6

Magnesium

BACKGROUND INFORMATION

Overview

Total body magnesium (Mg) content is approximately 25 g (1,000 mmol), of which 50 to 60 percent resides in bone in the normal adult. One-third of skeletal magnesium is exchangeable, and it is this fraction that may serve as a reservoir for maintaining a normal extracellular magnesium concentration (Elin, 1987). Extracellular magnesium accounts for about 1 percent of total body magnesium. The normal serum magnesium concentration is 0.75 to 0.95 mmol/liter (1.8 to 2.3 mg/dl).

Magnesium is a required cofactor for over 300 enzyme systems (Wacker and Parisi, 1968). It is required for both anaerobic and aerobic energy generation and for glycolysis, either indirectly as a part of the Mg-ATP complex or directly as an enzyme activator (Garfinkel and Garfinkel, 1985). Magnesium has also been shown to be required for mitochondria to carry out oxidative phosphorylation (Wacker and Parisi, 1968). The mitochondrial enzymes utilize the magnesium chelate of ATP and ADP as the actual substrates for phosphate transfer reactions.

Magnesium transport into or out of cells appears to require the presence of carrier-mediated transport systems (Gunther, 1993; Romani et al., 1993). The efflux of magnesium from the cell is coupled to sodium transport and requires energy. Magnesium influx also appears to be linked to sodium and bicarbonate transport but



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DRI DIETARY REFERENCE INTAKES FOR Calcium, Phosphorus, Magnesium, Vitamin D, and Fluoride 6 Magnesium BACKGROUND INFORMATION Overview Total body magnesium (Mg) content is approximately 25 g (1,000 mmol), of which 50 to 60 percent resides in bone in the normal adult. One-third of skeletal magnesium is exchangeable, and it is this fraction that may serve as a reservoir for maintaining a normal extracellular magnesium concentration (Elin, 1987). Extracellular magnesium accounts for about 1 percent of total body magnesium. The normal serum magnesium concentration is 0.75 to 0.95 mmol/liter (1.8 to 2.3 mg/dl). Magnesium is a required cofactor for over 300 enzyme systems (Wacker and Parisi, 1968). It is required for both anaerobic and aerobic energy generation and for glycolysis, either indirectly as a part of the Mg-ATP complex or directly as an enzyme activator (Garfinkel and Garfinkel, 1985). Magnesium has also been shown to be required for mitochondria to carry out oxidative phosphorylation (Wacker and Parisi, 1968). The mitochondrial enzymes utilize the magnesium chelate of ATP and ADP as the actual substrates for phosphate transfer reactions. Magnesium transport into or out of cells appears to require the presence of carrier-mediated transport systems (Gunther, 1993; Romani et al., 1993). The efflux of magnesium from the cell is coupled to sodium transport and requires energy. Magnesium influx also appears to be linked to sodium and bicarbonate transport but

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DRI DIETARY REFERENCE INTAKES FOR Calcium, Phosphorus, Magnesium, Vitamin D, and Fluoride by a different mechanism. The molecular characteristics of the magnesium transport proteins have not been described. Magnesium transport in mammalian cells may be influenced by hormonal and pharmacological factors including β-agonists, growth factors, and insulin (Gunther, 1993; Hwang et al., 1993; Romani et al., 1993). It has been suggested that a hormonally regulated magnesium uptake system controls intracellular magnesium concentration in cellular compartments. The magnesium concentration in these compartments would then serve to regulate the activity of magnesium-sensitive enzymes. Magnesium presence is important for maintaining an adequate supply of purine and pyrimidine nucleotides required for the increased DNA and RNA synthesis that occurs during cell proliferation (Rubin, 1975; Switzer, 1971). Replicating cells must be able to synthesize new protein, and this synthesis has been reported to be highly sensitive to magnesium depletion. Many hormones, neurotransmitters, and other cellular effectors regulate cellular activity via the adenylate cyclase system, and the activation of adenylate cyclase requires the presence of magnesium. There is also evidence for magnesium binding through which magnesium directly increases adenylate cyclase activity (Maguire, 1984). Magnesium is necessary for sodium, potassium-ATPase activity, which is responsible for active transport of potassium (Dorup and Clausen, 1993). Magnesium regulates the outward movement of potassium in myocardial cells (Matsuda, 1991). The arrhythmogenic effect of magnesium deficiency may be related to magnesium's role in maintaining intracellular potassium. Magnesium has been called “nature's physiological calcium channel blocker” (Iseri and French, 1984). During magnesium depletion, intracellular calcium rises. Since calcium plays an important role in skeletal and smooth muscle contraction, a state of magnesium depletion may result in muscle cramps, hypertension, and coronary and cerebral vasospasms. Magnesium depletion is found in a number of diseases of cardiovascular and neuromuscular function, in malabsorption syndromes, in diabetes mellitus, in renal wasting syndromes, and in alcoholism (Ma et al., 1995). These observations have led to studies regarding the role of inadequate magnesium intake in the development of disease, as opposed to abnormal handling of magnesium caused by the disease process. It is important to ensure that such evaluations are undertaken in apparently normal individuals for whom dietary intake is the primary independent variable.

