High Dose Zinc Increases Hospital Admissions Due to Genitourinary Complications

Physiology/Medical Disease High Dose Zinc Increases Hospital Admissions Due to Genitourinary Complications Aaron R. Johnson, Alejandro Munoz, Justin L. Gottlieb and David F. Jarrard* From the Departments of Surgery (Division of Urology) (ARJ, AM, DFJ) and Ophthalmology and Visual Sciences (JLG), University of Wisconsin School of Medicine and Public Health and University of Wisconsin Comprehensive Cancer Center (DFJ), Madison, Wisconsin

Purpose: Zinc is a common dietary supplement that is widely believed to have beneficial health effects. To assess the impact of high dose supplemental zinc on genitourinary diseases we analyzed a recent randomized trial comparing zinc, antioxidants and their combination to placebo for complications related to the genitourinary tract. Materials and Methods: In a further analysis of the recent Age-related Eye Disease Study we examined the data pool for primary International Classification of Diseases, 9th revision codes given for hospital admissions related to urological problems. The Age-Related Eye Disease Study randomized 3,640 patients with age related macular degeneration to 1 of 4 study arms, including placebo, antioxidants (500 mg vitamin C, 400 IU vitamin E and 15 mg ␤-carotene), 80 mg zinc and antioxidant plus zinc. Statistical analyses using Fisher’s exact test were performed. Results: We found a significant increase in hospital admissions due to genitourinary causes in patients on zinc vs nonzinc formulations (11.1% vs 7.6%, p ⫽ 0.0003). The risk was greatest in male patients (RR 1.26, 95% CI 1.07–1.50, p ⫽ 0.008). In the study group of 343 patients requiring hospital admission the most common primary International Classification of Diseases, 9th revision codes included benign prostatic hyperplasia/urinary retention (benign prostatic hyperplasia), urinary tract infection, urinary lithiasis and renal failure. When comparing zinc to placebo, significant increases in urinary tract infections were found (p ⫽ 0.004), especially in females (2.3% vs 0.4%, RR 5.77, 95% CI 1.30 –25.66, p ⫽ 0.013). Admissions for urinary lithiasis approached significance in men on zinc compared to placebo (2.0% vs 0.5%, RR ⫽ 4.08, 95% CI 0.87–19.10). There was no increase in prostate or other cancers with zinc supplementation. A significant decrease in prostate cancer diagnoses was seen in patients receiving antioxidants vs placebo (RR ⫽ 0.6, 95% CI 0.49 – 0.86, p ⫽ 0.049). Subgroup analysis revealed that this finding was significant in men who smoked but not in nonsmokers. Conclusions: Zinc supplementation at high levels results in increased hospitalizations for urinary complications compared to placebo. These data support the hypothesis that high dose zinc supplementation has a negative effect on select aspects of urinary physiology. Key Words: prostate, prostatic neoplasms, zinc, prostatic hyperplasia, complications

porter down-regulation.3 This led to concern that increased zinc intake may potentiate BPH development and progression.4 In a case-control study from Greece higher intakes of dietary zinc from meat and seed sources had the most significant correlation with the overall risk of BPH (OR 1.89).5 In contrast, zinc levels are decreased in prostate cancer, leading to the proposition that zinc may have a protective role against prostate cancer.3 Zinc was also found to suppress prostate cancer growth and invasion.6 However, the recent Health Professionals Follow-Up Study showed an increased relative risk of prostate cancer (2.29) in men consuming more than 100 mg zinc daily.7 Combined with studies demonstrating a role for zinc for enhancing telomerase activity,8 an enzyme involved in prostate tumor progression, high dose zinc may have an permissive role in regard to prostate cancer development.9,10 Other aspects of zinc homeostasis that may impact the GU system are data indicating a protective role for zinc on renal stone formation, potentially through inhibiting crystal formation in urine.11,12 However, Ozgurtas et al recently found high levels of urinary zinc in patients producing calcium oxalate stones, suggesting that zinc may actually promote urinary stone formation.13

inc is used as a dietary supplement by an estimated 15% of the population in the United States.1 In healthy adults eating a mixed diet an equilibrium or positive balance is achieved with an intake of 11 mg zinc daily. Zinc is contained in foods such as meats, certain vegetables (beans and chickpeas) and nuts. With the addition of multivitamin formulas zinc intake can be many times the recommended daily allowance. Many individuals consume large amounts of supplementary zinc because of the perceived health benefits that have been promoted in alternative magazines and books. The negative health impact of zinc deficiency is well documented.2 However, it is unclear what impact chronic high dose zinc has on human health and specifically on the GU system. Prostate epithelial cells and the prostate contain some of the highest concentrations of zinc in the human body. Zinc levels are heterogeneous in the normal prostate but higher levels exist in BPH tissues, potentially due to efflux trans-

Z

Submitted for publication March 24, 2006. * Correspondence: K6/527 University of Wisconsin Clinical Science Center, 600 Highland Ave., Madison, Wisconsin 53792 (telephone: 608-263-9534; FAX: 608-263-0454; e-mail: jarrard@ surgery.wisc.edu).

