Reduction of dietary magnesium by only 50% in the rat disrupts bone and mineral metabolism.

INTRODUCTION: The objective of this study was to determine the effect of a moderate reduction of dietary magnesium [50% of nutrient requirement (50% NR)] on bone and mineral metabolism in the rat, and to explore possible mechanisms for the resultant reduced bone mass. METHODS: Female rats were 6 weeks of age at the start of study. Serum magnesium (Mg), calcium (Ca), parathyroid hormone (PTH), 1,25(OH)(2)-vitamin D, alkaline phosphatase, osteocalcin, and pyridinoline were measured during the study at 3- and 6-month time points in control (dietary Mg of 100% NR) and Mg-deficient animals (dietary Mg at 50% NR). Femurs and tibias were also collected for mineral content analyses, micro-computerized tomography, histomorphometry, and immunohistochemical localization of substance P, TNFalpha, and IL-1beta at 3 and 6 months. RESULTS: Although no significant change in serum Mg was observed, Mg deficiency developed, as assessed by the reduction in bone Mg content at the 3- and 6-month time points (0.69+/-0.05 and 0.62+/-0.04% ash, respectively, in the Mg depletion group compared to 0.74+/-0.04 and 0.67+/-0.04% ash, respectively, in the control group; p=0.0009). Hypercalcemia did not develop. Although serum Ca level remained in the normal range, it fell significantly with Mg depletion at 3 and 6 months (10.4+/-0.3 and 9.6+/-0.3 mg/dl, respectively, compared to 10.5+/-0.4 and 10.1+/-0.6 mg/dl, respectively, in the control group; p=0.0076). The fall in serum Ca in the Mg-depleted animals was associated with a fall in serum PTH concentration between 3 and 6 months (603+/-286 and 505+/-302 pg/ml, respectively, although it was still higher than the control). The serum 1,25(OH)(2)-vitamin D level was significantly lower in the Mg depletion group at 6 months (10.6+/-7.1 pg/ml) than in the control (23.5+/- 12.7 pg/ml) (p<0.01 by the t-test). In Mg-deficient animals, no difference was noted in markers of bone turnover. Trabecular bone mineral content gain was less over time in the distal femur with Mg deficiency at 3 and 6 months (0.028+/-0.005 and 0.038+/-0.007 g, respectively, compared to 0.027+/-0.004 and 0.048+/-0.006 g, respectively, in the control group; p<0.005). Histomorphometry at these time points demonstrated decreased trabecular bone volume (15.76+/-1.93 and 14.19+/-1.85%, respectively, compared to 19.24+/-3.10 and 17.30+/-2.59%, respectively, in the control group; p=0.001). Osteoclast number was also significantly increased with Mg depletion (9.07+/-1.21 and 13.84+/-2.06, respectively, compared to 7.02+/-1.89 and 10.47+/-1.33, respectively, in the control group; p=0.0003). Relative to the control, immunohistochemical staining intensity of the neurotransmitter substance P and of the cytokines TNFalpha and IL-1beta was increased in cells of the bone microenvironment in the Mg depletion group, suggesting that inflammatory cytokines may contribute to bone loss. CONCLUSION: These data demonstrate that Mg intake of 50% NR in the rat causes a reduced bone mineral content and reduced volume of the distal femur. These changes may be related to altered PTH and 1,25(OH)(2)-vitamin D formation or action as well as to an increase release of substance P and the inflammatory cytokines TNFalpha and IL-1beta.

Alterations in growth plate and articular cartilage morphology are associated with reduced SOX9 localization in the magnesium-deficient rat.

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.

Magnesium deficiency: effect on bone and mineral metabolism in the mouse.

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 TNF alpha 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.

Alterations in osteoclast morphology following osteoprotegerin administration in the magnesium-deficient mouse.

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.

Low intracellular magnesium levels promote platelet-dependent thrombosis in patients with coronary artery disease.

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.

Beneficial antithrombotic effects of the association of pharmacological oral magnesium therapy with aspirin in coronary heart disease patients.

