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1 From the Friedman School of Nutrition Science and Policy, Tufts University, Boston, MA
2 Presented at the conference "Multivitamin/Mineral Supplements and Chronic Disease Prevention," held at the National Institutes of Health, Bethesda, MD, May 15–17, 2006. 3 Reprints not available. Address correspondence to IH Rosenberg, Friedman School of Nutrition Science and Policy, Tufts University, 150 Harrison Avenue, Boston, MA 02111. E-mail: irwin.rosenberg{at}tufts.edu.
ABSTRACT
Some 100 y after the description and naming of the first vitamin, this conference on the state-of-the-science has shown that remarkable and exciting advances have been made in our understanding of the biology, chemistry, and metabolism of vitamins, explaining their essentiality in the diet. A great deal more needs to be done in the translation of this knowledge into an understanding of the benefit of vitamin supplements to disease prevention and to health and well-being. Not only are advances in fundamental science and biology necessary, but more attention must be paid to genomics, epigenetics, behavioral science, and new techniques for evidence analysis of studies. Information relating individual vitamins or small combinations of vitamins to disease prevention is stronger than that for multivitamins, formulations that cry out for greater standardization. This large task of translating emerging science to better policy in the field of vitamin and multivitamin-mineral supplement use should occupy our attention intensively in the years to come. Issues needing more attention include the content and labeling of such products and the effects of the products on nutrient adequacy as well as in chronic degenerative disease prevention. In this quest, the development of more and better surrogate markers will be critical. Dose-response assessments of safety are badly needed for updating Tolerable Upper Intake Levels. At its best, all of these disparate types of research will require a robust interaction between the public and private sectors in a regulatory framework that supports and rewards investment in good science.
Key Words: Multivitamin-multimineral supplements • vitamins • research needs
INTRODUCTION
My assigned task is to identify some of the challenges and opportunities that we face at the time of this state-of-the-science conference on the application of advancing science to the safe and effective use of vitamin and mineral supplements. This conference comes slightly <100 y after the first "vital amine" was characterized by the Polish investigator Casimir Funk, whose work was based on the work of Eijkman and colleagues in the Dutch Indies in the quest for the cause of beri-beri. In 1929 Eijkman was recognized for his work with a Nobel Prize in Medicine. The year before, the first Nobel Prize of the vitamin era was awarded to ADR Windaus for work on the chemistry of steroids and vitamin D. Ten more Nobel Prizes for vitamin research and discovery would follow, the last award to Dorothy Hodgkin in 1964 for identifying the structure of vitamin B-12. This was also the last of the vitamins to be described in this remarkable era of vitamin discovery in the first half of the 20th century. We have come a long way in 100 y in the elaboration of the functions in metabolism, the functions in gene regulation, and the contributions to health of this disparate group of compounds, accidentally called vitamins, and it is only proper that we review the state-of-the-science of application of this knowledge in this sphere of multivitamin-multimineral supplements and chronic disease. To approach my task, I will use the outline of the questions thoughtfully prepared by the conference organizers and, when possible, emphasize the research challenges and opportunities that have been stated and formulated by previous speakers. Our goal, I believe, is to narrow the gap between the reasonably advanced science of vitamins and the scientific basis for their very widespread use as dietary supplements by more than one-half the population of this nation.
CONTENT AND LABELING
Previous speakers addressed issues relating to the description of current patterns and prevalence of the public's use of multivitamin-multimineral supplements. Clearly, good research design requires at least some standardization of the nomenclature and content of "multivitamins." As Yetley (1) and Rock (2) reported, the term multivitamin currently encompasses hundreds, if not thousands, of products with varied content and dose of vitamins and minerals. Not only is this heterogeneity a significant challenge for good research on how this disparate group of products is used by the public, but lack of standardization is an obstacle to informative labeling and guidance to consumers.
The term multivitamins was first used some 60 y ago in marketing by Miles Laboratories, which came out with One-A-Day multivitamins. These were first a combination of vitamins A and D and later included other B vitamins and some minerals. Miles Laboratories was the first to use the concept of insurance in their marketing efforts, which has had such a lasting effect on the vitamin supplement marketplace. Certainly, the concept of daily use of multivitamins for insurance is largely unmodified to the present day as it guides marketing.
