Intakes of Calcium and Vitamin D and Risk of Colorectal Cancer in Women

Jennifer Lin1, Shumin M. Zhang1,2, Nancy R. Cook1,2, JoAnn E. Manson1,2,3, I-Min Lee1,2 and Julie E. Buring1,2,4

1 Division of Preventive Medicine, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA
2 Department of Epidemiology, Harvard School of Public Health, Boston, MA
3 Channing Laboratory, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA
4 Department of Ambulatory Care and Prevention, Harvard Medical School, Boston, MA

Correspondence to Dr. Jennifer Lin, Division of Preventive Medicine, Brigham and Women's Hospital, Harvard Medical School, 900 Commonwealth Avenue East, Boston, MA 02215 (e-mail: jhlin{at}rics.bwh.harvard.edu).

Received for publication August 25, 2004. Accepted for publication December 2, 2004.


    ABSTRACT
 TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 References
 
In vivo and in vitro studies have suggested a protective role of calcium and vitamin D in the development of colorectal cancer. However, epidemiologic data have been inconclusive. The authors prospectively assessed intakes of calcium and vitamin D in relation to risk of colorectal cancer in a large, prospective, female cohort from the US Women's Health Study. In 1993, 39,876 women aged ≥45 years and free of cardiovascular disease and cancer were enrolled in the study. During an average follow-up of 10 years, 223 of 36,976 women eligible for the present study developed colorectal cancer. Intakes of calcium and vitamin D from dietary sources and supplements were assessed with a baseline food frequency questionnaire. Cox proportional hazards regression was used to estimate relative risks and 95% confidence intervals. Intakes of total calcium and vitamin D were not associated with risk of colorectal cancer; multivariate relative risks comparing the highest with the lowest quintile were 1.20 (95% confidence interval: 0.79, 1.85; p for trend = 0.21) for total calcium and 1.34 (95% confidence interval: 0.84, 2.13; p for trend = 0.08) for total vitamin D. Intakes of both nutrients from specific types of sources, including diet and supplements, were also not significantly associated with colorectal cancer risk. Data provide little support for an association of calcium and vitamin D intake with colorectal cancer risk.

calcium; colorectal neoplasms; prospective studies; vitamin D; women


Abbreviations: CI, confidence interval


    INTRODUCTION
 TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 References
 
The role of calcium and vitamin D as colorectal anticarcinogens has been extensively assessed in both in vitro and in vivo studies (1Go–4Go). Calcium has been hypothesized to reduce risk of colorectal cancer by binding to carcinogenic bile acids and ionized fatty acids, thereby reducing the potential proliferation effects of these compounds on the colonic mucosa (2Go, 5Go). Calcium has also been hypothesized to promote differentiation of colonic cells through binding to the calcium-sensing receptors, resulting in a wide range of biologic actions such as the activation of isozymes of protein kinase C (2Go, 6Go). Alternations in the expression of protein kinase C isoforms have been observed in human and rodent colon cancer cells (7Go, 8Go). Vitamin D has the potential to regulate cell proliferation; the most active form, 1,25-dihydroxyvitamin D3, has been shown to regulate cell proliferation and differentiation in human colon cancer cell lines (1Go, 2Go). In addition, 1,25-dihydroxyvitamin D3 acts directly on calcium homeostasis by increasing intracellular calcium flux (1Go, 9Go). Although it is biologically plausible for both calcium and vitamin D to protect against the development of colorectal cancer, data from observational studies have not been clear (10Go, 11Go).

An inverse association between total (dietary combined with supplemental) calcium intake and colorectal cancer risk has been observed in some case-control and cohort studies (12Go–21Go). However, other studies have observed no such association (22Go–30Go). Two meta-analyses, each pooling at least 10 studies, reached different conclusions; one reported no association (10Go), while the other reported an inverse association between calcium intake and colorectal cancer risk (31Go). With respect to the randomized trials of calcium supplementation, only fixed doses were examined, and no dose-response relation could be established from these trials (32Go, 33Go). Observational findings on the association between total vitamin D intake and colorectal cancer have also been inconclusive. Although most studies have reported an inverse association between vitamin D intake and colorectal cancer (14Go, 15Go, 18Go, 19Go, 27Go, 34Go, 35Go), few have reported a significant dose-response trend (14Go, 15Go, 18Go). Other studies found that total vitamin D intake was unrelated to risk of colorectal cancer or colorectal adenomas (16Go, 17Go, 36Go).

