JTT-305, an orally active calcium-sensing receptor antagonist, stimulates transient parathyroid hormone release and bone formation in ovariectomized rats

• Published in: European journal of pharmacology 2011-10, Vol.668 (1-2), p.331-336
• Main Authors: Kimura, Shuichi, Nakagawa, Takashi, Matsuo, Yushi, Ishida, Yuji, Okamoto, Yoshihisa, Hayashi, Mikio
• Format: Article
• Language: English
• Subjects: Administration, Oral; Animals; Antagonist; antagonists; Benzoates - administration & dosage; Benzoates - pharmacokinetics; Benzoates - pharmacology; Biological and medical sciences; blood serum; bone density; Bone formation; Bone mineral density; bone resorption; Calcium-sensing receptor; Cercopithecus aethiops; COS Cells; Female; Humans; Medical sciences; mineralization; oral administration; Osteogenesis - drug effects; osteoporosis; Ovariectomy; Parathyroid hormone; Parathyroid Hormone - secretion; pharmacology; Pharmacology. Drug treatments; Propanolamines - administration & dosage; Propanolamines - pharmacokinetics; Propanolamines - pharmacology; Rats; Rats, Sprague-Dawley; Receptors, Calcium-Sensing - antagonists & inhibitors; Receptors, Calcium-Sensing - metabolism; Recombinant Proteins - pharmacology; secretion; tibia
• ISSN: 0014-2999; 1879-0712
• DOI: 10.1016/j.ejphar.2011.07.015

Intermittent administration of parathyroid hormone (PTH) has a potent anabolic effect on bone in humans and animals. Calcium-sensing receptor (CaSR) antagonists stimulate endogenous PTH secretion through CaSR on the surface of parathyroid cells and thereby may be anabolic agents for osteoporosis. JTT-305 is a potent oral short-acting CaSR antagonist and transiently stimulates endogenous PTH secretion. The objective of the present study was to investigate the effects of JTT-305 on PTH secretion and bone in ovariectomized rats. Female rats, immediately after ovariectomy (OVX), were orally administered vehicle or JTT-305 (0.3, 1, or 3mg/kg) for 12weeks. The serum PTH concentrations were transiently elevated with increasing doses of JTT-305. In the proximal tibia, JTT-305 prevented OVX-induced decreases in both the cancellous and total bone mineral density (BMD) except for the 0.3mg/kg dose. At the 3mg/kg dose, JTT-305 increased the mineralizing surface and bone formation rate in histomorphometry. The efficacy of JTT-305 at the 3mg/kg dose on the BMD corresponded to that of exogenous rat PTH1–84 injection at doses between 3 and 10μg/kg. In conclusion, JTT-305 stimulated endogenous transient PTH secretion and bone formation, and consequently prevented bone loss in OVX rats. These results suggest that JTT-305 is orally active and has the potential to be an anabolic agent for the treatment of osteoporosis.