Decreased Parathyroid Hormone Secretion Research Articles

New calcimimetics for secondary hyperparathyroidism in CKD G5D: do they offer advantages?

Secondary hyperparathyroidism is one of the most frequent metabolic abnormalities found in patients with chronic kidney disease. The calcium-sensing receptor senses extracellular calcium and is the principal regulator of parathyroid hormone secretion. Cloning of the calcium-sensing receptor led to the development of calcimimetics, drugs that decrease parathyroid hormone secretion through the positive allosteric modulation of this receptor. Cinacalcet was the first oral calcimimetic approved by the US Food and Drug Administration (FDA) in 2004 for the treatment of secondary hyperparathyroidism in adult patients on dialysis. Although cinacalcet has demonstrated safety and effectiveness, it has two main problems: gastrointestinal side effects that result in poor adherence, and the inhibitory action on CYP2D6 with the possibility of interactions with commonly used medications. To address the problem of oral compliance, Etelcalcetide, a small synthetic polycationic peptide IV calcimimetic was introduced in 2017. This drug showed a 10% greater decrease in serum parathyroid hormone values compared to cinacalcet but no better gastrointestinal tolerance, with greater risk of hypocalcemia. Several structural modifications were introduced in cinacalcet to produce a new compound called evocalcet. This drug, which was introduced in Japan in 2018, has considerably enhanced bioavailability and decreased both the inhibitory effect on CYP2D6 and half of the gastrointestinal side effects of cinacalcet. Finally, a novel non-peptidic injectable calcimimetic agent, upacicalcet, became available in Japan in 2021. This agent has greater clearance by hemodialysis and shows no effect on gastric emptying. More studies are needed comparing the old calcimimetics to the new ones to establish their future role in the treatment of secondary hyperparathyroidism in chronic kidney disease (CKD) G5D.

Abstract #1088796: Non-Ischemic Cardiomyopathy in Setting of Functional Hypoparathyroidism Secondary to Hypomagnesemia

Magnesium (Mg) is involved in many biochemical reactions and low levels can have negative effects on the entire cardiovascular system. These can occur directly or indirectly via dysfunction in calcium homeostasis. We present a case of severe hypomagnesemia leading to functional hypoparathyroidism in the setting of newly diagnosed cardiomyopathy (CMO) and the importance of aggressive electrolyte repletion as a mainstay in the management of heart failure. 71 year-old male with history of squamous cell lung cancer status post cisplatin-based chemoradiation, CKD, DM2, and GERD presented with dyspnea on exertion and recurrent hypocalcemia. Two months prior, he was diagnosed with non-ischemic CMO with ejection fraction (EF) of 10% in the setting of TSH >100. On admission, he had Mg 0.5 mg/dL (1.6-2.5 mg/dL), calcium (Ca) 6.9 mg/dL (8.4-10.4 mg/dL), ionized calcium (iCa) 3.0 mg/dL (4.4-5.4 mg/dL), phosphorous 5.4 (2.5-4.5 mg/dL) and inappropriately normal parathyroid hormone (PTH) of 50 pg/mL (15-65 pg/mL). Since prior admission TSH and free T4 had improved to 26.96 and 1.3, respectively after adding levothyroxine. On exam, he had tachycardia, bilateral rhonchi, and pitting edema in the lower extremities. NT-BNP was 16,474 and EKG showed sinus tachycardia with lateral T-wave inversions. Chvostek sign was negative, with no perioral numbness or paresthesia. Electrolytes were repleted aggressively. He was discharged on oral Ca and Mg supplements in addition to heart failure medical therapy. Labs on discharge showed improvement in Mg to 2.0 mg/dL, iCa 3.8 mg/dL, phosphorous 3.3 mg/dL, and PTH of 89 pg/mL. Seven months later, his EF% doubled on echocardiogram. Follow up EF% did not recover further despite euthyroidism due to noncompliance with Ca and Mg supplements. Hypomagnesemia is a potential cause of CMO and medications are a significant risk factor that must be considered. Our patient was exposed to cisplatin, chronic PPI use and loop diuretics, which can all chronically decrease Mg stores in the body. Low Mg leads to defects in cyclic AMP generation in the parathyroid gland, which causes decreased PTH secretion and low Ca. This is evidenced by the inappropriately normal PTH in our patient despite low Ca levels. Of note, he had history of hypothyroidism but low EF persisted despite appropriate repletion and normalization of T4 levels. Previous cases have reported hypocalcemia-induced CMO, but few have described the hypomagnesemia as an underlying cause of this finding. This case underlines the importance of monitoring and repletion of Mg and Ca in addition to goal-directed medical therapy for optimized heart failure management.

