Evidence for parathyroid failure in magnesium deficiency.

Serum immunoreactive parathyroid hormone (IPTH) was low to nondetectable in spite of hypocalcemia in a patient with chronic magnesium deficiency. The administration of magnesium led to parallel increases in serum IPTH, serum calcium, and renal phosphate clearance. These findings support the view that magnesium depletion may result in impaired synthesis or release of parathyroid hormone in man, or both.

Thyrocalcitonin, EGTA, and urinary electrolyte excretion.

The infusion of thyrocalcitonin (TCT) into thyroparathyroidectomized rats, given either no exogenous parathyroid hormone or a constant infusion of this hormone, leads to a transient phosphaturia and a decreased excretion of urinary magnesium, calcium, and hydroxyproline without a change in glomerular filtration rate. The changes in phosphate excretion may be due to a direct effect of the hormone upon renal tubular function or they may be a consequence of the fall in plasma calcium brought about by the action of TCT upon bone. In support of this latter alternative is the fact that the infusion of sodium ethylenebis-oxyethylenenitrilotetraäcetic acid (EGTA, a specific chelator of calcium) also leads to phosphaturia presumably as a consequence of hypocalcemia. However, EGTA infusion leads to enhanced urinary hydroxyproline excretion and sustained phosphaturia. These latter observations are interpreted to mean that alterations in the local ionic environment of osteolytic cells lead to changes in their activity and constitute a local regulatory system whose activity is modulated by the hormones, thyrocalcitonin and parathyroid hormone.

Calcium metabolism in newborn infants. The interrelationship of parathyroid function and calcium, magnesium, and phosphorus metabolism in normal, "sick," and hypocalcemic newborns.

Serum immunoreactive parathyroid hormone (iPTH) and plasma total calcium, ionized calcium, magnesium, and phosphorus levels were determined during the first 9 days of life in 137 normal term infants, 55 "sick" infants, and 43 hypocalcemic (Ca <7.5 mg/100 ml; Ca(++)<4.0 mg/100 ml) infants. In the cord blood, elevated levels of plasma Ca(++) and Ca were observed, while levels of serum iPTH were either undetectable or low. In normal newborns during the first 48 h of life there was a decrease in plasma Ca and Ca(++), while the serum iPTH level in most samples remained undetectable or low; after 48 h there were parallel increases in plasma Ca and Ca(++) and serum iPTH levels. Plasma Mg and P levels increased progressively after birth in normal infants. In the sick infants, plasma Ca, Ca(++) and P levels were significantly lower than in the normal newborns, while no significant differences were found in the plasma Mg levels. The general pattern of serum iPTH levels in the sick infants was similar to that observed in the normal group, though there was a tendency for the increase in serum iPTH to occur earlier and for the iPTH levels to be higher in the sick infants. In the hypocalcemic infants, plasma Mg levels were consistently lower than in the normal infants after 24 h of age, while no significant differences were found in the plasma P levels. Hyperphosphatemia was uncommon and did not appear to be a contributing factor in the pathogenesis of hypocalcemia in most infants. Most of the hypocalcemic infants, including those older than 48 h, had inappropriately low serum iPTH levels. Evidence obtained from these studies indicates that parathyroid secretion is normally low in the early new born period and impaired parathyroid function, characterized by undetectable or low serum iPTH, is present in most infants with neonatal hypocalcemia. Additional unknown factors appear to contribute to the lowering of plasma Ca in the neonatal period. The net effect of unknown plasma hypocalcemic factor(s) on the one hand and parathyroid activity on the other may account for differences in plasma Ca levels observed between normal, sick, and hypocalcemic infants. Depressed plasma Mg is frequently present in hypocalcemic infants. To what degree the hypomagnesemia reflects parathyroid insufficiency or the converse, to what degree parathyroid insufficiency and hypocalcemia are secondary to hypomagnesemia, is uncertain.

Thyrocalcitonin and the response to parathyroid hormone.

