Affiliations of authors: Department of Nutrition, Harvard School of Public Health, Boston, MA; Departments of Nutrition and Epidemiology, Harvard School of Public Health, and Channing Laboratory, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston; Channing Laboratory, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, and Division of Medical Oncology, Dana-Farber Cancer Institute, Boston; Department of Epidemiology, Harvard School of Public Health, and Channing Laboratory, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School.
Correspondence to: Edward Giovannucci, M.D., Sc.D., Dept. of Nutrition, Harvard School of Public Health, 665 Huntington Ave., Bldg. 2, Boston, MA 02115 (e-mail: edward.giovannucci{at}channing.harvard.edu).
![]() |
ABSTRACT |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
![]() |
INTRODUCTION |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
Results from epidemiologic studies are inconsistent. Although some studies do not support a benefit (1013), the majority of studies have found a weak but statistically nonsignificant inverse association between high calcium intake and risk of colorectal or colon cancer (1419). In two male prospective cohorts, the Western Electric Study and the Finnish Alpha-Tocopherol, Beta-Carotene Cancer Prevention Study, higher calcium intake was statistically significantly associated with lower risk of colorectal cancer (20,21). Lack of repeated dietary measurements in most observational studies, possibly resulting in misclassification of long-term nutrient intake, may have contributed to these inconsistent results.
Randomized trials (2227) conducted to assess the relationship between supplemental calcium intake and recurrence of colorectal adenomas, which are precursors for colorectal cancers, or other biomarkers, such as fecal bile acid concentrations or colorectal mucosal cell proliferation, have also yielded inconsistent results. In recently published results from a randomized clinical trial, the Calcium Polyp Prevention Study (27), daily supplementation with 1200 mg of calcium resulted in a statistically significant 20% decreased risk of recurrent colorectal adenomas. Because only one relatively high dose was examined, the doseresponse relationship could not be established from this study. Because the relationship between surrogate markers and the ultimate endpoint is complex and only a small proportion of colon adenomas progress to cancer (28), establishing the association between calcium intake and colon cancer remains important.
We had previously investigated the association between calcium intake and risk of colorectal cancer in two large cohorts of U.S. women and menthe Nurses' Health Study (NHS) and the Health Professionals Follow-up Study (HPFS), respectively. Consistent with most other epidemiologic studies (15,1719,29), we found a modest inverse, but not statistically significant, association between calcium intake and risk of colorectal (16) and colon cancer (14). However, these studies had insufficient power to exclude effects of the magnitude suggested by the recent randomized trial (27). The extended follow-up and better assessment of long-term diet through multiple dietary assessments in these two cohorts allowed us to increase the statistical power to examine moderate associations, to assess dietary and supplemental calcium separately, to define the doseresponse relationships, to examine risk by subsites within the colon, and to investigate whether other factors modified the relationship between calcium and colon cancer risk.
![]() |
SUBJECTS AND METHODS |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
In 1976, 121 700 registered U.S. nurses from 30 to 55 years of age were mailed a questionnaire requesting information on various exposures and medical diagnoses (30). Follow-up questionnaires were mailed to the participants every 2 years to update this information. A 61-item semiquantitative food frequency questionnaire was included in the 1980 mailing, and 98 462 women returned this questionnaire. Food frequency questionnaires containing 121136 items were also incorporated into the 1984, 1986, 1990, and 1994 follow-up questionnaires. Overall follow-up rates have been very high. Up to 1996, the follow-up as a percentage of potential person-years was 98% complete. This study was approved by the Human Research Committee at the Brigham and Women's Hospital (Boston, MA).
HPFS Cohort
In 1986, 51 129 U.S. male dentists, podiatrists, pharmacists, optometrists, osteopaths, and veterinarians, from 40 to 75 years of age, were mailed a questionnaire (31). As in the NHS, information on medical history and exposure has been updated by biennial follow-up questionnaires. In 1986, participants were also requested to complete a 131-item semiquantitative food frequency questionnaire. Participants were also mailed a food frequency questionnaire in 1990 and 1994. Up to 1996, the follow-up as a percentage of potential person-years was 97% complete. This study was approved by the Harvard School of Public Health Human Subjects Committee.