Parathyroid Hormone Level Changes Following Radioiodine Therapy for Thyroid Cancer: A Prospective Observational Study

ObjectiveOur objective was to analyze the effect of radioiodine (RAI) therapy on parathyroid hormone (PTH) secretion. MethodsA total of 137 patients were included and divided into 2 groups based on pretherapy PTH levels. The residual thyroid tissue volume was classified into 4 grades (0-3), and a value of 0 indicated that there was no apparent residual tissue. We analyzed the PTH level changes among different time points in each group and the factors that could predict the PTH level changes. ResultsIn 113 patients with normal parathyroid gland function, the PTH level at baseline, 1 day, 7 days, 1 month, 3 months, and 6 months after RAI therapy did not show any significant difference; in 24 patients with decreased parathyroid gland function, the level of PTH immediately decreased after the implementation of RAI therapy but gradually returned to a pre-RAI therapy level within 6 months. On the seventh day after therapy, the mean value of PTH in patients with a residual thyroid tissue volume of extent of 0/1 was 8.0 ± 2.3 pg/mL, which was significantly higher than that in patients with a residual thyroid tissue volume of extent of 2/3 (P = .011). Similar phenomena were observed 1 month, 3 months, and 6 months after therapy. ConclusionRAI therapy had a significant transient adverse effect on parathyroid gland function in patients with decreased PTH secretion pretherapy, and the extent was associated with the amount of residual thyroid tissue.

Calcium loss in sweat does not stimulate PTH release: A study of Bikram hot yoga

It has been hypothesized that sweat loss during exercise causes a disruption in calcium homeostasis that activates bone resorption and over time leads to low bone mineral density. The purpose of this small pilot study was to determine whether dermal calcium loss from a bout of excessive sweating during light intensity physical activity triggers an increase in biomarkers of bone resorption. Biochemical markers related to bone homeostasis were measured before and after a 90 min Bikram hot yoga practice performed in a room heated to 105 °F with 40 % humidity. Participants were five females with a mean age of 47.4 ± 4.7 years. Nude body weight, serum total calcium (Ca2+), free ionized calcium, albumin, parathyroid hormone (PTH) and CTX-I were measured before and after a Bikram hot yoga practice. Mean estimated sweat loss was 1.54 ± 0.65 L, which elicited a 1.9 ± 0.9 % decrease in participant’s body weight. Mean Ca2+ concentration in sweat was 2.9 ± 1.7 mg/dl and the estimated mean total calcium lost was 41.3 ± 16.4 mg. Serum ionized Ca2+ increased from 4.76 ± 0.29 mg/dl to 5.35 ± 0.36 mg/dl after the Bikram hot yoga practice (p = 0.0118). Serum PTH decreased from pre- 33.9 ± 3.3 pg/ml to post- 29.9 ± 2.1 pg/ml yoga practice (p = 0.0015) when adjusted for hemoconcentration (PTHADJ), implying a decrease in PTH secretion. We conclude that calcium loss in sweat during 90 min of Bikram hot yoga did not trigger an increase in PTH secretion and did not initiate bone resorption.

One-year safety and efficacy of intravenous etelcalcetide in patients on hemodialysis with secondary hyperparathyroidism.

