Parathyroid Hormone Deficiency Research Articles

Predictors of lumbar spine trabecular bone score in women with postsurgical hypoparathyroidism

Hypoparathyroidism is a rare disease that markedly reduces bone remodeling, leading to increased bone mineral density and changes in bone microarchitecture. However, it is currently unclear how these changes affect fracture risk. In this study, we investigated bone mass by dual-energy x-ray absorptiometry, the occurrence of morphometric vertebral fractures, and bone microarchitecture by assessing trabecular bone score in women with postsurgical hypoparathyroidism. We included 67 women with hypoparathyroidism aged 52.9 ± 12.3 years and 63 age (52.9 ± 12.3 years) and body mass index-matched controls, which were assessed for femoral and lumbar spine bone mineral density, trabecular bone score, and vertebral fractures by dual-energy x-ray absorptiometry. Women with hypoparathyroidism had significantly higher bone mineral density at the lumbar spine, femoral neck, and total hip compared with controls despite similar trabecular bone score values. Vertebral fracture assessment indicated that two women with hypothyroidism presented vertebral fractures, both aged over 65 years. Conversely, no vertebral fractures were detected in control women. In a multivariate linear regression model, we found that older age, diabetes, and lower lumbar spine mineral density were significant predictors of lower trabecular bone score values. Our findings indicate that vertebral fractures are not common among women with postsurgical hypoparathyroidism aged under 65 years. Moreover, trabecular bone score values were similar in women with hypoparathyroidism and age-matched controls and were associated with traditional risk factors for fractures, such as older age, type 2 diabetes, and lower spine bone mineral density. Lay summaryChronic parathyroid hormone deficiency decreases bone turnover and modifies skeletal properties, although the impact of these changes on fracture risk remains unclear. We studied 67 women with postsurgical hypoparathyroidism and 63 age and body mass index-matched healthy controls and found that bone mineral density is increased in women with hypoparathyroidism despite similar trabecular bone score values and a low occurrence of morphometric vertebral fractures. This suggests that the low bone turnover in hypoparathyroidism increases bone mass, but this is not accompanied by improved bone microarchitecture, indicating that trabecular bone score may be a valuable tool to complement the assessment of skeletal health and the risk of fractures in this condition.

Preclinical development of EXT608, an investigational parathyroid hormone derivative with extended half-life for the treatment of hypoparathyroidism.

Hypoparathyroidism, a deficiency of parathyroid hormone (PTH), results in hypocalcemia, hyperphosphatemia, and hypercalciuria. The disease is poorly controlled by calcium and vitamin D supplements or native PTH(1-84) replacement therapy. A version of PTH is being developed using D-VITylation technology, whereby vitamin D is conjugated to a therapeutic peptide, which confers a long plasma half-life by virtue of binding to the abundant vitamin D binding protein (DBP). D-VITylation of PTH caused no reduction in activity at the PTHR1 receptor, and resulted in a plasma elimination half-life of 7-15h in rats and 24-32h in cynomolgus monkeys. Analysis of steady-state pharmacokinetics as a function of dose showed flat profiles with smaller peak:trough ratios at low doses, indicative of slower subcutaneous absorption. In thyroparathyroidectomized (TPTx) rats, PTH(1-34)-vitamin D conjugates restored serum calcium and phosphate levels into the normal range over the 24h dosing period, and increased bone turnover markers and reduced bone mineral density. Urinary calcium was initially elevated, but normalized by the end of treatment on day 27. In healthy monkeys, a single dose of PTH(1-34)-vitamin D conjugates elevated serum calcium levels above the normal range for a period of 24-48h while simultaneously reducing urinary calcium. Therefore, the lead compound, EXT608, is a promising candidate as a therapeutic that can truly mimic the endogenous activity of PTH and warrants further study in patients with hypoparathyroidism.

Interactions between PTH and adiposity: appetizing possibilities.

