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Dairy Food, Calcium, and Risk of Cancer in the NIH-AARP Diet and Health Study
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Yikyung Park, ScD; Michael F. Leitzmann, MD; Amy F. Subar, PhD; Albert Hollenbeck, PhD; Arthur Schatzkin, MD
Arch Intern Med. Feb 23 2009;169(4):391-401.
our study is one of the first cohort studies to examine dairy food and calcium intakes in relation to total cancer as well as low-incidence cancers. Moreover, our prospective design avoids the recall and selection biases that can affect results from case-control studies. Our study had high statistical power, with more than 53 000 total cancers and at least 100 cases of most individual cancers. In conclusion, our findings suggest that calcium intake consistent with current recommendations is associated with a lower risk of total cancer in women and cancers of the digestive system, especially colorectal cancer, in both men and women.....RRs for total cancer incidence in women decreased up to approximately 1300 mg/d of total calcium intake, and no further risk reduction was observed above 1300 mg/d.__Dairy food and calcium intakes have been hypothesized to play roles that differ among individual cancer sites. Dairy food, which is relatively high in potentially anticarcinogenic nutrients such as calcium, vitamin D, and conjugated linoleic acid, has been postulated to protect against the development of colorectal and breast cancer.4, 23 Calcium has been shown to reduce proliferation, to stimulate differentiation, and to induce apoptosis in cells in the gastrointestinal tract and breast.24-25 Also, the binding of calcium to bile and fatty acids in the gastrointestinal tract has been hypothesized to reduce damage to large-bowel mucosa.24 Nevertheless, high calcium intake has been hypothesized to increase the risk of prostate cancer by suppressing 1,25(OH)2 vitamin D, thereby offsetting a potential anticarcinogenic effect of vitamin D.26 Dairy food has also been found to increase insulin-like growth factor 1, a potent mitogen associated with an increased risk of prostate cancer.27-28_
For specific cancers in men, dairy food intake was inversely associated with cancers of the head and neck, esophagus, stomach, colorectum, and bladder, whereas it was positively associated with prostate cancer (Table 2). Dietary and supplemental calcium intakes were also significantly inversely associated with colorectal cancer. Total calcium intake was significantly related to a lower risk of colorectal cancer and showed a weak inverse association with kidney cancer. On the other hand, total calcium intake was not related to prostate cancer.
In women, intake of dairy food was significantly inversely associated with colorectal cancer and showed a weak inverse association with stomach cancer (Table 3). Dietary, supplemental, and total calcium intakes were also inversely related to colorectal cancer. Supplemental calcium intake was also inversely associated with liver cancer, while total calcium intake was related to an increased risk of NHL. Dairy food, dietary, supplemental, and total calcium intakes were not related to breast, ovarian, or endometrial cancer.
When we examined the associations among men and women combined, we found that the results for esophageal, stomach, liver, pancreatic, and brain cancer were similar to those for men alone. We also observed that total calcium intake was now significantly inversely associated with kidney cancer (multivariate RRQ5 vs Q1 = 0.77; 95% CI, 0..63-0.94; P for trend, .01).
Overall, our findings suggest that calcium intake plays a role in preventing cancers of the digestive system. However, we cannot exclude the possibility of confounding by vitamin D found in dairy food and supplements. Vitamin D, which is tightly related to calcium regulation in the body, has been inversely associated with digestive system cancers in other studies.44
"Total calcium intake was related to a 16% lower risk of cancers of the digestive system in men (multivariate RRQ5 vs Q1 = 0.84; 95% CI, 0.77-0.92) and a 23% lower risk in women (multivariate RRQ5 vs Q1 = 0.77; 95% CI, 0.69-0.91, Figure 2). Similar inverse association with cancers of the digestive system was observed for dairy food intake in both men and women (data not shown). Total calcium and dairy food intakes were not associated with cancer in any other anatomical systems."
