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From The July 2001 Issue of Nutrition Science News
Mining Mineral Supplements
by Robert A. DiSilvestro, Ph.D.
6 considerations when using minerals for supplements and food fortifiers
Using minerals as dietary supplements and food fortifiers is certainly not new, but their applications are expanding far beyond their common use to treat medical conditions related to classic mineral deficiencies. Today, minerals are used to correct subtle nutritional deficiencies in relatively healthy people; to compensate for increased mineral needs caused by health problems; to enhance exercise training; and to correct large-scale, overt mineral deficiencies in Third World countries.
Variables concerning mineral use for a supplement or food fortifier extend beyond the amount of mineral intended for consumption. Six other points should be considered when formulating a product, depending on the particular application.
Absorption tendencies, also called bioavailability, are given the most attention since this is where formulators begin when designing a product. Mineral absorption rates vary for different supplements or food fortifiers, just as they vary for natural foods. Bioavailability can also mean the ability of the mineral to become biologically functional. For example, certain forms of iron can be absorbed but vary in their ability to increase hemoglobin, which carries oxygen to tissues. Another critical feature of bioavailability is excretion—how long the mineral resides in the body and exerts its effect.
Mineral oxides (e.g., ZnO) are generally considered the poorest-absorbed form of mineral preparations.1 However, this form is used in many products because of its small size, which makes it convenient to add in multivitamin supplements, plus it is fairly inert in food fortification applications, which preserves food shelf life, texture, taste, and the like. Mineral sulfates are generally better absorbed than oxides, though reactions with food components are possible (for example, oxidation of lipids can cause food to go rancid).ie 1
Alternatives to oxides include mineral gluconates, which are an acidic form of the natural sugar glucose. A clinical study of 10 subjects in Belgium showed zinc gluconate was better absorbed than zinc sulfate.2 Studies that compare gluconates to sulfates in minerals other than zinc are few in number. But when mineral gluconates have been used in human studies, the minerals appear to be absorbed enough to produce positive results.3
Amino acid chelates—a stable chemical complex between the mineral and more than one site on an amino acid, the building blocks of protein—are another form of mineral preparations. Various processes that produce different degrees of chelate stability—and possibly differences in absorption properties—mean that results for one chelated product may not equal identical results for another. Many products declare minerals "amino acid chelates" because they contain a loose mixture of the metal plus an amino acid, but do not provide data that they have true chelation properties.
Many studies on mineral chelate bioavailability have been conducted by their producers and have not been published in peer-reviewed publications. Nonetheless, independent researchers have published a few journal articles detailing results that show better absorption for certain amino acid chelates than for their inorganic counterparts. In one such study, researchers compared bread fortified with an iron chelate (bis-glycinate) to iron sulfate-enriched bread. They reported double the apparent absorption from the chelate than from the sulfate.4
In a few other studies involving agricultural animals, researchers have reported that zinc amino acid chelates have absorption properties superior to zinc sulfate. One example is a study at the department of animal science at the University of Illinois, Urbana, involving chickens and a proprietary zinc methionine chelate.1 However, in other studies, researchers have not seen differences between chelates and sulfates. These conflicting results could be due to differences in the chelates or to methodology problems. There are a number of different approaches for evaluating bioavailability. Moreover, even for a single approach, there are different conditions under which the bioavailability can be evaluated.
Picolinate chelates are also used for some minerals. Picolinate, a chemical relative of the B vitamin niacin, can form tight bonds with certain minerals. Chromium is the best-known example of a mineral-picolinate product (used for its body composition effects5), but other mineral picolinates are available. Chromium picolinate is a better alternative than inorganic chromium, which is generally accepted as being poorly absorbed. One study found chromium picolinate absorption to be 2.8 percent (within a range of 1.5 to 5.2 percent), compared to inorganic chromium chloride, which had an absorption rate of 0.4 percent.6
There are some old, and sometimes conflicting, studies for zinc. One clinical study reported zinc picolinate was absorbed better than zinc gluconate and zinc citrate.7
Calcium has been combined with a number of ligands, including lactate and citrate. The absorption of these two complexes after a single acute dose in young adults seems positive.8 Researchers are not yet certain whether one form of calcium is absorbed significantly better than others.
Calcium carbonate is the most widely used form of calcium in dietary supplements. A meta-analysis of 15 studies involving 184 subjects, conducted at the Center for Mineral Metabolism and Clinical Research at the University of Texas Southwestern Medical School in Dallas, revealed calcium citrate to be approximately 22-27 percent better absorbed than calcium carbonate, whether taken on an empty stomach or with meals.9 However, in a study of 37 adults conducted at Creighton University in Omaha, Neb., researchers found that when taken with food, calcium carbonate is just as absorbable as calcium citrate.10 Meanwhile, a novel Japanese calcium supplement derived from powdered bovine marrow-free bone was found to have absorbability comparable with that of calcium lactate and greater than that of calcium carbonate when measured in rats.11
Calcium citrate malate (CCM) is a patented product licensed to both a leading producer and marketer of branded fruit juices as well as to the world's largest dietary supplements company. Several animal and human studies have examined CCM's absorption rate and its ability to alter bone density, the latter being a more important outcome than just how much is absorbed.12 Moreover, clinical studies have shown supplementation with CCM does not influence zinc or iron nutriture, a common concern because studies with other calcium forms have shown antagonistic interactions between minerals.13,14
Certainly the many forms of calcium available, and the diversity of results, points to the need for more research in this area before a firm recommendation can be made on the best form to use.