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DRI DIETARY REFERENCE INTAKES FOR Calcium, Phosphorus, Magnesium, Vitamin D, and Fluoride Physiology of Absorption, Metabolism, and Excretion In both children and adults, fractional intestinal magnesium absorption is inversely proportional to the amount of magnesium ingested (Kayne and Lee, 1993). In balance studies, under controlled dietary conditions in healthy older men, an average of 380 mg (15.8 mmol)/day of ingested magnesium resulted in net absorption of approximately 40 to 60 percent; true absorption ranged from 51 to 60 percent for various foodstuffs when subjects were on a constant diet (Schwartz et al, 1984). Net absorption has been estimated to be 15 to 36 percent at higher daily intakes (550 to 850 mg [22.9 to 35.4 mmol]) and with varying levels of dietary bran and oxalate (Schwartz et al., 1986). Magnesium is absorbed along the entire intestinal tract, but the sites of maximal magnesium absorption appear to be the distal jejunum and ileum (Kayne and Lee, 1993). Both an unsaturable passive and saturable active transport system for magnesium absorption may account for the higher fractional absorption at low dietary magnesium intakes (Fine et al., 1991a). A principal factor that regulates intestinal magnesium transport has not been described. Vitamin D and its metabolites 25-hydroxyvitamin D (25(OH)D) and 1,25-dihydroxyvitamin D (1,25(OH)2D) enhance intestinal magnesium absorption to a small extent (Hardwick et al., 1991; Krejs et al., 1983). Recently, a low magnesium diet in rats was shown to increase intestinal calbindin-D9k. Although these preliminary data suggest a role for this vitamin D-dependent, calcium-binding protein in intestinal magnesium absorption, the severe magnesium deficiency imposed may have resulted in renal damage (not described) (Hemmingsen et al., 1994). The kidney is the principal organ involved in magnesium homeostasis (Quamme and Dirks, 1986). The renal handling of magnesium in humans is a filtration-reabsorption process; there is no tubular secretion of magnesium. Approximately 65 percent of filtered magnesium is reabsorbed in the loop of Henle and 20 to 30 percent in the proximal convoluted tubule (Quamme and Dirks, 1986). Magnesium reabsorption in the proximal convoluted tubule appears to be passive; it follows changes in salt and water reabsorption and is associated with the rate of fluid flow. In the loop of Henle, there appears to be an additional active transport system: a decrease in magnesium reabsorption in this segment is independent of sodium chloride transport in either hypermagnesemia or hypercalcemia (Quamme, 1989). In vivo studies in animals and humans, however, have demonstrated a tubular maximum for magnesium that proba-

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DRI DIETARY REFERENCE INTAKES FOR Calcium, Phosphorus, Magnesium, Vitamin D, and Fluoride bly reflects a composite of these tubular reabsorptive processes (Quamme and Dirks, 1986). During experimental magnesium depletion in humans, magnesium decreases in the urine to very low levels (< 20 mg [1 mmol]/day) within 3 to 4 days (Fitzgerald and Fourman, 1956; Heaton, 1969; Shils, 1969). Despite the close regulation of magnesium by the kidney, no one has described a hormone or factor that is responsible for renal magnesium homeostasis. Because patients with either primary hyper- or hypoparathyroidism usually have normal serum magnesium concentrations and a normal tubular maximum for magnesium, it is probable that parathyroid hormone (PTH) is not an important regulator of magnesium homeostasis (Rude et al., 1980). Glucagon, calcitonin, and ADH affect magnesium transport in the loop of Henle in a manner similar to PTH, but the physiological relevance of these actions is unknown (Quamme and Dirks, 1986). Little is known about the effect of vitamin D on renal magnesium handling. Excessive alcohol intake has been shown to cause renal magnesium wasting, which, if a diet is marginal in magnesium content, could place an individual at risk for magnesium depletion. Indeed, nearly all chronic alcoholics have symptoms of magnesium depletion (Abbott et al., 1994). However, the evidence does not substantiate the suggestion that alcoholism is due to magnesium deficiency. A growing list of medications has been found to result in increased renal magnesium excretion. Diuretics commonly used in the treatment of hypertension, heart failure, and other edematous states may cause hypermagnesuria (Ryan, 1987). Factors Affecting the Magnesium Requirement Bioavailability As mentioned previously, net absorption of dietary magnesium in a typical diet is approximately 50 percent. High levels of dietary fiber from fruits, vegetables, and grains decrease magnesium absorption and/or retention (Siener and Hesse, 1995; Wisker et al., 1991). Men consuming 355 mg (14.8 mmol)/day of magnesium were in positive magnesium balance on a low-fiber (9 g/day) diet but in negative balance on a high-fiber (59 g/day) diet (Kelsay et al., 1979). Similar trends were observed in young women consuming 243 to 252 mg (10.0 to 10.5 mmol)/day of magnesium and receiving a lower fiber (23 g/day) versus higher fiber (39 g/day) diet (Wisker et al., 1991).

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DRI DIETARY REFERENCE INTAKES FOR Calcium, Phosphorus, Magnesium, Vitamin D, and Fluoride Nutrient-Nutrient Interactions Phosphorus. Many foods high in fiber contain phytate, which may decrease intestinal magnesium absorption, probably by binding magnesium to phosphate groups on phytic acid (Brink and Beynen, 1992; Franz, 1989; Wisker et al., 1991). The ability of phosphate to bind magnesium may explain decreases in intestinal magnesium absorption seen in subjects on high phosphate diets (Franz, 1989; Hardwick et al., 1991; Reinhold et al., 1991). Calcium. Most human studies of effects of dietary calcium on magnesium absorption have shown no effect (Fine et al., 1991a; Hardwick et al., 1991; Spencer et al., 1978b), but one has reported decreased magnesium absorption rates (Greger et al., 1981). Perfusion of the jejunum of normal subjects with 0 to 800 mg (0 to 20 mmol) calcium had no effect on magnesium absorption (Brannan et al., 1976). Increased calcium intake did not affect magnesium balance when as much as 2,000 mg (50 mmol)/day of calcium was given to adult men (Spencer et al., 1978b, 1994), or when an additional 1,000 mg (25 mmol)/day of calcium was given to adolescents (Andon et al., 1996). Magnesium intake ranging from 241 to 826 mg (10 to 34.4 mmol)/day did not alter calcium balance at either 241 mg (10 mmol) or 812 mg (20.3 mmol)/day of calcium (Spencer et al., 1994). However, intakes of calcium in excess of 2,600 mg (65 mmol)/day have been reported to decrease magnesium balance (Greger et al., 1981; Seelig, 1993). Several studies have found that high sodium and calcium intake may result in increased renal magnesium excretion (Kesteloot and Joossens, 1990; Martinez et al., 1985; Quamme and Dirks, 1986), which may be secondary to the interrelationship of the proximal tubular reabsorption of filtered sodium, calcium, and magnesium (Quamme and Dirks, 1986). Overall, at the dietary levels recommended in this report, the interaction of magnesium with calcium is not of concern. Protein. Dietary protein may also influence intestinal magnesium absorption; magnesium absorption is lower when protein intake is less than 30 g/day (Hunt and Schofield, 1969). A higher protein intake (94 g/day) may increase renal magnesium excretion (Mahalko et al., 1983), presumably because an increased acid load increases urinary magnesium excretion (Wong et al., 1986). However, the increased urinary magnesium excretion did not change overall magnesium retention, which indicates an ability of subjects to adapt to this level of

