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Tue 15 Apr 2008 04:00 AM

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Multivitamins and your health

They've been in, out and back in fashion: the latest thinking on multivitamin pills.

They've been in, out and back in fashion: A look at the latest thinking on multivitamin pills.

Although physician-scientists and supplement manufacturers are often at odds, they don't spend much time sparring over multivitamins. In fact, many doctors recommend a daily multivitamin and practice what they preach, downing a pill each morning.

The daily multivitamin has become an icon of good health in America. It wasn't always that way - and surprising new data suggest a reappraisal may be in order.

Vitamins are organic chemicals that are essential for the body’s metabolism.

Vitamin basics

Vitamins are organic (carbon-containing) chemicals that are essential for the body's metabolism. Because the human body cannot manufacture vitamins, they must be supplied by foods or dietary supplements.

The only major exception is vitamin D, which can be produced in the skin - but since sunlight is required to make vitamin D, many modern Americans don't make enough on their own.

Supplement skepticism

Most of the 13 vitamins were discovered in the early 20th century, when scientists found that diseases such as scurvy, rickets, and pellagra were caused by deficiencies of these essential substances. Vitamin supplements were here to stay.

But by mid-century, a new generation of scientists disputed the value of vitamin supplements. This was not a debate about the importance of vitamins, since everyone agrees they are essential for health. Instead, the issue became whether or not vitamin supplements add to health.

The skeptics rightly pointed out that only tiny amounts of vitamins are needed to prevent deficiency diseases. In the U.S. and other industrial societies, economic progress and improved nutrition have virtually eliminated vitamin-deficiency diseases.

f a balanced diet can do the trick, why pop vitamin pills? The debate was on.


In the late 1980s and early 1990s, the pendulum swung sharply in favor of vitamin supplements, both in medical circles and in the popular view. Two developments helped fuel the change.

First, a series of test-tube and animal studies suggested that antioxidants (vitamin E, vitamin C, vitamin A, and beta carotene, which is converted to vitamin A in the body) might protect against heart disease, cancer, and other ills.

Indeed, observational human studies, including several from Harvard, reported that people who took antioxidants were healthier than those who did not.

Doctors know that observational studies (which don't have "treatment" and "control" groups but instead try to gauge over time how a behavior such as taking a daily vitamin affects an individual's health) can never prove cause and effect.

Despite the absence of the randomized clinical trials that are needed to confirm or refute such preliminary research, many physicians jumped on the antioxidant bandwagon, often with both feet. For example, a 1999 survey reported that 39% of cardiologists were taking vitamin E.

The second big boost to supplements did not come from medical science, but from the U.S. Congress. The 1994 Dietary Supplement and Health Education Act largely removed "dietary supplements" from the jurisdiction of the FDA.

Manufacturers could put what they wanted in supplements and could claim great benefits without providing proof. The boom was on - and yearly sales of supplements in the U.S. soared from $4 billion to over $21 billion.

The antioxidant bust

Medical science provided the hope and industry the hype; it was a perfect storm. But although the hype goes on, additional research has provided clear-cut evidence that antioxidant supplements do not protect against heart disease or cancer. In some cases, in fact, they may actually do more harm than good.

For example, beta carotene increases the risk of lung cancer in male smokers; excess amounts of vitamin A are linked to an increased risk of fractures; and antioxidant supplements may increase the overall death rate in adults.

Without belaboring the evidence, much less the reasons for the turnabout, it's clear that antioxidant supplements have toppled from their pedestals and should also come off your medicine shelf.

Even after we took antioxidants off the shelf, we left multivitamins in place. Not high-dose, costly, designer "mega-vitamins," mind you, but humble, inexpensive generics containing just 100% of the Recommended Dietary Allowance (RDA) for the basic vitamins, perhaps with a smattering of minerals.

Such supplements seemed safe, and a new theory suggested they might be quite helpful.

New hope, round 2

The next wave of optimism was based on three B vitamins: B6, B12, and especially folic acid. The hope was based on a series of test-tube, animal, and - you guessed it - observational studies that implicated homocysteine in heart disease.

This "villain" is an amino acid that's present in everyone's blood. Study after study linked high levels of homocysteine to a high risk of heart disease, and study after study showed that folic acid, alone or with B6 and B12, could reduce homocysteine levels.

Based on solid research, there was reason to hope that B vitamins, even in the amounts found in ordinary multivitamins, might reduce the risk of heart disease.
But a series of randomized clinical trials has dashed these hopes: except in people who have inherited a metabolic glitch that sends homocysteine levels sky-high, B vitamin supplements do not protect the heart.

