Some Vitamin, Mineral Supplements May Be Harmful

Several commonly used vitamin and mineral supplements were significantly associated with increased total mortality risk in 38,772 older women from the Iowa Women’s Health Study who were followed for a mean of 19 years.

Supplemental iron was most strongly associated with increased mortality (hazard ratio of 1.10 in a fully adjusted model), Jaakko Mursu, Ph.D., of the University of Eastern Finland, Kuopio, and colleagues reported in the Oct. 10 issue of Archives of Internal Medicine.

The use of multivitamins, vitamin B₆, folic acid, magnesium, zinc, and copper also was associated with a higher risk of mortality (hazard ratios, 1.06, 1.10, 1.15, 1.08, 1.08, and 1.45, respectively) after adjustment for age, education level, place of residence, diabetes mellitus, high blood pressure, body mass index, waist to hip ratio, hormone therapy, physical activity, smoking status, alcohol intake, energy intake, saturated fatty acids intake, whole grain products intake, and fruit and vegetable intake.

Conversely – and in contrast to findings from some prior studies – calcium supplementation was associated with decreased mortality risk in adjusted models (hazard ratio of 0.91 for the fully adjusted model), the investigators found (Arch. Intern. Med. 2011;171:1625-33).

Participants in the Iowa Women’s Health Study were enrolled in 1986 and those included in the current study had a mean age of 61.6 years. Participants completed a 16-page self-administered questionnaire that included information on food frequency and supplement use. Additional self-reports were provided in 1997 and 2004. As of Dec. 31, 2008, 40% of those included in the current analysis had died.

Self-reported supplement use increased over time, with 62.7%, 75.1%, and 85.1% reporting the use of at least one supplement daily in the 1986, 1997, and 2004 questionnaires, respectively.

The most commonly used supplements were calcium, multivitamins, vitamin C, and vitamin E; the most commonly used combinations were calcium and multivitamins; calcium, multivitamins, and vitamin C; and calcium and vitamin C.

"Although we cannot rule out benefits of supplements, such as improved quality of life, our study raises a concern regarding their long-term safety."

On analyses performed for shorter follow-up intervals of 10, 6, and 4 years, the findings for iron and calcium were replicated; about 15% of the deaths in original participants occurred in each of the following periods: 1986 through 1996, 1997 through 2003, and 2004 through 2008.

"In multivariable adjusted analyses across the shorter follow-up intervals, beginning with the baseline and each follow-up questionnaire, the most consistent findings ... were for supplemental iron (hazard ratios,1.20, 1.43, and 1.56...) and calcium (0.89, 0.90, 0.88)," the investigators said.

Furthermore, increased consistency of use of iron was associated with increased mortality risk; the hazard ratio for mortality (versus nonuse) for those who reported using iron at only one survey was 1.35, compared with 1.62 and 1.60 for use at two and at all three surveys, respectively, they said.

The findings, though observational, are concerning given the popularity of dietary supplements, the investigators said, noting that about half of all adults were using supplements in 2000, and that 66% of women participating in the Iowa Women’s Health Study used at least one supplement daily at baseline, with an increase to 85% in 2004. More than a quarter of participants used four or more.

"Supplemental nutrient intake clearly is beneficial in deficiency conditions. However, in well-nourished populations, supplements often are intended to yield benefit by preventing chronic disease," the investigators noted, adding that studies have produced inconsistent results in regard to the benefits and harms of supplementation.

Several randomized controlled trials and meta-analyses – particularly those evaluating the use of calcium and vitamins B, C, D, and E – have shown no benefit in terms of total mortality rate and in some cases have shown possible harm, they said.

This study provides further evidence that most dietary supplements are unrelated to total mortality rate, and that some are associated with increased total mortality rate.

The strengths of this study are the large sample size and longitudinal design, as well as the fact that the women were questioned three times about diet and supplement use during the course of the follow-up.

"The use of repeated measures enabled evaluation of the consistency of the findings and decreased the risk that the exposure was misclassified," the investigators wrote.

The limitations of the study include the potential for residual confounding despite extensive adjustment, and the possibility that some supplements may have been taken for "reasonable cause in response to symptoms or clinical disease."

