In postmenopausal women, the use of several common vitamin and mineral supplements was associated with an increased risk of death, researchers found.
After adjustment for multiple potential confounders, use of multivitamins and vitamin B6, folic acid, iron, magnesium, zinc, and copper supplements was associated with greater all-cause mortality through 19 years of follow-up (HRs 1.06 to 1.45), according to Jaakko Mursu, PhD, of the University of Eastern Finland in Kuopio, and colleagues.
Use of a daily calcium supplement, on the other hand, was associated with a lower risk of death (HR 0.91, 95% CI 0.88 to 0.94), the team reported in the Oct. 10 issue of the
Archives of Internal Medicine.
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"Based on existing evidence, we see little justification for the general and widespread use of dietary supplements," they wrote, citing a body of literature generally supporting no association with mortality, with some suggestions of harm. "We recommend that they be used with strong medically based cause, such as symptomatic nutrient deficiency disease."
Agreeing in an invited commentary were Goran Bjelakovic, MD, DMSc, and Christian Gluud, MD, DMSc, of Copenhagen University Hospital.
"We cannot recommend the use of vitamin and mineral supplements as a preventive measure, at least not in a well-nourished population," they wrote. "Those supplements do not replace or add to the benefits of eating fruits and vegetables and may cause unwanted health consequences."
Taking dietary supplements to improve health and prevent diseases is widespread, with about half of U.S. adults using one or more in 2000, according to Mursu and colleagues. Annual sales top $20 billion.
The long-term impact of supplementation is unknown, however, and some studies have suggested a relationship between supplements and increased mortality.
As Rita Redberg, MD, of the University of California San Francisco, wrote in an editor's note, "manufacturers are not required to disclose to the FDA or to consumers the evidence they have regarding their products' safety, nor must they empirically back up claims of purported benefits."
In light of this uncertainty, Mursu and colleagues examined the use of vitamin and mineral supplements among 38,772 postmenopausal women participating in the Iowa Women's Health Study. The mean age of the women at baseline in 1986 was 61.6.
The participants reported their use of supplements in 1986, 1997, and 2004. The percentage who reported using at least one supplement daily increased from 62.7% to 85.1% during the study. In 2004, more than one-quarter of the women (27%) said they used four or more.
The most commonly used supplements were calcium, multivitamins, vitamin C, and vitamin E.
Through 2008, 40.2% of the women died.
After adjustment for demographics, dietary and lifestyle factors, comorbidities, and use of hormone replacement therapy, the following supplements were associated with a greater risk of death during follow-up:
- Multivitamins: HR 1.06 (95% CI 1.02 to 1.10)
- Magnesium: HR 1.08 (95% CI 1.01 to 1.15)
- Zinc: HR 1.08 (95% CI 1.01 to 1.15)
- Iron: HR 1.10 (95% CI 1.03 to 1.17)
- Vitamin B6: HR 1.10 (95% CI 1.01 to 1.21)
- Folic acid: HR 1.15 (95% CI 1.00 to 1.32)
- Copper: HR 1.45 (95% CI 1.20 to 1.75)
Absolute increases in risk ranged from 2.4% with multivitamins to 18% with copper.
After multivariate adjustment, use of calcium supplementation was associated with a lower risk of death (HR 0.91, 95% CI 0.88 to 0.94). The absolute risk reduction was 3.8%.
To account for the multiple comparisons made, however, the researchers set a
P value of less than 0.003 to establish significance. Only the increase associated with multivitamins, calcium, and copper remained significant using this threshold.
"However, many of the additional statistical tests were confirmatory, strengthening confidence that findings were not explainable by chance," Mursu and colleagues noted.
In particular, the findings related to iron and calcium remained consistent when the analysis was restricted to follow-up from 1986 to 1996, from 1997 to 2003, and from 2004 to 2008.
In addition, the mortality risk associated with iron supplementation increased in a dose-response fashion.
The relationship was not significant for doses of 200 mg/day or less, but was significant for a dose of 201 to 400 mg/day (HR 1.35) and for a dose of 400 mg/day or more (HR 1.57).
"Iron is suggested to catalyze reactions that produce oxidants and thus promote oxidative stress," the authors noted, acknowledging that they did not examine possible mechanisms in the current study.
"However, we cannot rule out the possibility that the increase in total mortality rate was caused by illnesses for which use of iron supplements is indicated," they wrote. "Chronic disease, major injury, and/or operations may cause anemia, which is then treated with supplemental iron. However, we could find no evidence for such reverse causality."
In their commentary, Bjelakovic and Gluud said that "one should consider the likely U-shaped relationship between micronutrient status and health," with risks associated with both insufficient and excessive intake.
"Therefore, we believe that politicians and regulatory authorities should wake up to their responsibility to allow only safe products on the market," they wrote.
Added Redberg, "A better investment in health would be eating more fruits and vegetables, among other activities. Because commonly used vitamin and mineral supplements have no known benefit on mortality rate and have been shown to confer risk, this article has been given our 'Less Is More' designation."
Mursu and colleagues noted that their study was limited by the possibility of residual confounding and changes in supplement use during the study, the inability to exclude the chance that some supplements were taken in response to symptoms or clinical disease, the lack of data on nutritional status or detailed information on the supplements used, and the study sample comprised of white women, which limits the generalizability of the findings.
The study was partially supported by grants from the National Cancer Institute and the Academy of Finland, by the Finnish Cultural Foundation, and by the Fulbright program's Research Grant for a Junior Scholar.
One of Mursu's co-authors is an unpaid member of the scientific advisory board of the California Walnut Commission.
Bjelakovic and Gluud reported that they had no conflicts of interest.
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