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.

Magnesium deficiency-induced osteoporosis in the rat: uncoupling of bone formation and bone resorption.

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.

Oral magnesium supplementation inhibits platelet-dependent thrombosis in patients with coronary artery disease.

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.

Combined effect of vitamin D3 analogs and paclitaxel on the growth of MCF-7 breast cancer cells in vivo.

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.

Magnesium deficiency induces bone loss in the rat.

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.

Assessment of press-fit hip femoral components retrieved at autopsy.

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.

Intracellular magnesium predicts functional capacity in patients with coronary artery disease.

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

Sexual dimorphism in plasma leptin concentration.

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.

Deliberations and evaluations of the approaches, endpoints and paradigms for magnesium dietary recommendations.

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.

Hyperparathyroidism.

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.

Magnesium deficiency: possible role in osteoporosis associated with gluten-sensitive enteropathy.

Osteoporosis and magnesium (Mg) deficiency often occur in malabsorption syndromes such as gluten-sensitive enteropathy (GSE). Mg deficiency is known to impair parathyroid hormone (PTH) secretion and action in humans and will result in osteopenia and increased skeletal fragility in animal models. We hypothesize that Mg depletion may contribute to the osteoporosis associated with malabsorption. It was our objective to determine Mg status and bone mass in GSE patients who were clinically asymptomatic and on a stable gluten-free diet, as well as their response to Mg therapy. Twenty-three patients with biopsy-proven GSE on a gluten-free diet were assessed for Mg deficiency by determination of the serum Mg, red blood cell (RBC) and lymphocyte free Mg2+, and total lymphocyte Mg. Fourteen subjects completed a 3-month treatment period in which they were given 504-576 mg MgCl2 or Mg lactate daily. Serum PTH, 25-hydroxyvitamin D, 1,25-dihydroxyvitamin D and osteocalcin were measured at baseline and monthly thereafter. Eight patients who had documented Mg depletion (RBC Mg2+ < 150 microM) underwent bone density measurements of the lumbar spine and proximal femur, and 5 of these patients were followed for 2 years on Mg therapy. The mean serum Mg, calcium, phosphorus and alkaline phosphatase concentrations were in the normal range. Most serum calcium values fell below mean normal and the baseline serum PTH was high normal or slightly elevated in 7 of the 14 subjects who completed the 3-month treatment period. No correlation with the serum calcium was noted, however. Mean serum 25-hydroxyvitamin D, 1,25-dihydroxyvitamin D and osteocalcin concentrations were also normal. Despite only 1 patient having hypomagnesemia, the RBC Mg2+ (153 +/- 6.2 microM; mean +/- SEM) and lymphocyte Mg2+ (182 +/- 5.5 microM) were significantly lower than normal (202 +/- 6.0 microM, p < 0.001, and 198 +/- 6.8 microM, p < 0.05, respectively). Bone densitometry revealed that 4 of 8 patients had osteoporosis of the lumbar spine and 5 of 8 had osteoporosis of the proximal femur (T-scores < or = -2.5). Mg therapy resulted in a significant rise in the mean serum PTH concentration from 44.6 +/- 3.6 pg/ml to 55.9 +/- 5.6 pg/ml (p < 0.05). In the 5 patients given Mg supplements for 2 years, a significant increased in bone mineral density was observed in the femoral neck and total proximal femur. This increase in bone mineral density correlated positively with a rise in RBC Mg2+. This study demonstrates that GSE patients have reduction in intracellular free Mg2+, despite being clinically asymptomatic on a gluten-free diet. Bone mass also appears to be reduced. Mg therapy resulted in a rise in PTH, suggesting that the intracellular Mg deficit was impairing PTH secretion in these patients. The increase in bone density in response to Mg therapy suggests that Mg depletion may be one factor contributing to osteoporosis in GSE.

Magnesium transport induced ex vivo by a pharmacological dose of insulin is impaired in non-insulin-dependent diabetes mellitus.

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.

Disorders of magnesium metabolism.

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.