1) In the absence of the thyroid gland, the infusion of parathyroid hormone leads to a prompt rise in plasma calcium and to prompt increase in the rate of excretion of calcium in the urine.2) In the presence of the thyroid gland, the parathyroid hormone-induced rise in plasma calcium is less marked; the rate of urinary calcium excretion falls initially and rises only after 20 to 30 hours of continuous parathyroid hormone infusion.3) The infusion of exogenous thyrocalcitonin along with the parathyroid hormone into a thyroparathyroidectomized animal leads to a pattern of response similar to that seen in the animal with an intact thyroid gland.4) Thyrocalcitonin has little apparent effect upon the immediate changes in renal function induced by parathyroid hormone.5) We conclude that bone is a major site of action of thyrocalcitonin and that it probably inhibits bone resorption.

Renal adenylate cyclase and the interrelationship between parathyroid hormone and vitamin D in the regulation of urinary phosphate and adenosine cyclic 3',5'-monophosphate excretion.

This study examined the role of cyclic AMP in the phosphaturic response to parathyroid hormone in vitamin D-deficient rats. Infusion of purified bovine parathyroid hormone (13.3 mug/h) into control, D-fed, or D-deficient, thyroparathyroidectomized rats produced a sixfold increase in renal phosphate and cyclic AMP excretion in D-fed rats, but only a two- to threefold increase in both parameters in D-deficient animals. Intravenous injection of parathyroid hormone over the dosage range from 1-50 mug/kg resulted in a dose-dependent increase in phosphate and cyclic AMP excretion with both D-fed and D-deficient thyroparathyroidectomized rats. However, the D-deficient rats responded to these injections of parathyroid hormone with a two- to threefold increase in both renal phosphate and cyclic AMP excretion at the highest dose of 50 mug/kg, whereas the D-fed animals' response was 35-fold and 11-fold over control excretion levels of phosphate and cyclic AMP, respectively. To directly examine the role of the renal cortical adenylate cyclase system in the blunted phosphaturic and urinary cyclic AMP responses to parathyroid hormone in D-deficient rats, we prepared a plasma membrane fraction enriched in this enzyme activity from the renal cortex of D-fed and D-deficient thyroparathyroidectomized rats. The renal cortical adenylate cyclase of D-deficient rats showed significantly (P less than 0.001) less activation by parathyroid hormone over the hormone concentration range from 0.3 to 7.0 mug/ml than was observed with the enzyme prepared from D-fed animals. Basal adenylate cyclase activity and the fluoride-stimulated enzyme activity were not altered by the state of D-deficiency. These experiments demonstrate that the blunted phosphaturic response to parathyroid hormone observed in D-deficient rats is associated with the reduced responsiveness of the renal cortical adenylate cyclase to the hormone. Moreover, the defect in the renal membrane adenylate cyclase system appears to be localized at the level of PTH binding to membrane receptors or, alternatively, at the level of transmission of the hormone-receptor binding signal to the catalytic moiety of this membrane enzyme.

Serum calcitonin-lowering effect of magnesium in patients with medullary carcinoma of the thyroid.

The effect of magnesium chloride or magnesium sulfate infusion on circulating levels of immunoreactive calcitonin (iCT) was evaluated on nine occasions in three patients with metastatic medullary carcinoma of the thyroid. One patient was normocalcemic and had normal circulating levels of immunoreactive parathyroid hormone (iPTH), one patient was hypocalcemic and had surgical hypoparathyroidism, and one patient had mild to moderate hypercalcemia associated with bone metastases. The basal serum iPTH levels were undetectable in the latter two patients. In every instance magnesium administration produced a rapid and striking fall in circulating iCT and usually a detectable fall in serum calcium. During the hypermagnesemic state, serum iPTH fell from normal to undetectable in the patient with normal parathyroid function, while serum iPTH levels remained undetectable in the hypoparathyroid patient and in the patient with hypercalcemia associated with bone metastases. The results of these studies indicate that: (a) contrary to what has been reported in normal experimental animals, magnesium administration lowers circulating iCT in human subjects with thyroid medullary carcinoma and (b) the calcium-lowering effect produced by magnesium in patients with medullary carcinoma may, in part at least, be due to a redistribution of body calcium that is not mediated by the actions of either parathyroid hormone or clacitonin.

Renal parathyroid hormone-dependent adenylate cyclase activity after repletion of vitamin D-deficient rats with vitamin D-2.

