For healthy people, supplements may help prevent vitamin and mineral deficiencies when the
diet does not provide all necessary nutrients. They can also supply amounts of nutrients
larger than the diet can provide. Larger amounts of some nutrients may help to protect against
future disease. Many of these nutrients will be briefly discussed here. However, for more
information, refer to individual nutrient articles.
People may consume diets that are deficient in one or more nutrients for a variety of
reasons. The typical Western diet often supplies less than adequate amounts of several
essential vitamins and minerals.1 Recent nutrition surveys in the U.S. have found
large numbers of people consume too little
calcium, magnesium, iron,
zinc, and, possibly, copper and manganese.2 3
Weight-loss, pure vegetarian, macrobiotic, and several other diets can also place
some people at risk of deficiencies that vary with the type of diet. Certain groups of people
are at especially high risk of dietary deficiencies. Studies have found that elderly people
living in their own homes often have dietary deficiencies of vitamin D, vitamin A, vitamin E, calcium, and zinc,4 and occasionally of vitamin B1 and vitamin B2.5 Premenopausal women have been found often to consume
low amounts of calcium, iron,
vitamin A, and vitamin C.6
Dietary deficiency of vitamin A is uncommon
in healthy people except in older age groups.7 Although vitamin A is important for
the function of the immune system, vitamin A
supplementation did not help prevent
infections in elderly people living in nursing homes, in one study.8 Due to
concerns about birth defects9 and
bone loss,10 people should not take over 10,000 IU of supplemental vitamin A in the
form of retinol without consulting a doctor.
Beta-carotene is a precursor to vitamin A,
but may have a separate role in human health. Controlled research has shown that beta-carotene
supplements can increase the numbers of some white blood cells and enhance cancer-fighting immune functions in healthy people who take 25,000 to
100,000 IU per day.11 12 However, some studies of smokers have reported
that supplements of synthetic beta-carotene increased the risk of both heart disease13 14 and lung cancer.15 16 Other
trials found no positive or negative effect of synthetic beta-carotene on the risk of many
other diseases, including several types of cancer,17 18 19
20 21 22 23 24 angina pectoris,25 diabetes,26 age-related eye
disease,27 28 or
intermittent claudication.29 Natural beta-carotene, though similar to
synthetic, was found in one preliminary study to reverse pre-cancerous changes, while
synthetic beta-carotene did not.30 No other studies have investigated whether
natural beta-carotene could be more effective than synthetic in preventing other diseases, but
the potential harm from taking synthetic beta-carotene suggests it should be avoided by
smokers.
Some of the B-vitamins, including thiamine (vitamin B1), riboflavin (vitamin B2), and niacin (vitamin B3), may be adequately supplied by the
typical Western diet, because they are added to white flour products and other foods that have
been depleted of those vitamins. Another vitamin,
biotin, is produced by intestinal bacteria in amounts that, along with typical dietary
biotin intake, provide enough of this vitamin to prevent deficiency in healthy people. Pantothenic acid (vitamin B5), on the other hand,
appears to be in short supply in the typical diet. In one study, 49% of a group of male and
female adolescents were consuming less-than-adequate amounts of pantothenic acid in their
diet.31 No research has investigated whether supplements of these B-vitamins
prevent disease.
Vitamin B6 (pyridoxine) deficiency, at
least in a mild form, may exist in 10 to 25% of people living in Western
societies,32 and may be most common in the elderly.33 34
35 The possible role of vitamin B6 in the prevention of heart disease by helping to regulate blood homocysteine levels is discussed below. No other
research on preventive effects of vitamin B6 supplementation has been done.
Folic acid deficiency has been considered
somewhat common in the U.S. It affects about 11% of healthy people,36 with a higher
prevalence among African-Americans and Mexican-Americans.37 Recently, however, the
U.S. Food and Drug Administration (FDA) mandated that some grain products provide supplemental
folic acid. This appears to be causing a reduction in the prevalence of folic acid deficiency
in the general population.38 Nonetheless, some authorities believe the recent
increases in folic acid content of the food supply are not enough to optimally prevent
diseases such as heart disease and birth defects (see discussions
below).39
The B-vitamins folic acid, B12, and pyridoxine (vitamin B6) are important for the
control of homocysteine levels in the
blood.49 Elevated homocysteine levels are associated with several diseases,
including heart disease,50 stroke,51 Alzheimer’s disease,52 and osteoporosis,53 and some, though not all,
research suggests that homocysteine has a direct role in causing these diseases. Daily
supplementation with these B-vitamins, typically at least 400 mcg of folic acid, 10 mg of vitamin B6, and 50 mcg of vitamin B12, lowers elevated homocysteine levels in
most people.54 55 56 Some studies have shown that
supplementing with one or more of these vitamins helps prevent or reverse hardening of the
arteries (atherosclerosis) and may also reduce the risk of bone fractures.57
58
Severe vitamin C deficiency is uncommon in
people who consume Western diets, but mild insufficiency is found in 6% of healthy
adults59 and larger numbers of college students60 and
smokers.61 On the basis of extensive analyses of published vitamin C studies, some
authorities have suggested that optimal intake for disease prevention may be at least 90 to
100 mg per day.62 63 However, supplementation with over 200 mg per day
of vitamin C by healthy people does not result in higher vitamin C concentrations in the
body,64 and may be no more helpful for preventing disease than smaller amounts.
