title: Pharmacodynamic responses to combined treatment regimens with the calcium sensing receptor antagonist JTT-305/MK-5442 and alendronate in osteopenic ovariectomized rats.
abstract: Parathyroid hormone (PTH) is the anabolic standard of care for patients with severe osteoporosis. The CaSR allosteric antagonist JTT-305/MK-5442, a PTH secretagogue, could offer an oral osteoanabolic treatment alternative for postmenopausal women with osteoporosis. Here we disclose the pharmacokinetic profile of JTT-305/MK-5442 and its activity on bone remodeling in ovariectomized (OVX) osteopenic rats. Daily treatments (0.3 to 2.4 mg/kg/d) for 12 weeks resulted in plateaued BMD increases (3.8 to 5.3%) at axial and appendicular skeletal sites. However, treatment effects were not statistically significant, in agreement with effects seen in animals treated with low dose PTH (1-84) (5 μg/kg/d). In a consecutive study we tested JTT-305/MK-5442 effects on bone formation in OVX-rats challenged with combined alendronate (ALN) treatment paradigms. At 7 month, JTT-305/MK-5442 treatment significantly increased BMD in lumbar vertebrae (LV), while no change in BMD was observed in femora or tibiae. ALN add-on co-treatment produced incremental increases in LV, distal femur (DF) and proximal tibia (PT) BMD over the respective ALN control. Histological analyses confirmed modest increases in mineralized surface (MS/BS) and bone formation rate (30.5±1.9%) on trabecular surfaces by JTT-305/MK-5442. As expected, ALN administration profoundly reduced bone formation, however, JTT-305/MK-5442 significantly stimulated MS/BS and BFR in ALN treated groups. In summary, JTT-305/MK-5442 acts as a PTH secretagogue in the osteopenic OVX-rat, eliciting consistent, though modest effects on remediation of BMD due to estrogen depletion. Induction of bone formation by JTT-305/MK-5442 at trabecular bone surfaces appears to be resilient to ALN-mediated suppression of bone formation. This study provides for the first time, a mechanistic evaluation of combination treatment of a PTH secretagogue with ALN.
authors.affiliation: Bone Biology, Merck Research Laboratories, West Point, PA, USA.
authors.forename: John E
authors.initials: JE
authors.lastname: Fisher
authors.forename: Kevin
authors.initials: K
authors.lastname: Scott
authors.forename: Nan
authors.initials: N
authors.lastname: Wei
authors.forename: Jing Z
authors.initials: JZ
authors.lastname: Zhao
authors.forename: Tara
authors.initials: T
authors.lastname: Cusick
authors.forename: Monica
authors.initials: M
authors.lastname: Tijerina
authors.forename: Bindhu
authors.initials: B
authors.lastname: Karanam
authors.forename: Le
authors.initials: L
authors.lastname: Duong
authors.forename: Helmut
authors.initials: H
authors.lastname: Glantschnig
mesh_terms: D019386:Alendronate / Q000008:administration & dosage*; D000818:Animals; D001565:Benzoates / Q000008:administration & dosage*; D015519:Bone Density / Q000187:drug effects; D050071:Bone Density Conservation Agents / Q000008:administration & dosage*; D001851:Bone Diseases, Metabolic / Q000188:drug therapy* / Q000209:etiology / Q000378:metabolism / Q000473:pathology; D016723:Bone Remodeling / Q000187:drug effects; D004195:Disease Models, Animal; D004357:Drug Synergism; D004359:Drug Therapy, Combination; D004967:Estrogens / Q000172:deficiency; D005260:Female; D010052:Ovariectomy; D010281:Parathyroid Hormone / Q000097:blood; D011412:Propanolamines / Q000008:administration & dosage*; D051381:Rats; D017207:Rats, Sprague-Dawley; D044169:Receptors, Calcium-Sensing / Q000037:antagonists & inhibitors*
chemical_list: D001565:Benzoates; D050071:Bone Density Conservation Agents; D004967:Estrogens; C568849:JTT 305; D010281:Parathyroid Hormone; D011412:Propanolamines; D044169:Receptors, Calcium-Sensing; D019386:Alendronate