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    ASBMR 2012 Annual Meeting

    Effects of 5 Years of Denosumab on Bone Histology and Histomorphometry: the FREEDOM Study Extension

    Category: Osteoporosis - Treatment (Clinical)

    Oral Presentations, Presentation Number: 1134
    Session: Concurrent Oral Session 23: Osteoporosis - Treatment (Clinical)
    Sunday, October 14, 2012 3:00 PM - 3:15 PM, Minneapolis Convention Center, Auditorium-Main

    * Jacques P. Brown, CHU de Québec Research Centre, CANADA, Rachel Wagman, Amgen, Incorporated, USA, David Dempster, Columbia University, USA, David Kendler, Associate Professor University of British Columbia, CANADA, Paul Miller, Colorado Center for Bone Research, USA, Michael Bolognese, Bethesda Health Research, USA, Ivo Valter, Center for Clinical Research, Estonia, Jens-erik Beck Jensen, Hvidovre Hospital, Denmark, Cristiano Zerbini, Centro Pualista de Investigação Clinica, BRAZIL, Jose Ruben Zanchetta, Instituto de Investigaciones Metabolicas (IDIM), ARGENTINA, Nadia Daizadeh, Amgen Inc, USA, Ian Reid, University of Auckland, NEW ZEALAND

    Purpose:Denosumab (DMAb), a fully human monoclonal antibody to RANKL, reduces bone resorption, increases bone mineral density, and decreases risk for vertebral, nonvertebral, and hip fractures in postmenopausal women with osteoporosis.1 Consistent with DMAb’s mechanism of action, transiliac crest bone biopsies from subjects treated with DMAb for 1 to 3 years demonstrated reduced bone turnover, which was reversible with treatment cessation.2,3 Since long-term treatment with DMAb has shown sustained reduction in bone turnover and low incidence of vertebral and non-vertebral fractures through 6 years,4 we evaluated the effects of DMAb on remodeling at the tissue level.

     

    Methods:Transiliac crest bone biopsy assessment was conducted as a substudy of the phase 3 pivotal fracture trial (FREEDOM1) extension

     

    Results:A total of 41 subjects participated in the bone biopsy substudy at month 24, which corresponded to year 5 of study participation (13 cross-over and 28 long-term subjects). Demographics for this subset were comparable with that of the overall FREEDOM study extension population. Mean (SD) number of months from the last dose of DMAb to the first dose of tetracycline was 5.7 (0.5) months. Qualitative bone histology, assessed in all samples was unremarkable, showing normally mineralized lamellar bone. Five subjects in the long-term group did not have osteoid that could be visualized; samples in 4 of 5 were intact and were reported to show normal mineralization. Structural indices, including cancellous bone volume, trabecular number and surface were similar between the cross-over and long-term groups. Consistent with DMAb’s mechanism of action, resorption was decreased as reflected by eroded surface in both cross-over and long-term subjects compared with placebo-treated subjects in FREEDOM (Table). A total of 10/13 (77%) cross-over subjects and 14/28 (50%) long-term subjects had specimens with double-tetracycline label in trabecular and/or cortical compartments; 5 cross-over subjects and 10 long-term subjects were evaluable for dynamic trabecular bone parameters at month 24. Dynamic remodeling indices were low for the cross-over and long-term groups, and consistent with reduced bone turnover with DMAb therapy (Table).

     

    Conclusions:DMAb treatment through 5 years results in normal bone quality with reduced bone turnover, consistent with its mechanism of action.

    1. Cummings, NEJM 2009

    2. Reid, JBMR 2010

    3. Brown, JBMR 2011

    4. Papapoulos, JBMR 2012

    Disclosures: J. Beck Jensen, Amgen, Eli-Lilly, MSD, Takeda/Nycomed: Consulting fees or other remuneration (payment). D. Kendler, Amgen Inc: Research Grants. P. Miller, Procter & Gamble Pharmaceuticals, sanofi-aventis, Roche, Eli Lilly, Merck & Co, Novartis, Amgen, Takeda, Radius, GE: Research Grants. J. Brown, Amgen, Eli Lilly, Novartis: Speaker's Bureau. I. Reid, Amgen, Novartis, Merck: Research Grants. R. Wagman, Amgen Inc: Stock options or bond holdings in a for-profit corporation or self-directed pension plan. I. Reid, Eli-Lilly, sanofi-aventis, Merck, Amgen, Novartis: Consulting fees or other remuneration (payment). P. Miller, Warner Chilcott, Merck, Eli Lilly, Amgen, Novartis, Roche, GlaxoSmithKline, Wright: Speaker's Bureau. J. Brown, Abbott, Amgen, Bristol-Myers Squibb, Eli Lilly, Merck, Novartis, Pfzer, Roche, sanofi-aventis, Servier, Warner Chilcott: Research Grants. D. Kendler, Amgen Inc: Consulting fees or other remuneration (payment). P. Miller, Warner Chilcott, Merck, Eli Lilly, Amgen, Novartis, Roche, GSK, Baxter, Wright: Consulting fees or other remuneration (payment). R. Wagman, Amgen Inc: Employment (full or part-time). J. Zanchetta, Amgen, Eli Lilly, MSD, GSK, Pfizer: Consulting fees or other remuneration (payment). C. Zerbini, sanofi-aventis, Merck, Pfizer: Consulting fees or other remuneration (payment). D. Dempster, Amgen Inc: Consulting fees or other remuneration (payment). J. Zanchetta, Amgen, Eli Lilly, MSD, Radius: Research Grants. D. Dempster, Amgen Inc: Research Grants. J. Brown, Amgen, Eli Lilly, Merck, Novartis, sanofi-aventis, Warner Chilcott: Consulting fees or other remuneration (payment). N. Daizadeh, Amgen Inc: Employment (full or part-time). M. Bolognese, Amgen Inc: Speaker's Bureau. D. Kendler, Amgen Inc: Speaker's Bureau. C. Zerbini, sanofi-aventis, Pfizer, Servier: Speaker's Bureau. D. Dempster, Amgen Inc: Speaker's Bureau. C. Zerbini, Pfizer, sanofi-aventis, Amgen, Merck, GSK, Roche, Novartis: Research Grants. N. Daizadeh, Amgen Inc: Stock options or bond holdings in a for-profit corporation or self-directed pension plan.

    * Presenting Authors(s): Jacques P. Brown, CHU de Québec Research Centre, CANADA

    Attachments

    Bone Histomorphometry Analysis for Subjects in FREEDOM and FREEDOM extension study