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

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.

Potential of Calcilytics as a Novel Treatment for Post-Surgical Hypoparathyroidism

“…In a phase 2 clinical trial involving adults with ADH1, encaleret corrected hypocalcemia, reduced hypercalciuria, and increased PTH secretion [ 6 ]. We previously reported that AXT914, another calcilytic, increased PTH secretion and corrected abnormal calcium and phosphorus homeostasis in rats with post-surgical hypoparathyroidism [ 7 ]. Furthermore, the biochemical improvements induced by AXT914 treatment persisted even after the drug was discontinued, which implies that AXT914 might have facilitated the recovery of parathyroid tissue autotransplanted into the sternocleidomastoid (SCM) muscle, although the precise mechanism remains unclear [ 7 ].…”

“…2019-07188). A total of 33 nine-week-old female Wistar rats were used to create a model of post-surgical hypoparathyroidism resulting from total parathyroidectomy and autotransplantation, as previously described [ 7 ]. Both parathyroid glands of each rat were removed, minced into small pieces, and put into a small pocket made in the SCM muscle.…”