0022-5347/07/1772-0639/0 THE JOURNAL OF UROLOGY® Copyright © 2007 by AMERICAN UROLOGICAL ASSOCIATION

639

Vol. 177, 639-643, February 2007 Printed in U.S.A. DOI:10.1016/j.juro.2006.09.047

640

ZINC INCREASES GENITOURINARY HOSPITALIZATIONS

Zinc levels impact multiple aspects of normal immune function. Decreased zinc impairs neutrophil recruitment and chemotaxis.14 Natural killer cell activity is also impaired by a lack of zinc, in part by its requirement in normal p58 killer cell inhibitory receptor function.15 However, significant evidence indicates that an excess of zinc in vivo inhibits the normal function of multiple aspects of the immune response, including T-cell function.16 Indeed, the immunosuppressive effects of zinc have been proposed as a therapeutic tool for adjuvant use in immunosuppressive therapy.17 Thus, optimal immune function occurs within a narrow range of zinc concentrations. Despite the enthusiasm with which the public has used high dose zinc for health reasons little is known regarding its impact on GU disease. We studied in more detail the urological impact of supplemental zinc in a group of randomized patients participating in AREDS, a placebo controlled study, to evaluate the effect of high dose zinc and antioxidants on ARMD progression.18 There was a significant odds decrease for advanced ARMD with antioxidants plus zinc, thus, demonstrating the beneficial effect of zinc combinations for eye disease. Our analysis of primary ICD-9 hospital codes demonstrated an overall increased risk of GU hospitalization for patients on zinc with increased admissions for UTIs and urinary stones. These data suggest that high dose zinc has negative effects on the GU system and its use should be limited to diseases such as ARMD, in which a clear benefit has been demonstrated, until further data are available. MATERIALS AND METHODS Patient data from the recent AREDS, an 11-center, doublemasked clinical trial that enrolled participants with ARMD, was used to evaluate the association between supplementation and hospitalization.18 Data were collected and analyzed on 3,640 patients. Participants were randomly assigned to 1 of 4 groups to receive daily oral tablets containing antioxidants (500 mg vitamin C, 400 IU vitamin E and 15 mg ␤-carotene), zinc (80 mg as zinc oxide and 2 mg copper as cupric oxide), antioxidants plus zinc or placebo. Mean followup was 6.3 years. Of the participants 56% were female and average participant age was 69 years (range 55 to 80). During followup 2.4% of the participants were lost and 14.7% withdrew from study.18 There were no significant differences between the randomized groups with regard to patient age, body mass, smoking history or other baseline characteristics. We examined AREDS data for hospital admission ICD-9 codes related to urological problems. ICD-9 codes were grouped into 5 groups, including BPH/retention (600 and 788.2), renal failure (584 –586), urinary lithiasis (592), UTI (590, 595, 597 and 599) and neoplasm (185, 186, 187, 188.0 – 188.9 and 189), and incontinence (788.3). In addition to primary ICD-9 codes, the total number of hospitalizations, and patient age and sex were recorded. If a patient had multiple hospitalizations, ICD-9 codes and the interval between admissions were examined to assess whether the multiple hospitalizations could be considered independent of each other. If rehospitalization for UTI, urinary stones or another diagnosis occurred within 30 days, this hospitalization was discarded and viewed as 1 event. All cancer admissions were considered as only 1 hospitalization.

