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Insufficient dietary magnesium (Mg) intake has been associated in humans with low bone mass. Mg deficiency in the rat has suggested bone loss is due to increased bone resorption and/or inadequate bone formation during remodeling. The purpose of this study was to assess the effect of a low Mg diet on bone and mineral metabolism in the young and mature BALB/c mouse and explore the hypothesis that inflammatory cytokines may contribute to Mg deficiency-induced osteoporosis. Using an artificial diet, we induced targeted Mg depletion (0.002% Mg) with all other nutrients maintained at the normal level. In all Mg-depleted mice, hypomagnesemia developed and skeletal Mg content fell significantly. The serum Ca in Mg-deficient mice was higher than in control mice; however, serum PTH levels were not significantly different. Osteoprotegerin (OPG) in dosages that inhibit osteoclastic bone resorption did not prevent hypercalcemia in Mg-deficient animals. No significant difference in serum Ca was observed between groups when dietary Ca was reduced by 50%, suggesting that a compensatory increase in intestinal absorption might account for the hypercalcemia. Growth plate width decreased 33% in young Mg-deficient animals and chondrocyte columns decreased in number and length, suggesting that Mg deficiency reduced bone growth. Trabecular bone volume in the metaphysis of the tibia in these animals was decreased and osteoclast number was increased by 135%. Osteoblast number was significantly reduced. Immunohistochemistry revealed that substance P increased 230% and 200% in megakaryocytes and lymphocytes, respectively, after 1 day of Mg depletion. IL-1 increased by 140% in osteoclasts by day 3 and TNFa increased in osteoclasts by 120% and 500% in megakaryocytes on day 12. This study demonstrates a profound effect of Mg depletion on bone characterized by impaired bone growth, decreased osteoblast number, increased osteoclast number in young animals, and loss of trabecular bone with stimulation of cytokine activity in bone. [ABSTRACT FROM AUTHOR]

Plasma membranes were prepared from mineralized guinea pig bone in order to study Mg2+ and Ca2+ modulation of skeletal adenylate cyclase. Plasma membrane preparation was accomplished by crushing the bone in liquid N2 and subsequent multiple washings in buffer containing EGTA to remove all Ca2+ prior to adenylate cyclase assay. Skeletal adenylate cyclase was found to be dependent on GTP and Mg2+ and responsive to bovine 1-34 PTH. Ca2+ caused a competitive inhibition of Mg2+ -activated skeletal adenylate cyclase. The apparent KaMg was 1.9 +/- 0.3 in the presence of 0.2 microM Ca2+ but increased to a mean of 7.2 +/- 1.3 in the presence of 5.0 microM Ca2+. Analysis of the Ca2+ inhibition curves at concentrations from .05 microM-1.0 mM were consistent with the presence of two Ca2+ inhibition sites, one with an apparent Ki of 1-2 microM and the other with an apparent Ki of approximately 500 microM. Lowering the Mg2+ concentration increased the contribution of the high affinity Ca2+ binding site to the overall Ca2+ inhibition, and raising the Mg2+ concentration had the opposite effect. While bPTH 1-34 enhanced adenylate cyclase activity, it did not increase the affinity of Mg2+ for skeletal adenylate cyclase nor did it alter the KiCa or the pattern of Ca2+ inhibition. These data may explain the skeletal resistance to PTH during Mg deficiency.(ABSTRACT TRUNCATED AT 250 WORDS) [ABSTRACT FROM AUTHOR]

Hypercalcemia of malignancy is a commonly encountered serious clinical problem that often requires aggressive therapy. In order to combine the rapid hypocalcemic effects of calcitonin with the more delayed effect of a bisphosphonate, we administered etidronate, 7.5 mg/kg/day intravenously and salmon calcitonin, 100 IU subcutaneously, every 12 hours for 3 days in 9 patients with hypercalcemia associated with malignancy. The mean serum calcium concentration fell from 3.33 +/- 0.1 mmol/liter (mean +/- SEM) to 2.88 +/- 0.1 mmol/liter within 24 hours (P less than 0.001). All patients had a fall in the serum calcium concentration of greater than 0.5 mmol/liter and it returned to normal in 7 of the 9 patients. We conclude that the combination of salmon calcitonin with etidronate more effectively lowers the serum calcium concentration in patients with hypercalcemia of malignancy then the use of either agent alone. [ABSTRACT FROM AUTHOR]

