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 |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
calcium; colorectal neoplasms; prospective studies; vitamin D; women
![]() |
INTRODUCTION |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
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 (1221
). However, other studies have observed no such association (22
30
). Two meta-analyses, each pooling at least 10 studies, reached different conclusions; one reported no association (10
), while the other reported an inverse association between calcium intake and colorectal cancer risk (31
). 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 (32
, 33
). 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 (14
, 15
, 18
, 19
, 27
, 34
, 35
), few have reported a significant dose-response trend (14
, 15
, 18
). Other studies found that total vitamin D intake was unrelated to risk of colorectal cancer or colorectal adenomas (16
, 17
, 36
).
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 (28, 29
, 37
). 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 (38
40
). Intakes of phosphorus and fiber may reduce calcium absorption in the gut (41
, 42
). Moreover, calcium and vitamin D are metabolically related since the absorption of calcium in the gut relies on adequate vitamin D (9
, 43
). 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 |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
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 (45) and additional information from manufacturers. Nutrient intakes were energy adjusted based on the residuals from the regression of nutrient intake on total caloric intake (46
).
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 (47). 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 (48
). Correlation coefficients between intake and plasma concentration of vitamin D were 0.35 for total vitamin D and 0.25 for dietary vitamin D (49
).
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, 2324.9, 2526.9, 2729.9, 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 (50
52
), 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 |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
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.
|
|
|
|
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 |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
Epidemiologic studies on the association between calcium intake and colorectal cancer risk have been inconclusive (10, 11
). Although some cohort studies observed a lower risk with a higher intake of calcium (15
, 16
, 18
), several other prospective cohort studies have shown either a nonsignificant inverse association (30
, 34
, 35
) or a null association (27
30
). In the case-control studies, at least six (12
, 13
, 19
22
) observed an inverse association between colon or colorectal cancer risk and calcium intake, but several others did not find such an association (23
26
, 29
). A meta-analysis pooling six cohort studies and 18 case-control studies found no association between calcium intake and colorectal cancer risk (10
). 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) (31
).
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) (16). 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) (17
). 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 (32, 33
). 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) (33
). 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) (32
). 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) (53
). 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) (19
, 30
). 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 (1619
, 27
, 34
36
). 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 (9
, 54
, 55
). 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 (56
). 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 (49
). 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 (3840
). However, the Calcium Polyp Prevention trial observed an opposite pattern, although the interaction was not statistically significant (53
). 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 (41
, 42
, 57
). 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 (57, 58
). 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) (43
). 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 (59
). 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 |
---|
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 |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|