marginally decreased risk of colorectal adenomas (highest vs. lowest quintile, RR ¼ 0.89; 95% CI: 0.78–1.02). The inverse associations appeared stronger for advanced adenoma (RR ¼ 0.77; 95% CI: 0.63–0.95), but the number of studies was small [59]. Results for the randomized control trials provide more definitive causal association, but the current data are sparse. To date, the largest study on this topic is the Women’s Health Initiative (WHI) [41]. As noted earlier, results from the WHI trial did not support a strong effect of calcium and vitamin D on colorectal cancer during 7 years of follow-up [41]. However, the results need to be interpreted with caution because of several important limitations of this study, as discussed earlier [61,62]. In brief, the dose of vitamin D supplement was relatively low because the expected increase of 25(OH)D for an increment of 400 IU/d would be w3 ng/mL. In the observational studies of 25(OH)D showing
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significant associations, the difference between high and low quintiles was generally 20 ng/mL or higher. Secondly, the compliance was suboptimal because only 50–60% of women took 80% of the scheduled supplementation. Moreover, some interactions may have been missed in the original analysis. Re-analysis of WHI trial showed that calcium plus vitamin D supplementation among women concurrently assigned to oestrogen therapies were associated an increased risk (Hazard Ratio ¼ 1.50, 95% CI: 0.96–2.33). Among women concurrently assigned to placebos arms of the oestrogen trials, calcium plus vitamin D indicated suggested benefits (Hazard Ratio ¼ 0.71, 95% CI: 0.46–1.09) (p for interaction ¼ 0.018) [63]. Thus, the WHI trial was probably inadequate in testing the vitamin D and colorectal cancer hypothesis. It is also possible that vitamin D supplement could have more impact on cancer mortality than on cancer incidence. A meta-analysis of 18 randomized trials including 57,311 participants on intakes of vitamin D and calcium supplements found that intake of ordinary doses of vitamin D, but not calcium, supplements (trial size-adjusted mean daily vitamin D dose was 528 IU, comparable with the dose in WHI) seems to be associated with reduction in total mortality rates. The summary relative risk for all-cause mortality was 0.93 (95% CI: 0.87–0.99) [64]. Pre-diagnostic serum levels of 25(OH)D in relation to colorectal cancer UV-B converts 7-dehydrocholesterol into vitamin D in the skin and then hydroxylated in the liver to produce 25(OH)D, which can be converted by 1-a-hydroxylase into 1,25(OH)2D [53]. Circulating 1, 25(OH)2D is tightly regulated largely by renal 1-a-hydroxylase activity and does not typically reflect the vitamin D status, except at extreme deficiency [53]. In contrast, 25(OH)D is less tightly controlled and accounts not only for skin exposure to UV-B radiation, but also for total vitamin D intake and for factors such as skin pigmentation, physical activity and adiposity [53]. In addition, 25(OH)D has about 2–3 weeks of half-life (t1/2) in the circulatory system, and thus can provide a fairly good indicator of longterm vitamin D status. Studies that have examined 25(OH)D levels prospectively in relation to subsequent risk of colorectal cancer or adenoma have generally supported an inverse association. Among the largest studies are the Nurses’ Health Study (NHS) [65] and the European Prospective Investigation into Cancer (EPIC) study [66]. The NHS study, based on 193 incident colorectal cancer cases and with adjustment for established or potential confounding factors including physical activity and obesity, found a monotonic reduction in risk across quintiles of 25(OH)D concentration, with an RR of 0.53 (95% CI: 0.27–1.04) for highest vs. lowest quintile [65]. In the EPIC study, 1,248 colorectal cancer cases were identified and matched to 1248 control subjects by age, gender, study center, follow-up time, fasting status, and time of day of blood donation [66]. Compared to a serum 25(OH)D concentration of 20–29 ng/mL, lower levels of a 25(OH)D concentration were associated with an increase in colorectal cancer risk (<10 ng/mL: OR ¼ 1.32, 95% CI: 0.87–2.01; 10–19 ng/mL: OR ¼ 1.28, 95% CI: 1.05– 1.56), whereas higher concentrations were associated with a decreased risk of colorectal cancer (30– 39 ng/mL: OR ¼ 0.88, 95% CI: 0.68–1.13; 40 ng/mL: RR ¼ 0.77, 95% CI: 0.56–1.06) [66]. Pooled analyses of studies on 25(OH)D levels confirm a significant inverse association [58,67,68]. As shown in the most recent 2010 meta-analysis of all current studies, based on 1,822 colon and 868 rectal cancers, increasing circulating 25(OH)D levels was associated with a significant reduction in colorectal cancer (top vs. bottom quantiles, OR ¼ 0.66, 95% CI: 0.54–0.81) [67]. The inverse association was stronger for rectal cancer (OR ¼ 0.50, 95% CI: 0.28–0.88) than colon cancer (OR ¼ 0.77, 95% CI: 0.56– 1.07) but no significant difference was noted (p value for difference between colon and rectal cancer ¼ 0.20) [67]. This association is further supported by a decrease in colonic adenomas, precursors to colorectal cancer, with higher serum 25(OH)D. A meta-analysis published in 2008 showed that 25(OH)D was inversely associated with risk of colorectal adenomas (high vs. low circulating levels, RR ¼ 0.70, 95% CI: 0.56–0.87) [59]. The inverse associations appeared stronger for advanced adenoma (RR ¼ 0.64, 95% CI: 0.45–0.90), but the number of studies was small [59]. Taken together, observational studies provide evidence of a decreased risk of colorectal cancer or adenoma associated with higher serum 25(OH)D and controlling for multiple covariates had little influence on the findings. Although optimal 25(OH)D levels to reduce colorectal cancer risk needs to be established in future studies, the dose–response appears linear up to a 25(OH)D level of at least 30 ng/ mL. The results are somewhat inconsistent in determining whether the association is stronger for colon cancer or for rectal cancer, possibly due to small numbers.
