Most Important Minerals & Their Deficiencies

Calcium, as part of calcium phosphate, is the main structural component of bones and teeth. In addition, calcium is involved in a long list of reversible activating and regulatory actions. In fact, calcium movements in and out of cells or cell organelles are essential to many basic physiological functions, including neurological actions and cardiac muscle contraction. Part of calcium’s functions inside cells is to act as what is called a “second messenger.” This name arises because the shifting of calcium between pools is often a way that a hormone or other signaling molecule starts a process within a cell. In addition to intracellular second messenger functions, calcium also seems to serve as an extracellular messenger outside cells. Calcium is well suited to the activator/regulator roles, because this metal is a strong enough chelate former to complex with a signaling molecule, such as a receptor, but a weak enough chelate former to also fall back off the molecule. The bone function of calcium seems to be better preserved than the activator/regulator functions, since bone releases some calcium if the body’s supply falls off. However, not all activating/regulatory functions are necessarily preserved perfectly in times of low calcium supply. The activator/regulator functions are so essential to life, and are so sensitive to changes in calcium concentrations, that the body needs powerful mechanisms to maintain calcium homeostasis. These mechanisms exist especially for plasma calcium levels, and for the transport of calcium in and out of cells and in and out of cell organelles. This movement maintains the cytoplasmic concentration of ionized calcium (calcium ion in a relatively unbound state) in the micro-molar range (over a thousand-fold less than plasma calcium concentrations). This low cytoplasmic calcium ion concentration is essential to calcium’s second messenger functioning.

RICKETS

Rickets is a name for a pattern of bone development impairment generally ascribed to a vitamin D deficiency. Since vitamin D promotes calcium absorption, it stands to reason that calcium deficiency can also cause or contribute to rickets. If this is the case, then calcium supplementation can reverse, or help reverse, rickets in some situations. It remains to be seen whether similar findings would occur in other settings.

BONE IN CHILDREN AND ADOLESCENTS WITHOUT RICKETS

Calcium supplements are often given to children by parents, with or without the advice of their physicians, because it makes sense to be concerned about calcium intake. The feeling is that adequate calcium intake is important to reach full bone growth, plus to help prevent osteoporosis later in life. There are studies to support this notion.

OSTEOPOROSIS PREVENTION AND TREATMENT IN ADULTS

The term “osteoporosis” describes a certain condition of low bone density that can have multiple causes and ages of onset. However, this term is most often used to describe a specific state that occurs in older women and sometimes in older men. Prevention is preferable to treatment, since it is impossible to produce high bone density once osteoporosis is present. Treatment is limited to inhibiting disease progression. It makes sense that calcium intake can be a factor in osteoporosis prevention, since calcium is so intimately connected to bone health. Still, it should be noted that osteoporosis is very multifactorial in nature, and the relative contributions of various factors are not well characterized. The general strategy for osteoporosis prevention is to maximize bone mass gain at younger ages and minimize bone loss at older ages. Bone mass tends to peak about age 30, and bone loss accelerates in women after menopause. Thus, most studies on osteoporosis prevention look at bone gain in young adult women or bone loss in postmenopausal women. In this light, it can be asked: How much does calcium intake contribute to osteoporosis prevention? This is not an easy question to answer. When examining the pre-30-year-old population, one is looking into a crystal ball (predicting future osteoporosis development). When examining older women, and asking what caused or prevented osteoporosis, one is taking a trip in a time machine (interpreting distant past history’s contribution to a current state). What is generally done for intervention studies, such as those for calcium supplementation, is one of two approaches. One approach is to study postmenopausal women for slowing of bone loss and reduction of fracture incidence. The other approach is to examine bone mass gain in young adult women, even though we cannot quantitatively translate a given gain into a degree of osteoporosis risk reduction.

BLOOD LIPID ALTERATIONS

A high calcium intake is proposed to reduce serum cholesterol and produce other desirable blood lipid changes. The mechanisms are thought to involve calcium binding to lipids and forming insoluble complexes. This action can inhibit intestinal absorption of cholesterol, reduce re-uptake of bile acids (which could accelerate cholesterol degradation), and lower fat absorption. There are a series of experimental animal studies and human intervention trials that support the concept that high calcium intake, via supplements or foods, can affect lipid profiles. However, the picture is not completely clear cut. Epidemiological work is not fully supportive, and two large intervention studies in hypertensive and non-hypertensive people don’t find an effect for calcium. In addition, among the intervention studies showing an effect, in some cases, the effect is small, or is studied in a small number of people.