Other minerals also can be combined with citrate or lactate. The absorption of other minerals as lactates or citrates has not been extensively evaluated, even though magnesium citrate supplements have been used in humans. A caution here is that high doses of magnesium citrate can produce diarrhea.15
Food extracts provide another approach to mineral products. For example, the calcium in milk and the magnesium in almonds are known to be well absorbed.8,16 It is reasonable to assume that minerals extracted from these foods would also be well absorbed. However, unbiased testing has been limited.
Absorption antagonisms between minerals in which one mineral inhibits the absorption of another mineral, are well known. Classic examples are calcium with magnesium and zinc with copper. For example, high intake of calcium can raise magnesium requirements in various species, presumably by lowering calcium absorption.17 The simplest approach is not to combine certain minerals, or recommend they be taken separately at different times of the day.
However, certain mineral combinations may be less antagonistic than others. The idea is supported by a recent, unpublished study conducted at our laboratory at Ohio State University in Columbus. Based on copper enzyme activities, we found that in rats, a proprietary zinc amino acid chelate with glycine shows less ill effects on copper status than zinc sulfate.
Functional cooperation between minerals can, ironically, occur between the same minerals that produce absorption antagonisms. A good example is calcium with magnesium, which can have functional overlaps such as promoting bone health. Thus, it can be both good and bad to provide such mineral combinations.
One approach is to provide both minerals, but at different times of day in different products. Another is to accept the antagonism but provide enough of each mineral so each can be of benefit. If it is eventually shown that certain mineral complexes are only mildly antagonistic, then providing these forms together would enhance patient compliance.
Targeting minerals to specific tissues or functional molecules, such as a metal-containing enzyme, is an area ripe for research. Once a mineral is absorbed, it has to get to its functional sites—a principal tenet of bioavailability. We often assume that if a mineral makes its way past the intestine, the rest will take care of itself. This may be true to a great extent, but some mineral complexes may get the metals to functional sites especially well. Although this is true in theory, more study is needed to show it actually happens.
A different approach may be feasible for enhancing one particular tissue's mineral accumulation or increasing a mineral's function. This could involve providing agents that do not directly associate with the mineral. In other words, one way to get more mineral to a functional protein is to increase production of that protein.
For example, suppose it is desirable to increase the actions of antioxidant metal-containing proteins such as the superoxide dismutases (which contain copper, manganese, and zinc), glutathione peroxidases (which contain selenium), or metallo thionein (which contains copper and zinc). Certain agents can increase the production of these proteins, which will in turn allow more ingested minerals to incorporate into recipient proteins. In this regard, a number of flavonoids or other phytochemicals may prove useful.18 In a recent review article, I have outlined current studies that have found some phytochemicals to increase production of certain mineral-containing proteins.18
In terms of tissue targeting, we have found, in unpublished data, an interesting relationship between zinc and lycopene, a phytochemical that may promote prostate health. In rats, adding lycopene-rich tomato extracts to the diet increased prostate zinc concentrations by 50 percent. It will be interesting to explore whether other such relationships exist between minerals and phytochemicals.
Sensory effects of mineral food fortification have to be considered on a food-by-food basis. That includes taste and texture, as well as negative reactions with other food components, such as fats turning rancid. Possibly, mixing like with like can be a helpful formulation guide. For example, a mineral lactate may mix well with dairy products. However, this may not be the only way to mix minerals with foods. Adding a proprietary iron bis-glycinate chelate to a 3.3 percent-fat liquid milk resulted in significant improvements in hemoglobin among mild to severely anemic South American children without increasing hemoglobin in normal children.19
Toxicity issues can result from impurities in the mineral preparations, the mineral in general, or specific side effects of a particular metal complex. Impurity depends on the provider and the product. For example, certain calcium supplements, including dolomite and some oyster-shell extracts, can be prone to lead contamination.20
As far as general toxicity of a given mineral, some compromise must be reached between maximum absorption and minimum toxicity. The simplest approach is to limit the amounts of a mineral that would typically be consumed. However, it is also theoretically possible that certain mineral complexes can be better absorbed than other forms and still be less toxic. But any mineral preparation can be toxic if too much is consumed.
