低钙透析液对CAPD患者钙磷代谢的影响

目的观察低钙腹膜透析液（1．25mmol／L）（LCD）与标准钙离子浓度（1．75mmol／L）的腹膜透析液（SCD）对CAPD患者钙磷代谢的影响。方法选择血钙高于正常或高钙磷乘积的CAPD患者57例，随机分成两组：SCD组24例；LCD组33例。观察两组患者血钙、磷、镁、全段甲状旁腺激素（iPTH）和皮肤瘙痒情况的变化，及不良反应。观察时间为6个月。结果共53例完成6个月的观察，其中SCD22例，LCD31例。6个月后两组的血钙水平均有所下降，但LCD组血钙水平较前明显下降（P〈0．05），SCD组无统计学意义（P〉0．05）；SCD组患者的血清磷、镁及钙磷乘积无明显变化，而LCD组上述指标明显下降，与SCD组比较具有统计学意义（P〈0．05）；与SCD相比，LCD组的iPTH水平明显升高（P〈0．05）；LCD患者皮肤瘙痒情况有所改善，但无统计学意义（P〉0．05）。观察期间LCD组患者无低血压、低钙抽搐等情况发生。结论低钙腹膜透析液能够较好控制血钙水平，降低血磷，减轻对甲状旁腺的抑制，可能在预防和改善动力缺失性骨病的发生和发展过程中发挥重要的作用。     

Evidence for Skeletal Resistance to Parathyroid Hormone in Magnesium Deficiency: STUDIES IN ISOLATED PERFUSED BONE

Hypocalcemia during magnesium (Mg) depletion has been well described, but the precise mechanism(s) responsible for its occurrence is not yet fully understood. The hypocalcemia has been ascribed to decreased parathyroid hormone (PTH) secretion as well as skeletal resistance to PTH. Whereas the former is well established, controversy exists as to whether or not Mg depletion results in skeletal resistance to PTH. These studies examine the skeletal response to PTH in normal dogs and dogs fed a Mg-free diet for 4-6 mo. Isolated tibia from normal (serum Mg 1.83+/-0.1 mg/100 ml) and experimental dogs (serum Mg 1.34+/-0.15 mg/100 ml) were perfused with Krebs-Henseleit buffer during a constant infusion of 3 ng/ml of synthetic bovine PTH 1-34 (syn b-PTH 1-34). The arteriovenous (A-V) difference for immunoreactive PTH (iPTH) across seven normal bones was 37.5+/-3%. In contrast, the A-V difference for iPTH was markedly depressed to 10.1+/-1% across seven bones from Mg-depleted dogs. These findings correlated well with a biological effect (cyclic AMP [cAMP] production) of syn b-PTH 1-34 on bone. In control bones, cAMP production rose from a basal level of 5.8+/-0.2 to 17.5+/-0.7 pmol/min after syn b-PTH 1-34 infusion. In experimental bones, basal cAMP production was significantly lower than in controls, 4.5+/-0.1 pmol/min, and increased to only 7.1+/-0.4 pmol/min after syn b-PTH 1-34 infusion. Even when PTH concentrations were increased to 20 ng/ml, cAMP production by experimental bones was lower than in control bones perfused with 3 ng/ml. Histological examination of bones from Mg-deficient dogs showed a picture compatible with skeletal inactivity. These studies demonstrate decreased uptake of iPTH and diminished cAMP production by bone, which indicates skeletal resistance to PTH in chronic Mg deficiency.     

Hypocalcemia may not be essential for the development of secondary hyperparathyroidism in chronic renal failure.