Consistent with previous studies,3, 23 we found that intakes of dairy food and calcium were significantly inversely associated with risk of colorectal cancer. In a pooled analysis of 10 cohort studies,3 a 15% to 20% lower risk of colorectal cancer was observed for total calcium (RR, 0.78; 95% CI, 0.69-0.88 for the highest vs lowest quintile) and milk (RR, 0.85; 95% CI, 0.78-0.94 for <70 g/d vs ≥250 g/d). Furthermore, randomized clinical trials have found that calcium supplementation reduced recurrence of colorectal adenomas, which are precursors of colorectal cancer.30-31
In women, supplemental calcium intake was inversely associated with liver cancer, but it was positively related to NHL. Given that the association with liver cancer was observed only in women and that the number of liver cancer cases was small, this finding is likely due to chance. Few studies45-48 that have investigated the association between dairy food or calcium intake and NHL have suggested that the intake of dairy food was associated with an increased risk of NHL. Further investigation of dairy food and calcium intakes in relation to cancers in liver and NHL is warranted.
The associations between dairy food and calcium intakes and breast cancer have been either null or inverse.4, 49-52 Cohort studies that found dairy food and calcium intakes to be inversely associated with breast cancer suggested that the associations may differ by menopausal status50-51 or estrogen receptor status of the tumor.52 Our study, which was conducted mainly among postmenopausal women, found that dairy food and calcium intakes were not associated with breast cancer. Further studies examining the associations by tumor characteristics of breast cancer and by menopausal status might be informative.
Despite the existence of plausible biologic mechanisms, the effects of dairy food and calcium intakes on prostate cancer are unclear. Epidemiologic studies have found null53-55 as well as positive7, 56-58 associations for intakes of dairy food and calcium. Among studies that observed a positive association between calcium intake and prostate cancer, a significantly increased risk was generally found only with very high calcium intake (2000 mg/d compared with approximately <750 mg/d) or in advanced prostate cancer.7, 56 However, our study found that calcium, even at a very high intake (≥2000 mg/d vs 500-<750 mg/d), was not associated with prostate cancer.59
ABSTRACT
Background- Dairy food and calcium intakes have been hypothesized to play roles that differ among individual cancer sites, but the evidence has been limited and inconsistent. Moreover, their effect on cancer in total is unclear.
Methods- Dairy food and calcium intakes in relation to total cancer as well as cancer at individual sites were examined in the National Institutes of Health (NIH)-AARP (formerly known as the American Association of Retired Persons) Diet and Health Study. Intakes of dairy food and calcium from foods and supplements were assessed with a food frequency questionnaire. Incident cancer cases were identified through linkage with state cancer registries. A Cox proportional hazard model was used to estimate relative risks and 2-sided 95% confidence intervals (CIs).
Results- During an average of 7 years of follow-up, we identified 36 965 and 16 605 cancer cases in men and women, respectively. Calcium intake was not related to total cancer in men but was nonlinearly associated with total cancer in women: the risk decreased up to approximately 1300 mg/d, above which no further risk reduction was observed. In both men and women, dairy food and calcium intakes were inversely associated with cancers of the digestive system (multivariate relative risk for the highest quintile of total calcium vs the lowest, 0.84; 95% CI, 0.77-0.92 in men, and 0.77; 95% CI, 0.69-0.91 in women). Decreased risk was particularly pronounced with colorectal cancer. Supplemental calcium intake was also inversely associated with colorectal cancer risk.
Conclusion- Our study suggests that calcium intake is associated with a lower risk of total cancer and cancers of the digestive system, especially colorectal cancer.
INTRODUCTION
Because of the benefit of calcium on bone health,1 dietary guidance has emphasized intakes of both calcium and dairy food. For example, the Institute of Medicine recommends 1200 mg/d of calcium for adults aged 50 years and older,1 and the 2005 dietary guidelines for Americans2 recommend 3 cups per day of fat-free or low-fat dairy food.
The role of dairy food and calcium intakes in cancer, however, has engendered considerable controversy owing to observations from epidemiologic studies of protective, null, and even positive associations for different organ sites.3-7 Dairy food and calcium intakes have been consistently inversely associated with colorectal cancer,3 whereas few studies have suggested possible inverse associations with lung and breast cancer.4-5 On the other hand, positive associations have been reported for prostate and ovarian cancer.6-7
Because of limited evidence on the relationship of dairy food and calcium intakes to cancers at individual sites, especially cancers with a relatively low incidence, it has been difficult to assess the overall effect of dairy food and calcium intakes on total cancer. Therefore, in a large cohort of men and women, we examined whether intakes of dairy food and calcium were associated with risk of total cancer as well as cancer at multiple individual sites.
