Treatment Of Hypoparathyroidism Research Articles

Development of PTH Eluting Microspheres for the Treatment of Hypoparathyroidism

Parathyroid hormone (PTH) replacement has been demonstrated to be superior to conventional treatment with calcium supplementation and vitamin D analogs for the treatment of hypoparathyroidism. In this investigation we evaluated the feasibility of using PTH microsphere encapsulation as a potential delivery system for PTH. Using the spontaneous emulsion technique, PTH microspheres were created by encapsulating PTH (1-34) in a copolymer of polyglycolic and polylactic acid (PLGA). Additional microspheres were constructed by coencapsulating calmodulin with PTH (1-34) in the PLGA microspheres. Microsphere production was confirmed using electron microscopy. PTH release was measured in vitro using an enzyme-linked immunosorbent assay. The bioactivity of PTH released from the microspheres was confirmed in vivo using a hypoparathyroid rat model by measuring serum calcium concentrations before and 3 h after subcutaneous injection of PTH microspheres. PTH microsphere and PTH/calmodulin microspheres could be created using the spontaneous emulsion technique. Physiologically significant PTH release was measured in vitro for 20 days. PTH release was calcium sensitive and exhibited negative feedback. This effect was augmented by coencapsulation with calmodulin. PTH released from the microspheres caused a significant rise in serum calcium levels from an average of 6.35 (6.19-6.48 mg/dL) to 8.55 mg/dL (8.22-8.73). PTH released from the PTH/calmodulin microspheres resulted in an increase in serum calcium from a mean of 6.8 (6.7-6.9 mg/dL) to 8.1 mg/dL (7.8-8.2). The PLGA microspheres can be used to provide calcium sensitive controlled release of biologically active PTH and offer a potential mean of providing biomimetic hormone replacement therapy.

Treatment of hypoparathyroidism by active vitamin D

Oral administration of active vitamin D is used as a standard medication for the treatment of hypoparathyroidism in our country. Although the dose required for the control of serum calcium level might be different dependent on the pathological type of hypoparathyroidism, the determination of maintenance dose and follow-up are performed by the measurements of serum and urinaly calcium levels. In the future, the clinical use of parathyroid hormone is expected for the treatment of hypoparathyroidism, since it is physiological.

Allotransplantation of Cultured Parathyroid Progenitor Cells Without Immunosuppression: Clinical Results

Hypoparathyroidism is a well-known consequence of extensive thyroid and parathyroid surgery. Allotransplantation of cultured parathyroid cells can be considered as an alternative to vitamin D3 and calcium supplementation in treatment of hypoparathyroidism. We present the long-term allotransplant activity in 85 patients who had undergone cellular allotransplantation for surgical hypoparathyroidism. Also, a modified technique to prepare parathyroid explants is described for obtaining a new nonimmunogenic cell population. From March 1990 to December 2004, 85 patients underwent 116 allotransplantations of cultured parathyroid cells. Mean recipient age was 46.2+/-11.1 years. Donors were selected from patients undergoing parathyroidectomy for secondary and tertiary hyperparathyroidism. After 6 weeks of cultivation and freezing, the parathyroid cells decreased their normal human leukocyte antigen (HLA) class I ABC expression and were free of HLA class II positive cells. The viability of cultured cells was 95.15+/-2.94%. Eighty-five patients underwent primary allotransplantation. Of these, 25 patients subsequently underwent a repeat procedure. In six cases, the parathyroid cells were obtained from the same donor and in 19 cases from a different donor. For all patients, the mean cellular allograft survival was 6.35+/-13.08 months. In 64 patients (55.1%), the allografts retained their endocrine function for more than 2 months. The present study has shown that in some patients parathyroid cell allotransplantation may be considered a method of treatment for permanent hypoparathyroidism after thyroid surgery. Graft function and/or survival did not depend on the baseline viability or secretory activity of cultured cells used for transplantation.

