title: Relationship between bone mineral density changes with denosumab treatment and risk reduction for vertebral and nonvertebral fractures.
abstract: Dual-energy X-ray absorptiometric bone mineral density (DXA BMD) is a strong predictor of fracture risk in untreated patients. However, previous patient-level studies suggest that BMD changes explain little of the fracture risk reduction observed with osteoporosis treatment. We investigated the relevance of DXA BMD changes as a predictor for fracture risk reduction using data from the FREEDOM trial, which randomly assigned placebo or denosumab 60 mg every 6 months to 7808 women aged 60 to 90 years with a spine or total hip BMD T-score < -2.5 and not < -4.0. We took a standard approach to estimate the percent of treatment effect explained using percent changes in BMD at a single visit (months 12, 24, or 36). We also applied a novel approach using estimated percent changes in BMD from baseline at the time of fracture occurrence (time-dependent models). Denosumab significantly increased total hip BMD by 3.2%, 4.4%, and 5.0% at 12, 24, and 36 months, respectively. Denosumab decreased the risk of new vertebral fractures by 68% (p < 0.0001) and nonvertebral fracture by 20% (p = 0.01) over 36 months. Regardless of the method used, the change in total hip BMD explained a considerable proportion of the effect of denosumab in reducing new or worsening vertebral fracture risk (35% [95% confidence interval (CI): 20%-61%] and 51% [95% CI: 39%-66%] accounted for by percent change at month 36 and change in time-dependent BMD, respectively) and explained a considerable amount of the reduction in nonvertebral fracture risk (87% [95% CI: 35% - >100%] and 72% [95% CI: 24% - >100%], respectively). Previous patient-level studies may have underestimated the strength of the relationship between BMD change and the effect of treatment on fracture risk or this relationship may be unique to denosumab.
authors.affiliation: Amgen Inc., Thousand Oaks, CA 91320, USA. maustin@amgen.com
authors.forename: Matthew
authors.initials: M
authors.lastname: Austin
authors.forename: Yu-Ching
authors.initials: YC
authors.lastname: Yang
authors.forename: Eric
authors.initials: E
authors.lastname: Vittinghoff
authors.forename: Silvano
authors.initials: S
authors.lastname: Adami
authors.forename: Steven
authors.initials: S
authors.lastname: Boonen
authors.forename: Douglas C
authors.initials: DC
authors.lastname: Bauer
authors.forename: Gerolamo
authors.initials: G
authors.lastname: Bianchi
authors.forename: Michael A
authors.initials: MA
authors.lastname: Bolognese
authors.forename: Claus
authors.initials: C
authors.lastname: Christiansen
authors.forename: Richard
authors.initials: R
authors.lastname: Eastell
authors.forename: Andreas
authors.initials: A
authors.lastname: Grauer
authors.forename: Federico
authors.initials: F
authors.lastname: Hawkins
authors.forename: David L
authors.initials: DL
authors.lastname: Kendler
authors.forename: Beatriz
authors.initials: B
authors.lastname: Oliveri
authors.forename: Michael R
authors.initials: MR
authors.lastname: McClung
authors.forename: Ian R
authors.initials: IR
authors.lastname: Reid
authors.forename: Ethel S
authors.initials: ES
authors.lastname: Siris
authors.forename: Jose
authors.initials: J
authors.lastname: Zanchetta
authors.forename: Cristiano A F
authors.initials: CA
authors.lastname: Zerbini
authors.forename: Cesar
authors.initials: C
authors.lastname: Libanati
authors.forename: Steven R
authors.initials: SR
authors.lastname: Cummings
mesh_terms: D015502:Absorptiometry, Photon; D000368:Aged; D000369:Aged, 80 and over; D000911:Antibodies, Monoclonal / Q000494:pharmacology / Q000627:therapeutic use*; D061067:Antibodies, Monoclonal, Humanized; D015519:Bone Density / Q000187:drug effects*; D050071:Bone Density Conservation Agents / Q000494:pharmacology / Q000627:therapeutic use*; D000069448:Denosumab; D004311:Double-Blind Method; D005260:Female; D050723:Fractures, Bone / Q000473:pathology / Q000517:prevention & control*; D006801:Humans; D008875:Middle Aged; D010919:Placebos; D040242:Risk Reduction Behavior; D016103:Spinal Fractures / Q000473:pathology / Q000517:prevention & control*
chemical_list: D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D050071:Bone Density Conservation Agents; D010919:Placebos; D000069448:Denosumab
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