BackgroundSecondary hyperparathyroidism (sHPT), a common complication of chronic kidney disease, is characterized by elevated serum parathyroid hormone (PTH). Etelcalcetide is an intravenous calcimimetic that increases sensitivity of the calcium-sensing receptor to calcium and decreases PTH secretion. This open-label extension (OLE) trial evaluated the long-term effects of etelcalcetide for sHPT treatment in patients receiving hemodialysis.MethodsThis 52-week, multicenter, single-arm OLE enrolled patients from three parent trials: two randomized, double-blind, placebo-controlled trials and one open-label, single-arm, ‘switch’ study from cinacalcet to etelcalcetide. The primary endpoint was to investigate the nature, frequency, severity and relation to treatment of all adverse events (AEs) reported throughout the trial. Secondary endpoints included the proportion of patients with >30% reduction from baseline in PTH and the percentage change from baseline in PTH, albumin-corrected calcium (Ca), phosphate (P) and the calcium–phosphate product (Ca × P).ClinicalTrials.gov identifier: NCT01785875; Amgen study: 20120231.ResultsOverall, 89.8% of the patients experienced one or more treatment-emergent AE. The most common were decreased blood Ca (43.3%), diarrhea (10.8%), vomiting (10.4%) and nausea (9.6%); symptomatic hypocalcemia occurred in 3.7% of the patients. Approximately 68% of patients achieved >30% reduction in PTH, and ∼56% achieved PTH ≤300 pg/mL. Mean percent changes from baseline ranged from −25.4% to −26.1% for PTH, −8.3% to −9.1% for Ca, −3.6% to −4.1% for P and −12.0% to −12.6% for Ca × P.ConclusionsEtelcalcetide effectively lowered PTH and its effect was sustained, while no new safety concerns emerged over a 1-year treatment period.

Parathyroid-specific deletion of dicer-dependent microRNAs abrogates the response of the parathyroid to acute and chronic hypocalcemia and uremia

MicroRNAs (miRNAs) down-regulate gene expression and have vital roles in biology but their functions in the parathyroid are unexplored. To study this, we generated parathyroid-specific Dicer1 knockout (PT-Dicer(-/-) ) mice where parathyroid miRNA maturation is blocked. Remarkably, the PT-Dicer(-/-) mice did not increase serum parathyroid hormone (PTH) in response to acute hypocalcemia compared with the >5-fold increase in controls. PT-Dicer(-/-) glands cultured in low-calcium medium secreted 5-fold less PTH at 1.5 h than controls. Chronic hypocalcemia increased serum PTH >4-fold less in PT-Dicer(-/-) mice compared with control mice with no increase in PTH mRNA levels and parathyroid cell proliferation compared with the 2- to 3-fold increase in hypocalcemic controls. Moreover, uremic PT-Dicer(-/-) mice increased serum PTH and FGF23 significantly less than uremic controls. Therefore, stimulation of the parathyroid by both hypocalcemia and uremia is dependent upon intact dicer function and miRNAs. In contrast, the PT-Dicer(-/-) mice responded normally to activation of the parathyroid calcium-sensing receptor (Casr) by both hypercalcemia and a calcimimetic that decreases PTH secretion, demonstrating that they are dicer-independent. Therefore, miRNAs are essential for the response of the parathyroid to both acute and chronic hypocalcemia and uremia, the major stimuli for PTH secretion.

Cinacalcet hydrochloride and phosphate metabolism

The inhibitory effect of cinacalcet hydrochloride (cinacalcet) on blood phosphorus (P) levels is widely-accepted. However, this effect is only observed in patients on dialysis. Reduction in parathyroid hormone (PTH) induced by cinacalcet increases blood P levels with decreased urinary P excretion in pre-dialysis patients with chronic kidney disease (CKD). Similar results observed in normal and CKD rats provide a pharmacological validation of the trade-off hypothesis. The lowering effect of cinacalcet on blood P levels in dialysis patients is attributed to decreased P mobilization from the bone caused by the decreased PTH secretion. It is unlikely that this P-lowering effect of cinacalcet would bring any benefits on the enhanced parathyroid gland function and bone metabolism. On the other hand, the P-lowering effect of this drug is considered to contribute to its inhibitory effects on the development and progression of vascular calcification in dialysis patients. Further studies should examine this beneficial cinacalcet effect would lead to the reduction of the mortality risk.

Novel calcium sensing receptor ligands: a patent survey

Introduction: In the parathyroid gland, the calcium sensing receptor responds to small changes in circulating levels of Ca2+, and consequently stimulates or inhibits the secretion of parathyroid hormone (PTH). Thus, ligands potentiating the action of calcium (calcimimetics) lead to decreased PTH secretion and can thus be useful for the treatment of hyperparathyroidism. On the other hand, ligands which antagonize the action of calcium (calcilytics) stimulate PTH secretion, favoring bone tissue regeneration.Areas covered: This review first discusses the rapid development of calcimimetics (only one of which has been approved for the treatment of hyperparathyroidism) followed by that of calcilytics (none of which has as yet been approved for the treatment of osteoporosis). Peer-reviewed articles generated by these patents are also surveyed.Expert opinion: The rapid progress in developing a clinically approved calcimimetic has not been matched by an identical success in finding an orally available calcilytic useful for the treatment of osteoporosis. However, the growing importance of osteoporosis as a debilitating disease is a stimulating factor in discovering such compounds.