Furthermore, 99.2 % of women in the Iowa Women’s Health Study were white, thus generalization to other populations, ethnic groups, and men is problematic.

"Although we cannot rule out benefits of supplements, such as improved quality of life, our study raises a concern regarding their long-term safety ... it is not advisable to make a causal statement of excess risk based on these observational data; however, it is noteworthy that dietary supplements, unlike drugs, do not require rigorous (randomized controlled trial) testing, and observational studies are often the best available method for assessing the safety of long-term use," they wrote.

Therefore, based on existing evidence, they argue that there is little justification for the general and widespread use of dietary supplements.

"We recommend that they be used with strong medically based cause, such as symptomatic nutrient deficiency disease," they concluded.

"Until recently, the available data regarding the adverse effects of dietary supplements has been limited and grossly underreported."

This "large, well-designed, and well-conducted" trial adds to the existing evidence that certain supplements can be harmful, and the findings concur with those of other recent observational studies, Dr. Goran Bjelakovic and Dr. Christian Gluud said in an editorial accompanying the report (Arch. Intern. Med. 2011;171:1633-4).

"The belief that antioxidant supplements are beneficial seems likely to have resulted from a collective error. Perhaps oxidative stress is one of the keys to extension of our life span," they suggested.

Indeed, the shift in the use of dietary supplementation for prevention of deficiency to use for promoting wellness and prevention of diseases – with many consumers believing that supplements are safe for use without the supervision of their physician – is problematic.

"Until recently, the available data regarding the adverse effects of dietary supplements has been limited and grossly underreported. We think the paradigm ‘the more the better’ is wrong," they said.

Rather, there are likely risks with both insufficient and too-large intake, added Dr. Bjelakovic and Dr. Gluud, both of whom are with the Copenhagen trial unit, center for clinical intervention research, Cochrane Hepato-Biliary Group, Rigshospitalet, Copenhagen, University Hospital.

"Therefore, we believe that politicians and regulatory authorities should wake up to their responsibility to allow only safe products on the market," they said, also noting that in a well-nourished population, the use of vitamin and mineral supplements as a preventive measure should not be recommended.

A possible exception based on these and other findings is with vitamin D₃ supplementation, particularly when there is insufficient vitamin D supply from the sun and diet; this may apply to older women, and perhaps older men. The matter of calcium supplementation may require further study, they said.

This study was partially supported by a grant from the National Cancer Institute and by grants from the Academy of Finland, the Finnish Cultural Foundation, and the Fulbright program. One of the study authors (David R. Jacobs Jr., Ph.D.) reported being an unpaid member of the scientific advisory board of the California Walnut Commission. None of the other authors had relevant financial disclosures to report. Neither Dr. Bjelakovic nor Dr. Gluud had relevant financial disclosures to report.

Several commonly used vitamin and mineral supplements were significantly associated with increased total mortality risk in 38,772 older women from the Iowa Women’s Health Study who were followed for a mean of 19 years.

Supplemental iron was most strongly associated with increased mortality (hazard ratio of 1.10 in a fully adjusted model), Jaakko Mursu, Ph.D., of the University of Eastern Finland, Kuopio, and colleagues reported in the Oct. 10 issue of Archives of Internal Medicine.

The use of multivitamins, vitamin B₆, folic acid, magnesium, zinc, and copper also was associated with a higher risk of mortality (hazard ratios, 1.06, 1.10, 1.15, 1.08, 1.08, and 1.45, respectively) after adjustment for age, education level, place of residence, diabetes mellitus, high blood pressure, body mass index, waist to hip ratio, hormone therapy, physical activity, smoking status, alcohol intake, energy intake, saturated fatty acids intake, whole grain products intake, and fruit and vegetable intake.

Conversely – and in contrast to findings from some prior studies – calcium supplementation was associated with decreased mortality risk in adjusted models (hazard ratio of 0.91 for the fully adjusted model), the investigators found (Arch. Intern. Med. 2011;171:1625-33).

