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Two doses of sclerostin antibody in cynomolgus monkeys increases bone formation, bone mineral density, and bone strength†

  1. Michael S Ominsky1,
  2. Fay Vlasseros2,
  3. Jacquelin Jolette2,
  4. Susan Y Smith2,
  5. Brian Stouch3,
  6. George Doellgast3,
  7. Jianhua Gong1,
  8. Yongming Gao1,
  9. Jin Cao1,
  10. Kevin Graham4,
  11. Barbara Tipton4,
  12. Jill Cai5,
  13. Rohini Deshpande5,
  14. Lei Zhou6,
  15. Michael D Hale6,
  16. Daniel J Lightwood7,
  17. Alistair J Henry7,
  18. Andrew G Popplewell7,
  19. Adrian R Moore7,
  20. Martyn K Robinson7,
  21. David L Lacey1,
  22. W Scott Simonet1,
  23. Chris Paszty1,*

Article first published online: 8 JAN 2010

DOI: 10.1002/jbmr.14

Issue

Journal of Bone and Mineral Research

Journal of Bone and Mineral Research

Volume 25, Issue 5, pages 948–959, May 2010

Additional Information

How to Cite

Ominsky, M. S., Vlasseros, F., Jolette, J., Smith, S. Y., Stouch, B., Doellgast, G., Gong, J., Gao, Y., Cao, J., Graham, K., Tipton, B., Cai, J., Deshpande, R., Zhou, L., Hale, M. D., Lightwood, D. J., Henry, A. J., Popplewell, A. G., Moore, A. R., Robinson, M. K., Lacey, D. L., Simonet, W. S. and Paszty, C. (2010), Two doses of sclerostin antibody in cynomolgus monkeys increases bone formation, bone mineral density, and bone strength. J Bone Miner Res, 25: 948–959. doi: 10.1002/jbmr.14

Author Information

  1. 1

    Metabolic Disorders, Amgen, Inc., Thousand Oaks, CA, USA

  2. 2

    Bone Research, Charles River Laboratories, Preclinical Services Montreal, Senneville, Quebec, Canada

  3. 3

    Pharmacokinetics and Drug Metabolism, Amgen, Inc., Thousand Oaks, CA, USA

  4. 4

    Protein Sciences, Amgen, Inc., Thousand Oaks, CA, USA

  5. 5

    ATO Cell Sciences and Technology, Amgen, Inc., Thousand Oaks, CA, USA

  6. 6

    Biostatistics, Amgen, Inc., Thousand Oaks, CA, USA

  7. 7

    UCB-Celltech, Slough, United Kingdom

*Metabolic Disorders, M/S 14-1-B, One Amgen Center Drive, Amgen, Inc., Thousands Oaks, CA 91320-1799, USA.

  1. †

    Parts of the manuscript were presented at the 28th Annual Meeting of the American Society for Bone and Mineral Research, in Philadelphia, PA, September 15–19, 2006

Publication History

  1. Issue published online: 30 APR 2010
  2. Article first published online: 8 JAN 2010
  3. Accepted manuscript online: 8 JAN 2010 12:00AM EST
  4. Manuscript Accepted: 17 DEC 2009
  5. Manuscript Revised: 11 NOV 2009
  6. Manuscript Received: 24 SEP 2009

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Keywords:

  • sclerostin;
  • antibody;
  • bone formation;
  • bone strength;
  • primate

Abstract

The development of bone-rebuilding anabolic agents for treating bone-related conditions has been a long-standing goal. Genetic studies in humans and mice have shown that the secreted protein sclerostin is a key negative regulator of bone formation. More recently, administration of sclerostin-neutralizing monoclonal antibodies in rodent studies has shown that pharmacologic inhibition of sclerostin results in increased bone formation, bone mass, and bone strength. To explore the effects of sclerostin inhibition in primates, we administered a humanized sclerostin-neutralizing monoclonal antibody (Scl-AbIV) to gonad-intact female cynomolgus monkeys. Two once-monthly subcutaneous injections of Scl-AbIV were administered at three dose levels (3, 10, and 30 mg/kg), with study termination at 2 months. Scl-AbIV treatment had clear anabolic effects, with marked dose-dependent increases in bone formation on trabecular, periosteal, endocortical, and intracortical surfaces. Bone densitometry showed that the increases in bone formation with Scl-AbIV treatment resulted in significant increases in bone mineral content (BMC) and/or bone mineral density (BMD) at several skeletal sites (ie, femoral neck, radial metaphysis, and tibial metaphysis). These increases, expressed as percent changes from baseline were 11 to 29 percentage points higher than those found in the vehicle-treated group. Additionally, significant increases in trabecular thickness and bone strength were found at the lumbar vertebrae in the highest-dose group. Taken together, the marked bone-building effects achieved in this short-term monkey study suggest that sclerostin inhibition represents a promising new therapeutic approach for medical conditions where increases in bone formation might be desirable, such as in fracture healing and osteoporosis. © 2010 American Society for Bone and Mineral Research

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