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American Journal of Epidemiology Advance Access originally published online on March 22, 2007
American Journal of Epidemiology 2007 165(10):1178-1186; doi:10.1093/aje/kwm026
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American Journal of Epidemiology Copyright © 2007 by the Johns Hopkins Bloomberg School of Public Health All rights reserved; printed in U.S.A.

ORIGINAL CONTRIBUTIONS

Calcium and Vitamin D Intakes in Relation to Risk of Distal Colorectal Adenoma in Women

Kyungwon Oh1, Walter C. Willett2,3,4, Kana Wu2, Charles S. Fuchs5 and Edward L. Giovannucci2,3,4

1 Division of Chronic Disease Surveillance, Korea Centers for Disease Control and Prevention, Seoul, Korea
2 Department of Nutrition, Harvard School of Public Health, Boston, MA
3 Department of Epidemiology, Harvard School of Public Health, Boston, MA
4 Channing Laboratory, Department of Medicine, Harvard Medical School and Brigham and Women's Hospital, Boston, MA
5 Department of Adult Oncology, Dana Farber Cancer Institute, Boston, MA

Correspondence to Dr. Edward L. Giovannucci, Department of Nutrition, Harvard School of Public Health, 665 Huntington Avenue, Boston, MA 02115 (e-mail: edward.giovannucci{at}channing.harvard.edu).

Received for publication June 26, 2006. Accepted for publication November 1, 2006.


   ABSTRACT
TOP
 ABSTRACT
INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 References
 
The authors examined intakes of calcium and vitamin D, and interaction with retinol, in relation to risk of adenoma of the distal colon or rectum among 48,115 US women who were free of colorectal cancer or polyps, completed a food frequency questionnaire in 1980, and underwent endoscopy by 2002. They documented 2,747 cases of adenoma (1,064 large, 1,531 small, 2,085 distal colon, and 779 rectal). Total calcium intake was weakly associated with distal colorectal adenoma risk (multivariable relative risk (RR) for extreme quintiles = 0.88, 95% confidence interval (CI): 0.74, 1.04; ptrend = 0.06), particularly for large adenoma (RR = 0.73, 95% CI: 0.56, 0.96; ptrend = 0.02). Total vitamin D intake was weakly associated with reduced risk of distal colorectal adenoma (RR = 0.79, 95% CI: 0.63, 0.99; ptrend = 0.07), but more strongly with distal colon adenoma risk (RR = 0.67, 95% CI: 0.52, 0.87; ptrend = 0.004). The combinations of high vitamin D and low retinol intake (RR = 0.55, 95% CI: 0.28, 1.10) further decreased risk of distal colorectal adenoma when compared with the opposite extreme. Higher total calcium and vitamin D intakes were associated with reduced risk, and the actions of vitamin D may be attenuated by high retinol intake.

adenoma; calcium; vitamin D

Abbreviations: CI, confidence interval; FFQ, food frequency questionnaire; RR, relative risk; 25-(OH)D, 25-hydroxyvitamin D


   INTRODUCTION
TOP
 ABSTRACT
 INTRODUCTION
MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 References
 
Calcium intake has been proposed to reduce colorectal cancer risk by reducing cell proliferation and promoting cell differentiation in colonic cells (1, 2). In an earlier review and meta-analysis, calcium intake was not associated with reduced risk of colorectal cancer (3, 4). However, more recently, a pooled analysis (5) and epidemiologic studies (6–9) showed that calcium intake was inversely related to colorectal cancer or adenoma risk. Additionally, in randomized clinical trials (10–12), calcium supplementation has reduced adenoma risk.

Vitamin D may reduce colorectal cancer risk through effects on cell differentiation and proliferation, apoptosis, and inhibition of angiogenesis (13–17). Most studies suggest that total (dietary plus supplemental) vitamin D intake is associated with reduced risk of colorectal cancer (18–23) and adenoma (24); however, if only dietary vitamin D intake is considered, significant inverse associations are observed in only a few studies (18, 21). In addition, in some studies (9, 10, 25, 26), but not all (7, 11, 22, 27), associations between calcium and vitamin D intakes and risks of colorectal cancer or adenoma recurrence have been modified by other risk factors. In particular, higher retinol intake may antagonize the actions of vitamin D because of competition for retinoid X receptors, which are required for vitamin D receptor function (13, 28). However, to our knowledge, whether the relations between calcium or vitamin D intake and distal colorectal adenoma risk are modified by retinol intake has not been examined in detail.

