A microassay for serum dialyzable calcium and magnesium by ion chromatography

We describe a method for determining dialyzable calcium and dialyzable magnesium in 50-microliter volumes of routinely handled aerobic serum. Calcium and magnesium concentrations were measured by ion chromatography after a 1-min equilibrium dialysis. Day-to-day precision (coefficient of variation, CV) was 3.8% for dialyzable calcium and 4.5% for dialyzable magnesium. Dilution of serum with water 1:1 as well as storage at 4 or -20 degrees C had no significant effects. Reference intervals for dialyzable calcium (58.1-68.1 mg/l) and magnesium (12.3-17.1 mg/l) were determined for 26 healthy adults. Lack of interference and the ability to determine simultaneously several analytes on a single specimen are advantages of the chromatographic method.     

Effect of intravenous administration of cimetidine on renal excretion of calcium, phosphates, magnesium and adenosine cyclic monophosphate

An effect of cimetidine on parathyroid glands functioning in healthy subjects was evaluated. Serum calcium, phosphate, and magnesium concentrations together with renal excretion++ of these ions in healthy subjects as well as cAMP excretion++ in selected individuals were determined before and following intravenous administration of cimetidine (Altratmet Lek Ljublijana) in total dose of 500 mg (50 mg injected rapidly as a bolus following with 450 mg in an intravenous infusion during 60 minutes). No significant changes in serum calcium, phosphates, and magnesium concentrations were noted. Renal clearance of calcium and magnesium remained unchanged whereas renal phosphate excretion++ increased from 10.69 +/- 4.9 mL/min to 15.1 +/- 5.41 mL/min (p less than 0.02). Excretion++ of 3.5 cAMP increased from 2.65 +/- 2.19 nM/min to 5.16 +/- 2.0 nM/min (p less than 05). The obtained results do not exclude stimulating effect of intravenous cimetidine on parathyroid glands. Cimetidine given intravenously in the bleeding gastric or duodenal ulcers in the course of the primary hyperparathyroidism+ may decrease serum phosphate levels due to increased exretion of this ion with the urine.     

The impact of diets with different magnesium contents on magnesium and calcium in serum and tissues of the rat

The impact of three different magnesium diets (70, 1,000 and 9,000 ppm) on total, ionized and bound magnesium as well as ionized calcium in serum and total calcium and magnesium in femoral bone, skeletal muscle, heart and liver of male Sprague-Dawley rats was investigated. The percentage of ionized serum magnesium was unproportionally high in rats fed a low magnesium (70 ppm) diet. Femoral magnesium was correlated with ionized and total serum magnesium. In contrast, there was generally no correlation between total serum magnesium and the magnesium fractions in skeletal muscle, heart and liver. In rats fed the magnesium deficient diet, total cardiac concentration of magnesium was even significantly increased along with total calcium content, while there were no effects on total muscle and liver magnesium. Within the single groups, ionized serum calcium was never proportional to dietary magnesium, but in all three magnesium diet groups together, it was inversely correlated with dietary magnesium. Moreover, ionized serum calcium was inversely correlated with both ionized and total serum magnesium. In all 3 groups together, the concentrations of total calcium and magnesium in heart and skeletal muscle were correlated, within the single groups correlation existed only in the 1000 ppm group. Magnesium influx via calcium channels during low magnesium intake has been seen in non cardiac tissues [35,36], but nothing similar is known about non selective channels for divalent cations in the heart [33]. Thus, magnesium uptake by cardiac cells along with calcium seems to be possible, especially at low intracellular magnesium concentrations, but is still poorly investigated. We suggest that the calcium-antagonistic effect of magnesium is related to the turnover rate of magnesium rather than to its tissue concentrations.     

Serum calcium and magnesium concentrations and the use of a calcium-magnesium-borogluconate solution in the treatment of Friesian mares with retained placenta

The purpose of the present study was to compare serum calcium and magnesium concentrations in mares with or without a retained placenta (RP) and to evaluate treatment of mares with RP with oxytocin versus oxytocin combined with Ca-Mg-borogluconate solution. Blood samples were obtained within 12 h of foaling from Friesian mares with and without an RP (n = 90 and 65, respectively). Serum Ca and Mg concentrations were analyzed by atomic absorption spectrophotometry. In total, we treated 112 cases of RP in 101 Friesian mares by infusion of either oxytocin dissolved in saline solution or oxytocin dissolved in Ca-Mg-borogluconate solution. We defined RP as the failure to expel all or a part of the fetal membranes up to 3 h after delivery of the foal. We defined a positive response to the treatment as the passage of the entire placenta within 2 h after the infusion. Mares with RP had significantly lower serum calcium levels within 12 h of foaling than mares without RP. Serum magnesium levels showed no difference. Sixty-four percent of the mares treated with oxytocin in Ca-Mg-borogluconate solution responded positively to the treatment, compared to 44% of the mares treated with oxytocin in saline solution (P < 0.05).     