The use of magnesium in the treatment of acute myocardial infarction remains controversial despite preliminary experimental evidence that magnesium plays a beneficial role as a regulator of thrombosis. This study examines whether oral magnesium treatment inhibits platelet-dependent thrombosis (PDT) in patients with coronary artery disease (CAD). In a randomized prospective, double-blind, crossover, and placebo-controlled study, 42 patients with CAD (37 men, 5 women, mean age 68 +/- 9 years) on aspirin received either magnesium oxide tablets (800 to 1,200 mg/day) or placebo for 3 months (phase 1) followed by a 4-week wash-out period, and the crossover treatment for 3 months (phase 2). PDT, platelet aggregation, platelet P-selectin flow cytometry, monocyte tissue factor procoagulant activity (TF-PCA), and adhesion molecule density were assessed before and after each phase. PDT was evaluated by an ex vivo perfusion model using the Badimon chamber. Median PDT was significantly reduced by 35% in patients who received magnesium versus placebo (delta change from baseline -24 vs 26 mm2/mm; p = 0.02, respectively). There was no significant effect of magnesium treatment on platelet aggregation, P-selectin expression, monocyte TF-PCA, or adhesion molecules. Oral magnesium treatment inhibited PDT in patients with stable CAD. This effect appears to be independent of platelet aggregation or P-selectin expression, and is evident despite aspirin therapy. These findings suggest a potential mechanism whereby magnesium may beneficially alter outcomes in patients with CAD. [ABSTRACT FROM AUTHOR]

Insufficient dietary magnesium (Mg) intake has been associated with low bone mass in humans,and recent basic science studies have indicated that this bone loss may be secondary to increased release of substance P and TNFc Much less is known about the effects of low Mg intake on cartilage. We have evaluated growth plate and articular cartilage in rats following a 6 month dietary Mg restriction. Histomorphometry demonstrated significantly decreased distal femur articular cartilage chondrocyte density and decreased tibial growth plate width in experimental animals compared to controls. Growth plates of Mg-restricted animals showed reduced chondrocyte column formation. Extracellular matrix of both articular cartilage and growth plates in experimental animals contained reduced amounts of proteoglycans. Immunolocalization of Sox9 was decreased in both articular and growth plate cartilage in experimental animals compared to controls, suggesting that reduced Mg intake causes cartilage changes that may be secondary to reduced levels of the SOX9 transcription factor.

In the present study, we used osteoprotegerin (OPG), which blocks osteoclastogenesis, to correct and thus explain the hypercalcemia that is seen during dietary Mg deficiency in the mouse. Control and Mg-deficient mice received injections for 12 days of either OPG or vehicle only. Serum Ca was similar in Mg-deficient mice treated with OPG and in control mice receiving OPG (9.2 +/- 0.3 mg/dl vs. 9.2 +/- 0.5). Both groups had significantly higher serum Ca than controls or Mg-deficient animals receiving vehicle alone. Surprisingly, Mg-depleted mice that received OPG in doses that inhibit osteoclastic bone resorption remained hypercalcemic. Because mature osteoclasts still present in the marrow might be hyperactive, we examined osteoclast morphology at the light microscopic and ultrastructural level. Light microscopic examination of trabecular bone showed few osteoclasts in OPG-treated mice. Ultrastructural examination revealed that osteoclasts in OPG-treated mice have decreased contact with the endosteal bone surface and absence of a ruffled border. Because the morphology of the existing pool of mature osteoclasts did not enhance resorption, another mechanism, such as increased intestinal absorption of Ca in Mg-deficient mice, likely contributes to the hypercalcemia observed during Mg deficiency.

The use of magnesium in the treatment of acute myocardial infarction remains controversial despite preliminary experimental evidence that magnesium plays a beneficial role as a regulator of thrombosis. The aim of our study was to determine whether oral magnesium treatment inhibits platelet-dependent thrombosis (PDT) in stable patients with coronary artery disease (CAD). In a randomized prospective, double-blind, cross-over and placebo controlled study, 42 patients with stable CAD (37 men, 5 women, mean age 68 +/- 9 years) on aspirin received either magnesium oxide tablets (800-1,200 mg/day) or placebo for 3 months (Phase 1) followed by a 4-week washout period, and the cross-over treatment for 3 months (Phase 2). PDT, platelet aggregation, platelet P-selectin flow-cytometry, monocyte tissue factor procoagulant activity (TF-PCA) and adhesion molecules density were assessed before and after each phase. PDT was evaluated by an ex-vivo perfusion model using the Badimon chamber. Median PDT was significantly reduced by 35 percent in patients who received magnesium versus placebo (D change from baseline: -24 vs. 26 microm2/mm; p = 0.02, respectively). There was no significant effect of magnesium treatment on platelet aggregation, P-selectin expression, monocyte TF-PCA or adhesion molecules. Oral magnesium treatment inhibits PDT in patients with stable CAD. This effect appears to be independent of platelet aggregation or P-selectin expression, and is evident despite aspirin therapy. These findings suggest a potential mechanism whereby magnesium may beneficially alter outcomes in patients with CAD.