Assessment of Nutrient Intake
The food frequency questionnaires inquired about the average frequency of consumption of selected foods and beverages during the past year. Participants chose from nine possible answers ranging from never or less than one serving per month to six or more servings per day. We computed nutrient intakes by multiplying the frequency of consumption of a specific food or beverage item by its nutrient content and then summed the contributions from all foods and beverages. Nutrient intakes were energy adjusted using the residuals method (32).
Calcium intake from dairy sources alone was calculated by summing the contributions of all dairy products and food items containing dairy products, such as mashed potatoes (milk), clam chowder (milk), or pizza (cheese) (see Appendix I). Calcium intake from nondairy sources was computed by subtracting calculated dairy calcium intake from total dietary calcium intake. Total milk intake was calculated as the sum of intake of skim milk, whole milk, and 1%2% milk (skim milk and 1%2% milk were combined into one question before the 1994 questionnaire), and total intake of fermented milk products was computed by summing the intake of sour cream, yogurt, and cheese intake for each participant.
On each biennial questionnaire (except for the 1980 NHS questionnaire), participants were also asked to provide information on their current use and dosage of calcium supplements (<400 mg/day, 400900 mg/day, 9011300 mg/day, and 1301 mg/day). Participants who did not respond to one or more of the follow-up questionnaires were assigned the information from the most recently completed questionnaire. Current calcium supplement users who did not supply information on dosage of calcium supplementation were assigned to the 400900 mg/day category, the category with the highest frequency among current calcium supplement users.
The reproducibility and validity of the food frequency questionnaires administered in the NHS and HPFS cohorts have been described previously (3336). Pearson correlation coefficients between calcium intake computed from the food frequency questionnaires and average intake of two 1-week diet records of 127 men was 0.53 for calcium both with and without supplements (35); for 191 women, the correlation coefficients for calcium were 0.63 with and 0.70 without supplements (Sampson L: personal communication). Overall, there was a good correlation between calcium intake from the food frequency questionnaires and the dietary records of both women and men. The difference in the correlation between women and men was compatible with statistical variability because of the relatively small sample size.
Exclusion of Participants at Baseline
Participants without a completed food frequency questionnaire at baseline (i.e., 1980 for NHS cohort, 1986 for HPFS cohort) or participants with unreasonably high (>3500 calories/day for women; >4200 calories/day for men) or low intakes (<600 calories/day for women; <800 calories/day for men) and those who had left a large number of items blank (>10 items for women; >70 items for men) were excluded from the analysis. We also excluded participants with a history of ulcerative colitis or previous cancer (except for nonmelanoma skin cancer). This left us with 87 998 women and 47 344 men for follow-up (1980 to May 31, 1996 for the NHS cohort; 1986 to January 31, 1996 for the HPFS cohort).
Case and Death Ascertainment
We asked participants who had reported a diagnosis of colon or rectal cancer on the follow-up questionnaires for permission to obtain and evaluate their hospital and pathology reports. Those reports were reviewed by physicians, who extracted information on histology, anatomic location, and stage of cancer. Only primary adenocarcinomas were included in our analysis.
Between 1980 and May 31, 1996, 529 incident female colon cancer cases were identified; between 1986 and January 31, 1996, 313 male colon cancers were identified. All female and male colon cancer cases were confirmed by medical records. Because the vast majority of colorectal cancer cases are colon cancer cases, we also included 97 female and 86 male colorectal cancer cases with missing information on anatomic site in our analysis, yielding a total of 626 female and 399 male cancer cases for the analysis. These additional cases were confirmed by medical records, by autopsy or death reports, or by reconfirming the self-reported diagnosis from the participants. Exclusion of these cases yielded similar results. Colon cancers located in the cecum, ascending colon, or transverse colon were considered proximal (right-sided) colon cancers, whereas those located in the descending or sigmoid colon were considered distal (left-sided) colon cancers.
The National Death Index or reports from family members were used to ascertain death among participants. We also requested permission to obtain and evaluate medical records from next of kin of participants who had died of cancer and had not already been recorded in our database.