Hypocalcemia is the main factor responsible for the genesis of secondary hyperparathyroidism in chronic renal disease. Studies with parathyroid cells obtained from uremic patients indicate that there is a shift in the set point for calcium-regulated hormone (parathyroid hormone [PTH] secretion. Studies were performed in dogs to further clarify this new potential mechanism. Hypocalcemia was prevented in uremic dogs by the administration of a high calcium diet. Initially, ionized calcium was 4.79 +/- 0.09 mg/dl and gradually increased up to 5.30 +/- 0.05 mg/dl. Despite a moderate increase in ionized calcium, immunoreactive PTH (iPTH) increased from 64 +/- 7.7 to 118 +/- 21 pg/ml. Serum 1,25(OH)2D3 decreased from 25.4 +/- 3.8 to 12.2 +/- 3.6 pg/ml. Further studies were performed in two other groups of dogs. One group received 150-200 ng and the second group 75-100 ng of 1,25(OH)2D3 twice daily. The levels of 1,25(OH)2D3 increased from 32.8 +/- 3.5 to a maximum of 69.6 +/- 4.4 pg/ml. In the second group the levels of serum 1,25(OH)2D3 after nephrectomy remained normal during the study. Amino-terminal iPTH did not increase in either of the two groups treated with 1,25(OH)2D3. In summary, the dogs at no time developed hypocalcemia; however, there was an 84% increase in iPTH levels, suggesting that hypocalcemia, per se, may not be the only factor responsible for the genesis of secondary hyperparathyroidism.     

Osteomalacia and Hyperparathyroid Bone Disease in Patients with Nephrotic Syndrome

Patients with nephrotic syndrome have low blood levels of 25 hydroxyvitamin D (25-OH-D) most probably because of losses in urine, and a vitamin D-deficient state may ensue. The biological consequences of this phenomenon on target organs of vitamin D are not known. This study evaluates one of these target organs, the bone. Because renal failure is associated with bone disease, we studied six patients with nephrotic syndrome and normal renal function. The glomerular filtration rate was 113+/-2.1 (SE) ml/min; serum albumin, 2.3+/-27 g/dl; and proteinuria ranged between 3.5 and 14.7 g/24 h. Blood levels of 25-OH-D, total and ionized calcium and carboxy-terminal fragment of immunoreactive parathyroid hormone were measured, and morphometric analysis of bone histology was made in iliac crest biopsies obtained after double tetracycline labeling. Blood 25-OH-D was low in all patients (3.2-5.1 ng/ml; normal, 21.8+/-2.3 ng/ml). Blood levels of both total (8.1+/-0.12 mg/dl) and ionized (3.8+/-0.21 mg/dl) calcium were lower than normal and three patients had true hypocalcemia. Blood immuno-reactive parathyroid hormone levels were elevated in all. Volumetric density of osteoid was significantly increased in three out of six patients and the fraction of mineralizing osteoid seams was decreased in all. Evidence for an increase in active lacunae (bone-osteoclast interface) occurred in three out of six patients and in inactive (Howship's lacunae) bone resorption in six out of six. The data indicate that the loss of 25-OH-D in urine of patients with nephrotic syndrome and normal renal function may result in a decrease of blood levels of ionized calcium, secondary hyperparathyroidism and enhanced bone resorption. In addition, the vitamin D-deficient state causes osteomalacia as evidenced by defective mineralization and increased osteoid volume.     

Pathogenesis of hypocalcemia in magnesium depletion: Normal end-organ responsiveness to parathyroid hormone

Hypocalcemia in the hypomagnesemic state in man is usually attributed to refractoriness of end-organs to the calcemic action of parathyroid hormone. We studied the responsiveness of end-organs to bovine parathyroid extract (PTE) in magnesium-depleted and control dogs by the following three methods after thyroparathyroidectomy: (a) assessment of the calcemic response to a set dose of PTE (0.3 U/kg per hr); (b) assessment of PTE dose required to attain normocalcemia; (c) evaluation of regression lines of plasma calcium concentration on PTE dose. The calcemic response of magnesium-depleted thyroparathyroidectomized puppies to a set dose of PTE was similar to that of control puppies. There was no significant difference in the dose of PTE required to attain normocalcemia nor in the dose-response relations between the plasma calcium concentration and the PTE dose. In a group of magnesium-depleted puppies with intact thyroid and parathyroid glands, the dose of PTE required to attain normocalcemia was similar to that required in thyroparathyroidectomized animals, indicating calcitonin was not a factor contributing to hypocalcemia. We conclude that hypocalcemia in magnesium-depleted puppies is not due to refractoriness of end-organs to the calcium-mobilizing action of parathyroid hormone. Defective synthesis or diminished secretion of parathyroid hormone is suggested as an explanation.     

Bone and parathyroid inhibitory effects of S-2(3-aminopropylamino)ethylphosphorothioic acid. Studies in experimental animals and cultured bone cells.

