Findings from Flawed Study Used To
Discredit Multivitamin/Mineral Supplements
Starting in 1983, the Life Extension Foundation® warned of dangers associated with commercial multivitamin/mineral formulas.
Our earliest concern was that free radicals generated by supplemental iron would increase cancer and heart disease risk. Our fears were born out shortly thereafter in published studies showing that elevation in markers of iron intake increased risk (by more than fivefold) of common degenerative diseases including heart attack and cancer.1-17
Back in 1983, commercial companies bragged in their advertising about how much iron their multivitamins contained. Despite our repeated warnings, very few commercial supplement companies removed iron from their multivitamin formulas as the public perception was that supplemental iron was beneficial.
The result of this misconception was that individuals using commercial supplements were obtaining miniscule quantities of antioxidants to protect against free radicals, while simultaneously ingesting large amounts of iron (and sometimes copper) that are known free radical generators.18
Based on findings from a newly released study, the media is attacking the safety of multivitamin/mineral supplements.19 The nutrient these researchers identify as causing the greatest numbers of deaths is iron!
It would be convenient for Life Extension® to use the findings from this negative study to bolster our argument against supplemental iron intake (unless individual blood markers indicate iron deficiency). The problem is that the study the media is using to attack multi-nutrient supplements has so many fundamental flaws that it is impossible to extract reliable data from it.
The name of this report is the Iowa Women’s Health Study. Based on its numerous flaws, we can’t accept the author’s contention that supplemental iron was the culprit behind increased mortality.
The media, of course, lumps ALL nutrients together and claims they are “no fountain of youth for women.” As you’ll read, the findings from this latest study are so distorted that they don’t apply to most multivitamin users today, let alone the aggressive disease prevention program followed by Life Extension members.
People Often Don't Take Dietary Supplements Until They Get Sick
It’s a sad fact that most common diseases of aging are preventable, yet most people don’t engage in healthier lifestyle choices until after serious illness manifestation.
The classic example is an individual who never swallowed a single dietary supplement until they’re diagnosed with cancer. They then go from zero to low intakes of supplemental nutrients to swallowing 40 or more pills a day in what too often is a futile attempt to cure advanced stage disease.
In the Iowa Women’s Health Study, the authors admit they did not factor in the increased intake of dietary supplements that occur in response to the development of symptoms or diagnosis of serious disease. Stated differently: If a woman was diagnosed with stage 4 breast cancer and began ingesting 40 supplements daily, but died six months later, she would have been counted as being a heavy supplement user who died prematurely.
In other words, women who did not begin supplementing until after symptoms and/or disease manifested would have been classified from a statistical standpoint as being part of the group that ingested large quantities of supplements but died early nonetheless.
This flaw by itself could render the overall findings of the Iowa Women’s Health Study meaningless because much of the lay public today mistakenly associates dietary supplements as something very important to initiate after serious disease appears.
We at Life Extension hear this often, as people call us with recently diagnosed illness and state they are now ready to take every supplement they should have been using all along.
Women Taking Supplements Also Took More Dangerous Hormone Drugs
If a woman is going to the trouble of swallowing a multivitamin/mineral supplement each day, she is also more likely to take hormone drugs her doctor recommends.
Unfortunately, a popular hormone drug being recommended at the time of this study period was PremPro® (a combination of Premarin® and Provera®). These unnatural to the human body forms of estrogen and progestin have been linked to a host of lethal diseases that cause premature illness and death.20,21,22,23,24
In the Iowa Women’s Health Study, about twice as many women who took multivitamin/mineral supplements also took non-bioidentical hormone replacement therapy which is associated with early mortality. In numerical terms, 13.5% of the supplement users took hormone therapy at baseline compared to only 7.2% of non-supplement users. This ratio showing more supplement users taking hormone drugs persisted to the end of the observational period.
In technical terms, this is known as a ‘confounding factor’ because the increase in mortality caused by these dangerous hormone drugs would skew the results in a way that would show higher death rates in women taking these hormone drugs who also happened to be taking a multivitamin/mineral supplement.
The differences between groups at baseline are profoundly important to the integrity of the analysis. In fact, in order to fairly and accurately investigate the effects of any intervention, both the active treatment group and the control group must be balanced in their characteristics. If not, then this creates a powerful source of bias that can have unexpected results. This flaw alone may have rendered the study’s findings meaningless from both a statistical and real world standpoint.