Rats fed a diet deficient in both vitamin D and Ca2+ exhibited a greater depression of the renal parathyroid hormone (PTH)-dependent adenylate cyclase than was observed in rats fed diets deficient in either vitamin D or calcium. Total serum Ca2+ was decreased from a control level of 11.2 mg/dl to 8.5 mg/dl in rats fed the diet deficient in calcium alone, and to 5.4 mg/dl in rats fed the diet deficient in vitamin D. Serum calcium was decreased further to 4.3 mg/dl in rats fed the diet deficient in both vitamin D and Ca2+. Serum immuno-reactive PTH was significantly elevated over control levels when rats were fed the test diets; however, there were no significant differences between the elevated levels in the three experimental groups. Repletion of rats deficient in vitamin D only with a single oral dose of 3200 I.U. vitamin D-2 resulted in restoration of serum calcium to normal levels, a return of serum PTH to the control state, and an associated increase in PTH-dependent adenylate cyclase activity to the control level by 72 h. Repletion of rats deficient in both vitamin D and Ca2+ with the same dose of vitamin D-2 raised serum Ca2+ to 7.2 mg/dl by 72 h, but did not cause a reduction in circulating PTH, nor did it result in any significant improvement in the responsiveness of the membrane adenylate cyclase to PTH. These results suggest that elevated PTH is a factor in the down regulation of the PTH-dependent adenylate cyclase, but do not rule out a role for calcium as a regulatory factor.

Effects of fluoride on parathyroid hormone secretion and intracellular second messengers in bovine parathyroid cells.

Fluoride ion (F-) alone or in conjunction with aluminum (Al3+) has been shown to stimulate the activity of guanine nucleotide-binding proteins (G proteins) in cell membrane preparations from a variety of cell types and in intact hepatic cells. Several studies have indicated that G proteins are involved in the regulation of parathyroid hormone (PTH) secretion. Intracellular second messengers which modulate PTH secretion (e.g., cAMP) have also been found to be regulated by G proteins. We have, therefore, employed F- as a probe to investigate the possible role of G proteins in the modulation of PTH release and the intracellular second messengers that have been implicated in the control of PTH secretion. F- produces a dose-dependent inhibition of PTH release with a maximal inhibitory effect (67%) at 5 mM. F- exerts its inhibitory effect within 5 min and the degree of suppression of PTH secretion gradually increases over 1 hr. F- (5 mM) inhibits PTH secretion at 0.5 mM Ca2+ to the level observed with 2 mM Ca2+ alone; moreover, the effects of F- and high Ca2+ are not additive. While 1 mM F- suppresses PTH secretion by only 21%, and 10 microM Al3+ has virtually no effect at all, together they inhibit PTH release approximately to the level (63% inhibition) observed with 5 mM NaF alone. In the presence of 10(-5) M dopamine, F- produces a concentration-dependent inhibition of cAMP accumulation (0.684 +/- 0.033 pmoles/10(5) cells at 0 mM F- vs. 0.256 +/- 0.048 at 5 mM F-). However, the F- -induced decrease in cAMP cannot account for the inhibition of PTH release by this agent, since addition of methylisobutylxanthine (10(-4) M) by F- -treated cells raises intracellular cAMP content above that of control cells but fails to reverse the inhibition of PTH release. The cytosolic calcium concentration in Fura-2-loaded cells increases from 210 +/- 20 nM to 340 +/- 44 nM after 5 mM F- was added to incubation media. Prior removal of extracellular Ca2+ by EGTA totally blocks the F- -induced rise in cytosolic Ca2+ without preventing the inhibition of PTH release by NaF. F- also produces a time- and dose-dependent increase in the accumulation of IP, IP2, and IP3 in cells prelabeled with [3H]inositol and incubated with 10 mM Li+, consistent with activation of phospholipase C. We conclude that F- is a potent inhibitor of PTH secretion.(ABSTRACT TRUNCATED AT 400 WORDS)

Effects of extracellular calcium and magnesium on cytosolic calcium concentration in Fura-2-loaded bovine parathyroid cells.

