The role of multivitamins and minerals in preventive healthcare

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1 This CME is supported by an educational grant from The Centrum Foundation Parkhurst Exchange wants to help you keep your patients healthy, so we ve teamed up with McGill University s Continuing Medical Education Department to offer a series of M1-accredited CME programs in the field of preventive healthcare. Read the main review article here, then go to the McGill CME website mcgill.ca/cme to complete the quiz, participate in the forum and apply for MAINPRO-M1 CME credits. This CME activity is needs-based and designed for primary care physicians. It is under the direction of Dr. Michael Rosengarten, Associate Dean of Continuing Medical Education at McGill University. This program meets the accreditation criteria of The College of Family Physicians of Canada and has been accredited for up to 2 MAINPRO-M1 credits. The role of multivitamins and minerals in preventive healthcare by Dr. Joe Schwarcz, Director, McGill Office for Science and Society Learning objectives Enhance primary care physicians ability to: counsel patients on the use of multivitamins assess the benefits of multivitamins for different patient groups understand the evidence for disease prevention claims minimize the risks of drug interactions with multivitamins and minerals More than 250 years have passed since Introduction James Lind published his classic Treatise on Scurvy, and it s been almost 100 years since Casimir Funk isolated the first vitamin, thiamine. Since then, thousands of research papers have been published on vitamins, and 12 Nobel Prizes have been awarded for research in the field. In spite of all this activity, and in spite of the great popularity of dietary supplements with consumers, general agreement on the benefits of vitamin and mineral supplementation is difficult to reach. Some of the main questions today regard dosing, possible risks, different needs for different population groups and the efficacy of multivitamins in the promotion of health and prevention of chronic disease. Roughly half the population takes dietary supplements, with multivitamins making up the single largest class of such products. Some take them with the belief that they improve health or prevent chronic disease, others take them as nutritional insurance. Are these views justified? What advice can be given to patients who ask about multivitamins? When is it appropriate to recommend their use? This article will first examine some of the difficulties involved in making recommendations about multivitamin use. We will then look at where clear benefits Joe Schwarcz, PhD Chem, is Director of McGill University s Office for Science and Society, which is dedicated to demystifying science for the public, the media and students. Professor Schwarcz has received numerous awards for teaching chemistry and for interpreting science for the public. Among these are the Royal Society of Canada s McNeil Award and the American Chemical Society s prestigious Grady-Stack Award. 58 parkhurst exchange january 2008

2 have been established for specific populations and where they have not. We will also explore the possibility of preventing heart disease and cancer with multivitamins and, finally, the risks of multivitamin use will be examined along with potentially harmful interactions with drugs. Studying the effects of multivitamins Unfortunately, there s no clear definition of what constitutes a multivitamin supplement. Attempts to investigate the benefits of such products are complicated by variations in the combinations and doses of individual micronutrients as well as by individual patient variables. For ex ample, multivitamin takers are more likely to engage in proactive health behaviour, a confounding factor in observational studies which make up the majority of studies dealing with multivitamins. In an observational study, subjects are not assigned a particular intervention, such as taking vitamins, but are questioned on self-administered choices. For example, the Nurses Health Study, administered by the Harvard University School of Public Health, has followed the health status of over 100,000 nurses since 1980, when they were first asked to fill out questionnaires about diet and supplements. By 1998, multivitamin use, and especially folic acid content, was found to be associated with a significantly reduced risk of colon cancer. 1 Such asso ciations, however, can t tease out other lifestyle factors, and they can t prove cause and effect. Randomized placebo-controlled trials using single nutrients or simple combinations of nutrients haven t always borne out the results suggested by observational studies. Beta-carotene is a case in point. Several observational studies had linked an increased beta-carotene intake with a reduced risk of cancer not surprising, given that the nutrient is both an antioxidant and a vitamin A precursor. Inspired by such observational studies, a randomized controlled trial using supplements was designed. 