"WHI" Take a Multivitamin?
April 1, 2009 7 minutes read
"WHI" Take a Multivitamin?
Abstract & Commentary
By Danna Park, MD, FAAP. Dr. Park is Medical Director, Integrative Healthcare Program, Mission Hospitals, Asheville, NC; she reports no financial relationship to this field of study.
Synopsis: In the United States, approximately $23 billion are spent on multivitamins yearly. At least half of all Americans take some kind of supplement, the majority of which are multivitamin/minerals.1 As part of the Women's Health Initiative (WHI), which looked at three overlapping trials of hormone therapy, vitamin D and calcium supplementation, and dietary modification, use of multivitamins in the 161,806 participants was also assessed for effects on risk of a variety of cancers, cardiovascular disease (CVD), and total mortality. Although the study reported that multivitamin use did not impact risk of cancer, CVD, or total mortality, the majority of users took a multivitamin/mineral that contained 100% or less of the RDA for the nutrients included. In addition, some participants took other supplements that were not included in the multivitamin data results. This part of the WHI was complicated by multiple different preparations of supplements, variable doses of a variety of nutrients, possible reporting bias by participants, and overlapping WHI studies, one which included supplementation with calcium carbonate/ vitamin D and another that was a dietary modification trial. In addition to these complications, and subsequent simplification of the multivitamins taken into three broad categories, it may be that the amount of nutrients was not adequate or too variable to have an effect, or that the quality of the individual sources of the vitamins was not ideal to have an impact on the outcomes measured.
Source: Neuhouser M, et al. Multivitamin use and risk of cancer and cardiovascular disease in the Women's Health Initiative Cohorts. Arch Intern Med 2009;169:294-304.
This study was done as part of the women's Health Initiative (WHI, www.nhlbi.nih.gov/whi/). WHI, a 15-year project that commenced in 1991, "was designed to test the effects of postmenopausal hormone therapy, dietary modification, and calcium and vitamin D supplements on heart disease, fractures, and breast and colorectal cancer."1 The 161,808 women either participated in randomized controlled trials (three of them) or in an observational study. The controlled trials were overlapping, meaning that women could be randomized into one, two, or all three: hormone therapy trial, dietary modification trial, or the calcium/vitamin D trial. As was widely publicized in 2002, the hormone therapy arms (estrogen-alone and estrogen + progesterone) were stopped early due to increased incidence of myocardial infarction, stroke, deep venous thrombosis, increased risk of breast cancer in the estrogen + progesterone group, and possible increased risk of dementia and/or cognitive impairment.
The data from the WHI multivitamin study did not specify which women were in which WHI randomized controlled trials. However, it is important to know the design of two of those RCTs as they could have impacted the results of this multivitamin study.
The calcium and vitamin D group (CaD) included 36,282 postmenopausal women, randomized into two groups: The first took 1,000 mg of calcium carbonate and 400 IU of vitamin D daily; the second took a placebo. If women were already taking calcium supplements, they continued to take them no matter which group they were assigned to. Follow-up was 7-11 years, with the study question being whether supplementation of calcium and vitamin D reduced colorectal cancer risk and/or fractures.
In the dietary modification study, 48,835 postmenopausal women were randomized to one of two groups: dietary modification or comparison. The dietary intervention was a 20% total daily fat intake, with five or more fruit/vegetable servings/d, and six or more grains servings/d. In addition, participants self-monitored food intake and attended group nutrition meetings regularly.
As part of the data collected in the controlled and observational trials, multivitamin and supplement use were documented and categorized. The documentation was done at the yearly clinical visit for the women in the controlled trials, and at the three-year clinic visit for the women in the observational group; the women brought the bottles of vitamins and supplements they were taking and only those that were taken at least once a week were recorded. Direct transcription of the ingredients was performed with a validity study showing high correlation between doses transcribed and actual label photocopies. For study purposes, multivitamin preparations were divided into three categories according to amounts of individual nutrients: 1) multivitamins alone (10 or more vitamins and no minerals, and all nutrient levels at or below 100% of the RDA); 2) multivitamins with minerals (20-30 multivitamins and minerals, with all nutrient levels at or below 100% of the RDA); and 3) stress multivitamins (multivitamins/minerals with doses of some individual nutrients greater than 100% of the RDA). Supplement mixtures that contained less than 10 vitamins or minerals, such as B complex preparations or antioxidant preparations, were not considered multivitamins. The study reported use of some individual supplements, such as calcium (including antacids), vitamin C, or vitamin E, and classified other supplements used under a separate category ("Single supplement not including C, E or calcium"), but did not specify what these supplements were. Of the 161,808 participants, 67,150 women (41.5%) used multivitamins. If women used supplements with less than 10 vitamins/minerals, that information was not included in the above totals.
