Treatment Of Hypoparathyroidism Research Articles

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.

Treatment of Hypoparathyroidism by Re-Establishing the Effects of Parathyroid Hormone.

The conventional treatment of hypoparathyroidism (HypoPT) includes active vitamin D and calcium. Despite normalization of calcium levels, the conventional treatment is associated with fluctuations in calcium levels, hypercalciuria, renal impairment, and decreased quality of life (QoL). Replacement therapy with parathyroid hormone (PTH)(1-84) is an option in some countries. However, convincing beneficial effects have not been demonstrated, which may be due to the short duration of action of this treatment. Recently, palopegteriparatide (also known as TransCon PTH) has been marketed in Europe and is expected also to be approved in other countries. Palopegteriparatide is a prodrug with sustained release of PTH(1-34) designed to provide stable physiological PTH levels for 24 hours/day. A phase 3 study demonstrated maintenance of normocalcemia in patients with chronic HypoPT, with no need for conventional therapy. Furthermore, this treatment lowers urinary calcium and improves QoL. Another long-acting PTH analog with effects on the parathyroid hormone receptor (eneboparatide) is currently being tested in a phase 3 trial. Furthermore, the treatment of autosomal dominant hypocalcemia type 1 with a calcilytic (encaleret) is also being tested. All in all, improved treatment options are on the way that will likely take the treatment of HypoPT to the next level.

Initiation of Continuous rhPTH Infusion With Insulin Pump in an Inpatient Setting

Abstract Hypoparathyroidism is one of the few remaining hormonal insufficiencies not treated with replacement of its missing hormone. Conventional therapy involves multiple daily oral doses of calcium, active vitamin D, and magnesium, which is not only cumbersome for patients, but carries risk of nephrocalcinosis and is inadequate in patients with enteral malabsorption. Subcutaneous parathyroid hormone 1-34 (PTH[1-34]) has been tested as a hormonal replacement therapy for treatment of hypoparathyroidism. PTH(1-34) delivered by continuous infusion via insulin pump decreases or eliminates the need for oral medications, stabilizes serum and urine calcium at normal levels with minimal fluctuation, and significantly reduces PTH doses. In this case report, we describe the clinical application of PTH(1-34) via insulin pump in an adolescent with autoimmune polyendocrinopathy syndrome type 1 (APS1). Transition to a PTH pump reduced hospital admissions for calcium abnormalities and allowed our patient to discontinue all scheduled daily conventional therapy.

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.

Functional calcium-responsive parathyroid glands generated using single-step blastocyst complementation

Patients with permanent hypoparathyroidism require lifelong replacement therapy to avoid life-threatening complications, The benefits of conventional treatment are limited, however. Transplanting a functional parathyroid gland (PTG) would yield better results. Parathyroid gland cells generated from pluripotent stem cells in vitro to date cannot mimic the physiological responses to extracellular calcium that are essential for calcium homeostasis. We thus hypothesized that blastocyst complementation (BC) could be a better strategy for generating functional PTG cells and compensating loss of parathyroid function. We here describe generation of fully functional PTGs from mouse embryonic stem cells (mESCs) with single-step BC. Using CRISPR-Cas9 knockout of Glial cells missing2 (Gcm2), we efficiently produced aparathyroid embryos for BC. In these embryos, mESCs differentiated into endocrinologically mature PTGs that rescued Gcm2-/- mice from neonatal death. The mESC-derived PTGs responded to extracellular calcium, restoring calcium homeostasis on transplantation into mice surgically rendered hypoparathyroid. We also successfully generated functional interspecies PTGs in Gcm2-/- rat neonates, an accomplishment with potential for future human PTG therapy using xenogeneic animal BC. Our results demonstrate that BC can produce functional endocrine organs and constitute a concept in treatment of hypoparathyroidism.

Prevention of hypocalcemia and hypoparathyroidism after total thyroidectomy. Recommendations of the Francophone Association of Endocrine Surgery (AFCE) with the French Society of Endocrinology (SFE) and the French Society of Nuclear Medicine (SFMN).