Vitamin D can be obtained from the diet or
from sunlight exposure, but these sources can be insufficient, especially in older people and
vegans during the winter months.65
In healthy adult Western European populations, 6 to 14% percent have been reported to be
vitamin D deficient,66 but good data are not available for the US. Vitamin D
insufficiency is associated with bone loss and
fractures in older people.67 68 Reduced bone loss from vitamin D
supplements has been reported in some,69 70 though not all,71
studies. In one double-blind study, supplementation with 800 IU per day of vitamin D prevented
bone loss more effectively than 200 IU per day in
postmenopausal women.72 In addition, vitamin D supplementation has been shown
to reduce the risk of falls in older people.73 While vitamin D is known to be toxic
in very high amounts, up to 2000 IU per day is considered safe.74
A nationwide study recently reported that 27% of the U.S. population had low blood levels
of vitamin E.75 Supplementing with
at least 100 IU per day of vitamin E is associated with lowered risk of heart disease,76 77 and a
double-blind study found that 400 to 800 IU of vitamin E per day reduced the risk of nonfatal
heart attacks, but not fatal
ones.78 However, another double-blind trial found no benefit from 400 IU per day of
vitamin E supplementation on the risk of non-fatal heart attacks,79 while another
study found that 50 IU per day had no effect on heart attack risk.80 A more recent
study found that taking large amounts of vitamin E (400 IU per day or more) may result in a
small increase in all-cause mortality,81 while another study found that 400 IU per
day increased the risk of heart failure.82 Because of these studies, some doctors
are advising people not to take large amounts of vitamin E. On the other hand, circumstantial
evidence suggests that “mixed tocopherols,” as opposed to the more widely used
alpha-tocopherol, may be safer and more beneficial with respect to heart-disease
prevention.83 84
A reduced risk of prostate cancer in
smokers was reported in a double-blind trial with 50 IU per day of vitamin E.85
However, similar studies have not found vitamin E supplements to protect against other
cancers.86 87 88 89
Vitamin K deficiency severe enough to cause
bleeding problems is rare in healthy people. However, low vitamin K in the blood90
91 and in the diet92 has been associated with osteoporosis. Preliminary research has suggested that
supplements of at least 1 mg per day of vitamin K reduce indicators of bone loss in some
women.93 94 95 96
Compared with recent calcium intake
recommendations, most people have calcium-deficient diets, and less than 10% of women in the
U.S. have adequate dietary intakes.97 Good calcium nutrition throughout life is
essential for achieving peak bone mass and preventing deficiency-related bone
loss.98 Calcium supplements are effective in increasing bone mass in
children99 100 101 and slowing bone loss in adults according
to most,102 103 104 105 106
107 though not all,108 double-blind studies. Calcium supplements have also
been shown to reduce the risk of bone fractures in some elderly adults.109
110 111 112 The protective effect of calcium on bone is one of
very few health claims permitted by the FDA. In order to achieve the 1,500 mg per day calcium
intake deemed optimal by many researchers for
postmenopausal women, 800 to 1,000 mg of supplemental calcium are generally added to diets
that commonly contain between 500 and 700 mg of calcium per day.
Phosphorus is a necessary nutrient, but
diets are almost always adequate in this mineral.113 Some authorities have
suggested that excess intake of phosphorus is hazardous to normal calcium and bone metabolism.114 However,
this idea has been challanged.115 In any case, for most people there does not seem
to be a need for phosphorus supplementation. For this reason, many multivitamin-mineral supplements do not contain
phosphorus. The only exception is for elderly people, whose diets tend to be lower in
phosphorus. Calcium interferes with phosphorus absorption, so older people who are taking a
calcium supplement might benefit from taking additional phosphorus.116
Dietary magnesium deficiency may occur in
up to 25% of adult women in the U.S. and in even higher numbers of elderly people of both
sexes.117 Magnesium supplements of at least 250 mg per day may help prevent bone
loss.118 119
While potassium is lower in modern diets
compared with so-called primitive diets, true deficiencies are uncommon.120
Some,121 though not all,122 research suggests that raising potassium
intake may help prevent high blood pressure.
Other research suggests higher potassium intake may help prevent stroke.123 However, the maximum amount of
supplemental potassium allowed in one pill (99 mg) is far below the recommended amounts (at
least 2,400 mg per day). Multiple potassium pills should not be taken in an attempt to get a
higher amount, since they can irritate the stomach. The best way to get extra potassium is to
eat several servings per day of fruits, vegetables, or their juices.
Iron deficiency is not uncommon among some
groups of healthy people, including some
vegetarians,124 menstruating girls and women,125 pregnant women,126 and female and
adolescent athletes.127
Nonetheless, many people in these groups are not iron deficient 128 and excessive
iron intake has been associated in some studies with heart disease,129 some cancers,130 diabetes,131 increased risk of infection,132 and exacerbation of rheumatoid arthritis.133 While none of
these links has yet been proven, people should avoid iron supplements unless they have been
diagnosed with having, or being at high risk of,
iron deficiency.
Zinc deficiency is not common in Western
countries, except in people with low incomes.137 138 Zinc supplements
(10 mg per day) have prevented growth impairment in deficient American and Canadian
children.139 Supplementation with 25 to 150 mg of zinc per day has been shown to
increase immune function in healthy
people.140 141 142 143 However, too much zinc has
been reported to impair immune function and some healthcare practitioners recommend no more
than 30 to 50 mg per day.144 It is unknown whether these immune system changes are
sufficient to cause or prevent infections or
other diseases in people taking zinc supplements. Regular supplementation with zinc should be
accompanied by copper supplements to prevent
zinc-induced copper deficiency.