Nonetheless, this author feels that the calcium effect could be real, at least in some people. This opinion is based on the fact that effects are seen by different research groups, and there is a considerable effect seen in some studies. Since the effect is not totally consistent between studies, either in terms of whether an effects is seen at all, or whether the effect is small or large, possibly a strong effect will only occur when certain processes are strongly affecting serum lipid profiles. More research should be done to determine if this notion is true and, if so, to identify the relevant processes.

In a sense, iodine is the most heavily used mineral supplement in the world because so many people use iodized salt. However, in a more narrow definition of supplement (i.e., in a pill or capsule), iodine is not widely used. Iodine is another mineral that is not a metal. Rather, in the body, this element exists as iodide, a negatively charged ion. Iodide is an essential component of thyroid hormones T3 and T4. Iodine deficiency impairs the functions of these thyroid hormones, which has deleterious effects on various body processes. In severe cases, this deficiency can produce a goiter, which is an enlarged thyroid gland. Iodine intake can be tied to the soil levels. As a result, iodine deficiency has often occurred in geographical areas where soil iodine is low, especially if combined with low intake of saltwater fish, a good iodine source. In many countries, iodine deficiency has been largely eliminated by adding iodine to salt, or in some cases, to vegetable oils. In the U.S., salt is typically iodized, including much of the salt that finds its way into processed foods. Many multi-vitamin–mineral supplements also contain iodine. Even so, iodine deficiency is still a major problem in some parts of the world where iodine-fortified products are not widely available or are not consumed. In contrast to the parts of the world where iodine deficiency abounds, in other parts of the world, including the U.S., iodine nutrient gets little attention compared to other nutritional issues. Even so, a few people in industrialized countries like the U.S. and Australia still become iodine deficient. There is also some question as to whether mild forms of iodine deficiency occur with some regularity in a number of industrialized countries. Although this issue hasn’t drawn large amounts of attention yet, this may change. A mild deficiency would be a problem, since it could produce serious effects, such as impairment of mental and physical development in children pre- and post birth. If this mild deficiency does occur with some regularity, then in some of these cases iodine supplementation may prove to be a viable response. Nonetheless, it does not seem that the nutrition community thinks that mild iodine deficiency represents a major threat in countries such as the U.S. For the most part, few claims for iodine supplementation have appeared in popular nutrition advertising. Occasionally, there have been scattered claims that iodine supplementation could help obese people lose weight. The rationale is that there can be a connection between poor thyroid function and obesity, and that iodine deficiency can cause poor thyroid function. Although at face value these ideas are true, there is no evidence that most obesity is caused by poor thyroid function due to iodine deficiency.

There has also been some attention given to the idea that iodine supplementation could help women with fibrocystic breast disease. The Internet contains many sites reporting this use, and often the claim is made that the purpose of the iodine supplements is the correction of an iodine deficiency. However, such sites neglect to point out that the work that examines this effect of iodine uses doses that are huge compared to the iodine RDA. This means that iodine is being used as a drug, not as a means to correct a deficiency. The adult RDA for iodine is 150μg but 80μg/kg body weight is a typical dose tested for treatment of fibrocystic breast disease. The main rationale for this use of iodine is a paper published in 1993, which evaluates three previous studies. It is noteworthy that different forms of iodine are used among the studies and even within the studies. Each of the three reviewed studies report subjective or objective improvement in some but not all of the women. In one trial, there are reports of side effects with sodium iodide. The review concludes that molecular iodine works better than sodium iodide or protein-bound iodide. Whether or not these studies constitute enough data to say that relevant women can be safely and effectively treated with molecular iodine is debatable.

Magnesium biomedical research is currently both very exciting and very frustrating. It is exciting because there is the possibility that many people can benefit their health by increasing their magnesium intake. This excitement is reflected by the current and recent past existence of journals solely or mostly dedicated to magnesium research. On the other hand, magnesium research can be frustrating for two reasons. One, funding for nutrition related magnesium research has not been a high priority among potential sources of research support. Two, in many areas of magnesium biomedical research, conclusions are hard to draw due to seemingly contradictory results. In fact, this author found this chapter to be the most difficult to write because hardly any issue is clear cut (including even relative bio-availabilities of different supplement forms). The need for more research on magnesium is blatant, considering that there are a number of reports contending that marginal magnesium deficiency is not uncommon. In addition, a number of health applications are backed by some evidence, but need more research to make a definitive judgment.