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DRI DIETARY REFERENCE INTAKES FOR Calcium, Phosphorus, Magnesium, Vitamin D, and Fluoride protein given the level of magnesium provided (258 mg [10.8 mmol]/day). Other studies in adolescents have shown improved magnesium absorption and retention when protein intakes were higher (93 versus 43 g protein/day) (Schwartz et al., 1973). Special Populations Physical Activity. Dietary magnesium intake in athletes has been reported to be at or above recommended intakes (Clarkson and Haymes, 1995; Kleiner et al., 1994; Niekamp and Baer, 1995), presumably due to their higher food intake. Plasma/serum magnesium concentrations have been reported to fall with chronic endurance exercise activity, while red blood cell values appear to rise (Deuster and Singh, 1993). Although the decrease in plasma magnesium has been suggested to reflect magnesium depletion in athletes (Clarkson and Haymes, 1995), no clear demonstration of magnesium depletion directly related to exercise has been shown. Magnesium supplements did not enhance performance in a study of marathon runners (Terblanche et al., 1992). Intake of Magnesium The U.S. Department of Agriculture Continuing Survey of Food Intakes by Individuals (CSFII) in 1994, adjusted by the method of Nusser et al. (1996), indicated that the mean daily magnesium intake in males aged 9 and older was 323 mg (13.5 mmol) (fifth percentile = 177 mg [7.4 mmol]; fiftieth percentile = 310 mg [12.9 mmol]; ninety-fifth percentile = 516 mg [21.5 mmol]) (Cleveland et al., 1996) (see Appendix D for data tables). The mean daily intake for females aged 9 and older was 228 mg [9.5 mmol] (fifth percentile = 134 mg [5.6 mmol]; fiftieth percentile = 222 mg [9.3 mmol]; ninety-fifth percentile = 342 mg [14.3 mmol]). In both sexes, intake decreased at age 70 and older. These intakes were similar to those found in the National Health and Nutrition Examination Survey (NHANES) III from 1988–1991 (Alaimo et al., 1994). National survey data for Canada are not currently available. Other surveys have reported lower intakes in both men and women (Hallfrisch and Muller, 1993). The NHANES III study demonstrated ethnic differences in intake. In that report, non-Hispanic black subjects were found to consume less than either non-Hispanic white or Hispanic subjects. Another study demonstrated that elderly Hispanic males consumed a

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DRI DIETARY REFERENCE INTAKES FOR Calcium, Phosphorus, Magnesium, Vitamin D, and Fluoride mean of 237 ± 62 mg (9.9 ± 2.6 mmol)/day, while Hispanic females consumed a mean of 232 ± 71 mg (9.7 ± 3.0 mmol)/day (Pluckebaum and Chavez, 1994). Food and Water Sources of Magnesium Magnesium is ubiquitous in foods, but the magnesium content of foods varies substantially. Because chlorophyll is the magnesium chelate of porphyrin, green leafy vegetables are rich in magnesium. Foods such as unpolished grains and nuts also have high magnesium content, whereas meats, starches, and milk are more intermediate. Analyses from the 1989 Total Diet Study of the U.S. Food and Drug Administration indicated that approximately 45 percent of dietary magnesium was obtained from vegetables, fruits, grains, and nuts, whereas about 29 percent was obtained from milk, meat, and eggs (Pennington and Young, 1991). Refined foods generally have the lowest magnesium content. With the increased consumption of refined and/or processed foods, dietary magnesium intake in the United States appears to have decreased over the years (Marier, 1986). Total magnesium intake is usually dependent on caloric intake, which explains the higher intake levels seen in the young and in adult males and the lower levels seen in women and in the elderly. Water is a variable source of intake; typically, water with increased “hardness” has a higher concentration of magnesium salts. Since this varies depending on the area from which water comes, much like fluoride, and the manner in which it is stored, magnesium intake from water is usually not estimated except in controlled diet studies. This omission may lead to underestimating total intake and its variability. Intake from Supplements Based on a national survey in 1986, 14 percent of men and 17 percent of women in the United States took supplements containing magnesium (Moss et al., 1989). Approximately 8 percent of young children (2 to 6 years of age) used magnesium-containing supplements. Women and men who use magnesium supplements took similar doses, about 100 mg (4.2 mmol)/day, although the ninety-fifth percentile of intake was somewhat higher for women, 400 mg (16.7 mmol)/day, than for men, who were taking 350 mg (14.6 mmol)/day. Children who took magnesium had a median daily intake of 23 mg (1 mmol) and a ninety-fifth percentile daily supplemental intake of 117 mg (4.9 mmol).

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DRI DIETARY REFERENCE INTAKES FOR Calcium, Phosphorus, Magnesium, Vitamin D, and Fluoride Effects of Inadequate Magnesium Intake Severe magnesium depletion leads to specific biochemical abnormalities and clinical manifestations that can be easily detected. Hypocalcemia is a prominent manifestation of magnesium deficiency in humans (Rude et al., 1976). Magnesium deficiency must become moderate to severe before symptomatic hypocalcemia develops. Even mild degrees of magnesium depletion, however, may result in a significant fall in the serum calcium concentration, as demonstrated in a 3-week study of dietary-induced experimental human magnesium depletion (Fatemi et al., 1991). Magnesium is also important in vitamin D metabolism and/or action. Patients with hypocalcemia and magnesium deficiency are resistant to pharmacological doses of vitamin D, 1α hydroxyvitamin D, and 1,25(OH) 2D (for a review, see Fatemi et al. [1991]). Neuromuscular hyperexcitability is the initial problem cited in individuals who have or are developing magnesium deficiency (Rude and Singer, 1980). Latent tetany, as elicited by a positive Chvostek's and Trousseau 's sign, or spontaneous carpal-pedal spasm may be present. Frank, generalized seizures may also occur. Although hypocalcemia may contribute to the neurological signs, hypomagnesemia without hypocalcemia may result in neuromuscular hyperexcitability. There is emerging evidence that habitually low intakes of magnesium and resulting abnormal magnesium metabolism are associated with etiologic factors in various metabolic diseases. In considering data from such studies, it is important to separate the identification of associations between the effect of the disease on magnesium status from the effect of inadequate intake on magnesium status and subsequent risk of disease. The specific disease states in which magnesium status is implicated are discussed in the following sections. Cardiovascular In normal subjects, experimental magnesium depletion results in increased urinary thomboxane concentration, angiotensin II-induced plasma aldosterone levels, and blood pressure—indicating a potential effect of magnesium deficiency on vascular function (Nadler et al., 1993; Rude et al., 1989). Magnesium depletion is associated with cardiac complications, including electrocardiographic changes, arrhythmias, and increased sensitivity to cardiac glycosides (Rude, 1993). Atrial and ventricular premature systoles, atrial fibrillation, and ventricular tachycardia and fibrillation have been re-