S-2-(3-aminopropylamino)ethylphosphorothioic acid (WR 2721) is a radio- and chemoprotective agent which produces hypocalcemia in humans. Intravenous injection of 30 mg/kg WR 2721 in rats and 15 mg/kg in dogs lowers serum calcium by 19 and 25%, respectively. Hypocalcemia in dogs is associated with a fall in serum immunoreactive parathyroid hormone (PTH), which suggests that the mechanism of its hypocalcemic effect is acute hypoparathyroidism. Despite this effect on PTH, in eight chronically parathyroidectomized rats on a low phosphate diet, WR 2721 reduced serum calcium from 9.4 +/- 0.6 to 7.7 +/- 0.5 mg/dl (P less than 0.01) at 3 h. Furthermore, in dogs rendered hypercalcemic by continuous infusion of PTH, WR 2721 reduced serum calcium from 11.0 +/- 0.5 to 10.6 +/- 0.5 mg/dl (P less than 0.01). To determine whether WR 2721 causes hypocalcemia by enhancing the exit of calcium from the circulation or inhibiting its entry, the drug was infused 3 h after administration of 45Ca to rats. WR 2721 did not significantly increase the rate of disappearance of 45Ca from the circulation even though serum calcium fell by 19%. However, serum 45Ca specific activity was higher at 1.5 h (P less than 0.01) and 3 h (P less than 0.05) in rats given WR 2721 than in rats given vehicle alone, which suggests that WR 2721 blocks the entry of nonradioactive calcium into the circulation, presumably from bone. In incubations with fetal rat long bone labeled in utero with 45Ca, 10(-3) M WR 2721 inhibited PTH-stimulated, but not base-line release of 45Ca. Bone resorption by primary culture of chick osteoclasts was inhibited by WR 2721 at concentrations as low as 10(-4) M in the absence of hormonal stimulation. These studies suggest that WR 2721 lowers serum calcium predominantly by blocking calcium release from bone. This acute hypocalcemic effect is at least in part independent of its effect on the parathyroid glands, and is most likely a direct effect of the agent on bone resorption.     

Positive correlation of serum bio-intact PTH(1-84) but not intact PTH with parathyroid gland size in hemodialysis patients.

To evaluate the usefulness of newly-developed bio-intact parathyroid hormone (Bio-PTH) assay, which measures exclusively intact PTH(1-84) molecule, serum PTH level determined by Bio-PTH assay, in comparison with second-generation intact PTH (I-PTH) assay, was examined for its correlation with parathyroid gland size. Serum PTH was determined in 46 male HD patients, together with bone formation markers bone alkaline phosphatase, intact osteocalcin, N-terminal propeptide of type I collagen, and bone resorption markers deoxypyridinoline, pyridinoline, beta-crossLaps. Maximal diameter of parathyroid gland was determined with ultrasonography as the parathyroid gland size. Serum Ca and Pi correlated significantly with parathyroid gland size rationalizing our method to define parathyroid gland size. Serum Bio-PTH was correlated significantly in a positive manner with parathyroid gland size (R = 0.308, P = 0.0474), whereas serum I-PTH did not. Furthermore, parathyroid gland size did not exhibit a significant correlation with any of bone formation markers or bone resorption markers. The lack of correlation between bone markers and parathyroid gland size in HD patients may be explained by the occurrence of refractoriness of bone to PTH. In conclusion, serum Bio-PTH assay could provide a better assay than I-PTH assay to estimate parathyroid function in HD patients, due mainly to its exclusive correlation with parathyroid gland size.     

Autosomal dominant hypocalcemia with a novel CASR mutation: a case study and literature review

Autosomal dominant hypocalcemia type 1 (ADH1) is a rare inherited disorder characterized by hypocalcemia with low parathyroid hormone (PTH) levels and high urinary calcium. Its clinical presentation varies from mild asymptomatic to severe hypocalcemia. It is caused by gain-of-function mutations in the calcium-sensing receptor gene (CASR) which affect PTH secretion from the parathyroid gland and calcium resorption in the kidney. Here, we describe a case who presented with symptoms of recurrent seizure caused by hypocalcemia with a novel CASR variant. We comprehensively analyzed the phenotypic features of this presentation and reviewed the current literature to better understand clinical manifestations and the genetic spectrum.     