Differences in results from epidemiologic data may be due to methodological limitations. A lack of information on calcium supplements may have attenuated the association of calcium intake with incident colorectal cancer (28Go, 29Go, 37Go). In addition, other aspects of dietary factors may modify the effect of calcium on colorectal cancer. For example, some animal studies have found that the protective effect of calcium on colorectal cancer may be limited to animals fed relatively high-fat diets (38Go–40Go). Intakes of phosphorus and fiber may reduce calcium absorption in the gut (41Go, 42Go). Moreover, calcium and vitamin D are metabolically related since the absorption of calcium in the gut relies on adequate vitamin D (9Go, 43Go). To date, interactions between these dietary factors and calcium intake in relation to colorectal cancer have not been well studied.

In this prospective study from a large female cohort, we examined calcium and vitamin D intake from both common dietary sources and supplements in relation to risk of colorectal cancer. We additionally evaluated whether the effect of calcium on colorectal cancer risk was modified by intakes of total fat, phosphorus, total fiber, and vitamin D.


    MATERIALS AND METHODS
 TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 References
 
Study cohort
The Women's Health Study is a randomized, double-blind, placebo-controlled 2 x 2 factorial trial evaluating low-dose aspirin and vitamin E for the primary prevention of cancer and cardiovascular disease (44Go). Beginning in 1993, 39,876 US female professionals aged 45 years or older and free of cardiovascular disease and cancer were enrolled in the trial. We included 36,976 women in the present study after excluding 2,900 who did not provide sufficient dietary information at baseline, had an implausible total energy intake (<600 or ≥3,500 kcal/day), or failed to provide information on potential risk factors at baseline.

Dietary assessment
On the 131-item baseline food frequency questionnaire, participants were asked to report average intake of foods and beverages during the past year. Nine responses were possible, ranging from "never or less than once per month" to "six or more times per day." Participants also reported use of calcium supplements and multivitamins according to duration and dosage. Responses for individual food items were converted to an average daily intake of the food item in servings per day. Major dietary sources of calcium and vitamin D included whole milk, cream, sour cream, ice cream, cream cheese, hard cheese, butter, skim or low-fat milk, yogurt, cottage or ricotta cheese, sherbet, ice milk, and frozen yogurt. Total milk intake included skim or low-fat milk and whole milk. Total intake of cheese was calculated by summing the daily intakes of cream cheese, hard cheese, and cottage or ricotta cheese. Total intake of fermented milk was calculated by summing the daily intakes of sour cream, yogurt, and cheese. Individual nutrient intake was computed by multiplying the frequency of responses by the nutrient content of specified portion sizes based on US Department of Agriculture food-composition data (45Go) and additional information from manufacturers. Nutrient intakes were energy adjusted based on the residuals from the regression of nutrient intake on total caloric intake (46Go).

Total calcium and vitamin D intake was calculated from dietary sources and supplements. Supplemental calcium was calculated based on individual calcium supplements or multivitamins containing calcium. Information on vitamin D supplements was based on multivitamins containing vitamin D. We took into account the multivitamin brand when calculating the amount of intake from supplements. Intakes of dietary calcium and vitamin D were calculated from all dietary sources without supplements.

The reproducibility and validity of calcium and vitamin D intake have been assessed in the Nurses' Health Study, which enrolled a cohort of female nurses with profiles similar to those of the participants in the current study. Pearson's correlation coefficients between responses from the food frequency questionnaire and those from four 1-week dietary records spaced over a year were 0.56 for total calcium and 0.51 for dietary calcium (47Go). With respect to milk intake, the correlation coefficients between the food frequency questionnaire and dietary records were 0.69 for skim or low-fat milk and 0.56 for whole milk (48Go). Correlation coefficients between intake and plasma concentration of vitamin D were 0.35 for total vitamin D and 0.25 for dietary vitamin D (49Go).