New insights into the role of calcium-sensing receptor activation

The discovery of the calcium-sensing receptor (CaSR) prompted the identification of substances that affect its function. Cinacalcet, for example, is a drug that allosterically modifies the receptor so as to increase its sensitivity to circulating calcium (thus the name "calcimimetic") and in this way decreases parathyroid hormone secretion. Clinical use of cinacalcet is already approved for the treatment of primary and secondary hyperparathyroidism, but research is ongoing to identify further potential actions of this drug. The effects and functions of the CaSR have been evaluated in different systems and tissues, beyond parathyroid glands, such arterial walls. A complete understanding of the properties of calcimimetics are of obvious clinical interest, since therapeutic indications may be affected accordingly.

Increased parathyroid expression of klotho in uremic rats

Klotho is a protein of significant importance for mineral homeostasis. It helps to increase parathyroid hormone (PTH) secretion and in the trafficking of Na+/K+-ATPase to the cell membrane; however, it is also a cofactor for fibroblast growth factor (FGF)-23 to interact with its receptor, FGFR1 IIIC, resulting in decreased PTH secretion. Studies on the regulation of parathyroid klotho expression in uremia have provided varying results. To help resolve this, we measured klotho expression in the parathyroid and its response to severe uremia, hyperphosphatemia, and calcitriol treatment in the 5/6 nephrectomy rat model of secondary hyperparathyroidism. Parathyroid klotho gene expression and protein were significantly increased in severely uremic hyperphosphatemic rats, but not affected by moderate uremia and normal serum phosphorus. Calcitriol suppressed klotho gene and protein expression in severe secondary hyperparathyroidism, despite a further increase in plasma phosphate. Both FGFR1 IIIC and Na+/K+-ATPase gene expression were significantly elevated in severe secondary hyperparathyroidism. Parathyroid gland klotho expression and the plasma calcium ion concentration were inversely correlated. Thus, our study suggests that klotho may act as a positive regulator of PTH expression and secretion in secondary hyperparathyroidism.

Parathyroid cell resistance to fibroblast growth factor 23 in secondary hyperparathyroidism of chronic kidney disease

Although fibroblast growth factor 23 (FGF23) acting through its receptor Klotho-FGFR1c decreases parathyroid hormone expression, this hormone is increased in chronic kidney disease despite an elevated serum FGF23. We measured possible factors that might contribute to the resistance of parathyroid glands to FGF23 in rats with the dietary adenine-induced model of chronic kidney disease. Quantitative immunohistochemical and reverse transcription-PCR analysis using laser capture microscopy showed that both Klotho and FGFR1 protein and mRNA levels were decreased in histological sections of the parathyroid glands. Recombinant FGF23 failed to decrease serum parathyroid hormone levels or activate the mitogen-activated protein kinase signaling pathway in the glands of rats with advanced experimental chronic kidney disease. In parathyroid gland organ culture, the addition of FGF23 decreased parathyroid hormone secretion and mRNA levels in control animals or rats with early but not advanced chronic kidney disease. Our results show that because of a downregulation of the Klotho-FGFR1c receptor complex, an increase of circulating FGF23 does not decrease parathyroid hormone levels in established chronic kidney disease. This in vivo resistance is sustained in parathyroid organ culture in vitro.

Parathyroid hormone measurement in CKD

The Kidney Disease Outcomes Quality Initiative (K/DOQI) guidelines recommend that serum parathyroid hormone (PTH) concentration of patients with chronic kidney disease (CKD) should be measured regularly and maintained within target ranges that are defined according to the stage of CKD (e.g., 150-300 pg/ml in patients with CKD stage 5). The quality of the PTH assay is of paramount importance, as it contributes to the therapeutic decision. Indeed, when the PTH concentration is above these target values, drugs that decrease PTH secretion, such as active vitamin D compounds or calcimimetic agents, may be given and the doses are then adapted according to the evolution of the PTH concentration. By contrast, if the PTH concentration is below the target range, any treatment that may decrease PTH secretion is stopped to avoid adynamic bone disease and associated extra-skeletal calcifications. The aim of this article is to discuss the main features and pitfalls related to PTH measurement in the setting of CKD.