A newly developed calcium-sensitive dye, Fura-2, was employed in dispersed bovine parathyroid cells to study the effects of extracellular calcium and magnesium on cytosolic calcium concentration and parathyroid hormone (PTH) release. In comparison with control cells, Fura-2-loaded parathyroid cells showed the same maximal rate of PTH release, set-point for extracellular Ca++ (the calcium concentration producing half of the maximal inhibition of PTH release), and maximal inhibition of PTH release (71.6%) by high extracellular Ca++. At an extracellular Mg++ concentration of 0.5 mM, raising extracellular Ca++ in a stepwise fashion from 0.5 mM to 2.0 mM produced a dose-dependent, statistically significant (p less than 0.01) increase in cytosolic Ca++ from 198 +/- 24 nM (0.5 mM Ca++) to 411 +/- 21 nM (2.0 mM Ca++) which closely paralleled the concomitant decrease in PTH release. An elevation of extracellular Mg++ from 0.5 mM to 5 mM, at an extracellular Ca++ of 0.5 mM, resulted in a transient spike of cytosolic Ca++ which lasted for approximately 30 seconds, followed by a small but stable increase in the cytosolic Ca++ concentration (174 +/- 7 nM vs. 237 +/- 10 nM, n = 4, p less than 0.01). Prior removal of extracellular calcium by addition of an excess of EGTA did not abolish the transient spike induced by high extracellular magnesium concentrations in Fura-2-loaded cells, suggesting that this rapid increase in cytosolic Ca++ arises, at least in part, from intracellular stores of Ca++. This is supported by the observation that pretreating cells with ionomycin resulted in disappearance of the magnesium-induced spike.(ABSTRACT TRUNCATED AT 250 WORDS)

Parathyroid function and magnesium depletion in the rat.

Hypocalcemia is characteristically observed in magnesium deficiency in a number of animal species. Previous studies demonstrated impaired release of PTH in magnesium-depleted hypocalcemic humans. However, an enigma remains in that, unlike in other animals, hypercalcemia, rather than hypocalcemia, accompanies magnesium deficiency in the rat. Because intact parathyroids are necessary for the development of this hypercalcemia, it has been postulated that magnesium depletion stimulates, rather than impairs, PTH secretion in the rat. In an effort to more directly evaluate this thesis, sequential measurements of circulating immunoreactive PTH (iPTH) were made over a 30-day period in rats maintained on a magnesium-deficient diet and in match-fed controls. In the control rats, serum calcium, magnesium, and iPTH remained relatively constant throughout the study. By contrast, during the first 4 days of a low magnesium diet, serum magnesium decreased to 1.0 mg/dl, serum calcium increased moderately, while serum iPTH increased to a mean level that was twice that in controls. After 5 days, when serum magnesium progressively fell to levels less than 0.6 mg/dl and serum calcium continued to rise, serum iPTH fell to levels significantly lower than the control value. In a second set of experiments, the effect of hypocalcemia on circulating iPTH in magnesium deficiency was evaluated. Circulating iPTH was greatly increased and not significantly different in magnesium-deficient and magnesium-replete animals who were rendered chronically hypocalcemic by diets deficient in either calcium or vitamin D. The results of this study indicate that: 1) in the rat, an increase in PTH secretion occurs early in the genesis of magnesium deficiency in the presence of a modest increase in serum calcium; however, the subsequent further increase in serum calcium counteracts the stimulatory effect of hypomagnesemia on PTH secretion; 2) unlike the human parathyroid gland, the rat parathyroid gland responds appropriately to both hypo- and hypercalcemia in magnesium deficiency; and 3) the hypercalcemia that occurs in the magnesium-deficient rat is not due to increased PTH secretion and must be accounted for by another mechanism.

Elevated circulating immunoreactive calcitonin in the magnesium-deficient normocalcemic rat.

Previous studies indicate that magnesium, like calcium, stimulates the release of calcitonin (CT) from the thyroid gland. On the other hand, C-cell hyperplasia has been noted in magnesium-deficient dogs and rats. To explore further possible interrelationships between magnesium and CT, 21-day-old Sprague-Dawley male rats fed a control diet (0.043% Mg and 0.47 Ca) were match-fed with rats given either a control low calcium diet (0.043% Mg and 0.15% Ca) or a low magnesium-low calcium diet (0.001% Mg and 0.15% Ca). The low calcium content in the magnesium-deficient diet prevented the development of hypercalcemia characteristic of the magnesium-deficient rat. After 17 days, animals were killed by decapitation. Blood was obtained from some animals in the basal state and in other animals 1 min postpentagastrin or 1 min postmagnesium chloride infusion. No significant difference was found in the serum calcium level in the three groups, while the mean serum immunoreactive CT (iCT) level was significantly higher in magnesium-deficient rats both before and after pentagastrin. An acute iv infusion of MgCl2 resulted in significant increases in serum iCT in both the control and magnesium-deficient animals. The results of this study demonstrate that basal serum iCT levels and their response to pentagastrin are increased in magnesium-deficient, normocalcemic animals. The further increase in serum iCT after magnesium infusion in magnesium-depleted animals appears paradoxical and indicates that the relationship between extracellular magnesium and iCT release is not a simple feedback mechanism. It is possible that the increase in circulating iCT may be a response to extracellular-intracellular differences in magnesium concentration. Alternatively, the increased C-cell activity may be secondary to some unknown metabolic alteration induced by magnesium deficiency, rather than to magnesium deficiency per se.