Ascertainment of colorectal cancer cases
Every 6 months during the first year and annually thereafter, participants were asked on follow-up questionnaires whether they had been diagnosed with colon cancer. When a case of colorectal cancer was reported, we asked the participants for permission to obtain their medical records and pathology reports. An endpoint committee of physicians reviewed the records. During a follow-up of 10 years, we documented 223 cases of colorectal cancer among the 36,976 women in the present study. Among the cases, 91 had primary tumors of the proximal colon; 81 cases, of the distal colon; and 46, of the rectum. For five cases, information was insufficient to identify the colon cancer as either proximal or distal.

Statistical analysis
Intakes of calcium and vitamin D as well as their dietary sources were divided into quintiles on the basis of the distribution of the nutrient intake among all women. The baseline distribution of risk factors for colorectal cancer was age adjusted (in 5-year groups) and compared according to the quintiles of nutrient intake. We tested proportions with the stratified Cochran-Mantel-Haenszel test, and means were assessed with multiple linear regression.

We used Cox proportional hazards regression to estimate relative risks and 95 percent confidence intervals for colorectal cancer, comparing the incidence rate for a given quintile of nutrient intake with the rate for the lowest quintile. Analyzed models were first adjusted for age (in years) and randomized treatment assignment (aspirin vs. placebo, vitamin E vs. placebo). The multivariate models were additionally adjusted for risk factors for colorectal cancer assessed at baseline, including body mass index (weight (kg)/height (m)2: <23, 23–24.9, 25–26.9, 27–29.9, ≥30), physical activity (total expenditure in kcal/week, in quartiles), family history of colorectal cancer in a first-degree relative (yes, no), history of colon or rectal polyps (yes, no), multivitamin use (never, past, current), smoking status (never, past, current), alcohol consumption (never, <15 g/day, ≥15 g/day), postmenopausal hormone therapy (never, past, current), saturated fat intake (g/day, in tertiles), red meat intake (servings/day, in tertiles), and total energy intake (kcal/day, in quintiles). We examined whether the association between total calcium intake and colorectal cancer risk differed according to total fat intake (<median, ≥median g/day), phosphorus intake (<median, ≥median mg/day), total fiber intake (<median, ≥median g/day), and total vitamin D intake (<median, ≥median IU/day). Because it has been hypothesized that different tumor locations may have different etiologies (50Go–52Go), we further examined the association of calcium and vitamin D intake with tumor subsites (proximal and distal colon).

To avoid the potential bias that preexisting, undiagnosed colorectal cancer might have changed calcium and vitamin D intake, we carried out additional analyses by excluding cases diagnosed within the first year of follow-up. We added to the multivariate model information on symptomatic examination (yes, no) and regular screening test of colonoscopy/sigmoidoscopy (yes, no) acquired during this time period. Tests for trend were performed by fitting the median of nutrient intake for each quintile as a continuous variable in the models. Statistical interactions between intakes of calcium (continuous variable with the median value of each quintile) and other dietary factors (binary variables), including total fat, phosphorus, total fiber, and total vitamin D, in relation to colorectal cancer risk were assessed by using likelihood ratio tests comparing models with and without the interaction term. All p values were two sided.


    RESULTS
 TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 References
 
In this cohort, median intake values were 882 mg/day for total calcium and 271 IU/day for total vitamin D. The median values for intake from dietary sources were 705 mg/day for calcium and 205 IU/day for vitamin D. The percentages of women who had used calcium and vitamin D supplements were 41 and 32, respectively.

Table 1 presents the baseline distributions of risk factors for colorectal cancer according to intakes of total calcium and vitamin D. Aside from being older, women who consumed greater amounts of calcium and vitamin D tended to be more health conscious; they were leaner, more likely to have a colonoscopy or sigmoidoscopy screening test, more likely to be current users of postmenopausal hormone therapy and multivitamins, more physically active, less likely to be current smokers, and consumed less alcohol, total calories, saturated fat, and red meat. Intakes of calcium and vitamin D were less clearly related to total fiber intake, but calcium intake was positively associated with phosphorus intake and inversely associated with total fat intake. Family history of colorectal cancer in a first-degree relative and history of colorectal polyps did not appear to be strongly related to intakes of calcium and vitamin D.