It's another disappointment, but instead of becoming fed up or angry about the twists and turns of medical research, we should be grateful to scientists who methodically investigate the complexities of human biology instead of running with prevailing assumptions.

Antioxidants don't help, and neither do the "three Bs." In response to this research, both the authoritative U.S. Preventive Services Task Force and a 2006 National Institutes of Health State-of-the-Science Conference concluded that multivitamins do not offer protection against heart disease or cancer.

It’s clear that antioxidant supplements have toppled from their pedestals.

Without disputing these conclusions, many doctors have continued recommending (and taking) multivitamins. The best reason is that they are a convenient and inexpensive way to get vitamin D (more on that later).

And they appeal to many scientists the way prayer appeals to many agnostics: "just in case." But for multivitamins to have merit as a sort of nutritional insurance policy, they must at least be safe. Are they?

New worries

A widely publicized 2007 study raised the possibility that multivitamins might increase the risk of advanced prostate cancer. But the possible risk was observed only in men who took more than seven multivitamins a week, particularly when they took other supplements as well. Because of these limitations and others, the study did little to shake faith in the good old humble one-a-day.

But research raises the possibility that one of the virtues of the multivitamin may have become its Achilles' heel. The double-edged sword is folic acid, the same B vitamin that played a central role in the homocysteine saga. The issue now is not heart disease, but cancer, especially colorectal cancer.

Folic acid, up close and personal

Folic acid, also known as folate, was discovered in 1931. For many decades, scientists thought its role was limited to promoting the production of red blood cells, and that anemia was the only consequence of folate deficiency.

Next, it became clear that a shortage of folic acid can lead to devastating birth defects of the spinal cord and nervous system.

And scientists have learned that this vitamin has a crucial role in DNA production and in repairing defects in the genetic code that might otherwise turn healthy cells into cancer cells.

Most of the attention has focused on cancer of the colon and rectum. Between 1997 and 2003, five studies linked multivitamins in general, and folic acid in particular, to a reduced risk of colorectal cancer.

High doses were not required; each of the studies associated protection with as little as 400 micrograms (mcg) a day, the amount in most ordinary multivitamins.

But benefit was limited to people who took multivitamins for 10 to 15 years or, in one study, to people who had a lapse of 10 years or more between regular multivitamin use and their enrollment in the study.

That means that in all five favorable studies, the bulk of multivitamin consumption occurred in the 1980s and early-to-mid 1990s.

New news about folate

None of the five studies that linked past multivitamin and folic acid use to a reduced risk of colorectal cancer was a randomized clinical trial. Having learned the bitter lessons of antioxidants and homocysteine, scientists knew the next step was just such a trial.

To see if folic acid could help prevent colorectal tumors, a large team of American scientists studied 1,021 volunteers. All were at high risk for cancer because of recent histories of colorectal adenomas, benign polyps that can give rise to cancer, but none had polyps or cancer at the time that the trial began in 1994.

About half of the subjects were randomly assigned to take 1,000 mcg of folic acid a day, while the other half took a placebo. Colonoscopies were performed after three years of treatment and again three to five years later.

At the first round of colonoscopies, there were no differences between the two groups. But after the second evaluation, one group had fallen behind; its members were 67% more likely to have advanced (premalignant) adenomas, and they were over two times more likely to have three or more adenomas.

Men in the bad news group were also three times more likely to have been diagnosed with prostate cancer, but these results were less impressive since the numbers were small (24 cases vs. 9 cases), details of PSA screening were not available, and the study was designed to focus on the colon, not the prostate.

Still, the researchers were surprised to learn that the people with more colorectal adenomas and more prostate cancers were the ones taking folic acid.

It's only one study, it involved only people who were at high risk, and it used a high dose of folic acid, 1,000 mcg, which is two-and-a-half times the RDA and the amount found in most multivitamins (400 mcg).

That might be reassuring for folks who take multivitamins - except, perhaps, for the estimated 30% of people over 60 who have colon polyps. And another 2007 report speculates that the results of this careful randomized clinical trial may actually apply to a larger group of people.

Instead of studying a group of volunteers, researchers in the U.S. and U.K. tracked the colorectal cancers diagnosed in the U.S. and Canada between 1986 and 2002. For the first 10 years, both countries enjoyed a modest but consistent yearly drop in the incidence of colorectal cancers.
But in the mid-1990s, there was an upward blip in both countries. It was a small increase, amounting to an additional four to six extra cases per 100,000 people in each country, but it translates to about 15,000 extra cases of colorectal cancer in the U.S. alone.

