Affiliations of authors: Department of Biomedical Sciences, Dental School (LCC, RBF, PF), and Greenebaum Cancer Center (MT), University of Maryland, Baltimore, MD.
Correspondence to: Leslie Costello, PhD, Deartment of Biomedical Sciences, Dental School, University of Maryland, Baltimore, 666 W. Baltimore St., Baltimore, MD 21201 (e-mail: lcc001{at}dental.umaryland.edu)
Leitzmann et al. (1) reported that the use of zinc supplements in high amounts (i.e., >100 mg/day) or for a prolonged time (i.e., 10 years) was associated with an increased risk of developing advanced prostate cancer. Several issues concerning their study need to be addressed. First, the Ptrend (i.e., <.003) that was reported tested whether the relative risk of advanced prostate cancer was the same among the four dose groups and the nonusers. However, no P values were reported for pair-wise comparisons of each dose group with the nonusers. Although the Ptrend provides information about the differences among all groups, it does not provide the statistical comparison of each zinc-user group with the nonuser group, which is necessary to support the main conclusion of the report. In addition, the 95% confidence interval (i.e., 1.06 to 4.95) that was reported for the relative risk of advanced prostate cancer for men who consumed more than 100 mg of zinc per day versus men who consumed no zinc can indicate only that the P value was less than .05. However, if one were to adjust for multiple comparisons, for example, by using the common Bonferroni correction for each of the four dose groups versus nonusers, a P value of less than .0125 would be required for statistical significance. Therefore, the difference between the greater than 100 mg of zinc per day group and the nonuser group reported by Leitzmann et al. might not, in fact, be statistically significant.
Second, the small sample size is of concern. Leitzmann et al. (1) report only 10 advanced prostate cancer cases among the group of men who consumed 101 mg or more of supplemental zinc per day and only 11 cases among the group that consumed 75100 mg of supplemental zinc per day. We used a chi-square test to compare the proportion of advanced prostate cancer cases among the men who consumed more than 100 mg zinc/day (10 cases of 412 men) with that among the men who did not consume supplemental zinc (317 cases from the total population of 35 121 men). The expected frequency of advanced prostate cancers in men who used zinc was less than 5, which fails to satisfy the requirement for the validity of a large-sample analysis [e.g., see (2)]. The expected frequency for the extended users (23/412) was also less than 5. The small number of advanced prostate cancer cases causes concern about the reliability of the conclusion regarding relative risk because the conclusion depends on the assumption of large sample approximation in calculating standard errors and confidence intervals [e.g., see (3)].
The 20%25% lower relative risk values of some zinc-user groups reported by Leitzmann et al. (1) seemingly indicate a possible protective effect of zinc, as has been reported in another study (4). Unfortunately, Leitzmann et al. (1) do not discuss or refer to any of several published studies [see (5) for review] that report results that conflict with their findings. Discussion of these divergent results would make apparent the complexity and current lack of unanimity regarding this extremely important issue. The absence of such a discussion leads the readers to the erroneous assumption that the Leitzmann et al. report (1) is the sole and incontrovertible study.
In addition, two important relationships should be recognized in regard to all of these studies. First, high cellular zinc levels have been shown to impede the malignant activities of neoplastic prostate cells (6). This finding suggests that treatments to increase cellular zinc accumulation may prevent the development and progression of prostate cancer. Second, ingestion of high levels of zinc decreases the intestinal absorption and assimilation of zinc, which ultimately affects the circulating and tissue levels of zinc (7). Any direct effect of zinc on the normal or malignant prostate cells is dependent on the plasma level of zinc and its uptake by these cells, not simply on the ingested level of zinc. These parameters need to be considered in the analysis and interpretation of any potential effects of dietary zinc on the development and progression of prostate cancer.
Epidemiologic studies have produced contradictory results that lead us to conclude that the effect of dietary zinc on prostate cancer is not only complex but is confounded by unknown factors. Thus, Leitzmann and colleagues are correct to conclude that this association warrants further investigation. Presently, any definitive conclusions about the effects, either beneficial or harmful, of zinc supplementation on prostate cancer risk are, in our view, premature and unfounded. The resolution of this important issue requires well-controlled prospective studies of the efficacy of zinc alone and in combination with other supplements, along with basic research studies to elucidate the mechanisms by which zinc affects normal and malignant prostate.
REFERENCES
1 Leitzmann MF, Stampfer MJ, Wu K, Colditz GA, Willett WC, Giovannucci EL. Zinc supplement use and risk of prostate cancer. J Natl Cancer Inst 2003;95:10047.
2 Altman DG. Practical statistics for medical research. London (U.K.): Chapman and Hall; 1991. p. 253.
3 Woodward M. Epidemiology: study design and data analysis. London (U.K.): Chapman and Hall/CRC; 1999. p. 452.
4 Kristal AR, Stanford JL, Cohen JH, Wicklund K, Patterson RE. Vitamin and mineral supplement use is associated with reduced risk of prostate cancer. Cancer Epidemiol Biomarkers Prev 1999;8:88792.
5 Platz EA, Helzlsouer KJ. Selenium, zinc, and prostate cancer. Epidemiol Rev 2001;23:93101.[ISI][Medline]
6 Costello LC, Franklin RB. The intermediary metabolism of the prostate: a key to understanding the pathogenesis and progression of prostate malignancy. Oncology 2000;59:26982.[CrossRef][ISI][Medline]
7 King JC, Shames DM, Woodhouse LR. Zinc homeostasis in humans. J Nutr 2000;130: 1360S1366S.
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