Although parathyroid hormone (PTH) is best known for its role as a regulator of skeletal remodelling and calcium homeostasis, more recent evidence supports a role for it in energy metabolism and other non-classical targets. In this report, we summarize evidence for an effect of PTH on adipocytes. This review is based upon all peer-reviewed papers, published in the English language with PubMed as the primary search engine. Recent preclinical studies have documented an effect of PTH to stimulate lipolysis in both adipocytes and liver cells and to cause browning of adipocytes. PTH also reduces bone marrow adiposity and hepatic steatosis. Although clinical studies are limited, disease models of PTH excess and PTH deficiency lend support to these preclinical findings. This review supports the concept of PTH as a polyfunctional hormone that influences energy metabolism as well as bone metabolism.

Management of hypoparathyroidism: a Position Statement of the Expert Group of the Polish Society of Endocrinology.

Over the past few years, there have been significant advances in our understanding of hypoparathyroidism (HypoPT) in terms of its epidemiology, clinical presentation, etiology, and skeletal and renal complications. Moreover, the available treatment options for HypoPT have changed. This position statement of the Expert Group of the Polish Society of Endocrinology summarizes the current state of knowledge and provides recommendations for optimal management to assist clinicians in the diagnosis, treatment, and monitoring of HypoPT in Poland. The specific aspects of HypoPT management in children, pregnant and lactating women, and patients with chronic kidney disease are also discussed. HypoPT is a rare disorder characterized by hypocalcemia and the lack or deficiency of parathyroid hormone (PTH). Hypoparathyroidism can be associated with complications, including nephrocalcinosis, nephrolithiasis, renal insufficiency, cataract, seizures, cardiac arrhythmia, depression, and an increased risk of infection. Minimizing complications of HypoPT requires careful evaluation and close monitoring of laboratory parameters. Conventional management of HypoPT has focused on maintaining serum calcium levels using oral calcium and active vitamin D. However, this approach is limited because it does not restore normal PTH function, is often associated with inadequate biochemical control, and raises concerns as to long-term side effects. HypoPT is the only classic endocrine insufficiency that is not commonly treated with the substitution of the missing hormone. Recently, recombinant human PTH(1-84) has become available, offering hope that the use of the missing hormone in the treatment of HypoPT will help achieve better control and reduce the risk of complications. However, this treatment is currently unavailable in Poland.

Hypocalcemia in combination with hyperphosphatemia impairs muscle cell differentiation in vitro

PurposeHypoparathyroidism is a rare endocrine disorder characterized by low or absent secretion of parathyroid hormone (PTH), which leads to decreased calcium and increased phosphorus levels in the serum. The diagnosis of hypoparathyroidism is based on the identification of the aforementioned biochemical abnormalities, which may be accompanied by clinical manifestations. Symptoms of hypoparathyroidism, primarily attributed to hypocalcemia, include muscle cramps or spasms, facial, leg, and foot pain, seizures, and tingling in the lips or fingers. The treatment of hypoparathyroidism depends on the severity of symptoms and the underlying pathology. Over the long term, calcium supplements, active vitamin D analogs, and thiazide diuretics may be needed. In fact, in patient cohorts in which optimal disease control still remains elusive, replacement therapy with recombinant parathyroid hormone analogs may be contemplated. Despite the predominantly neuromuscular symptoms of hypoparathyroidism, further effects of parathyroid hormone deficiency at the muscle cell level remain poorly understood. Thus, the aim of our study was to evaluate the effects of hypocalcemia in combination with hyperphosphatemia on muscle cells differentiation in vitro.MethodsC2C12 cells, an in vitro model of muscle cells, were differentiated for 2 or 6 days in the presence of hypocalcemia (CaCl2 0.9 mmol/l) and moderate (PO4 1.4 mmol/l) or severe (PO4 2.9 mmol/l) hyperphosphatemia, or combinations of both conditions. Cell differentiation and expression of genes linked to muscle differentiation were evaluated.ResultsThe combination of hypocalcemia with hyperphosphatemia induced a significant reduction (50%) in differentiation marker levels, such as MyoD (protein 1 for myoblast determination) and myogenin on the 1st day of differentiation, and MHC (myosin heavy chains) after 6 days of differentiation compared to control. Furthermore, this condition induced a statistically significant reduction of insulin-like growth factor-1 (IGF-1) mRNA expression and inhibition of IGF signaling and decrease in ERK phosphorylation compared to control cells.ConclusionsOur results showed that a condition of hypocalcemia with hyperphosphatemia induced an alteration of muscle cell differentiation in vitro. In particular, we observed the reduction of myogenic differentiation markers, IGF-1 signaling pathway, and ERK phosphorylation in differentiated skeletal myoblasts. These data suggest that this altered extracellular condition might contribute to the mechanisms causing persistence of symptoms in patients affected by hypoparathyroidism.