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TABLE 1. Age-adjusted baseline characteristics of participants in the Women's Health Study, according to intakes of total calcium and total vitamin D, United States, 1993–2004

 
Intake of total calcium was not shown to be associated with risk of colorectal cancer in the models adjusted for age and random treatment assignment and for additional risk factors for colorectal cancer (table 2). The multivariate relative risk for the highest relative to the lowest quintile of total calcium intake was 1.20 (95 percent confidence interval (CI): 0.79, 1.85; p for trend = 0.21). Intake of calcium from either diet or supplements was also not associated with risk of colorectal cancer; the multivariate relative risks for the highest relative to the lowest quintile were 0.90 (95 percent CI: 0.53, 1.54; p for trend = 0.81) for dietary calcium and 1.30 (95 percent CI: 0.90, 1.87; p for trend = 0.13) for supplemental calcium. Similarly, intake of total vitamin D or intake from diet or supplements was not associated with colorectal cancer risk (table 2). The multivariate relative risks comparing the highest with the lowest quintile of intake were 1.34 (95 percent CI: 0.84, 2.13; p for trend = 0.08) for total vitamin D, 0.96 (95 percent CI: 0.60, 1.55; p for trend = 0.99) for dietary vitamin D, and 1.36 (95 percent CI: 0.95, 1.95; p for trend = 0.10) for vitamin D supplements. When we repeated the analysis of intakes of calcium and vitamin D from diet by excluding supplement users, we observed no change in the results (data not shown). Additionally, when repeating the analysis by treating calcium and vitamin D intake as a continuous variable (increment by 1 standard deviation of each intake) in the multivariate model, we found no obvious change in the results. The multivariate relative risks were 1.14 (95 percent CI: 1.01, 1.29) for total calcium, 1.00 (95 percent CI: 0.84, 1.18) for dietary calcium, 1.13 (95 percent CI: 1.01, 1.28) for calcium supplements, 1.08 (95 percent CI: 0.94, 1.25) for total vitamin D, 0.96 (95 percent CI: 0.82, 1.12) for dietary vitamin D, and 1.15 (95 percent CI: 1.00, 1.33) for vitamin D supplements.


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TABLE 2. Relative risks and 95% confidence intervals of colorectal cancer according to quintile of intake of calcium and vitamin D, Women Health's Study, United States, 1993–2004

 
In this cohort, dairy products accounted for 53 percent and 39 percent of dietary calcium and vitamin D, respectively. When examining total intake of dairy products, we found no significant association with intake of dairy products (table 3). We also observed no significant association for intake of either low-fat or high-fat dairy products (data not shown). Intakes of individual dairy products, including fermented milk products, milk, cheese, and yogurt, were also not significantly associated with colorectal cancer risk (table 3).


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TABLE 3. Relative risks and 95% confidence intervals of colorectal cancer according to quintile of intake of specific dietary sources of calcium and vitamin D, Women Health's Study, United States, 1993–2004

 
Tests for the interaction of calcium intake with four nutrient intakes, including total fat, phosphorus, vitamin D, and total fiber, were not statistically significant; the multivariate {chi}2 values were 1.18 (p = 0.28) for total fat intake, 0.002 (p = 0.96) for phosphorus intake, 0.19 (p = 0.66) for vitamin D intake, and 3.68 (p = 0.06) for total fiber intake. Analyses of the associations between calcium intake and colorectal cancer according to intakes of these nutrients are given in table 4.


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TABLE 4. Relative risks and 95% confidence intervals of colorectal cancer according to quintile of total calcium intake, by modifying dietary factors, Women Health's Study, United States, 1993–2004

 
We further examined whether the risk associated with intakes of calcium and vitamin D differed by either tumor site. Calcium intake was not significantly associated with either tumor site. However, vitamin D intake was found to be positively associated with risk of distal colon cancer (relative risk for the highest vs. the lowest quintile = 2.47, 95 percent CI: 1.25, 4.91; multivariate p for trend = 0.005). Intakes of calcium and vitamin D from either diet or supplements were not significantly inversely associated with tumor sites (data not shown). We did not test the association for rectal cancer because the number of cases was small.