Postoperative hypoparathyroidism, resulting from removal and/or devascularization of one or more parathyroid glands, is a feared complication of total thyroidectomy. Two forms, which are distinguished by their frequency, their time to onset and their duration as well as by their presentation, must be individualized: early postoperative hypocalcemia, often secondary to early hypoparathyroidism is a frequent and often transient situation occurring within the first days after surgery; permanent hypoparathyroidism, which is rarer, manifests when parathyroid function remains impaired for more than six months after surgery. Because of their severity, these conditions must be known and ideally prevented during total thyroidectomy. The objective of this article is to provide surgeons with practical recommendations for the prevention, diagnosis, and treatment of hypoparathyroidism after total thyroidectomy. These recommendations, which are the fruit of a medico-surgical consensus, were developed by the Francophone Association of Endocrine Surgery (AFCE), the French Society of Endocrinology (SFE) and the French Society of Nuclear Medicine and Molecular Imaging. (SFMN). The content, grade and level of evidence for each recommendation was decided after consultation within a panel of experts, based on an analysis of recent literature.

Abstract #1407986: Abaloparatide Administration Through the Simplicity Patch: A Therapeutic Option for Refractory Hypoparathyroidism Post-thyroidectomy

Hypoparathyroidism (HPT), characterized by hypocalcemia is typically managed with oral replacement of calcium and vitamin D. Some fail to achieve normocalcemia despite high doses. Such refractory HPT cases have benefited from recombinant PTH (rPTH). Abaloparatide, initially approved for the treatment of osteoporosis, has never been used for refractory HPT. Our case report discusses its administration in refractory HPT through the Simplicity patch. 39 y/o female with iatrogenic HPT failed to achieve normocalcemia despite high doses of vitamin D, calcium supplementation, and rPTH injection. Due to the patient’s recurrent hypocalcemia episodes requiring frequent hospitalizations, we elected to attempt controlling the refractory HPT with a subcutaneous administration of Abaloparatide. A review of the cases that used teriparatide administration through insulin delivery mechanisms was studied meticulously. We opted for Abaloparatide administration via the Simplicity patch. 1mL of Abaloparatide (equivalent to 2000mcg) was transferred to the Simplicity patch so that each click administered a 20mcg dose of Abaloparatide. The patient was closely monitored for 5 days. On day 1, we administered 1 to 2 clicks, spaced 2 hours apart. The patient’s serum calcium levels were carefully monitored with serial calcium profile testing. Over the next 4 days, based on the patient’s response and calcium levels, we created a click-dosing schedule. Her calcium levels were then closely followed weekly for 4 weeks, and monthly thereafter. Two months after the initiation of the therapy, she was able to maintain her calcium levels at 9mg/dl. Follow-up labs indicated better control of the calcium status and we were able to wean off the oral calcium and vitamin D supplementation by end of 4 months. Four months after initiation of Abaloparatide with the Simplicity patch, she was able to sustain normal calcium levels and reported no hypocalcemic events. rPTH(1-84) has been approved for the treatment of chronic refractory HPT since 2015. Studies have compared the use of teriparatide for refractory HPT. Administration of teriparatide as divided doses were associated with better control of calcium levels when compared to once-a-day dosing. Higher calcium levels with fewer fluctuations and normal urinary calcium levels were noted in twice-a-day dosing. Several studies have also explored utilizing insulin pumps to administer continuous infusion of rPTH and noted that it was associated with less fluctuation in their serum calcium levels. Abaloparatide is available as a subcutaneous injection, just like teriparatide. It has never been used for refractory HPT. They have a similar mechanism of action and pharmacokinetics. The ease of using the Simplicity patch, allowed us to divide the doses into a customizable click-dosing schedule. Our patient demonstrated a good response to the click-dosing, without any side effects. With the increasing availability of different insulin delivery mechanisms and newer rPTH, there is a need for large-scale trials to further explore the role of Abaloparatide in the management of chronic HPT, using insulin delivery systems.

Is parathyroid allotransplantation a viable option in the treatment of permanent hypoparathyroidism? A review of the literature.

The standard clinical treatment for hypoparathyroidism, replacement of calcium and vitamin metabolites (calcitriol), has been used for decades; however, evidence points to its inefficiency in acting on the pathophysiology of the disease, which may precipitate or aggravate conditions already related to hypoparathyroidism. Therapies based on recombinant human parathyroid hormone have emerged in recent years but still have low availability due to their high cost. Parathyroid allotransplantation (Pt-a) has been reported as a strategy for treating more severe cases. This narrative review highlights relevant aspects of conventional permanent hypoparathyroidism treatment and provides a comprehensive and critical review of the reports of applications of Pt-a, especially those carried out in recent years. Particular focus is placed on the following key points: parathyroid immunogenicity, immunosuppression regimens (short-term or chronic), techniques to reduce the expression of immunogenic molecules, follow-up time, and reductions in calcium and vitamin D supplementation. Pt-a has been considered a safe and relatively low-cost therapy and is believed to have the potential to cure the disease, in addition to treating symptoms. However, there is considerable heterogeneity in treatment protocols; therefore, more studies are required to improve the standardization of the procedure and thus improve the consistency of outcomes.

