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Multivitamins and prostate cancer: A new worry?

Multivitamins and prostate cancer: A new worry?

(This article was first printed in the October 2007 issue of the Harvard Men's Health Watch.)

About a third of American adults take some type of multivitamin on a regular basis. In nearly every case, the goal is better health. In 2003, the authoritative U.S. Preventive Services Task Force concluded that there was no firm evidence to support this hope. At the same time, though, it did not find evidence that multivitamins are harmful. Multivitamins have remained popular as a sort of insurance policy or, perhaps, as proof that hope can outweigh evidence.

The absence of benefit is one thing, the presence of harm quite another. A 2007 report in the Journal of the National Cancer Institute concludes that “our finding of a markedly increased prostate cancer risk among men using multivitamins is of concern and warrants further study.” Since prostate cancer is the most common internal malignancy and the second leading cause of cancer death in men, it is indeed a concern. And since more than 50% of men at high risk for prostate cancer take supplements to ward off the disease, it’s a big concern.

The report is bound to generate further study (surely a good thing). But before you transfer the contents of your medicine chest to the trash bin, let’s take a closer look at the research, along with a quick tour through the often confusing information about supplements and prostate cancer.

The new study

To explore the link between multivitamins and prostate cancer, scientists at the National Cancer Institute studied 295,344 men who volunteered to participate in the National Institutes of Health’s AARP Diet and Health Study. When the men enrolled in 1995 and 1996, they were between the ages of 50 and 71 and free of cancer. Each man provided information about his diet and supplement use as well as other demographic, lifestyle, and health-related factors.

The researchers tracked the men for five years. During that time, 8,765 men were diagnosed with localized prostate cancer, 1,476 men developed advanced prostate cancer, and 179 died from the disease.

When the results were analyzed, there was no link between multivitamin use and the risk of developing localized prostate cancer. But advanced and fatal cancers were another story: Compared with men who did not take multivitamins, men who took them more than seven times a week were 32% more likely to develop advanced prostate cancer and 98% more likely to die from the disease.

That’s the basis for concern, which is justified. But a closer look should prevent concern from becoming alarm.

Behind the headlines

The NIH-AARP study has many virtues. It has an extremely large number of subjects, and it collected detailed information about each. Because all the volunteers lived in six states and two metropolitan areas, it was possible to track them closely through eight cancer registries and several Social Security databases. The analysis was thorough and used sophisticated statistical methods.

The study also has limitations. Like all observational studies, it can establish associations but not causality (see "Studying the studies"). Even if we accept a link between multivitamins and prostate cancer, the study was not designed to say if the vitamins caused the cancers.

Studying the studies

Scientists can learn a lot about health and biology by experimenting in the laboratory or by studying animal models of disease. But the best way to learn about human health is by investigating people. Several methods are available.

Observational studies
Observational studies provide objective information about large groups of people. There are two basic approaches.

Cohort analysis begins when researchers recruit a group of apparently healthy individuals and establish health profiles for each member of the group. Their next step is to observe the cohort over time, relying on various combinations of questionnaires, medical tests, and health records. Finally, the investigators compare members of the cohort who have remained healthy with those who have fallen ill, trying to identify the factors associated with illness. Cohort analysis is a powerful technique, but it’s slow, difficult, and expensive, typically involving thousands of subjects over many years. The NIH-AARP study of multivitamins and prostate cancer is an observational cohort study.

Case control studies have the same goals as cohort analyses, but they proceed from the opposite direction. Researchers begin by identifying a group of patients who are already ill. Next, they compare the patients with an equal number of demographically similar healthy people to identify any factors that may account for the difference between illness and health. Because case control studies use many fewer subjects, they are much less difficult and expensive than cohort studies; because they look back instead of forward, they are also much faster. In general, though, cohort analysis is a more potent investigative tool.

Clinical trials
In contrast to observational studies, which are essentially passive (researchers watch people without intervening in their lives), clinical trials are active: Researchers ask some of their subjects to take medications or undergo procedures while assigning others to different interventions. By comparing outcomes, scientists can find out which intervention is best or if an intervention is better than no treatment at all.

