An Observational Study
In one study of concern, 38,772 women (mean age, 62 years) filled out a questionnaire three times over an 18-year period regarding dietary supplement use. During a total follow-up period of 22 years, the risk of dying from any cause was said to be 6% higher among women who took a multivitamin supplement than among women who did not take a multivitamin. In addition, the use of individual supplements of vitamin B6, folic acid, iron, magnesium, zinc, and copper were said to be associated with increased mortality rates.
One problem with this study is that the researchers did not report actual mortality rates. They compared "adjusted" mortality rates between supplement users and nonusers, by adjusting for a wide range of factors including caloric intake, cigarette smoking, body mass index, blood pressure, educational level, diabetes, use of hormone-replacement therapy, physical activity, and intake of fruits and vegetables. For each of these factors, the supplement users were in the "healthier" category (for example, less diabetes, less obesity, more physical activity, fewer smokers, and higher intake of fruits and vegetables), and would therefore have been expected to have lower mortality rates than the nonusers. In consequence, the mortality rate of the supplement users was presumably adjusted upward (higher mortality), when compared with the mortality rate of the nonusers. When the researchers adjusted the data only for age and caloric intake, there was no statistically significant difference in mortality rate between supplement users and nonusers, a point that was not discussed in the media coverage of this study.
Another problem with this study is that it was observational in nature. In contrast to randomized controlled trials, observational studies cannot prove a direct cause-and-effect. There are tons of observational studies in the history of medical research that have later been contradicted by follow up randomized controlled trials. One widely known example is of that of hormone replacement therapy. Numerous observational studies suggested that the use of hormone-replacement therapy by postmenopausal women would prevent heart disease, but subsequent randomized controlled trials demonstrated that hormone-replacement therapy either has no effect or actually increases the risk of heart disease.
In the other study I wanted to discuss, 35,533 men were randomly assigned to receive 400 IU per day of vitamin E (in the form of alpha-tocopherol) or placebo for an average of 5.5 years, and the men were then followed for a total of approximately 7 years. During that time, the incidence of prostate cancer was significantly higher by 17% in the vitamin E group than in the placebo group.
This was a relatively well-designed study. However, a major flaw in the study was the form of vitamin E that was used is not the same form that is found in food. Vitamin E is found in 4 different forms in food: alpha-, beta-, gamma-, and delta-tocopherol. However, as is the case with most vitamin E research, the men in this study were given only alpha-tocopherol. Early research suggested that most, if not all, of the biological activity of vitamin E is due to alpha-tocopherol, but it is now known that at least one of the other components-gamma-tocopherol-has important functions. Furthermore, treatment with large doses of alpha-tocopherol has been shown to diminish levels of gamma-tocopherol, potentially upsetting the natural balance of the different forms of vitamin E in the body. "Mixed tocopherols," on the other hand, a supplement that contains all four types of vitamin E, would not be expected to cause such an imbalance.
In other studies that looked at vitamin E and prostate cancer, both alpha-tocopherol and gamma-tocopherol inhibited the growth of human prostate cancer cells in vitro (in a test tube), but gamma-tocopherol was the stronger acting form of the two. In another study, higher blood levels of alpha-tocopherol and gamma-tocopherol were each associated a lower risk of developing prostate cancer, but the protective effect of gamma-tocopherol was higher than that of alpha-tocopherol.
Clinical trials that used alpha-tocopherol in doses lower than 400 IU per day did not find an adverse effect on prostate cancer incidence. In a double-blind study of male smokers, compared with placebo, supplementation with 50 IU per day for 5-8 years significantly decreased the incidence of prostate cancer by 32%. In a double-blind study of male physicians, supplementation with 200 IU per day (400 IU every other day) for 8 years resulted in a nonsignificant 3% decrease in prostate cancer incidence, compared with placebo. Thus, what we can infer from this is that the effect of alpha-tocopherol on prostate cancer appears to be dose-related: protective at low doses (50 IU per day), neutral or modestly protective at intermediate doses (200 IU per day), and harmful at high doses (400 IU per day).
Looking reflectively at all of the research together, it seems that alpha-tocopherol has a protective effect against prostate cancer. However, when alpha-tocopherol is given by itself in large doses (400 IU per day or more), it diminishes the amount of gamma-tocopherol, which could more than negate any beneficial effect that alpha-tocopherol might have. If that is the case, then taking vitamin E in the form of mixed tocopherols would not be expected to increase prostate cancer risk, and might even be helpful in the prevention of prostate cancer. Further research is still needed to confirm that hypothesis.
In conclusion, it is important when reading research study results to evaluate the method of the study, the means they used, and then how do they evaluate the results. And as always, the best advice is to be informed consumers of medicine and supplements. Take any blanket statements with a grain of salt. It is most important to think about an individual and their particular needs when deciding whether to supplement with a vitamin or not. I do like one line of media coverage from the multi-vitamin study that stated, “ It’s important to remember, supplement, not substitute. There is nothing in a pill that can replace eating well.”