Statistical Analysis
Starting from the month the baseline questionnaire was returned, each participant contributed follow-up time until the month in which cancer was diagnosed, the date of death, or if they were noncases (alive and not diagnosed with colorectal cancer), the end of the study period (May 31, 1996 for the NHS cohort; January 31, 1996 for the HPFS cohort), whichever came first. Incidence rates were calculated by dividing the number of incident colon cancer cases by the number of total person-years.
We adjusted relative risks [RR] for potential confounders by implementing the MantelHaenzel estimator (37) and pooled logistic regression (38,39). Data from each cohort were first analyzed separately and then, when appropriate, RRs were pooled by the use of a method described by DerSimonian and Laird (40). Categories of calcium intake were based on increments of 100 mg/day calcium; above 800 mg the increments were 8011000 mg/day and 10011250 mg/day. The upper cut point depended on the range of intake and thus was lower for dairy calcium compared with total calcium. Smaller increments (i.e., 2550 mg/day) were used for nondairy calcium because of the limited distribution. All categories were defined a priori. The basic multivariate model included known and suspected nondietary risk factors (age, family history, body mass index, physical activity, pack-years of smoking before age 30, and aspirin use) as well as red meat and alcohol consumption. Potential confounding effects of single nutrients were examined separately because many dietary variables are strongly correlated. Having several correlated nutrients as well as their interactions together in one multivariate model would have resulted in multicolinearity and, thus, less reliable estimates. However, the nutrients such as total fat, fiber, iron, methionine, folate, vitamin D, vitamin E, vitamin C, total vitamin A, or carotene intake as well as multivitamin use, when added separately to the basic multivariate models, did not change the overall results and were therefore not added to the final models. In addition, potential confounding of endoscopy was also examined. Trend tests were conducted by using median intake of the defined calcium categories as exposure scores. All P values are two-sided.
To evaluate long-term nutrient intake, we used the repeated dietary information from the baseline and all follow-up food frequency questionnaires (i.e., NHS: 1980, 1984, 1986, 1990, and 1994; HPFS: 1986, 1990, and 1994) and computed a cumulative average nutrient intake, which is the average of all available nutrient intakes for a participant up to the beginning of each follow-up cycle (41).
On the 1980 questionnaire, women were also asked to report whether they had changed their milk intake considerably over the past 10 years. Because consistency in milk intake over time may be a good indicator for consistent calcium intake, we also investigated associations between calcium intake and colon cancer risk after exclusion of women with a change in milk intake. In men, the baseline questionnaire did not include a comparable question on changes in overall milk intake.
![]() |
RESULTS |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
|
Table 2 shows multivariate-adjusted RR by category of cumulative average calcium intake in both cohorts. Multivariate adjustment did not substantially alter the age-adjusted estimates. In men, associations were similar for total, dietary, and dairy calcium. In men, total and dietary calcium intake above the second lowest category (>601700 mg/day) was associated with an approximately 30% lower risk of colon cancer. In women, there was no appreciable association between cumulative updated calcium intake and colon cancer. In both cohorts, no evidence for an inverse association between higher intake of nondairy calcium (after exclusion of calcium supplement users) and colon cancer risk was found. There was also no association between nondairy calcium and colon cancer risk among participants with low (<500 mg/day) or among those with high (
500 mg/day) dairy calcium intake (data not shown).
|
In men, a higher total milk intake at baseline (>1.1 servings/day versus 0.5 servings/day) suggested a lower risk of colon cancer (RR = 0.58; 95% CI = 0.29 to 1.17), but this is not the case in women (RR = 0.93; 95% CI = 0.76 to 1.15). Results were similar when analysis was restricted to women without a change in milk intake over the past 10 years. In men, intake of fermented milk products was not associated with colon cancer risk (data not shown). In women, there was a slight but not statistically significant association between higher intake of fermented milk products at baseline and risk of colon cancer (>1 serving/day versus 0.07 servings/day: RR = 0.86; 95% CI = 0.63 to 1.16), but this association was attenuated when we used the cumulative updated intake of fermented milk products.