Background: Although reduced intracellular levels of magnesium have been described in patients with acute myocardial infarction, its significance as a regulator of thrombosis remains unknown., Methods and Results: To determine whether reduced intracellular levels of magnesium enhance platelet-dependent thrombosis, we evaluated 42 patients with coronary artery disease (CAD) by exposing porcine aortic media to their flowing unanticoagulated venous blood for 5 minutes by using an ex vivo perfusion (Badimon) chamber. Baseline analysis demonstrated significant associations between intracellular levels of magnesium, platelet-dependent thrombosis (P =.02), and platelet P-selectin (CD62P) expression (P <.05). Patients were divided into 2 groups: below (n = 22) and above (n = 20) the median intracellular levels of magnesium (1.12 microg/mg protein). There were no significant differences in age, body mass index, serum lipids, fibrinogen, platelet count, or serum magnesium levels between the two groups. Platelet-dependent thrombosis was significantly higher in patients with intracellular levels of magnesium below compared with above median (150 +/- 128 vs 45 +/- 28 microm(2)/mm, P <.004). Neither platelet aggregation nor CD62P expression was significantly different between the two groups., Conclusions: Platelet-dependent thrombosis was significantly increased in patients with stable CAD with low intracellular levels of magnesium, suggesting a potential role for magnesium supplementation in CAD.

Magnesium (Mg) intake has been linked to bone mass and/or rate of bone loss in humans. Experimental Mg deficiency in animal models has resulted in impaired bone growth, osteopenia, and increased skeletal fragility. In order to assess changes in bone and mineral homeostasis that may be responsible, we induced dietary Mg deficiency in adult Simonsen albino rats for 16 weeks. Rats were fed either a low Mg diet (0.002 percent) or a normal control Mg diet (0.063 percent). Blood was obtained at baseline, 4 weeks, 8 weeks, 12 weeks and 16 weeks in both groups for serum Mg, calcium, PTH, and 1.25(OH)2-vitamin D determinations. Femora were harvested at 4 weeks and 16 weeks for mineral analysis and histomorphometry. Serum Mg fell in the Mg depleted group to 0.6 mg/dl (mean) by 16 weeks (controls = 2.0 mg/dl). The serum calcium (Ca) concentration was higher in the Mg depleted animals at 16 weeks, 10.8 mg/dl (controls = 8.9 mg/dl). Serum PTH concentration fell progressively in the Mg deficient rats to 30 pg/ml by week 16 (control = 96 pg/ml). Serum concentration of 1.25(OH)2-vitamin D also fell progressively in the Mg deficient animals by 16 weeks to 14 pg/ml (control = 30 pg/ml). While the percent ash weights of Ca and phosphorus in the femur were not different at any time point, the percent ash weight of Mg progressively fell to 0.54 percent vs control (0.74 percent) by 16 weeks. The percent ash weight of potassium also fell progressively in the Mg deficient group to approximately 30 percent of control by 16 weeks. Histomorphometric analyses showed a significant drop in trabecular bone volume in Mg deficient animals by 16 weeks (percent BV/TV = 13.2 percent vs 17.3 percent in controls). Evaluation of the endosteal bone surface features showed significantly greater bone resorption in the Mg depleted group as reflected in increased number of tartrate-resistant positive osteoclasts/mm bone surface (7.8 vs 4.0 in controls) and an elevated percent of bone surface occupied by osteoclasts (percent OcS/BS = 12.2 percent vs 6.7 percent in controls. This increased resorption occurred in the presence of an inappropriate lowered bone forming surface relative to controls; a decreased number of osteoblasts per mm bone surface (0.23 vs 0.94 in control) and a decrease in percent trabecular surface lined by osteoid (percent OS/BS = 0.41 vs 2.27 percent in controls) were also noted. Our findings demonstrate a Mg-deficiency induced uncoupling of bone formation and bone resorption resulting in a loss of bone mass. While the fall in PTH and/or 1.25(OH)2-D may explain a decrease in osteoblast activity, the mechanism for increased osteoclast activity is unclear. These data suggest that Mg deficiency may be a risk factor for osteoporosis.