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DRI DIETARY REFERENCE INTAKES FOR Calcium, Phosphorus, Magnesium, Vitamin D, and Fluoride ported in hypomagnesemic patients (Hollifield, 1987; Rude, 1993). Significantly higher retention rates after magnesium load tests have been reported in patients with ischemic heart disease compared to normal controls (Rasmussen et al., 1988). This suggests that a low magnesium concentration may also play a role in cardiac ischemia. However, the extent to which the disease modifies the indicators of magnesium deficiency rather than the deficiency resulting in the disease manifestations varies with the symptom and the individual studied. The development of atheromatous disease has been associated with magnesium in epidemiological observational studies. Areas with increased water hardness (which is due to high calcium and magnesium content) tend to have lower cardiovascular death rates (Altura et al., 1990; Hammer and Heyden, 1980; Leoni et al., 1985; Luoma et al., 1983; Neri and Johansen, 1978; Neri et al., 1985; Rubenowitz et al., 1996). Problems with evaluating epidemiological studies have been identified (Comstock, 1979), and some studies have not found such an association (Hammer and Heyden, 1980; Leoni et al., 1985). However, as presented by Tucker (1996) and Beaton (1996), a congruence of positive studies may suggest an association of dietary intake and disease. Animals on low magnesium diets develop arterial wall degeneration and calcification as well as hypertriglyceridemia, hypercholesterolemia, and atherosclerosis (Altura et al., 1990; Orimo and Ouchi, 1990). Controlled human studies that support this relationship are lacking. Magnesium depletion in patients with cardiac diseases may be due to concomitant medications, such as diuretics, as well as to dietary magnesium depletion. Although cardiac arrhythmia may be associated with the primary cardiac disorders, magnesium depletion may further predispose to cardiac arrhythmias by decreasing intracellular potassium. Accumulation of magnesium may reduce the morbidity and mortality of patients in the period following myocardial infarction. Two large, placebo-controlled, randomized, double-blind studies of patients with myocardial infarction have shown that intravenous magnesium therapy reduces the incidence of therapy-requiring arrhythmias to approximately one-half that seen in control patients (Antman, 1996; Seelig and Elin, 1996). In one study of patients with acute myocardial infarction, magnesium therapy given before thrombolytic therapy decreased mortality by 24 percent (Woods and Fletcher, 1994). Another large study of myocardial infarction did not find favorable effects of magnesium that was administered after thrombolytic therapy (ISIS-4, 1995). Debate currently centers over

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DRI DIETARY REFERENCE INTAKES FOR Calcium, Phosphorus, Magnesium, Vitamin D, and Fluoride the time of administration of magnesium in terms of its favorable effects (for review see Antman [1996]). Evidence does not support the concept that the patients were magnesium deficient prior to onset of the acute attack, only that magnesium therapy was beneficial to outcome. Blood Pressure Epidemiologic evidence suggests that magnesium may play an important role in regulating blood pressure (Ascherio et al., 1992; Joffres et al., 1987; Ma et al., 1995; McCarron, 1983; Witteman et al., 1989). In these studies, populations that have low dietary intake of magnesium have been reported to have an increased incidence of hypertension. In one of the earlier studies, dietary intake of magnesium in 44 normotensive subjects was significantly greater than intake in 46 untreated hypertensive subjects (McCarron, 1983). In the Honolulu heart study, magnesium intake was the dietary variable that had the strongest association with blood pressure (Joffres et al., 1987). In another nutritional survey of 58,218 Caucasian women, those who reported intakes of less than 200 mg (8.33 mmol)/day of magnesium had a significantly higher risk of developing hypertension than did women whose intakes were greater than 300 mg (12.5 mmol)/day. In a large prospective study of 30,681 men without diagnosed hypertension, dietary magnesium intake was inversely related to systolic and diastolic blood pressure and to change in blood pressure during a 4-year follow-up period (Ascherio et al., 1992). In this study, however, only dietary fiber had an independent inverse association. Another study of 15,248 subjects found that dietary magnesium intake was inversely associated with systolic and diastolic blood pressure (Ma et al., 1995). Intervention studies with magnesium therapy for hypertensive patients have led to conflicting results. Several studies have shown a positive blood-pressure-lowering effect of magnesium supplements (Dyckner and Wester, 1983; Geleijnse et al., 1994; Motoyamo et al., 1989; Widman et al., 1993; Witteman et al., 1994); others have not (Cappuccio et al., 1985; Sacks et al., 1995; Wallach and Verch, 1986; Yamamoto et al., 1995; Zemel et al., 1990). Other dietary factors may also play a role. A recent study demonstrated that a diet of fruits and vegetables, which increased magnesium intakes from an average of 176 mg (7.3 mmol)/day to 423 mg (17.6 mmol)/day, significantly lowered blood pressure in adults who were not classified as hypertensive (systolic blood pressure < 140 mm Hg; diastolic blood pressure < 95 mm Hg ) (Appel et al., 1997). The addition of