Magnesium affects a multitude of physiological processes. The basis for these effects can be put into several categories. One category is that magnesium is needed as a cofactor for a large number of enzyme-catalyzed reactions, especially reactions that require ATP for energy. These ATP-requiring enzymes include those that add phosphate to other enzymes (enzyme phosphorylation) and the formation of the cell signaling molecule cyclic adenosine monophosphate (cAMP). Both these actions regulate many processes within cells. Another broad category of magnesium biochemical function is intracellular free magnesium ions acting as a physiological modulator. These modulations include competing with calcium for entrance into cells via cell membrane channel passage. Generally, mineral competitions are viewed from a negative perspective (i.e., one mineral competes with another for intestinal absorption, which can create a deficiency). In contrast, a competition between calcium and magnesium for cell membrane channels seems to keep many cellular processes in balance. This balancing act may also occur outside cells where magnesium is thought to antagonize calcium promotion of blood clotting. Besides affecting calcium function, magnesium also modulates potassium function, though the effects are quite different. One action of magnesium on potassium is to block channels where potassium can leave cells. This helps maintain the  unequal distribution of intracellular and extracellular potassium in favor of the former. Magnesium also influences this potassium distribution via the need for magnesium for the enzyme Na,K-ATPase. This enzyme pumps sodium out of cells and potassium in. There may also be other ways that magnesium affects potassium distribution. These relationships between magnesium and potassium are manifest in severe magnesium deficiency, where there are body potassium depletion and low serum potassium readings. The impact of intracellular magnesium ion concentrations on cellular processes appears to be far reaching, including effects on the synthesis of membrane phospholipids and lipid second messengers. These synthesis patterns are thought to be altered by low magnesium intake in a manner that can produce profound disturbances on cell function, especially in cardiac cells. Magnesium also stabilizes certain structures by binding to phosphate groups. Examples include binding to the phospholipids in cell membranes and to the phosphates in nucleic acids. Magnesium has indirect antioxidant functions, which are likely mediated by the biochemical functions already mentioned. Although magnesium had not been traditionally viewed as an antioxidant, magnesium-deficient animals show signs of a pro-oxidant state. These signs include: high sensitivity of lipoproteins to oxidation, above normal serum values for molecules associated with a pro-inflammatory state, high values for lipid peroxides, low plasma values for radical scavenging capacity, and activities for antioxidant enzymes, high magnitude of neurogenic oxidative responses in vivo, and poor myocardial tolerance to oxidant stress. In addition, magnesium deficiency in cultured cells can increase production of free radicals and the radical precursor hydrogen peroxide. The exact biochemical mechanisms responsible for each magnesium indirect antioxidant action are hard to identify since there are so many possibilities. Among these is the ability of magnesium to influence the stability and lipid composition of cell membranes, which in turn may influence cell tendencies to produce certain radicals. Another possibility is that since magnesium is needed for regulation of so many processes, some of these processes likely control production of pro-oxidant and antioxidant molecules. A lot of this regulation may be mediated by the pro-inflammatory molecule substance P, which reaches high levels in magnesium-deficient rats. The magnesium functions just discussed only involve about a third of the body’s magnesium. This statement is made because about two thirds of the body’s magnesium is found in bone. This has led to the reasonable supposition that magnesium function includes a role or roles in bone health. The exact nature of this function has not been clear, but there is evidence for several possible functions. These functions include magnesium affecting hydroxyapatite crystal structure and controlling bone cell proliferation. Furthermore, magnesium antioxidant effects could restrict bone resorption. In addition, magnesium may affect bone health via effects that occur outside the bone. For example, magnesium affects secretion of parathyroid hormone (PTH) and insulin-like growth factor, both of which influence bone metabolism. The effects of magnesium deficiency on PTH are unusual. As a deficiency progresses, serum PTH levels can rise or fall at different times, but during the rise, there can be poor receptor reactivity to the hormone. 

Substantially low serum magnesium usually indicates magnesium deficiency due to excess renal losses. Examples of situations that can cause magnesium depletion are as follows:

• Very low calorie intakes (including self-imposed situations such as anorexia nervosa and so-called protein-sparing fasts)
• Parathyroid disease
• Chronic alcoholism
• Chronic diarrhea
• Certain drugs, especially some diuretics, certain antibiotics, and selected cancer chemotherapy drugs such as cisplatin
• Gitelman syndrome
• Uncontrolled diabetes (though body magnesium redistribution can also be a factor) Besides being caused by renal magnesium losses, magnesium deficiency can also occur due to poor absorption, though this reason is less common.22 Examples of causes of poor magnesium absorption are gastrointestinal problems, such as malabsorption disorders as well as excessive vomiting and diarrhea. On the basis of experimental magnesium depletion in human volunteers, the clinical manifestations of magnesium deficiency include anorexia, nausea, vomiting, lethargy, weakness, personality change, tetany (e.g., positive Trousseau’s or Chvostek’s sign or spontaneous carpopedal spasm), and tremor and muscle fasciculations. The neurological signs, particularly tetany, correlate with the development of low serum calcium and potassium. In cases of substantial hypomagnesemia, oral magnesium supplements can often be effective, though in very severe cases, parenteral administration can be justified. It can also be important to treat the root cause of the problem, if possible. A first clue to the cause can be a measure of urinary magnesium to distinguish a case of excessive losses from poor absorption.