OR21-6 AZP-3601, a Long-Acting Parathyroid Hormone (PTH) Analog, Normalizes Blood Calcium in Thyroparathyroidectomized (TPTX) Rats Without Causing Deleterious Changes in Bone

Abstract PTH peptides can be effective in normalizing blood calcium (Ca++) levels in cases of hypoparathyroidism (HP), but long-term effects on bone are not well understood. AZP-3601 is a long-acting PTH/PTHrP(1-36) analog currently being investigated as a potential treatment option for HP. As compared to conventional PTH1-34, AZP-3601 binds with higher affinity to the R0 conformation of the PTH receptor and thereby induces more sustained signaling responses in cells as well as more prolonged calcemic responses in vivo, despite having a very short circulating half-life. Using the TPTX rat model of HP, we investigated whether the distinct mode-of-action used by AZP-3601 results in different down-stream effects in bone than those induced by PTH1-34, when the peptides are administered long-term (31 days) either by daily sc injection (AZP-3601 and PTH1-34) or by continuous infusion (PTH1-34), and at doses aimed to optimally normalize blood Ca++ levels. Methods Male TPTX rats (strain S-D, age 9 weeks, and 2 weeks post TPTX surgery) were injected daily with either AZP-3601 at a dose of 0.7 nmol/kg or PTH1-34 at a dose of 50 nmol/kg, or were continuously infused via Alzet mini-pump with PTH1-34 at a dose of 3.0 nmol/kg/day. Vehicle treatments and sham surgery rats were used as controls. Tail-vein blood was collected on days 1, 7 14, 21 and 28 at 6 hours post-injection and analyzed for total Ca++. Rats were euthanized on day 31 (24 hours after last injection) and blood and femurs collected for analysis. Results All peptide-treatments increased serum Ca++ levels on days 7-21 to within or near the normal range (8.8-11.7 mg/dL versus 10.8-11.9 mg/dL in sham-operated rats) and to levels significantly higher than those in vehicle-treated TPTX rats (6.9-7.9 mg/dL, P<0.01). Bone mCT analysis revealed that relative to TPTX-vehicle controls, PTH1-34 continuous infusion significantly decreased (p<0.001) distal femur trabecular bone volume relative to tissue volume (BV/TV), trabecular number (Tb.N) and trabecular thickness (Tb.Th), while PTH1-34 daily injection significantly increased (P<0.001) distal femur BV/TV, Tb.Th and Tb.N, as well as mid-femur cortical thickness (Ct.Th, P<0.001). In contrast, AZP-3601 daily injection caused no change in trabecular or cortical bone parameters. Serum levels of the bone formation marker P1NP were significantly increased by daily injection of PTH1-34 (P<0.001 vs. TPTX-vehicle) but were not changed by other treatments. Conclusion With long-term (31 days) treatment and at doses that similarly normalized serum Ca++ in TPTX rats, effects on bone were catabolic for PTH1-34 by continuous infusion, anabolic for PTH1-34 by daily injection, and neutral for AZP-3601 by daily injection. The distinct MOA used by AZP-3601 may thus result in less of an impact on bone than either daily injection or sustained, continuous delivery of PTH(1-34), when used as a long-term treatment for HP. Presentation: Monday, June 13, 2022 12:15 p.m. - 12:30 p.m.