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DRI DIETARY REFERENCE INTAKES FOR Calcium, Phosphorus, Magnesium, Vitamin D, and Fluoride nonfat dairy products to the high fruit and vegetable diet, which increased calcium intake as well, resulted in further lowering of blood pressure. Potassium intake was also greatly increased in both dietary regimens studied. One study of hypertensive patients revealed low serum magnesium concentrations (Albert et al., 1958). No difference was detected in serum magnesium levels in other studies, however (Gadallah et al., 1991; Tillman and Semple, 1988). In patients with essential hypertension, free magnesium levels in erythrocytes were inversely related to both the systolic and diastolic blood pressure (Resnick et al., 1984). It is unclear whether the decrease in serum magnesium concentration was due to magnesium depletion or to pathophysiological events that lead to hypertension. The possible relationship between hypertension and magnesium depletion is an important consideration, as the two coexist in a high proportion of individuals with diabetes and alcoholism (Resnick et al., 1991). However, the role of long-term dietary intake of magnesium in the prevalence of hypertension seen in the United States and Canada has not been established. Skeletal Growth and Osteoporosis Magnesium plays a major role in bone and mineral homeostasis and can also directly affect bone cell function as well as influence hydroxyapatite crystal formation and growth (Cohen, 1988). Magnesium deficiency may be a risk factor for postmenopausal osteoporosis. Significant reductions in the serum magnesium and bone mineral content (BMC), but not red blood cell magnesium concentration or bone magnesium content, have been described in women with postmenopausal osteoporosis compared to age-matched controls (Reginster et al., 1989). No correlations were found in a 4-year clinical trial of magnesium intake and BMC in pre- and postmenopausal women consuming about 250 mg (10.4 mmol)/day of magnesium (Freudenheim et al., 1986), or in four of five skeletal sites measured in postmenopausal women also consuming an average of 253 mg ± 11 mg (10.5 ± 0.4 mmol)/day of magnesium (Angus et al., 1988). In contrast, BMC of the radius in postmenopausal Japanese-American women was weakly positively correlated with magnesium intake (Yano et al., 1985), while elderly women who consumed less than 187 mg (7.8 mmol)/day had a significantly lower bone mineral density (BMD) compared with women whose average magnesium intake from diet was more than 187 mg (7.8 mmol)/day (Tucker et al., 1995).

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DRI DIETARY REFERENCE INTAKES FOR Calcium, Phosphorus, Magnesium, Vitamin D, and Fluoride Calculation: (7.5 kg/270 days) × 470 mg/kg × 2.5 = 33 mg/day (rounded up to 35) This value is to be added to the EAR for the woman's age group. EAR for Pregnancy All ages + 35 mg (1.5 mmol)/day Based on the 1994 CSFII intake data for 33 pregnant women and adjusted for day-to-day variation (Nusser et al., 1996), the median magnesium intake of pregnant women is 292 mg (12.2 mmol)/day, and the seventy-fifth percentile of intake is 332 mg (13.8 mmol)/day (see Appendix D). The EAR of 290 mg (12.1 mmol)/day for pregnant women ages 19 through 30 years and the EAR of 300 mg (12.7 mmol)/day for pregnant women ages 31 through 50 would fall close to the median of magnesium intake. The seventy-fifth percentile of intake, 332 mg (15.3 mmol)/day, is near the magnesium EAR of 335 mg (15.2 mmol)/day for pregnant women ages 14 through 18 years. Determination of the RDA: Pregnancy The variance in requirements cannot be determined from the available data for pregnant women. Thus a CV of 10 percent is assumed. This results in an increase in the RDA for pregnancy for magnesium as follows: EAR for Pregnancy   14 through 18 years 335 mg (14.0 mmol)/day 19 through 30 years 290 mg (12.7 mmol)/day 31 through 50 years 300 mg (12.7 mmol)/day RDA for Pregnancy   14 through 18 years 400 mg (16.7 mmol)/day 19 through 30 years 350 mg (15.0 mmol)/day 31 through 50 years 360 mg (15.0 mmol)/day Special Considerations Diabetes Mellitus. Infants of mothers with Type I insulin-dependent diabetes mellitus are at risk of hypocalcemia and hypomagnesemia, possibly due to magnesium deficiency in the mother (Mimouni et al., 1986; Tsang et al., 1976). Lower intracellular magnesium concentrations have been recently reported in women with

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DRI DIETARY REFERENCE INTAKES FOR Calcium, Phosphorus, Magnesium, Vitamin D, and Fluoride gestational diabetes (Bardicef et al., 1995). It is not known whether this is a sequellae of the condition or a factor in its causation. Pregnant Adolescents, Multiparous Births. A prospective study of 53 nulliparous teenagers found no difference in serum or erythrocyte magnesium concentrations between those pregnant adolescents who developed pregnancy-induced hypertension and those who had normal term deliveries, with both groups having decreasing concentrations of magnesium over gestation (Boston et al., 1989). However, Caddell and coworkers (1975) found a greater renal retention of a parenteral load of magnesium in pregnant adolescents and women with twin pregnancies, suggesting that magnesium requirements during these periods may be increased. Lactation Indicators Used to Set the EAR Human Milk Content. The concentration of magnesium in human milk averages between 25 to 35 mg (1.0 to 1.5 mmol)/liter and is not influenced by the mother 's magnesium intake (Moser et al., 1983, 1988). Assuming a milk production of 780 ml/day, a lactating woman may secrete from 9 to 26 mg (0.4 to 1.1 mmol)/day of magnesium in her milk (Allen et al., 1991). Despite the secretion of magnesium in milk during lactation, plasma and erthyrocyte magnesium concentrations do not differ between lactating and nonlactating women at daily magnesium intakes of approximately 250 mg (10.4 mmol) (Moser et al., 1983), and milk concentrations do not change throughout lactation (Dewey et al., 1984; Moser et al., 1983; Rajalakshmi and Srikantia, 1980). Balance Studies. A magnesium balance study in six lactating women, six nonlactating postpartum women, and seven women who were never pregnant found lower urinary magnesium concentrations in lactating women compared with women who were never pregnant (Dengel et al., 1994). A positive magnesium balance of 20 mg (0.84 mmol)/day was reported in lactating women consuming a daily magnesium intake of 217 mg (9 mmol). However, there was only a 5-day adaptation period, and although the women appeared to conserve magnesium, the small number of subjects may have lead to an insufficient ability to detect a difference. Whether the increased bone resorption that occurs during lactation contributes to the mag-