2 Shockingly, instead of offering any benefit, the supplements increased the risk of lung cancer, albeit only among smokers and asbestos workers. This finding was significant enough to justify the current recommendation that smokers avoid beta-carotene supplements, but not beta-carotene rich foods. On the other hand, observational studies that suggested a reduced risk of birth defects with an adequate intake of folic acid have been corroborated by randomized controlled trials. The results were impressive enough to support the general recommendation that all pregnant women supplement their diet with 400 µg of folic acid daily, and for governments to launch folate fortification programs for wheat products. This program has worked remarkably well, with birth defects attributed to folic acid deficiency now significantly reduced. Only a few randomized controlled trials have been carried out using multivitamins (see Table on p. 60), but because of confounding factors, their relevance for Western populations is unclear. When to recommend multivitamins There certainly is no universal agreement on this issue. Health Canada won t go further than recommending a supplement for women of childbearing age, the Canadian Medical Association takes no official position, and the Dietitians of Canada suggest getting our vitamins from food but point out that some segments of the population can benefit from supplements. Like its Reviewers Jeffrey Blumberg, PhD, FACN, CNS Professor, Friedman School of Nutrition Science and Policy; Director, Antioxidants Research Laboratory Jean Mayer USDA Human Nutrition Research Center on Aging, Tufts University, Boston, MA Daniel Lalla, MDCM, FCFP Faculty lecturer, Department of Family Medicine, McGill University; Staff, Brome- Missisquoi-Perkins Hospital, Cowansville, QC Ivan Rohan, MD, CCFP Department of Family Medicine, McGill University The author/reviewers have received an honorarium from the accrediting body for this program. january 2008 parkhurst exchange 59

3 Linxian General Population Trial 4 population: 30,000 men and women aged 40-69, in the Linxian province of China health: unusually high cancer rates intervention: various combinations of vitamin A (10,000 IU), zinc oxide (45 mg), riboflavin (5.2 mg), niacin (40 mg), vitamin C (180 mg), beta-carotene (25,000 IU), selenium (50 µg) and vitamin E (60 mg) results: only the combination of beta-carotene, vitamin E and selenium showed any benefit, with a 9% decrease in death rate after 5 years shortfalls: diet low in fruits, vitamin blood levels low by Western standards, so that intervention may have just corrected subnormal intake Supplementation en Vitamines Et Mineraux Antioxydants 5 population: 12,000 French men and women Examples of randomized controlled trials on multivitamins intervention: vitamin C (120 mg), vitamin E (30 mg), beta-carotene (10,000 IU), selenium (100 µg) and zinc (20 mg) supplement over 8 years results: small reduction in cancer incidence in men but not in women shortfalls: reduced prostate cancer risk in men who had normal prostate-specific antigen levels (PSA) at the beginning of the study, but increased risk in men who had a higher PSA at outset Age-Related Eye Disease Study (AREDS) 6 population: 4,600 American men and women with some degree of macular degeneration intervention: supplement containing vitamins C (500 mg) and E (400 IU), beta-carotene (25,000 IU), zinc (80 mg) and copper (2 mg) results: reduction in the progression of age-related macular degeneration Canadian counterpart, the American Medical Association makes no official recommendation, but a widely quoted review paper in its journal concludes that it appears prudent for all adults to take multivitamins due to widespread inadequate diets. To date, the most concerted effort to resolve the questions swirling around the use of multivitamins was undertaken by the National Institutes of Health in the U.S. In 2006, a 13-member expert panel concluded that there s insufficient evidence for or against recommending vitamin supplements for chronic disease prevention except in the follwing three cases. 3 Supplementation with B vitamins in women of child-bearing age is beneficial, as is supplementation with calcium and vitamin D in post-menopausal women to prevent bone fractures. And the progression of macular degeneration can be reduced with a mix of specifically defined doses of beta-carotene, zinc, vitamin C and vitamin E. Women of childbearing age Approximately 400 pregnancies in Canada every year result in spina bifida or anencephaly. Spina bifida is usually not fatal but results in serious disability; anencephaly is a fatal condition. Sufficient evidence exists to demonstrate that the B vitamin folic acid can reduce the occurrence of spina bifida and anencephaly by at least 50% when taken daily before conception and during early pregnancy. The usual