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Sclerostin Antibody Increases Callus Size and Strength but does not Improve Fracture Union in a Challenged Open Rat Fracture Model

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Abstract

Open fractures remain a challenge in orthopedics. Current strategies to intervene are often inadequate, particularly in severe fractures or when treatment is delayed. Sclerostin is a negative regulator of bone growth and sclerostin-neutralizing antibodies (Scl-Ab) can increase bone mass and strength. The application of these antibodies to improve orthopedic repair has shown varied results, and may be dependent on the location and severity of the bony injury. We examined Scl-Ab treatment within an established rat osteotomy model with periosteal stripping analogous to open fracture repair. In one study, Scl-Ab was given 25 mg/kg bi-weekly, either from the time of fracture or from 3 weeks post-fracture up to an end-point of 12 weeks. A second study treated only delayed union open fractures that did not show radiographic union by week 6 post-fracture. Outcome measures included radiographic union, microCT analysis of bone volume and architecture, and histology. In the first study, Scl-Ab given from either 0 or 3 weeks significantly improved callus bone volume (+52%, p < 0.05 and +58%, p < 0.01) at 12 weeks, as well as strength (+48%, p < 0.05 and +70%, p < 0.05). Despite these improvements, union rate was not changed. In the second study treating only established delayed fractures, bony callus volume was similarly increased by Scl-Ab treatment; however, this did not translate to increased biomechanical strength or union improvement. Sclerostin antibody treatment has limited effects on the healing of challenging open fractures with periosteal stripping, but shows the greatest benefits on callus size and strength with earlier intervention.

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Acknowledgements

The authors received materials support (Scl-AbIII) for this study from Amgen Inc. and UCB Pharma (Brussels, Belgium).

Author contributions

Study design: DGL, MMM, ML, HZK. Study conduct: AM, MMM, LP, KM. Data collection: AM, LP, KM, TLC. Data interpretation: AM, MMM, DGL, TLC. Drafting manuscript: AM and AS. Revising manuscript content: AM, AS, DGL, MMM, TLC, HZK, ML. Approving final version of manuscript: all authors. AM takes responsibility for the integrity of the data analysis.

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Authors and Affiliations

  1. Orthopaedic Research & Biotechnology Unit, The Children’s Hospital at Westmead, Westmead, Australia

    Alyson Morse, Michelle M. McDonald, Aaron Schindeler, Lauren Peacock, Kathy Mikulec, Tegan L. Cheng & David G. Little

  2. Discipline of Paediatrics and Child Health, Faculty of Medicine, University of Sydney, Sydney, Australia

    Alyson Morse, Aaron Schindeler, Tegan L. Cheng & David G. Little

  3. Bone Biology Program, The Garvan Institute of Medical Research, Sydney, Australia

    Michelle M. McDonald

  4. Amgen Inc, Thousand Oaks, USA

    Min Liu

  5. UCB Pharma, Slough, UK

    Hua Zhu Ke

Authors
  1. Alyson Morse
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  2. Michelle M. McDonald
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  3. Aaron Schindeler
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  4. Lauren Peacock
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  5. Kathy Mikulec
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  6. Tegan L. Cheng
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  7. Min Liu
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  8. Hua Zhu Ke
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  9. David G. Little
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Corresponding author

Correspondence to David G. Little.

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Conflict of interest

The authors received materials support (Scl-AbIII) for this study from Amgen Inc. and UCB (Brussels, Belgium). Prof Little has received additional funding and materials support from Amgen Inc. and UCB Pharma for pre-clinical research separate to this submission. Prof Little has received funding support from Novartis Pharma AG, N8 Medical and Celgene for pre-clinical research separate to this submission. Dr McDonald received salary support from the IBMS Greg Mundy Fellowship and receives a Practitioner Fellowship (National Health & Medical Research Council). Authors Dr Liu and Prof Ke are or have been employees of Amgen Inc. Prof Ke is an employee of UCB, Alyson Morse, Aaron Schindler, Lauren Peacock, Kathy Mikulec, and Tegan L Cheng have no conflict of interest.

Human and Animal Rights and Informed Consent

All applicable international, national, and/or institutional guidelines for the care and use of animals were followed. All procedures performed in studies involving animals were in accordance with the ethical standards of the institution or practice at which the studies were conducted.

Appendix

Appendix

See Tables 4, 5 and 6.

Table 4 The number of rats within the studies, the number included within analysis, and the number excluded
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Table 5 Union grading of fractures assessed fortnightly between W4 and W12 for Study A.
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Table 6 Union grading of fractures assessed fortnightly between W2 and W12 for Study B
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Morse, A., McDonald, M.M., Schindeler, A. et al. Sclerostin Antibody Increases Callus Size and Strength but does not Improve Fracture Union in a Challenged Open Rat Fracture Model. Calcif Tissue Int 101, 217–228 (2017). https://doi.org/10.1007/s00223-017-0275-2

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  • DOI: https://doi.org/10.1007/s00223-017-0275-2

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