Original Communication Prospective study on milk products, calcium and cancers of the colon and rectum

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1 (2001) 55, ß 2001 Nature Publishing Group All rights reserved /01 $ Original Communication Prospective study on milk products, calcium and cancers of the colon and rectum RJärvinen 1 *, P Knekt 2,3, T Hakulinen 4,5 and A Aromaa 2,3 1 Department of Clinical Nutrition, University of Kuopio, Kuopio, Finland; 2 National Public Health Institute, Helsinki, Finland; 3 The Social Insurance Institution, Helsinki and Turku, Finland; 4 Finnish Cancer Registry, Helsinki, Finland; and 5 Unit of Cancer Epidemiology, Radiumhemmet, Karolinska Institute, Stockholm, Sweden Objective: To study the relationship between consumption of milk and milk products, calcium, lactose and vitamin D and occurrence of colorectal cancers. Design: Prospective cohort study. Subjects: A total of 9959 men and women aged 15 y or older without history of cancer at baseline. During a 24 y follow-up, 72 new cancers of the large bowel (38 in the colon and 34 in the rectum) were detected. Results: Consumption of milk and total milk products was suggested to be inversely related to colon cancer incidence, whereas no similar association was seen for rectal cancer. The relative risk between the highest and lowest quartiles of intake adjusted for potential confounding factors was 0.46 (95% confidence interval , P for trend 0.09) for milk and 0.37 (95% CI ¼ , P for trend 0.06) for total milk products. Lactose intake showed a similar inverse relationship with colon cancer: the relative risk was 0.31 (95% CI ¼ , P for trend 0.03). Intake of vitamin D or total dietary calcium was not significantly related to colorectal cancer risk, whereas calcium provided by fermented milk products was associated with increased colorectal cancer incidence; in the highest quartile the multivariate adjusted relative risk for colorectal cancer was 2.07 (95% CI ¼ ). Conclusions: Our results indicate that individuals showing high consumption of milk have a potentially reduced risk of colon cancer; however, the association does not appear to be due to intake of calcium, vitamin D, or to specific effects of fermented milk. Sponsorship: This study was supported by a grant from the Swedish Cancer Foundation. Descriptors: cohort studies; colorectal neoplasms; dietary calcium; lactose; milk; vitamin D (2001) 55, Introduction Colorectal cancer is one of the most common cancers found in affluent countries. Despite the presence of a hereditary component, colorectal cancers are closely associated with environmental factors, as indicated by ecological comparisons, immigrant studies, and animal experiments (Potter, 1996; Lipkin et al, 1999). Dietary calcium is hypothesized to be protective against colorectal cancers. In vitro studies *Correspondence: R Järvinen, Department of Clinical Nutrition, University of Kuopio, PO Box 1627, Fin Kuopio, Finland. Ritva.Jarvinen@uku.fi Guarantors: R Järvinen and P Knekt. Contributors: RJ prepared the manuscript and interpreted the results. PK designed the study and carried out the statistical analyses. TH provided the cancer incidence data. AA prepared the baseline data. All investigators contributed to the paper. Received 6 November 2000; revised 24 April 2001; accepted 28 April 2001 and experiments in animals, also partly supported by human intervention studies, indicate that high calcium intake can decrease proliferation of colonic cells and inhibit colon neoplasms (Baron et al, 1999; Holt, 1999; Lipkin et al, 1999). Calcium may combine with bile acids and free fatty acids, thereby reducing their toxic effects in the lumen of the colon (Newmark et al, 1984). Furthermore, calcium has direct antiproliferative and differentiation-inducing effects on colonic epithelial cells (Lipkin et al, 1999). It has been shown that calcium, especially in combinations as found in milk, effectively precipitates luminal cytolytic substances and reduces cytotoxicity of fecal water, an accepted risk marker for colon cancer (Govers et al, 1996; Glinghammar et al, 1997). In general, the epidemiological evidence does not suggest an important effect of calcium intake on the risk of colorectal cancers (Bergsma- Kadijk et al, 1996; Jain, 1998; Martinez & Willett, 1998). Nevertheless, two previous prospective studies presented significant reduced risks of colorectal cancers with high calcium intake levels (Garland et al, 1985; Pietinen et al, 1999), and suggestive inverse relationships between

