Why take vitamin and mineral supplements?

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

What is the potential importance of taking vitamin A?

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.

What is the potential importance of taking beta-carotene?

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 disease^{13 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.

What is the potential importance of taking B-vitamins?

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.

What is the potential importance of taking folic acid?

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 requirement for folic acid doubles during pregnancy,⁴⁰ and insufficient intake of folic acid has been linked to low birth weight and an increased incidence of neural tube defects in newborns. Supplementation with 400 mcg per day of folic acid prior to, and shortly after, conception is effective in preventing neural tube defects.⁴¹

What is the potential importance of taking vitamin B12?

Vitamin B12 deficiency is not common among healthy young people,⁴² except for vegans (vegetarians who also avoid dairy and eggs).⁴³ However, about 12 to 15% of the elderly in the U.S. have been found deficient in this vitamin.^{44 45} Vitamin B12 deficiency may also occur in people who take acid-blocking drugs or antacids for long periods of time.⁴⁶ Although vitamin B12 deficiency in the elderly is often due to age-related declines in absorption of vitamin B12 from food, vitamin B12 supplements can be absorbed sufficiently in members of this age group if they do not have pernicious anemia or other significant gastrointestinal disorders.⁴⁷ Supplementation with 100 mcg per day of vitamin B12 was adequate to reverse vitamin B12 deficiency in healthy elderly people, according to one recent report.⁴⁸

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}

What is the potential importance of taking vitamin C?

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.

What is the potential importance of taking vitamin D?

Vitamin D can be obtained either from the diet or from sunlight exposure, but these sources can be insufficient, especially in older people and vegans during the winter months.⁶⁵ and in vegans, during the winter months.⁶⁶ Six to fourteen percent of healthy adult Western European populations have been reported to be vitamin D deficient,⁶⁷ but good data are not available for the U.S. Vitamin D insufficiency is associated with bone loss and fractures in older people.^{68 69} Reduced bone loss from vitamin D supplements has been reported in some,^{70 71} though not all,⁷² 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.⁷³ In addition, vitamin D supplementation has been shown to reduce the risk of falls in older people.⁷⁴ While vitamin D is known to be toxic in very high amounts, up to 2000 IU per day is considered safe.⁷⁵

What is the potential importance of taking vitamin E?

A nationwide study recently reported that 27% of the U.S. population had low blood levels of vitamin E.⁷⁶ Supplementing with at least 100 IU per day of vitamin E is associated with lowered risk of heart disease,^{77 78} 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.⁷⁹ 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,⁸⁰ while another study found that 50 IU per day had no effect on heart attack risk.⁸¹ 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,⁸² while another study found that 400 IU per day increased the risk of heart failure.⁸³ 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.^{84 85}

A reduced risk of prostate cancer in smokers was reported in a double-blind trial with 50 IU per day of vitamin E.⁸⁶ However, similar studies have not found vitamin E supplements to protect against other cancers.^{87 88 89 90}

What is the potential importance of taking vitamin K?

Vitamin K deficiency severe enough to cause bleeding problems is rare in healthy people. However, low vitamin K in the blood^{91 92} and in the diet⁹³ 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.^{94 95 96 97}

What is the potential importance of taking calcium?

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.⁹⁸ Good calcium nutrition throughout life is essential for achieving peak bone mass and preventing deficiency-related bone loss.⁹⁹ Calcium supplements are effective in increasing bone mass in children^{100 101 102} and slowing bone loss in adults according to most,^{103 104 105 106 107 108} though not all,¹⁰⁹ double-blind studies. Calcium supplements have also been shown to reduce the risk of bone fractures in some elderly adults.^{110 111 112 113} 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.

What is the potential importance of taking phosphorus?

Phosphorus is a necessary nutrient, but diets are almost always adequate in this mineral.¹¹⁴ Some authorities have suggested that excess intake of phosphorus is hazardous to normal calcium and bone metabolism.¹¹⁵ However, this idea has been challanged.¹¹⁶ 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.¹¹⁷

What is the potential importance of taking magnesium?

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.¹¹⁸ Magnesium supplements of at least 250 mg per day may help prevent bone loss.^{119 120}

What is the potential importance of taking potassium?

While potassium is lower in modern diets compared with so-called primitive diets, true deficiencies are uncommon.¹²¹ Some,¹²² though not all,¹²³ research suggests that raising potassium intake may help prevent high blood pressure. Other research suggests higher potassium intake may help prevent stroke.¹²⁴ 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.

What is the potential importance of taking iron?

Iron deficiency is not uncommon among some groups of healthy people, including some vegetarians,¹²⁵ menstruating girls and women,¹²⁶ pregnant women,¹²⁷ and female and adolescent athletes.¹²⁸ Nonetheless, many people in these groups are not iron deficient ¹²⁹ and excessive iron intake has been associated in some studies with heart disease,¹³⁰ some cancers,¹³¹ diabetes,¹³² increased risk of infection,¹³³ and exacerbation of rheumatoid arthritis.¹³⁴ 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.