Findings of Reduced Mortality Overlooked by Media
The Iowa Women’s Health Study initially showed that women who supplemented with vitamins C, D, E and calcium had significantly lower risks of mortality.25
The study authors then blended this positive data with the negative results of iron and copper use and other multivariable adjustments to conclude increased mortality associated with multivitamin/mineral supplementation.
These “multivariable adjustments” were at the discretion of the study authors and could have been skewed either way to show positive or negative outcomes. Based on the negative remarks expressed at the beginning of the report, there appeared to be author bias against the use of multivitamin/mineral supplements.
This bias was especially troubling when recent positive findings were omitted from the initial discussion. For example, a study published in July 2011 in the European Journal of Nutrition with the purpose to prospectively evaluate the association of vitamin/mineral supplementation with mortality from cancer, cardiovascular conditions, and all-causes arrived at a completely opposite result.
In lay terms, this European study indicated that long-term users of antioxidant vitamin supplements had a 48% reduced risk of cancer mortality and 42% lower all-cause mortality.26 Yet the media did not even bother to mention these impressive findings. Apparently they thought a better headline grabber would be to frighten users of dietary supplements with the blatantly flawed Iowa Women’s Health Study.
Too Much Vitamin A!
Popular multi-nutrient formulas used during the majority period of when the Iowa Women’s Health Study was conducted contained far too much preformed vitamin A and inadequate amounts of vitamin D. One popular formula provided 25,000 IU of preformed vitamin A and only 400 IU of vitamin D.
Even today the average amount of preformed vitamin A in most multi-nutrient formulas is far too high in relation to vitamin D content.
The problem with this potency ratio is that in the presence of excess preformed vitamin A, the beneficial effects of vitamin D can be neutralized.27
Vitamins A and D compete for each other’s function in the body. Preformed vitamin A, found in excess amount in many commercial supplements, can thwart vitamin D’s protective effects.27 This is not an issue with beta-carotene, as it converts to vitamin A in the body only on demand.
Consumption of excess preformed vitamin A, as found in commercial multivitamins and modern cod liver oil, may cause bone toxicity in those with inadequate vitamin D status. One study showed that women with the highest intake of preformed vitamin A had 2.1 times more hip fractures.28 A meta-analysis found that people who took preformed vitamin A supplements had a 16% increase in overall mortality,29 perhaps through antagonism of vitamin D.
When vitamin A supplements are given to children with low vitamin A status, the children have far fewer infections.30 When children hospitalized with pneumonia were given higher doses of preformed vitamin A, however, it worsened the clinical course, suggesting that the vitamin should not be given unless there is clinical evidence of deficiency (or concurrent measles infection).31
While vitamin A is critical in regulating cellular proliferation—and thus helping to protect against malignant diseases—when taken in excess amounts, preformed vitamin A can suppress the even more important anti-cancer effects of vitamin D. 32
Published studies confirm that 400 IU of vitamin D a day, even if taken by itself, is not enough to protect against age-related disease.33,34,35,36,37 In the presence of excess preformed vitamin A, as is still found in most commercial multivitamins, the effects of the small amount of vitamin D they contain may be nullified.
If it were not for the fundamental flaws in the Iowa Women’s Health Study, the excess vitamin A and insufficient vitamin D could be the reason that multivitamin/mineral supplements failed to reduce mortality.
The Problem with Questionnaires
A significant challenge in attempting to evaluate the effects of a long-term regimen on human populations is huge variables and relatively long human life spans. This often means a surrogate method must be used in an attempt to gather accurate data.
The Iowa Women’s Health Study used questionnaires to gather data—it was not a direct intervention study. This is an important difference because questionnaires are notoriously unreliable in accurately capturing information. Contrast this approach to actively providing a group of test subjects a vitamin supplement, following these people over time to ensure compliance, and then evaluating the results.
The questionnaire used in the Iowa Women’s Health Study is even more unreliable since the supplement portion of the questionnaire was not validated separately. Study questionnaires are typically validated to help ensure that the questions actually assess what they are intending to.
The purpose of “validating” a questionnaire is to confirm or establish its accuracy or soundness. The supplement portion of this questionnaire was not validated, meaning they did not validate that the supplement questions accurately assessed supplement use.