2 calcium intake and colon cancer risk have been reported in other prospective studies (Bostick et al, 1993; Kato et al, 1997). The active hormone form of vitamin D plays an important role in calcium homeostasis but it may also have direct antiproliferative effects on cancer cells, including cells of the large intestine (Lipkin et al, 1999). Epidemiological evidence on the relationship between vitamin D intake and colorectal cancer is, however, inconclusive (Potter, 1996; Jain, 1998; Martinez & Willett, 1998). Lactose is a nutrient occurring almost exclusively in milk, whose relationship to colorectal cancer risk has been rarely reported. Fermented milk products may affect colorectal cancer development by modifying intestinal microflora and colonic metabolisms (Goldin & Gorbach, 1984; Fernandes & Shahani 1990; Lidbeck et al, 1992). However, observations from analytical epidemiologic studies have not greatly supported this hypothesis (Kampman et al, 1994a c; Boutron et al, 1996; Kearney et al, 1996). Milk is one of the staple foods of the Finnish diet, and milk consumption by Finns is among the highest in the world. The use of fermented milk, mainly buttermilk and cultured whole milk, also has a long tradition in Finland. Our intention was to study the relationship between intake of different dairy products, dietary calcium, vitamin D, and lactose and the risk of large bowel cancers in a longitudinal study based on a cohort of Finnish men and women. Population and methods The Social Insurance Institution s Mobile Clinic carried out a large-scale health examination survey in Finland during Total populations or random samples of populations from rural, semiurban and industrial communities in six different geographical regions were investigated. Approximately one in five of the participants were interviewed for their dietary habits in The number of participants with available dietary data and without diagnosed cancer at baseline was 9959, forming the population cohort of the present study. Data on habitual food consumption of the participants during the proceeding year were collected in an interview performed by trained personnel. A performed questionnaire listing more than 100 different foods common in the diet of Finns at that time was used to guide the interviews. Consumption of foods was estimated per day, week, month or year according to choice of the respondent. Plastic or rubber food models or samples of food were used to aid estimation of the amount of food consumed. Intakes of individual food items eaten as such or provided as a part of mixed dishes were computed per day. A food composition database used to calculate the intakes of nutrients and covering all food items was compiled, based on Finnish food composition tables (Rastas et al, 1989). More detailed description of the dietary survey method and reproducibility of the dietary data over shortterm and long-term intervals was presented in a previous study (Järvinen et al, 1993). Intraclass correlations coefficients for the intake of milk and milk products, dietary calcium and lactose between measurements repeated 4 7 y apart varied from 0.53 to 0.55, whereas the correlation coefficients for cheese consumption (0.30) and dietary vitamin D (0.42) were lower. A mailed questionnaire checked by the study nurse during the baseline examination provided data on sociodemographic factors, medical history, smoking, and use of medicines and vitamin supplements. Height and weight in light indoor clothing without shoes were measured and body mass index (kg=m 2 ) was calculated to estimate the degree of obesity. Cancer cases occurring in the cohort were identified through linkage to the Finnish Cancer Registry, which has a nearly complete record of all cancer cases diagnosed in Finland (Teppo et al, 1994). All primary colorectal cancer cases were included in the analyses. Each subject in the baseline population with available dietary data and with no diagnosed cancer was considered to be at risk. During a follow-up until late 1991, a total of 72 colorectal cancer cases (38 in the colon and 34 in the rectum) were diagnosed (International Classification of Diseases, seventh revision, codes ; World Health Organization, 1955). The mean follow-up time from the date of baseline examination to the diagnosis of colorectal cancer, death or December 31, 1991 was 19.6 y. The number of men and women with colorectal cancer was the same, but there were more women (n ¼ 23) among the colon cancer cases and more men (n ¼ 21) among the rectal cancer cases. At baseline colorectal cancer cases were older (mean age 53.7 y) than the noncases (mean age 39.0 y) and their body mass index was nonsignificantly higher than that of the noncases; the age and sex-adjusted mean body mass index values were 25.2 and 24.8 kg=m 2, respectively. Colorectal cancer cases did not differ from the others by the type of region, occupation or smoking habits (data not shown). The associations between dietary variables and risks of cancers in the colon, rectum, and colon and rectum combined were investigated, using Cox s proportional hazards model (Cox, 1972). This model provides the relative hazard as a measure of relative estimate. The relative risks and the 95% confidence intervals were calculated between quartiles of the dietary variables, using the