Hypercalcaemia in two dogs caused by excessive dietary supplementation of vitamin D

A three-year-old Border collie was presented with a two-week history of lethargy, stiff gait, polydipsia and polyuria. Biochemical analysis revealed hypercalcaemia. Serum concentrations of 25-hydroxyvitamin D (25[OH]D) and 1,25-dihydroxyvitamin D (1,25[OH]2D) were markedly elevated and parathyroid hormone was undetectable. Subsequent analysis of the dog's diet revealed that the food contained excessive amounts of vitamin D. The hypercalcaemia resolved following treatment with bisphosphonates and dietary change. Hypervitaminosis D was diagnosed in a second unrelated dog, which had been fed the same brand of dog food as case 1. The dog was also hypercalcaemic and had markedly elevated serum concentrations of 25(OH)D and 1,25(OH)2D. Hypervitaminosis D in dogs has been reported to occur secondarily to ingestion of either rodenticides containing cholecalciferol or antipsoriatic ointments that contain vitamin D analogues. Hypervitaminosis D has also been reported following the treatment of hypoparathyroidism. To the authors' knowledge, this is the first report of hypervitaminosis D in dogs following the accidental over supplementation of a commercial diet with vitamin D. While the benefits of adequate dietary vitamin D are well established in dogs, the potential deleterious effects of over supplementation of vitamin D should also be acknowledged.

Falecalcitriol as a new therapeutic agent for secondary hyperparathyroidism

The 26 and 27 positions of vitamin D molecular structure of calcitriol were fluorinated with 3 atoms of fluorine each and the new compound was named falecalcitriol (F6). This new compound was found to be 10 to 100 times more active compared with calcitriol depending on the target organs. As a mechanism of strong action of F6 it was discovered that F6 is hydroxylated at 23 position which has almost the same activity as the mother compound. It was also demonstrated that the PTH suppressive effect was relatively stronger than the calcium absorption action from the intestine. Thus F6 was authorized to be applied to the treatment of secondary hyperparathyoroidism in hemodialysed patients as well as to the treatment of hypoparathyroidism.

Development of a parathyroid hormone-controlled release system as a potential surgical treatment for hypoparathyroidism

Background/Purpose The aim of this study was to develop a surgically implantable controlled release delivery system for parathyroid hormone (PTH) that will maintain calcium homeostasis without the adverse side effects of long-term calcium and vitamin D replacement and can be used for the treatment of hypoparathyroidism. Methods Biodegradable poly(lactide-co-glycolide) (PLGA) microspheres loaded with PTH were made using a modification of the double emulsion (water/oil/water) solvent evaporation technique. To simulate the release of PTH from microspheres after implantation in an animal, the in vitro release profile for the PTH microspheres was determined by incubating the PTH microspheres in phosphate-buffered saline, serially sampling the effluent, and determining the concentration of PTH in the effluent over time using an enzyme-linked immunosorbent assay. Results (1) PTH was successfully incorporated into PLGA microspheres. (2) Controlled release of PTH was demonstrated in vitro over a 3-week period. (3) Release of physiological significant concentrations of PTH was achieved using this methodology. Conclusions Controlled release of physiological concentrations of PTH can be achieved using PLGA microsphere encapsulation.

PCKM-mPTH recombinant plasmid therapy for hypoparathyroidism: an in vivo experimental research with rats