Fibroblast growth factor 23 acts on the parathyroid to decrease parathyroid hormone secretion

The aim of this article is to describe the intriguing action of fibroblast growth factor 23 on the parathyroid. Fibroblast growth factor 23 inhibits renal phosphate reabsorption and calcitriol production. It is the principal phosphaturic factor in a bone-kidney axis coordinating systemic phosphate homeostasis and bone mineralization. Fibroblast growth factor 23 acts at its target tissues by binding to the Klotho-FGFR1c complex and it has recently been confirmed that the fibroblast growth factor 23 receptor is present not only in renal tissue but also in the parathyroid. Fibroblast growth factor 23 leads to a decrease in parathyroid hormone mRNA and serum parathyroid hormone levels by the mitogen-activated protein kinase pathway both in vivo and in vitro. Fibroblast growth factor 23 is secreted by osteocytes and acts through its receptor the heterodimer of Klotho-FGFR1c in the kidney and parathyroid. In the kidney it leads to phosphaturia and decreased calcitriol synthesis, and in the parathyroid it activates the mitogen-activated protein kinase pathway to decrease parathyroid hormone gene expression and secretion. The decreased parathyroid hormone levels would then also contribute to a decrease in calcitriol synthesis. A bone-kidney-parathyroid hormonal network is now apparent which regulates phosphate, calcium and calcitriol homeostasis. Fibroblast growth factor 23 is the major factor regulating phosphate, and parathyroid hormone the major factor for calcium and calcitriol balances between these factors.

The parathyroid is a target organ for FGF23 in rats

Phosphate homeostasis is maintained by a counterbalance between efflux from the kidney and influx from intestine and bone. FGF23 is a bone-derived phosphaturic hormone that acts on the kidney to increase phosphate excretion and suppress biosynthesis of vitamin D. FGF23 signals with highest efficacy through several FGF receptors (FGFRs) bound by the transmembrane protein Klotho as a coreceptor. Since most tissues express FGFR, expression of Klotho determines FGF23 target organs. Here we identify the parathyroid as a target organ for FGF23 in rats. We show that the parathyroid gland expressed Klotho and 2 FGFRs. The administration of recombinant FGF23 led to an increase in parathyroid Klotho levels. In addition, FGF23 activated the MAPK pathway in the parathyroid through ERK1/2 phosphorylation and increased early growth response 1 mRNA levels. Using both rats and in vitro rat parathyroid cultures, we show that FGF23 suppressed both parathyroid hormone (PTH) secretion and PTH gene expression. The FGF23-induced decrease in PTH secretion was prevented by a MAPK inhibitor. These data indicate that FGF23 acts directly on the parathyroid through the MAPK pathway to decrease serum PTH. This bone-parathyroid endocrine axis adds a new dimension to the understanding of mineral homeostasis.

Fibroblast growth factor-23 regulates parathyroid hormone and 1α-hydroxylase expression in cultured bovine parathyroid cells

Fibroblast growth factor-23 (FGF23) is a circulating factor that decreases serum levels of inorganic phosphate (Pi) as well as 1,25-dihydroxyvitamin D(3). Recent studies also suggest a correlation between serum levels of FGF23 and parathyroid hormone (PTH) in patients with chronic kidney disease. It is, however, unknown whether FGF23 directly modulates PTH expression, or whether the correlation is secondary to abnormalities in Pi and vitamin D metabolism. The objective of the current study was therefore to elucidate possible direct effects of FGF23 on bovine parathyroid cells in vitro. Treatment of parathyroid cells with a stabilized form of recombinant FGF23 (FGF23(R176Q)) induced a rise in early response gene-1 mRNA transcripts, a marker of FGF23 signaling. FGF23(R176Q) potently and dose-dependently decreased the PTH mRNA level within 12 h. In agreement, FGF23(R176Q) also decreased PTH secretion into conditioned media. In contrast, FGF23(R176Q) dose-dependently increased 1alpha-hydroxylase expression within 3 h. FGF23 (R176Q) did not affect cell viability nor induce apoptosis, whereas a small but significant increase in cell proliferation was found. We conclude that FGF23 is a negative regulator of PTH mRNA expression and secretion in vitro. Our data suggest that FGF23 may be a physiologically relevant regulator of PTH. This defines a novel function of FGF23 in addition to the previously established roles in controlling vitamin D and Pi metabolism.