We previously reported the relations of calcium and vitamin D intakes with adenoma risk in the Nurses' Health Study (27). In the present study, we extended this follow-up to 22 years and 2,747 adenoma cases to examine calcium and vitamin D intakes in relation to distal colorectal adenoma risk, and to investigate whether these relations are modified by retinol intake.


   MATERIALS AND METHODS
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
RESULTS
 DISCUSSION
 References
 
Study population
The Nurses' Health Study was initiated in 1976 when 121,700 female registered nurses in the United States aged 30–55 years completed a mailed questionnaire about their lifestyle factors and medical history. Every 2 years, a follow-up questionnaire was sent to these women to update their information and identify newly diagnosed major illnesses. A food frequency questionnaire (FFQ) was first administered in 1980. Deaths in the cohort were ascertained by reports from family members, the postal service, and a search of the National Death Index. We estimate that more than 98 percent of deaths were reported to us through these sources (29). In this analysis, we included participants who returned the 1980 FFQ and who had no diagnosis of cancer (excluding nonmelanoma skin cancer), inflammatory bowel disease, familial polyposis, or colorectal polyp prior to 1980. To reduce the potential for detection bias, we restricted the analysis to women who reported having undergone at least one colonoscopy or sigmoidoscopy between 1980 and 2002. Over 90 percent of the adenomas were diagnosed during endoscopic procedures for screening or for unrelated gastrointestinal conditions. Sigmoidoscopies do not examine the proximal colon; thus, we analyzed only adenomas of the distal colorectum to prevent misclassification and potential detection bias.

A total of 48,115 women met all the criteria for analysis. This study and analyses were approved by the institutional review boards of the Brigham and Women's Hospital and the Harvard School of Public Health.

Ascertainment of colorectal adenoma
The ascertainment of adenoma cases and controls has been described previously (30). On each questionnaire, we inquired whether participants underwent sigmoidoscopy or colonoscopy; the indication for the procedure; whether colon or rectal polyps had been diagnosed; and, if so, the date of diagnosis. When a participant reported a diagnosis of colorectal adenoma, we sought her permission to obtain pertinent medical records and pathology reports. Study investigators, blinded to the exposure information, reviewed the medical records to record the histologic type, the anatomic location, and the size of reported polyps. We considered for analysis only those cases of distal colorectal adenoma confirmed by histopathologic report (including carcinoma in situ), irrespective of whether the women also had adenomas proximal to the descending colon or had hyperplastic polyps. Eligible for analysis were 2,747 distal colorectal, 2,085 distal colon, and 779 rectal adenoma cases. A total of 1,064 women were classified as having large adenomas (≥1 cm) and 1,531 as having small adenomas; information on size was not available for 152 cases.

Dietary assessment
The semiquantitative FFQ used in 1980 included 61 items (31). A common unit or portion size for each food was specified, and each woman was asked how often, on average, during the previous year she had consumed that amount of the item. Nine response options were given, ranging from "almost never" to "six or more times per day." In 1980, the questionnaire included seven specific dairy foods: skim or low-fat milk, whole milk, ice cream, yogurt, cottage cheese, hard cheese, and butter. In 1984, a second dietary questionnaire, expanded to 116 items, included these seven items and four more: cream, sour cream, sherbet or ice milk, and cream cheese. Similar dietary questionnaires were administered in 1986, 1990, 1994, and 1998. The average daily intake of nutrients was calculated by multiplying the frequency of consumption of each item by its nutrient content and summing the nutrient contributions of all foods. Multivitamin and mineral supplement use (dose, frequency, and duration) was also assessed. Total calcium, vitamin D, retinol, and folate intake included the intakes from foods and multivitamins and specific supplements.

The reproducibility and validity of the FFQ in a sample of this cohort have been described previously (31, 32). Correlation coefficients between intakes from 1980 dietary records and the 1984 FFQ were 0.56 for energy-adjusted total calcium and 0.51 for dietary calcium. In a parallel study of men (33), the questionnaire provided a reasonable measure of retinol intake; correlation coefficients between intakes from 1986 dietary records and the 1986 FFQ were 0.75 for energy-adjusted total retinol and 0.55 for dietary retinol (33, 34). At the time of the original validation study, diet record values for vitamin D were not available. However, the major sources of vitamin D (dairy products, especially low-fat or skim milk) were measured reasonably well and have been shown to predict plasma vitamin D levels (35). Pearson correlation coefficients between dietary record data and the 1984 FFQ were 0.79 for skim or low-fat milk and 0.62 for whole milk (32).