To investigate the effect of gene therapy with pCKM-mPTH recombinant plasmid on hypoparathyroidism. Thirty male Sprague Dawley rats were randomly divided into three groups: group A, undergoing fake operation and then injection of normal saline into the quadriceps muscle of the left leg; group B, undergoing parathyroidectomy and injection of blank pcDNA3.1(+) plasmid into the quadriceps muscle of the left leg; and group C, undergoing parathyroidectomy injection of pCKM-mPTH plasmid containing gene of mutated proparat-hormone into the quadriceps muscle of the left leg. Peripheral blood was collected from each rat before operation and 3, 5, 6, 7, 9, 12, 15, 20 and 30 days after operation. Radioimmunoassay was used to detect the level of parathyroid hormone. The level of paratheproid hormone (PTH) of the group B was 10.61 ng/dl +/- 0.86 ng/dl before injection of blank plasmid and gradually decreased after the injection, for example, 10.39 ng/dl +/- 0.36 ng/dl 1 day after the injection and 9.45 ng/dl +/- 2.64 ng/dl 60 days after the injection. The level of PTH of the group C was 10.75 ng/dl +/- 0.45 ng/dl before the injection of pCKM-mPTH plasmid and gradually increased after the injection, for example, 28.39 +/- 0.22 ng/dL 1 day after the injection, significantly higher than that before the injection, peaked on the 6th day (43.28 ng/dl +/- 2.45 ng/dl), then gradually decreased, and reached 15.32 ng/dl +/- 0.26 ng/dl on the 60th day. However, the levels of PTH in the group C at any time-point were all significantly higher than those of the group B (all P < 0.01). Symptoms of hypoparathyroidism were not observed in the rats of the group C. pCKM-mPTH recombinant plasmid therapy is effective in treatment of hypoparathyroidism.

Calcium sensitive feedback release of parathyroid hormone as a potential treatment of hypoparathyroidism

Introduction. The most common cause of hypoparathyroidism is iatrogenic injury to the parathyroid glands during thyroid resection. To avoid adverse side effects of long-term calcium and vitamin D therapy, we are investigating ways to maintain calcium homeostasis through the controlled release of parathyroid hormone (PTH) from poly(lactide-co-glycolide) (PLGA) microspheres. An ideal delivery vehicle for this purpose would be biodegradable and sensitive to calcium concentrations. Since calmodulin undergoes a conformational change when bound with calcium, we hypothesized that calmodulin, co-encapsulated with PTH, may alter the PTH release kinetics from biodegradable PLGA microspheres. Methods. Using double emulsion solvent evaporation technique, PLGA microspheres loaded with 0.5 mg of PTH and 50 mg of calmodulin were made. In vitro release profiles for the microspheres were determined by incubating them in a Tris-HCl buffer at pH 7.5, 37°C and varying calcium chloride (CaCl 2) concentration. The effluent was serially sampled and PTH concentration measured. First, we compared release of PTH with (2mM) CaCl 2 and without CaCl 2 in the buffer. Second, we constructed the release profile with CaCl 2 at concentrations of 1 and 2 mM. Next, bioactivity of the PTH released from these microspheres was evaluated in vivo by injecting 25 mg subcutaneously in a rat and obtaining serial serum levels. Results. (1) In experiments in which effect of calcium chloride was compared to no CaCl 2, after 3 h, 2 mM Ca 2+ buffer had reduced the release of PTH by 20%. In the experiments with buffer containing 1 and 2 mM of CaCl 2, the microspheres released 110 ng less of PTH at a CaCl 2 concentration of 2 mM than at 1 mM. When the buffers were reversed, rate of release of PTH from the microspheres increased in the microspheres that were initially in 2 mM CaCl 2 and decreased in those which were at 1 mM CaCl 2. (2) When these microspheres were injected subcutaneously in a rat, serum calcium rose from baseline of 10.6 to 12.2 mg/dl. Conclusions. Calmodulin can be used to develop calcium sensitive PLGA microspheres for the delivery of PTH. Bioactivity of PTH is preserved with coencapsulation of calmodulin.