Rescue of Calcium-sensing Receptor Mutants by Allosteric Modulators Reveals a Conformational Checkpoint in Receptor Biogenesis

The calcium-sensing receptor (CaR), a member of G protein-coupled receptor family C, regulates systemic calcium homeostasis by activating G(q)- and G(i)-linked signaling in the parathyroid, kidney, and intestine. CaR is ubiquitinated by the E3 ligase dorfin and degraded via the endoplasmic reticulum-associated degradation pathway (Huang, Y., Niwa, J., Sobue, G., and Breitwieser, G. E. (2006) J. Biol. Chem. 281, 11610-11617). Here we provide evidence for a conformational or functional checkpoint in CaR biogenesis using two complementary approaches. First we characterized the sensitivity of loss- or gain-of-function CaR mutants to proteasome inhibition by MG132. The stabilization of loss-of-function mutants and insensitivity of gain-of-function mutants to MG132 suggests that receptor sensitivity to calcium influences susceptibility to proteasomal degradation. Second, we used the allosteric activator NPS R-568 and antagonist NPS 2143 to promote the active and inactive conformations of wild type CaR, respectively. Overnight culture in NPS R-568 increased expression of CaR, whereas NPS 2143 had the opposite effect. NPS R-568 and NPS 2143 differentially regulated maturation and cell surface expression of wild type CaR, directly affecting maximal signaling responses. NPS R-568 rescued expression of loss-of-function CaR mutants, increasing plasma membrane expression and ERK1/2 phosphorylation in response to 5 mM Ca(2+). Disorders of calcium homeostasis caused by CaR mutations may therefore result from altered receptor biogenesis independent of receptor function, i.e. a protein folding disorder. The allosteric modulators NPS R-568 and NPS 2143 not only alter CaR sensitivity to calcium and hence signaling but also modulate receptor expression.

Les calcimimétiques, mécanismes d’action et applications thérapeutiques

The extracellular calcium-sensing receptor (CaR) on the parathyroid cell surface negatively regulates secretion of parathyroid hormone (PTH). Its activation by small changes in the extracellular concentration of ionized calcium (ec[Ca2+]) decreases PTH secretion and secondarily bone turnover. CaR is an ideal target for compounds that may be developed to modulate its activity - activating calcimimetics and inhibiting calcilytics. Calcimimetics can amplify the sensitivity of the CaR to ec(Ca2+), thereby suppressing PTH levels and in turn reducing blood Ca++. They dose-dependently reduce the secretion of PTH in cultured parathyroid cells, in animal models and in humans. In uremic animals, these compounds prevent parathyroid cell hyperplasia when given at the onset of the disease and stop cell proliferation if they are administered afterwards, when the hyperplasia already exists. They normalize plasma PTH levels and bone remodeling. In uremic patients undergoing hemodialysis, calcimimetics reduce plasma PTH concentrations in the short (12 weeks) and long (2 years) terms. They also reduce serum levels of calcium-phosphorus product. Calcimimetics are therefore an alternative for the treatment of secondary hyperparathyroidism, particularly in dialysis patients, when increased serum levels of calcium-phosphorus product, the attendant risk of cardiovascular calcification, and its lack of efficacy limit use of the standard treatment.

Dolomite supplementation improves bone metabolism through modulation of calcium-regulating hormone secretion in ovariectomized rats