An unusual patient with hypercalciuria, recurrent nephrolithiasis, hypomagnesemia and G227R mutation of Paracellin-1. An unusual patient with hypercalciuria and hypomagnesemia unresponsive to thiazide diuretics

A 19-year-old female patient with hypercalciuria and recurrent nephrolithiasis/urinary tract infection unresponsive to thiazide type diuretics is presented. The patient first experienced nephrolithiasis at the age of 4 years. Afterwards, recurrent passages of stones and urinary tract infection occurred. On diagnostic evaluation at the age of 19 years, she also had hypocitraturia and hypomagnesemia. Her serum calcium concentrations were near the lower limit of normal (8.5-8.8 mg/dl; normal range: 8.5-10.5), her serum magnesium concentrations were 1.15-1.24 mg/dl (normal range: 1.4-2.5) and urinary calcium excretion was 900 mg/24 h. PTH concentrations were increased (110-156 pg/ml; normal range: 10-65). We tried to treat the patient with hydrochlorothiazide at a dose of 50 mg/day. During treatment with thiazide diuretics, PTH concentration remained high and the patient had recurrent urinary tract infections and passages of stones. Serum magnesium concentration did not normalize even under the parenteral magnesium infusion. Her mother had a history of nephrolithiasis 20 years ago. Severe hypomagnesemia in association with hypercalciuria/urinary stones is reported as a rare autosomal recessive disorder caused by impaired reabsorption of magnesium and calcium in the thick assending limp of Henle's loop. Recent studies showed that mutations in the CLDN16 gene encoding paracellin-1 cause the disorder. In exon 4, a homozygous nucleotide exchange (G679C) was identified for the patient. This results in a point mutation at position Glycine227, which is replaced by an Arginine residue (G227R). The mother was heterozygous for this mutation. G227 is located in the fourth transmembrane domain and is highly conserved in the claudin gene family. This case indicates the pathogenetic role of paracellin-1 mutation in familial hypomagnesemia with hypercalciuria and nephrocalcinosis and further underlines the risk of stone formation in heterozygous mutation carriers.     

Dilantin and salicylate effects on hepatic thyroxine bio-availability and dialyzable thyroxine

Earlier studies have shown that drugs such as dilantin inhibit T4 binding by thyroid hormone binding globulin (TBG) and cause a displacement of T4 from TBG to prealbumin with no change in the albumin-bound T4 fraction. Since recent studies have shown albumin-bound T4 is freely transported into liver, the present studies are designed to investigate drug effects on T4 transport in liver. The effect of salicylate and diphenylhydantoin (Dilantin) on T4 in human serum were examined both in vitro by using equilibrium dialysis and in vivo in the rat liver by using a tissue sampling single injection technique. Serum was obtained from 6 healthy normal volunteers and was made either 0 or 0.5 mM Dilantin and either 0 or 10 mM sodium salicylate. The portal vein injection vehicle contained 125I-T4/3H-water (highly diffusible internal reference) mixed with either a) Ringer's (0.1 g/dl albumin), b) 5% T4 antiserum, or c) 80% human serum. The free dialyzable fraction in vitro was raised by 40 and 125% after the addition of Dilantin and salicylate respectively. However, the percent of total T4 that was transported into liver on one pass, 17 +/- 1%, was not different in the control, the salicylate treated, or the Dilantin-treated sera. Therefore, in contrast to the in vitro dialyzable measurement of free T4, which is elevated by toxic concentrations of Dilantin or salicylate, the bio-available fraction of T4 as determined by the single pass perfusion technique, is unchanged in rat liver in vivo. These drug-induced changes in free T4 in vitro and bio-available T4 in vivo are similar to the ones reported previously in non-thyroidal illness.     