When we examined risk by cancer site, inverse associations between higher calcium intake and colon cancer were observed for distal colon cancer, whereas no associations were observed for proximal colon cancer (Table 3). After pooling RR estimates for men and women (those without a change in milk intake), we found an approximately 40%50% lower risk of distal colon cancer among those subjects with a calcium intake of 701800 mg/day or higher compared with those subjects having a calcium intake of less than or equal to 500 mg/day. When history of endoscopy, multivitamin use, or intake of total vitamin D, phosphorus, or folate were added separately to these multivariate models, RR estimates for total calcium intake were similar to those shown in Table 3
.
|
|
|
![]() |
DISCUSSION |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
Even though epidemiologic studies on the association between calcium and colon cancer risk have been inconsistent, modest but statistically nonsignificant inverse associations have been observed in the majority of studies (1419,29). Some, but not all, casecontrol studies (4450) have reported a statistically significant inverse association between calcium intake and colorectal or colon cancer risk. When analyses were stratified by sex, inverse associations appeared to be stronger in women (47,50).
In two male prospective cohorts, the Western Electric Study and the Finnish Alpha-Tocopherol, Beta-Carotene Cancer Prevention Study, higher calcium intake was associated with lower risk of colorectal cancer with RR estimates (comparing lowest with highest quantile of calcium intake) ranging from 0.60 (95% CI = 0.40 to 0.90) (21) to 0.32 (P.05) (20). In another prospective study of 11 888 male and female residents of a retirement community (13), dietary calcium intake was not associated with colorectal cancer risk. The Netherlands Cohort Study (51) did not observe an inverse association between total dietary calcium intake or intake of fermented dairy products and colorectal cancer risk but did suggest a modest inverse association between calcium from unfermented dairy products and colorectal cancer risk (lowest versus highest quintile: multivariate RR = 0.71; 95% CI = 0.48 to 1.05).
A recent meta-analysis of 24 studies on the association between calcium intake and colorectal adenoma or cancer (52) concluded that existing data are not consistent with a considerable protective effect of calcium on risk of colorectal cancer (pooled RR = 0.86; 95% CI = 0.74 to 0.98) or colorectal adenoma (pooled RR = 1.13; 95% CI = 0.91 to 1.39).
Randomized trials (2227) of supplemental calcium and recurrence of colorectal adenomas (which are precursors for colorectal cancers) or other biomarkers, such as fecal bile acid concentrations or colorectal mucosal cell proliferation, have also yielded inconsistent results. In the Calcium Polyp Prevention Study, participants with a history of colorectal adenoma were randomly assigned to receive daily either 1200 mg of calcium or placebo. Supplementation resulted in a statistically significant, albeit moderate, lower risk of recurrent adenomas (RR = 0.81; 95% CI = 0.67 to 0.99) (27). Another recent trial from Europe (53) also observed a modest, but not statistically significant, decreased risk of colorectal adenoma recurrence after daily supplementation with 2000 mg of calcium (RR = 0.66; 95% CI = 0.38 to 1.17). Because only relatively high doses were examined, the doseresponse relationship could not be established from these two studies.
Beneficial effects of calcium have been hypothesized to be more pronounced in the proximal colon because effects of fatty acids and bile acids on colon cell proliferation may be stronger proximally (52,54). However, only few observational studies (14,5557) have investigated associations by cancer site. In this analysis, inverse associations were observed between calcium intake and distal colon cancer but not for proximal cancer. In one casecontrol study (55) with 746 colon cancer case subjects and control subjects, researchers found inverse associations between calcium intake and colon cancer risk to be strongest in the sigmoid colon (per 295 mg/day increase in calcium intake: ascending colon: RR = 0.91; 95% CI = 0.78 to 1.05; transverse and descending colon: RR = 0.87; 95% CI = 0.74 to 1.01; sigmoid colon: RR = 0.86; 95% CI = 0.77 to 0.97). Another large casecontrol study (57) based on 1993 case subjects and 2410 control subjects found inverse associations between higher calcium intake and colon cancer risk to be stronger (and statistically significant) for distal colon cancers than for proximal colon cancers. Proximal cancers are commonly detected at a more advanced stage than distal colon cancers, which might have resulted in recall bias (52). However, inverse associations between calcium intake and colon cancer risk were also more pronounced for the sigmoid colon in a prospective cohort of 11 000 men of Japanese descent residing in Hawaii (56) (lowest versus highest tertile of calcium intake: sigmoid colon: RR = 1.7; 95% CI = 1.1 to 2.8; 113 case subjects). Findings from randomized clinical trials with regard to colon subsites are inconclusive. In the trial by Bonithon-Kopp et al. (53), inverse associations between calcium supplementation and adenoma recurrence were restricted to proximal adenomas, whereas no relationship with colon subsite was observed in the trial by Baron et al. (27).