Participants in the Iowa Women’s Health Study were enrolled in 1986 and those included in the current study had a mean age of 61.6 years. Participants completed a 16-page self-administered questionnaire that included information on food frequency and supplement use. Additional self-reports were provided in 1997 and 2004. As of Dec. 31, 2008, 40% of those included in the current analysis had died.

Self-reported supplement use increased over time, with 62.7%, 75.1%, and 85.1% reporting the use of at least one supplement daily in the 1986, 1997, and 2004 questionnaires, respectively.

The most commonly used supplements were calcium, multivitamins, vitamin C, and vitamin E; the most commonly used combinations were calcium and multivitamins; calcium, multivitamins, and vitamin C; and calcium and vitamin C.

"Although we cannot rule out benefits of supplements, such as improved quality of life, our study raises a concern regarding their long-term safety."

On analyses performed for shorter follow-up intervals of 10, 6, and 4 years, the findings for iron and calcium were replicated; about 15% of the deaths in original participants occurred in each of the following periods: 1986 through 1996, 1997 through 2003, and 2004 through 2008.

"In multivariable adjusted analyses across the shorter follow-up intervals, beginning with the baseline and each follow-up questionnaire, the most consistent findings ... were for supplemental iron (hazard ratios,1.20, 1.43, and 1.56...) and calcium (0.89, 0.90, 0.88)," the investigators said.

Furthermore, increased consistency of use of iron was associated with increased mortality risk; the hazard ratio for mortality (versus nonuse) for those who reported using iron at only one survey was 1.35, compared with 1.62 and 1.60 for use at two and at all three surveys, respectively, they said.

The findings, though observational, are concerning given the popularity of dietary supplements, the investigators said, noting that about half of all adults were using supplements in 2000, and that 66% of women participating in the Iowa Women’s Health Study used at least one supplement daily at baseline, with an increase to 85% in 2004. More than a quarter of participants used four or more.

"Supplemental nutrient intake clearly is beneficial in deficiency conditions. However, in well-nourished populations, supplements often are intended to yield benefit by preventing chronic disease," the investigators noted, adding that studies have produced inconsistent results in regard to the benefits and harms of supplementation.

Several randomized controlled trials and meta-analyses – particularly those evaluating the use of calcium and vitamins B, C, D, and E – have shown no benefit in terms of total mortality rate and in some cases have shown possible harm, they said.

This study provides further evidence that most dietary supplements are unrelated to total mortality rate, and that some are associated with increased total mortality rate.

The strengths of this study are the large sample size and longitudinal design, as well as the fact that the women were questioned three times about diet and supplement use during the course of the follow-up.

"The use of repeated measures enabled evaluation of the consistency of the findings and decreased the risk that the exposure was misclassified," the investigators wrote.

The limitations of the study include the potential for residual confounding despite extensive adjustment, and the possibility that some supplements may have been taken for "reasonable cause in response to symptoms or clinical disease."

Furthermore, 99.2 % of women in the Iowa Women’s Health Study were white, thus generalization to other populations, ethnic groups, and men is problematic.

"Although we cannot rule out benefits of supplements, such as improved quality of life, our study raises a concern regarding their long-term safety ... it is not advisable to make a causal statement of excess risk based on these observational data; however, it is noteworthy that dietary supplements, unlike drugs, do not require rigorous (randomized controlled trial) testing, and observational studies are often the best available method for assessing the safety of long-term use," they wrote.

Therefore, based on existing evidence, they argue that there is little justification for the general and widespread use of dietary supplements.

"We recommend that they be used with strong medically based cause, such as symptomatic nutrient deficiency disease," they concluded.

"Until recently, the available data regarding the adverse effects of dietary supplements has been limited and grossly underreported."

This "large, well-designed, and well-conducted" trial adds to the existing evidence that certain supplements can be harmful, and the findings concur with those of other recent observational studies, Dr. Goran Bjelakovic and Dr. Christian Gluud said in an editorial accompanying the report (Arch. Intern. Med. 2011;171:1633-4).

"The belief that antioxidant supplements are beneficial seems likely to have resulted from a collective error. Perhaps oxidative stress is one of the keys to extension of our life span," they suggested.

Indeed, the shift in the use of dietary supplementation for prevention of deficiency to use for promoting wellness and prevention of diseases – with many consumers believing that supplements are safe for use without the supervision of their physician – is problematic.