dose suggested is 400 µg daily, as part of a multivitamin supplement also containing iron. Prevention of bone fractures While the roles of calcium and vitamin D in bone formation are well established, a number of other nutritional factors are also involved in determining bone strength. Protein content of the diet, caffeine intake, as well as dietary magnesium, fluoride and boron can all impact on the risk of osteoporosis, a condition responsible for some 25,000 hip fractures a year in Canada. Numerous trials have explored the possibility of reducing the risk of osteoporotic fractures by means of calcium and/or vitamin D supplementation, with most but not all studies showing favourable, albeit not dramatic results. The Women s Health Initiative clinical trial, for example, randomly assigned either a placebo or 1,000 mg of elemental calcium, given as calcium carbonate, with 400 IU of vitamin D 3 daily to over 36,000 healthy post-menopausal women. 7 After 60 parkhurst exchange january 2008

4 7 years of follow-up, a small but significant improvement in hip bone density in the supplement takers was noted, but there was no significant reduction in hip fractures. The results, however, were confounded by the fact that the majority of women in both groups took calcium on their own, so that mean daily intakes of the mineral were 1,100 mg and 2,000 mg in the placebo and treatment groups, respectively. The supplements slightly increased the risk of kidney stones. As with other dietary supplements, there s no expert consensus on recommendations, but a total daily intake of 1,000-1,500 mg of calcium along with 800 IU of vitamin D 3 is a reasonable target. This requires a vitamin D supplement. As far as the form of calcium goes, the carbonate is best taken with meals whereas the citrate is very well absorbed and can be taken at any time. Slowing macular degeneration Age-related macular degeneration (AMD) affects over 2 million Canadians. There s no cure for the disease, but specific dietary supplements may slow the deterioration. The U.S. National Eye Institute s Age-Related Eye Disease Study (AREDS), published in 2001, demonstrated a reduction in the progress of AMD with a supplement containing 25,000 IU of beta-carotene, 500 mg vitamin C, 400 IU vitamin E, 80 mg zinc and 2 mg copper. 6 Supplements that conform to this formula are available for use by patients who have AMD or are at risk. Since beta-carotene supplements have been linked to lung cancer in smokers, special formulas without this nutrient are also available. There s no clear-cut evidence, however, that any supplement will prevent AMD. Some multivitamin supplements do incorporate the relevant nutrients in the same amounts as used in AREDS, and these may be a suitable choice for people over age 50 who desire to take mul tivitamins. Can multivitamins prevent heart disease? There s no doubt that in the test tube, antioxidants such as vitamins E and C, betacarotene, and the mineral selenium, can reduce the free radical damage that plays a role in the development of atherosclerosis. The B vitamins also have been presumed to have a protective effect because they are an important factor in lowering the levels of homocysteine in the blood, which is an independent cardiovascular risk factor. But whether or not B vitamin supplements actually reduce the risk of cardiovascular disease is a different question. Dr. Eliseo Guallar and colleagues at Johns Hopkins University identified 11 randomized controlled trials where patients were given antioxidant supplements or B vitamins while the status of their coronary arteries was monitored. 8 Two of the antioxidant trials used only vitamin E, three used a combination of vitamins E and C, and the others used various combinations of vitamins E and C, beta-carotene and selenium. There were also several trials that used only the B vitamins. In other words, all of the supplement methodologies that had been promoted to reduce cardiac risk were explored and none reduced the progression of atherosclerosis. Neither did they prevent the closure of coronary arteries that had been opened up by balloon angioplasty. The Johns Hopkins researchers conclude that the widespread use of vitamin-mineral supplements to prevent atherosclerosis isn t supported by the scientific evidence as construed from randomized controlled trials. Can multivitamins prevent cancer? Since cancers can be initiated by free radicals, antioxidant vitamins and minerals are expected to have a preventive effect. Indeed, the anti-cancer potential of fruits and vegetables has been assumed to be largely due to the presence of antioxidant Myths Multivitamins don t provide energy, and taking them can t make up for the inadequacies of an improper diet. Natural vitamins aren t superior to synthetic ones, with one possible exception: Vitamin E as naturally occurring RRR-a-tocopherol is more bioavailable and more bioefficient than synthetic a-tocopherol, although this can be adjusted by using about 2 times the dose of the latter to approximate that of the former. Low-cost drugstore brands are in general not inferior to expensive multi-level marketed products, but some differences may exist as has been shown by private certification labs (e.g. january 2008 parkhurst exchange 61