Fisher’s exact test was used to compare the different arms for urinary system related hospitalizations across factors such as age and sex. Each arm was compared against placebo. Additionally, 3 sets of contrasts were also obtained and tested, including placebo vs other, antioxidant arms vs arms without antioxidants and zinc arms vs arms without zinc with p ⬍0.05 considered significant. RR and the 95% CI were calculated for the 2 ⫻ 2 tables. All calculations were performed in R for Windows® XP™, version 2.1.1. RESULTS There were a total of 420 hospitalizations due to GU reasons observed in 343 distinct patients, of whom 42 had multiple GU hospitalizations (range 2 to 9). Subsequent analysis was based on the 393 GU hospitalizations for independent disease processes. Of the patients 305 had 1, 31 had 2, 4 had 3, 2 had 4 and 1 had 6 hospitalizations. Mean time to first hospitalization was 3.1 years (range 4 to 2,941 days). Of AREDS patients 90% had at least 5 years of followup and 76% of GU hospitalizations occurred within 5 years of followup. There were a total of 3,678 hospitalizations in the 3,640 participants in the AREDS trial. When urological specific hospitalizations were compared to the number of hospitalizations overall, we found a statistically significant increase in admissions for patients receiving zinc vs nonzinc formulations (11.1% vs 7.6%, RR 1.47, 95% CI 1.19 –1.80, p ⫽ 0.0003). Of men and women on supplements 8.0% on placebo, 7.1% on antioxidants, 11.2% on zinc, and 11.0% on antioxidants and zinc were hospitalized for GU causes (see figure). Subgroup analysis revealed significant increases in GU hospitalizations in males but not in females (RR 1.26, 95% CI 1.07-1.50, p ⫽ 0.008 and RR 1.07, 95% CI 0.69-1.71, p ⫽ 0.81, respectively) receiving zinc formulations vs placebo. When antioxidant vs nonantioxidant groups were analyzed, no alteration in the frequency of hospitalizations was noted (9.0% vs 9.6%, RR 0.94, 95% CI 0.76-1.14, p ⫽ 0.936). ICD-9 codes for urological admissions were further analyzed. In the study group requiring admission (393 hospitalizations) the most common primary ICD-9 codes were BPH/ urinary retention (BPH) (55), UTI (47), urinary lithiasis (21) and renal failure (18) (table 1). In the zinc only arm of the study a significant increase in admissions was seen due to UTI compared to placebo (p ⫽ 0.004). This risk was significant in females when analyzed alone (2.3% vs 0.4%, RR 5.77, 95% CI 1.30-25.66, p ⫽ 0.013), while it approached significance in men when analyzed separately (8 in the zinc arm vs 3 in the placebo arm) (p ⫽ 0.14). The risk of a urinary stone approached significance in men on zinc (2.0% vs 0.5%, RR 4.08, 95% CI 0.87-19.10, p ⫽ 0.061), which was not seen in women, who had fewer stone events than men (5 vs 16). Notably in the arms that combined zinc with antioxidants a statistically significant increase in hospitalizations for these diagnoses was no longer seen (UTI and stones p ⫽ 0.140 and 0.085, respectively). Significant increases in hospitalizations were not seen in the zinc arm for renal failure (p ⫽ 0.342), although it approached significance for BPH/retention in men (p ⫽ 0.099). In other epidemiological studies an association between high dose zinc intake and prostate cancer was found.7 Therefore, we analyzed primary hospitalization codes for GU cancer admissions separately. There were no statistical differ-

ZINC INCREASES GENITOURINARY HOSPITALIZATIONS

641

the majority of patients with prostate cancer. However, stage (localized vs metastatic) was analyzed (table 2). We assessed the potential decrease in risk when smoking status was addressed in patients on antioxidants alone. In 115 men who were smoking at enrollment there were 0 of 40 prostate cancers in the antioxidant arm vs 3 of 21 in the placebo arm (p ⫽ 0.037). A significant decrease in risk was also seen when former and current smokers were combined (oxidant vs placebo 4 of 263 vs 12 of 243, p ⫽ 0.04). No significant differences were seen in former smokers when assessed alone or in patients who never smoked (p ⫽ 0.17 and 1, respectively). Thus, the decreased risk with antioxidants was only significant in smokers. The database was also analyzed to determine if differences in GU hospitalizations occurred between different age groups. The mean age of patients in the study was 69 years and the average age of patients hospitalized during the study was 74.1 years, including 73.55 in men and 74.47 in women. According to decade 14 patients (8.0%) 50 to 59 years old, 119 (6.1%) 60 to 69 years old and 114 (7.5%) 70 to 79 years old were admitted to the hospital during followup (p ⫽ 0.225), indicating no differences among these populations. Overall there were no differences in GU hospitalization based on sex (p ⫽ 0.84).