180. Use of Skeletal Muscle for Regulated Expression of Parathyroid Hormone To Treat Hypoparathyroidism

Hypoparathyroidism is a condition in which reduction of serum calcium levels causes muscle cramps and spasms, and in extreme cases seizures and death. Current treatment for hypoparathyroidism involves daily oral supplements of the vitamin D analog calcitriol. This treatment is able to control some of the symptoms, including hypocalcemia and hyperphosphatemia, but the associated hypercalciurea remains poorly controlled, and if left untreated can lead to renal failure. Recent clinical studies showed that daily subcutaneous injections of recombinant hPTH1-34 normalized both serum and urine calcium levels in hypoparathyroid patients. Two daily injections achieved better control over calcium levels and required a lower daily dose (Winer et al, J Clin Endocrinol Metab. 2003, 88(9):4214–20). While these results suggest a new option for treating hypoparathyroidism, this approach requires the delivery of high PTH doses at each injection time to maintain adequate circulating levels, increasing the risk of side effects. More frequent administration of lower doses requires multiple daily injections, thus raising patient compliance issues. Both of these problems could be addressed via a gene therapy approach in which an externally regulated PTH expression cassette was transduced into skeletal muscle, and induced with a small orally available molecule. Careful dosing of the amount of transgene and the inducer molecule could then lead to production of therapeutic levels of circulating hormone.

Vitamin D and its analogs in the treatment of hypoparathyroidism

Hypoparathyroidism patients devided two groups. One group is low PTH group and the other is pseudo hypoparathyroidism group. Hypoparathyroidism in these patients has been managed by 1,25- (OH)(2)D(3) or 1alpha-OHD(3). However inappropriately high doses active vitamin D usually lead to marked hypercalciuria. It is important to control serum Ca level (absolute hypo within normal values) without hypercalciuria.

Severe Vitamin D(dihydrotachysterol)-intoxication with temporary anemia and hypercalcemia responsive to bisphosphonates

Severe Vitamin D(dihydrotachysterol)-intoxication with temporary anemia and hypercalcemia responsive to bisphosphonates. HISTORY AND FINDINGS: A 31-year old female patient presented with pain of her skeletal system. 6 months prior to her presentation, she underwent thyroid surgery for Graves disease. She also suffered from endocrine orbitopathy. Afterwards, she expirienced surgical hypoparathyroidism and received dihydrotachy-sterol (A.T.10 (R)) in a dose of up to 4 mg per day. The physical examination was unremarkable except for the presence of Graves' ophthalmopathy and a swelling at the left ancle. INVESTIGATIONS: Upon admittance, she had severe hypercalcemia (serum calcium: 4.1 mmol/l) with plasma intact PTH levels below the limit of detection, renal failure (serum creatinine: 5.5 mg/dl) and normocytic anemia (initial hemoglobin: 8.3 g/dl, upon rehydration: 6.6 g/dl). TREATMENT AND COURSE: Upon rehydration and induced diuresis, the renal function improved and the serum calcium came down rapidly in the early treatment phase. However, serum calcium remained elevated at around 3.0 mmol/l after 4 weeks. Only after the use of the bisphosphonate pamidronate (15 mg), serum calcium returned into the normal range and remained there. Treatment for hypoparathyroidism had to be reinstituted only 20 weeks after dihydrotachysterol had been discontinued. The anemia had resolved without any treatment at that time. CONCLUSIONS: Treatment with dihydrotachysterol and other long-acting Vitamin D preparations has to be monitored closely because of the risk of severe hypercalcemia, which may be difficult to treat. In our case, dihydrotachysterol was still active until week 20 after the drug was discontinued. Anemia should be considered as a side effect of dihydrotachysterol intoxication and does not warrant elaborate differential diagnosis in this context. A single administration of a bisphosphonate turned out to be of major therapeutic benefit and resulted in a lasting correction of hypercalcemia. Therefore, bisphosphonates should become part of the treatment regimen for vitamin D intoxication.

Severe calcinosis cutis associated with treatment of hypoparathyroidism in a dog

A 6-month-old, female border collie was referred for evaluation of hypocalcemia, hyperphosphatemia, fever, and painful ventral abdominal skin. She had recently been treated intravenously and subcutaneously (SC) with a diluted 10% calcium gluconate solution. The medical evaluation supported the diagnosis of primary hypoparathyroidism, but the subsequent hospital course was complicated by severe calcinosis cutis, which caused extensive skin necrosis and marked debilitation. This patient illustrates that administration of a calcium gluconate solution SC can be associated with extensive morbidity when administered to hyperphosphatemic patients.