Results from some epidemiologic studies (15,17,21,29,55) also support an inverse association between dairy product or milk intake and colorectal or colon cancer risk. Thus, the question arises as to whether one or more component(s) in dairy products other than calcium, for example, casein (58), may be responsible for those observed associations. In our study, supplemental calcium intake was significantly associated with decreased risk even among participants with low dietary calcium intake, suggesting that calcium may be the relevant component. Use of supplemental calcium in participants with high dietary calcium intake appeared to be of no further benefit, providing additional support for a possible threshold effect of calcium intake on colon cancer risk.
Calcium can bind secondary bile acids and ionized fatty acids, both of which have been hypothesized to promote epithelial cell proliferation in the colon (68). According to this hypothesis, people with higher fat intake should benefit most from higher calcium intake (8). In men, inverse associations between calcium intake and distal colon cancer risk appeared to be restricted to those with higher total fat intake, but in women, fat intake did not modify the association with calcium intake. Also, we did not observe evidence of an overall effect of total dietary fat in these cohorts. In the human body, calcium absorption is tightly regulated and primarily involves vitamin D, parathyroid hormone, and phosphorus (42,43). Vitamin D can increase absorption of calcium in the gastrointestinal tract and decrease renal calcium loss (42,43). Higher phosphorus intake may decrease calcium absorption in the gastrointestinal tract, although this may be balanced by decreased renal excretion of calcium (59). Our data provide some indication that participants with higher intake of vitamin D may benefit most from higher calcium intake with regard to their colon cancer risk. In men, but not in women, there was also some suggestion of a more pronounced inverse association between higher calcium intake and colon cancer risk among participants in the lowest tertile of phosphorus intake. Other factors that can affect absorption and bioavailability of calcium are dietary fiber (43) and the source of ingested calcium (i.e., dairy calcium versus calcium from other dietary sources, such as plant products) (59,60). Some components in plants, such as phytate, cellulose, or oxalate may reduce calcium absorption (59). In our study, calcium from nondairy sources was not associated with colon cancer risk, even among participants with low dairy calcium intake. Given that calcium intake from nondairy sources was low in our cohorts, we cannot exclude the possibility that calcium intake from nondairy sources may have been too low to exert a protective effect on colon cancer risk.
Our data also suggest that beneficial effects of calcium on colon cancer risk may be restricted to aspirin nonusers only. In the recent randomized trial of calcium supplementation and recurrent colorectal adenomas (27), protective effects of calcium supplementation were more pronounced among nonusers of aspirin or other nonsteroidal anti-inflammatory drugs. This finding deserves further examination.
Although residual confounding cannot be ruled out entirely, arguing against confounding as an explanation for our results are 1) similarity of age-adjusted and multivariate associations, 2) associations seen for both women and men, and 3) associations seen for both dietary and supplemental calcium separately. Our results suggest that relatively moderate calcium intake may decrease the risk of distal colon cancer but that high calcium intake may not appreciably lower risk further. Considering the public health importance of colon cancer (61), even a modest protective effect of higher calcium intake on colon cancer could result in the prevention of a large number of colon cancer cases. Future studies investigating this relationship should concentrate on specific cancer subsites and on better characterizing the doseresponse relationship.
![]() |
APPENDIX I |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
![]() |
NOTES |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
We thank Laura Sampson (Department of Nutrition, Harvard School of Public Health) for her valuable advice and support in this study.
![]() |
REFERENCES |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
1
Lipkin M. Preclinical and early human studies of calcium and colon cancer prevention. Ann N Y Acad Sci 1999;889:1207.