lowest quartile as the reference category. Quartile ranges were determined separately for men and women. Multivariate analyses including adjustments for age, sex, body mass index, occupation, smoking, geographical region and dietary energy intake were carried out. Age, body mass index and energy intake were added as continuous variables in the model whereas occupation (agricultural, industrial, services, white collar, housewives), smoking (never smoker, ex-smoker, smoker of pipe or cigar, current smoker of < 15 cigattes=day, current smoker of 15 cigarettes=day), and geographical area (six regions) were included as categorical variables. Further adjustment for other potential dietary confounders, such as folic acid and dietary fiber, or excluding cancer cases diagnosed during the first year of the follow-up 1001

3 1002 whose dietary habits could have changed due to developing cancer, did not noticeably affect the results (data not shown). A test for trend was performed by introducing the dietary variable as a continuous variable in the model. A linear regression model was used to calculate age- and sex-adjusted intakes of foods and nutrients among colorectal cancer cases and noncases. Results The mean consumption of milk and other dairy products and intakes of calcium, lactose, and vitamin D did not differ significantly between colorectal cancer cases and noncases (Table 1). However, consumption of milk and total milk products and intake of calcium and lactose was nonsignificantly lower among the colorectal cancer cases. Correlation coefficients calculated between the dietary variables demonstrate close relationships (r > 0.8) between consumption of milk (mainly whole milk) and milk products and intakes of calcium and lactose (Table 2). Use of Table 1 Mean daily intake of different dairy products, related nutrients and intake of energy among colorectal cancer cases and noncases at baseline Daily intake a Colorectal cancer cases (n ¼ 72) Noncases (n ¼ 9887) P-value Milk products (g) b Milk (g) c Fermented milk (g) d Cheese (g) Cream (g) Ice cream (g) Butter (g) Calcium (mg) Vitamin D (mg) Lactose (g) Energy (MJ) a Adjusted for age and sex. b Butter not included. c Whole milk, low-fat and skimmed milk. d Buttermilk, cultured whole milk, yoghurt. fermented milk (mainly buttermilk and cultured whole milk) was inversely related to milk consumption. Consumption of cheese and other milk products, eg cream and ice cream, was not closely correlated with other variables. Intake of vitamin D showed low correlations (r ¼ 0.3) with consumption of milk and milk products. Milk fortified by vitamins was not available in Finland at the time of the baseline study. A nonsignificant inverse relationship between total consumption of milk products and colon cancer risk was demonstrated; the relative risk (adjusted for age, sex, body mass index, occupation, smoking, geographical region, and energy intake) between the highest and lowest quartile of intake was 0.37 (95% confidence interval ¼ , P for trend 0.06; Table 3). This association was apparently attributed mainly to consumption of milk, which showed a similar nonsignificant inverse relationship with colon cancer risk, whereas consumption of fermented milk was not associated with colon cancer risk, and the risk of colon cancer was nonsignificantly increased with higher cheese consumption (Table 3). On the other hand a nonsignificant increased risk for rectal cancer was found with higher consumption of total milk products and higher consumption of fermented milk. Consumption of other milk products, eg cream and ice cream, was not associated with colorectal cancer risk (results not shown). Butter consumption (not included in total milk products) was not associated with colon cancer occurrence, but a nonsignificantly increased risk of rectal cancer was suggested at the highest level of butter consumption (Table 3). Calcium intake was not significantly associated with the risk for colon or rectal cancers. Multivariate adjusted relative risk between the highest and lowest quartile was 0.63 (95% CI ¼ , P for trend 0.17) for colon cancer and 3.01 (95% CI ¼ , P for trend 0.19) for rectal cancer (Table 4). Lactose intake was nonsignificantly associated with cancers of the rectum and colon and rectum combined, but showed an inverse relationship with the occurrence of colon cancer; multivariate adjusted relative risk was 0.31 (95% CI ¼ , P for trend 0.03) in the highest versus lowest quartile of lactose intake. Dietary vitamin D was not associated with colon cancer risk, Table 2 Correlation coefficients a between intakes of different dairy products, related nutrients and dietary energy (n ¼ 9959) Dietary variable Milk products Milk Fermented milk Cheese Cream Ice cream Butter Calcium Vitamin D Lactose Energy Milk products 1.00 Milk Fermented milk Cheese Cream Ice cream Butter Calcium Vitamin D Lactose Energy a Pearson s correlation coefficient.