"Until recently, the available data regarding the adverse effects of dietary supplements has been limited and grossly underreported. We think the paradigm ‘the more the better’ is wrong," they said.

Rather, there are likely risks with both insufficient and too-large intake, added Dr. Bjelakovic and Dr. Gluud, both of whom are with the Copenhagen trial unit, center for clinical intervention research, Cochrane Hepato-Biliary Group, Rigshospitalet, Copenhagen, University Hospital.

"Therefore, we believe that politicians and regulatory authorities should wake up to their responsibility to allow only safe products on the market," they said, also noting that in a well-nourished population, the use of vitamin and mineral supplements as a preventive measure should not be recommended.

A possible exception based on these and other findings is with vitamin D₃ supplementation, particularly when there is insufficient vitamin D supply from the sun and diet; this may apply to older women, and perhaps older men. The matter of calcium supplementation may require further study, they said.

This study was partially supported by a grant from the National Cancer Institute and by grants from the Academy of Finland, the Finnish Cultural Foundation, and the Fulbright program. One of the study authors (David R. Jacobs Jr., Ph.D.) reported being an unpaid member of the scientific advisory board of the California Walnut Commission. None of the other authors had relevant financial disclosures to report. Neither Dr. Bjelakovic nor Dr. Gluud had relevant financial disclosures to report.

Several commonly used vitamin and mineral supplements were significantly associated with increased total mortality risk in 38,772 older women from the Iowa Women’s Health Study who were followed for a mean of 19 years.

Supplemental iron was most strongly associated with increased mortality (hazard ratio of 1.10 in a fully adjusted model), Jaakko Mursu, Ph.D., of the University of Eastern Finland, Kuopio, and colleagues reported in the Oct. 10 issue of Archives of Internal Medicine.

The use of multivitamins, vitamin B₆, folic acid, magnesium, zinc, and copper also was associated with a higher risk of mortality (hazard ratios, 1.06, 1.10, 1.15, 1.08, 1.08, and 1.45, respectively) after adjustment for age, education level, place of residence, diabetes mellitus, high blood pressure, body mass index, waist to hip ratio, hormone therapy, physical activity, smoking status, alcohol intake, energy intake, saturated fatty acids intake, whole grain products intake, and fruit and vegetable intake.

Conversely – and in contrast to findings from some prior studies – calcium supplementation was associated with decreased mortality risk in adjusted models (hazard ratio of 0.91 for the fully adjusted model), the investigators found (Arch. Intern. Med. 2011;171:1625-33).

Participants in the Iowa Women’s Health Study were enrolled in 1986 and those included in the current study had a mean age of 61.6 years. Participants completed a 16-page self-administered questionnaire that included information on food frequency and supplement use. Additional self-reports were provided in 1997 and 2004. As of Dec. 31, 2008, 40% of those included in the current analysis had died.

Self-reported supplement use increased over time, with 62.7%, 75.1%, and 85.1% reporting the use of at least one supplement daily in the 1986, 1997, and 2004 questionnaires, respectively.

The most commonly used supplements were calcium, multivitamins, vitamin C, and vitamin E; the most commonly used combinations were calcium and multivitamins; calcium, multivitamins, and vitamin C; and calcium and vitamin C.

"Although we cannot rule out benefits of supplements, such as improved quality of life, our study raises a concern regarding their long-term safety."

On analyses performed for shorter follow-up intervals of 10, 6, and 4 years, the findings for iron and calcium were replicated; about 15% of the deaths in original participants occurred in each of the following periods: 1986 through 1996, 1997 through 2003, and 2004 through 2008.

"In multivariable adjusted analyses across the shorter follow-up intervals, beginning with the baseline and each follow-up questionnaire, the most consistent findings ... were for supplemental iron (hazard ratios,1.20, 1.43, and 1.56...) and calcium (0.89, 0.90, 0.88)," the investigators said.

Furthermore, increased consistency of use of iron was associated with increased mortality risk; the hazard ratio for mortality (versus nonuse) for those who reported using iron at only one survey was 1.35, compared with 1.62 and 1.60 for use at two and at all three surveys, respectively, they said.

