In this large population-based cohort study, we observed that ten-year average intake of supplemental zinc was associated with a small, non-statistically significant reduced risk of prostate cancer overall. However, risk of advanced prostate cancer (regionally invasive or distant metastatic) decreased significantly with greater intake of supplemental zinc. Dietary zinc and total zinc intake (diet plus10-yr average supplemental zinc) were not associated with prostate cancer risk.
There have been only a few prior epidemiological studies of supplemental zinc and prostate cancer, and these have had divergent findings. In a case-control study, Kristal et al
. found a significant inverse association for single zinc supplement use of 7 days/week compared to no-use (OR = 0.55, 95% CI 0.30 – 1.00, p for trend = 0.04), which was the strongest association of seven supplements studied [12
]. The association was similar when limited to advanced disease (OR = 0.65, 95%CI 0.33 – 1.25), but no longer statistically significant. In the Health Professionals Follow-up Study, neither high dose of supplemental zinc nor long duration of supplemental zinc use (from multivitamins and individual supplements) was associated with risk of prostate cancer [13
]. However, when the analysis was restricted to advanced or fatal prostate cancer, both high dose per day (RR = 2.29, 95% CI 1.06 – 4.95, for >100 mg/day vs. none, p for trend =0.003) and long duration (RR = 2.37, 95% CI 1.42 – 3.95, for 10+ years vs. none, p for trend <0.001) were associated with increased
risk. The only randomized clinical trial to our knowledge with zinc as part of the intervention and with prostate cancer reported as an outcome was the S.U.V.I.M.A.X. trial which demonstrated a moderate, non-significant reduction in prostate cancer risk (HR = 0.88, CI 0.60 – 1.29) after 8 years of follow-up [14
]. However, this trial randomized men to either a placebo or a supplement with nutritional doses of vitamin C, vitamin E, beta-carotene, selenium, and zinc, so the effect of zinc cannot be separated from the effect of this combination of minerals and vitamins. This trial reported an almost 50% statistically significant risk reduction among men with normal baseline PSA (<3 micro/L) and a borderline statistically significant increased
risk among those with elevated PSA at baseline, suggesting that this combination may have an adverse effect on already established or faster growing tumors. Our findings of a reduced risk of advanced prostate cancer associated with zinc supplement use are most consistent with those of Kristal et al
., and are in direct contrast to those from the Health Professional Study.
Our results exploring dietary zinc intake are consistent with two previous observational studies, which found no association with prostate cancer risk [16
]. These two case-control studies were from geographically distinct locations—Utah [17
] and China [16
]. We found no association between total (dietary plus supplemental) zinc intake and prostate cancer risk, consistent with an observational study by Key et al
]. In contrast, two case-control studies, one in Hawaii [19
] on total zinc intake and one in Italy on dietary intake only [15
], found statistically significant increased risks among men consuming the highest amounts of zinc. Studies of blood or toenail measures of zinc status and prostate cancer risk have generally been quite small; two reported a significant decreased risk associated with higher zinc status [23
], while one found no association [25
Several factors affect zinc absorption. It is well-established that zinc absorption is reduced when zinc status is high [26
] . Therefore we hypothesized that zinc supplement use would provide the most benefit to those with lower zinc intake; however our results did not support this. Zinc absorption is also inhibited by phytic acid found in vegetables and grains [27
]. We found an inverse association between supplemental zinc and prostate cancer in those men with high consumption of vegetables, suggesting that supplemental zinc may be beneficial among those who absorb less zinc due to the phytate content of the diet.
Our study had several strengths, including a large sample size, a prospective design, detailed assessment of exposure, and the ability to control potential confounders. Assessment of supplement intake included exact composition of multivitamins (one of the major sources of zinc intake), thereby, distinguishing between regular multivitamins and those marketed for “men’s health” with higher amounts of zinc. A validation study of our supplement assessment for other nutrients showed excellent correlation with supplements recorded at a home visit and with biomarkers of nutrient status [30
]. Due to the prospective design of our study, any measurement error in the assessment of zinc intake from supplements or diet should not have been differential between cases and controls.
Another strength of our study was our attempt to separate the effects of supplemental zinc per se
from the health behavior of taking multivitamin pills. About 80% of men who consume supplemental zinc get it from multivitamins only, and furthermore, a large majority of men who take individual zinc supplements also take multivitamins. Therefore, it is difficult to separate the effect of use of multivitamins from any effect of zinc itself. The increased risk of prostate cancer associated with multivitamin use in this study () may be attributed to bias due to a correlation between multivitamin use and PSA screening. The increased risk could also represent a real adverse effect of multivitamins on prostate cancer risk as supported by two recent studies [31
]. We attempted to separate the effect of supplemental zinc from use of multivitamins using three methods: a) we controlled for multivitamin use in all analyses, b) we created an upper category of 10-year average dose of supplemental zinc that could only be achieved by use of individual supplements or formulations of multivitamins with high zinc (e.g. those marketed for “men’s heath”) and not by 10 year daily use of common multivitamin formulations (commonly containing 15 mg zinc), and c) we directly looked at zinc supplement use other than multivitamin use (from individual supplements and other combinations).
Limitations of this study included its primarily Caucasian and well-educated population; these factors may affect the generalizability of our results. There also may have been some men that had asymptomatic, undiagnosed prostate cancer leading to inclusion as a “non-case” and this may obscure a potential association between zinc intake and prostate cancer risk. We also had a short follow-up, however, we assessed supplement zinc intake over the last 10 years prior to baseline, which may be reasonable period of time relevant to prostate cancer development. Another limitation is that we only had information about previous PSA-testing within 2 years prior to baseline but not after baseline. Since detection of early stage prostate cancer is highly dependent on having a PSA test, our finding that zinc supplementation only reduced the risk of advanced disease may be due to the limitation of incomplete control for PSA screening, rather that due to a mechanism whereby zinc only slows prostate cancer progression but does not affect initiation.
Although zinc supplements have been promoted as beneficial for “men’s health” with implications for a consequent reduction in prostate cancer risk, we did not observe a significant association in this cohort. We did, however, find a significant reduced risk among men who have high vegetable intake (with possible low zinc absorption) and in late-stage prostate cancer. Thus, our results provide partial support for the meaningful biological mechanisms that suggest an important role of zinc in the prostate. If future studies support these results, it may suggest that zinc supplements may be beneficial for some subgroups of men or for the most adverse forms of the disease.