Statistical analysis
The endpoint was prevalence of distal colorectal adenoma at endoscopy. Controls consisted of women who did not have an adenoma of the distal colorectum at endoscopy, irrespective of whether they had adenomas of the proximal colon or had hyperplastic polyps. In additional analyses, we assessed the adenomas by size because large adenomas (≥1 cm) may be more likely to reflect the influence of a tumor promoter, and we also separately analyzed adenomas of the distal colon and rectum. We divided women into five categories according to quintiles of total calcium and vitamin D intakes. Calcium and vitamin D intakes were considered with and without intake of supplements. In multivariable analysis, the relative risks estimated by the odds ratios were simultaneously adjusted for potential confounding variables by using multiple logistic regression (SAS Institute, Inc., Cary, North Carolina). To best represent the participants' long-term dietary patterns during follow-up, we used the average method based on all available measurements of diet up to the beginning of each 2-year interval. For covariates, we used established and suspected risk factors, including age at endoscopy; body mass index; pack-years of smoking; alcohol consumption; family history of colorectal cancer; history of previous endoscopy; postmenopausal hormone use; regular aspirin use; vigorous physical activity; energy intake; energy-adjusted intakes of fiber, folate, phosphorus, and retinol; and red meat intake, as well as indication for endoscopy. Tests for trend were conducted by assigning the median value to each quintile and modeling this value as a continuous variable. The log-likelihood ratio test was used to assess the significance of interaction terms. We also conducted analyses stratified by dietary and nondietary risk factors.


   RESULTS
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
DISCUSSION
 References
 
At baseline in 1980, women with a high intake of total calcium were older and had a higher prevalence of vigorous exercise, postmenopausal hormone use, multivitamin use, and aspirin use, but they had a lower prevalence of smoking (table 1). Women with a high intake of total calcium had higher intakes of phosphorus, folate, and fiber but lower intakes of red meat and alcohol. A similar pattern was observed for total vitamin D intake.


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  		TABLE 1. Age-standardized characteristics according to quintiles of total calcium and total vitamin D intake by US women in 1980

 
Total calcium intake was associated with reduced risk of distal colorectal adenoma when adjusted for age only. After adjustment for dietary and nondietary risk factors, these associations were weakened (relative risk (RR) = 0.88, 95 percent confidence interval (CI): 0.74, 1.04; ptrend = 0.06) (table 2). We found a statistically significant inverse association between total calcium intake and large-adenoma risk (RR = 0.73, 95 percent CI: 0.56, 0.96; ptrend = 0.02). However, there were no appreciable associations for risks of small, distal colon, or rectal adenoma. To assess more extremes of total calcium intake, we categorized this variable into deciles. The relative risk of colorectal adenoma for the highest (>1,451 mg/day) versus the lowest (≤584 mg/day) deciles was 0.91 (95 percent CI: 0.73, 1.14; ptrend = 0.07), and the relative risk of large adenoma was 0.79 (95 percent CI: 0.55, 1.13; ptrend = 0.05). When we examined absolute intake categories, the results were similar to those from the quintiles or deciles analyses (RR for ≥1,200 mg/day vs. <600 mg/day (referent) = 0.93, 95 percent CI: 0.78, 1.12). In addition, dietary calcium intake alone was not associated with distal colorectal adenoma risk in analyses of quintiles (median intakes for each quintile = 489.3 mg, 610.3 mg, 709.3 mg, 824.8 mg, and 1,025.0 mg) or deciles or absolute intake (data not shown).


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  		TABLE 2. Relative risks (95% confidence intervals)* of distal colorectal adenoma according to quintiles of total calcium intake among women in the Nurses' Health Study, United States, 1980–2002

