title: Odanacatib for the treatment of postmenopausal osteoporosis: development history and design and participant characteristics of LOFT, the Long-Term Odanacatib Fracture Trial.
abstract: CONCLUSIONS
  Odanacatib is a cathepsin K inhibitor investigated for the treatment of postmenopausal osteoporosis. Phase 2 data indicate that 50 mg once weekly inhibits bone resorption and increases bone mineral density, with only a transient decrease in bone formation. We describe the background, design and participant characteristics for the phase 3 registration trial.
  
  
  BACKGROUND
  Odanacatib (ODN) is a selective cathepsin K inhibitor being evaluated for the treatment of osteoporosis. In a phase 2 trial, ODN 50 mg once weekly reduced bone resorption while preserving bone formation and progressively increased BMD over 5 years. We describe the phase III Long-Term ODN Fracture Trial (LOFT), an event-driven, randomized, blinded placebo-controlled trial, with preplanned interim analyses to permit early termination if significant fracture risk reduction was demonstrated. An extension was planned, with participants remaining on their randomized treatment for up to 5 years, then transitioning to open-label ODN.
  
  
  METHODS
  The three primary outcomes were radiologically determined vertebral, hip, and clinical non-vertebral fractures. Secondary end points included clinical vertebral fractures, BMD, bone turnover markers, and safety and tolerability, including bone histology. Participants were women, 65 years or older, with a BMD T-score≤-2.5 at the total hip (TH) or femoral neck (FN) or with a prior radiographic vertebral fracture and a T-score≤-1.5 at the TH or FN. They were randomized to ODN or placebo tablets. All received weekly vitamin D3 (5600 international units (IU)) and daily calcium supplements as needed to ensure a daily intake of approximately 1200 mg.
  
  
  RESULTS
  Altogether, 16,713 participants were randomized at 387 centers. After a planned interim analysis, an independent data monitoring committee recommended that the study be stopped early due to robust efficacy and a favorable benefit/risk profile. Following the base study closeout, 8256 participants entered the study extension.
  
  
  CONCLUSIONS
  This report details the background and study design of this fracture end point trial and describes the baseline characteristics of its participants.
authors.affiliation: Michigan Bone & Mineral Clinic, Detroit, MI, USA, hgbone.md@att.net.
authors.forename: H G
authors.initials: HG
authors.lastname: Bone
authors.forename: D W
authors.initials: DW
authors.lastname: Dempster
authors.forename: J A
authors.initials: JA
authors.lastname: Eisman
authors.forename: S L
authors.initials: SL
authors.lastname: Greenspan
authors.forename: M R
authors.initials: MR
authors.lastname: McClung
authors.forename: T
authors.initials: T
authors.lastname: Nakamura
authors.forename: S
authors.initials: S
authors.lastname: Papapoulos
authors.forename: W J
authors.initials: WJ
authors.lastname: Shih
authors.forename: A
authors.initials: A
authors.lastname: Rybak-Feiglin
authors.forename: A C
authors.initials: AC
authors.lastname: Santora
authors.forename: N
authors.initials: N
authors.lastname: Verbruggen
authors.forename: A T
authors.initials: AT
authors.lastname: Leung
authors.forename: A
authors.initials: A
authors.lastname: Lombardi
mesh_terms: D000368:Aged; D001713:Biphenyl Compounds / Q000009:adverse effects / Q000494:pharmacology / Q000627:therapeutic use*; D015519:Bone Density / Q000187:drug effects; D050071:Bone Density Conservation Agents / Q000009:adverse effects / Q000494:pharmacology / Q000627:therapeutic use*; D056657:Cathepsin K / Q000037:antagonists & inhibitors; D004311:Double-Blind Method; D005260:Female; D005272:Femur Neck / Q000503:physiopathology; D006621:Hip Joint / Q000503:physiopathology; D006801:Humans; D015663:Osteoporosis, Postmenopausal / Q000150:complications / Q000188:drug therapy* / Q000503:physiopathology; D058866:Osteoporotic Fractures / Q000209:etiology / Q000503:physiopathology / Q000517:prevention & control*; D018579:Patient Selection; D012107:Research Design; D016896:Treatment Outcome
chemical_list: D001713:Biphenyl Compounds; D050071:Bone Density Conservation Agents; C534130:CTSK protein, human; D056657:Cathepsin K; C527128:odanacatib