DISCUSSION Percent of patients hospitalized with genitourinary disease as primary ICD-9 code in each of 4 randomized study arms. Hospitalization rates were significantly associated with zinc treatment arm in males and in combined patient population but not in females (Fisher’s exact test p ⫽ 0.053 and 0.0027, respectively, vs 0.89).

ences in renal, bladder or prostate cancer admissions in patients on zinc (table 2). However, in men receiving antioxidants alone there was a significant decrease in hospitalizations, that is for prostate cancer admissions (1.4% vs 4%, RR 0.65, 95% CI 0.49 – 0.86, p ⫽ 0.049). This decrease was not seen when antioxidants were combined with zinc and compared to placebo (p ⫽ 0.842). Grade was not evaluable in

Zinc is a widely used supplement that is commonly believed to have beneficial effects on the prostate and other aspects of the GU system. In the current analysis of hospital admissions of elderly patients randomized to different supplements for ARMD we found that zinc supplementation had detrimental effects on the genitourinary system. We confirm that there is a risk of increased hospitalization due to GU reasons in patients on zinc formulations, as previously reported in AREDS.18 Further analysis revealed that these increased admissions were due to a significant increase in UTIs and urinary stones. Overall zinc given during the 6-year period did not alter the risk of being hospitalized with GU cancer. However, the antioxidant formulation used demonstrated a significant decrease in prostate cancer admis-

TABLE 1. Common primary GU ICD-9 codes requiring hospitalization No. Hospitalizations

UTI⫹ Pyelonephritis Men: Placebo Antioxidant Zinc Antioxidant ⫹ zinc Women: Placebo Antioxidant Zinc Antioxidant ⫹ zinc Men ⫹ women: Placebo Antioxidant Zinc Antioxidant ⫹ zinc

3 4 8 3 2 7 12 5 5 11 20 11

All values less than p ⫽ 0.02 are shown.

p Value vs Placebo (Fisher’s exact test)

0.14

0.17 0.01

0.01 0.14

BPH/ Retention 9 14 16 15

p Value vs Placebo (Fisher’s exact test)

Urinary Stones

0.10 0.14

2 0 8 6

p Value vs Placebo (Fisher’s exact test)

Renal Failure

Total No.

0.06 0.17

2 2 3 1

402 428 394 397

1 1 0 0

1 1 0 3

2 1 4 3

497 525 525 502

9 15 16 15

3 1 8 9

4 3 7 4

899 953 919 899

0.09

642

ZINC INCREASES GENITOURINARY HOSPITALIZATIONS TABLE 2. Primary ICD-9 cancer codes in patients requiring hospitalization

Men ⫹ women Prostate Ca (known stage): Localized Metastatic Unknown Bladder Ca Kidney Ca

No. Placebo

No. Antioxidant

No. Zinc

No. Antioxidant ⫹ Zinc

899 14 8 0 6 2 1

953 5* 3 1 1 3 1

919 10 8 1 1 3 4

899 12 8 1 3 4 4

All hospitalizations for GU cancer were counted only once per patient. * Vs placebo Fisher’s exact test p ⫽ 0.049.

sions. In sum these data suggest an adverse effect for high dose supplemental zinc on GU tract admissions in subsets of elderly patients. As noted, UTIs requiring hospitalization were seen at a significantly higher rate in patients on zinc compared to the placebo group. This included admissions for pyelonephritis and UTIs as the primary ICD-9 codes. Zinc is essential to optimal immune system function. Patients who are deficient in zinc may benefit from supplementation. However, high dose supplementation may impair the immune system, resulting in deficits similar to those in deficiency. In vitro an excess of zinc inhibits T-cell function.19 In healthy men 150 mg zinc daily resulted in a decrease in the lymphocyte stimulation response to phytohemagglutinin and impaired neutrophil responses.16 In the current analysis the increase in hospital admissions for UTIs in all patients and female patients also receiving high dose zinc was significant compared to placebo. An increase in hospitalizations due to infections in men was also seen (8 vs 4). However, the lower number of total events did not attain significance. This sex based bias suggests a greater risk in women, who are a group more susceptible to UTIs, than in men in general. Interestingly the addition of the antioxidant formulation to zinc resulted in a decrease in infections in each group. It is not clear why this occurred but it may be a protective effect of the antioxidant combination or of vitamin E alone. Recently a reanalysis of the AREDS groups showed that patients with ARMD receiving zinc had improved survival from all causes.20 Although this may have been due to improved ARMD leading to less depression and dependence, advantageous immune responses were also postulated. Our current analysis of GU admissions does not support a role for improved immune function. In contrast to archival studies suggesting that zinc might be an inhibitor of stone formation,11,12 we found that urinary stones requiring hospital admission occurred at an increased rate in patients on zinc supplementation. Modern studies suggest a role for zinc in urinary stone pathogenesis.13 Inorganic ions such as zinc and copper may be critical for the initiation of calculi in the urinary tract of some stone formers. This increased risk was seen in men and not in women, likely due to the lower number of events in women (5 vs 16 in men). The current randomized study would support a role for high dose zinc for promoting urinary stone formation. Prostate tissues contain some of the highest concentrations of zinc in the human body and it was proposed that supplemental zinc may have beneficial effects on prostate homeostasis.21 We found no decrease in admissions for BPH/ retention in patients on zinc in the current study to support