To eliminate bias, scientists randomly assign the volunteers to the various treatment groups. In a double-blind trial, all the treatments look and taste alike, so neither the subjects nor the researchers can be influenced by their expectations. This randomized double-blind clinical trial is the gold standard for clinical research. It’s a high standard, but it is really the only way to prove if an intervention is beneficial — or, for that matter, harmful.

A second limitation concerns the information about multivitamins. The NIH-AARP questionnaire did not ascertain which multivitamins were taken or their actual content. In addition, we have only a snapshot of vitamin use; the men reported their use at the start of the study, but not how long they’d been taking the pills or if they continued to take them during the follow-up period.

The results also failed to establish a relationship between dose and response. Although taking more than seven a week was linked to the risk of advanced and fatal prostate cancers, taking seven multivitamins a week was not linked to prostate cancer any more than one to six pills a week or no use at all. And we don’t know if the men who took more than 7 multivitamins a week took 8, 15, or even more.

Finally, there’s the issue of what statisticians call confounding variables. The scientists carefully adjusted their results for known or suspected prostate cancer risk factors, including age, race, family history, body mass index, smoking and drinking, exercise, diet, marital status, and the use of other supplements. They also corrected for the reported frequency of prostate cancer screening tests, including PSA blood tests and digital rectal exams. At the end, the apparent link between heavy multivitamin use and advanced or fatal prostate cancer was strongest in men with a family history of the disease or those who also took one or more additional supplements. Men with a family history have an increased risk of the disease, and perhaps the men who took high dose multivitamins did so because of warning symptoms or other reasons to worry about their prostate.

Other multivitamin studies

The NIH-AARP study is sure to trigger new interest in multivitamins and prostate cancer. Until now, though, attention has been limited, and the results, mixed.

A 1999 case control study of 1,363 residents of King County, Washington, found no link between heavy use of multivitamins and prostate cancer, even in men taking seven or more multivitamins a week for 1.5 years or longer. In contrast, a 2005 cohort study of 475,726 men reported that men who used multivitamins more than 15 times a month were 15% more likely to die from prostate cancer than nonusers.

It’s clear that the effect of multivitamins on prostate cancer is unclear. And the same is true of other supplements. Here’s a quick overview.

Folic acid. A 2007 randomized clinical trial administered 1,000 micrograms (mcg) of folic acid (2.5 times the RDA) or a placebo to 651 men. Over a six-year period, 7% of the men taking a high dose of folic acid developed prostate cancer versus 3% of those who took a placebo. But since the trial focused on colon cancer, not prostate cancer, the results are not conclusive. And most multivitamins have just 400 mcg of folic acid.

Beta carotene. In 1994, the ATBC randomized clinical trial reported that beta carotene produced a 23% increase in the risk of prostate cancer in smokers. Two years later, however, another randomized clinical trial called CARET failed to demonstrate a similar link. That same year, Harvard’s Physicians’ Health Study found that beta carotene supplements appear to reduce the risk of prostate cancer in men with very low dietary consumption of carotenoids. In 2006, the PLCO Trial reported similar findings. Supplements of lycopene, an antioxidant in the carotenoid family, have been disappointing, but it still makes sense to eat lots of tomatoes and other lycopene-rich foods.

Vitamin E. The ATBC Study reported that vitamin E supplements produced a 34% reduction in the risk of prostate cancer in smokers. However, the HOPE and HOPE-TOO trials found no protection; but less than 15% of the participants were smokers. More recently, the PLCO Trial reported that vitamin E reduces the risk of prostate cancer in current and recent smokers but not in nonsmokers. Harvard’s Health Professionals Follow-up Study also linked vitamin E supplements to protection in smokers but not nonsmokers.

Zinc. A Harvard study reported that the prolonged use of high-dose zinc supplements was associated with an increased risk of prostate cancer; men who took more than 100 mg a day for 10 years or more were 2.4 times more likely to develop advanced cancer than nonusers. In contrast, a Johns Hopkins study found no link between a man’s zinc levels and his risk of prostate cancer.