Calcium homeostasis during therapeutic plasma exchange

Because the removal of substantial quantities of plasma calcium during plasma exchange is rarely attended by clinically significant hypocalcemia, we evaluated calcium homeostasis during this procedure. Twenty-one procedures were performed on 10 patients with various neurological disorders. The reduction by plasma exchange in the serum concentrations of total calcium, ionized calcium, magnesium, and phosphate was significantly less than predicted (p less than 0.001) based on plasma volume of the patient and size of the exchange. However, N-terminal parathomone (PTH) levels increased to 242 +/- 120 percent midway into the procedure and were 207 +/- 84 percent after plasma exchange; urinary cyclic adenosine monophosphate (cAMP) levels rose by 165 +/- 35 percent. These data demonstrate a rapid compensatory response in N-terminal PTH and urinary cAMP to the reduction by plasma exchange of serum concentrations of total calcium, ionized calcium, and phosphate. The routine administration of supplemental calcium during plasma exchange may therefore be unnecessary in patients with normal parathyroid function.     

Urinary cyclic AMP analyzed as a function of the serum calcium and parathyroid hormone in the idfferential diagnosis of hypercalcemia.

Urinary cyclic AMP (UcAMP) appropriate for the serum calcium concentration was determined in normal subjects during the base-line state and during alteration in their serum calcium concentrations by saline and calcium infusions. This was compared to the UcAMP in 76 patients with hypercalcemia and 5 patients with hypocalcemia. In 54 of 56 patients with primary hyperparathyroidism, the UcAMP was inappropriately high for their serum calcium concentration, the 2 exceptions having renal failure. In four patients with vitamin D intoxication, sarcoidosis, milkalkali syndrome, and thiazide-induced hypercalcemia and in five patients with hypocalcemia due to hypoparathyroidism, the UcAMP was appropriately low for their serum calcium concentration. In 16 patients with nonparathyroid neoplasms, 10 had UcAMP levels that were inappropriately high suggesting ectopic parathyroid hormone (PTH)-mediated hypercalcemia and 6 had UcAMP levels that were appropriately low suggesting that their hypercalcemia was due to osteolytic factors other than PTH. Correlations between UcAMP, serum calcium concentration, and carboxyl-terminal immunoreactive PTH suggest that random UcAMP is a sensitive accurate reflection of circulating biologically active PTH. If there is adequate renal function (serum creatinine concentration less than 2.0 mg/dl), a random UcAMP expressed as mumol/g creatinine and analyzed as a function of the serum calcium concentration completely separates patients with PTH and non-PTH-mediated hypercalcemia.     

A double-blind placebo-controlled crossover trial of intravenous magnesium sulfate for foscarnet-induced ionized hypocalcemia and hypomagnesemia in patients with AIDS and cytomegalovirus infection

Foscarnet (trisodium phosphonoformate hexahydrate) is an antiviral agent used to treat cytomegalovirus disease in immunocompromised patients. One common side effect is acute ionized hypocalcemia and hypomagnesemia following intravenous administration. Foscarnet-induced ionized hypomagnesemia might contribute to ionized hypocalcemia by impairing excretion of preformed parathyroid hormone (PTH) or by producing target organ resistance. Prevention of ionized hypomagnesemia following foscarnet administration could blunt the development of ionized hypocalcemia. To determine whether intravenous magnesium ameliorates the decline in ionized calcium and/or magnesium following foscarnet infusions, MgSO(4) at doses of 1, 2, and 3 g was administered in a double-blind, placebo-controlled, randomized, crossover trial to 12 patients with AIDS and cytomegalovirus disease. Overall, increasing doses of MgSO(4) reduced or eliminated foscarnet-induced acute ionized hypomagnesemia. Supplementation, however, had no discernible effect on foscarnet-induced ionized hypocalcemia despite significant increases in serum PTH levels. No dose-related, clinically significant adverse events were found, suggesting that intravenous supplementation with up to 3 g of MgSO(4) was safe in this chronically ill population. Since parenteral MgSO(4) did not alter foscarnet-induced ionized hypocalcemia or symptoms associated with foscarnet, routine intravenous supplementation for patients with normal serum magnesium levels is not recommended during treatment with foscarnet.     