The average dietary copper intake in the
U.S. has been found to be below accepted standards.145 However, the significance of
this is unclear, since symptomatic copper deficiency is quite rare.146
Supplementation with 3 mg per day of copper may help prevent bone loss.147 Since
zinc can interfere with copper absorption, copper should be taken whenever zinc supplements are taken for more than a few
weeks.148
Dietary intake of manganese is adequate for
most people, according to recent studies in the U.S.149 However, manganese, along
with other trace minerals, is often low in refined and processed foods.150
151 People whose diets consist primarily of these types of foods may have low manganese
intake. Manganese deficiency has been associated with osteoporosis in an unpublished study.152 A
double-blind trial found that a combination of mineral supplements including manganese
prevented bone loss in postmenopausal
women.153 No other studies have investigated the health effects of manganese
supplementation. Manganese may be especially important to include when iron is supplemented, since iron can reduce manganese
absorption and cause lower body levels of manganese.154
Chromium nutrition has been difficult to
study because of technical problems in analyzing foods and human body fluids for chromium
content. Partly for this reason, there is disagreement about the extent of chromium deficiency
in Western societies. Many studies have found sub-optimal levels of chromium in the diet,
compared to published recommendations.155 156 157 However,
some authorities question the validity of the recommended minimum requirements.158
Chromium deficiency has been associated with blood sugar and cholesterol abnormalities.159 Also,
chromium levels in the body decline as people get older, which is when these problems often
appear.160 Therefore, while chromium supplements have not been tested for their
ability to prevent diabetes or heart disease, many healthcare practitioners recommend
chromium supplements as a reasonable precaution. A few single case reports have described
possible serious side effects in people taking large amounts of chromium, from 600 to 2400 mcg
per day, 161 162 163 although it is not clear whether
chromium was responsible for these reactions.
Dietary intake of selenium appears to be
adequate in most people. This is according to recent studies in the U.S. based on the
Recommended Dietary Allowance of 70 mcg per day of selenium.164 However, a
double-blind study found that people given a supplement of 200 mcg of yeast-based selenium per
day for 4.5 years had a 50% drop in the cancer
death rate over seven years compared with the placebo group.165 Higher amounts of
selenium than are available in the diet may be necessary for this protective effect. The upper
end of safe long-term selenium intake has been estimated to be 350 to 400 mcg per
day.166
Molybdenum is an essential trace element
with low potential for toxicity.167 Since little is known about human needs and
deficiencies are quite rare, estimated requirements are based on what people typically receive
in their diets.168 Cancer and cardiovascular disease prevention studies in
China found no benefit from a supplement containing molybdenum and vitamin C.169 170 No other
research has investigated disease prevention with molybdenum supplements.
1. Pao EM, Mickle SJ. Problem nutrients in the United States. Food
Technology 1981;35:58–79.
2. Pennington JA, Young BE, Wilson DB. Nutritional elements in U.S.
diets: results from the Total Diet Study, 1982 to 1986. J Am Diet Assoc
1989;89:659–64.
3. Pennington JA. Intakes of minerals from diets and foods: is there a
need for concern? J Nutr 1996;126(9 Suppl):2304S–8S.
4. Ryan AS, Craig LD, Finn SC. Nutrient intakes and dietary patterns of
older Americans: a national study. J Gerontol 1992;47:M145–50.
5. Zheng JJ, Rosenberg IH. What is the nutritional status of the elderly?
Geriatrics 1989;44:57–8, 60, 63–4 [review].
6. Kurinij N, Klebanoff MA, Graubard BI. Dietary supplement and food
intake in women of childbearing age. J Am Diet Assoc 1986;86:1536–40.
7. Ryan AS, Craig LD, Finn SC. Nutrient intakes and dietary patterns of
older Americans: a national study. J Gerontol 1992;47:M145–50.
8. Murphy S, West KP, Greenough WB, et al. Impact of vitamin A
supplementation on the incidence of infection in elderly nursing-home residents: a randomized
controlled trial. Age Ageing 1992;21:435–9.
9. Rothman KJ, Moore LL, Singer MR, et al. Teratogenicity of high vitamin
A intake. N Engl J Med 1995;333:1369–73.
10. Melhus H, Michaelsson 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;129:770–8.
11. Hughes DA, Wright AJ, Finglas PM, et al. The effect of beta-carotene
supplementation on the immune function of blood monocytes from healthy male nonsmokers. J
Lab Clin Med 1997;129:309–17.
12. Murata T, Tamai H, Morinobu T, et al. Effect of long-term
administration of beta-carotene on lymphocyte subsets in humans. Am J Clin Nutr
1994;60:597–602.
13. Virtamo J, Rapola JM, Ripatti S, et al. Effect of vitamin E and beta
carotene on the incidence of primary nonfatal myocardial infarction and fatal coronary heart
disease. Arch Intern Med 1998;158:668–75.
14. Rapola JM, Virtamo J, Ripatti S, et al. Randomised trial of
alpha-tocopherol and beta-carotene supplements on incidence of major coronary events in men
with previous myocardial infraction. Lancet 1997;349:1715–20.
15. Omenn GS, Goodman GE, Thornquist MD, et al. Effects of a combination
of beta carotene and vitamin A on lung cancer and cardiovascular disease. N Engl J
Med 1996;334:1150–5.
16. Albanes D, Heinonen OP, Taylor PR, et al. Alpha-tocopherol and
beta-carotene supplements and lung cancer incidence in the Alpha-Tocopherol, Beta-Carotene
Cancer Prevention Study: effects of base-line characteristics and study compliance. J Natl
Cancer Inst 1996;88:1560–70.
17. Hennekens CH, Burning JE, Manson JE, et al. Lack of effect of
long-term supplementation with beta carotene on the incidence of malignant neoplasms and
cardiovascular disease. N Engl J Med 1996;334:11145–9.
18. Heinonen OP, Albanes D, Virtamo J, et al. Prostate cancer and
supplementation with alpha-tocopherol and beta-carotene: incidence and mortality in a
controlled trial. J Natl Cancer Inst 1998;90:440–6.
19. Varis K, Taylor PR, Sipponene P, et al. Gastric cancer and
premalignant lesions in atrophic gastritis: a controlled trial on the effect of
supplementation with alpha-tocopherol and beta-carotene. Scand J Gastroenterol
1998;33:294–300.