Effect of various chloride salts on the utilization of phosphorus, calcium, and magnesium

Only part of the effect of dietary protein on urinary calcium excretion can be ascribed to sulfur amino acids. We hypothesized that chloride, another factor often associated with isolated proteins, and another amino acid, lysine, affect utilization of calcium. The effects of supplemental dietary chloride, inorganic or organic, on calcium, phosphorus, and magnesium utilization were studied in two rat studies. Weanling Sprague-Dawley rats were fed semi-purified diets that contained moderate (1.8 mg Cl/g diet) or supplemental (15.5 mg Cl/g diet) chloride as sodium chloride, potassium chloride, or lysine monohydrochloride with or without calcium carbonate for 56 or 119 days. Rats fed supplemental sodium chloride or potassium chloride had higher urinary phosphorus excretion, more efficient phosphorus absorption, but unchanged tissue phosphorus levels after 7 and 16 weeks of dietary treatment as compared to rats fed moderate chloride. Rats fed supplemental sodium chloride or potassium chloride excreted more calcium in urine at 7 weeks and absorbed calcium less efficiently at 16 weeks. Tissue calcium concentrations were unaffected, but total tibia magnesium and plasma magnesium concentrations were lower in rats fed supplemental sodium chloride or potassium chloride than those fed moderate chloride. Lysine chloride with or without additional calcium elevated urinary calcium excretion even more than sodium chloride and potassium chloride ingestion. Rats fed lysine chloride with supplemental calcium had smaller apparent absorption and urinary losses of phosphorus and magnesium after 16 weeks and lower tibia and plasma magnesium concentrations than rats fed lysine chloride.     

Concentrations of trace elements in sera of newborns, young infants, and adults

Concentrations of trace elements in newborns, infants, and adults may be significantly different from each other. Serum trace element reference ranges for different age groups are of value for diagnostic purposes. Inductively coupled plasma-mass spectrometry was applied to the determination of the 21 trace elements Ba, Be, Bi, Ca, Cd, Co, Cs, Cu, La, Li, Hg, Mg, Mn, Mo, Pb, Rb, Sb, Sn, Sr, TI, and Zn in a total of 117 sera of individuals representing different age groups. After microwave-assisted acid digestion with high-purity reagents, 20 umbilical cord sera, 5 sera of fully breast-fed infants, 6 sera of formula-fed infants, 66 sera of patients suffering internal diseases, and 20 sera of healthy blood donors were analyzed for trace elements. One serum and two whole-blood reference materials were analyzed for quality control. Experimental concentrations were in good agreement with certified values. Umbilical cord serum concentrations of the essential elements Ca, Co, Cu, and Mg and of the nonessential and toxic elements Ba, Be, Li, Pb, and Sb were elevated compared to the elemental concentrations in the sera of infants and adults. Serum levels of Ba, Ca, Co, Mn, Pb, and Sb of infants were much higher and serum Cu was significantly lower than in adults. Serum Cu increased significantly with age (newborns: 353 microg/L; infants: 755 microg/L; healthy adults: 810 microg/L), whereas for other trace elements no age-dependence could be established.     

Correlation between manifestations of digoxin toxicity and serum digoxin,calcium, potassium,and magnesium concentrations and arterial pH.

In 18 patients with gastrointestinal manifestations of digoxin toxicity the mean serum digoxin concentration (+/- SEM) was 3.16 micrograms/l (+/- 0.25), the calcium to potassium ratio 0.31 (+/- 0.01), and the mean arterial pH 7.406 (+/- 0.017). In contrast 19 patients with digoxin induced automaticity had a mean serum digoxin concentration of 1.24 micrograms/l (+/- 0.15; p less than 0.001), a calcium to potassium ratio of 0.38 (+/- 0.01; p less than 0.01), and an arterial pH of 7.498 (+/- 0.008; p less than 0.001). Eight out of 13 patients with digoxin induced cardiotoxicity had serum concentrations of the drug within the therapeutic range (0.8-2.0 micrograms/l). The calcium to potassium ratio, however, was lower than in the patients with automaticity (0.31 +/- 0.02; p less than 0.01) and the arterial pH was 7.370 (+/- 0.033; p less than 0.05). Serum magnesium concentrations were similar in all groups. In this study patients with digoxin induced gastrointestinal symptoms had high serum concentrations of the drug, whereas those with drug induced automaticity had therapeutic concentrations. This second group, however, was identified by their higher calcium to potassium ratios and higher pH values.     