The authors tried to justify this by explaining “an evaluation with similar instruments” was validated; however, “similar” is not the same as this supplement questionnaire being validated.
No objective measurements of compliance or non-compliance (such as evaluating blood vitamin levels) with vitamin use were undertaken to confirm if the questionnaires accurately reflected whether people were or were not taking supplements. Iron blood levels would have been especially important to assess since women who took iron-containing supplements showed increased mortality.
This failure to validate the supplement portion of the questionnaire is another flaw that could render the Iowa Women’s Health Study’s findings meaningless. How many people do you know who claim to take their nutrients but often skip days?
The Iowa Women’s Health Study attempted to assess vitamin/mineral intake over a 22-year period, a significant challenge for even validated questionnaires, let alone one that was not validated to assure who was really taking vitamins/minerals on a regular basis.
This Study Has Nothing to Do With Life Extension Members
Life Extension members do not take low-potency multivitamin formulas spiked with high amounts of iron and copper. This recipe for a shorter life span was identified decades ago.
Life Extension members do regularly ingest omega-3 fatty acids, curcumin and other nutrients that were not included in the Iowa Women’s Health Study questionnaire. Inclusion of omega-3s alone could have resulted in the “supplemented” group achieving a significant reduction in overall mortality.38,39,40
Life Extension members usually take high-potency antioxidant formulas that provide gamma tocopherol (which is critical to balance the effects of alpha tocopherol in the body)41,42 and vitamin K (which works with vitamin D to keep calcium in bones where it belongs).43,44
The multivitamin formulas used by Life Extension members contain very little preformed vitamin A but lots of vitamin D. Based on consistently strong data showing reduced mortality, most members supplement with even higher amounts of vitamin D.
There are trade industry groups that view the Iowa Women’s Health Study as an attempt to discredit dietary supplements. The reality is that this study has no relationship to what health-conscious people should be doing today to reduce their mortality risk.
If it were not for the many obvious flaws contained in the Iowa Women’s Health Study, Life Extension could use it as ammunition to validate our recommendations made decades ago that are still overlooked by most of conventional and alternative medicine.
Life Extension still contends that certain commercial multivitamin preparations may be doing more harm than good. To rely on the seriously flawed Iowa Women’s Health Study to support this position, however, would be hypocritical since it is not even possible to validate which study participants were consistently taking multivitamin/mineral supplements.
Science by Ambush
There’s little that can be done to stop tabloid journalism, where the media from time to time proclaims that dietary supplements have no value or are even dangerous.
The Iowa Women’s Health Study now making headline news was initiated 25 years ago and strategically released at a time of year (October 10, 2011) when the public is not overly distracted by other events.
The impact of the blatantly flawed study will be to foster apathy and fear on the public, who are misled to think that taking a simple multivitamin supplement may cause them to die sooner.
This is great news for pharmaceutical interests of course, since the more that people neglect their health the greater the demand will be for costly medical interventions.
As Life Extension has done since 1980, we carefully analyze the underlying facts. We then expose the media’s “ambush against science” as a charade to capture attention in a world increasingly comprised of sound bite hype and devoid of the type of in-depth investigation that we at Life Extension thrive on.
Those who rely on media headlines for their health information face enormous risks to their personal mortality, as flawed reports like the Iowa Women’s Health Study are routinely put on seemingly divine pedestals and then grossly misinterpreted by those who report on them.
Life Extension Foundation members gain rapid access to comprehensive analyses of published studies that provide scientific guidance to achieving a longer life span.
- Salonen JT, Nyyssonen K, Korpela H, Tuomilehto J, Seppanen R, Salonen R. High stored iron levels are associated with excess risk of myocardial infarction in eastern Finnish men. Circulation. 1992 Sep;86(3):803-811.
- Wells BJ, Mainous AG 3rd, King DE, Gill JM, Carek PJ, Geesey ME. The combined effect of transferrin saturation and low density lipoprotein on mortality. Fam Med. 2004 May;36(5):324-9.
- Klipstein-Grobusch K, Grobbee DE, den Breeijen JH, Boeing H, Hofman A, Witteman JC. Dietary iron and risk of myocardial infarction in the Rotterdam Study. Am J Epidemiol. 1999 Mar 1;149(5):421-8
- van der A DL, Peeters PH, Grobbee DE, Marx JJ, van der Schouw YT. Dietary haem iron and coronary heart disease in women. Eur Heart J. 2005 Feb;26(3):257-62.