Involvement of mTOR pathway in neurodegeneration in NSF-related developmental and epileptic encephalopathy.

Membrane fusion is mediated by soluble N-ethylmaleimide-sensitive factor attachment protein receptor (SNARE) proteins. During neurotransmitter exocytosis, SNARE proteins on a synaptic vesicle and the target membrane form a complex, resulting in neurotransmitter release. N-ethylmaleimide-sensitive factor (NSF), a homohexameric ATPase, disassembles the complex, allowing individual SNARE proteins to be recycled. Recently, the association between pathogenic NSF variants and developmental and epileptic encephalopathy (DEE) was reported; however, the molecular pathomechanism of NSF-related DEE remains unclear. Here, three patients with de novo heterozygous NSF variants were presented, of which two were associated with DEE and one with a very mild phenotype. One of the DEE patients also had hypocalcemia from parathyroid hormone deficiency and neuromuscular junction impairment. Using PC12 cells, a neurosecretion model, we show that NSF with DEE-associated variants impaired the recycling of vesicular membrane proteins and vesicle enlargement in response to exocytotic stimulation. In addition, DEE-associated variants caused neurodegenerative change and defective autophagy through overactivation of the mammalian/mechanistic target of rapamycin (mTOR) pathway. Treatment with rapamycin, an mTOR inhibitor or overexpression of wild-type NSF ameliorated these phenotypes. Furthermore, neurons differentiated from patient-derived induced pluripotent stem cells showed neurite degeneration, which was also alleviated by rapamycin treatment or gene correction using genome editing. Protein structure analysis of NSF revealed that DEE-associated variants might disrupt the transmission of the conformational change of NSF monomers and consequently halt the rotation of ATP hydrolysis, indicating a dominant negative mechanism. In conclusion, this study elucidates the pathomechanism underlying NSF-related DEE and identifies a potential therapeutic approach.

OR21-1 The PaTH Forward Trial: Efficacy and Safety of TransCon PTH Through Week 84 for Adults With Hypoparathyroidism

