Dietary Calcium and Risk for Prostate Cancer
Dietary Calcium and Risk for Prostate Cancer
We found little evidence to support a positive association between calcium intake and prostate cancer risk in this case-control study. On the contrary, we found no association between total calcium and prostate cancer risk and an inverse association between calcium from food and risk for prostate cancer among all men. An inverse association between total calcium and prostate cancer was limited to black men in analyses using healthy controls, although no evidence of an association was found among white men. Also, a high calcium intake correlated with lower risk for high-grade cancer but not low-grade cancer.
One meta-analysis reported that prospective cohort studies suggest a weak positive association between the highest and lowest category of calcium intake and prostate cancer risk and that case-control studies indicate no association. Theoretically, higher calcium intakes could increase prostate cancer risk by reducing the biologically active form of vitamin D, which can inhibit prostate cancer cell growth. This theory may explain, in part, the positive association between prostate cancer risk and high levels of calcium intake. Two prospective studies, for example, observed an elevated risk for prostate cancer for a calcium intake of 2,000 mg per day or more. The mean total calcium intake among our study participants was relatively low, approximately 800 mg per day. According to the US Department of Agriculture, an adequate calcium intake is 1,000 mg per day for men aged 51 to 70 years and 1,200 mg per day for men aged 70 or older. On the basis of these guidelines, only 27% of our study population had adequate calcium intake, so we did not have sufficient variation to test whether extremely high intakes (ie, ≥2,000 mg/d) correlated with prostate cancer risk. Our results suggest that among men with low to moderate calcium intake, an adequate calcium intake (ie, 1,000 mg/d) may reduce the risk for prostate cancer. Viewed alternatively, our study suggests that very low calcium intake may increase prostate cancer risk relative to adequate intake. Coupled with the data that high calcium intake may increase prostate cancer risk, our study supports the notion that most nutrients, particularly micronutrients and specifically calcium, may have a J-shaped or U-shaped relationship with disease, whereby deficiencies and excesses correlate with higher risk and adequate intakes correlate with lower risk.
In our study, calcium supplements contributed approximately 100 mg per day to total calcium in each participant group. Although total calcium intake may be a more informative measure than calcium intake from food only, we observed in analyses of all races inverse associations between prostate cancer and calcium from food but not total calcium. This finding suggests that calcium intake from supplements may not reduce prostate cancer risk as supplement users may expect and that adequate calcium from food sources alone may be sufficient to reduce prostate cancer risk. However, a level of supplemental calcium that could reduce prostate cancer risk and a level that could increase risk should be identified.
Few studies have examined whether associations between calcium and prostate cancer risk differ by race/ethnicity. Skin pigmentation has a strong effect on vitamin D status; people with darker skin have more melanin, which reduces the ability to synthesize vitamin D from sunlight radiation. As a result, blacks are more prone to vitamin D deficiency and reduced levels of calcium absorption. Our finding that blacks have lower calcium intake compared with whites is consistent with the literature. Our results further suggest that calcium intake affects prostate cancer risk differentially by race. The limited number of studies that have considered this possibility found no clear association between dietary calcium and prostate cancer risk among whites or blacks. One study, however, reported a correlation between an increase in dairy consumption and a higher risk for prostate cancer among whites but not blacks. In the same study, ORs for quartiles of calcium intake from food were less than 1 among blacks (P = .06) and greater than 1 among whites (P = .22), although ORs were not statistically significant. Our results also suggest an inverse association between calcium intake and prostate cancer risk among black men but not white men. These results may reflect the lower (but not significantly lower) caloric intake among blacks compared with whites, despite our attempt to control for total calories. Given that most studies of calcium and prostate cancer risk have included samples made up largely of white men and that we show a difference in the effect of calcium on prostate cancer risk between black and white men, future studies are needed to validate our findings and understand the biological mechanisms responsible for our observations.
Dietary factors may impose different risks for subgroups of prostate cancers. Our results are consistent with the lack of an association between calcium and low-grade prostate cancer. In contrast to previous reports of null and positive associations with high-grade prostate cancer, we found an inverse association between high-grade prostate cancer and dietary calcium. Another study also noted lower risk for high-grade prostate cancer (defined as Gleason score 8–10) among men in the Prostate Cancer Prevention Trial who had a high calcium intake. Given the inverse association between calcium intake and prostate cancer risk we observed among black men, we considered the possibility that high-grade prostate cancer was more common in black case patients compared with white case patients and thus responsible for the inverse relationship between calcium intake and high-grade prostate cancer. However, in our study population, 44% of black men and 50% of white men with prostate cancer had high-grade prostate cancer. Again, our finding may imply that adequate calcium intake (ie, 1,000 mg/d) among people with a low- to moderate-calcium diet could reduce the risk for high-grade prostate cancer. We were unable to test the notion that a very high calcium intake may contribute to prostate cancer progression because our sample included few men who had a very high calcium intake.