Magnesium and the Risk of Cardiovascular Events: A Meta-Analysis of Prospective Cohort Studies

Background

Prospective studies that have examined the association between dietary magnesium intake and serum magnesium concentrations and the risk of cardiovascular disease (CVD) events have reported conflicting findings. We undertook a meta-analysis to evaluate the association between dietary magnesium intake and serum magnesium concentrations and the risk of total CVD events.

Methodology/Principal Findings

We performed systematic searches on MEDLINE, EMBASE, and OVID up to February 1, 2012 without limits. Categorical, linear, and nonlinear, dose-response, heterogeneity, publication bias, subgroup, and meta-regression analysis were performed. The analysis included 532,979 participants from 19 studies (11 studies on dietary magnesium intake, 6 studies on serum magnesium concentrations, and 2 studies on both) with 19,926 CVD events. The pooled relative risks of total CVD events for the highest vs. lowest category of dietary magnesium intake and serum magnesium concentrations were 0.85 (95% confidence interval 0.78 to 0.92) and 0.77 (0.66 to 0.87), respectively. In linear dose-response analysis, only serum magnesium concentrations ranging from 1.44 to 1.8 mEq/L were significantly associated with total CVD events risk (0.91, 0.85 to 0.97) per 0.1 mEq/L (P_nonlinearity = 0.465). However, significant inverse associations emerged in nonlinear models for dietary magnesium intake (P_nonlinearity = 0.024). The greatest risk reduction occurred when intake increased from 150 to 400 mg/d. There was no evidence of publication bias.

Conclusions/Significance

There is a statistically significant nonlinear inverse association between dietary magnesium intake and total CVD events risk. Serum magnesium concentrations are linearly and inversely associated with the risk of total CVD events.     

The effects of fasting and refeeding on serum parathormone and calcitonin concentrations in young and old male rats.

Although fasting and refeeding reveal the existence of age-related changes in carbohydrate and lipid metabolism, the effects of aging on mineral metabolism in refed animals are unknown. We therefore investigated hormonal regulation of calcium metabolism in young (4 months) and old (26 months) male rats fasted for 48 hours and then refed for 4 or 24 hours. Serum concentrations of total and ionized calcium and parathormone were similar in control young and old rats. Serum calcitonin level was higher, and the concentrations of albumin and inorganic phosphate and alkaline phosphatase activity were lower in fed old rats. In young fasted rats, the serum ionized and total calcium was decreased, and phosphate concentration was increased. In old rats, fasting resulted in the increase of serum parathormone level. Fasting reduced serum alkaline phosphatase activity to a similar extent in both age groups. In young rats, refeeding for 24h normalized serum calcium and phosphate levels and alkaline phosphatase activity, and decreased serum concentrations of PTH and calcitonin. In old refed rats, serum calcitonin concentration was raised by 77% compared to fed or fasted animals, whereas parathormone levels were normalized. Our results indicate that old fasted or refed rats maintain normal serum calcium concentration in a different way than young animals, possibly through the increase in serum levels of parathormone and/or calcitonin. Thus, dietary manipulations such as fasting and refeeding constitute an interesting model for the investigation of the effects of aging on the hormonal regulation of serum calcium level.     

Sodium and calcium balance in Mozambique tilapia, Oreochromis mossambicus, raised at different salinities

Mozambique tilapia, Oreochromis mossambicus, born and raised in five salinities, viz. (relatively soft) fresh water, 25, 50, 75% and full-strength sea-water, were analyzed for ionoregulatory performance (in particular sodium and calcium handling) and growth. This tilapia regulates its blood serum mineral composition rather effectively; however, in sea-water serum concentrations of sodium, chloride and calcium (in males only) were increased, as was the serum osmolarity. In sea-water, the total body sodium pool was significantly enlarged. With increasing salinity, sodium turnover increased. Serum calcium levels and the total body calcium pool were more strictly controlled than those of sodium. The lowest density of chloride cells in opercular epithelium and the lowest branchial Na+-K+-ATPase activity were observed in 50% sea-water; these values were higher in fish kept in waters of lower or higher salinities. Fish grew more rapidly in brackish water. Fish kept in brackish water appeared to depend on food-related calcium for growth as branchial calcium uptake provides no more than 20% of growth related Ca-accumulation.     