BLOOD PRESSURE

In theory, magnesium function could affect blood pressure via a number of different mechanisms. For example, magnesium effects on the sodium–potassium pump and on calcium ion flow can affect vascular tone and reactivity as well as dilation of blood vessels. Blood pressure could also be affected by the magnesium antioxidant actions named in the Function section, since oxidant stress is thought to contribute to hypertension. In addition, magnesium affects secretion of hormones, which can impact blood pressure. In light of these possible functional connections of magnesium to blood pressure, it is not surprising that in animals, magnesium deficiency can promote hypertension. However, these studies may depict situations that are more severe than would occur in most humans with hypertension. Still, a good number of human epidemiological studies show correlations between magnesium intake and blood pressure.101–104 In addition, there are some correlations between parameters of magnesium status assessment and blood pressure, though the results do not give a totally clear-cut relationship.105–109 Even with good results, epidemiological relationships may not actually reflect a major role for typical variations in magnesium intake and blood pressure. This statement is made because highmagnesium diets are typically high in other minerals as well as phytochemicals that could affect blood pressure. Thus, the apparent relationships of blood pressure with magnesium may just be a coincidental relationship that reflects other dietary patterns. One way to tease out what, if any, relationship magnesium has to blood pressure is the use of magnesium supplementation studies. Unfortunately, studies of magnesium supplementation and blood pressure have not yielded consistent results. One problem can simply be that many studies have a small sample size for a blood pressure study. Blood pressure studies typically require a good number of subjects because the main end point is not very stable, and it is affected by many factors including emotional ones. 

Another reason for the variable results could be that magnesium intake may impact blood pressure only under a combination of certain conditions. Such a circumstance combination could be as follows:

• Subjects initially have at least a marginal magnesium deficiency.
• The deficiency is corrected by the given dose of the given magnesium complex.
• The subjects initially have high blood pressure, but it is not so far advanced that physical changes do not allow magnesium to make an impact.
• The high blood pressure is due to a specific process that responds to magnesium. For the last issue, one proposition is that the specific process involves the renin–angiotensin aldosterone system. Another proposition, based on a study comparing responders and nonresponders, is that reduction in intra-erythrocyte sodium is a discriminating factor. The above-proposed scenario is supported by much of the research that has been done so far. However, in some cases, the study publications do not supply enough information to judge if this scenario is holding, especially for the last contention. Examples of where the scenario is supported, at least in part, are as follows:
• Virtually all studies on magnesium supplementation of people with normal blood pressure have not shown an effect.
• One study reports that responders to magnesium tended to have recently acquired hypertension.
• Some studies reporting no effect on blood pressure also report no effect on some markers of magnesium status.
• Some of the studies showing improvements in blood pressure also report increases in serum or plasma magnesium.
• One study separates responders and non-responders by starting urinary magnesium, while another study correlates rises in serum magnesium and falls in blood pressure. A number of studies with positive results have used forms of magnesium that are considered well absorbed or have used above-RDA doses of magnesium oxide. In a study where responders and non-responders are compared, discriminations can be found for starting plasma renin activities; in another study, discriminations can be found based on the reduction in intra-erythrocyte sodium. This response model may not be 100% true but it does seem to have some explanatory power. Even so, not all studies directly support the model, though they may not actually contradict it. For example, magnesium aspartate supplementation lowers blood pressure in a study where there is no predictive value for starting magnesium status or dietary intake. However, dietary intake does not necessarily predict status if some types of hypertensive subjects have high magnesium needs. In addition, in this study, magnesium intake may have been low in most subjects, which would mean that most would be good responders. The last comment can also apply to urinary magnesium data.