In addition, certain mineral complexes pose their own unique side-effect risks beyond those of the mineral in general. For example, chromium picolinate, which can enter cells intact, can produce hydroxyl radicals in cells.21 This concern derives from a cell-culture study with questionable application to most human situations. Conversely, in a New York University School of Medicine eight-week clinical study on 10 obese women taking 400 mcg/day chromium picolinate, researchers found no oxidative DNA damage.22 Still, such issues mean that various mineral complexes must be evaluated for side effects.
Evaluating Effectiveness
How do we evaluate whether our mineral supplement/fortification product effectively improves mineral function in the people consuming the product? There is no simple answer. Oftentimes, naïve approaches are taken, even by biomedical researchers. In many studies, for example, zinc and copper status is evaluated only via serum levels. It is well established that these levels can be affected by many factors other than nutritional state, such as physiological stress and inflammation.23 Therefore, this question should be evaluated by researchers with expertise in both mineral assessment and in the health issue of concern, with great care given to study design. This evaluation involves both art and science.
Sidebars:
Mineral Preparation Variables
New Delivery Systems
Robert A. DiSilvestro, Ph.D., is professor of nutrition at Ohio State University and author or co-author of more than 60 peer-reviewed research papers.
References:
1. Wedekind KJ, et al. Methodology for assessing zinc bioavailability: efficacy estimates for zinc-methionine, zinc sulfate, and zinc oxide. J Anim Sci 1992;70:178-87.
2. Neve J, et al. Some factors influencing the bioavailability of zinc in oral pharmaceutical dosage forms. J Pharm Belg 1993;48:2-11.
3. Dart RC, et al. Combined evidence-based literature analysis and consensus guidelines for stocking of emergency antidotes in the United States. Ann Emerg Med 2000 Aug;36(2):126-32.
4. Layrisse M, et al. Iron bioavailability in humans from breakfasts enriched with iron bis-glycine chelate, phytates and polyphenols. J Nutr 2000;130:2195-9.
5. Grant K, et al. Chromium and exercise training: effect on obese women. Med Sci Sports Exer 1997;29(8):992-8.
6. Gargas M, et al. Urinary excretion of chromium by humans following ingestion of chromium picolinate. Drug Metab Dispos 1994;22(4):522-9.
7. Barrie SA, et al. Comparative absorption of zinc picolinate, zinc citrate and zinc gluconate in humans. Agents Actions 1987;21:223-8.
8. Sheikh MS, et al. Gastrointestinal absorption of calcium from milk and calcium salts. New Engl J Med 1987;317:532-6.
9. Sakhaee K, et al. Meta-analysis of calcium bioavailability: a comparison of calcium citrate with calcium carbonate. Am J Ther 1999 Nov;6(6):313-21.
10. Heaney RP, et al. Absorption of calcium as the carbonate and citrate salts, with some observations on method. Osteoporos Int 1999;9(1):19-23.
11. Ohtani M, et al. Absorbability of calcium from a new calcium supplement prepared from bovine marrow-free bone in rats. J Nutr Sci Vitaminol (Tokyo) 1998 Dec;44(6):887-95.
12. Patrick L. Comparative absorption of calcium sources and calcium citrate malate for the prevention of osteoporosis. Altern Med Rev 1999 Apr;4(2):74-85.
13. McKenna AA, et al. Zinc balance in adolescent females consuming a low- or high-calcium diet. Am J Clin Nutr 1998 May;67(5):948-50.
14. Ilich-Ernst JZ, et al. Iron status, menarche, and calcium supplementation in adolescent girls. Am J Clin Nutr 1999 Mar;69(3):577.
15. Chen CC, et al. Magnesium citrate-bisacodyl regimen proves better than castor oil for colonoscopic preparation. J Gastroenterol Hepatol 1999 Dec;14(12):1219-22.
16. Fine KD, et al. Intestinal absorption of magnesium from food and supplements. J Clin Invest 1991 Aug;88(2):396-402.
17. Howard KA, et al. Magnesium requirements of kittens is increased by high dietary calcium. J Nutr 1998;128(12): 2601S-2S.
18. DiSilvestro RA. Antioxidant actions of flavonoids. In: Wildman R, editor. Nutraceuticals and functional foods. Boca Raton (FL): CRC Press; 2001. p 127-42.
19. Lost C, et al. Repleting hemoglobin in iron deficiency anemia in young children through liquid milk fortification with bioavailable iron amino acid chelate. J Am Coll Nutr 1998;17:187-94.
20. Whiting SJ. Safety of some calcium supplements questioned. Nutr Rev 1994;52:95-7.
21. Vincent JB. The biochemistry of chromium. J Nutr 2000;130:715-8.
22. Kato I, et al. Effect of supplementation with chromium picolinate on antibody titers to 5-hydroxymethyl uracil. Eur J Epidemiol 1998;14(6):621-6.
23. O'Dell BL, Sunde RA, editors. Handbook of nutritionally essential mineral elements. New York: Marcel Dekker Inc; 1997.
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