4 Table 3 Relative risks (RR) a and 95% confidence intervals (CI) for colorectal cancers by quartiles of intake of different dairy products Quartile ranges Colon cancer (n ¼ 38) Rectum cancer (n ¼ 34) Both cancers (n ¼ 72) 1003 Quartile of daily intake (g) Men Women No. of cases RR 95% CI No. of cases RR 95% CI No. of cases RR 95% CI Milk products b 1 < 693 < > 1271 > P-value for trend Milk c 1 < 511 < > 1131 > P-value for trend Fermented milk d 1 < 1 < > 160 > P-value for trend Cheese 1 < 3 < > 18 > P-value for trend Butter 1 < 36 < > 67 > P-value for trend a Adjusted for age, sex, body mass index, occupation, smoking, geographical area, and intake of energy. b Butter not included. c Whole milk, low-fat and skimmed milk. d Buttermilk, cultured whole milk, yoghurt. whereas a nonsignificant increased risk for rectal cancer at the highest intake level of vitamin D was suggested (Table 4). A small proportion of subjects (2.4%) reported use of vitamin D supplements. The relative risk for colorectal cancers among users of vitamin D supplements compared with nonusers was 0.58 (95% CI ¼ ) in analysis adjusting for nondietary factors, dietary energy, and intake of vitamin D from food. It was not possible to estimate the relationship between the use of calcium supplements and colorectal cancer risk due to a very low number of the supplement users (0.4%). To investigate the importance of different milk products and calcium in relation to large bowel cancer in more detail, we also studied the risks of cancers in categories of dietary calcium derived from unfermented milk, fermented milk products, and nondairy sources (Table 5). Dietary calcium provided by unfermented milk or nondairy foods was not significantly related to risk of large bowel cancers, whereas calcium from fermented milk products was associated with increased colorectal cancer risk. Multivariate adjusted relative risk in the highest vs lowest quartile was 3.76 (95% CI ¼ ) for rectal cancer and 2.07 (95% CI ¼ ) for cancers of the rectum and colon combined. Discussion A suggestive inverse relationship between consumption of milk and total milk products and risk of colon cancer was demonstrated in our study population. Among the nutrients provided by milk, lactose intake showed a significant inverse association with incidence of colon cancer, whereas the associations for dietary calcium and vitamin D were nonsignificant. Due to the high correlation between lactose intake and milk consumption, independent association between lactose intake and colon cancer could not be investigated. Although milk consumed by the study population was mainly whole milk, it was unlikely that the demonstrated inverse association with colon cancer was

5 1004 Table 4 Relative risks (RR) a and 95% confidence intervals (CI) for colorectal cancers by quartiles of intake of calcium, lactose and vitamin D Quartile ranges Colon cancer (n ¼ 38) Rectum cancer (n ¼ 34) Both cancers (n ¼ 72) Quartile of daily intake Men Women No. of cases RR 95% CI No. of cases RR 95% CI No. of cases RR 95% CI Calcium (mg) 1 < < P-value for trend Lactose (g) 1 < 32.6 < P-value for trend Vitamin D (mg) 1 < 2.58 < P-value for trend a Adjusted for age, sex, body mass index, occupation, smoking, geographical area, and intake of energy. Table 5 Relative risks (RR) a and 95% confidence intervals (CI) for colorectal cancers according to dietary calcium provided by different foods Quartile ranges Colon cancer (n ¼ 38) Rectum cancer (n ¼ 34) Both cancers (n ¼ 72) Quartile of calcium intake mg Men Women No. of cases RR 95% CI No. of cases RR 95% CI No. of cases RR 95% CI Unfermented milk products b 1 < < P-value for trend Fermented milk products c 1 < 60.6 < P-value for trend Nondairy foods 1 < < P-value for trend a Adjusted for age, sex, body mass index, occupation, smoking, geographical area, and intake of energy. b Whole milk, low-fat and skimmed milk, cream, ice cream. c Buttermilk, cultured whole milk, yoghurt, cheese, quark. due to the presence of milk fat, since no similar association was found for intake of butter, the major dietary fat derived from milk. Lactose intake may affect colon function via different mechanisms. Intake of lactose can favor the growth of lactic acid bacteria, which may have antimutagenic and anticarcinogenic properties (Fernandes & Shahani, 1990; Lidbeck et al, 1992). Unhydrolyzed lactose may have similar beneficial alterations in colonic function as other prebiotics fermented by colonic microflora (Szilagyi, 1998). Only a few previous studies have reported results on the relationship between lactose intake and colorectal cancer risk. In a recent large prospective study on diet and colon cancer risk in males from the USA, age-adjusted