RESULTS
During 3 383 377 person-years of follow-up, we identified 36 965 cancer cases in men and 16 605 cancer cases in women. The 10th to 90th percentiles of dietary and total calcium and dairy food intakes were 478 to 1247 mg/d, 526 to 1530 mg/d, and 0.3 to 2.9 servings per day, respectively, in men and 409 to 1101 mg/d, 494 to 1881 mg/d, and 0.3 to 2.7 servings per day, respectively, in women. Dairy food intake was positively correlated with dietary calcium intake (r = 0.83 in men and 0.82 in women) and total calcium intake (r = 0.68 in men and 0.47 in women), and dietary calcium intake was also positively correlated with total calcium intake (r = 0.83 in men and 0.60 in women). The prevalence of calcium-containing multivitamin use was 49% in men and 57% in women, and the prevalence of individual calcium supplement use (≥4 times/wk) was 14% in men and 41% in women.
Compared with participants in the lowest quintile of dairy food or total calcium intake, participants in the highest quintile were more likely to be white, non-Hispanic; college educated; physically active; and current menopausal hormone therapy users if female, but they were less likely to smoke cigarettes and to drink alcohol (Table 1). Women in the highest quintile of total calcium intake had a lower body mass index than those in the lowest quintile.
Total calcium intake was not associated with risk of total cancer incidence in men, but it was nonlinearly associated with the risk of total cancer incidence in women (P for nonlinearity, .05, Figure 1). In nonparametric regression analyses, the RRs for total cancer incidence in women decreased up to approximately 1300 mg/d of total calcium intake, and no further risk reduction was observed above 1300 mg/d. The association between total calcium intake and risk of total cancer did not differ by cancer stages or cancer grades (data not shown). In a secondary analysis excluding nonaggressive prostate cancer that contributed to a large proportion of total cancer cases, we observed a weak inverse association between total calcium intake and total cancer incidence in men. With the lowest quintile of total calcium intake as reference, the multivariate RRs for total cancer incidence in the second through the highest quintile were 1.00, 0.98, 0.99, and 0.96 (95% CI, 0.92-1.02; P for trend, .16) in men.
Dairy food and dietary and supplemental calcium intakes were not related to total cancer incidence in men, whereas dietary calcium, but not dairy food or supplemental calcium, intake was inversely related to total cancer incidence in women (Table 2 and Table 3). When cancers diagnosed during the first 2 years of follow-up were excluded, the association with total cancer became slightly stronger for dietary calcium intake in men (multivariate RR in the highest quintile vs the lowest quintile [RRQ5 vs Q1] = 0.96; 95% CI, 0.92-1.00; P for trend, .05 [n = 27 720 cases]) and for dairy food intake in women (multivariate RRQ5 vs Q1 = 0.93; 95% CI, 0.88-0.99; P for trend, .01 [n = 12 395 cases]).
Death from total cancer and death from cardiovascular disease in relation to dairy food and calcium intakes were examined. Dairy food and dietary, supplemental, and total calcium intakes were not associated with total cancer mortality in both men (n = 8787 deaths) and women (n = 4479 deaths): the multivariate RRQ5 vs Q1 for dairy food and total calcium intakes was 1.05 (95% CI, 0.97-1.14) and 1.02 (95% CI, 0..94-1.11), respectively, in men and 0.93 (95% CI, 0.84-1.04) and 0.97 (95% CI, 0.87-1.08), respectively, in women.
Total calcium intake was related to a 16% lower risk of cancers of the digestive system in men (multivariate RRQ5 vs Q1 = 0.84; 95% CI, 0.77-0.92) and a 23% lower risk in women (multivariate RRQ5 vs Q1 = 0.77; 95% CI, 0.69-0.91, Figure 2). Similar inverse association with cancers of the digestive system was observed for dairy food intake in both men and women (data not shown). Total calcium and dairy food intakes were not associated with cancer in any other anatomical systems.