ODP118 PTH (1-34) Replacement Therapy for Hypoparathyroidism due to Sporadic Calcium Sensing Receptor Gain-of-Function Point Mutation

Abstract Background The calcium sensing receptor (CASR) regulates parathyroid hormone secretion in response to extracellular calcium concentration. A gain-of-function mutation of the CASR lowers the set point for extracellular calcium sensing, resulting in both reduced parathyroid hormone secretion and increased urinary calcium excretion compared to other causes of hypoparathyroidism. Clinical Case After presenting with hypocalcemia-associated seizures at the age of two years, our patient had an undetectable serum parathyroid hormone level. He was started on calcitriol and calcium supplementation, however continued to have recurrent seizures throughout childhood. On ultrasound at age four, he exhibited nephrocalcinosis. DNA sequence analysis revealed a heterozygous T383G mutation nucleotide substitution on exon 3, resulting in the replacement of phenylalanine with cysteine at amino acid position 128. Our patient's base substitution likely represents a de novo mutation as we have confirmed that he has no family history of hypocalcemia. Notably, a different missense mutation at the same codon (F128L) co-segregated with autosomal dominant hypocalcemia in a large family, and functional studies confirm that mutation of this phenylalanine provides gain-of-function to the CASR. After enrolling in a clinical trial for continuous recombinant parathyroid hormone infusion at age seven, his symptoms of hypocalcemia abated. His seizures stopped, and anti-epileptic drugs were discontinued at age eight. After the clinical trial concluded, he was switched to teriparatide 10 micrograms three times daily, and serum calcium was maintained between 7.5 and 8.5 mg/dL. With the goal to minimize hypercalciuria and reduce the frequency of injections, teriparatide was discontinued, and recombinant parathyroid hormone (Natpara) 50 micrograms daily was started. This led to symptomatic hypocalcemia with muscle cramping and cognitive changes, and he was thus restarted on teriparatide with calcium carbonate supplementation. Despite maintenance of 24-hour urine calcium excretion ranging 325-388 mg, he developed bilateral flank pain. Computed tomography images revealed worsening nephrocalcinosis and bilateral nephrolithiasis. To reduce hypercalciuria and risk of stone formation, he was started on chlorthalidone, switched to calcium citrate, and encouraged to reduce dietary sodium intake. Conclusion This patient has a novel T383G activating mutation in CASR gene resulting in hypoparathyroidism and type 5 Bartter syndrome that has not been previously published in the literature. His hypocalcemia has remained stable on teriparatide for over 18 years, which to our knowledge, is the longest treatment duration using recombinant human parathyroid hormone for this purpose. We demonstrate a unique clinical challenge to balance treatment of hypoparathyroidism and hypocalcemia with teriparatide and supplemental calcium, while minimizing hypercalciuria and associated nephrocalcinosis. Presentation: No date and time listed

Parathyroid Allotransplantation: A Systematic Review.

Background: To date, there is no satisfactory treatment for patients with calcium and vitamin D supplementation refractive hypoparathyroidism. Parathyroid allotransplantation by design is a one-time cure through its restoration of the parathyroid function and, therefore, could be the solution. A systematic literature review is conducted in the present paper, with the aim of outlining the possibilities of parathyroid allotransplantation and to calculate its efficacy. Additionally, various transplantation characteristics are linked to success. Methods: This review is carried out according to the PRISMA statement and checklist. Relevant articles were searched for in medical databases with the most recent literature search performed on 9 December 2021. Results: In total, 24 articles involving 22 unique patient cohorts were identified with 203 transplantations performed on 148 patients. Numerous types of (exploratory) interventions were carried out with virtually no protocols that were alike: there was the use of (non-) cryopreserved parathyroid tissue combined with direct transplantation or pretreatment using in vitro techniques, such as culturing cells and macro-/microencapsulation. The variability increased further when considering immunosuppression, graft histology, and donor–recipient compatibility, but this was found to be reported in its entirety by exception. As a result of the large heterogeneity among studies, we constructed our own criterium for transplantation success. With only the studies eligible for our assessment, the pooled success rate for parathyroid allotransplantation emerged to be 46% (13/28 transplantations) with a median follow-up duration of 12 months (Q1–Q3: 8–24 months). Conclusions: Manifold possibilities have been explored around parathyroid allotransplantation but are presented as a double-edged sword due to high clinical diverseness, low expertise in carrying out the procedure, and unsatisfactory study quality. Transplantations carried out with permanent immunosuppression seem to be the most promising, but, in its current state, little could be said about the treatment efficacy with a high quality of evidence. Of foremost importance in pursuing the answer whether parathyroid allotransplantation is a suitable treatment for hypoparathyroidism, a standardized definition of transplantation success must be established with a high-quality trial.

Development of Surgically Transplantable Parathyroid Hormone-Releasing Microbeads.