Calcium. The Health Professionals Follow-up Study of 47,781 men found that a high consumption of calcium, whether from food or supplements, was associated with an increased risk of advanced prostate cancer. The risk was greatest in men getting very large amounts of calcium, more than 2,000 mg a day. More recently, the Physicians’ Health Study of 20,885 men reported that those who get lots of calcium from milk have a 32% increase in the risk of prostate cancer — and milk fat is not the culprit, since the results apply to skim milk as well as whole milk. In this study, risk began to rise with daily calcium consumption above 600 mg, quite a modest amount.

Concern about the high consumption of calcium is not limited to Harvard’s research. Scientists at the Fred Hutchinson Cancer Research Center in Seattle reported that men who consumed the most calcium were 2.12 times more likely to develop advanced prostate cancer than those consuming the least. The increased risk applied to calcium from either food or supplements; the men with the highest risk consumed more than 1,163 mg of calcium a day. The Cancer Prevention Study II Nutrition Cohort found that men who consumed more than 2,000 mg a day, whether from supplements or foods, were 60% more likely to develop prostate cancer than those who averaged less than 700 mg a day. But the Baltimore Longitudinal Study of Aging added reassuring perspective when it exonerated moderate levels of dietary calcium.

Vitamin D. The Harvard scientists who raised concern about large amounts of calcium speculate that the problem may be related to a lack of the active form of vitamin D. Indeed, a 13-year Harvard study of 2,399 men reported that men with high blood levels of both vitamin D and its precursor enjoyed a 45% lower risk of developing aggressive prostate cancer than those with below-average levels. Still, although many experts believe the RDA for vitamin D should be boosted to 800 IU a day, it’s far too early to conclude that supplements can protect men from prostate cancer.

Selenium. The Nutritional Prevention of Cancer Trial raised eyebrows (and hopes) in 1996 when it reported that supplements of selenium appeared to provide substantial protection against fatal prostate cancer. In a report that extended the follow-up period of this randomized clinical trial to 7.6 years, men who took supplements of 200 mcg a day enjoyed a 49% lower risk of prostate cancer than men who took a placebo. Two observational studies from Harvard also reported protection, but other studies disagree. Still, a meta-analysis of 16 individual trials linked a moderate consumption of selenium to a 26% reduction in the risk of developing prostate cancer.

What to do?

Faced with this morass of contradictory information, scientists know just what to do — more studies. Fortunately, several studies that are already under way should help clarify the situation. Since 1997, Harvard’s Physicians’ Health Study II has been conducting a randomized clinical trial of multivitamins, vitamin E, and vitamin C. Since the trial was planned to last 10 years, results should be available soon. Another large randomized clinical trial is testing selenium and vitamin E, separately and in combination, but these results are not expected for several years.

Until more data are available, what should you do for your prostate? Men who smoke may benefit from vitamin E, but smokers should stay away from beta carotene, which boosts the risk of lung cancer in smokers. Nonsmokers with very poor dietary levels of carotenoids may benefit from beta carotene. But for all these men, the best answer is to quit smoking and eat properly — at present, there is no good reason for well-nourished nonsmokers to take vitamin E or beta carotene. On balance, zinc supplements may do more harm than good; calcium appears safe in moderate amounts, but supplements that exceed the RDA of 1,200 mcg a day might boost the risk of prostate cancer.

Although more study is needed, there is reason to hope that selenium supplements of about 200 mcg a day may help. The same is true for 600 to 1,000 IU of vitamin D, as much for general health as for the prostate.

And what of multivitamins? Although they are widely recommended as a safe if unproven “insurance policy,” their main virtue is to provide vitamin D, which is hard to get from your diet. Men who eat well and take vitamin D stand to gain little. But should the NIH-AARP study of multivitamins and prostate cancer spell the end for these popular supplements? Not yet. The study raises a yellow flag, cautioning against excessive use, but it does not show harm from a daily supplement that sticks to the recommended daily amounts of the standard vitamins.

Above all, the study adds to the growing body of evidence that tells us not to count on supplements. Vitamin pills have never matched the benefits of vitamin-rich foods, such as vegetables, fruits, and whole grains. And some supplements may do more harm than good.


Harvard Men's Health Watch

Harvard Men's Health Watch

Harvard Men’s Health Watch addresses the health issues that matter to men the most. From prostate disease to hair loss, from exercise programs to heart health, this monthly newsletter helps men lead longer, healthier lives. Read more »