2 Vinas-Salas J, Biendicho-Palau P, Pinol-Felis C, Miguelsanz-Garcia S, Perez-Holanda S. Calcium inhibits colon carcinogenesis in an experimental model in the rat. Eur J Cancer 1998;34:19415.[Medline]
3 Pence BC, Buddingh F. Inhibition of dietary fat-promoted colon carcinogenesis in rats by supplemental calcium or vitamin D3. Carcinogenesis 1988;9:18790.[Abstract]
4 Pence BC. Role of calcium in colon cancer prevention: experimental and clinical studies. Mutat Res 1993;290:8795.[Medline]
5 Pence BC, Dunn DM, Zhao C, Patel V, Hunter S, Landers M. Protective effects of calcium from nonfat dried milk against colon carcinogenesis in rats. Nutr Cancer 1996;25:3545.[Medline]
6 Wargovich MJ, Eng VW, Newmark HL. Calcium inhibits the damaging and compensatory proliferative effects of fatty acids on mouse colon epithelium. Cancer Lett 1984;23:2538.[Medline]
7 Van der Meer R, Kleibeuker JH, Lapre JA. Calcium phosphate, bile acids and colorectal cancer. Eur J Cancer Prev 1991;1 Suppl 2:5562.[Medline]
8 Newmark HL, Wargovich MJ, Bruce WR. Colon cancer and dietary fat, phosphate, and calcium: a hypothesis. J Natl Cancer Inst 1984;72:13235.[Medline]
9 Buset M, Lipkin M, Winawer S, Swaroop S, Friedman E. Inhibition of human colonic epithelial cell proliferation in vivo and in vitro by calcium. Cancer Res 1986;46:542630.[Abstract]
10 Benito E, Stiggelbout A, Bosch FX, Obrador A, Kaldor J, Mulet M, et al. Nutritional factors in colorectal cancer risk: a casecontrol study in Majorca. Int J Cancer 1991;49:1617.[Medline]
11 Negri E, La Vecchia C, D'Avanzo B, Franceschi S. Calcium, dairy products, and colorectal cancer. Nutr Cancer 1990;13:25562.[Medline]
12 Tuyns AJ, Haelterman M, Kaaks R. Colorectal cancer and the intake of nutrients: oligosaccharides are a risk factor, fats are not. A casecontrol study in Belgium. Nutr Cancer 1987;10:18196.[Medline]
13 Wu AH, Paganini-Hill A, Ross RK, Henderson BE. Alcohol, physical activity and other risk factors for colorectal cancer: a prospective study. Br J Cancer 1987;55:68794.[Medline]
14 Kearney J, Giovannucci E, Rimm EB, Ascherio A, Stampfer MJ, Colditz GA, et al. Calcium, vitamin D, and dairy foods and the occurrence of colon cancer in men. Am J Epidemiol 1996;143:90717.[Abstract]
15 Macquart-Moulin G, Riboli E, Cornee J, Charnay B, Berthezene P, Day N. Casecontrol study on colorectal cancer and diet in Marseilles. Int J Cancer 1986;38:18391.[Medline]
16
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;88:137582.
17 Zaridze D, Filipchenko V, Kustov V, Serdyuk V, Duffy S. Diet and colorectal cancer: results of two casecontrol studies in Russia. Eur J Cancer 1992;29A:1125.