- Tuomainen TP, Punnonen K, Nyyssönen K, Salonen JT. Association between body iron stores and the risk of acute myocardial infarction in men. Circulation. 1998 Apr 21;97(15):1461-6.
- Tzonou A, Lagiou P, Trichopoulou A, Tsoutsos V, Trichopoulos D. Dietary iron and coronary heart disease risk: a study from Greece. Am J Epidemiol. 1998 Jan 15;147(2):161-6.
- Alissa EM, Ahmed WH, Al-Ama N, Ferns GA. Relationship between indices of iron status and coronary risk factors including diabetes and the metabolic syndrome in Saudi subjects without overt coronary disease. J Trace Elem Med Biol. 2007 21(4):242-54.
- Pierre F, Tache S, Petit CR, Van der Meer R, Corpet DE. Meat and cancer: haemoglobin and haemin in a low-calcium diet promote colorectal carcinogenesis at the aberrant crypt stage in rats. Carcinogenesis. 2003 Oct;24(10):1683-90.
- Stevens RG, Graubard BI, Micozzi MS, Neriishi K, Blumberg BS. Moderate elevation of body iron level and increased risk of cancer occurrence and death. Int J Cancer. 1994 Feb 1;56(3):364-9.
- Mainous AG 3rd, Gill JM, Everett CJ. Transferrin saturation, dietary iron intake, and risk of cancer. Ann Fam Med. 2005 Mar-Apr;3(2):131-7.
- Nelson RL. Iron and colorectal cancer risk: human studies. Nutr Rev. 2001 May;59(5):140-8.
- Moyo VM, Makunike R, Gangaidzo IT, et al. African iron overload and hepatocellular carcinoma. Eur J Haematol. 1998 60:28–34.
- Thompson KJ, Shoham S, Connor JR. Iron and neurodegenerative disorders. Brain Res Bull. 2001 55:155–64.
- Sian-Hülsmann J, Mandel S, Youdim MB, Riederer P. The relevance of iron in the pathogenesis of Parkinson's disease. J Neurochem. 2011 Sep;118(6):939-57.
- Jeong SY, Rathore KI, Schulz K, Ponka P, Arosio P, David S. Dysregulation of iron homeostasis in the CNS contributes to disease progression in a mouse model of amyotrophic lateral sclerosis. J Neurosci. 2009 Jan 21;29(3):610-9.
- Weinberg ED. Iron loading: a risk factor for osteoporosis. BioMetals. 2006 19:633–5.
- Richer S, Rudy D, Statkute L, Karofty K, Frankowski J. Serum iron, transferrin saturation, ferritin, and dietary data in age-related macular degeneration. Am J Ther. 2002 Jan-Feb;9(1):25-8.
- Brewer GJ. Risks of copper and iron toxicity during aging in humans. Chem Res Toxicol. 2010 Feb 15;23(2):319-26.
- Multivitamins may increase women's risk of death from cancer, heart disease. Available at: http://abclocal.go.com/kabc/story?section=news/health&id=8387517. Accessed Oct. 12, 2011.
- Slatore CG, Chien JW, Au DH, Satia JA, White E. Lung cancer and hormone replacement therapy: association in the vitamins and lifestyle study. J Clin Oncol. 2010 Mar 20;28(9):1540-6.
- Cushman M, Kuller LH, Prentice R, et al. Estrogen plus progestin and risk of venous thrombosis. JAMA. 2004 Oct 6;292(13):1573-80.
- Beral V. Breast cancer and hormone-replacement therapy in the Million Women Study. Lancet. 2003 Aug 9;362(9382):419-27.
- Anderson GL, Judd HL, Kaunitz AM, et al. Effects of estrogen plus progestin on gynecologic cancers and associated diagnostic procedures: the Women’s Health Initiative randomized trial. JAMA. 2003 Oct 1;290(13):1739-48.
- Manson JE, Hsia J, Johnson KC, et al. Estrogen plus progestin and the risk of coronary heart disease. N Engl J Med. 2003 Aug 7;349(6):523-34.
- Mursu J, Robien K, Harnack LJ, Park K, Jacobs DR Jr. Dietary Supplements and Mortality Rate in Older Women: The Iowa Women's Health Study. Arch Intern Med. 2011 Oct 10;171(18):1625-33.