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DRI DIETARY REFERENCE INTAKES FOR Calcium, Phosphorus, Magnesium, Vitamin D, and Fluoride nesium pool available for milk production, or whether renal conservation is sufficient to meet the increased need, is unknown. Urinary magnesium concentrations in the lactating women were similar to those of nonlactating postpartum women; however, the 24-hour urinary magnesium losses in these lactating women were similar to urinary losses in women determined to be magnesium depleted based on the results of magnesium loading tests (Caddell et al., 1975). Although this study found lower urinary magnesium excretion in lactating women consuming an estimated daily average magnesium intake of 217 mg (9 mmol), another study found no difference in urinary magnesium concentrations between lactating and never-pregnant women who consumed higher average daily intakes of magnesium, around 270 mg (11.3 mmol) (Klein et al., 1995). EAR and RDA Summary for Lactation Currently, no consistent evidence exists to support an increased requirement for dietary magnesium during lactation. It appears that decreased urinary excretion of magnesium and increased bone resorption during lactation may provide the necessary magnesium for milk production. Therefore, the EAR and RDA are estimated to be the same as that obtained for nonlactating women of similar age and body weight. EAR for Lactation   14 through 18 years 300 mg (12.5 mmol)/day 19 through 30 years 255 mg (11.3 mmol)/day 31 through 50 years 265 mg (11.3 mmol)/day RDA for Lactation   14 through 18 years 360 mg (15.0 mmol)/day 19 through 30 years 310 mg (13.3 mmol)/day 31 through 50 years 320 mg (13.3 mmol)/day Based on the 1994 CSFII intake data and adjusted for day-to-day variation (Nusser et al., 1996), the median intake of magnesium in 16 lactating women is 316 mg (13.2 mmol)/day; the fifth percentile of intake for the 16 women (of unspecified age) was 267 mg (11.1 mmol)/day (see Appendix D), which is slightly above the magnesium EAR for lactating women 19 through 30 years and close to the magnesium EAR of 265 mg (11.3 mmol)/day for lactating women ages 31 through 50 years. The twenty-

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DRI DIETARY REFERENCE INTAKES FOR Calcium, Phosphorus, Magnesium, Vitamin D, and Fluoride fifth percentile intake is 296 mg (12.3 mmol)/day, which is slightly below the EAR of 300 mg (13.8 mmol)/day for lactating women ages 14 through 18 years. Special Considerations Mothers Nursing Multiple Infants. Increased intakes of magnesium during lactation, as with calcium, should be considered in mothers nursing multiple infants concurrently. Magnesium requirements may be higher due to the increased milk production of a mother while nursing multiple infants. It is not known whether decreased urinary magnesium and increased maternal bone resorption provide sufficient amounts of magnesium to meet these increased needs. TOLERABLE UPPER INTAKE LEVELS Hazard Identification Magnesium, when ingested as a naturally occurring substance in foods, has not been demonstrated to exert any adverse effects. However, adverse effects of excess magnesium intake have been observed with intakes from nonfood sources such as various magnesium salts used for pharmacologic purposes. Thus, a Tolerable Upper Intake Level (UL) cannot be based on magnesium obtained from foods. All reports of adverse effects of excess magnesium intake concern magnesium taken in addition to that consumed from food sources. Therefore, for the purposes of this review, magnesium intake that could result in adverse effects was from that obtained from its pharmacological use. The primary initial manifestation of excessive magnesium intake from nonfood sources is diarrhea (Mordes and Wacker, 1978; Rude and Singer, 1980). Magnesium has a well-known cathartic effect and is used pharmacologically for that purpose (Fine et al., 1991b). The diarrheal effect produced by pharmacological use of various magnesium salts is an osmotic effect (Fine et al., 1991b) and may be accompanied by other mild gastrointestinal effects such as nausea and abdominal cramping (Bashir et al., 1993; Marken et al., 1989; Ricci et al., 1991). Osmotic diarrhea has not been reported with normal dietary intakes of magnesium. Magnesium ingested as a component of food or food fortificants has not been reported to cause this mild, osmotic diarrhea even when large amounts are ingested. Magnesium is absorbed much more efficiently from the normal concentrations found in the diet than it is from the higher doses

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DRI DIETARY REFERENCE INTAKES FOR Calcium, Phosphorus, Magnesium, Vitamin D, and Fluoride found in nonfood sources (Fine et al., 1991a). The presence of food likely counteracts the osmotic effect of the magnesium salts in the gut lumen (Fine et al., 1991a). In normal individuals, the kidney seems to maintain magnesium homeostasis over a rather wide range of magnesium intakes. Thus, hypermagnesemia has not been documented following the intake of high levels of dietary magnesium in the absence of either intestinal or renal disease (Mordes and Wacker, 1978). Hypermagnesemia can occur in individuals with impaired renal function and is most commonly associated with the combination of impaired renal function and excessive intake of nonfood magnesium (for example, as antacids) (Mordes and Wacker, 1978; Randall et al., 1964). Hypermagnesemia resulting from impaired renal function and/or intravenous administration of magnesium can result in more serious neurological and cardiac symptoms, but elevated serum magnesium concentrations greater than 2 to 3.5 mmol/liter (4.8 to 8.4 mg/dl) must be attained before onset of these symptoms (Rude and Singer, 1980). Intakes of nonfood magnesium have rarely been reported to cause symptomatic hypermagnesemia in individuals with normal renal function. Although magnesium supplements are used (see Table 2-2), comparatively few serious adverse reactions are reported until high doses are ingested (see data following). However, some individuals in the population may be at risk of a mild, reversible adverse effect (diarrhea) even at doses from nonfood sources that are easily tolerated by others. Thus, diarrhea was chosen as the most sensitive toxic manifestation of excess magnesium intake from nonfood sources. It is not known if all magnesium salts behave similarly in the induction of osmotic diarrhea. In the absence of evidence to the contrary, it seems prudent to assume that all dissociable magnesium salts share this property. Reports of diarrhea associated with magnesium frequently involve preparations that include aluminum, and therefore a specific magnesium-associated effect cannot be ascertained. Large pharmacological doses of magnesium can clearly result in more serious adverse reactions. An 8-week-old infant suffered metabolic alkalosis, diarrhea, and dehydration after receiving large amounts of magnesium oxide powder on each of two successive days (Bodanszky and Leleiko, 1985). Urakabe et al. (1975) reported that a female adult suffered from metabolic alkalosis and hypokalemia from the repeated daily ingestion of 30 g (1,250 mmol) of magnesium oxide. Several cases of paralytic ileus were encountered in adult patients who had taken large, cathartic doses of magnesium: in one case, two bottles of magnesium citrate and several