5 Recommendations At this point, there is insufficient evidence to formulate algorithms for multivitamin supplementation for the general population. This, however, doesn t preclude making some educated guesses on the appropriate use of such supplements. As a general rule, supplements are best taken with meals to maximize bioavailability and minimize stomach upset. Premenopausal women A multivitamin supplement with 400 µg folic acid and at least 20 mg iron, and at least IU vitamin D. Men of all ages A multivitamin with no more than 4 mg iron (iron can act as a free radical inducer), no more than 400 µg folic acid, and IU vitamin D. Postmenopausal women A multivitamin with no more than 4 mg iron, no more than 400 µg folic acid and IU vitamin D. A separate calcium supplement of mg elemental calcium if dietary calcium is insufficient. Special cases Smokers shouldn t take supplements containing more than the 1-3 mg beta-carotene usually found in multivitamins, but can likely benefit from an extra 250 mg of vitamin C. Alcohol impairs vitamin absorption, meaning that people who drink aren t likely to benefit from a multivitamin. Vegetarians often have an insufficient intake of vitamin B 12, which can be corrected with a multivitamin. People on severely restricted weight loss diets (<1,200 calories) are unlikely to meet their micronutrient needs and should take a multivitamin. species. Protection from cancer should be especially evident in the case of digestive tract cancers, where antioxidants present in food should exert their greatest effect. To investigate this notion, Goran Bjelakovic and his colleagues at the University of Nis in Serbia and Montenegro identified 14 rigorous placebo-controlled trials involving over 170,000 subjects. All the trials used oral supplements of varying amounts and combinations, taken daily or every other day over a number of years. 9,10 The results of the meta-analysis were unexpected: No protection against esophageal, gastric, colorectal, pancreatic or liver cancer was found, although selenium supplementation in a few of the trials did show some optimistic results. But in seven trials, all of high quality and involving over 130,000 subjects, the supplement takers actually had a higher rate of premature death. Bjelakovic s statistical analysis has been criticized based on the fact that the summary relative risk was driven entirely by the outlying result from a single trial based on an anomalous population of smokers, ex-smokers and occupationally exposed asbestos workers. Without this one study, Bjelakovic et al. wouldn t have achieved a statistically significant finding. It s also possible that people who are ill are more likely to take supplements, or that supplements have to be taken for longer periods to be effective, but these suppositions haven t been tested yet. The special case of folic acid Folic acid is especially critical in the earliest stages of development, which of course is why a decision was made to add it to flour. Animal experiments and theoretical considerations looking at folic acid s role in cell multiplication have also suggested that the vitamin may offer protection from heart disease and cancer. However, cancer cells also rely on folic acid for multiplication, and large doses may help them proliferate. Indeed, methotrexate is effective against some cancers because it blocks the conversion of folic acid to tetrahydrofolate, the active form of the vitamin. In adults, therefore, folic acid may prevent cancer, but make existing cancers worse. In the Nurses Health Study, women with the highest folic acid intake had the lowest risk of colon cancer. On the other hand, a Dartmouth study using higher doses (1,000 µg) in people who already had polyps in their colon showed an increased risk of developing cancerous polyps as well as a raised risk of prostate cancer. 11 These investigations have proven disappointing for consumers looking for a magic bullet against diseases that constitute major causes of death in our society. Future trials may shed light on why the promise of in vitro and animal experiments has not been borne out by intervention trials, but for now, patients should be advised that observational studies indicate that cancer and heart disease are more likely to be prevented by a proper diet and exercise than by taking multivitamins. Nutritional insurance Supplements should be regarded as just that, not as replacements for micronutrients in the diet. Fruits, vegetables and whole grains contain a blend of antioxidants, minerals and probably unrecognized compounds that are unlikely to be replicated in supplements. However, the majority of people don t eat properly all the time, with polls showing that less than 20% of 62 parkhurst exchange january 2008