Abstract Background Hypoparathyroidism is a rare disease characterized by deficiency of parathyroid hormone (PTH), resulting in abnormal mineral homeostasis. Conventional therapy (active vitamin D and calcium) targets short-term symptoms, but fails to restore normal PTH physiology, and may lead to complications such as nephrolithiasis, nephrocalcinosis, and renal insufficiency. TransCon PTH is an investigational long-acting prodrug of PTH(1-34) dosed once-daily for the treatment of adults with hypoparathyroidism. In the phase 2 PaTH Forward trial of TransCon PTH, 82% of participants achieved independence from conventional therapy at Week 4, a trend observed through Week 26 and 58. Here we report the Week 84 results from PaTH Forward trial. Methods The phase 2 PaTH Forward trial is a multicenter, randomized, double-blind, placebo-controlled, parallel-group, 4-week clinical trial with an open-label extension (OLE) period planned through Week 214. Participants received 4 weeks fixed dose of TransCon PTH (15, 18, or 21 mcg/d) or placebo co-administered with conventional therapy, followed by an OLE period during which TransCon PTH dose was titrated to maintain normocalcemia. Efficacy assessments at Week 84 included levels of 24-hour urine calcium (uCa) and sCa and independence from conventional therapy (defined as taking no active vitamin D and ≤600 mg calcium). After Week 58, a subset of 12 participants had frequent blood and urine sampling over 24 hours for evaluation of pharmacodynamic effect on sCa and uCa level and active PTH pharmacokinetic assessment (PD/PK substudy). Results Fifty-eight of 59 participants continued in the trial through Week 84. The average dose of TransCon PTH at Week 84 was 22.8 mcg/d. Fifty-four of 58 participants (93%) at Week 84 achieved independence from conventional therapy. Baseline mean 24-hour uCa was above normal (428 mg/24-hour) but normalized at Week 26 (173 mg/24-hour), and sustained through Week 58 (144 mg/24-hour), and Week 84 (131 mg/24-hour). Average values for sCa baseline were 8.8 mg/dL and remained in normal range at Weeks 26 (8.9 mg/dL), 58 (8.5 mg/dL) and 84 (8.5 mg/dL). The majority of adverse events (AE) were mild and unrelated to study drug; no serious AEs were reported. No AEs led to discontinuation of the study drug, nor from the trial. In the PD/PK substudy, mean sCa and uCa levels were stable in the normal range at all time points. Active PTH levels reflected steady physiologic exposure throughout the 24-hour period. Conclusion Week 84 results from the PaTH Forward trial investigating TransCon PTH for adults with hypoparathyroidism showed continued independence from conventional therapy for 93% of participants and maintenance of normal sCa and 24-hour uCa. Results from the PD/PK substudy demonstrated 24-hour stability of sCa and uCa levels and confirm infusion-like PK profile in a population of adults with hypoparathyroidism. TransCon PTH was generally well-tolerated through Week 84. Presentation: Monday, June 13, 2022 11:00 a.m. - 11:15 a.m.

A study of parathyroid hormone deficiency after total and near total thyroidectomy: its occurrence and time for recovery

<p class="abstract"><strong>Background:</strong> Parathyroid hormone (PTH) deficiency or hypoparathyroidism occurring after total thyroidectomy is not an uncommon postoperative complication. Patients developing PTH deficiency are likely to develop hypocalcemia if not treated in time. These patients will require immediate injectable followed by oral calcium supplements and activated vitamin D (1, 25-dihydroxycholecalciferol or calcitriol). The incidence of hypoparathyroidism reported in the literature varies between 1% to 37%. The aim of our study was to evaluate parathyroid hormone deficiency and the time taken for recovery of parathyroid function in total and near total thyroidectomy patients.</p><p class="abstract"><strong>Methods: </strong>An observational descriptive study was carried out at a tertiary care center with 50 patients who underwent total or near total thyroidectomy. Exclusion criteria- Patients in whom PTH was found to be below 10 pg/ml or above 65pg/ml preoperatively, those in whom neck dissection was done previously, those with abnormal calcium levels preoperatively and those on calcium replacement preoperatively.</p><p class="abstract"><strong>Results:</strong> 12% of patients developed PTH deficiency following total thyroidectomy, but only 2% continued to have prolonged depression of PTH level. A significant relation between fall in PTH on post op evening was found with the development of hypocalcaemia in the post op period.</p><p class="abstract"><strong>Conclusions: </strong>Immediate post operative PTH can be used as an indicator to predict hypocalcemia in the post operative period in patients undergoing total or near total thyroidectomy.</p>

Exogenous PTH 1-34 Attenuates Impaired Fracture Healing in Endogenous PTH Deficiency Mice via Activating Indian Hedgehog Signaling Pathway and Accelerating Endochondral Ossification