Microencapsulation of Human Parathyroid Cells: An “in Vitro” Study

Background. Patients affected by hypoparathyroidism of variable etiology are currently treated with exogenously administered vitamin D and calcium. Human parathyroid transplantation has long been investigated as a possible mean of treating these patients to prevent long-term hypocalcemia. However, the main obstacle for this treatment is represented by tissue rejection. A reliable method to efficiently protect the transplanted tissue from rejection and to allow long-term survival of the graft is the encapsulation of tissues or cells in alginate–polylysine–alginate membranes, which were successfully used for encapsulation of islets of Langerhans. The microencapsulation of parathyroid tissue fragments or of parathyroid cells becomes, therefore, a potential approach for the successful treatment of permanent symptomatic hypoparathyroidism without pharmacological immunosuppression.Materials and methods. We describe microencapsulation of differentiated human parathyroid cells derived from adenoma or hyperplastic glands. Long-term viability, cell growth, and parathyroid hormone production of microencapsulated cells were evaluated together with responsiveness to extracellular Ca2+.Results. Microencapsulated parathyroid cells maintained proliferative and differentiative properties for a long term in culture with a good response to extracellular Ca2+ concentration.Conclusions. These findings represent a crucial step toward the construction of functional bioartificial parathyroid organoids for the treatment of hypoparathyroidism in humans.

Hyperparathyroïdie néonatale secondaire à une hypoparathyroïdie maternelle méconnue

Vitamin D or its analogue (calcitriol) is an effective treatment for hypoparathyroidism during pregnancy. Normal babies are delivered and very few cases of associated neonatal hyperparathyroidism are reported. We report the case of a baby born to a mother suffering unknown hypoparathyroidism. He was delivered prematurely by cesarean section for birth asphyxia. His mother had had recurrent bouts of impetigo herpetiformis for several months. Severe demineralization associated with decreased plasma calcium level were observed at birth. The PTH level was very high (955 ng/mL) in the baby and very low in the mother, leading to the diagnosis. The baby was given intravenous calcium gluconate, oral 1 alpha-hydroxyvitamin D and mechanical ventilation. Normal plasma calcium level was reached on day 2. PTH level improved by one month of age. Because of impaired respiratory mechanics and bronchopulmonary dysplasia, the baby was kept on ventilation for 58 days. By 20 months of age, he was in good health despite a small height for his age. In such cases 1 alpha-hydroxyvitamin D seems to be very effective but plasma and urinary calcium levels need careful monitoring.

A Randomized, Cross-Over Trial of Once-Daily Versus Twice-Daily Parathyroid Hormone 1-34 in Treatment of Hypoparathyroidism

A Randomized, Cross-Over Trial of Once-Daily Versus Twice-Daily Parathyroid Hormone 1-34 in Treatment of Hypoparathyroidism

A case of severe hypocalcaemia mimicking myocardial infarction

Long-standing hypocalcaemia can be complicated by congestive heart failure. We report a 46-year-old woman with chronic severe hypocalcaemia due to untreated hypoparathyroidism. This patient developed severe heart dysfunction but when first presented was misdiagnosed as acute myocardial infarction based mainly on the biochemical, electrocardiographic and echocardiographic findings. The near-normal cardiac function a few months after the correction of hypocalcaemia demonstrates that even advanced forms of cardiomyopathy are potentially reversible with treatment of hypoparathyroidism.