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DRI DIETARY REFERENCE INTAKES FOR Calcium, Phosphorus, Magnesium, Vitamin D, and Fluoride doses of milk of magnesia, and in the other case, several doses of magnesium sulfate in a patient with mild renal impairment (Golzarian et al., 1994). Cardiorespiratory arrest was encountered in a suicidal patient given 465 g (19.1 mol) of magnesium sulfate as a cathartic to counteract an intentional drug overdose (Smilkstein et al., 1988). Deaths from very large exposures to magnesium in the form of magnesium sulfate or magnesium oxide have been reported following cardiac arrest, especially in individuals with renal insufficiency (Randall et al., 1964; Thatcher and Rock, 1928). Dose-Response Assessment Adolescents and Adults: Ages > 8 Years Data Selection. A review of the scientific literature revealed relatively few reports that were useful in establishing a UL for magnesium. Because magnesium has not been shown to produce any toxic effects when ingested as a naturally occurring substance in foods, a UL cannot be established for dietary magnesium at this time. In addition, studies involving intravenous administration of comparatively large doses of magnesium used in the treatment of preterm labor, pregnancy-induced hypertension, or other clinical conditions were not considered applicable for the derivation of ULs. Based on limited data described below, a UL can be established for magnesium from nonfood sources. Identification of a NOAEL (or LOAEL) and Critical Endpoint. As the primary initial manifestation of excessive magnesium intake, diarrhea was selected as the critical endpoint. The few studies that report mild diarrhea and other gastrointestinal symptoms from uses of magnesium salts were reviewed to identify a No-Observed-Adverse-Effect Level (NOAEL) (or Lowest-Observed-Adverse-EffectLevel [LOAEL]). Gastrointestinal symptoms, including diarrhea, developed in 6 of 21 patients (51-to 70-year-old males and females) receiving long-term magnesium chloride therapy at levels of 360 mg (15 mmol) of magnesium (Bashir et al., 1993). Gastrointestinal manifestations developed in 5 of 25 pregnant women being given 384 mg (16 mmol) of daily magnesium as magnesium chloride supplements for the prevention of preterm delivery, although one patient receiving the placebo treatment also developed diarrhea (Ricci et al., 1991). Diarrhea was also noted in 18 of 50 healthy white and black men and women (aged 31 through 50 years) who were ingesting 470 mg (19.6 mmol) of magnesium as magnesium oxide

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DRI DIETARY REFERENCE INTAKES FOR Calcium, Phosphorus, Magnesium, Vitamin D, and Fluoride daily (Marken et al., 1989). Levels of fecal output of soluble magnesium and fecal magnesium concentration were elevated in individuals with diarrhea induced by 168 to 2,320 mg (7 to 97 mmol) of magnesium as magnesium hydroxide (Fine et al., 1991b). However, other studies using similar or even higher levels of supplemental magnesium reported no diarrhea or other gastrointestinal complaints. Healthy 18- to 38-year-old males given diets enriched with magnesium oxide at levels up to 452 mg (18.9 mmol) daily for 6 days did not report the occurrence of any gastrointestinal symptoms (Altura et al., 1994). This study of the effect of magnesiumenriched diets on absorption involved the fortification of foods with magnesium, which may have different effects from the administration of magnesium supplements outside the normal diet. Furthermore, no diarrhea was reported in patients of varying ages receiving an average of 576 mg (24 mmol)/day of supplemental magnesium as magnesium oxide in a metabolic balance study for 28 days (Spencer et al., 1994). Diarrhea or other gastrointestinal complaints were not observed in patients receiving up to 1,200 mg (50 mmol) of magnesium in the form of an aluminum-magnesium-hydroxycarbonate antacid over a 6-week trial period (Nagy et al., 1988). In a longer-term study, a group of postmenopausal women received daily supplements of 226 to 678 mg (9.4 to 28.3 mmol) of magnesium as magnesium hydroxide for 6 months followed by 226 mg (9.4 mmol) of magnesium for 18 months without any observations of gastrointestinal complaints (Stendig-Lindberg et al., 1993). Diabetics were supplemented with 400 mg (16.7 mmol) of magnesium daily for 8 weeks in the form of magnesium oxide or magnesium chloride without any gastrointestinal complications (Nadler et al., 1992). Elderly subjects supplemented with 372 mg (15.5 mmol) of magnesium daily over a 4-week period did not report any diarrheal effects or other gastrointestinal complaints (Paolisso et al., 1992). The LOAEL identified for magnesium-induced diarrhea in adults is 360 mg (15 mmol)/day of magnesium from nonfood sources based on the results of Bashir et al. (1993). Studies by Fine et al. (1991b), Marken et al. (1989), and Ricci et al. (1991) provide evidence to support the use of this dose as the LOAEL. Uncertainty Assessment. Due to the very mild, reversible nature of osmotic diarrhea caused by ingestion of magnesium salts, an uncertainty factor (UF) of approximately 1.0 was selected. Unlike possible adverse effects of other nutrients, osmotic diarrhea is quite apparent to the individual and thus is not a symptom that is masked until serious consequences result.