20. MacLennan R, Macrae F, Bain C, et al. Randomized trial of intake of
fat, fiber, and beta-carotene to prevent colorectal adenomas. J Natl Cancer Inst
1995;87:1760–6.
21. Greenberg ER, Baron JA, Tosteson TD, et al. A clinical trial of
antioxidant vitamins to prevent colorectal adenoma. N Engl J Med
1994;331:141–7.
22. Malila N, Virtamo J, Virtanen M, et al. The effect of
alpha-tocopherol and beta-carotene supplementation on colorectal adenomas in middle-aged male
smokers. Cancer Epidemiol Biomarkers Prev 1999;8:489–93.
23. Rautalahti MT, Virtamo JR, Taylor PR, et al. The effects of
supplementation with alpha-tocopherol and beta-carotene on the incidence and mortality of
carcinoma of the pancreas in a randomized, controlled trial. Cancer
1999;86:37–42.
24. Liede K, Hietanen J, Saxen L, et al. Long-term supplementation with
alpha-tocopherol and beta-carotene and prevalence of oral mucosal lesions in smokers. Oral
Dis 1998;4:78–83.
25. Rapola JM, Virtamo J, Haukka JK, et al. Effect of vitamin E and beta
carotene on the incidence of angina pectoris. A randomized, double-blind, controlled trial.
JAMA 1996;275:693–8.
26. Liu S, Ajani U, Chae C, et al. Long-term beta-carotene
supplementation and risk of type 2 diabetes mellitus: a randomized controlled trial.
JAMA 1999;282:1073–5.
27. Teikari JM, Laatikainen L, Virtamo J, et al. Six-year supplementation
with alpha-tocopherol and beta-carotene and age-related maculopathy. Acta Ophthalmol
Scand 1998;76:224–9.
28. Teikari JM, Virtamo J, Rautalahti M, et al. Long-term supplementation
with alpha-tocopherol and beta-carotene and age-related cataract. Acta Ophthalmol
Scand 1997;75:634–40.
29. Tornwall M, Virtamo J, Haukka JK, et al. Effect of alpha-tocopherol
(vitamin E) and beta-carotene supplementation on the incidence of intermittent claudication in
male smokers. Arterioscler Thromb Vasc Biol 1997;17:3475–80.
30. Yeum K-J, Azhu S, Xiao S, et al. Beta-carotene intervention trial in
premalignant gastric lesions. J Am Coll Nutr 1995;14:536 [abstr #48].
31. Eissenstat BR, Wyse BW, Hansen RG. Pantothenic acid status of
adolescents. Am J Clin Nutr 1986;44:931–7.
32. Bender DA. Vitamin B6 requirements and recommendations. Eur J
Clin Nutr 1989;43:289–309 [review].
33. Bailey AL, Maisey S, Southon S, et al. Relationships between
micronutrient intake and biochemical indicators of nutrient adequacy in a
“free-living’ elderly UK population. Br J Nutr 1997;77:225–42.
34. van der Wielen RP, Lowik MR, Haller J, et al. Vitamin B-6
malnutrition among elderly Europeans: the SENECA study. J Gerontol A Biol Sci Med Sci
1996;51:B417–24.
35. Manore MM, Vaughan LA, Carroll SS, Leklem JE. Plasma pyridoxal
5’-phosphate concentration and dietary vitamin B-6 intake in free-living, low-income
elderly people. Am J Clin Nutr 1989;50:339–45.
36. Senti FR, Pilch SM. Analysis of folate data from the second National
Health and Nutrition Examination Survey (NHANES II). J Nutr
1985;115:1398–402.
37. Ford ES, Bowman BA. Serum and red blood cell folate concentrations,
race, and education: findings from the third National Health and Nutrition Examination Survey.
Am J Clin Nutr 1999;69:476–81.
38. Jacques PF, Selhub J, Bostom AG, et al. The effect of folic acid
fortification on plasma folate and total homocysteine concentrations. N Engl J Med
1999;340:1449–54.
39. Oakley GP Jr. Eat right and take a multivitamin. N Engl
J Med 1998;338:1060–1 [editorial].
40. Truswell AS. ABC of nutrition. Nutrition for pregnancy. Br Med
J 1985;291:263–6.
41. MRC Vitamin Study Research Group. Prevention of neural tube defects:
results of the Medical Research Council Vitamin Study. Lancet
1991;338(8760):131–7.
42. Wright JD, Bialostosky K, Gunter EW, et al. Blood folate and vitamin
B12: United States, 1988–94. Vital Health Stat 11
1998;(243):1–78.
43. Patchett S, Register UD. Vitamin B12 studies in total vegetarians
(vegans). J Nutr Med 1994;4:419–30.
44. Lindenbaum J, Rosenberg IH, Wilson PWF, et al. Prevalence of
cobalamin deficiency in the Framingham elderly population. Am J Clin Nutr
1994;60:2–11.
45. Pennypacker LC, Allen RH, Kelly JP, et al. High prevalence of
cobalamin deficiency in elderly outpatients. J Am Geriatr Soc
1992;40:1197–204.
46. Steinberg WM, King CE, Toskes PP. Malabsorption of protein-bound
cobalamin but not unbound cobalamin during cimetidine administration. Dig Dis Sci
1980;25:188–92.
47. Baik HW, Russell RM. Vitamin B12 deficiency in the elderly. Annu
Rev Nutr 1999;19:357–77 [review].
48. Verhaeverbeke I, Mets T, Mulkens K, Vandewoulde M. Normalization of
low vitamin B12 serum levels in older people by oral treatment. J Am Geriatr Soc
1997;45:124–5 [letter].