Finally, we reexamined the associations by adding to the multivariate model information on symptomatic examination and regular colonoscopy/sigmoidoscopy screening test acquired within the first 12 months of follow-up (207 cases after excluding the cases diagnosed within the first 12 months). The results were not appreciably changed; the multivariate relative risks comparing the highest four quintiles of total calcium intake with the lowest one were 0.74 (95 percent CI: 0.45, 1.21), 1.21 (95 percent CI: 0.78, 1.88), 0.96 (95 percent CI: 0.60, 1.54), and 1.29 (95 percent CI: 0.83, 2.02), respectively (p for trend = 0.11). Results regarding intake of total vitamin D were also unchanged; the multivariate relative risks comparing the highest four quintiles of total vitamin D intake with the lowest one were 0.79 (95 percent CI: 0.49, 1.29), 1.10 (95 percent CI: 0.71, 1.71), 0.98 (95 percent CI: 0.61, 1.57), and 1.38 (95 percent CI: 0.85, 2.24), respectively (p for trend = 0.09).


    DISCUSSION
 TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 References
 
In this prospective cohort study, we observed no indication that intakes of total calcium and vitamin D lower the risk of colorectal cancer. Intakes of calcium and vitamin D from diet and supplements were also not significantly related to the risk. In addition, we found no statistical interaction of calcium intake with intakes of total fat, phosphorus, total fiber, and vitamin D in relation to colorectal cancer risk.

Epidemiologic studies on the association between calcium intake and colorectal cancer risk have been inconclusive (10Go, 11Go). Although some cohort studies observed a lower risk with a higher intake of calcium (15Go, 16Go, 18Go), several other prospective cohort studies have shown either a nonsignificant inverse association (30Go, 34Go, 35Go) or a null association (27Go–30Go). In the case-control studies, at least six (12Go, 13Go, 19Go–22Go) observed an inverse association between colon or colorectal cancer risk and calcium intake, but several others did not find such an association (23Go–26Go, 29Go). A meta-analysis pooling six cohort studies and 18 case-control studies found no association between calcium intake and colorectal cancer risk (10Go). However, the other meta-analysis of 10 cohort studies reported a 14 percent lower risk of colorectal cancer in the highest versus lowest quintile of calcium intake (95 percent CI: 0.78, 0.95; p for trend = 0.02) (31Go).

The effect of calcium intake on colorectal cancer risk remains to be elucidated. One possible explanation for the different findings may be due to differences in the amount of calcium intake. For instance, in the Finnish cohort, intake of dietary calcium, mostly from milk products, was substantially higher than in most other populations (median intake in the highest intake group: 1,789 mg/day) (16Go). Consumption of dairy products was also high in the other population from the US midwestern and western regions, and the observed inverse association in this study was seen largely in the highest quintile of dietary calcium intake (≥1,330 mg/day; odds ratio = 0.6, 95 percent CI: 0.4, 0.9) (17Go). The inverse association due to high consumption of dairy products suggests that a greater intake of calcium may be necessary to exert a protective effect against the development of colorectal cancer.

Two randomized trials assessing the effect of calcium supplementation on recurrence of colorectal adenomas observed a similar magnitude of risk reduction (32Go, 33Go). In the Calcium Polyp Prevention Study, a 30 percent lower risk of recurrent adenomas was observed after 1 year of follow-up among participants taking 1,200 mg of calcium daily (relative risk = 0.70, 95 percent CI: 0.54, 0.89) (33Go). Another recent trial from Europe found that intake of 2,000 mg of calcium daily was associated with a nonsignificant 34 percent lower risk after 3 years of follow-up (relative risk = 0.66, 95 percent CI: 0.38, 1.17) (32Go). A subsequent study from the Calcium Polyp Prevention trial further suggested that a total calcium intake of >1,200 mg/day may be required to optimize its preventive efficacy, since participants who received the treatment and were in the highest intake group of baseline dietary calcium had the lowest risk of advanced colorectal adenomas (relative risk = 0.27, 95 percent CI: 0.12, 0.63) (53Go). However, we found no reduced risk of colorectal cancer among the highest total intake group in our cohort (≥1,350 mg/day).

Alternatively, the protective effect of calcium may be confined to specific tumor subsite. Both the Nurses' Health Study and the study of Wisconsin women observed an approximately 30 percent lower risk of distal colon cancer for women whose daily intake of calcium was ≥1,250 mg (p for trend in both studies = 0.06) (19Go, 30Go). However, our data provided little support for a protective effect at either tumor subsite, likely because of the limited number of cases.