18 Lee HP, Gourley L, Duffy SW, Esteve J, Lee J, Day NE. Colorectal cancer and diet in an Asian populationa casecontrol study among Singapore Chinese. Int J Cancer 1989;43:100716.[Medline]
19 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;137:130217.[Abstract]
20 Garland C, Shekelle RB, Barrett-Connor E, Criqui MH, Rossof AH, Paul O. Dietary vitamin D and calcium and risk of colorectal cancer: a 19-year prospective study in men. Lancet 1985;1:3079.[Medline]
21 Pietinen P, Malila N, Virtanen M, Hartman TJ, Tangrea JA, Albanes D, et al. Diet and risk of colorectal cancer in a cohort of Finnish men. Cancer Causes Control 1999;10:38796.[Medline]
22 Alder RJ, McKeown-Eyssen G, Bright-See E. Randomized trial of the effect of calcium supplementation on fecal risk factors for colorectal cancer. Am J Epidemiol 1993;138:80414.[Abstract]
23 Bostick RM, Fosdick L, Wood JR, Grambsch P, Grandits GA, Lillemoe TJ, et al. Calcium and colorectal epithelial cell proliferation in sporadic adenoma patients: a randomized, double-blinded, placebo-controlled clinical trial. J Natl Cancer Inst 1995;87:130715.[Abstract]
24 Barsoum GH, Hendrickse C, Winslet MC, Youngs D, Donovan IA, Neoptolemos JP, et al. Reduction of mucosal crypt cell proliferation in patients with colorectal adenomatous polyps by dietary calcium supplementation. Br J Surg 1992;79:5813.[Medline]
25 Gregoire RC, Stern HS, Yeung KS, Stadler J, Langley S, Furrer R, et al. Effect of calcium supplementation on mucosal cell proliferation in high risk patients for colon cancer. Gut 1989;30:37682.[Abstract]
26 Hofstad B, Vatn MH, Andersen SN, Owen RW, Larsen S, Osnes M. The relationship between faecal bile acid profile with or without supplementation with calcium and antioxidants on recurrence and growth of colorectal polyps. Eur J Cancer Prev 1998;7:28794.[Medline]
27
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;340:1017.
28 Schatzkin A, Kelloff G. Chemo- and dietary prevention of colorectal cancer. Eur J Cancer 1995;31A:1198204.
29 Kato I, Akhmedkhanov A, Koenig K, Toniolo PG, Shore RE, Riboli E. Prospective study of diet and female colorectal cancer: the New York University Women's Health Study. Nutr Cancer 1997;28:27681.[Medline]
30 Willett WC, Stampfer MJ, Colditz GA, Rosner BA, Hennekens CH, Speizer FE. Dietary fat and the risk of breast cancer. N Engl J Med 1987;316:228.[Abstract]
31 Rimm EB, Giovannucci EL, Willett WC, Colditz GA, Ascherio A, Rosner B, et al. Prospective study of alcohol consumption and risk of coronary disease in men. Lancet 1991;338:4648.[Medline]
32 Willett WC, Stampfer MJ. Implications of total energy intake for epidemiologic analyses. In: Willett WC, editor. Nutritional epidemiology. New York (NY): Oxford University Press; 1998. p. 273301.
33 Willett WC, Reynolds RD, Cottrell-Hoehner S, Sampson L, Browne ML. Validation of a semi-quantitative food frequency questionnaire: comparison with a 1-year diet record. J Am Diet Assoc 1987;87:437.[Medline]
34 Willett WC, Sampson L, Stampfer MJ, Rosner B, Bain C, Witschi J, et al. Reproducibility and validity of a semiquantitative food frequency questionnaire. Am J Epidemiol 1985;122:5165.[Abstract]
35 Rimm EB, Giovannucci EL, Stampfer MJ, Colditz GA, Litin LB, Willett WC. Reproducibility and validity of an expanded self-administered semiquantitative food frequency questionnaire among male health professionals. Am J Epidemiol 1992;135:111426; discussion 112736.
36 Feskanich D, Rimm EB, Giovannucci EL, Colditz GA, Stampfer MJ, Litin LB, et al. Reproducibility and validity of food intake measurements from a semiquantitative food frequency questionnaire. J Am Diet Assoc 1993;93:7906.[Medline]
37 Rothman KJ. Stratified analysis. In: Modern epidemiology. Boston (MA): Little, Brown and Company; 1986. p. 177236.
38 Cupples LA, D'Agostino RB, Anderson K, Kannel WB. Comparison of baseline and repeated measure covariate techniques in the Framingham Heart Study. Stat Med 1988;7:20522.[Medline]
39 D'Agostino RB, Lee ML, Belanger AJ, Cupples LA, Anderson K, Kannel WB. Relation of pooled logistic regression to time dependent Cox regression analysis: the Framingham Heart Study. Stat Med 1990;9: 150115.[Medline]
40 DerSimonian R, Laird N. Meta-analysis in clinical trials. Control Clin Trials 1986;7:17788.[Medline]
41 Willett WC. Issues in analysis and presentation of dietary data. In: Willett WC, editor. Nutritional epidemiology. New York (NY): Oxford University Press; 1998. p. 32145.