Vitamin D3 analogs and paclitaxel (Taxol) are able to inhibit the in vitro growth of a variety of malignant cells including breast cancer cells. These two compounds decrease growth by different mechanisms and they have nonoverlapping toxicities. We examined the abilities of three vitamin D3 compounds to inhibit growth of a human mammary cancer (MCF-7) in BNX triple immunodeficient mice either alone or with Taxol. Vitamin D3 analogs were 1,25(OH)2D3 (code name, Compound C), 1,25(OH)2-16-ene-23-yne-19-nor-26,27-F6-D3 (Compound LH), and 24a,26a,27a,-trihomo-22,24-diene-1,25(OH)2D3 (EB1089). At the doses chosen, the antitumor effect of vitamin D3 analogs alone was greater than that of Taxol alone, and an additive effect was observed when a vitamin D3 analog and Taxol were administered together. EB1089 was the most potent compound, and the EB1089 plus Taxol was the most active combination, decreasing the tumor mass nearly 4-fold compared to controls. Weight-gain in each of the experimental cohorts at the end of the study was less than the control group, but the gain was significantly less in only two experimental groups (those receiving either EB1089 or Compound C plus Taxol). None of the animals became hypercalcemic, and their complete blood counts, serum electrolyte analyses, and liver and renal functions were all fairly similar and within the normal range. In summary, this combination of a vitamin D3 analog and Taxol has the potential to be a therapy for breast cancer.

To determine whether increased intracellular levels of magnesium ([Mg]i) are associated with enhanced functional capacity, we performed symptom-limited exercise treadmill testing on 42 stable coronary artery disease (CAD) patients (37 men, 5 women, mean age 68 +/- 9 years). [Mg]i was found to be an independent and significant predictor of exercise duration (R = 0.31, p = 0.02) in a multivariate stepwise regression model. Patients with > normal [Mg]i of 1.23 microg/mg protein (n = 13) had a significantly greater mean functional capacity, measured in higher achieved metabolic equivalents (10.6 +/- 2.5 vs. 8.9 +/- 2.3, p < 0.05) and exercise duration (9.4 +/- 2.3 vs. 7.9 +/- 2.2 min, p < 0.05) compared to patients with [Mg]i

Eleven femurs with press-fit titanium hip components were retrieved at autopsy for clinical, radiographic, and histologic evaluation. Back-scattered electron microscopy (BEM), bone densitometry, and appositional bone index studies also were performed. The average patient age was 87 years; the average time in situ was 22 months (range: 2 to 60). All patients were functioning well and pain free. Radiographs and bone mineral density studies (BMD) showed mild proximal stress shielding in five cases. No cases of osteolysis or pedestal formation were observed. Histologic sections revealed an average of 26% bone-prosthesis contact. Bone surrounding the prosthesis appeared viable, and osteoclastic activity in the interfacial bone was minimal; the presence of macrophages and inflammatory cells was rare. The appositional bone index averaged 40%. Bone-prosthesis contact was seen consistently at the corners of the component in the multiple regions, mostly were prosthesis-endosteal cortical contact was made. BEM demonstrated intimate contact of bone with the rough titanium surface. Bone mineral density was lower in the lesser trochanter and medial proximal regions of the implanted femur than in the contralateral femur. Evidence of bone on-growth fixation in 11 femoral components suggests that cementless, stable bone fixation may be achievable in senior individuals and that "complete fit and fill," porous-coated, cementless prostheses may not be required for prosthesis stability.