SERUM LIPIDS IN NON-DIABETIC SUBJECTS

In some animal studies, moderately high magnesium intake affects serum or tissue lipid compositions in a manner that would be considered beneficial in humans. This effect does not necessarily involve prevention of a magnesium deficiency. One mechanism could be magnesium binding to lipids and bile salts in the GI tract and reducing their absorption. There also could be separate actions of magnesium on serum lipids that does involve correction of a marginal magnesium deficiency. Along these lines, in a few studies, serum- or platelet-ionized magnesium values show inverse correlations with certain serum lipid values. This could mean that marginal magnesium deficiency affects serum cholesterol. Alternatively, it could reflect a comparison between moderately high magnesium intake vs. low to adequate intake. Another possibility is that the correlations just reflect other dietary factors that coincide with high magnesium intake. There are two studies by overlapping authors that look at the response of serum lipids to increased magnesium intake. In these studies, which each involve about 400 subjects, magnesium intake is increased from about 400 mg/day to about 1000 mg by dietary intervention. The increased intake produces about a 10% decrease in serum cholesterol, LDL cholesterol, and triglycerides. Unfortunately, it is hard to decide whether these effects are due to magnesium alone, other dietary factors, or the combination of magnesium plus other dietary factors. This is one reason why supplementation studies can often make for cleaner results than diet intervention, though the latter can sometimes be the more effective treatment. There is one existing study on high-dose magnesium oxide that does not show lowered serum cholesterol. In the just discussed pair of studies, HDL cholesterol is not affected in the total subject population, but rises in subjects with initially low values for serum magnesium. This could mean that the effect on HDL cholesterol, unlike the effects on the other lipid parameters, involves correction of marginal magnesium deficiency. Although the average magnesium intake of the study subjects is reported to be above the adult RDAs, some individual subjects could have moderately low intake. Possibly, the HDL effect only occurs in the subjects with initially low magnesium intake, or in those with unusually high magnesium needs. Alternatively, low serum magnesium may just be a marker for a poor diet from other perspectives, which is corrected by the non-magnesium aspects of the diet intervention.

PREVENTION OF CARDIOVASCULAR DISEASE IN NON-DIABETIC SUBJECTS

The possible relationship of magnesium to serum lipids and blood pressure would impact risk of cardiovascular diseases. In addition, magnesium could affect this risk via its antioxidant and anti-inflammatory actions. For example, magnesium-deficient rats have lipoproteins with high susceptibility to atherosclerosis-related oxidation. Magnesium also impacts cardiac muscle integrity, in part via regulatory effects on antioxidant enzymes, and cardiac phospholipid composition.6 Furthermore, magnesium restricting of calcium movements can affect heart beat, vasospasm tendencies, platelet aggregation, vasodilatation, and other cardiovascular-relevant processes. There is also an idea, though still controversial, that magnesium is part of a pre-ischemia conditioning process that promotes later heart recovery from ischemic stress. A number of epidemiological studies have found correlations between magnesium intake, or blood magnesium status indicators, and risk of certain types of cardiovascular disease including stroke and ischemic heart disease. These studies have included analysis of geographical regions with high magnesium contents in drinking water. In one notable recent epidemiological study, done in Honolulu, initial magnesium intake is correlated with later risk of coronary events in over 7000 men for over 15 years. There have also been autopsy studies showing lower myocardial and skeletal magnesium contents in subjects dying from ischemic heart disease rather than accidents. However, as already noted for other contexts, these studies do not distinguish direct effects of magnesium intake from magnesium intake just being a marker for other good dietary habits. On the other hand, studies in experimental animals with induced atherosclerosis show directly that low magnesium intake can enhance atherosclerosis progress. However, such studies usually use more severe magnesium deficiency than is common in humans.

DIABETES

Several lines of reasoning suggest that marginal magnesium deficiency occurs in a good number of diabetic subjects. For example, a number of studies report low serum magnesium values in many, though not all, subjects with type 1 or type 2 diabetes. The causes of the low serum magnesium are thought to be high renal magnesium loss plus some magnesium distribution away from the blood into certain tissues. Another connection between diabetes and magnesium is that erythrocyte- ionized magnesium, though not determined in all that many diabetic subjects, tends to show low values. This can occur even in subjects with normal serum magnesium values. Similarly, low serum-ionized magnesium can be found in type 2 diabetic adults and children, even with normal mean serum total magnesium values. There is also a report of low muscle magnesium contents in type 1 diabetic subjects. Finally, a series of studies in diabetic subjects show inverse correlations between serum magnesium and measures relevant to primary or secondary symptoms of diabetes. If magnesium status is actually affecting the symptoms listed in these effects may be related, at least partly, to insulin sensitivity. Magnesium function could have mechanistic connections to insulin sensitivity via magnesium effects on insulin receptor binding, activity of the receptors after binding, and signaling inside the cells.