This study had several limitations. The FFQ may not have included all foods necessary for accurately assessing intake, especially fortified foods and foods unique to certain geographic locations or racial/ethnic groups. This study had biases common to case-control studies. Nonresponse bias may have resulted from the large portion of participants who did not complete the study questionnaires and were excluded from analyses; thus, we cannot exclude the possibility that participants who completed the study questionnaires differed from those who did not. The FFQ required participants to recall their intake in the previous 12 months, which is likely not the etiologically relevant period of exposure, though the exact etiologically relevant time is not known. Recall bias could have been different for cases and controls. We attempted to minimize recall bias by interviewing men before their biopsy and biopsy results. Selection bias was minimized by recruiting all participants from a population of veterans screened for prostate cancer at the DVAMC, but bias is possible if some participants had previous biopsies or an elevated PSA or both. Our sample was small, resulting in limited statistical power and variation in nutrient intakes. Our study was based on data from veterans screened for prostate cancer and receiving care in the VA system, the largest health care system in the United States and an equal-access setting; therefore, generalizability of our findings to non-VA populations is uncertain. The major strength of our study is that the population of veterans at the DVAMC is particularly useful for examining racial disparities because of the equal-access health system and the large proportion of blacks receiving care at the DVAMC.
We observed lower risk for prostate cancer with increasing intakes of calcium from food in both healthy and biopsy-negative controls. The inverse association between total calcium and prostate cancer was limited to black men. Among all men, the highest calcium intake in our study was related to lower risk for high-grade prostate cancer but was not associated with low-grade prostate cancer. Overall, our findings suggest that among men with diets that have moderate to low calcium intake, adequate calcium intake may reduce the risk for prostate cancer, particularly among black men, and reduce the risk for high-grade prostate cancer among all men. Because of the numerous benefits of calcium in preventing chronic diseases, more research is needed to clarify its role in prostate health. In particular, researchers should determine the levels at which dietary calcium may increase the risk for prostate cancer and examine whether the effect of calcium on prostate cancer risk differs by race/ethnicity.
Discussion
We found little evidence to support a positive association between calcium intake and prostate cancer risk in this case-control study. On the contrary, we found no association between total calcium and prostate cancer risk and an inverse association between calcium from food and risk for prostate cancer among all men. An inverse association between total calcium and prostate cancer was limited to black men in analyses using healthy controls, although no evidence of an association was found among white men. Also, a high calcium intake correlated with lower risk for high-grade cancer but not low-grade cancer.
One meta-analysis reported that prospective cohort studies suggest a weak positive association between the highest and lowest category of calcium intake and prostate cancer risk and that case-control studies indicate no association. Theoretically, higher calcium intakes could increase prostate cancer risk by reducing the biologically active form of vitamin D, which can inhibit prostate cancer cell growth. This theory may explain, in part, the positive association between prostate cancer risk and high levels of calcium intake. Two prospective studies, for example, observed an elevated risk for prostate cancer for a calcium intake of 2,000 mg per day or more. The mean total calcium intake among our study participants was relatively low, approximately 800 mg per day. According to the US Department of Agriculture, an adequate calcium intake is 1,000 mg per day for men aged 51 to 70 years and 1,200 mg per day for men aged 70 or older. On the basis of these guidelines, only 27% of our study population had adequate calcium intake, so we did not have sufficient variation to test whether extremely high intakes (ie, ≥2,000 mg/d) correlated with prostate cancer risk. Our results suggest that among men with low to moderate calcium intake, an adequate calcium intake (ie, 1,000 mg/d) may reduce the risk for prostate cancer. Viewed alternatively, our study suggests that very low calcium intake may increase prostate cancer risk relative to adequate intake. Coupled with the data that high calcium intake may increase prostate cancer risk, our study supports the notion that most nutrients, particularly micronutrients and specifically calcium, may have a J-shaped or U-shaped relationship with disease, whereby deficiencies and excesses correlate with higher risk and adequate intakes correlate with lower risk.
In our study, calcium supplements contributed approximately 100 mg per day to total calcium in each participant group. Although total calcium intake may be a more informative measure than calcium intake from food only, we observed in analyses of all races inverse associations between prostate cancer and calcium from food but not total calcium. This finding suggests that calcium intake from supplements may not reduce prostate cancer risk as supplement users may expect and that adequate calcium from food sources alone may be sufficient to reduce prostate cancer risk. However, a level of supplemental calcium that could reduce prostate cancer risk and a level that could increase risk should be identified.