Disorders in which magnesium (Mg) depletion is common have an associated high incidence of osteoporosis. Mg depletion in humans results in hypocalcemia, low serum parathyroid hormone (PTH) and 1, 25(OH)2-vitamin D levels, as well as PTH and vitamin D resistance which may serve as mechanisms for the development of osteoporosis. In order to determine if isolated Mg depletion will result in bone loss, we have induced dietary Mg deficiency in the rat. Adult (290 g) female rats were given either a low-Mg diet (2 mg/100 g chow; n = 6) or a normal control Mg diet (63 mg/100 g chow; n = 6). Dietary calcium (Ca) was normal in both groups (592 mg/100 g chow). At 12 weeks, blood was obtained for serum Mg, Ca, PTH, 1,25(OH)2-vitamin D, and osteocalcin determinations. The rats were then euthanized and the femurs obtained for mineral analysis and histomorphometry. Serum Mg in the low-Mg group was less than control (0.4 +/- 0.2 vs. 1.9 +/- 0.2 mg/dl, p < 0.001; mean +/- SD) while serum Ca was higher (11. 7 +/- 0.5 vs. 9.3 +/- 0.4 mg/dl, p < 0.001). PTH was suppressed in the Mg-deficient group (36 +/- 16 vs. 109 +/- 30 pg/ml in controls, p < 0.002). Serum 1,25(OH)2-vitamin D was also suppressed in the Mg-deficient animals (7.1 +/- 4.8 vs. 28.5 +/- 8.2 pg/ml in controls, p < 0.002). Serum osteocalcin levels were not different (19.8 +/- 2.5 ng/ml in Mg-deficient rats vs. 15.3 +/- 3.4 ng/ml in controls). While the ash weight of Ca and phosphorus in the femur did not change, the ash weight of Mg fell (low-Mg group 0.55 +/- 0.01%, controls 0.65 +/- 0.02%, p < 0.001). Histomorphometry demonstrated reduction in bone mass; the trabecular bone volume in the femur of the low-Mg group was reduced from control (7.7 +/- 0.2 vs. 13.7 +/- 1.9%, p < 0.002). A surprising new observation was an increase in osteoclast (OC) bone resorption with Mg depletion. The number of OC per millimeter bone surface was 16.9 +/- 1.3 in the low-Mg group versus 7.8 +/- 1.5 in controls (p < 0.001). The percentage of bone surface occupied by OC was 38.3 +/- 3.7 in the low-Mg group versus 17.7 +/- 2.4 in controls (p < 0.001). This increased resorption occurred with an inappropriate non-altered bone-forming surface relative to control (% osteoid surface: low-Mg group 2.4 +/- 0.7 vs. controls 2.6 +/- 0.4; % osteoid volume: low-Mg group 0.25 +/- 0.09 vs. controls 0.38 +/- 0.06; number of osteoblasts per millimeter bone surface: low-Mg group 0.9 +/- 0.3 vs controls 1.3 +/- 0.3). No increase in bone-forming surface or osteoblast number despite an increase in OC-resorbing surface and OC number strongly suggests impaired activation of osteoblasts and an uncoupling of bone formation and bone resorption. Our data demonstrate that Mg depletion in the rat alters bone and mineral metabolism which results in bone loss.

Leptin, the obese (ob) gene product, is thought to be a lipostatic hormone that contributes to body weight regulation through modulating feeding behavior and/or energy expenditure. The determinants of plasma leptin concentration were evaluated in 267 subjects (106 with normal glucose tolerance, 102 with impaired glucose tolerance, and 59 with noninsulin-dependent diabetes). Fasting plasma leptin levels ranged from 1.8-79.6 ng/mL (geometric mean, 12.4), were higher in the obese subjects, and were not related to glucose tolerance. Women had approximately 40% higher leptin levels than men at any level of adiposity. After controlling for body fat, postmenopausal women had still higher leptin levels than men of similar age, and their levels were not different from those in younger women. Multiple regression analysis showed that adiposity, gender, and insulinemia were significant determinants of leptin concentration, explaining 42%, 28%, and 2% of its variance, respectively. Neither age nor the waist/hip ratio was significantly related to leptin concentration. Thus, our data indicate that gender is a major determinant of the plasma leptin concentration. This sex difference is not apparently explained by sex hormones or body fat distribution. Leptin's sexual dimorphism suggests that women may be resistant to its putative lipostatic actions and that it may have a reproductive function.

The working group on magnesium considered a number of issues relevant to establishing allowances and to providing other pertinent information on this ion for the next edition of the Recommended Dietary Allowances (RDA). An accurate and specific marker for assessing the importance of magnesium nutriture in health and disease remains to be identified. Thus, it is unknown whether marginal magnesium depletion results in a disease. Although it is apparent that abnormal serum concentrations are unusual and obvious signs of acute depletion of magnesium are absent in the U.S. populace, one cannot assume that the associated cellular and intracellular pool sizes are optimal for health. There is a need for systematic studies of these and other parameters in healthy individuals with controlled intakes and during depletion. To address the question of how magnesium allowances should be set, previous editions of the RDA that included magnesium were reviewed; this review indicated the need for the adoption of objective criteria for acceptance of published balance studies and the inclusion in the discussion of an analysis of the balance studies and the specific calculations used in establishing the RDA. Such criteria and evaluations should be placed in a technical addendum to allow readers to evaluate the data. It is recommended that future RDA Committees consider expressing metabolic balance data on a basis other than weight, e.g., energy expenditure, lean body mass or body cell mass. Claims that magnesium nutriture has a role in preventing or ameliorating chronic disease such as heart disease and hypertension need to be critically evaluated if they are to be used to set the next RDA. The pharmacologic effects of magnesium are significant and need to be recognized. Because excess oral magnesium can be toxic to persons with advanced renal disease, more attention should be given to this topic by future RDA Committees.