Fracture healing is a complicated, long-term, and multistage repair process. Intermittent administration of parathyroid hormone (PTH) has been proven effective on intramembranous and endochondral bone formation during the fracture healing process, however, the mechanism is unclear. In this study, we investigated the role of exogenous PTH and endogenous PTH deficiency in bone fracture healing and explored the mechanism by using PTH knockout (PTH-/-) mice and ATDC5 cells. In a mouse femur fracture model, endogenous PTH deficiency could delay endochondral ossification whereas exogenous PTH promotes accumulation of endochondral bone, accelerates cartilaginous callus conversion to bony callus, enhances maturity of bony callus, and attenuates impaired fracture healing resulting from endogenous PTH deficiency. In fracture callus tissue, endogenous PTH deficiency could inhibit chondrocyte proliferation and differentiation whereas exogenous PTH could activate the IHH signaling pathway to accelerate endochondral ossification and rescue impaired fracture healing resulting from endogenous PTH deficiency. In vitro, exogenous PTH promotes cell proliferation by activating IHH signaling pathway on ATDC5 cells. In mechanistic studies, by using ChIP and luciferase reporter assays, we showed that PTH could phosphorylate CREB, and subsequently bind to the promoter of IHH, causing the activation of IHH gene expression. Therefore, results from this study support the concept that exogenous PTH 1-34 attenuates impaired fracture healing in endogenous PTH deficiency mice via activating the IHH pathway and accelerating endochondral ossification. Hence, the investigation of the mechanism underlying the effects of PTH treatment on fracture repair might guide the exploration of effective therapeutic targets for fracture.

A novel GCM2 mutation identified in an infant with familial isolated hypoparathyroidism

Background: Isolated hypoparathyroidism comprises a set of heterogeneous inherited diseases associated with abnormal calcium metabolism exclusively due to parathyroid hormone (PTH) deficiency. Isolated hypoparathyroidism can be either sporadic or inherited. Genetic causes that impair the synthesis or secretion of PTH, such as calcium-sensing receptor and PTH defects, or defects in the development of the parathyroid gland [glial cell missing 2, (GCM2)], have been established as causes of familial isolated hypoparathyroidism. Transcription factor GCM2 is a crucial regulator of parathyroid gland homeostasis. Transmission of pathogenic variants encoding GCM2 occurs in an autosomal recessive or dominant manner. Case Presentation: Herein, we describe the case of a 12-year-old boy, born to consanguineous parents, who presented with abnormal movement during the first week of birth. Laboratory results revealed hypocalcemia, hyperphosphatemia, and low PTH levels. Genetic testing detected a novel homozygous variant in the GCM2 gene, c.391C>T (p.Arg131*). Although this variant has not been previously described, it is likely the pathogenic cause of this condition. Conclusion: To the best of authors' knowledge, this variant has not been listed in any database. Proper replacement therapy is likely to have good long-term outcomes for our patient.

Living-donor fresh parathyroid tissue allotransplantation as treatment for permanent hypoparathyroidism: case report

Introduction: the standard hypoparathyroidism treatment consists of replacing calcium and active vitamin D (calcitriol), but it does not correct the underlying abnormality, parathyroid hormone (PTH) deficiency. Both the disease and its treatment are responsible for many morbidities that affect multiple organs and systems. Therefore, parathyroid allotransplantation has been described as an alternative treatment option, especially in refractory cases. Objectives: to verify if parathyroid allotransplantation is effective as a treatment for permanent hypoparathyroidism. Methodology: fresh parathyroid tissue was obtained from a 36-year-old male with a past medical history of hyperparathyroidism secondary to end-stage renal disease and immediately implanted in the recipient’s non-dominant forearm, a 57-year-old female with refractory hypoparathyroidism, despite high doses of calcium and calcitriol replacement. Corticosteroid immunosuppression was performed for 10 days. Results: the allograft showed no evidence of functionality eleven months after transplant. The procedure was considered safe. Conclusion: more studies are required to validate this technique and improve its results.

