title: Odanacatib in the treatment of postmenopausal women with low bone mineral density: three-year continued therapy and resolution of effect.
abstract: The selective cathepsin K inhibitor odanacatib (ODN) progressively increased bone mineral density (BMD) and decreased bone-resorption markers during 2 years of treatment in postmenopausal women with low BMD. A 1-year extension study further assessed ODN efficacy and safety and the effects of discontinuing therapy. In the base study, postmenopausal women with BMD T-scores between -2.0 and -3.5 at the lumbar spine or femur received placebo or ODN 3, 10, 25, or 50 mg weekly. After 2 years, patients (n = 189) were rerandomized to ODN 50 mg weekly or placebo for an additional year. Endpoints included BMD at the lumbar spine (primary), total hip, and hip subregions; levels of bone turnover markers; and safety assessments. Continued treatment with 50 mg of ODN for 3 years produced significant increases from baseline and from year 2 in BMD at the spine (7.9% and 2.3%) and total hip (5.8% and 2.4%). Urine cross-linked N-telopeptide of type I collagen (NTx) remained suppressed at year 3 (-50.5%), but bone-specific alkaline phosphatase (BSAP) was relatively unchanged from baseline. Treatment discontinuation resulted in bone loss at all sites, but BMD remained at or above baseline. After ODN discontinuation at month 24, bone turnover markers increased transiently above baseline, but this increase largely resolved by month 36. There were similar overall adverse-event rates in both treatment groups. It is concluded that 3 years of ODN treatment resulted in progressive increases in BMD and was generally well tolerated. Bone-resorption markers remained suppressed, whereas bone-formation markers returned to near baseline. ODN effects were reversible: bone resorption increased transiently and BMD decreased following treatment discontinuation.
authors.affiliation: Garvan Institute of Medical Research, St Vincent's Hospital, University of New South Wales, Sydney, NSW, Australia. j.eisman@garvan.org.au
authors.forename: John A
authors.initials: JA
authors.lastname: Eisman
authors.forename: Henry G
authors.initials: HG
authors.lastname: Bone
authors.forename: David J
authors.initials: DJ
authors.lastname: Hosking
authors.forename: Michael R
authors.initials: MR
authors.lastname: McClung
authors.forename: Ian R
authors.initials: IR
authors.lastname: Reid
authors.forename: Rene
authors.initials: R
authors.lastname: Rizzoli
authors.forename: Heinrich
authors.initials: H
authors.lastname: Resch
authors.forename: Nadia
authors.initials: N
authors.lastname: Verbruggen
authors.forename: Carolyn M
authors.initials: CM
authors.lastname: Hustad
authors.forename: Carolyn
authors.initials: C
authors.lastname: DaSilva
authors.forename: Romana
authors.initials: R
authors.lastname: Petrovic
authors.forename: Arthur C
authors.initials: AC
authors.lastname: Santora
authors.forename: B Avery
authors.initials: BA
authors.lastname: Ince
authors.forename: Antonio
authors.initials: A
authors.lastname: Lombardi
mesh_terms: D000368:Aged; D001713:Biphenyl Compounds / Q000627:therapeutic use*; D015519:Bone Density; D001862:Bone Resorption; D001842:Bone and Bones / Q000502:physiology; D024042:Collagen Type I / Q000378:metabolism; D004311:Double-Blind Method; D005260:Female; D006615:Hip / Q000473:pathology; D006801:Humans; D008159:Lumbar Vertebrae / Q000473:pathology; D008875:Middle Aged; D015663:Osteoporosis, Postmenopausal / Q000188:drug therapy*; D010455:Peptides / Q000378:metabolism; D010919:Placebos; D013997:Time Factors
chemical_list: D001713:Biphenyl Compounds; D024042:Collagen Type I; D010455:Peptides; D010919:Placebos; C052929:collagen type I trimeric cross-linked peptide; C527128:odanacatib