6 Canadians eat the recommended 7-10 servings of fruits, vegetables and whole grains daily. Some researchers feel that taking multivitamins therefore constitutes nutritional insurance, which seems to be a reasonable argument. This may apply especially to seniors who are likely to suffer from nutritional inadequacies, especially if taking medications that can interfere with vitamin absorption. Interactions with drugs Vitamin and mineral bioavailability can be affected by drugs, and likewise, drug efficacy can be affected by vitamins and minerals. Cimetidine, for example, lowers the absorption of folic acid, and isoniazid impairs the conversion of vitamin D into its active form. Iron absorption is enhanced by vitamin C. Calcium can decrease the efficacy of some antibiotics, as well as of thyroid hormones. Bisphosphonates shouldn t be taken within 4 hours of taking a calcium supplement. Vitamin E can increase the risk of bleeding with coumadin, although not in the doses found in multivitamins. Vitamin K, on the other hand, may reduce the efficacy of this anticoagulant. Vitamin A raises the risk of toxicity associated with isotretinoin, and vitamin B 6 can interfere with the action of levodopa or phenytoin. The foregoing underlines the importance of taking a detailed medication history that includes the use of dietary supplements. Reference to drug interaction databases can flag problems. Dosing of multivitamins The critical message in dosage of vitamins is that more isn t necessarily better. While there s debate about optimal doses, there s general agreement in regard to doses that present no concern in terms of safety. Up to 500 mg vitamin C, 400 IU of E and 5,000 IU of A don t worry researchers. Vitamin B 12 in the range µg may be beneficial, especially for seniors who have a greater difficulty absorbing this vitamin. There s no problem with 400 µg of folic acid or vitamin B 6 up to 25 mg daily. Selenium at a dose of 100 µg may offer protection against prostate cancer, and calcium in the range of 1,000-1,500 mg a day may improve bone strength and reduce the risk of colon cancer. The role of vitamin D in the prevention of osteomalacia and osteoporosis is well established, but recent research indicates that the vitamin may have numerous other potential benefits including protection from cancer, diabetes and multiple sclerosis. It s not clear, however, just how much vitamin D we need. The usual recommendation has been 200 IU daily for people under 50, 400 IU for those between and 600 IU for people over 70. But many researchers think that these recommendations should be increased to 1,000 IU a day given that no studies have suggested any risk at this level. Bottom line While there s no final word on the wisdom of taking a one-a-day type multivitamin, the potential benefits appear to outweigh the risks. The situation is likely to be clarified when results from the Physicians Health Study II, a 15-year randomized clinical multivitamin trial, become available. Test your knowledge! Go to to complete the quiz, participate in the forum and apply for MAINPRO-M1 CME credits. Find links to helpful resources on the McGill website and at References 1. Multivitamin Use, Folate, and Colon Cancer in Women in the Nurses Health Study. Ann Intern Med. 1998; 129: Effects of a Combination of Beta Carotene and Vitamin A on Lung Cancer and Cardiovascular Disease. N Engl J Med. 1996;334 (18): The Efficacy and Safety of Multivitamin and Mineral Supplement Use To Prevent Cancer and Chronic Disease in Adults: A Systematic Review for a National; Institutes of Health State-of-the- Science Conference. Ann Intern Med. 2006; 145: Nutrition Intervention Trials in Linxian, China: Multiple Vitamin/ Mineral Supplementation, Cancer Incidence, and Disease-Specific Mortality Among Adults With Esophageal Dysplasia. J Natl Cancer Inst. 1993;85(18): A Randomized Placebo-Controlled Trial of the Health effects of Antioxidant Vitamins and Minerals. Arch Intern Med. 2004;164: A Randomized, Placebo-Controlled, Clinical Trial of High-Dose Supplementation with Vitamins C and E and Beta Carotene for Age- Related Cataract and Vision Loss: AREDS. Arch. Ophthalmol. 119: Calcium plus Vitamin D Supplementation and the Risk of Fractures. N Engl J Med. 2006;354 (7): Vitamin-mineral Supplementation and the Progression of Atherosclerosis: A Meta-Analysis of Randomized Controlled Trials. Am J Clin Nutr. 2006;84: Mortality in Randomized Trials of Antioxidant Supplements for Primary and Secondary Prevention. JAMA. 2007;297: Clinical Trials of Vitamin and Mineral Supplements for Cancer Prevention. Am J Clin Nutr Jan;85(1): Folic Acid for the Prevention of Colorectal Adenomas. JAMA. 2007;297: General Reference Challenges and opportunities in the Translation of the Science of Vitamins. Am J Clin Nutr. 2007;85(suppl): january 2008 parkhurst exchange 63