Improving management of severe hypoparathyroidism: a case series.

Hypoparathyroidism is considered a rare endocrine disease. Despite being a deficiency of parathyroid hormone, the standard therapy is based on oral calcium and active vitamin D supplementation. This approach provides satisfactory management in most cases but may be inadequate for patients in the most complex spectrum of the disease. Other therapies are being explored, and among them, the use of recombinant human parathyroid hormone (PTH) has proved to decrease the requirements of calcium and active vitamin D to reach adequate therapeutic goals. We aimed to provide information on the effectiveness of the current recombinant parathyroid hormone analogs in the clinical management of difficult to control cases of hypoparathyroidism. We report our experience using teriparatide and PTH (1-84) through five complex cases of hypoparathyroidism of diverse etiologies. We describe each case and report the effectiveness of treatment in clinical practice. Four patients with postsurgical hypoparathyroidism and one patient with autoimmune hypoparathyroidism, all of them with suboptimal control under the standard treatment with calcium and calcitriol supplements or calcium gluconate infusion, are presented. They were all started on teriparatide or PTH (1-84), and all of them showed a diminishment of symptoms and were able to maintain normocalcemia without parenteral calcium despite a reduction of oral treatment. This article highlights the effectiveness and safety of hormonal replacement treatment in difficult to manage hypoparathyroidism and provides evidence which justifies its off-label prescription in the case of teriparatide. We consider that this treatment should be considered in cases in which standard treatment fails to reach adequate therapeutic goals.

The Russian registry of chronic hypoparathyroidism and clinical decision support system integration

According to available research, chronic hypoparathyroidism is a relatively rare disease characterized by low serum calcium levels and the absence or deficiency of parathyroid hormone. The chronic course of the disease is associated with the multicomponent medical therapy, careful dynamic monitoring to reduce the risks of various complications in different organs and systems as well as disability and mortality.The Russian registry of patients with chronic postsurgical and nonsurgical hypoparathyroidism has started its work in 2020, based on data of the Endocrinology Research Centre. The main goals of the Registry are the assessment of the actual prevalence, incidence of hypoparathyroidism, the key epidemiological characteristics, the analysis of the clinical features and medical therapy of chronic hypoparathyroidism in Russian Federation.This article covers all objectives of this project, the methodology for maintaining the registry of chronic postsurgical and nonsurgical hypoparathyroidism, the analytical possibilities of its use, including the integration of a decision support system designed to help specialists in real clinical practice follow the algorithms for diagnosis and treatment of the disease, approved by clinical guidelines.The registry of chronic postsurgical and nonsurgical hypoparathyroidism is located on a single platform for the registers of endocrinopathies, regulated by the Endocrinology Research Centre (http://gipopt.clin-reg.ru/).

Differential diagnosis of convulsions in the structure of dissociative (conversion motor) disorder and chronic postoperative hypoparathyroidism: case report and literature review

Hypoparathyroidism is a rare disorder of mineral metabolism, characterized by hypocalcemia as a result of the absence or deficiency of parathyroid hormone. The severity of the condition of patients with this disease is associated with both acute episodes of hypocalcemia due to cardiac arrhythmias, laryngo- or bronchospasm, generalized seizures, and manifestations of long-term complications of the disease, such as kidney pathology. In some cases, the normalization of phosphorus-calcium metabolism due to standard treatment with active metabolites / analogues of vitamin D and calcium salts does not lead to a reduction in clinical symptoms, which requires differential diagnosis with other conditions, including such neuropsychiatric disorders as epileptic seizures and their equivalents, syncope, and psychogenic nonepileptic seizures. We present a case report of a woman with convulsions, which developed due to dissociative (conversion motor) disorder, with chronic postoperative hypoparathyroidism, receiving standard treatment and having normo- and hypercalcemia.

