title: The cathepsin K inhibitor odanacatib suppresses bone resorption in women with breast cancer and established bone metastases: results of a 4-week, double-blind, randomized, controlled trial.
abstract: Metastatic bone disease (MBD) is a frequent complication in patients with breast cancer and is associated with significant morbidity. This study assessed the pharmacokinetics, efficacy, and safety of odanacatib, a selective Cat K inhibitor, in reducing markers of bone resorption in women with breast cancer and MBD.
  
  
  
  Women with breast cancer and MBD were randomized 2:1 (double-blind) to oral odanacatib 5 mg daily for 4 weeks or intravenous (I.V.) zoledronic acid (ZA) 4 mg given once at study initiation. Plasma samples were collected for pharmacokinetic analysis. Bone resorption was assessed by measuring urinary N-telopeptide of type I collagen corrected for creatinine (uNTx; primary objective, pmol BCE/µmol creatinine). Adverse events (AEs) were monitored throughout the 4-week study and up to 14 days after last dose.
  
  
  
  A total of 43 patients (mean age, 60 years) received odanacatib (n = 29) or ZA (n = 14); 40 patients completed 4 weeks of treatment. The mean percent change in uNTx values at week 4 was -77% (95% CI, -82 to -71; odanacatib) and -73% (95% CI, -80 to -62; ZA). Mean (standard deviation) plasma concentration of odanacatib was 511.7 (202.9) nM; the range was 63.7-844.8 nM. The most common AEs were nausea, vomiting, headache, and bone pain, which were generally not attributed to study drug.
  
  
  
  Odanacatib suppressed uNTx similarly to ZA after 4 weeks of treatment in women with breast cancer and MBD. Odanacatib was generally safe and well tolerated. These results suggest that Cat K inhibition is a potentially important, novel therapeutic approach for treating MBD.
authors.affiliation: Aarhus University Hospital, Noerrebrogade 44, Aarhus C, Denmark. andjense@rm.dk
authors.forename: Anders Bonde
authors.initials: AB
authors.lastname: Jensen
authors.forename: Christopher
authors.initials: C
authors.lastname: Wynne
authors.forename: Guillermo
authors.initials: G
authors.lastname: Ramirez
authors.forename: Weili
authors.initials: W
authors.lastname: He
authors.forename: Yang
authors.initials: Y
authors.lastname: Song
authors.forename: Yuliya
authors.initials: Y
authors.lastname: Berd
authors.forename: Hongwei
authors.initials: H
authors.lastname: Wang
authors.forename: Anish
authors.initials: A
authors.lastname: Mehta
authors.forename: Antonio
authors.initials: A
authors.lastname: Lombardi
mesh_terms: D000328:Adult; D015415:Biomarkers / Q000652:urine; D001713:Biphenyl Compounds / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics / Q000627:therapeutic use*; D050071:Bone Density Conservation Agents / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics / Q000627:therapeutic use*; D001859:Bone Neoplasms / Q000188:drug therapy* / Q000556:secondary; D001862:Bone Resorption / Q000188:drug therapy*; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000473:pathology; D056657:Cathepsin K / Q000037:antagonists & inhibitors; D024042:Collagen Type I / Q000652:urine; D004164:Diphosphonates / Q000627:therapeutic use; D004311:Double-Blind Method; D005260:Female; D006801:Humans; D007093:Imidazoles / Q000627:therapeutic use; D008875:Middle Aged; D016896:Treatment Outcome; D000077211:Zoledronic Acid
chemical_list: D015415:Biomarkers; D001713:Biphenyl Compounds; D050071:Bone Density Conservation Agents; D024042:Collagen Type I; D004164:Diphosphonates; D007093:Imidazoles; D000077211:Zoledronic Acid; D056657:Cathepsin K; C527128:odanacatib