title: Characterization of the effect of chronic administration of a calcium-sensing receptor antagonist, ronacaleret, on renal calcium excretion and serum calcium in postmenopausal women.
abstract: Ronacaleret is an orally-active calcium-sensing receptor (CaSR) antagonist that has the potential for therapeutic utility in the stimulation of PTH release, notably as a bone anabolic agent comparable to recombinant human PTH(1-34) (rhPTH(1-34)). A recent study has shown that, despite the ability to increase circulating PTH levels in postmenopausal women in a dose-dependent manner, minimal effects of ronacaleret on bone mineral density have been observed. Therefore, the purpose of this study was to characterize the PTH profile as well as calcium metabolism parameters as a marker of PTH biological activity following the administration of ronacaleret or rhPTH(1-34). Administration of ronacaleret led to lower peak levels of PTH than were observed with rhPTH(1-34), however, greater total PTH exposure was observed. Further, chronic administration of either agent was associated with increases in urinary calcium excretion and serum calcium levels, with the magnitude of the changes following ronacaleret significantly greater than that for rhPTH(1-34). The greater magnitude of effects observed with ronacaleret is likely due to the greater total PTH exposure, and is potentially reflective of a state comparable to mild hyperparathyroidism. It is not clear whether the administration of all calcilytics would lead to a similar result, or is due to characteristics specific to ronacaleret.
authors.affiliation: GlaxoSmithKline, King of Prussia, PA 19406, USA. stephen.caltabiano@gsk.com
authors.forename: Stephen
authors.initials: S
authors.lastname: Caltabiano
authors.forename: Colin T
authors.initials: CT
authors.lastname: Dollery
authors.forename: Mohammad
authors.initials: M
authors.lastname: Hossain
authors.forename: Milena T
authors.initials: MT
authors.lastname: Kurtinecz
authors.forename: John P
authors.initials: JP
authors.lastname: Desjardins
authors.forename: Murray J
authors.initials: MJ
authors.lastname: Favus
authors.forename: Rajiv
authors.initials: R
authors.lastname: Kumar
authors.forename: Lorraine A
authors.initials: LA
authors.lastname: Fitzpatrick
mesh_terms: D000328:Adult; D000368:Aged; D002118:Calcium / Q000097:blood* / Q000652:urine*; D003710:Demography; D005260:Female; D006801:Humans; D006934:Hypercalcemia / Q000097:blood / Q000652:urine; D007189:Indans / Q000008:administration & dosage* / Q000493:pharmacokinetics / Q000494:pharmacology; D007668:Kidney / Q000187:drug effects / Q000378:metabolism*; D008875:Middle Aged; D010281:Parathyroid Hormone / Q000097:blood / Q000494:pharmacology; D010446:Peptide Fragments / Q000097:blood; D010666:Phenylpropionates / Q000008:administration & dosage* / Q000493:pharmacokinetics / Q000494:pharmacology; D010710:Phosphates / Q000097:blood / Q000652:urine; D017698:Postmenopause / Q000097:blood* / Q000187:drug effects / Q000652:urine*; D011347:Procollagen / Q000097:blood; D044169:Receptors, Calcium-Sensing / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013997:Time Factors
chemical_list: D007189:Indans; D010281:Parathyroid Hormone; D010446:Peptide Fragments; D010666:Phenylpropionates; D010710:Phosphates; D011347:Procollagen; D044169:Receptors, Calcium-Sensing; C047202:procollagen Type I N-terminal peptide; C561716:ronacaleret; D002118:Calcium
keywords: Calcilytic; Calcium homeostasis; Calcium-sensing receptor; Kidney; Parathyroid hormone; Postmenopausal osteoporosis