Few studies have examined whether associations between calcium and prostate cancer risk differ by race/ethnicity. Skin pigmentation has a strong effect on vitamin D status; people with darker skin have more melanin, which reduces the ability to synthesize vitamin D from sunlight radiation. As a result, blacks are more prone to vitamin D deficiency and reduced levels of calcium absorption. Our finding that blacks have lower calcium intake compared with whites is consistent with the literature. Our results further suggest that calcium intake affects prostate cancer risk differentially by race. The limited number of studies that have considered this possibility found no clear association between dietary calcium and prostate cancer risk among whites or blacks. One study, however, reported a correlation between an increase in dairy consumption and a higher risk for prostate cancer among whites but not blacks. In the same study, ORs for quartiles of calcium intake from food were less than 1 among blacks (P = .06) and greater than 1 among whites (P = .22), although ORs were not statistically significant. Our results also suggest an inverse association between calcium intake and prostate cancer risk among black men but not white men. These results may reflect the lower (but not significantly lower) caloric intake among blacks compared with whites, despite our attempt to control for total calories. Given that most studies of calcium and prostate cancer risk have included samples made up largely of white men and that we show a difference in the effect of calcium on prostate cancer risk between black and white men, future studies are needed to validate our findings and understand the biological mechanisms responsible for our observations.
Dietary factors may impose different risks for subgroups of prostate cancers. Our results are consistent with the lack of an association between calcium and low-grade prostate cancer. In contrast to previous reports of null and positive associations with high-grade prostate cancer, we found an inverse association between high-grade prostate cancer and dietary calcium. Another study also noted lower risk for high-grade prostate cancer (defined as Gleason score 8–10) among men in the Prostate Cancer Prevention Trial who had a high calcium intake. Given the inverse association between calcium intake and prostate cancer risk we observed among black men, we considered the possibility that high-grade prostate cancer was more common in black case patients compared with white case patients and thus responsible for the inverse relationship between calcium intake and high-grade prostate cancer. However, in our study population, 44% of black men and 50% of white men with prostate cancer had high-grade prostate cancer. Again, our finding may imply that adequate calcium intake (ie, 1,000 mg/d) among people with a low- to moderate-calcium diet could reduce the risk for high-grade prostate cancer. We were unable to test the notion that a very high calcium intake may contribute to prostate cancer progression because our sample included few men who had a very high calcium intake.
This study had several limitations. The FFQ may not have included all foods necessary for accurately assessing intake, especially fortified foods and foods unique to certain geographic locations or racial/ethnic groups. This study had biases common to case-control studies. Nonresponse bias may have resulted from the large portion of participants who did not complete the study questionnaires and were excluded from analyses; thus, we cannot exclude the possibility that participants who completed the study questionnaires differed from those who did not. The FFQ required participants to recall their intake in the previous 12 months, which is likely not the etiologically relevant period of exposure, though the exact etiologically relevant time is not known. Recall bias could have been different for cases and controls. We attempted to minimize recall bias by interviewing men before their biopsy and biopsy results. Selection bias was minimized by recruiting all participants from a population of veterans screened for prostate cancer at the DVAMC, but bias is possible if some participants had previous biopsies or an elevated PSA or both. Our sample was small, resulting in limited statistical power and variation in nutrient intakes. Our study was based on data from veterans screened for prostate cancer and receiving care in the VA system, the largest health care system in the United States and an equal-access setting; therefore, generalizability of our findings to non-VA populations is uncertain. The major strength of our study is that the population of veterans at the DVAMC is particularly useful for examining racial disparities because of the equal-access health system and the large proportion of blacks receiving care at the DVAMC.
We observed lower risk for prostate cancer with increasing intakes of calcium from food in both healthy and biopsy-negative controls. The inverse association between total calcium and prostate cancer was limited to black men. Among all men, the highest calcium intake in our study was related to lower risk for high-grade prostate cancer but was not associated with low-grade prostate cancer. Overall, our findings suggest that among men with diets that have moderate to low calcium intake, adequate calcium intake may reduce the risk for prostate cancer, particularly among black men, and reduce the risk for high-grade prostate cancer among all men. Because of the numerous benefits of calcium in preventing chronic diseases, more research is needed to clarify its role in prostate health. In particular, researchers should determine the levels at which dietary calcium may increase the risk for prostate cancer and examine whether the effect of calcium on prostate cancer risk differs by race/ethnicity.
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