Our finding that total intake of vitamin D was not significantly associated with colorectal cancer risk was consistent with those from several other studies (16Go–19Go, 27Go, 34Go–36Go). The nonsignificant findings may be attributed to inadequate measures of vitamin D intake; natural dietary sources of vitamin D are limited. The synthesis of vitamin D3 in the skin induced by the ultraviolet radiation from the sun is an important source of vitamin D (9Go, 54Go, 55Go). The lack of information on sun exposure as an additional source of vitamin D may be one reason that our study and others failed to observe the protective effect of vitamin D (56Go). The finding that total vitamin D intake was moderately correlated with plasma vitamin D (25-hydroxyvitamin D) levels (r = 0.35) further suggests the possibility that intake of vitamin D in the present study may not reflect overall vitamin D status (49Go). In addition, the limited range of intake values for supplemental vitamin D, which accounted for more than one third of total vitamin D intake in our cohort, may also be partly responsible for the present results. It is also likely that our null results may be due to factors that influence vitamin D absorption or other confounding factors unknown to us.

Since calcium absorption in the gut may be affected by certain nutrients, it is also likely that consumption of those nutrients may have confounded the findings for calcium intake. In some animal studies, the protective effect of calcium on colorectal cancer was found to be more pronounced in animals fed relatively high-fat diets (38Go–40Go). However, the Calcium Polyp Prevention trial observed an opposite pattern, although the interaction was not statistically significant (53Go). In our cohort, total fat intake did not alter the association between calcium intake and colorectal cancer risk. Nutrients such as phosphorus and fiber can reduce calcium absorption in the gut by binding to calcium, which consequently reduces the bioavailability of calcium (41Go, 42Go, 57Go). We again observed no effect modification on the association according to either phosphorus or fiber intake.

Both vitamin D and calcium are metabolically related, and absorption of calcium in the gut relies on adequate vitamin D (57Go, 58Go). In a recent randomized trial testing the joint effects of calcium supplementation and vitamin D status on adenoma recurrence, calcium supplementation was found to be beneficial for those who had higher serum vitamin D levels (relative risk = 0.71, 95 percent CI: 0.57, 0.89) (43Go). The interaction between these two nutrients on colorectal carcinogenesis was also seen in another case-control study that observed a stronger inverse association of serum vitamin D levels with colorectal adenomas for subjects whose calcium intake was higher (59Go). Our finding that a higher intake of total vitamin D resulted in an adverse effect of calcium on colorectal cancer risk was unexpected, although the interaction was not statistically significant.

One strength of our study is the prospective design, which avoids selection and recall biases associated with case-control studies. We also had information on a wide range of potential risk factors for colorectal cancer to control for possible confounding effects. However, several limitations of our study should be considered. Assessing food and nutrient intake information only once at baseline likely resulted in measurement error due to random within-person variation. Additionally, because of the small number of cases, we had limited statistical power for the analyses according to tumor sites. We also cannot rule out the possibility that the present findings may be subject to chance since so many tests have been performed.

In conclusion, our findings do not support a protective role of calcium and vitamin D intakes against colorectal cancer incidence. However, given the strong evidence from both animal studies and in vitro studies, the benefits of these two nutrients cannot be ruled out. More detailed investigation of the interaction of calcium with other nutrients, including vitamin D, and additional questions better characterizing vitamin D status may be necessary to elucidate the true associations of calcium and vitamin D with risk of colorectal cancer.


    ACKNOWLEDGMENTS
 
This work was supported by grants CA47988 from the National Cancer Institute and HL43851 from the National Heart, Lung, and Blood Institute.

The authors acknowledge the contributions of the entire staff of the Women's Health Study under the leadership of David Gordon, as well as Mary Breen, Susan Burt, Marilyn Chown, Georgina Friedenberg, Inge Judge, Jean Mac-Fadyean, Geneva McNair, David Potter, Claire Ridge, and Harriet Samuelson. They also acknowledge the Endpoints Committee of the Women's Health Study (Dr. Wendy Y. Chen) and Gregory Kotler for his technical assistance with the manuscript.


    References
 TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 References
 

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