49. Stein JH, McBride PE. Hyperhomocysteinemia and atherosclerotic
vascular disease: pathophysiology, screening, and treatment. Arch Intern Med
1998;158:1301–6 [review].
50. Bostom AG, Silbershatz H, Rosenberg IH, et al. Nonfasting plasma
total homocysteine levels and all-cause and cardiovascular disease mortality in elderly
Framingham men and women. Arch Intern Med 1999;159:1077–80.
51. Perry IJ, Refsum H, Morris RW, et al. Prospective study of serum
total homocysteine concentration and risk of stroke in middle-aged British men.
Lancet 1995;346:1395–8.
52. Clarke R, Smith D, Jobst KA, et al. Folate, vitamin B12, and serum
total homocysteine levels in confirmed Alzheimer disease. Arch Neurol
1998;55:1449–55.
53. Brattstrom LE, Hultberg BL, Hardebo JE. Folic acid responsive
postmenopausal homocysteinemia. Metabolism 1985;34:1073–7.
54. Lobo A, Naso A, Arheart K, et al. Reduction of homocysteine levels in
coronary artery disease by low-dose folic acid combined with vitamins B6 and B12. Am J
Cardiol 1999;83:821–5.
55. Bronstrup A, Hages M, Pietrzik K. Lowering of homocysteine
concentrations in elderly men and women. Int J Vitam Nutr Res
1999;69:187–93.
56. Ubbink JB, van der Merwe A, Vermaak WJ, Delport R.
Hyperhomocysteinemia and the response to vitamin supplementation. Clin Investig
1993;71:993–8.
57. Peterson JC, Spence JD. Vitamins and progression of atherosclerosis
in hyperhomocyst(e)inaemia. Lancet 1998;351:263. [letter]
58. Sato Y, Honda Y, Iwamoto J, et al. Effect of folate and mecobalamin
on hip fractures in patients with stroke: a randomized controlled trial. JAMA
2005;293:1082–8.
59. Johnston CS, Thompson LL. Vitamin C status of an outpatient
population. J Am Coll Nutr 1998;17:366–70.
60. Johnston CS, Solomon RE, Corte C. Vitamin C status of a campus
population: college students get a C minus. J Am Coll Health
1998;46:209–13.
61. Schectman G, Byrd JC, Gruchow HW, et al. The influence of smoking on
vitamin C status in adults. Am J Public Health 1989;79:158–62.
62. Carr AC, Frei B. Toward a new recommended dietary allowance for
vitamin C based on antioxidant and health effects in humans. Am J Clin Nutr
1999;69:1086–107 [review].
63. Levine M, Rumsey SC, Daruwala R, et al. Criteria and recommendations
for vitamin C intake. JAMA 1999;281:1415 to 23 [review].
64. Levine M, Conry-Cantilena C, Wang Y, et al. Vitamin C
pharmacokinetics in healthy volunteers: evidence for a recommended dietary allowance. Proc
Natl Acad Sci 1996;93:3704–9.
65. Jacques PF, Felson DT, Tucker KL, et al. Plasma 25-hydroxyvitamin D
and its determinants in an elderly population sample. Am J Clin Nutr
1997;66:929–36.
66. Chapuy MC, Preziosi P, Maamer M, et al. Prevalence of vitamin D
insufficiency in an adult normal population. Osteoporos Int 1997;7:439–43.
67. LeBoff MS, Kohlmeier L, Hurwitz S, et al. Occult vitamin D deficiency
in postmenopausal US women with acute hip fracture. JAMA 1999;281:1505–11.
68. Diamond T, Smerdely P, Kormas N, et al. Hip fracture in elderly men:
the importance of subclinical vitamin D deficiency and hypogonadism. Med J Aust
1998;169:138–41.
69. Dawson-Hughes B, Dallal GE, Krall EA, et al. Effect of vitamin D
supplementation on wintertime and overall bone loss in healthy postmenopausal women. Ann
Intern Med 1991;115:505–12.
70. Graafmans WC, Lips P, Ooms ME, et al. The effect of vitamin D
supplementation on the bone mineral density of the femoral neck is associated with vitamin D
receptor genotype. J Bone Miner Res 1997;12:1241–5.
71. Komulainen M, Kroger H, Tuppurainen MT, et al. Prevention of femoral
and lumbar bone loss with hormone replacement therapy and vitamin D3 in early postmenopausal
women: a population-based 5-year randomized trial. J Clin Endocrinol Metab
1999;84:546–52.
72. Dawson-Hughes B, Harris SS, Krall EA, et al. Rates of bone loss in
postmenopausal women randomly assigned to one of two dosages of vitamin D. Am J Clin
Nutr 1995;61:1140–5.
73. Pfeifer M, Begerow B, Minne HW, et al. Effects of a short-term
vitamin D and calcium supplementation on body sway and secondary hyperparathyroidism in
elderly women. J Bone Miner Res 2000;15:1113–8.
74. Vieth R. Vitamin D supplementation, 25-hydroxyvitamin D
concentrations, and safety. Am J Clin Nutr 1999;69:842–56 [review].
75. Ford ES, Sowell A. Serum alpha-tocopherol status in the United States
population: findings from the Third National Health and Nutrition Examination Survey. Am J
Epidemiol 1999;150:290–300.
76. Rimm EB, Stampfer MJ, Ascherio A, et al. Vitamin E consumption and
the risk of coronary heart disease in men. N Engl J Med 1993;328:1450–6.
77. Stampfer MJ, Hennekens CH, Manson JE, et al. Vitamin E consumption
and the risk of coronary heart disease in women. N Engl J Med
1993;328:1444–9.
78. Stephens NG, Parsons A, Schofield PM, et al. Randomised controlled
trial of vitamin E in patients with coronary disease: Cambridge Heart Antioxidant Study
(CHAOS). Lancet 1996;347:781–6.