- Li K, Kaaks R, Linseisen J, Rohrmann S. Vitamin/mineral supplementation and cancer, cardiovascular, and all-cause mortality in a German prospective cohort (EPIC-Heidelberg). Eur J Nutr. 2011 Jul 22.
- Johansson S, Melhus H. Vitamin A antagonizes calcium response to vitamin D in man. J Bone Miner Res. 2001 Oct;16(10):1899-905.
- Melhus H, Michaëlsson K, Kindmark A, et al. Excessive dietary intake of vitamin A is associated with reduced bone mineral density and increased risk for hip fracture. Ann Intern Med. 1998 Nov 15;129(10):770-8.
- Bjelakovic G, Nikolova D, Gluud LL, Simonetti RG, Gluud C. Mortality in randomized trials of antioxidant supplements for primary and secondary prevention: systematic review and meta-analysis. JAMA. 2007 Feb 28;297(8):842-57.
- Chen H, Zhuo Q, Yuan W, Wang J, Wu T. Vitamin A for preventing acute lower respiratory tract infections in children up to seven years of age. Cochrane Database Syst Rev. 2008 Jan 23;(1):CD006090.
- Stephensen CB, Franchi LM, Hernandez H, Campos M, Gilman RH, Alvarez JO. Adverse effects of high-dose vitamin A supplements in children hospitalized with pneumonia. Pediatrics. 1998 May;101(5):E3.
- Rohde CM, Manatt M, Clagett-Dame M, DeLuca HF. Vitamin A antagonizes the action of vitamin D in rats. J Nutr. 1999 Dec;129(12):2246-50.
- Vieth R. Vitamin D supplementation, 25-hydroxyvitamin D concentrations, and safety. Am J Clin Nutr. 1999 May;69(5):842-56.
- Available at: http://www.nejm.org/doi/full/10.1056/NEJMra070553. Accessed Oct. 12, 2011.
- Rossini M, Viapiana O, Idolazzi L, Fracassi E, Gatti D, Adami S. [Rational and results of weekly treatment with calcidiol in postmenopausal and senile osteoporosis]. Minerva Med. 2007 Feb;98(1):53-68.
- Available at: http://www.ajcn.org/content/85/3/649.full. Accessed Oct. 12, 2011.
- Gorham ED, Garland CF, Garland FC, et al. Vitamin D and prevention of colorectal cancer. J Steroid Biochem Mol Biol. 2005 Oct;97(1-2):179-94.
- Marik PE, Varon J. Omega-3 dietary supplements and the risk of cardiovascular events: a systematic review. Clin Cardiol. 2009 Jul;32(7):365-72.
- Macchia A, Monte S, Pellegrini F, et al. Omega-3 fatty acid supplementation reduces one-year risk of atrial fibrillation in patients hospitalized with myocardial infarction. Eur J Clin Pharmacol. 2008 Jun;64(6):627-34.
- Einvik G, Klemsdal TO, Sandvik L, Hjerkinn EM. A randomized clinical trial on n-3 polyunsaturated fatty acids supplementation and all-cause mortality in elderly men at high cardiovascular risk. Eur J Cardiovasc Prev Rehabil. 2010 Oct;17(5):588-92.
- Christen S, Woodall AA, Shigenaga MK, Southwell-Keely PT, Duncan MW, Ames BN. gamma-tocopherol traps mutagenic electrophiles such as NO(X) and complements alpha-tocopherol: physiological implications. Proc Natl Acad Sci U S A. 1997 Apr 1;94(7):3217-22.
- Devaraj S, Leonard S, Traber MG, Jialal I. Gamma-tocopherol supplementation alone and in combination with alpha-tocopherol alters biomarkers of oxidative stress and inflammation in subjects with metabolic syndrome. Free Radic Biol Med. 2008 Mar 15;44(6):1203-8.
- Bolton-Smith C, McMurdo ME, Paterson CR, et al. Two-year randomized controlled trial of vitamin K1 (phylloquinone) and vitamin D3 plus calcium on the bone health of older women. J Bone Miner Res. 2007 Apr;22(4):509-19.
- Sugiyama T, Kawai S. Carboxylation of osteocalcin may be related to bone quality: a possible mechanism of bone fracture prevention by vitamin K. J Bone Miner Metab. 2001;19(3):146-9.