单采血小板前后献血者血清甲状旁腺素及电解质的变化

目的观察单采血小板前后献血者血清甲状旁腺素及电解质浓度的变化。方法选择单采血小板献血者45名,分为补钙组(n=11)和未补钙组(n=34),分别检测血小板采集前后血清甲状旁腺素(PTH)和钙、磷、钾、钠、镁离子浓度;献全血组(n=24)。结果单采后补钙组PTH浓度有统计学意义(t=2.472,P<0.05),未补钙组单采后磷浓度升高(t=3.191,P<0.05);单采血小板献血者采前血清磷、钙、钠的浓度低于对照组(t值分别为2.477,2.349和2.064,P<0.05),但仍在正常范围内。结论单采血小板会引起献血者血钙浓度短暂降低,但机体可自身迅速调节,不必常规补钙;单采血小板献血者采集前血清磷、钙、钠的浓度低于全血献血者。     

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.     

Inhibitory effects of hypermagnesemia on the renal action of parathyroid hormone.

Available evidence indicates that serum magnesium (Mg++) levels influence the secretion rate of parathyroid hormone (PTH). Whether serum Mg++ concentrations also modify the action of PTH on its target organs has not been definitively established. The present experiments were designed to study this possibility. The effect of infusing PTH on the urinary excretion of cyclic AMP (cAMP) and PO4= was examined in five normal dogs at two different levels of serum Mg++. At normal serum Mg++ concentrations (1.89 +/- 0.14 mg/100 ml), PTH infusion increased cAMP excretion from 1.76 +/- 0.27 to 4.87 +/- 1.00 nmol/min and fractional PO4= excretion (FEPO4) from 1.58 +/- 0.36% to 23.1 +/- 2.17%. When an identical amount of PTH was given to the same dogs at a serum Mg++ of 4.36 +/- 0.20 mg/100 ml, FEPO4 increased to only 6.02+/-1.89% and cAMP from 1.31 +/- 0.23 to 1.89 +/- 0.39 nmol/min. Identical results were obtained in thyroparathyroidectomized hypermagnesemic dogs. Increased serum Mg++ levels had no effect on the phosphaturia produced by the infusion of dibutyryl cAMP to thyroparathyroidectomized dogs. In vitro studies using rat renal cortical slices revealed a progressive decrease in cAMP production in response to PTH as the Mg++ concentrations were increased in the incubation medium. The overall results indicate that hypermagnesemia inhibits the phosphaturic response to PTH by decreasing the renal production of cAMP. Plasma magnesium, therefore, may participate in a double feedback mechanism, not only controlling the release of PTH, but also altering the biological activity of the hormone at the level of the target organ.     

Changes in serum and urinary calcium during phosphate depletion: studies on mechanisms

The changes in serum calcium and the renal handling of this ion were evaluated during phosphate depletion. 96 renal clearance studies were carried out in 10 dogs before and after prolonged phosphate depletion (30-160 days) and after repletion. Depletion was produced by reducing phosphate intake and administering aluminum hydroxide gel while intakes of sodium, calcium, and magnesium were constant. With phosphate depletion, serum phosphorus fell to less than 1.0 mg/100 ml and diffusible serum calcium either remained unchanged or rose transiently. Glomerular filtration rate (GFR) fell by 15 to 53%. Despite the reduced filtered load of calcium, its fractional excretion increased in most experiments. This hypercalciuria was not dependent upon changes in sodium or magnesium excretion, or the urinary concentration of complexing anions, and persisted after sodium restriction. Phosphate repletion reversed the effects on GFR and calcium excretion. The intravenous infusion of small quantities of phosphate (0.04 mmole/min) into either intact or thyroparathyroidectomized (T-PTX), phosphate-depleted animals caused a significant reduction in fractional excretion of calcium, but the intrarenal infusion of 0.02 mmole/min of phosphate into one kidney failed to produce an ipsilateral effect. The administration of parathyroid extract reduced fractional calcium excretion, but the latter remained significantly elevated. After T-PTX, fractional calcium excretion did not increase in the phosphate-depleted animals. Furthermore, serum calcium was normal after T-PTX until serum phosphorus increased slightly, and only then did hypocalcemia develop. These observations indicate that (a) phosphate depletion produces hypercalciuria through a reduction in tubular reabsorption of calcium which is not due to changes in the tubular reabsorption of other ions; this effect is not reversed by the direct intrarenal infusion of phosphate; (b) a state of functional hypoparathyroidsm occurs during phosphate depletion which may, in part, cause reduced tubular reabsorption of calcium; (c) other extra renal mechanism(s), possibly related to events occurring in bone as a result of phosphate depletion, may have an effect on urinary calcium excretion; and (d) in the phosphatedepleted state, parathyroid hormone is not required for the maintenance of a normal level of serum calcium.     