this proposal. In fact, a negative effect was suggested by the finding that men on zinc were admitted with a primary diagnosis of BPH/retention at almost double the rate of men on placebo (16 vs 9), although this did not attain statistical significance (p ⫽ 0.19). Increased dietary zinc was associated with BPH in a recent case-control study.5 In the recent Health Professionals Follow-Up study a 2.9-fold increased risk of prostate cancer was found in patients with a zinc intake of greater than 100 mg daily.7 Zinc supplements in excess may also decrease antioxidant defense pathways, such as erythrocyte superoxide dismutase, that are important in cancer and other disease prevention.22 In the current study involving an older, prostate cancer susceptible group no increase in hospital admissions for prostate cancer was seen in patients receiving high dose zinc during the 6-year followup. This would suggest a minimal impact of zinc in this population. However, we would not discount that longer term treatment may be necessary to see a difference between groups. A significant decrease in prostate cancer diagnosis was seen in patients on the antioxidant formulation (500 mg vitamin C, 400 IU vitamin E and 15 mg ␤-carotene). Previous studies suggest a role for vitamin E for prostate cancer prevention.23,24 This hypothesis is currently being tested in the 32,000 patient randomized Selenium and Vitamin E Chemoprevention Trial. Our data indicate that the decrease in prostate cancer risk with antioxidants was only significant in patients smoking at the time of study enrollment. This was also noted during a secondary analysis of the Alpha-Tocopherol Beta-Carotene Cancer Prevention Study, which showed a decrease in prostate cancer risk in male smokers on vitamin E.24 No decreased risk was found in patients who did not smoke. The current analysis was limited to primary ICD-9 codes, emphasizing the major reason for patient admissions. We purposely avoided secondary codes in an effort to avoid bias since the number of codes may vary among institutions and individuals. In addition, we attempted to avoid error by reviewing patient admission dates and coding patients only once for the same diagnosis. Potential biases in this study include the fact that data were generated as a secondary analysis from a randomized study treating patients with ARMD. Although it is not inherently evident how ARMD might bias GU results in the group of study patients, patients with ARMD might not be representative of the aging population in general. In addition, this study consisted of older patients (mean age 69 years) and results might not be applicable in younger patients. Finally, the number of patients diagnosed with prostate and other cancers was limited (larger CI), reflecting the possibility this decrease in cancer with antioxidants is a chance finding. Thus, the current results

ZINC INCREASES GENITOURINARY HOSPITALIZATIONS should be considered as hypothesis generating. Further randomized study is required to clarify the impact of zinc on the urinary system. CONCLUSIONS

8.

9.

We find on secondary analysis of a large, randomized trial that high dose zinc has significant negative effects on the GU system. Urolithiasis and infections were seen at a greater rate with the zinc supplementation provided. A protective effect for high dose zinc was not demonstrated for any aspect of the genitourinary system. These results suggest that patients receiving high dose zinc supplementation without a clear health indication should use caution until further trials are performed.

10.

ACKNOWLEDGMENTS

14.

11.

12. 13.

Gary Gensler, EMMES Corp. assisted with data set analysis. 15.

Abbreviations and Acronyms AREDS ARMD BPH GU ICD-9

⫽ ⫽ ⫽ ⫽ ⫽

Age-Related Eye Disease Study age related macular degeneration benign prostatic hyperplasia genitourinary International Classification of Diseases, 9th revision UTI ⫽ urinary tract infection

REFERENCES 1.

2. 3.

4.

5.

6.

7.