79. Yusuf S, Dagenais G, Pogue J, et al. Vitamin E supplementation and
cardiovascular events in high-risk patients. The Heart Outcomes Prevention Evaluation Study
Investigators. N Engl J Med 2000;342:154–60.
80. Virtamo J, Rapola JM, Ripatti S, et al. Effect of vitamin E and beta
carotene on the incidence of primary nonfatal myocardial infarction and fatal coronary heart
disease. Arch Intern Med 1998;158:668–75.
81. Miller ER III, Pastor-Barriuso R, Dalal D, et al. Meta-analysis:
high-dosage vitamin E supplementation may increase all-cause mortality. Ann Intern
Med 2005;142:37–46.
82. Lonn E, Bosch J, Yusuf S, et al. Effects of long-term vitamin E
supplementation on cardiovascular events and cancer: a randomized controlled trial.
JAMA 2005;293:1338–47.
83. Gaby, AR. Study Flaws Cast Doubt on Claims of Vitamin E Danger.
Healthnotes Newswire [online] 2004 Nov 18.
84. Gaby, AR. Does Vitamin E Increase Heart Failure Risk? Healthnotes
Newswire [online] 2004 Mar 31.
85. Heinonen OP, Albanes D, Virtamo J, et al. Prostate cancer and
supplementation with alpha-tocopherol and beta-carotene: incidence and mortality in a
controlled trial. J Natl Cancer Inst 1998;90:440–6.
86. The Alpha-Tocopherol, Beta Carotene Cancer Prevention Study Group.
The effect of vitamin E and beta carotene on the incidence of lung cancer and other cancers in
male smokers. N Engl J Med 1994;330:1029–35.
87. Liede K, Hietanen J, Saxen L, et al. Long-term supplementation with
alpha-tocopherol and beta-carotene and prevalence of oral mucosal lesions in smokers. Oral
Dis 1998;4:78–83.
88. Rautalahti MT, Virtamo JR, Taylor PR, et al. The effects of
supplementation with alpha-tocopherol and beta-carotene on the incidence and mortality of
carcinoma of the pancreas in a randomized, controlled trial. Cancer
1999;86:37–42.
89. Malila N, Virtamo J, Virtanen M, et al. The effect of
alpha-tocopherol and beta-carotene supplementation on colorectal adenomas in middle-aged male
smokers. Cancer Epidemiol Biomarkers Prev 1999;8:489–93.
90. Hart JP. Circulating vitamin K1 levels in fractured neck of femur.
Lancet 1984;2:283 [letter].
91. Tamatani M, Morimoto S, Nakajima M, et al. Decreased circulating
levels of vitamin K and 25-hydroxyvitamin D in osteopenic elderly men. Metabolism
1998;47:195–9.
92. Feskanich D, Weber P, Willett WC, et al. Vitamin K intake and hip
fractures in women: a prospective study. Am J Clin Nutr 1999;69:74–9.
93. Knapen MHJ, Hamulyak K, Vermeer C. The effect of vitamin K
supplementation on circulating osteocalcin (Bone Gla protein) and urinary calcium excretion.
Ann Intern Med 1989;111:1001–5.
94. Iwamoto I, Kosha S, Noguchi S, et al. A longitudinal study of the
effect of vitamin K2 on bone mineral density in postmenopausal women a comparative study with
vitamin D3 and estrogen-progestin therapy. Maturitas 1999;31:161–4.
95. Knapen MH, Jie KS, Hamulyak K, Vermeer C. Vitamin K-induced changes
in markers for osteoblast activity and urinary calcium loss. Calcif Tissue Int
1993;53:81–5.
96. Craciun AM, Wolf J, Knapen MH, et al. Improved bone metabolism in
female elite athletes after vitamin K supplementation. Int J Sports Med
1998;19:479–84.
97. Standing Committee on the Scientific Evaluation of Dietary Reference
Intakes, Food and Nutrition Board, Institute of Medicine. Dietary reference intakes for
calcium, phosphorus, magnesium, vitamin D and fluoride. Washington DC: National Academy
Press, 1997, 105–17 [review].
98. Consensus Development Conference Panel. Optimal calcium intake:
Consensus Development Conference statement. JAMA 1994;272:1942–8.
99. Lee WT, Leung SS, Wang SH, et al. Double-blind, controlled calcium
supplementation and bone mineral accretion in children accustomed to a low-calcium diet.
Am J Clin Nutr 1994;60:744–50.
100. Lloyd T, Andon MB, Rollings N, et al. Calcium supplementation and
bone mineral density in adolescent girls. JAMA 1993;270:841–4.
101. Nowson CA, Green RM, Hopper JL, et al. A co-twin study of the effect
of calcium supplementation on bone density during adolescence. Osteoporos Int
1997;7:219–25.
102. Smith EL, Gilligan C, Smith PE, Sempos CT. Calcium supplementation
and bone loss in middle-aged women. Am J Clin Nutr 1989;50:833–42.
103. Storm D, Eslin R, Porter ES, et al. Calcium supplementation prevents
seasonal bone loss and changes in biochemical markers of bone turnover in elderly New England
women: a randomized placebo-controlled trial. J Clin Endocrinol Metab
1998;83:3817–25.
104. Dawson-Hughes B, Dallal GE, Krall EA, et al. A controlled trial of
the effect of calcium supplementation on bone density in postmenopausal women. N Engl J
Med 1990;323:878–83.
105. Reid IR, Ames RW, Evans MC, et al. Long-term effects of calcium
supplementation on bone loss and fractures in postmenopausal women: a randomized controlled
trial. Am J Med 1995;98:331–5.
106. Devine A, Dick IM, Heal SJ, et al. A 4-year follow-up study of the
effects of calcium supplementation on bone density in elderly postmenopausal women.
Osteoporos Int 1997;7:23–8.