The findings, though observational, are concerning given the popularity of dietary supplements, the investigators said, noting that about half of all adults were using supplements in 2000, and that 66% of women participating in the Iowa Women’s Health Study used at least one supplement daily at baseline, with an increase to 85% in 2004. More than a quarter of participants used four or more.

"Supplemental nutrient intake clearly is beneficial in deficiency conditions. However, in well-nourished populations, supplements often are intended to yield benefit by preventing chronic disease," the investigators noted, adding that studies have produced inconsistent results in regard to the benefits and harms of supplementation.

Several randomized controlled trials and meta-analyses – particularly those evaluating the use of calcium and vitamins B, C, D, and E – have shown no benefit in terms of total mortality rate and in some cases have shown possible harm, they said.

This study provides further evidence that most dietary supplements are unrelated to total mortality rate, and that some are associated with increased total mortality rate.

The strengths of this study are the large sample size and longitudinal design, as well as the fact that the women were questioned three times about diet and supplement use during the course of the follow-up.

"The use of repeated measures enabled evaluation of the consistency of the findings and decreased the risk that the exposure was misclassified," the investigators wrote.

The limitations of the study include the potential for residual confounding despite extensive adjustment, and the possibility that some supplements may have been taken for "reasonable cause in response to symptoms or clinical disease."

Furthermore, 99.2 % of women in the Iowa Women’s Health Study were white, thus generalization to other populations, ethnic groups, and men is problematic.

"Although we cannot rule out benefits of supplements, such as improved quality of life, our study raises a concern regarding their long-term safety ... it is not advisable to make a causal statement of excess risk based on these observational data; however, it is noteworthy that dietary supplements, unlike drugs, do not require rigorous (randomized controlled trial) testing, and observational studies are often the best available method for assessing the safety of long-term use," they wrote.

Therefore, based on existing evidence, they argue that there is little justification for the general and widespread use of dietary supplements.

"We recommend that they be used with strong medically based cause, such as symptomatic nutrient deficiency disease," they concluded.

"Until recently, the available data regarding the adverse effects of dietary supplements has been limited and grossly underreported."

This "large, well-designed, and well-conducted" trial adds to the existing evidence that certain supplements can be harmful, and the findings concur with those of other recent observational studies, Dr. Goran Bjelakovic and Dr. Christian Gluud said in an editorial accompanying the report (Arch. Intern. Med. 2011;171:1633-4).

"The belief that antioxidant supplements are beneficial seems likely to have resulted from a collective error. Perhaps oxidative stress is one of the keys to extension of our life span," they suggested.

Indeed, the shift in the use of dietary supplementation for prevention of deficiency to use for promoting wellness and prevention of diseases – with many consumers believing that supplements are safe for use without the supervision of their physician – is problematic.

"Until recently, the available data regarding the adverse effects of dietary supplements has been limited and grossly underreported. We think the paradigm ‘the more the better’ is wrong," they said.

Rather, there are likely risks with both insufficient and too-large intake, added Dr. Bjelakovic and Dr. Gluud, both of whom are with the Copenhagen trial unit, center for clinical intervention research, Cochrane Hepato-Biliary Group, Rigshospitalet, Copenhagen, University Hospital.

"Therefore, we believe that politicians and regulatory authorities should wake up to their responsibility to allow only safe products on the market," they said, also noting that in a well-nourished population, the use of vitamin and mineral supplements as a preventive measure should not be recommended.

A possible exception based on these and other findings is with vitamin D₃ supplementation, particularly when there is insufficient vitamin D supply from the sun and diet; this may apply to older women, and perhaps older men. The matter of calcium supplementation may require further study, they said.

This study was partially supported by a grant from the National Cancer Institute and by grants from the Academy of Finland, the Finnish Cultural Foundation, and the Fulbright program. One of the study authors (David R. Jacobs Jr., Ph.D.) reported being an unpaid member of the scientific advisory board of the California Walnut Commission. None of the other authors had relevant financial disclosures to report. Neither Dr. Bjelakovic nor Dr. Gluud had relevant financial disclosures to report.