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    ASBMR 31st Annual Meeting

    Infrequent Co-treatment and Sequential Treatment of Anti-sclerostin Antibody with Zoledronic Acid Restores and Maintains Bone Mass in Murine Osteoporosis Models

    Category: Osteoporosis - Treatment (Preclinical)

    Oral Presentations, Presentation Number: 1063
    Session: Concurrent Oral Session 11: Osteoporosis Treatment (Preclinical) - Anabolic Agents
    Saturday, September 12, 2009 3:00 PM - 3:15 PM, Colorado Convention Center, Hall A

    Christine Halleux, Novartis Institutes for BioMedical Research, CHE, Shouih Hu, Novartis Institutes for Biomedical Research, USA, Beate Diefenbach, Morphosys AG, Germany, Josef Prassler, Morphosys AG, Germany, Marcel Merdes, Novartis Institutes for Biomedical Research, Switzerland, Anne Studer, Novartis Institutes for Biomedical Research, Switzerland, Holger Heine, Novartis Institutes for Biomedical Research, Switzerland, Steffen Hartmann, Novartis Institutes for Biomedical Research, Switzerland, Andrew Mackenzie, Novartis Institutes for Biomedical Research, Switzerland, Rainer Gamse, Novartis Pharma AG, SWITZERLAND, Uwe Junker, Novartis Institutes for Biomedical Research, Switzerland, * Michaela Kneissel, Novartis Institutes for Biomedical Research, SWITZERLAND

    The only available bone restoring osteoporosis (OP) therapy involves daily subcutaneous (sc.) injection of PTH 1-84 or fragment 1-34. Agents that can be administered infrequently opposed to PTH would provide considerable benefits for patients. Inhibition of the osteocyte secreted bone formation inhibitor sclerostin by blocking antibodies induces bone gain. The bisphosphonate zoledronic acid inhibits osteoclastic bone resorption for a prolonged time following intravenous application (iv.). Infrequent sequential or combined application of these two principles should therefore provide an ideal OP therapy. We thus tested the ability of an anti-sclerostin antibody, isolated from a human combinatorial antibody library (HuCAL GOLD®) by phage display, to induce bone mass changes when administered alone or in combination with zoledronic acid in murine OP models. Weekly iv. administration of the anti-sclerostin antibody induced in skeletally mature, in aged osteopenic, and in estrogen deprived (OVX) osteoporotic female OF1 and nude mice dose related bone mass and density increases from 5 mg/kg onwards. Effects were comparable to (25 mg/kg) or above (100 mg/kg) those of daily high dose sc. PTH(1-34) treatment (100 μg/kg) as evaluated by in vivo pQCT and ex vivo μCT and DEXA in the appendicular and axial skeleton. Moreover single high dose application (300 mg/kg) was sufficient to increase bone mass (+21%) as evaluated by pQCT in the proximal tibia metaphysis of aged osteopenic mice. Bone mass remained above control levels for 3 months. Bone gain was due to increased bone formation rates as evaluated by histomorphometry. Anti-sclerostin antibody induced bone mass increases could be preserved by a single iv. application of 100 μg/kg zoledronic acid, while animals without maintenance treatment lost bone gradually during the follow-up period proportional to the amount gained at different doses. Application of anti-sclerostin antibody or zoledronic acid blocked rapid bone mass loss (-14% in 3 weeks) induced in aged OVX mice as detected by pQCT. Combination of both principles resulted in additive respectively synergistic effects depending on the evaluated bone parameter and increased bone mass markedly above baseline values (+13%). In summary infrequent co-treatment and sequential treatment of anti-sclerostin antibody with zoledronic acid are efficacious ways to restore and maintain bone mass in preclinical OP models and might thus hold potential for clinical application.

    Disclosures: S. Hartmann, Novartis Institutes for Biomedical Research: Employment (full or part-time). J. Prassler, Morphosys AG: Employment (full or part-time). S. Hu, Novartis Institutes for Biomedical Research: Employment (full or part-time). M. Merdes, Novartis Institutes for Biomedical Research: Employment (full or part-time). B. Diefenbach, Morphosys AG: Employment (full or part-time). C. Halleux, Novartis Institutes for Biomedical Research: Employment (full or part-time). R. Gamse, Novartis Institutes for Biomedical Research: Employment (full or part-time). M. Kneissel, Novartis Institutes for Biomedical Research: Employment (full or part-time). A. Mackenzie, Novartis Institutes for Biomedical Research: Employment (full or part-time). A. Studer, Novartis Institutes for Biomedical Research: Employment (full or part-time). H. Heine, Novartis Institutes for Biomedical Research: Employment (full or part-time). U. Junker, Novartis Institutes for Biomedical Research: Employment (full or part-time).

    * Presenting Authors(s): Michaela Kneissel, Novartis Institutes for Biomedical Research, SWITZERLAND