For specific cancers in men, dairy food intake was inversely associated with cancers of the head and neck, esophagus, stomach, colorectum, and bladder, whereas it was positively associated with prostate cancer (Table 2). Dietary and supplemental calcium intakes were also significantly inversely associated with colorectal cancer. Total calcium intake was significantly related to a lower risk of colorectal cancer and showed a weak inverse association with kidney cancer. On the other hand, total calcium intake was not related to prostate cancer.
In women, intake of dairy food was significantly inversely associated with colorectal cancer and showed a weak inverse association with stomach cancer (Table 3). Dietary, supplemental, and total calcium intakes were also inversely related to colorectal cancer. Supplemental calcium intake was also inversely associated with liver cancer, while total calcium intake was related to an increased risk of NHL. Dairy food, dietary, supplemental, and total calcium intakes were not related to breast, ovarian, or endometrial cancer.
When we examined the associations among men and women combined, we found that the results for esophageal, stomach, liver, pancreatic, and brain cancer were similar to those for men alone. We also observed that total calcium intake was now significantly inversely associated with kidney cancer (multivariate RRQ5 vs Q1 = 0.77; 95% CI, 0.63-0.94; P for trend, .01).
COMMENT
In this large prospective cohort study, we found that total calcium intake was nonlinearly associated with total cancer incidence in women: the risk decreased up to approximately 1300 mg/d, after which no further risk reduction was observed. The associations with dairy food and calcium intakes differed among individual cancer sites. Dairy food and calcium intakes were inversely associated with cancers of the digestive system in both men and women, especially with colorectal cancer. Supplemental calcium intake was also inversely associated with colorectal cancer. Calcium intake was not related to breast or prostate cancer.
Dairy food and calcium intakes have been hypothesized to play roles that differ among individual cancer sites. Dairy food, which is relatively high in potentially anticarcinogenic nutrients such as calcium, vitamin D, and conjugated linoleic acid, has been postulated to protect against the development of colorectal and breast cancer.4, 23 Calcium has been shown to reduce proliferation, to stimulate differentiation, and to induce apoptosis in cells in the gastrointestinal tract and breast.24-25 Also, the binding of calcium to bile and fatty acids in the gastrointestinal tract has been hypothesized to reduce damage to large-bowel mucosa.24 Nevertheless, high calcium intake has been hypothesized to increase the risk of prostate cancer by suppressing 1,25(OH)2 vitamin D, thereby offsetting a potential anticarcinogenic effect of vitamin D.26 Dairy food has also been found to increase insulin-like growth factor 1, a potent mitogen associated with an increased risk of prostate cancer.27-28
We found that total calcium intake was nonlinearly inversely associated with total cancer in women. In contrast, the Women's Health Initiative Study, a randomized clinical trial of daily supplementation of 1000 mg of calcium combined with 400 IU of vitamin D for an average of 7 years, found no effect on total cancer incidence among postmenopausal women (hazard ratio, 0.98; 95% CI, 0.91-1.05 [total cancer cases,1634 in treatment group and 1655 in placebo group]).29 We note, however, that in the Women's Health Initiative Study, two-thirds of women had at least 800 mg/d of the total calcium at baseline and the total number of cancer cases was small.