High osmolality: a potent parathyroid hormone secretogogue in dispersed parathyroid cells.

We have examined possible mechanisms by which osmolality might modulate PTH secretion in dispersed bovine parathyroid cells. Increasing medium osmolality by adding sodium chloride causes a marked, dose-dependent increase in PTH release. The maximum effect (4-fold increase) is observed when osmolality is around 650 mosM, with half-maximal stimulation at about 400 mosM. When osmolality is increased to a similar extent with either sucrose or sodium chloride, PTH secretion is enhanced to a comparable degree, suggesting that osmolality itself, rather than ionic strength, is responsible for the increase in PTH secretion. Time course experiments show that the increased secretion of PTH with high osmolality occurs very rapidly (in less than 5 min). In contrast to the suppressive effects of high Ca2+ on PTH release, increasing calcium concentration in the incubation media does not inhibit the stimulation of PTH secretion by high osmolality. Moreover, the effects of dopamine (10(-5) M) and high osmolality on PTH release are additive, further suggesting that high osmolality and cAMP modulate PTH release by different mechanisms. In fact, direct measurement of cellular cAMP in cells exposed to high osmolality shows no change relative to control cells incubated with normal osmolality, 127 +/- 20 vs. 146 +/- 21 fmol/10(5) cells, respectively. Cytosolic Ca2+ increases from 257 +/- 29 nM to 703 +/- 50 nM after 200 mM NaCl is added to the incubation medium at low Ca2+ (0.5mM). Prior removal of extracellular calcium abolished this effect. Increasing the osmolality to a similar level by adding sucrose to the medium does not demonstrate any increase in cytosolic calcium. We conclude that high osmolality is a potent secretogogue in dispersed bovine parathyroid cells. Unlike dopamine and isoproterenol, high osmolality does not act through changes in intracellular cAMP. It also prevents the normal inhibitory effect of high Ca2+ on PTH release. Change of cytosolic Ca2+ is variable and suggests that the effect of high osmolality on PTH release cannot be explained by cytosolic Ca2+ alone. Further understanding of the mechanisms by which osmolality affects PTH release, therefore, may provide clues to the unusual inverse relationship between extracellular and cytosolic calcium and PTH release.

Platelet-derived growth factor stimulates bone resorption by monocyte monolayers.

Resorption of devitalized bone particles by monocytes grown in culture was stimulated by platelet-derived growth factor (PDGF) in a dose-dependent manner. Bone resorption in response to PDGF was time-dependent with a significant increase over control cultures evident by 72 hours. These data are the first to demonstrate stimulation of bone resorption by PDGF in a specific cell type known to resorb bone in vivo and in vitro.

Interaction of parathyroid hormone with membranes of kidney cortex: degradation of the hormone and activation of adenylate cyclase.