 
As shown in table 3, a significant inverse relation between total vitamin D intake and distal colorectal adenoma risk was observed in age-adjusted analyses. However, in multivariable analyses, the association of total vitamin D intake was attenuated (RR = 0.79, 95 percent CI: 0.63, 0.99; ptrend = 0.07). Total vitamin D intake was significantly and inversely associated with distal colon adenoma risk (RR = 0.67, 95 percent CI: 0.52, 0.87; ptrend = 0.004), but not with large or small adenoma or with rectal adenoma separately. Deciles analyses of total vitamin D revealed no statistically significant relation to distal colorectal adenoma, but a significant association was observed in the distal colon (RR of distal colon adenoma for the highest (>601 IU/day) vs. the lowest (≤135 IU/day) deciles = 0.74, 95 percent CI: 0.53, 1.02; ptrend = 0.03). In addition, when we evaluated quintiles (median intakes for each quintile = 96.2 IU, 144.3 IU, 182.3 IU, 225.8 IU, and 299.2 IU) or deciles of dietary vitamin D alone, no significant associations were found for risks of distal colorectal adenoma, large or small adenoma, and distal colon or rectal adenoma. We also conducted analyses by using the baseline diet (the 1980 questionnaire), but the relations of total calcium and total vitamin D intake to distal colorectal adenoma risks were not statistically significant (data not shown).


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  		TABLE 3. Relative risks (95% confidence intervals)* of distal colorectal adenoma according to quintiles of total vitamin D intake among women in the Nurses' Health Study, United States, 1980–2002

 
Furthermore, we examined whether associations for total calcium intake and vitamin D were modified by other risk factors. The null or weak relations between total calcium intake and distal colorectal adenoma risk were consistent across strata of intakes of total fat and fiber as well as age (data not shown). However, a suggestive inverse association between total calcium intake and adenoma risk was found among women with higher vitamin D intake (RR for the combination of high total calcium and high total vitamin D intake compared with the opposite extreme = 0.75, 95 percent CI: 0.61, 0.92, test for interaction = 0.27) (table 4), and total calcium intake was inversely associated with risk among regular aspirin users (test for interaction = 0.07, RR = 0.71, 95 percent CI: 0.51, 0.97; ptrend = 0.03). The associations between total vitamin D intake and distal colorectal adenoma risk did not differ by calcium intake and aspirin use, and they were only suggestively stronger among women older than age 65 years (test for interaction = 0.61, RR = 0.69, 95 percent CI: 0.50, 0.95; ptrend = 0.06). However, when we analyzed tertiles of total vitamin D and total calcium intake, the relative risk for the combination of high vitamin D and high calcium compared with low vitamin D and low calcium was 0.75 (95 percent CI: 0.61, 0.92).


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  		TABLE 4. Relative risks (95% confidence intervals)* of distal colorectal adenoma by different levels of calcium and vitamin D intake among women in the Nurses' Health Study, United States, 1980–2002

 
We examined the joint association between total vitamin D and retinol intakes (table 5). The inverse association between total vitamin D intake and colorectal adenoma risk appeared to be modified by retinol intake (test for interaction = 0.02), and, in this analysis, retinol intake was related to increased risk of colorectal adenoma (RR for >6,202 IU/day vs. ≤1,989 IU/day (referent) = 1.42, 95 percent CI: 1.19, 1.69); the relative risk for the combination of high total vitamin D and low retinol intake compared with the opposite extreme was 0.55 (95 percent CI: 0.28, 1.10). However, if retinol intake was high, higher vitamin D intake was not associated with lower risk of adenoma (RR = 1.10, 95 percent CI: 0.82, 1.49). When we conducted stratified analyses by strata of retinol, total vitamin D intake was inversely associated with adenoma risk among women in the lowest tertile of retinol intake (ptrend = 0.003) and in the middle tertile of retinol (ptrend = 0.01), but not among those in the top tertile of retinol intake (ptrend = 0.84).


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  		TABLE 5. Relative risks (95% confidence intervals)* of distal colorectal adenoma by different levels of vitamin D and retinol intake among women in the Nurses' Health Study, United States, 1980–2002

 
We examined whether the associations of vitamin D and retinol intake varied by adenoma size, location, multiplicity, and histology. Suggestive associations were observed for small adenomas and distal colon adenomas; when compared with those for low vitamin D and high retinol intake, the relative risks for the combination of high vitamin D and low retinol intake were 0.94 (95 percent CI: 0.38, 2.37) for large adenomas, 0.30 (95 percent CI: 0.09, 0.98) for small adenomas, 0.34 (95 percent CI: 0.13, 0.86) for distal colon adenomas, and 1.18 (95 percent CI: 0.43, 3.27) for rectal adenomas. However, we found little difference in the risks by histologic type; the relative risks for the combination of high vitamin D and low retinol intake were 0.52 (95 percent CI: 0.18, 1.51) for tubular adenomas (n = 1,312 cases) and 0.63 (95 percent CI: 0.14, 2.86) for tubular-villous or villous adenomas (n = 674 cases).