Hypoparathyroidism is an endocrine disorder that occurs because of the inability to produce parathyroid hormone (PTH) effectively. Previously, we reported the efficacy of tonsil-derived mesenchymal stem cells (TMSCs) differentiated into parathyroid-like cells for the treatment of hypoparathyroidism. Here, we investigated the feasibility of three-dimensional structural microbeads fabricated with TMSCs and alginate, a natural biodegradable polymer, to treat hypoparathyroidism. Alginate microbeads were fabricated by dropping a 2% (w/v) alginate solution containing TMSCs into a 5% CaCl2 solution and then differentiated into parathyroid-like cells using activin A and sonic hedgehog for 7 days. The protein expression of PTH, a specific marker of the parathyroid gland, was significantly higher in differentiated alginate microbeads with TMSCs (Al-dT) compared with in undifferentiated alginate microbeads with TMSCs. For in vivo experiments, we created the hypoparathyroidism animal model by parathyroidectomy (PTX) and implanted alginate microbeads in the dorsal interscapular region. The PTX rats with Al-dT (PTX+Al-dT) showed the highest survival rate and weight change and a gradual increase in serum intact PTH levels. We also detected a higher expression of PTH in retrieved tissues of PTX+Al-dT using immunofluorescence analysis. This study demonstrates that alginate microbeads are potential a new tool as a surgically scalable therapy for treating hypoparathyroidism.

Development of a Hypoparathyroid Male Rodent Model for Testing Delayed-Clearance PTH Molecules.

Parathyroid hormone (PTH) replacement is a promising approach in the management of hypoparathyroidism but long-acting analogues need to be developed. To date, animal models for testing PTH required parathyroidectomy by surgery. We have developed a nonsurgical rodent hypoparathyroid model and tested a delayed-clearance PTH molecule (DC-PTH). The aim of this study was to use cinacalcet to suppress calcium levels in normal rats and to reverse these effects with the administration of PTH or PTH analogues. Male Wistar rats were gavaged with either 30 mg/kg cinacalcet-HCl (cinacalcet) or vehicle only. Animals were then dosed with either single or repeated subcutaneous doses of PTH 1-34 or a DC-PTH at 20 nmol/kg. Control animals received vehicle only. Serum samples were analyzed for ionized calcium (iCa), phosphate, PTH, and DC-PTH. A pharmacokinetic-pharmacodynamic (PK-PD) model was built for cinacalcet, PTH 1-34, and DC-PTH using Phoenix64. Cinacalcet reduced iCa levels between 2 and 24 hours, returning to baseline by 72 hours post dose with nadir at 8 hours (analysis of variance P < .001), associated with a fall in rat PTH. For phosphate there was a variable biphasic response. Single-dose PTH abrogated the cinacalcet-induced fall in iCa for up to 2 hours. DC-PTH prevented the fall in iCa from 4 hours post dose and gave a prolonged response, with iCa levels quicker to return to baseline than controls. DC-PTH has a half-life of 11.5 hours, approximately 44 times longer than human PTH 1-34. The PK-PD models defined the reproducible effect of cinacalcet on iCa and that DC-PTH had prolonged biological activity. The administration of cinacalcet provides a robust and reproducible nonsurgical animal model of hypoparathyroidism. DC-PTH holds promise for the treatment of hypoparathyroidism in the future.

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.

The Importance of Cryopreserved Parathyroid Tissue Autotransplantation in the Hypoparathyroidism Treatment after Secondary Hyperparathyroidism Surgery

The Importance of Cryopreserved Parathyroid Tissue Autotransplantation in the Hypoparathyroidism Treatment after Secondary Hyperparathyroidism Surgery

Hypoparathyroidism: State of the Art on Cell and Tissue Therapies.

Hypoparathyroidism is an endocrine disorder characterized by low serum calcium levels, high serum phosphorus levels, and by inappropriate or absent secretion of the parathyroid hormone (PTH). The most common therapeutic strategy to treat this condition is hormone replacement therapy with calcium and vitamin D but, unfortunately, in the long term this treatment may not be sufficient to compensate for the loss of endocrine function. Glandular autotransplantation is considered the most effective technique in place of replacement therapy. Although it leads to excellent results in most cases, autotransplantation is not always possible. Allograft is a good way to treat patients who have not been able to undergo autograft, but this technique has limited success due to side effects related to tissue rejection. This therapy is supported by systemic immunosuppression, which leads to the onset of serious side effects in patients, with a risk of endocrine toxicity. Today, research on endocrine disorders is focused on discovering alternative graft therapies that can allow optimal results with the fewest possible side effects. In this review, we will make an update on the current state of the art about the cell and tissue therapy as treatment for hypoparathyroidism, to identify which type of therapeutic strategy could be valid for a future clinical use.