The researchers don't know what caused the blip. More intensive screening for colorectal cancer did not seem to account for the increase, since colonoscopy rates in the U.S. did not rise substantially until 2000, when Katie Couric's televised colonoscopy spurred acceptance of the test.

Instead of implicating better diagnosis, the scientists speculated that folic acid may have contributed to the uptick in colorectal cancers - not because of multivitamin

Scientists have many unanswered questions about folic acid and cancer.

The folate in foods

In the 1990s, government officials noted a link between folate deficiency and birth defects. They had two important responses to the problem. First, they raised the amount of folic acid allowed in multivitamins from the 1973 maximum of 100 mcg and then they raised the RDA from 200 mcg to the current level of 400 mcg.

Even more important, in 1996 both the FDA and the Canadian government issued regulations requiring manufacturers to fortify enriched grain products (including cereal, bread, flour, pasta, and rice) with folic acid.

Fortification did not become mandatory until 1998, but many manufacturers began voluntary compliance shortly after the 1996 edicts.

Fortification worked. Prior to September 1996, the average blood folic acid level in Americans who did not take supplements was 4.6 nanograms per milliliter (ng/mL); by 1998, the average level had more than doubled to 10 ng/mL. As a result, the incidence of spinal cord birth defects dropped by up to 50%.

Folate and cancer: A double-edged sword?

Scientists have many unanswered questions about folic acid and cancer. One popular theory, still unproven, suggests that timing and dose may explain folate's apparently contradictory effects on cancer.

According to this hypothesis, moderate amounts of folic acid may help protect against harmful mutations in DNA that could lead to the malignant transformation of healthy cells.

That could explain how long-term use of multivitamins in the 1980s and early '90s, before foods were fortified with folic acid, appeared to reduce the risk of colon cancer.

It could also explain why a moderately high intake of folate (about 450 mcg a day) appears to reduce the risk of breast cancer in Sweden, where foods are not fortified with folic acid.

But once tumors develop, the theory holds, folic acid may have the opposite effect, particularly if the doses are high. Tumor cells produce DNA faster than healthy cells, and they need more folic acid to fuel unchecked cell growth.

In fact, cancer cells latch onto folic acid more avidly than normal cells, and antifolate drugs have a well-established place in cancer chemotherapy. Perhaps that's why a high intake of folic acid (about 850 mcg a day) appears to increase the risk of breast cancer in American women.

What does all this have to do with the simple multivitamin? A typical multivitamin provides just 400 mcg of folic acid, only 40% of the dose that promotes precancerous colorectal adenomas.

But now that folic acid is added to so many fortified grains, it's easy to see how a healthy diet high in whole grains and folate-rich vegetables and legumes could easily combine with a multivitamin to boost a person's daily folate intake to 1,000 mcg or even more.

The last vitamin standing

One of the first principles of medicine is primum non nocere: first, do no harm.

There is no proof that a daily multivitamin is harmful. Still, it now seems possible that the high levels of folic acid achieved by well-intentioned people who take a multivitamin and eat healthful foods could increase the risk of colorectal and possibly prostate and breast cancers.

What's a man or woman to do? We certainly wouldn't advise retreat from a healthful diet, nor would it be easy to avoid folic acid even by subsisting on junk food. Perhaps, then, the answer is to give up the multivitamin, at least until scientists solve the puzzle of folic acid and cancer.

And with the demise of antioxidants and the homocysteine-lowering 3 Bs, the only downside to giving up multivitamins is a reduced intake of vitamins D and B12.

Vitamin B12 is found only in animal foods, so strict vegetarians need supplements. In addition, many older people don't make enough of the stomach acid needed to liberate B12 from animal products so that it can be absorbed.

But B12 is also added to fortified grain products and other foods, and this synthetic B12 is easy to absorb even without stomach acid. That means a single bowl of cereal can give you as much B12 as a multivitamin.

Vitamin D is another story. It's very hard to get enough vitamin D from food, and it's not wise to get it by exposing your skin to high doses of the cancer-causing ultraviolet energy in sunlight.

Fortunately, it's easy to get pure vitamin D supplements. Look for vitamin D3 (cholecalciferol), and shoot for 800 to 1,000 international units (IU) a day. It's the dose currently favored by many experts, and it's two to two-and-a-half times the amount in your old, newly spurned multivitamin.

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