Synthetic Human Parathyroid Hormone 1-34 vs Calcitriol and Calcium in the Treatment of Hypoparathyroidism

<h3>Objective.</h3> —To test the hypothesis that treatment with human parathyroid hormone 1-34 (PTH 1-34) can maintain normal serum calcium without hypercalciuria in patients with hypoparathyroidism. <h3>Design.</h3> —Randomized crossover trial lasting 20 weeks. Each 10-week arm consisted of a 2-week inpatient dose-adjustment phase followed by an 8-week outpatient phase. <h3>Setting.</h3> —Tertiary care center. <h3>Patients.</h3> —A total of 10 patients with hypoparathyroidism were enrolled consecutively over a 15-month period. Half of the patients were prior National Institutes of Health patients, and the other 5 patients were referred from outside physicians. <h3>Interventions.</h3> —A dose of PTH 1-34 was administered each morning by subcutaneous injection. Calcitriol was given orally twice daily with supplemental calcium carbonate. <h3>Main Outcome Measures.</h3> —Serum and urine calcium and phosphorus levels. <h3>Results.</h3> —Once-daily treatment with PTH 1-34 maintained serum calcium in the normal range with decreased urine calcium excretion (<i>P</i>&lt;.05 at 2 weeks and<i>P</i>&lt;.01 at 10 weeks) compared with calcitriol treatment. Biochemical markers of bone turnover increased significantly (<i>P</i>&lt;.01 at 10 weeks) during PTH 1-34 treatment. <h3>Conclusions.</h3> —Treatment of hypoparathyroidism with PTH 1-34 reduces urine calcium excretion compared with treatment with calcitriol and calcium.

Synthetic human parathyroid hormone 1-34 vs calcitriol and calcium in the treatment of hypoparathyroidism

To test the hypothesis that treatment with human parathyroid hormone 1-34 (PTH 1-34) can maintain normal serum calcium without hypercalciuria in patients with hypoparathyroidism. Randomized crossover trial lasting 20 weeks. Each 10-week arm consisted of a 2-week inpatient dose-adjustment phase followed by an 8-week outpatient phase. Tertiary care center. A total of 10 patients with hypoparathyroidism were enrolled consecutively over a 15-month period. Half of the patients were prior National Institutes of Health patients, and the other 5 patients were referred from outside physicians. A dose of PTH 1-34 was administered each morning by subcutaneous injection. Calcitriol was given orally twice daily with supplemental calcium carbonate. Serum and urine calcium and phosphorus levels. Once-daily treatment with PTH 1-34 maintained serum calcium in the normal range with decreased urine calcium excretion (P<.05 at 2 weeks and P<.Ol at 10 weeks) compared with calcitriol treatment. Biochemical markers of bone turnover increased significantly (P<.Ol at 10 weeks) during PTH 1-34 treatment. Treatment of hypoparathyroidism with PTH 1-34 reduces urine calcium excretion compared with treatment with calcitriol and calcium.

Cerebral calcinosis and learning disabilities in hypoparathyroidism: A cause and effect or a coincidence?

A 12-year-old child is described in whom the presentation of learning difficulties and history of previous cataract removal led to a diagnosis of primary hypoparathyroidism. Cranial computed tomography revealed extensive calcinosis, previously described only in adults with long-standing hypoparathyroidism, and neuropsychologic evaluation revealed a marked symmetrical decrease in intellectual function. The possibility of the severe complication of brain calcinosis necessitates prompt diagnosis and treatment of hypoparathyroidism.

Renal Handling of Calcium in Hypoparathyroidism

Treatment of hypoparathyroidism usually requires the use of pharmacological doses of parent vitamin D or near physiological amounts of the hydroxylated metabolites, calcitriol or alphacalcidol. Vitamin D intoxication and hypercalcaemia may be a problem but can be minimised by the use of small doses of vitamin D or its metabolites combined with large amounts of oral calcium. The response to treatment can be easily monitored by measuring serum and urinary calcium and creatinine concentrations. This allows the derivation of two simple indices reflecting calcium load presented to the kidney (calcium excretion in mmol/l glomerular filtrate) and renal tubular calcium reabsorption (TmCa/GFR). These can be used to predict the requirement of calcium supplements and also identify those patients at particular risk of hypercalcaemia.