Discovery of a Long-Acting Parathyroid Hormone 1-34 Analogue to Treat Hypoparathyroidism.

Hypoparathyroidism (HP) is a rare disease with clinical manifestations of hypocalcemia and hyperphosphatemia, resulting from deficient or absent parathyroid hormone (PTH) secretion. Conventional treatment for patients with HP involves extensive calcium and vitamin D supplementation. In 2015, PTH1-84 was approved by the United States Food and Drug Administration as an adjunct for HP patients who cannot be well-controlled on conventional treatment. However, PTH1-84 therapy requires a daily injection, leading to poor patient compliance. The purpose of this study was to develop a long-acting PTH1-34 analogue by increasing its affinity to albumin. Three PTH1-34 variants were generated by substituting two of the three lysine (Lys) residues with arginine, reserving a single Lys as the modification site in each sequence. A series of side chains, containing fatty acid, deoxycholic acid, or biotin groups, were synthesized to modify these PTH1-34 variants by using a solid-liquid phase synthesis approach. In vitro bioactivity and albumin affinity tests were used to screen these new PTH1-34 analogues. Finally, Lys27-AAPC was selected from 69 synthesized analogues as a candidate therapeutic compound because it retained potency and exhibited a high albumin-binding capacity. In pharmacodynamic experiments, Lys27-AAPC demonstrated enhanced and prolonged efficacy in serum calcium elevating relative to PTH1-84. Moreover, a lyophilized powder for injection containing Lys27-AAPC was developed for further testing and represented a potential long-acting HP treatment.

Changes in Serum Calcium and Treatment of Hypoparathyroidism During Pregnancy and Lactation: A Single-center Case Series.

Hypoparathyroidism (hypo-PT) is rare, and studies on hypo-PT, especially during pregnancy and lactation, are limited. This was a retrospective study on a relatively large case series in a single center from mainland China. A total of 19 patients with 25 pregnancies, diagnosed with hypo-PT before pregnancy, were enrolled. Data on clinical characteristics and treatment strategies at onset time and around pregnancy period were collected. During pregnancy, except for 2 patients with missing data, 5 patients with 6 pregnancies (6/23, 26.1%) experienced improved hypo-PT condition, defined as an increased serum calcium level; 4 patients with 4 pregnancies (4/23, 17.4%) experienced worsened hypo-PT condition, defined as a more than 0.2 mmol/L decline in the serum calcium level; and 3 patients with 3 pregnancies (3/23, 13.0%) remained in stable hypo-PT condition. The prevalence of adverse pregnancy outcomes was 30.4% (4/23 for preterm delivery; 3/23 for miscarriage). The serum calcium and 24-hour urine calcium levels significantly increased during lactation compared with pregnancy (2.57 ± 0.34 vs 1.99 ± 0.11 mmol/L, P < 0.001; 12.28 ± 5.41 vs 8.63 ± 3.22 mmol/L, P = 0.013), and 5 patients with 5 lactations (5/12, 41.7%) developed hypercalcemia in the first 2 months after delivery. Female patients with hypo-PT had different changes in calcium homeostasis and a high prevalence of adverse outcomes during pregnancy. Thus, they should be monitored closely to maintain the optimal serum calcium level. Decreasing drug dosage during the lactation period should be considered to avoid hypercalcemia.

