title: A phase 2, randomized, placebo-controlled, dose-ranging study of the calcium-sensing receptor antagonist MK-5442 in the treatment of postmenopausal women with osteoporosis.
abstract: BACKGROUND
  MK-5442 is an orally bioavailable calcium-sensing receptor antagonist that is hypothesized to stimulate bone formation by stimulating endogenous secretion of a pulse of PTH. Earlier clinical and preclinical studies demonstrated increased bone mineral density (BMD) after treatment.
  
  
  OBJECTIVE
  Our objective was to identify a dose of MK-5442 that produces osteoanabolic effects without excessive hypercalcemia.
  
  
  METHODS
  This was a randomized, double-blind, placebo-controlled, parallel-group trial of private or institutional practice.
  
  
  METHODS
  In total, 383 postmenopausal women with osteoporosis were administered daily oral MK-5442 (2.5, 5, 7.5, 10, or 15 mg) or placebo.
  
  
  METHODS
  Serum PTH and calcium, bone turnover markers, areal BMD, and safety were evaluated.
  
  
  RESULTS
  A dose-dependent transient increase in PTH occurred after an MK-5442 dose and lasted more than 3.5 hours. Compared with placebo, significant increases in bone formation markers (serum procollagen 1 N-terminal peptide and bone-specific alkaline phosphatase) were observed by 6 months, whereas bone resorption markers (serum C-telopeptide of type 1 collagen, urine N-telopeptides of type 1 collagen) initially decreased but were also significantly increased by 6 months. Despite the biochemical marker changes suggestive of an anabolic response, there were no statistically significant differences between any dose of MK-5442 and placebo in percent change from baseline at month 6 in any of the BMD endpoints. The frequency of hypercalcemia (trough serum calcium ≥ 10.8 mg/dL) was greater with higher MK-5442 doses.
  
  
  CONCLUSIONS
  In postmenopausal women with low bone mass, treatment with MK-5442 resulted in transient pulses of PTH. Bone formation markers increased quickly and bone resorption markers decreased temporarily, suggestive of an anabolic window. However, there were no increases in BMD versus placebo.
authors.affiliation: Osteoporoseklinikken (J.H.), 0176 Oslo, Norway; Osteoporosis Prevention and Treatment Center (S.G.), Division of Geriatric Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania 15213; Clinical Research Center (F.C.), Helen Hayes Hospital, West Haverstraw, and Department of Medicine, Columbia University, New York, New York 10027; Helderberg (G.E.), Clinical Trials Centre, South Africa 7129; and Merck & Co Inc (A.S., A.L., N.H., S.S., S.D., E.R., A.E.D.), Whitehouse Station, New Jersey 08889.
authors.forename: Johan
authors.initials: J
authors.lastname: Halse
authors.forename: Susan
authors.initials: S
authors.lastname: Greenspan
authors.forename: Felicia
authors.initials: F
authors.lastname: Cosman
authors.forename: Graham
authors.initials: G
authors.lastname: Ellis
authors.forename: Arthur
authors.initials: A
authors.lastname: Santora
authors.forename: Albert
authors.initials: A
authors.lastname: Leung
authors.forename: Norman
authors.initials: N
authors.lastname: Heyden
authors.forename: Suvajit
authors.initials: S
authors.lastname: Samanta
authors.forename: Steven
authors.initials: S
authors.lastname: Doleckyj
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Rosenberg
authors.forename: Andrew E
authors.initials: AE
authors.lastname: Denker
mesh_terms: D000368:Aged; D001565:Benzoates / Q000008:administration & dosage* / Q000627:therapeutic use; D015415:Biomarkers / Q000097:blood; D015519:Bone Density / Q000187:drug effects*; D050071:Bone Density Conservation Agents / Q000008:administration & dosage* / Q000627:therapeutic use; D016723:Bone Remodeling / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D005260:Female; D006801:Humans; D008875:Middle Aged; D015663:Osteoporosis, Postmenopausal / Q000097:blood / Q000188:drug therapy*; D010281:Parathyroid Hormone / Q000097:blood; D011412:Propanolamines / Q000008:administration & dosage* / Q000627:therapeutic use; D044169:Receptors, Calcium-Sensing / Q000037:antagonists & inhibitors*; D016896:Treatment Outcome
chemical_list: D001565:Benzoates; D015415:Biomarkers; D050071:Bone Density Conservation Agents; C568849:JTT 305; D010281:Parathyroid Hormone; D011412:Propanolamines; D044169:Receptors, Calcium-Sensing