title: A phase 2 study of MK-5442, a calcium-sensing receptor antagonist, in postmenopausal women with osteoporosis after long-term use of oral bisphosphonates.
abstract: In women with osteoporosis treated with alendronate for >12 months and oral bisphosphonates for >3 of the last 4 years, switching to MK-5442, a calcium receptor antagonist, stimulated endogenous parathyroid hormone (PTH) secretion and increased bone turnover marker levels, but produced a decline in bone mineral density (BMD) at all sites.
  
  
  BACKGROUND
  This study assessed the effects of switching from long-term oral bisphosphonate therapy to the calcium-sensing receptor antagonist MK-5442 on BMD and bone turnover markers (BTMs) in post-menopausal women with osteoporosis.
  
  
  METHODS
  This randomized, active and placebo-controlled, dose-ranging study enrolled 526 postmenopausal women, who had taken alendronate (ALN) for ≥12 months preceding the trial and any oral bisphosphonate for ≥3 of the preceding 4 years and had spine or hip BMD T-scores ≤-2.5 or ≤-1.5 with ≥1 prior fragility fracture. Women were randomized to continue ALN 70 mg weekly or switch to MK-5442 (5, 7.5, 10, or 15 mg daily) or placebo.
  
  
  RESULTS
  Switching from ALN to MK-5442 produced a dose-dependent parathyroid hormone (PTH) pulse of threefold to sixfold above baseline at 1 h, with PTH levels that remained twofold to threefold above baseline at 4 h and returned to baseline by 24 h. Switching to MK-5442 or placebo increased BTM levels compared to baseline within 3 months and MK-5442 10 mg increased BTM levels compared to placebo by 6 months. With all MK-5442 doses and placebo, spine and hip BMD declined from baseline, and at 12 months, BMD levels were below those who continued ALN (all groups P < 0.05 vs ALN). There was also a dose-dependent increase in the incidence of hypercalcemia with MK-5442.
  
  
  CONCLUSIONS
  Switching from ALN to MK-5442 resulted in a pulsatile increase in PTH and increases in BTMs, but a decline in BMD compared with continued ALN. MK-5442 is not a viable option for the treatment of osteoporosis.
authors.affiliation: Helen Hayes Hospital, West Haverstraw, NY, USA. cosmanf@helenhayeshosp.org.|Department of Medicine, Columbia University, New York, NY, USA. cosmanf@helenhayeshosp.org.
authors.forename: F
authors.initials: F
authors.lastname: Cosman
authors.affiliation: CGM Research Trust, The Princess Margaret Hospital Christchurch, Christchurch, New Zealand.
authors.forename: N
authors.initials: N
authors.lastname: Gilchrist
authors.affiliation: Oregon Osteoporosis Center, Portland, OR, USA.
authors.forename: M
authors.initials: M
authors.lastname: McClung
authors.affiliation: Department of Orthopaedics, Hadassah Hebrew University Hospital, Jerusalem, Israel.
authors.forename: J
authors.initials: J
authors.lastname: Foldes
authors.affiliation: Mediclinic Panorama, Cape Town, South Africa.|Department of Obstetrics and Gynaecology, Faculty of Health, Sciences, Stellenbosch University, Stellenbosch, South Africa.
authors.forename: T
authors.initials: T
authors.lastname: de Villiers
authors.affiliation: Merck & Co, Inc., Kenilworth, NJ, USA.
authors.forename: A
authors.initials: A
authors.lastname: Santora
authors.affiliation: Merck & Co, Inc., Kenilworth, NJ, USA.
authors.forename: A
authors.initials: A
authors.lastname: Leung
authors.affiliation: Merck & Co, Inc., Kenilworth, NJ, USA.
authors.forename: S
authors.initials: S
authors.lastname: Samanta
authors.affiliation: Merck & Co, Inc., Kenilworth, NJ, USA.
authors.forename: N
authors.initials: N
authors.lastname: Heyden
authors.affiliation: Merck & Co, Inc., Kenilworth, NJ, USA.
authors.forename: J P
authors.initials: JP
authors.lastname: McGinnis
authors.affiliation: Merck & Co, Inc., Kenilworth, NJ, USA.
authors.forename: E
authors.initials: E
authors.lastname: Rosenberg
authors.affiliation: Merck & Co, Inc., Kenilworth, NJ, USA.
authors.forename: A E
authors.initials: AE
authors.lastname: Denker
mesh_terms: D000284:Administration, Oral; D000368:Aged; D001565:Benzoates / Q000627:therapeutic use*; D015415:Biomarkers / Q000097:blood; D015519:Bone Density / Q000187:drug effects; D050071:Bone Density Conservation Agents / Q000627:therapeutic use*; D004164:Diphosphonates / Q000008:administration & dosage* / Q000627:therapeutic use; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D004334:Drug Administration Schedule; D005260:Female; D005272:Femur Neck / Q000503:physiopathology; D006621:Hip Joint / Q000503:physiopathology; D006801:Humans; D008159:Lumbar Vertebrae / Q000503:physiopathology; D008875:Middle Aged; D015663:Osteoporosis, Postmenopausal / Q000188:drug therapy* / Q000503:physiopathology; D010281:Parathyroid Hormone / Q000097:blood; D011412:Propanolamines / Q000627:therapeutic use*; D044169:Receptors, Calcium-Sensing / Q000037:antagonists & inhibitors
chemical_list: D001565:Benzoates; D015415:Biomarkers; D050071:Bone Density Conservation Agents; D004164:Diphosphonates; C568849:JTT 305; D010281:Parathyroid Hormone; D011412:Propanolamines; D044169:Receptors, Calcium-Sensing
keywords: Bisphosphonate; Calcium-sensing receptor antagonist; Osteoporosis; PTH; Postmenopausal; Randomized clinical trial