Hypoparathyroidism Associated with the DNA Variants in Non-Coding Sequence Region of Calcium-Sensing Receptor

A stable narrow range of extracellular calcium concentration in the blood is essential for life. The calcium-sensing receptor (CaSR), a member of the G protein-coupled receptors family, is required to adjust the set point of blood extracellular calcium concentration, thus regulate parathyroid hormone (PTH) secretion and renal calcium excretion. Loss or gain function of CaSR mutations may result in either hyper- or hypocalcaemia. The CaSR activating mutations increase its sensitivity to extracellular ionized calcium (Ca2+). As consequence, PTH synthesis and secretion are suppressed continuously at normal ionized calcium concentrations. Patients display hypocalcaemia, hyperphosphatemia and lower levels of PTH. Urinary calcium excretion is increased due to the decreased circulating inappropriately PTH level and the activation of the renal tubular CaSR. Therefore, CaSR becomes a good potential clinical therapeutic target for hypoparathyroidism treatment. In order to define new drugs and improve medical management of hypoparathyroidism patients, this study attempts to identify new CaSR variants and analyse in detail the functional change of these CaSR variants, thus better understand the molecular mechanism involved. The study is based on collected hypoparathyroidism patients in our clinical site. In the study we enrolled in 10 patients, obtained all their clinical results and DNA results from seven patients. Our results indicated that the effect of serum intact PTH level correlated to change of serum Ca2+ and phosphate level. The CaSR carrying newly identified DNA variants displayed strong phosphorylation of phospholipase C and mitogen-activated protein kinases. Although the size of clinical cases need to be accumulated, current cases have showed a tendency that the identified multiple DNA variants in CaSR gene revealed an effect on the diagnostic criterion of the hypocalcaemic syndrome. It is undeniable that our research has certain limitations. So far, we tested several DNA variants at the same time, further functional examination for individual DNA variant would largely help to be better understand the mechanisms of CaSR regulation on extracellular calcium concentration.

TransCon PTH as a Hormone Replacement Therapy for Patients with Hypoparathyroidism: 6-Month Update from the PaTH Forward Open-Label Extension

Background: Hypoparathyroidism (HP) is characterized by insufficient levels of parathyroid hormone (PTH), resulting in hypocalcemia, hyperphosphatemia, hypercalciuria, and a reduced quality of life (QoL). PTH replacement therapy should restore physiologic levels of PTH and restore downstream physiologic levels of calcitriol, promoting independence from Ca and active vitamin D supplements and normalization of QoL.TransCon PTH is an investigational long-acting prodrug of PTH(1–34) for the treatment of HP. During the initial 4-week fixed-dose period of the PaTH Forward Trial, TransCon PTH enabled 82% of subjects to achieve independence from standard of care (SoC; no active vitamin D and Ca ≤ 500 mg/day) compared to 15% with placebo. Here, we report 6-month (Week 26) results from the open-label extension (OLE). Methods: PaTH Forward is a phase 2, double-blind, placebo-controlled trial evaluating TransCon PTH in adult HP patients treated with SoC. Subjects received fixed doses of TransCon PTH 15, 18, or 21 µg PTH(1–34)/day or placebo for 4 weeks, followed by an OLE period during which TransCon PTH dose was titrated (6–30 µg PTH[1–34]/day) per individual dosing requirement. Safety and efficacy endpoints were evaluated at predefined timepoints over the OLE. Endpoints were evaluated at Week 26 including 1) sCa, 2) 24-hour uCa, 3) independence from active vitamin D, and 4) independence from therapeutics doses of oral calcium. QoL was assessed by the SF-36 and the Hypoparathyroidism Patient Experience Scales (HPES). Results: All 59 subjects completed the initial 4-week period and continued in the OLE; 58 subjects continue in the OLE beyond 6 months (1 withdrew unrelated to safety or efficacy). TransCon PTH enabled independence from SoC (no active vitamin D and Ca ≤ 500 mg/day) in 91% of subjects and independence from all supplements (no active vitamin D and no Ca) in 76% of subjects by Week 26. Mean 24-hour uCa decreased from a baseline mean of 415 mg/24h to 178 mg/24h by Week 26 (n = 44) while maintaining sCa, and reducing sP and CaxP to fall within the normal range. The mean scores for all SF-36 summary and domains increased from below normal at baseline to within the normal range by Week 26. The HPES Symptom and Impact scores continuously improved through 26 weeks for TransCon PTH and placebo subjects switching to TransCon PTH. TransCon PTH continued to be well-tolerated with no treatment-related serious or severe adverse events. Conclusions: Results from the OLE of the PaTH Forward Trial demonstrated that TransCon PTH continued to enable independence from active vitamin D and Ca supplements for most subjects while maintaining normal sCa, sP, uCa, and demonstrating enhanced quality of life, supporting its potential as a hormone replacement therapy for patients with HP. TransCon PTH will be further evaluated in the phase 3 PaTHway Trial.