title: Further reductions in nonvertebral fracture rate with long-term denosumab treatment in the FREEDOM open-label extension and influence of hip bone mineral density after 3 years.
abstract: Limited data exist on the efficacy of long-term therapies for osteoporosis. In osteoporotic postmenopausal women receiving denosumab for 7 years, nonvertebral fracture rates significantly decreased in years 4-7 versus years 1-3. This is the first demonstration of a further benefit on fracture outcomes with long-term therapy for osteoporosis.
  
  
  BACKGROUND
  This study aimed to evaluate whether denosumab treatment continued beyond 3 years is associated with a further reduction in nonvertebral fracture rates.
  
  
  METHODS
  Participants who completed the 3-year placebo-controlled Fracture REduction Evaluation of Denosumab in Osteoporosis every 6 Months (FREEDOM) study were invited to participate in an open-label extension. The present analysis includes 4,074 postmenopausal women with osteoporosis (n = 2,343 long-term; n = 1,731 cross-over) who enrolled in the extension, missed ≤1 dose during their first 3 years of denosumab treatment, and continued into the fourth year of treatment. Comparison of nonvertebral fracture rates during years 1-3 of denosumab with that of the fourth year and with the rate during years 4-7 was evaluated.
  
  
  RESULTS
  For the combined group, the nonvertebral fracture rate per 100 participant-years was 2.15 for the first 3 years of denosumab treatment (referent) and 1.36 in the fourth year (rate ratio [RR] = 0.64; 95 % confidence interval (CI) = 0.48 to 0.85, p = 0.003). Comparable findings were observed in the groups separately and when nonvertebral fracture rates during years 1-3 were compared to years 4-7 in the long-term group (RR = 0.79; 95 % CI = 0.62 to 1.00, p = 0.046). Fracture rate reductions in year 4 were most prominent in subjects with persisting low hip bone mineral density (BMD).
  
  
  CONCLUSIONS
  Denosumab treatment beyond 3 years was associated with a further reduction in nonvertebral fracture rate that persisted through 7 years of continuous denosumab administration. The degree to which denosumab further reduces nonvertebral fracture risk appears influenced by the hip bone density achieved with initial therapy.
authors.affiliation: Geneva University Hospital, Geneva, Switzerland. Serge.Ferrari@unige.ch.
authors.forename: S
authors.initials: S
authors.lastname: Ferrari
authors.affiliation: McMaster University, Hamilton, ON, Canada.
authors.forename: J D
authors.initials: JD
authors.lastname: Adachi
authors.affiliation: Bern University Hospital, Bern, Switzerland.
authors.forename: K
authors.initials: K
authors.lastname: Lippuner
authors.affiliation: Amgen Inc., Thousand Oaks, CA, USA.
authors.forename: C
authors.initials: C
authors.lastname: Zapalowski
authors.affiliation: Colorado Center for Bone Research, Lakewood, CO, USA.
authors.forename: P D
authors.initials: PD
authors.lastname: Miller
authors.affiliation: University of Liège, Liège, Belgium.
authors.forename: J-Y
authors.initials: JY
authors.lastname: Reginster
authors.affiliation: Karolinska Institutet, Södersjukhuset, Stockholm, Sweden.
authors.forename: O
authors.initials: O
authors.lastname: Törring
authors.affiliation: University of British Columbia, Vancouver, BC, Canada.
authors.forename: D L
authors.initials: DL
authors.lastname: Kendler
authors.affiliation: Amgen Inc., Thousand Oaks, CA, USA.
authors.forename: N S
authors.initials: NS
authors.lastname: Daizadeh
authors.affiliation: Amgen Inc., Thousand Oaks, CA, USA.
authors.forename: A
authors.initials: A
authors.lastname: Wang
authors.affiliation: Amgen Inc., Thousand Oaks, CA, USA.
authors.forename: C D
authors.initials: CD
authors.lastname: O'Malley
authors.affiliation: Amgen Inc., Thousand Oaks, CA, USA.
authors.forename: R B
authors.initials: RB
authors.lastname: Wagman
authors.affiliation: Amgen Inc., Thousand Oaks, CA, USA.
authors.forename: C
authors.initials: C
authors.lastname: Libanati
authors.affiliation: New Mexico Clinical Research & Osteoporosis Center, Albuquerque, NM, USA.
authors.forename: E M
authors.initials: EM
authors.lastname: Lewiecki
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D015519:Bone Density / Q000187:drug effects*; D050071:Bone Density Conservation Agents / Q000008:administration & dosage* / Q000627:therapeutic use; D000069448:Denosumab / Q000008:administration & dosage* / Q000627:therapeutic use; D004311:Double-Blind Method; D004334:Drug Administration Schedule; D005260:Female; D005500:Follow-Up Studies; D006621:Hip Joint / Q000503:physiopathology; D006801:Humans; D015994:Incidence; D008875:Middle Aged; D015663:Osteoporosis, Postmenopausal / Q000188:drug therapy* / Q000453:epidemiology / Q000503:physiopathology; D058866:Osteoporotic Fractures / Q000453:epidemiology / Q000503:physiopathology / Q000517:prevention & control*
chemical_list: D050071:Bone Density Conservation Agents; D000069448:Denosumab
keywords: Denosumab; Fracture threshold; Hip bone mineral density; Long-term osteoporosis therapy; Nonvertebral fracture; Treatment to goal