Refractory Hypoparathyroidism and treatment with recombinant human PTH [rhPTH 1-34: Teriparatide]

Hypoparathyroidism is an uncommon endocrine disease characterized by low serum calcium levels, high serum phosphate levels, and absent or inappropriately low levels of parathyroid hormone (PTH). For chronic management, current treatments include oral calcium, and active forms of vitamin D supplements. However, often large doses of these supplements are used to relieve the symptoms caused by hypocalcemia, without guaranteeing a physiological normalization of calcium-phosphate homeostasis and are associated with long-term complications, including renal impairment, and extraskeletal calcifications. Over the past two decades, several studies have investigated replacement therapy with recombinant human PTH [rhPTH (1-84) and rhPTH (1-34), also called teriparatide] for subjects affected by chronic hypoparathyroidism, not adequately controlled with conventional therapy. The main aim of thesis is to conduct a Phase III, open-label, non-comparative, single-center, pharmacological experimental study, on adult subjects of both sexes with chronic hypoparathyroidism not adequately controlled with conventional therapy, to evaluate efficacy e and safety of teriparatide, as hormone replacement therapy. In addition, a review regarding classification, epidemiology, clinical manifestations and conventional and new therapeutic approaches of hypoparathyroidism is carried out. At last, concerning the epidemiology of hypoparathyroidism, an Italian retrospective observational study on chronic hypoparathyroidism is described. The Phase III pharmacological-experimental study conducted on adult subjects with chronic hypoparathyroidism was part of a project within Call "Rare Diseases" 2008 of Italian Ministry of Health, approved by the national regulatory agency AIFA, as well as by the Ethics Committee of AUO-Careggi, University of Florence (Principal Investigator: Prof. Maria Luisa Brandi; Code EUDRACT: 2013-001890-26). The study was divided into four main phases: recruitment phase, optimization phase, treatment phase, and analysis of results. Thirty patients with chronic hypoparathyroidism inadequately controlled with conventional therapy of calcium and calcitriol supplements were screened, and evaluated at baseline visit, among whom ten patients completed the period of treatment with teriparatide. The study showed that teriparatide, administered for a period of 3 months, was effective in maintaining the mean serum calcium levels within the normal range, allowing a significant reduction of supplements with oral calcium and calcitriol. However, some episodes of mild hypocalcemia and hypercalcemia were reported. Since it has been considered only a short period of 3 months, these episodes described could be justified by the period of adaptation to the drug. Moreover, some episodes of hypercalciuria reported could be justified, instead, by the initial rise in bone turnover due to the action of PTH. No serious adverse event was described, but the occurrence of two cases of bone-joint pain and headache were reported. The retrospective observational study on epidemiology of chronic hypoparathyroidism has been conducted by twenty Italian centers for Endocrinology and Endocrine Surgery with expertise in hypoparathyroidism, from March 2014 to September 2015. The study was coordinated by Prof. ML Brandi, Head of Unit of Bone and Mineral Metabolism Diseases, University Hospital of Florence. This study showed that the most common etiology of chronic hypoparathyroidism was postsurgical hypoparathyroidism, followed by idiopathic hypoparathyroidism, syndromic forms of genetic hypoparathyroidism, forms of defective PTH action, non-syndromic forms of genetic hypoparathyroidism, and lastly others forms of acquired hypoparathyroidism. These data are in line with those of other investigators. Among postsurgical hypoparathyroidism, the most of cases occurred after a total thyroidectomy, followed by parathyroidectomy with multiple removal of the parathyroid glands. Several cases of idiopathic forms were collected, probably due to the scarcity of genetic investigations and instrumental exams usually performed. Regarding therapeutic chronic management of hypoparathyroidism, in about all cases, standard treatment options were used, including oral calcium and vitamin D (its metabolites and analogs), except for only few cases treated with rhPTH (1-34). In more than half of all cases 25-hydroxyvitamin D level was under 30 ng/dL, and in 41,5% serum magnesium level was low, demonstrating a lack of supplement. In conclusion, this study represents one of the first large scale assessment of epidemiology of chronic hypoparathyroidism based on expert medical-surgical centers in hypoparathyroidism in Italy.