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DRI DIETARY REFERENCE INTAKES FOR Calcium, Phosphorus, Magnesium, Vitamin D, and Fluoride Derivation of the UL. Because excessive magnesium intake from nonfood sources causes adverse effects, the UL will be established for magnesium from nonfood sources. The UL for magnesium for adolescents and adults is established at 350 mg (14.6 mmol)/day, based on a LOAEL of 360 mg (15 mmol)/day and a UF very close to 1.0. Although a few studies have noted mild diarrhea and other mild gastrointestinal complaints in a small percentage of patients at levels of 360 to 380 mg (15.0 to 15.8 mmol)/day, it is noteworthy that many other individuals have not encountered such effects even when receiving substantially more than this UL of supplementary magnesium, as indicated previously. UL for Adolescents and Adults > 8 years 350 mg (14.6 mmol) of supplementary magnesium Infants: Ages 0 through 12 Months No specific toxicity data exist on which to establish a UL for infants, toddlers, and children. The lack of any available data regarding the effects of magnesium supplements in infants makes it impossible to establish a specific UL for infants. Thus, it is important to get magnesium via food sources only in this age group. UL for Infants 0 through 12 months Not possible to establish for supplementary magnesium Children: Ages 1 through 8 Years It is assumed that children are as susceptible to the osmotic effects of nonfood sources of magnesium as are adults. Thus, adjusting the value for adults on a body-weight basis established a UL for children at a magnesium intake of 5 mg/kg/day (0.2 mmol/kg/day) (see Table 1-3 for reference weights). UL for Children 1 through 3 years 65 mg (2.7 mmol) of supplementary magnesium   4 through 8 years 110 mg (4.6 mmol) of supplementary magnesium

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DRI DIETARY REFERENCE INTAKES FOR Calcium, Phosphorus, Magnesium, Vitamin D, and Fluoride Pregnancy and Lactation No evidence suggests increased susceptibility to adverse effects of supplemental magnesium during pregnancy and lactation. Therefore, the UL for pregnant and lactating women is set at 350 mg (14.6 mmol)/day —the same value as used for other adults. UL for Pregnancy 14 through 50 years 350 mg (14.6 mmol) of supplementary magnesium UL for Lactation 14 through 50 years 350 mg (14.6 mmol) of supplementary magnesium Special Considerations Individuals with impaired renal function are at greater risk of magnesium toxicity. However, as noted above, magnesium levels obtained from food are insufficient to cause adverse reactions even in these individuals. Patients with certain clinical conditions (for example, neonatal tetany, hyperuricemia, hyperlipidemia, lithium toxicity, hyperthyroidism, pancreatitis, hepatitis, phlebitis, coronary artery disease, arrhythmia, and digitalis intoxication [Mordes and Wacker, 1978]) may benefit from the prescribed use of magnesium in quantities exceeding the UL in the clinical setting. Exposure Assessment In 1986, the most recent year that data were available to estimate nonfood nutrient supplement intakes, approximately 15 percent of adults in the United States reported taking a supplement containing magnesium (although it is unclear whether supplements were taken on a daily basis) (Moss et al., 1989). Of those, the ninetieth percentile of daily supplemental magnesium intake was 200 mg (9.1 mmol) for men and 240 mg (10 mmol) for women; the ninety-fifth percentile was 350 mg (14.4 mmol) for men and 400 mg (16.6 mmol) for women. Thus, approximately 5 percent of the men and over 5 percent of the women who used magnesium supplements exceeded the UL of 350 mg (14.6 mmol)/day in 1986. Children's intakes from nonfood nutrient supplements were estimated to be much lower. The ninetieth percentile of intake for children 2 to 6 years of age who used magnesium supplements in 1986 was 70 mg (2.9 mmol)/day, which is approximately the UL for a 2-year-old child weighing 14 kg; the ninety-fifth percentile of in-

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DRI DIETARY REFERENCE INTAKES FOR Calcium, Phosphorus, Magnesium, Vitamin D, and Fluoride take from supplements was 117 mg (4.9 mmol)/day, or approximately the UL (115 mg [4.8 mmol]/day) for a 6-year-old child weighing 23 kg. Assuming older children were taking the higher doses, it appears that about 5 percent of the users in this study were exceeding the UL. Risk Characterization Using data from 1986, almost 1 percent of all adults in the United States took a nonfood magnesium supplement that exceeded the reference UL of 350 mg (14.6 mmol)/day in the 2-week period preceding the survey (Moss et al., 1989). It is important to note that many of the individuals whose intakes of supplemental magnesium exceeded the UL may be self-selected as not experiencing diarrhea, but this is uncertain. More recent data on estimates of supplement intakes of a national sample have not been published, but it is unlikely that usage has declined. The data on supplement use in 1986 also indicate that at least 5 percent of young children who used magnesium supplements exceeded the UL for magnesium, 5 mg (0.2 mmol)/kg/day. However, because less than 10 percent of the children had taken a magnesium supplement in the past 2 weeks, less than 1 percent of all children would be at risk of adverse effects. These estimates assume that older children (with a higher UL) are taking the higher doses; the percentage at risk would be higher if dosage were not related to age (and, therefore, to body size). More information on supplement use by specific ages is needed. RESEARCH RECOMMENDATIONS The ability to determine reference dietary intakes for magnesium is, as indicated throughout this chapter, hampered by available data. Areas of investigation that are particularly needed include the following: Reliable data on population intakes of magnesium are required based on dietary surveys that include estimates of intakes from food, water, and supplements in healthy populations in all life stages. Biochemical indicators that provide an accurate and specific marker(s) of magnesium status must be investigated in order to assess their ability to predict functional outcomes that indicate adequate magnesium status over prolonged periods.

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DRI DIETARY REFERENCE INTAKES FOR Calcium, Phosphorus, Magnesium, Vitamin D, and Fluoride Basic studies need to be initiated in healthy individuals, including experimental magnesium depletion studies that measure changes in various body magnesium pools. Magnesium balance studies may be one indicator utilized. If so, strict adherence to criteria suggested in the chapter would improve their application to dietary recommendations. Moreover, a determination of the most valid units to use in expressing estimates of requirements (body weight, fat-free mass, or total body unit) is needed. Investigations are needed to assess the inter-relationships between dietary magnesium intakes, indicators of magnesium status, and possible health outcomes that may be affected by inadequate magnesium intakes, such as hypertension, hyperlipidemia, atherosclerotic vascular disease, altered bone turnover, and osteoporosis. Based on the evidence of abnormal magnesium status and health outcomes (as noted above), intervention studies to improve magnesium status and to assess its impact on specific health outcomes would be appropriate. The toxicity of pharmacological doses of magnesium requires investigation.