6 analyses suggested a significantly decreased risk with lactose intake; however, in multivariate analysis this association was attenuated (Kearney et al, 1996). Consistent with the findings of several previous studies (Bergsma-Kadijk et al, 1996; Jain, 1998; Martinez & Willett, 1998), dietary calcium was not significantly related to risk of colon cancer or cancers of the colon and rectum combined. The two previous cohort studies that reported a significant inverse relationship between calcium intake and colorectal cancer risk based their findings in men with high average intake level of calcium (Garland et al, 1985; Pietinen et al, 1999). In the present study, calcium intake in men was clearly higher than that in women; however, due to the small number of colon cancer cases we were not able to carry out analyses separately in men and women. In contrast to colon cancer, a nonsignificantly increased risk of rectal cancer was found with higher calcium intake level, mainly due to calcium provided by fermented milk products. However, this association was probably not caused by the intake of calcium per se but by the presence of some other as yet undetermined substance(s) found in fermented milk products or associated with the consumption of these foods. In the present study dietary vitamin D was not found to be beneficial against colorectal cancer. Differences in the use of vitamin supplements and exposure to sunlight may, however, confound the estimates for vitamin D nutrition. In some recent studies suggesting an inverse relationship between vitamin D and colon cancer, the effect was mainly attributed to supplemental vitamin (Bostick et al, 1993; Kearney et al, 1996; Martinez et al, 1996). The potential confounding effect of supplemental vitamin D on colorectal cancer risk was apparently small in the present study, since the number of participants reporting the use of supplements containing vitamin D was small and their risk for colorectal cancers did not differ significantly from that of the others. In line with the findings from another prospective study (Kearney et al, 1996), a nonsignificant positive association was suggested between intake of vitamin D and rectal cancer risk. In the present study population, fish consumption contributed greatly to the intake of dietary vitamin D. In our previous study, we reported an increased colorectal cancer risk with high consumption of salted and smoked fish (Knekt et al, 1999). Despite the implicated beneficial effects of fermented milk in colon metabolism (Fernandes & Shahani, 1990; Lidbeck et al, 1992), no significant relationship between consumption of fermented milk and colorectal cancer risk was found in the present study. Some case control studies reported inverse relationships between consumption of yoghurt and colon=colorectal cancer (Peters et al, 1992; Boutron et al, 1996). Among the present study population fermented milk was mainly buttermilk; yoghurt consumption was very low at the time of the baseline study. Large prospective studies from the USA, The Netherlands, and Finland found no significant associations between total consumption of fermented milk and risk of colon= colorectal cancers (Kampman et al, 1994b; Kearney et al, 1996; Pietinen et al, 1999) or colorectal adenomas (Kampman et al, 1994a). Inconsistencies between the anticipated effects of fermented milk and the findings of epidemiological studies may be dependent on differences in the bacterial species studied experimentally and used in commercial production of fermented milk products (Goldin & Gorbach, 1984; Pool-Zobel et al, 1993). Potential anticarcinogenic properties of bacterial species also vary greatly between the strains and only certain strains of lactic acid bacteria may affect the outcome of colorectal cancers (Lidbeck et