PRO43 Methods to Identify Patients with Chronic Hypoparathyroidism in the United States (US) Using Claims Data

Few studies have examined large populations of patients with chronic hypoparathyroidism (cHP), a rare endocrine disease characterized by low serum calcium concentrations due to parathyroid hormone (PTH) deficiency. This study employed two strategies to identify and describe cHP population in a US claims database.

Abstract #1003636: Heterozygous GATA3 Gene Mutation and Isolated Hypoparathyroidism Diagnosed in Adulthood

Hypoparathyroidism is a disorder of calcium metabolism that presents with hypocalcemia and hyperphosphatemia. It is caused by a deficiency of parathyroid hormone (PTH). It can be seen as an isolated disorder or it can be a component of a syndrome. Although genetic causes of hypoparathyroidism are not common, a number of genes have been identified that can lead to a disorder in parathyroid gland formation or PTH synthesis and secretion. Some can lead to destruction of the parathyroid gland. We herein present a case of isolated hypoparathyroidism diagnosed in adulthood secondary to a rare genetic mutation in the GATA3 gene.

PTH resistance

Parathyroid hormone (PTH), which is primarily regulated by extracellular calcium changes, controls calcium and phosphate homeostasis. Different diseases are derived from PTH deficiency (hypoparathyroidism), excess (hyperparathyroidism) and resistance (pseudohypoparathyroidism, PHP). Pseudohypoparathyroidism was historically classified into subtypes according to the presence or not of inherited PTH resistance associated or not with features of Albright's hereditary osteodystrophy and deep and progressive ectopic ossifications. The growing knowledge on the PTH/PTHrP signaling pathway showed that molecular defects affecting different members of this pathway determined distinct, yet clinically related disorders, leading to the proposal of a new nomenclature and classification encompassing all disorders, collectively termed inactivating PTH/PTHrP signaling disorders (iPPSD).

A Single Administration of AZP-3601, a Novel, Long-Acting PTH Analog, Induces a Significant and Sustained Calcemic Response: Preliminary Data From a Randomized, Double-Blind, Placebo-Controlled Phase 1 Study

Hypoparathyroidism is a rare disease characterized by a deficiency in parathyroid hormone (PTH) that results in hypocalcemia and hyperphosphatemia. Current treatment approaches, including high dose oral calcium and active vitamin D, as well as recombinant human PTH (1–84), do not provide adequate or consistent control of either serum calcium or clinical symptoms over a full 24-hour period. AZP-3601 is a novel 36 amino-acid PTH analog that has been designed to potently bind to the R0 conformation of the PTH1 receptor, which results in prolonged signaling responses in vitro and prolonged calcemic responses in animals despite having a short circulating half-life. A Phase 1 double-blind, placebo-controlled, single and multiple ascending dose study is being conducted to evaluate the safety, tolerability and pharmacodynamics of AZP-3601 in healthy adults. Here we report data from the first cohorts of the single ascending dose portion of the study. Sequential cohorts of 4 (cohort 1) to 8 (cohort 2 to 4) healthy male subjects aged 18–60 years, with a body mass index of 19–28 kg/m2, were assigned to receive 5, 10, 20 or 40μg of AZP-3601 or placebo at a ratio of 3:1. The study drug was administered in the morning by subcutaneous injection in the abdominal wall and was well tolerated with no remarkable adverse events. As compared with placebo controls, AZP-3601 treatment produced a clear, dose-dependent increase in mean albumin-adjusted serum calcium values from baseline. The normal physiological diurnal variation of albumin-adjusted serum calcium was gradually attenuated with 5 and 10μg AZP-3601, and was completely eliminated with 20μg. With the dose of 40μg AZP-3601, mean albumin-adjusted serum calcium values were significantly increased but stayed within normal laboratory range and remained elevated through at least 24 hours post-administration. We observed a dose-dependent decrease in mean endogenous serum PTH that was significantly correlated with the concomitant increase in mean serum calcium. These data provide initial evidence of the pharmacodynamic effect of AZP-3601 in healthy humans characterized by a sustained calcemic response for at least 24 hours following a single administration.