Primary hyperparathyroidism is the most prevalent cause of hypercalcemia. Although renal stone disease and osteitis fibrosis were prominent complications of this disorder in the past, the advent of biochemical screening has resulted in earlier detection. This has changed the clinical presentation of primary hyperparathyroidism, so that as many as 80% of patients do not have any sign or symptom that can be attributed solely to the disease. Improvement in assays for PTH has allowed for accurate bio-chemical diagnosis in over 90% of cases. Neck exploration is the treatment of choice for any patient who presents with signs, symptoms, or complications of hypercalcemia or hyperparathyroidism. Medical therapy is indicated in patients who either cannot undergo surgery because of medical contraindication, failed prior neck surgery, unresectable parathyroid carcinoma or simply refuse surgery. Medical therapy is not optimal, although sex steroid replacement therapy in the postmenopausal woman has met with some success. Calcitonin, phosphate, and bisphosphonates may be used, but their long-term efficacy is not clear. Recent studies have suggested that a large proportion of patients with asymptomatic primary hyperparathyroidism do not demonstrate progression of disease in terms of renal dysfunction, bone disease, or biochemical changes in calcium or PTH. Guidelines have been established for medical follow-up of such patients. If any such patient develops signs or symptoms during medical follow-up, surgery is then indicated.

Diabetes mellitus may be associated with magnesium depletion, which in turn may contribute to metabolic complications of diabetes including vascular disease and osteoporosis. Intracellular depletion is thought to be due to osmotically induced renal magnesium loss; however, impaired ability of insulin to increase intracellular magnesium during insulin deficiency or insulin resistance could also play a role. Magnesium deficiency per se has also been reported to result in insulin resistance. In order to determine if magnesium transport is altered in non-insulin-dependent diabetes mellitus (NIDDM), we measured intracellular Mg(2+) in circulating lymphocytes obtained from nine normal subjects and seven patients with NIDDM. Ionized intracellular Mg(2+) was determined by fluorescent spectroscopy using Mg-fura-2. A 30 min incubation of insulin with lymphocytes obtained from normal subjects resulted in an increase in Mg(2+) of 8.6 +/- 3.6 percent (mean +/- SEM) at 100 mu U/ml which reached a plateau at approximately 250 mu U/ml (11.0 +/- 1.7 percent). The mean lymphocyte Mg(2+) in the patients (0.198 +/- 0.011 mM) was not significantly lower than normal (0.218 +/- 0.017). Insulin (500 mU/ml) added acutely during the fluorescence reading caused a rapid 31 +/- 3.9 percent rise in intracellular Mg(2+) in the normal subjects, which was significantly greater than the 18 +/- 1.6 percent rise observed in the NIDDM subjects (P < 0.01). The effect of magnesium deficiency was also studied in 3 normal subjects experimentally Mg deficient for 3 weeks. The mean lymphocyte Mg(2+) fell from 0.198 +/- 0.009 mM pre-diet to 0.153 +/- 0.006 mM post-diet. and the insulin-induced rise in Mg(2+) fell from 27.2 percent pre-magnesium depletion to 12.7 percent post-magnesium depletion. These data suggest that insulin resistance and magnesium depletion may result in a vicious cycle of worsening insulin resistance and decrease in intracellular Mg(2+) which may limit the role of magnesium in vital cellular processes.

Magnesium depletion is more common than previously thought. It seems to be especially prevalent in patients with diabetes mellitus. It is usually caused by losses from the kidney or gastrointestinal tract. A patient with magnesium depletion may present with neuromuscular symptoms, hypokalemia, hypocalcemia, or cardiovascular complication. Physicians should maintain a high index of suspicion for magnesium depletion in patients at high risk and should implement therapy early.