Vitamin D intake was more strongly related to distal colorectal adenoma risk among women older than age 65 years, although the interactions were not statistically significant (p = 0.61). We thus examined whether hormone use may account for the stronger association for older women (test for interaction between vitamin D intake and hormone use = 0.07). No appreciable association was observed for premenopausal women or for current users of postmenopausal hormones, but adenoma risk was significantly reduced among past users of postmenopausal hormones (n = 683 cases; RR = 0.56, 95 percent CI: 0.36, 0.89; ptrend = 0.03) and suggestively so among never users (n = 790 cases; RR = 0.82, 95 percent CI: 0.54, 1.27; ptrend = 0.37).


   DISCUSSION
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
References
 
In this large, prospective study, higher intakes of total calcium and vitamin D were associated with reduced risk of distal colorectal adenoma. In addition, high retinol intake negated the apparent benefit of high vitamin D intake.

The associations of calcium intake with colorectal cancer or adenoma risk have been inconsistent; some studies (18, 20, 23, 27, 36–41) and a meta-analysis (3) reported that calcium intake was not significantly associated with risk. However, in a pooled analysis (5), total calcium intake of up to approximately 1,000 mg/day was significantly inversely associated with colorectal cancer risk, with little benefit for greater intakes. More recently, Flood et al. (7) reported that both dietary and total calcium intake were inversely associated with colorectal cancer risk. In clinical trials (10, 11) and a meta-analysis (12), calcium supplementation was also related to reduced adenoma recurrence. The relation of calcium intake to distal colorectal adenoma risk in our study was stronger for large adenomas (RR = 0.73, 95 percent CI: 0.56, 0.96; ptrend = 0.02). Likewise, in the Calcium Polyp Prevention Study (10), a protective effect of higher calcium intake was more pronounced for advanced polyps.

An inverse association between total vitamin D intake and colorectal cancer has more consistently been seen in epidemiologic studies (18–24). However, most studies that have taken into account only dietary vitamin D intake (22, 23, 25, 36, 39, 40, 42, 43), although not all (18, 21), have not found a significantly reduced risk of colorectal cancer or adenoma. Consistent with the results of many studies, total vitamin D intake was inversely associated with distal colorectal adenoma risk, whereas dietary vitamin D intake was not related to the risk in our study. In addition, a significant inverse association was observed for risk of distal colon adenoma but not for rectal adenoma. Some studies reported that an inverse association with vitamin D intake was more pronounced for distal colon cancer (19, 22), whereas a stronger relation was observed with rectal cancer or adenoma in other studies (18, 27). In our prior report based on follow-up to 1988 only, total calcium intake was not significantly related to lower risk of distal colorectal adenoma, and total vitamin D intake was only weakly associated with lower risk (27).

Differences in the observed relations of total calcium and vitamin D intakes may be due to greater power, better assessment of long-term diet through use of multiple questionnaires, and adjustment of vitamin D intake for retinol intake. However, in a recent clinical trial (44), daily supplementation of 1,000 mg of calcium with 400 IU of vitamin D had no effect on the incidence of colorectal cancer among postmenopausal women, suggesting either that the supplementation may be effective primarily for preventing earlier stages of the disease, that the dose used (especially, vitamin D) was too low to provide maximal benefits in preventing cancer, or that calcium and vitamin D in observational studies are confounded. Furthermore, in that trial, a suggestive inverse association was observed among women in the placebo group of the concurrent estrogen and/or progesterone component of that study. Similarly, in our study, vitamin D was associated with lower adenoma risk in only postmenopausal women not on estrogen replacement therapy.

Calcium intake may protect against colorectal adenoma and cancer by binding bile and fatty acids in the lumen of the colon and rectum, by increasing apoptosis, and by inhibiting the proliferation of the colonic epithelial cells (2, 45–48). Vitamin D intake may influence colorectal carcinogenesis through its effects on cell proliferation and differentiation, apoptosis, cell cycle regulation, metastasis, and angiogenesis (15, 17). Holt et al. (16) reported that 25-hydroxyvitamin D (25-(OH)D) levels were inversely associated with colorectal epithelial cell proliferation. In addition, 25-(OH)D levels were positively associated with apoptosis rates in the colorectal epithelium in adenoma-free patients (45).