Plasma membranes prepared from rat renal cortex contain both a parathyroid hormone-sensitive adenylate cyclase and a potent proteolytic activity which degrades the hormone into peptide fragments. The degree and pattern of degradation was determined by subjecting incubation mixtures to gel filtration and ion exchange chromatography. Estimation of the degree of degradation by acid precipitation of the intact hormone was inadequate since metabolism of the hormone apparently generated acid-insoluble fragments. When parathyroid hormone was incubated with membrane fraction, the capacity of its stimulatory effect on adenylate cyclase decreased steadily. This decrease of PTH activitiy could be closely related to the degradation of intact hormone by the same membrane preparation. The adenylate cyclase and degradative activity appeared to exist in similar membrane structures since they could not be separated by centrifugation through sucrose density gradients. The degradation of the hormone could not be inhibited by Trasylol and pancreatic or soybean trypsin inhibitors and was only slightly inhibited by ribonuclease and benzamidine. Histone (1 mg per ml), on the other hand, was able to decrease the degradation of the hormone and prevent the loss of its activity. Radioimmunoassay of the incubation mixtures showed that the rapid degradation of both amino- and carboxy-terminal regions of the hormone was prevented by histone. The oxidized, inactive hormone was also degraded to the same extent by the renal cortical membrane. Furthermore, the degradative activity was also found in plasma membrane preparations of renal medulla and liver. This lack of hormone and tissue specificity suggests that similar degradative activity exists in all tissues and that caution should be exercised in estimating hormonal potency based on activation of adenylate cyclase.

1,25-dihydroxycholecalciferol stimulates osteoclasts in rat bones in the absence of parathyroid hormone.

Three experiments were carried out to test the time course of effects of 1,25-dihydroxyvitamin D3 [1,25-(OH)2D3] on the ultrastructural morphometry of osteoclasts. The addition of lactose to a vitamin D-deficient diet with a high calcium and phosphate content, fed to weanling rats for 4 weeks, ensured normacalcemia and normophosphatemia and allowed thyroparathyroidectomy without ill effects. In these vitamin D-deficient thyroparathyroidectomized rats, iv injection of 50 ng 1,25-(OH)2D3 resulted in significant changes in the osteoclasts in the metaphysis of the tibiae compared to those in corresponding controls; the size of these cells, their nuclei, ruffled borders, and clear zones enlarged after 6 h and the number of osteoclasts increased after 48 h. Serum calcium and serum phosphate levels increased after 12 h in one experiment, but not in a second experiment. Serum 25-hydroxyvitamin D and serum immunoreactive parathyroid hormone levels were undetectable. Mineralization of metaphyseal bone matrix was normal, as quantified by histomorphometry. When, dependent on the mineral content in the diet, mineralization was impaired and the volume density of the osteoid seams was increased, activation of osteoclasts by 1,25(OH)2D3 was not seen until 12--24 h after injection. It is concluded that a physiological dose of 1,25-(OH)2D3 stimulates the activity of osteoclasts in the absence of parathyroid hormone.

Immunocytological evidence for parathyroid hormone in human fetal parathyroid glands.

Immunostaining with antiserum to bovine parathyroid hormone (PTH) was used to delineate the immunoreactive PTH (iPTH)-containing cells of parathyroid glands from 1 anencephalic and 29 normal human fetuses. The antiserum (GPO 3) cross-reacted with human PTH and recognized the carboxyl-terminal fragments of the PTH molecule. No iPTH-containing cells were observed in the parathyroid glands of the 6 fetuses younger than 10 weeks, in spite of the fact that organized parathyroid glands were identified by histological methods. By contrast, iPTH-containing cells were observed in all fetuses older than 10 weeks of gestation, including the anencephalic fetus. All cells were immunoreactive either at the cellular periphery or as a more diffuse cytoplasmic staining around the nucleus. No immunoreactive cells were observed in the thyroid or thymic parenchyma. The specificity of the immunocytological reaction was tested by the usual procedures. Previous in vitro studies suggested that parathyroid function might be active at 12 weeks of gestation. Our data suggest that iPTH is synthetized by parathyroid glands as as early as 10 weeks of gestation and is also present in the anencephalic fetus. The physiological significance of the early presence of PTH within the fetal parathyroid glands remains to be established.

Impaired release of parathyroid hormone in magnesium deficiency.

Parathyroid hormone release and end-organ responsiveness to parathyroid extract (PTE) were evaluated in a 25-year-old woman with magnesium deficiency associated with hypocalcemia and inappropriately low levels of serum immunoreactive parathyroid hormone (iPTH). End-organ responsiveness to PTE was demonstrated by increases in serum calcium and in urinary phosphorus, cyclic AMP, and hydroxyproline. When the serum calcium was increased from a baseline of 6.9 mg/100 ml to levels of 8.0 mg/100 ml and higher by calcium infusion, the serum iPTH decreased from the low normal range to below the limits of detectability. The intravenous administration of 3 mg/kg of body weight of magnesium led to an abrupt and striking increase in circulating iPTH with a 2-fold increase in one minute, a 6-fold increase in two minutes, and an 8-fold increase in five minutes. The very rapid increase in serum iPTH produced by magnesium infusion in this study suggests an effect of magnesium on hormone secretion rather than an effect on hormone synthesis. The evidence provided by this investigation indicates that the release of parathyroid hormone is impaired in magnesium deficiency and that the level of circulating calcium required for the suppression of parathyroid hormone secretion is lower than that in normal subjects.