Calcimimetic compound NPS R-568 stimulates calcitonin secretion but selectively targets parathyroid gland Ca(2+) receptor in rats.

N-(3-[2-Chlorophenyl]propyl)-(R)-alpha-methyl-3-methoxybenzylamine (NPS R-568) is an orally active compound that activates Ca(2+) receptors on parathyroid cells and rapidly suppresses plasma levels of parathyroid hormone (PTH) and Ca(2+) (ED(50), 1 and 10 mg/kg, respectively). We now show that increased calcitonin secretion contributes to NPS R-568-induced hypocalcemia. In parathyroidectomized thyroid-intact rats in which normocalcemia was restored by PTH infusion, NPS R-568 rapidly reduced plasma Ca(2+) levels, indicating that decreased PTH secretion was not solely responsible for the hypocalcemia seen in normal animals. NPS R-568 decreased plasma Ca(2+) levels in thyroidectomized parathyroid-intact rats, but the rate of onset of hypocalcemia was slower than in controls. In contrast, NPS R-568 had no effect on plasma Ca(2+) levels in PTH-infused, thyroparathyroidectomized rats, providing evidence that increased calcitonin secretion caused the hypocalcemia in PTH-infused parathyroidectomized rats. NPS R-568 rapidly increased plasma calcitonin levels to a peak at 10 to 20 min after oral dosing (ED(50) 40 mg/kg). NPS R-568 did not affect the rate of disappearance of (45)Ca from blood, indicating that hypocalcemia resulted from decreased influx of Ca(2+) into the circulation and not from increased efflux. This suggests that NPS R-568-induced hypocalcemia resulted solely from reduced efflux of Ca(2+) from bone after increased calcitonin and reduced PTH secretion. Thus, NPS R-568 causes hypocalcemia by activating Ca(2+) receptors on C cells and parathyroid cells; however, NPS R-568 is about 40 times more potent in reducing PTH levels than in increasing calcitonin levels.     

Physiological doses of calcium regulatory hormones do not normalize bone cells in uraemic rats.

BACKGROUND: Low bone turnover despite normal parathyroid hormone (PTH) concentrations has been found in many patients with end-stage renal failure. Hyporesponsiveness to the calcaemic action is also a known feature of uraemia. Hyporesponsiveness of bone surface cells involved in bone modelling has not been demonstrated to date. It was the purpose of this study using a rat model of moderate renal failure to investigate whether doses of PTH and calcitriol that reverse the effect of parathyroidectomy on calcaemia also normalize bone surface cell activity. MATERIALS AND METHODS: Sham-operated pair-fed male Spraque-Dawley rats were compared with subtotally nephrectomized (SNX), parathyroidectomized (PTX) rats that received either solvent or calcitriol (5 pmol kg -1 h-1) + 1,34 rat PTH (100 ng kg -1 h-1) by osmotic mini-pump. Histomorphometric measurements were carried out in the vertebral body (L5). RESULTS: In SNX/PTX animals, calcitriol + 1,34 rat PTH caused a modest increase in serum calcium (S-Ca) within the normal range. Osteoclast surface per cent was significantly lower in solvent-treated SNX/PTX rats than in sham-operated controls [3.7 +/- 2.8 osteoclast surface/bone surface (OcS/BS%) vs. 6.3 +/- 3.9], and this was not normalized by PTH + calcitriol (3.3 +/- 3). In contrast, osteoblast surface per cent and osteoid surface per cent were increased over values in sham-operated rats; as a result, co-administration of calcitriol and 1,34 rat PTH caused a highly significant increase in fractional bone volume (BV/TV). CONCLUSIONS: The results show that administration of PTH and calcitriol in doses that raise serum calcium fails to normalize the percentage of osteoclast surface, but was effective in raising osteoblast number and osteoblast volume in experimental renal failure. The results argue for abnormal response of bone cells to calcium-regulating hormones and/or the action of factors other than calcium regulatory hormones in the genesis of skeletal abnormalities of renal failure.     