Magnesium (Mg) deficiency occurs frequently in chronic alcoholism and may contribute to the increased incidence of osteoporosis and cardiovascular disease seen in this population. Mg deficiency is primarily due to renal Mg-wasting and is exacerbated by dietary Mg deprivation, gastrointestinal losses with diarrhea or vomiting, as well as concomitant use of drugs such as diuretics and aminoglycosides. Osteoporosis is prevalent in the alcoholic population. Mg deficiency may contribute to increased bone loss by its effects on mineral homeostasis. In Mg depletion, there is often hypocalcemia due to impaired parathyroid hormone (PTH) secretion, as well as renal and skeletal resistance to PTH action. Serum concentrations of 1,25-vitamin D are also low. These changes are seen with even mild degrees of Mg deficiency and may contribute to the metabolic bone disease seen in chronic alcoholics. Hypomagnesemia in alcoholics may also contribute to increased cardiovascular disease by altering platelet function. Mg deficiency has been demonstrated to enhance platelet reactivity. In these studies, Mg was shown to inhibit platelet aggregation against various aggregation agents. Patients with Mg deficiency were shown to have increased platelet aggregation that was normalized with Mg therapy. The antiplatelet effect of Mg may be related to the finding that Mg inhibits the synthesis of thromboxane A2 and 12-hydroxyeicosatetraenoic acid, eicosanoids thought to be involved in platelet aggregation. Mg also inhibits the thrombin-induced Ca2+ influx in platelets, as well as stimulates synthesis of prostaglandin I2, the potent antiaggregatory eicosanoid. Therefore, Mg deficiency may increase platelet aggregation and cause increased hypertension and atherosclerotic cardiovascular disease in alcoholics.

Magnesium (Mg) deficiency is a common yet underdiagnosed problem in the ICU. Since only 1% of total body Mg is in the extracellular fluid, serum Mg concentrations may not adequately reflect Mg status. Utilizing techniques to measure intracellular Mg concentrations, Mg depletion has been shown to be present in about one half of all ICU patients. These patients have significantly higher morbidity and mortality rates than Mg-replete patients. Accurate identification of patients with Mg depletion requires a knowledge of the risk factors associated with Mg deficiency. These factors include poorly controlled diabetes mellitus, alcohol ingestion, severe diarrhea and steatorrhea, and the use of a number of pharmacologic agents that induce renal Mg wasting. Manifestations of Mg deficiency include hypokalemia, hypocalcemia, neuromuscular hyperexcitability, respiratory muscle weakness, and intractable arrhythmias. Mg deficiency may also play a role in the genesis of myocardial ischemia. In this article, we review the assessment, causes, and manifestations of Mg deficiency and suggest guidelines for adequate treatment.

Magnesium is a prominent intracellular cation required for the function of hundreds of enzyme systems. Magnesium depletion is observed frequently in hospitalized patients and is usually secondary to renal or intestinal magnesium loss. Clinically, magnesium deficiency may present with neuromuscular hyperexcitability, hypocalcemia, hypokalemia, and cardiac arrhythmias. Magnesium therapy appears to improve survival in patients with myocardial infarction. The diagnosis of magnesium deficiency is usually made by a low-serum magnesium concentration, although the magnesium tolerance test may be more indicative of low magnesium states. In acutely ill patients, magnesium is usually give parenterally; oral magnesium may be given for long-term repletion.

Magnesium (Mg) is critical for the function of numerous enzyme systems. Mg deficiency thereby may result in many and varied clinical manifestations. Mg deficiency is common as approximately 10% of patients admitted to city hospitals are hypomagnesemic. Mg deficiency is usually due to losses from the gastrointestinal tract or from the kidney. A serum Mg concentration of < 1.5 mEq/l usually indicates Mg deficiency, however, intracellular Mg deletion may be present despite a normal serum Mg concentration. Acute clinical manifestations of Mg deficiency include neuromuscular hyperexcitability, cardiac arrhythmias, and biochemical abnormalities of hypokalemia and hypocalcemia. Chronic Mg depletion may contribute to hypertension, atherosclerotic vascular disease, altered glucose homeostasis, and metabolic bone disease. Therapy of the acute manifestations usually requires parenteral Mg administration of 24-48 mEq Mg/day for 3-5 days. Long-term Mg repletion may be accomplished by the administration of 300-600 mg of Mg orally/day.

Glucocorticoid excess results in osteoporosis by inhibiting bone formation as well as by increasing bone resorption. The cellular mechanism for the glucocorticoid effect is unknown but has been postulated to be due to enhancement of the cyclic AMP response to PTH. This study examined the effect of in vivo administration of a glucocorticoid on adenylate cyclase activity in plasma membranes isolated from mineralized bone. Glucocorticoid excess was induced by implanting cortisone subcutaneously in adult female guinea pigs. At the end of 3 weeks skeletal plasma membranes were obtained, and adenylate cyclase activity was compared with that of normal age-matched guinea pigs. The specific activity of basal adenylate cyclase activity was significantly greater in the cortisone-treated animals (77.7 +/- 10 vs. 41.9 +/- 4.4 pmol cAMP/mg protein/15 min, p < 0.005), but PTH stimulated both to an equal degree. In contrast to the increased specific activity of intact adenylate cyclase, the specific activity of the catalytic unit was lower in the membranes from cortisone-treated animals. We also examined the effect of cortisone treatment on the modulation of adenylate cyclase by divalent cations. Neither the KaMg or the ability of Ca2+ to inhibit enzyme activity was found to differ between normal and cortisone-treated animals. In addition, PTH caused an increase in Mg2+ affinity in both sets of membranes to a comparable degree. The effect of cortisone could not be attributed to altered amounts of Ni present in these membranes; we were unable to satisfactorily quantitate the amounts of Ns.(ABSTRACT TRUNCATED AT 250 WORDS)

