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Balicatib, a cathepsin K inhibitor, stimulates periosteal bone formation in monkeys

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Abstract

Summary

Balicatib, an inhibitor of the osteoclastic enzyme cathepsin K, was tested in ovariectomized monkeys, a model for osteoporosis. As expected, ovariectomy-induced bone mass changes were partially prevented by balicatib treatment. Bone turnover was significantly decreased at most sites, but unlike most bone resorption inhibitors, periosteal bone formation rates were increased.

Introduction

Selective inhibitors of the osteoclastic enzyme cathepsin K have potential in osteoporosis treatment. This study evaluated the efficacy of balicatib (AAE581), a novel inhibitor of human cathepsin K, on bone mass and dynamic histomorphometric endpoints in ovariectomized monkeys.

Methods

Eighty adult female Macaca fascicularis underwent bilateral ovariectomies and were dosed twice daily by oral gavage with balicatib at 0, 3, 10, and 50 mg/kg for 18 months (groups O, L, M, H, respectively). Approximately 1 month after treatment initiation, the 50 mg/kg dose was decreased to 30 mg/kg. Twenty animals underwent sham—ovariectomies (group S). Bone mass was measured at 3–6 month intervals. At 18 months, vertebra and femur were collected for histomorphometry.

Results

In both spine and femur, group O animals lost bone mineral density (BMD), and all other groups gained BMD between 0 and 18 months. In balicatib-treated animals, BMD change in the spine was intermediate between group S and O, with groups L and M significantly different from group O. In femur, all three doses of balicatib significantly increased BMD gain relative to group O, and group mean values were also higher than group S. Most histomorphometric indices of bone turnover in vertebra and femoral neck were significantly lower than group O with balicatib treatment, except that periosteal bone formation rates (Ps.BFR) were significantly higher. Ps.BFR in mid-femur was also significantly increased by treatment.

Conclusions

Balicatib partially prevented ovariectomy-induced changes in bone mass, inhibited bone turnover at most sites, and had an unexpected stimulatory effect on periosteal bone formation.

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Acknowledgments

We thank H. Tsusaki and the staff of Shin Nippon Biomedical Laboratories for carrying out the in-life part of the study. The staff of SkeleTech Inc. is thanked for performing biomarker, biomechanical, and histomorphometric analyses as well as for documentation. We also thank J. A. Gasser and M. Kneissel for advice in designing the study and interpreting results. The extensive assistance of P. Peterson in production of this manuscript is gratefully acknowledged.

Funding source

This study is funded by Novartis Pharma AG.

Conflicts of interest

R. Gamse and M. Missbach are employees of Novartis.

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Authors and Affiliations

  1. Think Bone Consulting, Inc, PO Box 1611, Langley, WA, 98260, USA

    C. Jerome

  2. Novartis Institutes for Biomedical Research, Basel, Switzerland

    M. Missbach & R. Gamse

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  1. C. Jerome
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  2. M. Missbach
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  3. R. Gamse
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Correspondence to C. Jerome.

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Jerome, C., Missbach, M. & Gamse, R. Balicatib, a cathepsin K inhibitor, stimulates periosteal bone formation in monkeys. Osteoporos Int 22, 3001–3011 (2011). https://doi.org/10.1007/s00198-011-1529-x

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  • DOI: https://doi.org/10.1007/s00198-011-1529-x

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