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A strength of using 25(OH)D levels includes examining prior to diagnosis the best single indicator of vitamin D status with subsequent risk, which minimizes potential reverse causation. Confounding can be reasonably controlled in the multivariable models through adjusting factors such as body mass index and physical activity. A limitation is that, although the t1/2 in the circulation of w2–3 week is fairly reasonable, the correlation with long-term vitamin D status is unclear. Some of the variability picked up by 25(OH)D levels might be due to relatively recent exposures, and may not reflect long-term status. Predicted 25(OH)D score in relation to colorectal cancer As noted earlier, circulating 25(OH)D can be influenced by several factors. Thus, using known predictors of 25(OH)D level can derive a predicted 25(OH)D score. This approach has been used in the Health Professionals Follow-up Study [69]. With a sample of 1095 men in this cohort who had circulating 25(OH)D levels measured, the authors first used a multiple linear regression to develop a predicted 25(OH)D score based on geographical region, skin pigmentation, dietary intake, supplement intake, body mass index, and leisure time physical activity (a surrogate of potential exposure to sunlight UV-B). The score was then calculated for each of the approximately 47,000 cohort members and was examined prospectively in relation to subsequent risk of cancer incidence and mortality. For colorectal cancer, based on 691 cases diagnosed from 1986 to 2000, a predicted 10 ng/mL increment in 25(OH)D was associated with a reduced risk (RR ¼ 0.63, 95% CI: 0.48–0.83). This association persisted when controlled for body mass index or physical activity. Summary Overall, the current epidemiologic evidence supports a beneficial role of calcium and vitamin D in colorectal carcinogenesis [4,56,60]. Because of the limitations of observational studies [70], these data do not prove a cause–effect relation, but they are strongly suggestive of such an effect. Confounding seem unlikely entirely account for all these associations. In addition, these associations were supported by numerous in vitro, animal and clinical studies that indicate that calcium and vitamin D may have anti-cancerous benefits against colorectal cancer and possibly other cancers. The optimal dose and duration of calcium on colorectal cancer remains to be established. Similarly for vitamin D, in the US, the current recommended daily vitamin D intake (e.g., 600–800 depending on age) [71] may not meet the optimal requirement [72,73], especially of certain groups of people at higher risk of vitamin D deficiency. These people include individuals who live in regions with low sunlight intensity, who avoid sunlight or thoroughly use sunscreen, who have darker skin, who are old, who live in a nursing home, and who are overweight or obese [60]. Given that few foods contain vitamin D, supplements are the simplest, safest way to get vitamin D. For most people, solar UV-B exposure remains the major source of vitamin D. However, unprotected sun exposure is commonly discouraged because of the concerns of skin damage and cancer. Given the potential benefits from these nutrients against colorectal cancer, optimal dose and duration needs to be considered in formulating recommendations and guidelines.
Practice points Although cause–effect is not definitely proven, the current overall epidemiologic evidence supports significant inverse associations between calcium and vitamin D and colorectal cancer risk. Although more research on optimal dose for both calcium and vitamin D is warranted, intake of calcium of not more than 1000 mg/d and vitamin D of 1000–2000 IU/d, achieving a level of at least 30 ng/mL, appears important for colorectal cancer prevention.
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Research agenda The optimal dose and duration of the calcium and vitamin D on colorectal cancer needs to be elucidated; in particular, future randomized control trials of higher doses of calcium and vitamin D with longer duration might provide more insights of these nutrients on colorectal cancer prevention. The potential interaction of calcium with phosphorous, magnesium, fat, retinol, vitamin D and hormone replace therapy (HRT) merits attention. Whether the effect of calcium on colorectal cancer differs by sub-sites (e.g., colon vs. rectum, proximal colon vs. distal colon) needs to be clarified. The potential interaction of vitamin D status with intakes of calcium and retinol needs to be established. Research of vitamin D and colorectal cancer risk in ethnic groups other than whites are warranted. The effect of calcium and vitamin D on colorectal cancer survival and mortality requires more research.
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