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In this issue of the Journal, Grau et al. (1) present the results of a study investigating whether calcium supplementation, vitamin D, and vitamin D receptor (VDR) polymorphisms—alone or in combination—affect the risk of colorectal adenoma recurrence. This study provides the framework for consideration of issues related to the reported results, as well as to future cancer epidemiologic studies. These issues include 1) the need for further examination of the protective benefits of calcium and vitamin D on colorectal cancer and its precursors, 2) the necessity of and potential approaches for epidemiologic studies that address both genetic and environmental factors, and 3) the public health implications of a protective effect of calcium and vitamin D on the risk of colorectal neoplasia. In Grau et al. (1), subjects were participants from the Calcium Polyp Prevention Study (2), a Phase III trial in which a statistically significantly reduced risk for adenoma recurrence was observed with supplementation of 1200 mg/day of calcium over 4 years as compared with placebo. Elaborating on these findings, Grau et al. observed that higher serum 25-hydroxyvitamin D (25-OHD) levels were associated with a protective effect on colorectal adenoma recurrence in the calcium-supplemented group but not in the placebo arm. 25-OHD is the precursor to 1,25-dihydroxyvitamin D (1,25-(OH)2D3), a hormone that has been demonstrated to have anti-proliferative and prodifferentiating effects in colon cancer cell lines (3–5). The mechanism by which the precursor 25-OHD might have protective effects among individuals supplemented with calcium is unclear, because calcium would ultimately tend to decrease the production of 1,25-(OH)2D3. Perhaps the presence of adequate calcium allows for the diversion of 1,25-(OH)2D3 to antineoplastic activities. Despite this uncertainty, the work of Grau et al. adds to the evidence from other published reports (6–8), which have demonstrated repeatedly that calcium and vitamin D modify each other’s effects. These observations, as well as the intricate biologic association between calcium and vitamin D, highlight the importance of including both nutrients as exposure variables in future epidemiologic studies. Without consideration of these nutrients together, it will be difficult to elucidate the mechanism of effect or to make recommendations regarding the appropriate intake of either. Another aspect of interest in the current work was the assessment of the association between TaqI or FokI VDR polymorphisms and risk of adenoma recurrence, either independently or in conjunction with vitamin D or calcium. Functional studies have revealed that specific polymorphic alleles may confer greater transcriptional activity than other alleles (9). Some epidemiologic studies (10,11) have reported associations between these polymorphisms and risk of colorectal adenoma and/or cancer. However, the current work revealed no association of either polymorphism with adenoma recurrence, results that are in agreement with those of Peters et al. (6). Discrepancies among association studies of polymorphic variants have been a topic of great recent interest. Possible explanations for the differences include the composition of the study populations, undetected gene–environment interactions, or laboratory error. Furthermore, studies of adenoma recurrence have their own limitations that need to be taken into account (12), including assessment of surrogate endpoints rather than cancer, short length of followup, and the inclusion of only individuals with a history of adenomatous polyps. Thus, clarification of associations between calcium, vitamin D, and VDR variants in additional studies with adequate statistical power is warranted. The observation of a protective effect of calcium and vitamin D on colorectal adenoma recurrence in the current work leads to the question of how to apply this information to the prevention of colorectal cancer. The evidence presented in this and other articles indicates that calcium and vitamin D may be important at several stages of carcinogenesis, presenting an interesting conundrum regarding recommended intake. Because milk is one of the primary sources of both calcium and vitamin D, should increased consumption of dairy products be advised? The possibility of a positive association between prostate cancer risk and consumption of dairy products (13), as well as the problem of lactose intolerance, militates against this approach. An alternative approach, suggested by Tangpricha et al. (14), involves vitamin D fortification of orange juice, which often has calcium added; the use of multivitamins containing vitamin D may also be an option. Although a recommendation for brief, daily sun exposure may be in order (15), such a recommendation clearly comes with its own set of challenges with regard to optimal dose and duration because the ability to endogenously synthesize vitamin D will vary by age, latitude, skin pigmentation, and use of sunscreen (16). It will be difficult to make recommendations until more precise information is available regarding the interaction of these nutrients with susceptibility genes, other nutrients, and the environment. Moreover, although an association of calcium with reduced risk of colorectal neoplasia has been observed in both observational and intervention studies, it must be emphasized that the effect is modest. Therefore, it may currently be more beneficial to focus colorectal cancer prevention efforts on those factors for which higher risk reduction can

Research and Public Health Implications of the Intricate Relationship Between Calcium and Vitamin D in the Prevention of Colorectal Neoplasia