107. Welten DC, Kemper HCG, Post GB, van Stavberen WA. A meta-analysis of
the effect of calcium intake on bone mass in young and middle aged females and males. J
Nutr 1995;125:2802–13 [review].
108. Dawson-Hughes B. Calcium supplementation and bone loss: a review of
controlled clinical trials. Am J Clin Nutr 1991;54:274S–80S [review].
109. Recker RR, Hinders S, Davies KM, et al. Correcting calcium
nutritional deficiency prevents spine fractures in elderly women. J Bone Miner Res
1996;11:1961–6.
110. Chevalley T, Rizzoli R, Nydegger V, et al. Effects of calcium
supplements on femoral bone mineral density and vertebral fracture rate in vitamin-D-replete
elderly patients. Osteoporos Int 1994;4:245–52.
111. Reid IR, Ames RW, Evans MC, et al. Long-term effects of calcium
supplementation on bone loss and fractures in postmenopausal women: a randomized controlled
trial. Am J Med 1995;98:331–5.
112. Bendich A, Leader S, Muhuri P. Supplemental calcium for the
prevention of hip fracture: potential health-economic benefits. Clin Ther
1999;21:1058–72 [review].
113. Pennington JA, Schoen SA. Total diet study: estimated dietary
intakes of nutritional elements, 1982–1991. Int J Vitam Nutr Res
1996;66:350–62.
114. Calvo MS, Park YK. Changing phosphorus content of the U.S. diet:
potential for adverse effects on bone. J Nutr 1996;126:1168S–80S [review].
115. Standing Committee on the Scientific Evaluation of Dietary Reference
Intakes, Food and Nutrition Board, Institute of Medicine. Dietary reference intakes for
calcium, phosphorus, magnesium, vitamin D and fluoride. Washington DC: National Academy
Press, 1997, 181–6 [review].
116. Heaney RP, Nordin BEC. Calcium effects on phosphorus absorption:
implications for the prevention and co-therapy of osteoporosis. J Am Coll Nutr
2002;21:239–44.
117. Standing Committee on the Scientific Evaluation of Dietary Reference
Intakes, Food and Nutrition Board, Institute of Medicine. Dietary reference intakes for
calcium, phosphorus, magnesium, vitamin D and fluoride. Washington DC: National Academy
Press, 1997, 222–33 [review].
118. Dimai H-P, Porta S, Wirnsberger G, et al. Daily oral magnesium
supplementation suppresses bone turnover in young adult males. J Clin Endocrinol
Metab 1998;83:2742–8.
119. Stendig-Lindberg G, Tepper R, Leichter I. Trabecular bone density in
a two year controlled trial of peroral magnesium in osteoporosis. Magnesium Res
1993;6:155–63.
120. Pennington JA, Schoen SA. Total diet study: estimated dietary
intakes of nutritional elements, 1982–1991. Int J Vitam Nutr Res
1996;66:350–62.
121. Whelton PK, He J, Cutler JA, et al. Effects of oral potassium on
blood pressure: meta-analysis of randomized controlled clinical trials. JAMA
1997;277:1624–32.
122. Burgess E, Lewanczuk R, Bolli P, et al. Lifestyle modifications to
prevent and control hypertension. 6. Recommendations on potassium, magnesium and calcium.
Can Med Assoc J 1999;160(9 Suppl):S35–45 [review].
123. Suter PM. The effects of potassium, magnesium, calcium, and fiber on
risk of stroke. Nutr Rev 1999;57:84–8.
124. Craig WJ. Iron status of vegetarians. Am J Clin Nutr
1994;59:1233S–37S.
125. Looker AC, Dallman PR, Carroll MD, et al. Prevalence of iron
deficiency in the United States. JAMA 1997;277:973–6.
126. Anonymous. Recommendations to prevent and control iron deficiency in
the United States. Centers for Disease Control and Prevention. MMWR Morb Mortal Wkly
Rep 1998;47(RR-3):1–29.
127. Clarkson PM. Micronutrients and exercise: anti-oxidants and
minerals. J Sports Sci 1995;13:S11–24.
128. Lynch SR, Baynes RD. Deliberations and evaluations of the
approaches, endpoints and paradigms for iron dietary recommendations. J Nutr
1996;126:2404S–9S [review].
129. Sempos CT, Looker AC, Gillum RF. Iron and heart disease: the
epidemiologic data. Nutr Rev 1996;54:73–84 [Review].
130. Okada S. Iron-induced tissue damage and cancer: the role of reactive
oxygen species-free radicals. Pathol Int 1996;46:311–32 [Review].
131. Cutler P. Deferoxamine therapy in high-ferritin diabetes.
Diabetes 1989;38:1207–10.
132. Weinberg ED. Iron withholding: a defense against infection and
neoplasia. Am J Physiol 1984;64:65–102.
133. Blake DR, Bacon PA. Effect of oral iron on rheumatoid patients.
Lancet 1982;1:623 [letter].
134. van der Haar F. The challenge of the global elimination of iodine
deficiency disorders. Eur J Clin Nutr 1997;51 Suppl 4:S3–8 [review].
135. Lee K, Bradley R, Dwyer J, Lee SL. Too much versus too little: the
implications of current iodine intake in the United States. Nutr Rev
1999;57:177–81 [review].
136. Hollowell JG, Staehling NW, Hannon WH, et al. Iodine nutrition in
the United States. Trends and public health implications: iodine excretion data from National
Health and Nutrition Examination Surveys I and III (1971–1974 and 1988–1994).
J Clin Endocrinol Metab 1998;83:3401–8.
137. Hunt IF, Murphy NJ, Gomez J, Smith JC. Dietary zinc intake of
low-income pregnant women of Mexican descent. Am J Clin Nutr
1979;32:1511–8.