In one study (10), the effects of calcium supplementation on adenoma risk were stronger among participants with high fiber intake and with low total fat intake. Several studies also showed that the effect of calcium was modified by intakes of phosphorus (22), fat (26), and fiber (25), but other studies did not support these findings (22, 24, 27, 42, 49, 50). Calcium and vitamin D have been suggested to act synergistically to protect against colorectal cancer (9). In a recent study (51), 25-(OH)D levels were associated with reduced risk of recurrent adenoma among only those women receiving a calcium supplement, and a case-control study (52) reported that an inverse association of 25-(OH)D levels with colorectal adenoma risk was stronger among those with a higher calcium intake. In our analyses, little relation between calcium intake and distal colorectal adenoma risk was found across strata of intakes of total fat, fiber, and vitamin D except for a suggestively stronger association among those with a higher vitamin D intake. Similarly, the inverse association between vitamin D intake and adenoma risk did not differ across strata of calcium intake.

Higher retinol intake has been hypothesized to have a potential antagonistic effect on vitamin D actions. The complex of vitamin D receptor/1,25(OH)2D interacts with the retinoid X receptor to form a 1,25(OH)2D/vitamin D receptor/retinoid X receptor heterodimer complex. Retinoic acid receptors also function as heterodimers with retinoid X receptors proteins. Because vitamin D and retinol require retinoid X receptor proteins for their actions, a high level of retinol intake could potentially antagonize the actions of vitamin D (13, 28). In our study, the relation of vitamin D intake to adenoma risk was most pronounced among women with a lower retinol intake, suggesting that a higher retinol intake, approximately ≥4,800 IU/day, counters the beneficial effect of vitamin D on distal colorectal adenoma risk, particularly for colon adenoma. This finding could be due to chance and needs to be confirmed, but a similar pattern was observed for hip fracture risk in this cohort (53).

Regular aspirin use reduces colorectal adenoma and cancer risks in healthy men and women (54, 55). When analyses were stratified by aspirin use, the inverse association between total calcium intake and distal colorectal adenoma risk was stronger among regular aspirin users (test for interaction = 0.07). Consistent with previous studies that have examined whether the relation between 25(OH)D levels and risks of colorectal cancer (56) or adenoma (43, 57) is modified by age, we found that vitamin D intake was more strongly related to distal colorectal adenoma risk among women older than age 65 years, especially those not currently using postmenopausal hormones. These findings suggest that benefits for vitamin D may be stronger in women with low estrogen levels. An interaction between hormonal therapy and the vitamin D axis is biologically plausible because hormonal therapy increases hydroxylation of 25(OH)D to 1,25(OH)2D (58).

Because most screening endoscopies performed in our cohort were sigmoidoscopies rather than colonoscopies, we restricted our analysis to adenomas of the distal colon and rectum to minimize detection bias. Nonetheless, we examined the possibility that calcium and vitamin D may have a differential effect on proximal adenomas. Calcium intake was inversely associated with risk of proximal adenomas; multivariable relative risks for quintiles of calcium intake were 1 (referent), 1.02, 0.98, 0.91, and 0.75 (95 percent: 0.56, 1.00; ptrend = 0.03). However, vitamin D intake was not related to the risk; multivariable relative risks for quintiles of vitamin D intake were 1 (referent), 1.02, 1.30, 1.32, and 1.18 (95 percent CI: 0.80, 1.76; ptrend = 0.36).

This study included 2,747 cases of distal colorectal adenoma; dietary intake and risk factors were assessed prospectively multiple times, and many known or suspected risk factors for colorectal adenoma were well controlled. However, we did not measure sunshine exposure, which is a source of vitamin D. Another limitation is that we analyzed only adenomas of the distal colorectum to prevent misclassification and potential detection bias. However, the association of calcium and vitamin D intake with colorectal cancer risk may differ by site and sex; some studies (9, 43), but not all (7, 22), observed a more pronounced effect of calcium intake in the distal colon compared with the proximal colon, and the protective effects of vitamin D in men were stronger than in women (17). Thus, our results may not necessarily be applied to the proximal colon or to men.

In summary, our results provide evidence that a high calcium intake may reduce the risk of distal colorectal adenoma in women. In addition, a high vitamin D intake, combined with a low intake of retinol, may reduce the risk of distal colorectal adenoma.


   ACKNOWLEDGMENTS
 
This study was supported by research grants CA 55075 and CA 87969 from the National Institutes of Health, Department of Health and Human Services.

The authors are indebted to Gary Chase, Karen Corsano, Lisa Dunn, and Barbara Egan for their expert help.

Conflict of interest: none declared.


   References
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 References
 

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