A large body of evidence demonstrates the prevalence and adverse clinical consequences of magnesium deficiency in patients with diabetes mellitus. It would be prudent for physicians who treat these patients to consider magnesium deficiency as a contributing factor in many diabetic complications and in exacerbation of the disease itself. Repletion of the deficiency or prophylactic supplementation with oral magnesium may help avoid or ameliorate such complications as arrhythmias, hypertension, and sudden cardiac death and may even improve the course of the diabetic condition.

Magnesium (Mg) deficiency in man may result in hypocalcemia, impaired PTH secretion, and low serum concentrations of 1,25-dihydroxyvitamin D [1,25-(OH)2D]. To determine whether these changes are due to selective Mg depletion, we studied 26 normal subjects before and after a 3-week low Mg (less than 1 meq/day) diet. This diet induced Mg deficiency, as demonstrated by a fall in pre- to postdiet serum Mg levels from 0.80 +/- 0.01 to 0.61 +/- 0.02 mmol/L (P less than 0.001), an increase in Mg retention from 11 +/- 4% to 62 +/- 4% (P less than 0.001), and a fall in red blood cell free Mg2+ from 205 +/- 10 to 162 +/- 7 microM (P less than 0.001). Serum calcium (Ca) fell significantly from 2.36 +/- 0.02 to 2.31 +/- 0.03 mmol/L (P less than 0.05), and serum 1,25-(OH)2D fell from 55 +/- 4 to 43 +/- 3 pmol/L (P less than 0.05). PTH secretion was impaired, as demonstrated by a fall or no change in serum PTH in 20 of 26 subjects despite a fall in the serum Ca and Mg. In addition, an iv injection of Mg in eight subjects after the diet resulted in a significant rise in PTH from 15 +/- 2 to 19 +/- 2 ng/L (P less than 0.01), whereas a similar injection given to six of the subjects before the diet resulted in a significant fall from 28 +/- 5 to 13 +/- 3 ng/L (P less than 0.001). The fall in serum 1,25-(OH)2D may be due to both the decrease in PTH secretion and a renal resistance to PTH. PTH resistance was suggested, as no increase in serum 1,25-(OH)2D was observed in the six subjects in which the PTH concentration rose by mean of 68% after the diet. Also, the rise in serum 1,25-(OH)2D after a 6-h human PTH-(1-34) infusion was significantly less after Mg deprivation. The results demonstrate that mild Mg depletion can impair mineral homeostasis and may be implicated as risk factor for osteoporosis in disorders such as chronic alcoholism and diabetes mellitus, in which Mg deficiency and osteoporosis are both common.

A dose-ranging, baseline-controlled study was undertaken to assess the safety and effectiveness of a 24-hour infusion of etidronate disodium in treating patients with hypercalcemia of malignant disease. Patients with hypercalcemia refractory to at least 48 h of saline loading (greater than 3 1/day) with two albumin-adjusted serum calcium values between 11.1 and 12.0 mg/dl or one albumin-adjusted serum calcium greater than 12.0 mg/dl within 48 h of therapy were admitted to the study. A total of 26 patients were treated in a dose-escalating fashion with 5, 10, 15, 20 or 25 mg/kg of intravenous etidronate disodium over 24 h. Patients treated with 5, 10 or 15 mg/kg did not have significant reductions in albumin-adjusted serum calcium during the first 7 days. In the 6 patients who made up the 20 mg/kg group, adjusted serum calcium levels fell from an average of 13.8 +/- 0.5 mg/dl on day 1 before infusion to 11.7 +/- 0.3 mg/dl (p less than 0.05) by day 7. In the 8 patients in the 25 mg/kg group, adjusted serum calcium levels decreased from an average of 12.9 +/- 0.5 mg/dl on day 1 before infusion to 10.9 +/- 0.4 mg/dl (p less than 0.05) by day 7. All 8 patients in the 25 mg/kg group achieved a fall in albumin-adjusted serum calcium to less than 11.1 mg/dl within the 1 week with a minimum decrement of 0.6 mg/dl and a maximum of 5.5 mg/dl.(ABSTRACT TRUNCATED AT 250 WORDS)