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    ASBMR 31st Annual Meeting

    Sclerostin Monoclonal Antibody Stimulates Bone Formation and Improves the Strength and Density of the Fracture Callus and Lumbar Spine in a Primate Fibular Osteotomy Model

    Categories:
     Bone Biomechanics and Quality (Clinical)
     Osteoporosis - Treatment (Preclinical)
     Osteoblasts (Basic)

    Oral Presentations, Presentation Number: 1290
    Session: Concurrent Oral Session 47: Bone Biomechanics and Quality III
    Tuesday, September 15, 2009 11:15 AM - 11:30 AM, Colorado Convention Center, Room 205-207

    * Michael Ominsky, Amgen Inc., USA, Rana Samadfam, Charles River Laboratories, CANADA, Jacquelin Jolette, Charles River Laboratories, Preclinical Services Montreal, CANADA, Fay Vlasseros, Charles River Laboratories Preclinical Services Montreal, Canada, Susan Y. Smith, Charles River Laboratories, CANADA, Paul Kostenuik, Amgen Inc., USA, Chris Paszty, Amgen, Inc., USA, William Simonet, Amgen, Inc., USA, Hua Zhu (David) Ke, Amgen Inc., USA

    Sclerostin is a negative regulator of bone formation, and its inhibition by monoclonal antibody (Scl-Ab) results in increased bone formation and bone mineral density (BMD) in human and animal studies. Bone formation plays a dominant role in fracture healing, and recently Scl-Ab was shown to increase fracture callus density and strength in rodent fracture healing models. We now report its effects in a nonhuman primate fracture model. 3-5 year old male cynomolgus monkeys (cynos) underwent bilateral, transverse fibular osteotomies stabilized with an intramedullary pin. Animals were injected biweekly sc with vehicle (Veh, n=21) or 30 mg/kg Scl-Ab (n=22) for 10 weeks, and bones were collected for biomechanics and histologic analysis. As expected, Scl-Ab resulted in increases in the serum bone formation markers P1NP and osteocalcin compared to Veh. These biomarker increases were associated with Scl-Ab mediated increases in bone formation rate (BFR/BS) at the L2 vertebra and femur shaft, increases in percent change from baseline DXA BMD at the lumbar spine, hip, and distal radius, and increases in lumbar vertebral strength compared to Veh. At the fracture site, Scl-Ab treatment resulted in a significant increase in mean callus bone mineral content (BMC) as measured by pQCT compared to Veh. Threshold analysis demonstrated that Scl-Ab treated calluses were more mature as evidenced by significant increases in hard callus area and BMC compared to Veh. The Scl-Ab mediated improvements in callus maturity were associated with 48% greater mean torsional stiffness compared to vehicle controls, while maximum torque was increased by a non-significant 32% (n=12/group). Semi-quantitative scoring of longitudinal histologic sections of the fractured fibulae (n=9-10/group) demonstrated a lower incidence of delayed union and lesser amount of cartilage in the Scl-Ab treated group, while the extent of bone within the fracture gap and bone end bridging were increased. In summary, inhibition of sclerostin by treatment with Scl-Ab improved fracture healing in a fibular osteotomy model in cynos. In addition, these results demonstrated for the first time that inhibition of sclerostin significantly increased bone formation, mass and strength in male nonhuman primates. These results suggest that Scl-Ab not only has the potential to increase bone mass throughout the skeleton but may also have therapeutic potential to accelerate fracture healing.

    Disclosures: H. Ke, Amgen, Inc.: Employment (full or part-time). R. Samadfam, Amgen, Inc.: Consulting fees or other remuneration (payment). C. Paszty, Amgen, Inc.: Employment (full or part-time). H. Ke, Amgen, Inc.: Stock options or bond holdings in a for-profit corporation or self-directed pension plan. M. Ominsky, Amgen, Inc.: Employment (full or part-time). J. Jolette, Amgen, Inc.: Consulting fees or other remuneration (payment). C. Paszty, Amgen, Inc.: Stock options or bond holdings in a for-profit corporation or self-directed pension plan. S. Smith, Amgen, Inc.: Consulting fees or other remuneration (payment). P. Kostenuik, Amgen, Inc.: Employment (full or part-time). F. Vlasseros, Amgen, Inc.: Consulting fees or other remuneration (payment). W. Simonet, Amgen, Inc.: Employment (full or part-time). W. Simonet, Amgen, Inc.: Stock options or bond holdings in a for-profit corporation or self-directed pension plan. M. Ominsky, Amgen, Inc.: Stock options or bond holdings in a for-profit corporation or self-directed pension plan. P. Kostenuik, Amgen, Inc.: Stock options or bond holdings in a for-profit corporation or self-directed pension plan.

    * Presenting Authors(s): Michael Ominsky, Amgen Inc., USA

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