What is the potential importance of taking iodine?

Iodine deficiency is a concern in many developing countries,¹³⁵ Until recently it was considered abundant in Western diets, due to the introduction of iodized salt and the iodine added to many foods.¹³⁶ However, iodine intake has decreased considerably in recent years and may be low in as many as 12% of the total U.S. population, and 15% of women of childbearing age.¹³⁷ These numbers may be greater in countries where iodized salt is not available. Still, most people have adequate iodine intake unless they avoid iodized salt, seafood, and sea vegetables. People with thyroid diseases should check with their doctor before using iodine supplements.

What is the potential importance of taking zinc?

Zinc deficiency is not common in Western countries, except in people with low incomes.^{138 139} Zinc supplements (10 mg per day) have prevented growth impairment in deficient American and Canadian children.¹⁴⁰ Supplementation with 25 to 150 mg of zinc per day has been shown to increase immune function in healthy people.^{141 142 143 144} 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.¹⁴⁵ 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.

What is the potential importance of taking copper?

The average dietary copper intake in the U.S. has been found to be below accepted standards.¹⁴⁶ However, the significance of this is unclear, since symptomatic copper deficiency is quite rare.¹⁴⁷ Supplementation with 3 mg per day of copper may help prevent bone loss.¹⁴⁸ Since zinc can interfere with copper absorption, copper should be taken whenever zinc supplements are taken for more than a few weeks.¹⁴⁹

What is the potential importance of taking manganese?

Dietary intake of manganese is adequate for most people, according to recent studies in the U.S.¹⁵⁰ However, manganese, along with other trace minerals, is often low in refined and processed foods.^{151 152} 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.¹⁵³ A double-blind trial found that a combination of mineral supplements including manganese prevented bone loss in postmenopausal women.¹⁵⁴ 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.¹⁵⁵

What is the potential importance of taking chromium?

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.^{156 157 158} However, some authorities question the validity of the recommended minimum requirements.¹⁵⁹ Chromium deficiency has been associated with blood sugar and cholesterol abnormalities.¹⁶⁰ Also, chromium levels in the body decline as people get older, which is when these problems often appear.¹⁶¹ 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, ^{162 163 164} although it is not clear whether chromium was responsible for these reactions.

What is the potential importance of taking selenium?

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.¹⁶⁵ 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.¹⁶⁶ 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.¹⁶⁷

What is the potential importance of taking molybdenum?

Molybdenum is an essential trace element with low potential for toxicity.¹⁶⁸ Since little is known about human needs and deficiencies are quite rare, estimated requirements are based on what people typically receive in their diets.¹⁶⁹ Cancer and cardiovascular disease prevention studies in China found no benefit from a supplement containing molybdenum and vitamin C.^{170 171} 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. Lamberg-Allardt C, Karkkainen M, Seppanen R, Bistrom H. Low serum 25-hydroxyvitamin D concentrations and secondary hyperparathyroidism in middle-aged white strict vegetarians. Am J Clin Nutr 1993;58:684–9.

67. Chapuy MC, Preziosi P, Maamer M, et al. Prevalence of vitamin D insufficiency in an adult normal population. Osteoporos Int 1997;7:439–43.

68. 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.

69. 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.

70. 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.

71. 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.

72. 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.

73. 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.

74. 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.

75. Vieth R. Vitamin D supplementation, 25-hydroxyvitamin D concentrations, and safety. Am J Clin Nutr 1999;69:842–56 [review].

76. 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.

77. 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.

78. 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.

79. 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.

80. 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.

81. 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.

82. 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.

83. 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.

84. Gaby, AR. Study Flaws Cast Doubt on Claims of Vitamin E Danger. Healthnotes Newswire [online] 2004 Nov 18.

85. Gaby, AR. Does Vitamin E Increase Heart Failure Risk? Healthnotes Newswire [online] 2004 Mar 31.

86. 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.

87. 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.

88. 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.

89. 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.

90. 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.

91. Hart JP. Circulating vitamin K1 levels in fractured neck of femur. Lancet 1984;2:283 [letter].

92. 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.

93. 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.

94. 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.

95. 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.

96. 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.

97. 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.

98. 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].

99. Consensus Development Conference Panel. Optimal calcium intake: Consensus Development Conference statement. JAMA 1994;272:1942–8.

100. 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.

101. Lloyd T, Andon MB, Rollings N, et al. Calcium supplementation and bone mineral density in adolescent girls. JAMA 1993;270:841–4.

102. 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.

103. 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.

104. 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.

105. 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.

106. 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.

107. 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.

108. 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].

109. Dawson-Hughes B. Calcium supplementation and bone loss: a review of controlled clinical trials. Am J Clin Nutr 1991;54:274S–80S [review].

110. 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.

111. 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.

112. 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.

113. 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].