Briefel RR, Bialostosky K, Kennedy-Stephenson J, McDowell MA, Ervin RB and Wright JD: Zinc intake of the U.S. population: findings from the third National Health and Nutrition Examination Survey, 1988 –1994. J Nutr 2000; 130: 1367S. Prasad AS: Clinical, endocrinologic, and biochemical effects of zinc deficiency. Spec Top Endocrinol Metab 1985; 7: 45. Zaichick VY, Sviridova TV and Zaichick SV: Zinc in the human prostate gland: normal, hyperplastic and cancerous. Int Urol Nephrol 1997; 29: 565. Moyad MA: Zinc for prostate disease and other conditions: a little evidence, a lot of hype, and a significant potential problem. Urol Nurs 2004; 24: 49. Lagiou P, Wuu J, Trichopoulou A, Hsieh CC, Adami HO and Trichopoulos D: Diet and benign prostatic hyperplasia: a study in Greece. Urology 1999; 54: 284. Liang JY, Liu YY, Zou J, Franklin RB, Costello LC and Feng P: Inhibitory effect of zinc on human prostatic carcinoma cell growth. Prostate 1999; 40: 200. Leitzmann MF, Stampfer MJ, Wu K, Colditz GA, Willett WC and Giovannucci EL: Zinc supplement use and risk of prostate cancer. J Natl Cancer Inst 2003; 95: 1004.

16. 17. 18.

19.

20.

21.

22.

23.

24.

643

Nemoto K, Kondo Y, Himeno S, Suzuki Y, Hara S, Akimoto M et al: Modulation of telomerase activity by zinc in human prostatic and renal cancer cells. Biochem Pharmacol 2000; 59: 401. Jarrard DF: Does zinc supplementation increase the risk of prostate cancer? Arch Ophthalmol 2005; 123: 102. Costello LC, Franklin RB, Feng P and Tan M: Re: Zinc supplement use and risk of prostate cancer. J Natl Cancer Inst 2004; 96: 239. Sutor DJ and Wooley SE: Growth studies of calcium oxalate in the presence of various compounds and ions. II. Br J Urol 1970; 42: 296. Meyer JL and Angino EE: The role of trace metals in calcium urolithiasis. Invest Urol 1977; 14: 347. Ozgurtas T, Yakut G, Gulec M, Serdar M and Kutluay T: Role of urinary zinc and copper on calcium oxalate stone formation. Urol Int 2004; 72: 233. Chavakis T, May AE, Preissner KT and Kanse SM: Molecular mechanisms of zinc-dependent leukocyte adhesion involving the urokinase receptor and beta2-integrins. Blood 1999; 93: 2976. Rajagopalan S, Winter CC, Wagtmann N and Long EO: The Ig-related killer cell inhibitory receptor binds zinc and requires zinc for recognition of HLA-C on target cells. J Immunol 1995; 155: 4143. Chandra RK: Excessive intake of zinc impairs immune responses. JAMA 1984; 252: 1443. Rink L and Gabriel P: Zinc and the immune system. Proc Nutr Soc 2000; 59: 541. A randomized, placebo-controlled, clinical trial of high-dose supplementation with vitamins C and E, beta carotene, and zinc for age-related macular degeneration and vision loss: AREDS report no. 8. Age-related Eye Disease Study Research Group. Arch Ophthalmol 2001; 119: 1417. Duchateau J, Delespesse G and Vereecke P: Influence of oral zinc supplementation on the lymphocyte response to mitogens of normal subjects. Am J Clin Nutr 1981; 34: 88. Clemons TE, Kurinij N and Sperduto RD: Associations of mortality with ocular disorders and an intervention of highdose antioxidants and zinc in the Age-Related Eye Disease Study: AREDS Report No. 13. Arch Ophthalmol 2004; 122: 716. Costello LC and Franklin RB: Novel role of zinc in the regulation of prostate citrate metabolism and its implications in prostate cancer. Prostate 1998; 35: 285. Samman S and Roberts DC: The effect of zinc supplements on lipoproteins and copper status. Atherosclerosis 1988; 70: 247. Kristal AR, Stanford JL, Cohen JH, Wicklund K and Patterson RE: Vitamin and mineral supplement use is associated with reduced risk of prostate cancer. Cancer Epidemiol Biomarkers Prev 1999; 8: 887. Albanes D, Heinonen OP, Huttunen JK, Taylor PR, Virtamo J, Edwards BK et al: Effects of alpha-tocopherol and betacarotene supplements on cancer incidence in the AlphaTocopherol Beta-Carotene Cancer Prevention Study. Am J Clin Nutr 1995; 62: 1427S.