Mega Multivitamin Use Risks Prostate Cancer

BETHESDA, Md., May 15 -- Men who take multi-vitamin supplements more than once a day are twice as likely to die of prostate cancer as men who never take supplements, researchers confirmed.

They were also at elevated risk of advanced prostate cancer compared with never users, reported Karla A. Lawson, Ph.D., of the National Cancer Institute here, and colleagues.

The researchers reported the outcomes of the National Institutes of Health -- AARP Diet and Health Study in the May 16 issue of the Journal of the National Cancer Institute.

The large, prospective investigation adds credence to the possibility of harm from antioxidant supplements as found in prior systematic reviews and meta-analyses, according to an accompanying editorial.

The findings "underscore the possibility that antioxidant supplements could have unintended consequences for our health," wrote Goran Bjelakovic, M.D., of the University of Nis, Serbia, and Christian Gluud, M.D., of the Copenhagen University Hospital.

The few previous prospective studies had suggested that multivitamin use may protect men from developing prostate cancer but speed its progression once begun, Dr. Lawson and colleagues wrote.

Because more than a third of American adults take vitamins, the researchers noted, "any association between intake of multivitamin supplements and the risk or severity of prostate cancer would have important consequences for public health," the researchers wrote.

The prospective study included 295,344 men aged 50 to 71 and free of cancer at enrollment in 1995 and 1996.

Their multivitamin use was assessed at baseline using a self-administered, food-frequency questionnaire. Five percent used multivitamins more than seven times a week; 36% took a multivitamin daily.

Among the participants, 41% reported using a one-a-day type supplement, 12% reported using a theragran type (vitamins plus iron) supplement, and 6% reported use of a stress-tab type supplement (primarily B vitamins). Half of the supplements used were multivitamins.

Outcomes were followed using subsequent questionnaires, Social Security Administration death records, and state cancer registries.

Over five years of follow-up, 10,241 developed incident prostate cancer. These cases included 8,765 localized and 1,476 advanced cancers. A separate mortality analysis found 179 cases of fatal prostate cancer over six years of follow-up.

Among the findings in a multivariate adjusted analysis, the researchers reported (more than daily use versus never users):

• No association between multivitamin use and risk of prostate cancer overall (relative risk 1.06, 95% confidence interval 0.97 to 1.17).
• No association between multivitamin use and risk of localized prostate cancer (RR 1.02, 95% CI 0.92 to 1.14).
• Increased risk of advanced prostate cancer (RR 1.32, 95% CI 1.04 to 1.67).
• Elevated risk of fatal prostate cancers (RR 1.98, 95% CI 1.07 to 3.66).
• Higher incidence rates for advanced prostate cancer (143.8 versus 113.4 per 100,000 person-years).
• Higher incidence rates for fatal prostate cancer (18.9 versus 11.4 per 100,000 person-years).

The associations were strongest in men with a family history of prostate cancer or those who took selenium, ?-carotene, or zinc.

"Thus, excessive intake of certain individual micronutrients that are used in combination with multivitamins may be the underlying factor that is related to risk and not the multivitamins themselves," the researchers wrote.

Among men with prostate cancer in the family, heavy multivitamin use (more than seven times per week) more than doubled advanced prostate cancer risk (RR 2.48, 95% CI 1.45 to 4.23) and fatal prostate cancer risk (RR 16.41, 95% CI 2.62 to 102.68).

Heavy use of selenium yielded a 37% increased risk of localized prostate cancer (P=0.008 for interaction) Although based on a small sample, those who took more than seven multivitamins a week and were also taking a selenium supplement were at 5.8-fold higher risk of fatal prostate cancer than those not taking a selenium supplement (P=0.037 for interaction).

The association between heavy multivitamin use and advanced prostate cancer was somewhat modified by ?-carotene use (P=0.036 for trend).

Men who used a zinc supplement in addition to heavy multivitamin use were at significantly elevated risk of fatal prostate cancer (RR 4.36, 95% CI 1.83 to 10.39 versus daily or less than daily multivitamin use).

This "could be due to nonessential, potentially harmful trace elements contained in zinc supplements, such as cadmium, a known carcinogen," the researchers said.

They noted that their study was limited by lack of information on duration of multivitamin use.

Also, they said, heavy multivitamin users were more likely to have prostate cancer screening using prostate specific antigen.

While this could have biased diagnosis of localized prostate cancer, "increased multivitamin use due to early symptoms of prostate cancer cannot account for the increased risk of fatal prostate cancer among heavy multivitamin users because the association persisted and even strengthened when we disregarded those diagnosed in the initial years of follow-up," the researchers noted.

Regardless, they concluded, "the possibility that men taking high levels of multivitamins along with other supplements have increased risk of advanced and fatal prostate cancers is of concern and merits further evaluation."

The reason why dietary intake of vitamins has been shown beneficial with mixed or negative results for supplements, editorialists Drs. Bjelakovic and Gluud suggested, may be because of differences between natural and synthetic vitamins.

"Antioxidant supplements in pills are synthetic, factory processed, and may not be safe compared with their naturally occurring counterparts," they wrote.

Or, they added, it could be that the populations they have been tested in already get their full daily requirement of vitamins and trace elements from diet. They pointed out that the American diet provides 120% of the recommended dietary allowances for beta-carotene, vitamin A, and vitamin C, and that dietary vitamin E deficiency has never been reported in the United States.

They also suggested a possible mechanism for the negative findings: "Reactive oxygen species in moderate concentrations are essential mediators of reactions by which the body gets rid of unwanted cells. Thus, if administration of antioxidant supplements decreases free radicals, it may interfere with essential defensive mechanisms for ridding the organism of

damaged cells, including those that are precancerous and cancerous."

The editorialists also suggested a need for further study, possibly including testing of supplements similar to pharmaceutical products.