114. Pennington JA, Schoen SA. Total diet study: estimated dietary intakes of nutritional elements, 1982–1991. Int J Vitam Nutr Res 1996;66:350–62.

115. 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].

116. 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].

117. 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.

118. 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].

119. 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.

120. 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.

121. Pennington JA, Schoen SA. Total diet study: estimated dietary intakes of nutritional elements, 1982–1991. Int J Vitam Nutr Res 1996;66:350–62.

122. 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.

123. 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].

124. Suter PM. The effects of potassium, magnesium, calcium, and fiber on risk of stroke. Nutr Rev 1999;57:84–8.

125. Craig WJ. Iron status of vegetarians. Am J Clin Nutr 1994;59:1233S–37S.

126. Looker AC, Dallman PR, Carroll MD, et al. Prevalence of iron deficiency in the United States. JAMA 1997;277:973–6.

127. 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.

128. Clarkson PM. Micronutrients and exercise: anti-oxidants and minerals. J Sports Sci 1995;13:S11–24.

129. Lynch SR, Baynes RD. Deliberations and evaluations of the approaches, endpoints and paradigms for iron dietary recommendations. J Nutr 1996;126:2404S–9S [review].

130. Sempos CT, Looker AC, Gillum RF. Iron and heart disease: the epidemiologic data. Nutr Rev 1996;54:73–84 [Review].

131. Okada S. Iron-induced tissue damage and cancer: the role of reactive oxygen species-free radicals. Pathol Int 1996;46:311–32 [Review].

132. Cutler P. Deferoxamine therapy in high-ferritin diabetes. Diabetes 1989;38:1207–10.

133. Weinberg ED. Iron withholding: a defense against infection and neoplasia. Am J Physiol 1984;64:65–102.

134. Blake DR, Bacon PA. Effect of oral iron on rheumatoid patients. Lancet 1982;1:623 [letter].

135. 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].

136. 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].

137. 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.

138. 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.

139. 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.

140. Prentice A. Does mild zinc deficiency contribute to poor growth performance? Nutr Rev 1993;51:268–77 [review].

141. 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.

142. Fraker PJ, Gershwin ME, Good RA, Prasad A. Interrelationships between zinc and immune function. Fed Proc 1986;45:1474–9.

143. 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.

144. 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.

145. Chandra RK. Excessive intake of zinc impairs immune responses. JAMA 1984;252:1443–6.

146. Pennington JA, Schoen SA. Total diet study: estimated dietary intakes of nutritional elements, 1982–1991. Int J Vitam Nutr Res 1996;66:350–62.

147. Turnlund JR. Copper nutriture, bioavailability, and the influence of dietary factors. J Am Diet Assoc 1988;88:303–8 [review].

148. 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.

149. Sandstead HH. Requirements and toxicity of essential trace elements, illustrated by zinc and copper. Am J Clin Nutr 1995;61:62S–4S [review].

150. Pennington JA. Intakes of minerals from diets and foods: is there a need for concern? J Nutr 1996;126:2304S–8S [review].

151. Kimura M, Itokawa Y. Cooking losses of minerals in foods and its nutritional significance. J Nutr Sci Vitaminol (Tokyo) 1990;36:S25–33.

152. Pennington JAT. Bowes and Church’s Food Values of Portions Commonly Used, 17th ed. Philadelphia, PA: Lippincott Williams & Wilkins, 1997.

153. Raloff J. Reasons for boning up on manganese. Science News 1986:Sep 27;199 [review].

154. 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.

155. 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.

156. Anderson RA, Kozlovsky AS. Chromium intake, absorption and excretion of subjects consuming self-selected diets. Am J Clin Nutr 1985;41:1177–83.

157. 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.

158. Kumpulainen JT. Chromium content of foods and diets. Biol Trace Elem Res 1992;32:9–18 [review].

159. 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.

160. Anderson RA. Recent advances in the clinical and biochemical effects of chromium deficiency. Prog Clin Biol Res 1993;380:221–34 [review].

161. 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.

162. Cerulli J, Grabe DW, Guathier I, et al. Chromium picolinate toxicity. Ann Pharmacother 1998;32:428–31.

163. Wasser WG, Feldman NS. Chronic renal failure after ingestion of over-the-counter chromium picolinate. Ann Intern Med 1997;126:410 [letter].

164. Martin WR, Fuller RE. Suspected chromium picolinate-induced rhabdomyolysis. Pharmacotherapy 1998;18:860–2.

165. Pennington JA. Intakes of minerals from diets and foods: is there a need for concern? J Nutr 1996;126:2304S–8S [review].

166. 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.

167. 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.

168. Barceloux DG. Molybdenum. J Toxicol Clin Toxicol 1999;37:231–7 [review].

169. Food and Nutrition Board, National Research Council. Recommended Dietary Allowances, 10th ed. Washington DC: National Academy Press, 1989.

170. 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.

171. 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.