Calcified Tissue International

, Volume 92, Issue 3, pp 261–269 | Cite as

Effects of Odanacatib on Bone Mineralization Density Distribution in Thoracic Spine and Femora of Ovariectomized Adult Rhesus Monkeys: A Quantitative Backscattered Electron Imaging Study

  • Nadja Fratzl-Zelman
  • Paul Roschger
  • John E. Fisher
  • Le T. Duong
  • Klaus Klaushofer
Original Research

Abstract

Odanacatib (ODN) has been developed as a selective inhibitor of cathepsin K, the major cysteine protease in osteoclasts. In adult rhesus monkeys, treatment with ODN prevents ovariectomy-induced bone loss in lumbar vertebrae and hip. In this study, we evaluate the effects of ODN on bone mineralization density distribution (BMDD) by quantitative backscattered electron imaging in vertebral spongiosa, distal femoral metaphyseal and cortical shaft from monkeys (aged 16–23 years), treated with vehicle (n = 5) or ODN (6 mg/kg, n = 4 or 30 mg/kg, n = 4, PO daily) for 21 months. Dual-energy X-ray absorptiometry was measured in a subset of distal femoral samples. In lumbar vertebrae there was a shift to higher mineralization in samples from ODN-treated groups, compared to vehicle: CaMean (+4 %), CaPeak (+3 %), CaWidth (−9 %), CaLow (−28 %) in the 6 mg/kg group and CaMean (+5.1 %, p < 0.023), CaPeak (+3.4 %, p < 0.046), CaWidth (−15.7 %, p = 0.06) and CaLow (−38.2 %, p < 0.034) in the 30 mg/kg group. In distal femoral metaphyseal cancellous bone, there was a clear tendency toward a dose-dependent increase in matrix mineralization, as in the spine. However, primary and osteonal bone of the distal cortical diaphyses showed no significant change in BMDD, whereas bone mineral density was significantly increased after treatment. In ovariectomized monkeys, this study shows that ODN treatment increased trabecular BMDD, consistent with its previously reported ability to reduce cancellous remodeling. Here, ODN also showed no changes in BMDD in cortical bone sites, consistent with its actions on maintaining endocortical and stimulating periosteal bone formation.

Keywords

Bone mineralization density distribution (BMDD) Cathepsin K inhibitor Dual-energy X-ray absorptiometry (DXA) Nonhuman primate Osteopenia Quantitative backscattered electron imaging (qBEI) 

Notes

Acknowledgments

We thank Phaedra Messmer, Daniela Gabriel and Sonja Lueger for excellent technical assistance and performing the qBEI measurements. This study was supported by the AUVA (Research funds of the Austrian workers compensation board), the WGKK (Viennese sickness insurance funds), and research funding from Merck Sharp & Dohme.

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Copyright information

© Springer Science+Business Media New York 2012

Authors and Affiliations

  • Nadja Fratzl-Zelman
    • 1
    • 3
  • Paul Roschger
    • 1
  • John E. Fisher
    • 2
  • Le T. Duong
    • 2
  • Klaus Klaushofer
    • 1
  1. 1.Ludwig Boltzmann Institute of Osteology of WGKK and AUVA Trauma Centre Meidling, 1st Medical Department, Hanusch HospitalViennaAustria
  2. 2.Bone Biology GroupMerck Research LaboratoryWest PointUSA
  3. 3.Ludwig Boltzmann Institute of Osteology, UKH MeidlingViennaAustria

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