Serum calcium concentrations in white sucker, Catostomus commersoni Lacepède, and bluegill, Lepomis macrochirus Rafinesque, in northern Wisconsin lakes: relation to pH and waterborne calcium

We measured serum calcium concentrations in mature white suckers and bluegills collected from clear-water Wisconsin lakes before spawning. The mean serum calcium concentration in female white suckers was greater in a circumneutral lake than in two naturally acidic lakes, whereas mean concentrations in fish from the two acidic lakes did not differ. Serum calcium concentrations in female bluegills from four acidic and four circumneutral lakes varied among lakes, but no relation was apparent between serum calcium level and either lake pH or waterborne calcium. In contrast, a strong negative correlation between mean serum calcium concentration and relative density of bluegill populations in the eight lakes was observed, suggesting that serum calcium levels in this species are affected by density-dependent factors. Mean serum calcium concentrations were substantially lower in mature male bluegills than in females, which is the norm prior to spawning. We hypothesized that serum calcium levels in female white suckers are depressed by exposure to pH 6.0 or less in calcium-poor waters. The utility of serum calcium concentrations, measured before spawning, as a measure of pH-related stress on populations of white suckers and other synchronous spawners merits further study. However, this measure is probably not useful for evaluating acid stress on fish species such as the bluegill, which have asynchronous reproductive cycles.     

Acute effect of hydrochlorothiazide on renal calcium and magnesium handling in postmenopausal women

A single 50 mg dose of hydrochlorothiazide (HCTZ) decreases the urinary excretion of calcium (U(Ca)V), clearance (C(Ca)) and fractional excretion (FE(Ca)) of calcium. This is accompanied by an increase of total calcium and ionized calcium (Ca2+) concentrations in the serum. On the other hand, HCTZ increases fractional excretion of magnesium (FE(Mg)) and decreases serum Mg2+ concentrations. Moreover, HCTZ decreases markedly clearance of phosphate (C(Pi)) and fractional excretion of phosphate (FE(Pi)) and increases serum phosphate (Pi) concentrations in healthy postmenopausal women. It is concluded that intrinsic renal cellular control promptly uncouples calcium and magnesium tubular reabsorption even without K+ depletion.     

Effect of dietary calcium on serum BGP (osteocalcin).

The present study was designed to clarify the effects of dietary calcium (Ca) intake on serum BGP (osteocalcin) levels. Twelve women with a mean age of 21.2 years participated in the study. After one week of normal Ca intake (mean +/- SE, 535 +/- 2 mg/day), a low-Ca diet (163 +/- 1 mg/day) was given for one further week. Additional asparagine Ca (3 g as Ca/day) was also given to half of the subjects. Serum total and ionized Ca concentrations as well as BGP, PTH and 1,25(OH)2D3 were measured at the end of each period. Amounts of Ca and hydroxyproline excreted in urine were also determined. The plasma level of ionized Ca was significantly increased without any change in total Ca in either group. Low and high Ca intake decreased and increased urinary Ca excretion by 28% and 56%, respectively. Serum levels of BGP and 1,25(OH)2D3 were significantly augmented along with a transient increase in urinary hydroxyproline excretion after Ca deprivation. These results suggest that serum BGP is increased after one week of Ca restriction in healthy subjects.     

Platelet ionic calcium and serum total calcium in essential hypertension

A total of 44 cases comprising hypertensive (31) and normotensive group (13) were studied. Serum total calcium concentrations remained unaltered in hypertensives. Platelet cytosolic calcium in hypertensive group was significantly higher as compared to the normotensive controls. Platelet cytosolic calcium correlated with systolic and diastolic blood pressure and mean arterial pressure significantly.     

Bone fragility in sarcoidosis and relationships with calcium metabolism disorders: a cross sectional study on 142 patients

Introduction

The prevention of fragility fractures in patients with sarcoidosis is a serious concern and the potential risk of hypercalcemia limits vitamin D and calcium supplementation. The objective of this study was to evaluate the risk factors for low bone mineral density (BMD) and fractures in sarcoidosis. In particular, we aimed to determine the link among bone fragility and calcium and vitamin D metabolism in this population.

Methods

We performed a cross-sectional analysis on 142 consecutive patients with histologically proven sarcoidosis. BMD and prevalence of vertebral fractures on X-rays were assessed and the association with potential risk factors was studied by regression analysis.