After approximately eight years of follow-up in the clinical trials and observational study groups, there were 9,619 cases of breast, colorectal, endometrial, renal, bladder, stomach, lung, or ovarian cancer. There were 8,751 CVD events and 9,865 deaths. Multivariate statistical analysis showed no association of multivitamin use with cancer risk, CVD, or mortality.
Commentary
This was an enormous study with an ambitious undertaking. For providers who know how hard it is to "get a handle" on what supplements patients are taking, imagine trying to gather and focus these data for such a large number of women. There are a number of reasons why I wouldn't toss your or your patients' multivitamin supplements in the trash just yet.
The actual amounts of nutrients that study participants were taking were quite varied, and difficult to determine. For example, if a woman was in the "multivitamin alone" category, but was also in the CaD arm of the study, she could have been taking 800 IU of vitamin D total between the two, and 1,000 mg of calcium carbonate, as long as she wasn't also taking other uncategorized supplements. If she was in the stress multivitamin category, there is no way to determine the total amounts of vitamin D without reviewing the individual transcribed records. This becomes important in determining effectiveness in cancer prevention. The consensus on how much vitamin D is needed daily is yet to be determined; amounts between 700 and 1,000 IU daily for adults will establish a favorable 25(OH)D level in approximately 50% of adults (some will require more than this dose range) to prevent fractures and decrease incidence of colorectal cancer. A study in 2006 reported that these vitamin D concentrations could not be reached in most adults with recommended daily intakes of 200 IU of vitamin D for younger adults and 600 of IU vitamin D for older adults.2 The NIH-AARP study on dairy foods, calcium, and risk of cancer found an inverse relationship between incidence of colorectal cancer and intake of calcium (dietary and supplements) up to a total dose of 1,300 mg/d.3 More studies that look at optimal dosing of these two important nutrients are needed.
Optimal forms and bioavailability of nutrients also need more study. Given that women were able to continue and choose their own supplements and multivitamins, there was a variety of brands included in this study. The sources of the ingredients making up the multivitamins were not addressed. The bioavailability of certain nutrients such as vitamin E vary with the type of preparation used. For example, synthetic vitamin E, which is the cheapest form of vitamin E (dl-alpha tocopherol), has less bioavailability than d-alpha tocopherol. Natural vitamin E is a mixture of eight bioactive chemicals (four tocotrienols and four tocopherols), but the majority of multivitamins only contain the alpha-tocopherol form, in a dl-alpha or a d-alpha form. It may be that without optimal forms of certain nutrients, optimal outcomes in terms of cancer prevention and other chronic diseases will not be seen in studies.
How multivitamins are taken may affect absorption of certain nutrients as well. For example, calcium carbonate was used as the form of calcium supplementation in the CaD arm of the study. In a more pH-neutral environment, calcium carbonate is more insoluble and thus not as well absorbed. It can also impair absorption of riboflavin and vitamin C. Certain foods will also impair absorption, such as cereal grains (phytic acid in the grains bind with calcium to make calcium phytate). It is unknown if participants in the study were guided as to how to take their supplements in relation to other supplements and food to optimize bioavailability.
The conclusion we can safely draw from this study is that a variety of doses of a variety of supplements and/or multivitamin/multimineral products taken in a variety of combinations by a large number of women undergoing a variety of other study interventions at the same time do not seem to have an effect on cancer, CVD, or mortality. More studies are needed to determine optimal doses and forms of multivitamin preparations to adequately determine outcomes on chronic diseases, cancer, and mortality.
References
1. NIH State-of-the-Science Panel. National Institutes of Health State-of-the-science conference statement: Multivitamin/mineral supplements and chronic disease prevention. Ann Intern Med 2006;145:364-371.
2. Bischoff-Ferrari HA, et al. Estimation of optimal serum concentrations of 25-hydroxyvitamin D for multiple health outcomes. Am J Clin Nutr 2006;84:18-28.
3. Park Y, et al. Dairy food, calcium, and risk of cancer in the NIH-AARP Diet and Health Study. Arch Intern Med 2009;169:391-401.
In the United States, approximately $23 billion are spent on multivitamins yearly. At least half of all Americans take some kind of supplement, the majority of which are multivitamin/minerals.You have reached your article limit for the month. Subscribe now to access this article plus other member-only content.
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