Consistent with previous studies,3, 23 we found that intakes of dairy food and calcium were significantly inversely associated with risk of colorectal cancer.. In a pooled analysis of 10 cohort studies,3 a 15% to 20% lower risk of colorectal cancer was observed for total calcium (RR, 0.78; 95% CI, 0.69-0.88 for the highest vs lowest quintile) and milk (RR, 0.85; 95% CI, 0..78-0.94 for <70 g/d vs ≥250 g/d). Furthermore, randomized clinical trials have found that calcium supplementation reduced recurrence of colorectal adenomas, which are precursors of colorectal cancer.30-31
A limited number of studies, most with case-control designs, have examined dairy food and calcium intakes in relation to head and neck, esophageal, and stomach cancer. Few studies have observed inverse associations of dairy food and calcium intakes with head and neck32-33 and esophageal cancer34-36; other studies have found no associations with cancer in the head and neck,37 esophagus,38-42 or stomach.34-35,42-43 Our study is one of the first large prospective cohort studies to examine dairy food and calcium intakes in relation to these cancers. We found that intakes of dairy food and dietary calcium were inversely associated with cancers of the digestive system in men, while supplemental and total calcium intakes showed suggestive inverse associations in women. Calcium supplement use in men tended to be less prevalent and consistent and therefore more likely to be measured with error, which may explain why the calcium association in men was reflected in dairy food and dietary calcium intakes. In women, the associations for supplemental and total calcium intakes did not achieve statistical significance, but the numbers of cases of these cancers were small. Overall, our findings suggest that calcium intake plays a role in preventing cancers of the digestive system. However, we cannot exclude the possibility of confounding by vitamin D found in dairy food and supplements. Vitamin D, which is tightly related to calcium regulation in the body, has been inversely associated with digestive system cancers in other studies.44
In women, supplemental calcium intake was inversely associated with liver cancer, but it was positively related to NHL. Given that the association with liver cancer was observed only in women and that the number of liver cancer cases was small, this finding is likely due to chance. Few studies45-48 that have investigated the association between dairy food or calcium intake and NHL have suggested that the intake of dairy food was associated with an increased risk of NHL. Further investigation of dairy food and calcium intakes in relation to cancers in liver and NHL is warranted.
The associations between dairy food and calcium intakes and breast cancer have been either null or inverse.4, 49-52 Cohort studies that found dairy food and calcium intakes to be inversely associated with breast cancer suggested that the associations may differ by menopausal status50-51 or estrogen receptor status of the tumor.52 Our study, which was conducted mainly among postmenopausal women, found that dairy food and calcium intakes were not associated with breast cancer. Further studies examining the associations by tumor characteristics of breast cancer and by menopausal status might be informative.
Despite the existence of plausible biologic mechanisms, the effects of dairy food and calcium intakes on prostate cancer are unclear. Epidemiologic studies have found null53-55 as well as positive7, 56-58 associations for intakes of dairy food and calcium. Among studies that observed a positive association between calcium intake and prostate cancer, a significantly increased risk was generally found only with very high calcium intake (2000 mg/d compared with approximately <750 mg/d) or in advanced prostate cancer.7, 56 However, our study found that calcium, even at a very high intake (≥2000 mg/d vs 500-<750 mg/d), was not associated with prostate cancer.59
Our study has some limitations. First, we did not examine whether associations with intakes of dairy food and calcium differed by tumor subtype or tumor aggressiveness of site-specific cancers. It is possible that we missed some associations that may exist only for certain tumor subtypes or aggressive tumors. Second, although we adjusted for all potential risk factors available in our study for site-specific cancers, residual confounding by unknown or unmeasured risk factors may exist for some cancers. Third, in analyses of low-incidence cancers, especially cancers in women with small numbers of cases, we had limited statistical power to examine an association, and some findings may be attributable to chance. Finally, because diet was assessed only once at baseline, it may not reflect long-term usual intake as accurately as repeated measurements of diet during follow-up. Also, we could not examine whether dairy food and calcium intakes during earlier life periods or lifelong cumulative intakes are related to cancer risk.
Nevertheless, our study is one of the first cohort studies to examine dairy food and calcium intakes in relation to total cancer as well as low-incidence cancers. Moreover, our prospective design avoids the recall and selection biases that can affect results from case-control studies. Our study had high statistical power, with more than 53 000 total cancers and at least 100 cases of most individual cancers. Therefore, substantial effects of dairy food and calcium intakes were unlikely to have been missed. A further strength of our study is that we rigorously controlled for all potential risk factors, including both dietary and lifestyle factors for each site-specific cancer. In conclusion, our findings suggest that calcium intake consistent with current recommendations is associated with a lower risk of total cancer in women and cancers of the digestive system, especially colorectal cancer, in both men and women.
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