Although the term multivitamins calls out for better definition, the term vitamin as applied to a disparate group of essential nutrients with widely differing chemistry and biology is even more interesting and enduring. The first of the vital amines (vitamins) to be named was thiamine, in reference to the amine group in its chemical structure and the fact that it was apparently vital for life in the prevention of beri-beri (3). Around the same time, a fat-soluble essential nutrient (in contrast with the water-soluble thiamine) was identified as "fat soluble A" by Steenbock, McCollum, and others (3). This substance, which was vital but certainly not an amine, followed the nomenclature path of least resistance for organic substances that were essential in the diet and was called vitamin A, bumping thiamine down the list to vitamin B. In general, the fat-soluble substances were subsequently named with letters, and the water soluble ones as subnumbers of vitamin B, until vitamin B-12 was discovered and structurally identified in the1950s (4). All these vitamins are disparate in their chemistry, biochemistry, function, and availability in foods. Throughout evolution, food has been the source of these vital substances to organisms that did not have or had lost in the evolutionary process their ability to synthesize these essential compounds for metabolism and life. Their clustering in multivitamins has little scientific rationale, relating to the fact that they share—not exclusively with other vitamins, because some essential mineral nutrients fall in this category—a dietary requirement for health and life but notably in vastly differing amounts. Even within the designation of an individual vitamin, there are different isoforms, sometimes referred to as "vitamers," which differ from one another in bioavailability and even in efficiency in metabolic pathways and cycles. Vitamin isoforms present an additional challenge with regard to their use in combinations or even as individual vitamin supplements.
As we heard from Yetley (1) and also from Woo (5), there are at present no regulatory requirements with respect to the content of multivitamins. Sensible regulation, I believe, is helpful to both consumers and to industry and is needed, in this case, as a framework for research that will lead to greater standardization and better labeling of products in the marketplace. In this regard, I must note that the 1994 Dietary Supplement Health and Education Act (DSHEA) by Congress (6) has been distinctly unhelpful in setting a framework for better research and for rewarding companies that choose to do science-based marketing. Today, some 12 y later, the only contribution that I can see that DSHEA has made to improving our science and knowledge of dietary supplements and multivitamins in particular was the mandate that the National Institutes of Health establish the Office of Dietary Supplements. Much has happened in these 12 y to justify consideration and reconsideration of many of the elements of that 1994 legislation, and it will be hard to overcome the challenges of standardization, nomenclature, and safety considerations without some updating and modification of that legislation. I am not ready to paraphrase President Ronald Reagan in his response to the Berlin Wall when he said, "Mr. Gorbachov, tear that wall down! " with respect to DSHEA, but certainly some important modifications are in order.
WHO USES MULTIVITAMINS AND WHY?
On the question of who uses multivitamins and multiminerals, I am impressed with the data presented by Rock (2) and also with the difficulties enherent in collecting such data. The information about who uses supplements and why emphasizes the gap between established benefits and decisions for use. On the "why": if 52% of the population use multivitamin supplements in an effort to prevent disease as reported by Sloan (7), and 38% use them because it makes them feel better or have more energy, then we should ideally have a stronger scientific basis to underlie those expectations. As we have heard in this conference, the evidence for prevention of chronic disease is still quite rudimentary, especially for multivitamins, and the evidence that these substances are related to energy in the body is widely absent.
Most important in Rock's presentation and review about who uses multivitamins is the observation that has been consistent in many studies, that those who use them have a higher level of education, lower body mass index (ie, less obesity), higher levels of physical activity, and consistently better diets, even in their vitamin and mineral content. The use of multivitamins might be included along with several of their health-promoting behaviors, but attribution of health outcomes to the use of multivitamins or supplements will be flawed, if not impossible, because of the strong confounding association with other health-promoting and predicting behaviors.