138. Hambidge KM, Walravens PA, Brown RM, et al. Zinc nutrition of
preschool children in the Denver Head Start program. Am J Clin Nutr
1976;29:734–8.
139. Prentice A. Does mild zinc deficiency contribute to poor growth
performance? Nutr Rev 1993;51:268–77 [review].
140. Duchateau J, Delespesse G, Vereecke P. Influence of oral zinc
supplementation on the lymphocyte response to mitogens of normal subjects. Am J Clin
Nutr 1981;34:88–93.
141. Fraker PJ, Gershwin ME, Good RA, Prasad A. Interrelationships
between zinc and immune function. Fed Proc 1986;45:1474–9.
142. Fortes C, Forastiere F, Agabiti N, et al. The effect of zinc and
vitamin A supplementation on immune response in an older population. J Am Geriatr Soc
1998;46:19–26.
143. Girodon F, Lombard M, Galan P, et al. Effect of micronutrient
supplementation on infection in institutionalized elderly subjects: a controlled trial.
Ann Nutr Metab 1997;41:98–107.
144. Chandra RK. Excessive intake of zinc impairs immune responses.
JAMA 1984;252:1443–6.
145. Pennington JA, Schoen SA. Total diet study: estimated dietary
intakes of nutritional elements, 1982–1991. Int J Vitam Nutr Res
1996;66:350–62.
146. Turnlund JR. Copper nutriture, bioavailability, and the influence of
dietary factors. J Am Diet Assoc 1988;88:303–8 [review].
147. Eaton-Evans J, McIlrath EM, Jackson WE, et al. Copper
supplementation and bone-mineral density in middle-aged women. Proc Nutr Soc
1995;54:191A.
148. Sandstead HH. Requirements and toxicity of essential trace elements,
illustrated by zinc and copper. Am J Clin Nutr 1995;61:62S–4S [review].
149. Pennington JA. Intakes of minerals from diets and foods: is there a
need for concern? J Nutr 1996;126:2304S–8S [review].
150. Kimura M, Itokawa Y. Cooking losses of minerals in foods and its
nutritional significance. J Nutr Sci Vitaminol (Tokyo) 1990;36:S25–33.
151. Pennington JAT. Bowes and Church’s Food Values of Portions
Commonly Used, 17th ed. Philadelphia, PA: Lippincott Williams & Wilkins,
1997.
152. Raloff J. Reasons for boning up on manganese. Science News
1986:Sep 27;199 [review].
153. Strause L, Saltman P, Smith KT, et al. Spinal bone loss in
postmenopausal women supplemented with calcium and trace minerals. J Nutr
1994;124:1060–4.
154. Davis CD, Malecki EA, Gerger JL. Interactions among dietary
manganese, heme iron, and nonheme iron in women. Am J Clin Nutr
1992;56:926–32.
155. Anderson RA, Kozlovsky AS. Chromium intake, absorption and excretion
of subjects consuming self-selected diets. Am J Clin Nutr 1985;41:1177–83.
156. Anderson RA, Bryden NA, Polansky MM. Dietary chromium intake. Freely
chosen diets, institutional diet, and individual foods. Biol Trace Elem Res
1992;32:117–21.
157. Kumpulainen JT. Chromium content of foods and diets. Biol Trace
Elem Res 1992;32:9–18 [review].
158. Stoecker BJ. Chromium. In Shils ME, Olsen JA, Shike M, Ross AC
(eds). Modern nutrition in health and disease, 9th ed. Baltimore MD:
Williams & Wilkins, 1999, 277–82.
159. Anderson RA. Recent advances in the clinical and biochemical effects
of chromium deficiency. Prog Clin Biol Res 1993;380:221–34 [review].
160. Davies S, McLaren Howard J, Hunnisett A, Howard M. Age-related
decreases in chromium levels in 51,665 hair, sweat, and serum samples from 40,872
patients—implications for the prevention of cardiovascular disease and type II diabetes
mellitus. Metabolism 1997;46:469–73.
161. Cerulli J, Grabe DW, Guathier I, et al. Chromium picolinate
toxicity. Ann Pharmacother 1998;32:428–31.
162. Wasser WG, Feldman NS. Chronic renal failure after ingestion of
over-the-counter chromium picolinate. Ann Intern Med 1997;126:410 [letter].
163. Martin WR, Fuller RE. Suspected chromium picolinate-induced
rhabdomyolysis. Pharmacotherapy 1998;18:860–2.
164. Pennington JA. Intakes of minerals from diets and foods: is there a
need for concern? J Nutr 1996;126:2304S–8S [review].
165. Clark LC, Combs GF, Turnbull BW, et al. Effects of selenium
supplementation for cancer prevention in patients with carcinoma of the skin. JAMA
1996;276:1957–63.
166. Burk RF, Levander OA. Selenium. In Shils ME, Olsen JA, Shike M, Ross
AC (eds). Modern Nutrition in Health and Disease, 9th ed. Baltimore MD: Williams
& Wilkins, 1999, 265–76.
167. Barceloux DG. Molybdenum. J Toxicol Clin Toxicol
1999;37:231–7 [review].
168. Food and Nutrition Board, National Research Council. Recommended
Dietary Allowances, 10th ed. Washington DC: National Academy Press, 1989.
169. Taylor PR, Li B, Dawsey SM, et al. Prevention of esophageal cancer:
the nutrition intervention trials in Linxian, China. Linxian Nutrition Intervention Trials
Study Group. Cancer Res 1994;54:2029S–31S.
170. Blot WJ, Li JY, Taylor PR, et al. Nutrition intervention trials in
Linxian, China: supplementation with specific vitamin/mineral combinations, cancer incidence,
and disease-specific mortality in the general population. J Natl Cancer Inst
1993;85:1483–92.