al, 1992; Pool-Zobel et al, 1996). Furthermore, lactic acid bacteria commonly used in commercially manufactured fermented milk products survive poorly in the highly acidic gastric milieu (Rambaud et al, 1993; Pedrosa et al, 1995). Cheese represents another food processed by bacterial fermentation. In common with results from previous studies (Kearney et al, 1996; Boutron et al, 1996; Jain, 1998), no indication for a protective effect of cheese consumption against colorectal cancers was found; in contrast, higher cheese consumption was associated with a nonsignificantly elevated colon cancer risk. Similar increased colorectal cancer risk with cheese consumption was also reported in some previous studies (Bidoli et al, 1992; Fernandes et al, 1997). It has been suggested previously that the type of dairy product might be the important factor with regard to colorectal cancer development (Boutron et al, 1996). Among the present study population dietary calcium provided by fermented dairy products (mainly cheese and buttermilk) was associated with an increased risk of colorectal cancers. Although our finding may be due to other dietary or lifestyle factors associated with consumption of fermented milk products, it is possible that these foods may also contain a substance that directly affects the colorectal cancer process. Biogenic amines may be such a group; foods with high protein content and processed by bacterial fermentation or spoiled by bacteria contain variable amounts of different biogenic amines. Especially high concentrations of tyramine have been detected in some cheese varieties (McCabe, 1986). Tyramine is a mutagen precursor which after nitrosation to 3-diazotyramine can induce changes in bacteria and mammalian cell cultures (Wakabayashi et al, 1987) and was shown to be carcinogenic in animal studies (Fujita et al, 1987). Whether biogenic amines from exogenous sources have any importance in colorectal cancer development remains to be evaluated. Although colon and rectal cancers are often considered together, their etiological factors are known to differ in several aspects (Potter, 1996). Although the small number of cancer cases limits the conclusions, our results may indicate that the potential beneficial effect of milk and associated nutrients may be more apparent in colon cancer than in rectal cancer. As a matter of fact, higher consumption of dairy products (Benito et al, 1990) and calcium intake (Kearney et al, 1996) were associated with increased rectal cancer risk. 1005

7 1006 The prospective study design used here was an apparent advantage in our study. Since the dietary data were collected prior to the onset of the disease, potential response bias due to disease status (Malila et al, 1998) was avoided. The long follow-up period in our study suggests that we may have been able to detect risk factors that operate at early stages of carcinogenesis. On the other hand, potential changes in dietary habits during the follow-up may modify the relationship between exposure and outcome. In general, fairly stable consumption patterns over an interval of 4 7 y were suggested for milk and milk products and intake of calcium and lactose in this population (Järvinen et al, 1993). Furthermore, agreement for repeated estimates on the consumption of milk products and calcium intake was found to be approximately similar in different age categories investigated. If dietary data collected in older and younger persons at baseline represented with similar accuracy their diets 20 y later is, however, more questionable. Due to the comprehensive dietary survey method used in the present study, dietary energy intake could be adjusted for in the analysis. Nevertheless, several factors including physical activity, use of aspirin and alcohol consumption, suggested to be important in colorectal cancer development (Potter, 1999), could not be directly accounted for in our analysis. However, adjustment for dietary energy intake could have partly ameliorated the potential confounding effect of physical activity. We adjusted smoking habits in the analyses since heavy smoking was previously associated with colorectal cancer risk among this population (Knekt et al, 1998). 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