EFFECT ON NUTRIENT ADEQUACY
In their efforts to assess the effect of vitamin supplements on total nutrient intake and safety, Murphy et al (8) emphasized some of the newer definitions of adequacy of intake as essentially a probability construct. This then calls for more studies that correlate dietary adequacy and probability of insufficiency with measures of blood concentrations of vitamins and, even more importantly, with functional measures of vitamin sufficiency.
It may be important here to emphasize the need for advances in updating our statements and definition of requirements, as most recently set out in the Dietary Reference Intake series by the Institute of Medicine (9–14). There is a great need for more studies of dose response with respect to efficacy, health, and safety. Many of the studies have been lacking in adequate recognition that the effectiveness of these substances is not binary (present or absent) but, as in the rest of biology, is dependent on dose. I strongly endorse Murphy et al's suggestion that the formulation of combinations, that is, the clusters of vitamins and minerals in products, should bear more direct relation to the established public health problems that have been identified and can be ameliorated or overcome by these combinations. Elaboration of such combinations could be an important step to future research and future use.
STATE-OF-THE-SCIENCE ON CHRONIC DISEASE PREVENTION
This conference has explored the state-of-the-science on the efficacy of single and multivitamin-multimineral supplement use in chronic disease prevention. To address this question of efficacy, we now have stronger tools with better methods and even the orthodoxy of evidence-based practice centers. The improved methods of systematic review or meta-analysis cannot overcome the problem of design flaws in many of these studies, as identified by Heaney (15). Usually, such design flaws arise from an excessive concentration on the rules of randomized controlled trials and not enough on how a study design that captures and addresses the biology of the relation between vitamins and chronic disease. The positive advances in techniques of systematic review will need to be applied also to observational data in addition to randomized controlled trials, the latter of which were focused on at this conference. Both have their strengths and weaknesses and both will be needed if we are to understand and translate the rich science of the biology of vitamins to their application. In many cases, a randomized controlled trial of the duration that would be necessary to test a relation to chronic disease may not be feasible. All the more reason, then, for more application of cohort studies. These and other studies should build on progress in the basic biology of vitamins and minerals.
The explosion of information on nutritional biology, genomics, and epigenetics will need to be harnessed even more in the research agenda on vitamins and combinations of vitamins. Good study design will need to pay attention not only to dose and dose responses but also to duration and mechanism of effect. Because we cannot do a randomized controlled trial in each case, we need surrogate markers of efficacy and even safety. These markers or biomarkers of effects and intermediates along the pathway of effectiveness or harm will need to be validated by the best fundamental and human research.
COST-EFFECTIVENESS
I am doubtful whether concepts such as insurance, tuning-up metabolism, or optimal levels add much to our quest for better science in this field. Rather, they sound like marketing claims. If as scientists we are to use them, we should design research that validates or at least tests these concepts. Studies that seek to validate the concept of insurance by showing that multivitamin use saves money on health and perhaps even on health insurance are fatally confounded by the wide association in multivitamin users with other health-promoting and disease-preventing behaviors.
EVIDENCE-BASED ASSESSMENTS OF SAFETY
Evidence for harm in the moderate use of these multivitamins singly or in combination is sparse but not fully reassuring. Given their widespread use, we need studies of exposure with endpoints based on basic vitamin biology that provide dose-response outcomes. The next generation of Tolerable Upper Intake Levels in the Dietary Reference Intakes will demand more dose-response data on adverse effects.
CONCLUSION
Some 100 y after the description and naming of the first vitamin, this conference on the state-of-the-science has shown that remarkable and exciting advances have been made in our understanding of the biology, chemistry, and metabolism of vitamins, thus explaining their essentiality in the diet. A great deal more needs to be done in the translation of this knowledge into an understanding of the benefit of vitamin supplements to disease prevention and to health and well-being. Information relating individual vitamins or small combinations of vitamins to disease prevention is stronger than that for multivitamins, which do cry out for greater standardization. This large task of translating emerging science to better policy in the field of vitamin and multivitamin use should occupy our attention intensively in the years to come. At its best, that research will require a robust interaction between the public and private sectors in a regulatory framework that supports and rewards investment in good science.
ACKNOWLEDGMENTS
The author had no conflicts of interest.
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