A New Therapeutic Approach Using a Calcilytic (AXT914) for Postsurgical Hypoparathyroidism in Female Rats

• Published in: Endocrinology (Philadelphia) 2020-10, Vol.161 (10), p.1
• Main Authors: Lim, Yun-Sung, You, Byung Hoon, Kim, Hee-Bok, Lim, So Hyun, Song, Jae Geun, Bae, Min Goo, Han, Hyo-Kyung, Choi, Young Hee, Choi, Han Seok
• Format: Article
• Language: English
• Subjects: Animals; Antagonists (Biochemistry); Calcium metabolism disorders; Combined Modality Therapy; Complications; Disease Models, Animal; Drug Administration Schedule; Drug therapy; Female; Hypercalciuria - etiology; Hypercalciuria - prevention & control; Hypoparathyroidism; Hypoparathyroidism - drug therapy; Hypoparathyroidism - etiology; Hypoparathyroidism - pathology; Parathyroid glands; Parathyroid Glands - transplantation; Parathyroidectomy - adverse effects; Parathyroidectomy - methods; Postoperative Complications - drug therapy; Postoperative Complications - etiology; Postoperative Complications - pathology; Postoperative Period; Quinazolinones - administration & dosage; Rats; Rats, Wistar; Surgery; Therapies, Investigational; Thyroid Diseases - surgery; Thyroidectomy - adverse effects; Transplantation, Autologous
• ISSN: 0013-7227; 1945-7170
• DOI: 10.1210/endocr/bqaa145

Abstract Postsurgical hypoparathyroidism is the most common complication of thyroid surgery. Conventional therapy with high-dose calcium and vitamin D can correct hypocalcemia but can increase the risk of hypercalciuria, renal stones, or ectopic calcification. The aim of the present study was to investigate the efficacy of a calcium-sensing receptor antagonist, also called a calcilytic (AXT914), in rat models of postsurgical hypoparathyroidism. Two postsurgical hypoparathyroidism rat models were made by hemi-parathyroidectomy or total parathyroidectomy with autotransplantation in 10-week-old female Wistar rats. AXT914 or vehicle was administered orally for 2 to 3 weeks. Serum PTH, calcium, and phosphorus levels, and the urinary excretion of calcium were measured. Autotransplanted parathyroid tissues were collected and examined histologically. In the hemi-parathyroidectomy model, the oral administration of the calcilytic AXT914 (5 and 10 mg/kg) for 2 weeks increased serum PTH and calcium levels and decreased serum phosphorus levels and urinary calcium excretion. In the total parathyroidectomy with autotransplantation model, the oral administration of AXT914 (10 mg/kg) for 3 weeks increased serum PTH and calcium levels and decreased serum phosphorus levels. The serum PTH and calcium levels increased by AXT914 were maintained for 1 week, even after discontinuation of the drug. In conclusion, AXT914 increased PTH secretion in rat models of postsurgical hypoparathyroidism, thereby correcting abnormal calcium and phosphorus homeostasis. Furthermore, AXT914 improved the functional recovery of autotransplanted parathyroid tissues.