Parathyroid Cell Differentiation from Progenitor Cells and Stem Cells: Development, Molecular Mechanism, Function, and Tissue Engineering.

Parathyroid glands are endocrine organs which are located posterior to thyroid glands and control secretion of parathyroid hormone (PTH) in order to regulate blood calcium level. PTH maintains calcium homeostasis by acting on the bone, kidney, and small intestine. PTH deficiency leads to chronic hypocalcemia, organ calcinosis, kidney and heart failure, painful muscle spasms, neuromuscular problems, and memory problems. Since parathyroid cells have inadequate proliferation potential in culture conditions, their utilization as a cellular therapy option is very limited. Although studies conducted so far include parathyroid cell differentiation from various cell types, problems related to successful cellular differentiation and transplantation still remain. Recently, parathyroid tissue engineering has attracted attention as a potential treatment for the parathyroid-related diseases caused by hypoparathyroidism. Although major progression is made in the construction of tissue engineering protocols using parathyroid cells and biomaterials, PTH secretion to mimic its spontaneous harmony in the body is a challenge. This chapter comprehensively defines the derivation of parathyroid cells from various cell sources including pluripotent stem cells, molecular mechanisms, and tissue engineering applications.

SAT-LB72 Design of the PaTH Forward Phase 2 Trial of TransCon PTH, a Long-Acting PTH, in Patients With Hypoparathyroidism

Background:Hypoparathyroidism (HP) is caused by a deficiency in parathyroid hormone (PTH), which leads to hypocalcemia and hyperphosphatemia. Standard of care (SoC), i.e. large doses of calcium (Ca) and active vitamin D, worsens hypercalciuria and increases the serum Ca (sCa) x serum phosphate (sP) product. Studies have shown that continuous subcutaneous infusion of PTH(1-34) normalizes sCa, sP, serum magnesium, urine Ca (uCa) and bone turnover better than SoC or once- or twice-daily injections of PTH in HP patients. TransCon PTH, an investigational long-acting prodrug of PTH (1-34) transiently bound to an inert carrier via a linker, is under development as a potential once-daily replacement therapy for HP. Under physiological conditions, linker auto-cleavage occurs, releasing active PTH at a controlled rate with ~60 hour half-life. Phase 1 trial results demonstrated that once-daily TransCon PTH provided a flat, infusion like profile within the normal range of PTH 24 hours per day, increasing sCa while controlling uCa and decreasing sP, with no evidence of bone anabolic activity.Phase 2 Design:PaTH Forward is a global phase 2 trial evaluating the safety, tolerability, and efficacy of TransCon PTH in adult subjects with HP. Patients with HP treated with SoC were randomized at sites worldwide to daily TransCon PTH 15, 18 or 21 µg PTH(1-34) or daily blinded placebo via pen-injector for 4 weeks. The primary composite endpoint requires 1) normal albumin-adjusted sCa, and 2) normal Fractional Excretion of Ca (or ≥50% decrease from baseline), and 3) not taking active D, and 4) taking ≤1000 mg/d of Ca. After four weeks, all subjects enter an open-label extension period with the opportunity to receive TransCon PTH individually optimized to doses of 6 to 30 µg daily to evaluate long-term safety and efficacy. Other endpoints include the impact of treatment on patient experience, CaxP product, bone turnover markers, and bone mass by DXA and TBS to confirm the lack of anabolic effect.Preliminary Results:Approximately 55 subjects are expected to be randomized and dosed. Preliminary diary data on the initial 8 subjects completing 4 weeks of follow-up in the extension trial shows that all have discontinued SoC. Additional information will be presented at ENDO 2020. The Phase 2 trial is designed to inform the starting dose for a global pivotal phase 3 trial and evaluate TransCon PTH as a “true” PTH replacement therapy.