Dolomite, a mineral composed of calcium magnesium carbonate (CaMg (CO3)2), is used as a food supplement that supplies calcium and magnesium. However, the effect of magnesium supplementation on bone metabolism in patients with osteoporosis is a matter of controversy. We examined the effects of daily supplementation with dolomite on calcium metabolism in ovariectomized (OVX) rats. Dolomite was administered daily to OVX rats for 9 weeks. The same amount of magnesium chloride as that supplied by the dolomite was given to OVX rats as a positive control. Histological examination revealed that ovariectomy decreased trabecular bone and increased adipose tissues in the femoral metaphysis. Dolomite or magnesium supplementation failed to improve these bone histological features. Calcium content in the femora was decreased in OVX rats. Neither calcium nor magnesium content in the femora in OVX rats was significantly increased by dolomite or magnesium administration. Urinary deoxypyridinoline excretion was significantly increased in OVX rats, and was not affected by the magnesium supplementation. Serum concentrations of magnesium were increased, and those of calcium were decreased, in OVX rats supplemented with dolomite or magnesium. However, there was a tendency toward decreased parathyroid hormone secretion and increased calcitonin secretion in OVX rats supplemented with dolomite or magnesium. Serum 1,25-dihydroxyvitamin D(3) and osteocalcin levels were significantly increased in the supplemented OVX rats. These results suggest that increased magnesium intake improves calcium metabolism in favor of increasing bone formation, through the modulation of calcium-regulating hormone secretion.

Modulation and action of the calcium-sensing receptor.

The discovery and cloning of the calcium-sensing receptor (CaR) in 1993 has led to a better understanding of the regulation of calcium homoeostasis. Following activation by extracellular calcium ions, the CaR triggers a cascade of intracellular events. These events result in the release of secondary messengers, which have a number of biological effects, the most important of which is a reduction in parathyroid hormone (PTH) secretion. The way in which calcium acts on the CaR varies depending on the cell type. In the parathyroid gland cell, activation of the CaR by elevated serum levels of calcium leads to a decrease in PTH secretion. In the kidney, CaR activation is thought to have several different actions, leading to enhanced reabsorption of sodium chloride and increased calcium and magnesium excretion in the renal tubules. CaRs are also found in other tissues in the body that are not involved in calcium homoeostasis, suggesting that the CaR has actions that are not associated with calcium homoeostasis. In patients with end-stage renal disease, parathyroid gland hyperplasia is associated with downregulation of the CaR. Discovery of the CaR has allowed the development of a group of drugs called calcimimetics, which mimic or potentiate the actions of extracellular calcium on the CaR. These compounds have considerable potential for the treatment of primary and secondary hyperparathyroidism.

Index of Suspicion In the Nursery

A 9-day-old Hispanic boy presents to the emergency department with seizures and apnea. The seizure lasts for about 3 minutes and is characterized by stiffening of the body and laryngospasm. Laboratory evaluation reveals a serum calcium concentration of 6 mg/dL (1.5 mmol/L). Hypocalcemic tetany resolves after administration of intravenous calcium. The infant also has fever of 100.4°F (37.7°C). The infant was born at term, and his birthweight was 3.2 kg. He is the fifth child born of nonconsanguineous parentage. The antenatal period was uneventful. Because the family does not have insurance, the mother had not taken prenatal vitamins and supplements. The baby has been fed with human milk and formula. On physical examination upon admission to the hospital, his temperature is 99°F (36.9°C), pulse is 186 beats/min, respiratory rate is 54 breaths/min, blood pressure is 97/64 mm Hg, and weight is 3.83 kg. He has no dysmorphic features and is normocephalic, with an open and flat anterior fontanelle without craniotabes. No cataracts or Chvostek sign are present. Cardiovascular examination reveals a regular heart rate and rhythm, with no murmurs. The lungs are clear to auscultation bilaterally, and there is no hepatosplenomegaly. Neurologic findings are normal. Laboratory evaluation reveals: sodium, 136 mEq/L (136 mmol/L); potassium, 5.2 mEq/L (5.2 mmol/L); chloride, 101 mEq/L (101 mmol/L); bicarbonate, 26 mEq/L (26 mmol/L); blood urea nitrogen, 10 mg/dL (3.57 mmol/L); creatinine, 0.3 mg/dL (26.5 mcmol/L); glucose, 109 mg/dL (6.1 mmol/L); calcium, 6.6 mg/dL (1.65 mmol/L); phosphorous, 10.5 mg/dL (3.4 mmol/L); albumin, 3.0 g/dL (30 g/L); and magnesium, 2 mg/dL (0.82 mmol/L). The white blood cell count and differential count are normal. Findings on cerebrospinal fluid evaluation are normal. However, the 25-hydroxyvitamin D concentration is less than 7 ng/mL (17.5 nmol/L) (normal, 10 to 68 ng/mL [25 to 169.7 nmol/L]), the 1,25-dihydroxyvitamin D concentration is 45 …