Long-term therapy of viramin D-resistant richets with 25-hydroxycholecalciferol.

The long-term effects of the vitamin D metabolite, 25-hydroxycholecalciferol (25-HCC), were evaluated in 2 children with hypophosphatemic vitamin D-resistant rickets. Serial total balance studies demonstrated an apparent lack of correlation between the effects of the vitamin on intestinal absorption of calcium and phosphorus and both the onset of healing in 1 of the 2 patients treated with 5,000 to 7,500 u of the metabolite and the absence of demonstrable radiologic improvement in another patient in whom the final dosage was 20,000 u. per day. At first, the metabolite induced a positive calcium balance in both patients resulting largely from a reduction in intestinal calcium excretion. Despite a continued positive calcium balance, 1 of the 2 patients did not demonstrate further healing, while in the other patient healing was noted even when total calcium balance was negative. Serum phosphate levels did not return to normal in either patient, nor was phosphate excretion altered by 25-HCC. Serum alkaline phosphatase remained elevated in both. Serum immunoassayable parathyroid hormone levels were consistently normal to high-normal in the 2 patients throughout more than 24 months of observation. No instances of hypercalcemia and only occasional hypercalciuric episodes were noted.

Hypercalciuric hypophosphatemic rickets, mineral balance, bone histomorphometry, and therapeutic implications of hypercalciuria.

A 14-year-old Turkish boy had severe rickets that had been clinically evident since he was 2 years of age. When he was 5 years of age, he had normal serum calcium and phosphorus levels and increased alkaline phosphatase activity. Treatment with modest dosages of vitamin D (5000 U/d for 3 weeks) resulted in hypercalcemia. At 10 years of age, high-dose vitamin D (40,000 U/d) plus phosphorus (1.1 g/d) therapy for 20 days resulted in symptomatic nephrolithiasis. When, 14 years of age, he had normocalcemia, hypophosphatemia, increased alkaline phosphatase activity, and normal circulating parathyroid hormone concentration. Levels of 25-hydroxyvitamin D were normal but those of 1,25-dihydroxyvitamin D were markedly increased. Rickets and osteopenia were evident on radiographs, and osteomalacia was present on trabecular bone obtained at biopsy. Balance study results showed increased intestinal absorption of calcium and phosphorus, hypercalciuria, and increased urinary phosphorus excretion. This patient manifests an unusual form of hypophosphatemic rickets in which hypercalciuria is a cardinal feature. In contrast with most varieties of hypophosphatemia, this disorder is characterized by appropriately increased production of 1,25-dihydroxyvitamin D in response to hypophosphatemia. It is recommended that urinary calcium excretion be assessed in all patients with hypophosphatemic rickets so that appropriate therapy will be instituted.

Severe primary hyperparathyroidism in a neonate with two hypercalcemic parents: management with parathyroidectomy and heterotopic autotransplantation.

A neonate with severe primary hyperparathyroidism was successfully managed by parathyroidectomy and heterotopic autotransplantation (one third of one gland of the infant was implanted in the forearm). In vitro studies of parathyroid tissue from the infant revealed a severe defect in parathyroid suppressibility. Postoperatively, the infant had modest hypercalcemia, normal serum immunoreactive parathyroid hormone levels, hypermagnesemia, and relative hypocalciuria. The parents were related and both had asymptomatic hypercalcemia with mean serum immunoreactive parathyroid hormone levels that were within the normal range. Similar to the findings in the infant postoperatively, relative hypocalciuria in the presence of hypercalcemia was found in the mother; in contrast, the father had hypercalciuria. The presumed dominantly transmitted hypercalcemia in this kindred is consistent with familial hypocalciuric hypercalcemia with a confounding factor of ethanol possibly accounting for the hypercalciuria in the father.