Pharmacology of the extracellular calcium ion receptor

The calcium sensing receptor (CaSR) belongs to family 3 of G-protein coupled receptors. The CaSR, expressed at the surface of the parathyroid cells, controls parathyroid hormone (PTH) secretion and is the main regulator of calcium homeostasis. Its activity is regulated by small changes in the physiological concentrations of calcium and magnesium ions present in the serum and extracellular fluids, leading to the stimulation of the phospholipases C and A2. Molecules that potentiate the effect of extracellular calcium are called calcimimetics. They reduce the PTH level in vivo and have been proposed to be of therapeutic benefit for the treatment of both primary and secondary hyperparathyroidism. The blocking of CaSR by a calcilytic molecule results in the increase in serum PTH and might be of interest in the treatment of osteoporosis. The CaSR is also expressed in the thyroid, kidney, bone and in neuronal and glial cell populations, where it should be involved in the complex responses associated with calcium and magnesium ions present in the extracellular fluids.     

Exaggerated phosphaturic response to circulating parathyroid hormone in patients with familial X-linked hypophosphatemic rickets.

To determine whether the phosphaturic response to circulating parathyroid hormone (PTH) is exaggerated in patients with familial x-linked hypophosphatemic vitamin D-resistant rickets (FHR), we examined the phosphaturic response to parathyroid extract (PTE) (administered intravenously in the posthypercalcemic state) in two unrelated adult hemizygotes with FHR. In these two patients whose plasma concentration of PTH was normal (determined by radioimmunoassay). neither vitamin D nor phosphate therapy had been given during the past 10 yr. Two normal men and a hypophosphatemic man with intestinal malabsorption, hypocalcemia, and osteomalacia served as control subjects. In all subjects, calcium gluconate was adminstered intravenously from 6 p.m. to 12 midnight at a rate that maintained the concentration of serum calcium at 13-15 mg/100 ml during the administration of calcium. When normocalcemia had recurred the next morning, and the plasma PTH concentration and urinary excretion of cyclic 3', 5'-AMP were reduced. PTE was administered intravenously at successively increasing rates of 0.1, 0.4, and 0.8 U/kg per h, each rate lasting 90 min. Minutes after the initiation of PTE in the affected hemizygotes, fractional excretion of filtered phosphate increased from negligible values to values strikingly greater than those of similarly studied control subjects and plateaued at strikingly greater values throughout further administration of PTE. This phenomenon of exaggerated phosphaturia could not be attributed to volume expansion, decreases in serum concentration of calcium during the study, differences in percent of administered calcium retained, or hemodynamic changes. Only the phosphaturic response to PTE appeared to be exaggerated. At any cumulative dose of PTE, urinary excretion of cyclic 3', 5'-AMP in the hemizogytes was indistinguishable from that of control subjects. The findings in this study suggest that in patients with FHR, circulating PTH is required for the genetically transmitted abnormality to be physiologically expressed as a reduction in net renal reabsorption of phosphate, and that this physiological expression of the genetic abnormality is expressed fully at normal or nearly normal circulating levels of PTH.     

Estrogen receptors and biologic response in rat parathyroid tissue and C cells.

The expression of the PTH and calcitonin genes is dramatically decreased by 1,25(OH)2D3 in vivo, and the PTH gene expression is increased by hypocalcemia. We have now studied the effect of estrogens on the expression of these genes in vivo. 17 beta-Estradiol, given to ovariectomized rats, led to a fourfold increase in PTH mRNA and calcitonin mRNA levels. These effects occurred 24 h after single injections of 37-145 nmol estradiol, or after constant infusions of 12 pmol/d for 1 or 2 wk, where there was no effect on serum calcium levels. The estrogen receptor mRNA was demonstrated in the thyroparathyroid tissue by polymerase chain reaction. The estrogen binding was localized to the parathyroid and C cells by immunohistochemistry. Uterus weight was increased by repeated larger doses (73 nmol/d x 7) of estradiol, but not by the small doses (12 pmol/d for 1 or 2 wk) which were effective on the PTH and calcitonin genes, suggesting a sensitive endocrine effect. These results confirm that the parathyroid and C cells are target organs for estrogen, leading to an increased expression of PTH and calcitonin, which by their combined anabolic effect on bone would help prevent osteoporosis.