42 Norman AW. Vitamin D. In: Brown ML, editor. Present knowledge in nutrition. Washington (DC): International Life Sciences Institute, Nutrition Foundation; 1990. p. 10816.
43 Arnaud CD, Sanchez SD. Calcium and phosphorus. In: Brown ML, editor. Present knowledge in nutrition. Washington (DC): International Life Sciences Institute, Nutrition Foundation; 1990. p. 21223.
44 Arbman G, Axelson O, Ericsson-Begodzki AB, Fredriksson M, Nilsson E, Sjodahl R. Cereal fiber, calcium, and colorectal cancer. Cancer 1992;69:20428.[Medline]
45 De Stefani E, Mendilaharsu M, Deneo-Pellegrini H, Ronco A. Influence of dietary levels of fat, cholesterol, and calcium on colorectal cancer. Nutr Cancer 1997;29:839.[Medline]
46 Ferraroni M, La Vecchia C, D'Avanzo B, Negri E, Franceschi S, Decarli A. Selected micronutrient intake and the risk of colorectal cancer. Br J Cancer 1994;70:11505.[Medline]
47 Kune S, Kune GA, Watson LF. Casecontrol study of dietary etiological factors: the Melbourne Colorectal Cancer Study. Nutr Cancer 1987;9:2142.[Medline]
48 La Vecchia C, Braga C, Negri E, Franceschi S, Russo A, Conti E, et al. Intake of selected micronutrients and risk of colorectal cancer. Int J Cancer 1997;73:52530.[Medline]
49 Marcus PM, Newcomb PA. The association of calcium and vitamin D, and colon and rectal cancer in Wisconsin women. Int J Epidemiol 1998;27:78893.[Abstract]
50 Meyer F, White E. Alcohol and nutrients in relation to colon cancer in middle-aged adults. Am J Epidemiol 1993;138:22536.[Abstract]
51 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;54:318690.[Abstract]
52 Bergsma-Kadijk JA, van `t Veer P, Kampman E, Burema J. Calcium does not protect against colorectal neoplasia. Epidemiology 1996;7:5907.[Medline]
53 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;356:13006.[Medline]
54 McMichael AJ, Potter JD. Host factors in carcinogenesis: certain bileacid metabolic profiles that selectively increase the risk of proximal colon cancer. J Natl Cancer Inst 1985;75:18591.[Medline]
55 Peters RK, Pike MC, Garabrant D, Mack TM. Diet and colon cancer in Los Angeles County, California. Cancer Causes Control 1992;3:45773.[Medline]
56 Stemmermann GN, Nomura A, Chyou PH. The influence of dairy and nondairy calcium on subsite large-bowel cancer risk. Dis Colon Rectum 1990;33:1904.[Medline]
57 Kampman E, Slattery ML, Caan B, Potter JD. Calcium, vitamin D, sunshine exposure, dairy products and colon cancer risk (United States). Cancer Causes Control 2000;11:45966.[Medline]
58 van Boekel MA, Goeptar AR, Alink GM. Antimutagenic activity of casein against MNNG in the E. coli DNA repair host-mediated assay. Cancer Lett 1997;114:857.[Medline]
59 Allen LH. Calcium bioavailability and absorption: a review. Am J Clin Nutr 1982;35:783808.[Medline]
60 Schaafsma G. Bioavailability of calcium and magnesium. Eur J Clin Nutr 1997;51 Suppl 1:S136.[Medline]
61
Greenlee RT, Murray T, Bolden S, Wingo PA. Cancer statistics, 2000. CA Cancer J Clin 2000;50:733.
Manuscript received August 6, 2001; revised December 28, 2001; accepted January 28, 2002.
This article has been cited by other articles in HighWire Press-hosted journals:
![]() |
||||
|
Oxford University Press Privacy Policy and Legal Statement |