Results

Fragility fractures occurred in 23.5% of patients, despite a normal mean BMD in the study population. In a multivariate analysis, low dietary calcium, fracture, age, gender and menopause were associated with increased risk of low BMD. Low dietary calcium, high current corticosteroid dose and low creatinine clearance were associated with increased risk of fracture. Serum 25(OH)D between 10 and 20 ng/ml was significantly associated with higher BMD. Conversely, values greater than 20 ng/ml were associated with increased risk of fracture. Serum 25(OH)D level was inversely correlated with disease activity. Of note, vitamin D supplements increased serum 25(OH)D in a dose-dependent manner but had no effect on serum calcium level.

Conclusions

Sarcoidosis patients have a high risk of fracture despite not having a lowered BMD suggesting that other independent factors are involved. Current corticosteroid dose, low dietary calcium and serum 25(OH)D levels are associated with bone fragility. In sarcoidosis, calcium and vitamin D supplementation might be warranted, but desirable 25(OH)D serum levels might be lower than those advised for the general population.     

Genetic variability in response to dietary calcium

Supplemental dietary calcium has been shown to reduce blood pressure in spontaneously hypertensive rats while restricted calcium diets cause an elevation in blood pressure. This latter nutrient effect has been enhanced by modest sodium restriction and is associated with a reduction in serum ionized calcium concentration. To determine whether alterations of dietary calcium and sodium have a similar influence on blood pressure in genetically normotensive rats, Fisher 344, Wistar Furth, and ACI rats were fed either a low (0.1%) calcium, low (0.25%) sodium diet or normal (1.0%) calcium, normal sodium (0.45%) diet from 4 weeks of age through 29 weeks of age. Indirect measurements of systolic blood pressure showed that only the Fisher 344 rats consistently responded to the low calcium/low sodium diets with an elevation of blood pressure. There was considerable variation in serum electrolytes across strains in the normal diets but all three strains experienced a reduction in ionized calcium and an elevation in phosphorus and magnesium on the restricted diets. In the Fisher 344 rats there were significant (p less than .05) inverse correlations among systolic blood pressure and serum ionized and total calcium concentrations and positive correlations among systolic blood pressure, phosphorus, and magnesium. There was no significant correlation between serum electrolytes and blood pressure in the other two strains. The data indicate that there is genetic variability in the blood pressure response to alterations in dietary calcium and sodium. The pattern of change in serum electrolytes across strains suggests that diet-induced alterations of serum electrolytes, specifically calcium, are not necessarily predictive of a pressor response. It would appear that some other calcium-sensitive physiological process involved in blood pressure regulation must respond differentially to calcium availability across strains.     

Indices of calcium metabolism in women with hip fractures

We have assessed indices of calcium metabolism in 41 women with hip fractures and compared them with two elderly control groups. The women with hip fractures had lower serum concentrations of albumin, 25-hydroxyvitamin D and osteocalcin than the controls. Serum concentrations of calcium, alkaline phosphatase and parathyroid hormone, as well as urinary hydroxyproline/creatinine ratios were similar in the three groups of women. The small reduction in serum osteocalcin concentration in fracture patients is consistent with the hypothesis that reduced osteoblast function may contribute to the osteoporosis which results in hip fracture.     

Relation of serum calcium concentration to metabolic risk factors for cardiovascular disease.

Data from a health screening survey with over 18,000 adult participants were used to determine the relations between serum calcium concentration and the cardiovascular risk factors hypertension, hyperglycaemia, and hyperlipidaemia. Blood pressure and serum glucose and cholesterol concentrations were all positively related to each other independent of age, sex, kidney function, and obesity. Similar relations between the risk factors were found in subjects with hypertension or hyperglycaemia independent of the degree of overweight. These results suggested that there might be a metabolic syndrome of cardiovascular risk factors. Serum calcium concentration was positively related to systolic and diastolic blood pressures and serum glucose and cholesterol concentrations. Thus a common feature in the syndrome is an increased serum calcium concentration. The relations between serum calcium concentrations and the cardiovascular risk factors were not limited to the upper parts of the distribution, being seen over a wide range. Changes in calcium metabolism seem to be related to a metabolic syndrome of hypertension, impaired glucose tolerance, and hyperlipidaemia.