Does Activin Receptor Blockade by Bimagrumab (BYM338) Pose Detrimental Effects on Bone Healing in a Rat Fibula Osteotomy Model?
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Bimagrumab (BYM338) is a novel fully human monoclonal antibody that exerts strong promyogenic effects on skeletal muscle by blocking activin type II receptors (ActRII). We investigated whether such blockade of ActRII by bimagrumab manifests any detrimental effect on outcomes of bone healing in a rat fibula osteotomy model. Animals (n = 150) were divided into 11 groups and received weekly treatment with either bimagrumab (10 or 100 mg/kg) or vehicle. Progression and outcomes of bone healing were assessed by lateral radiographs in vivo as well as by peripheral quantitative computed tomography (pQCT), 4-point bending test, and microscopic examination of the excised fibula at Day 29 or later. The radiographic progression of bone healing showed no significant differences between treatment groups in any comparative setting. In 3-month-old animals, pQCT revealed slightly reduced immature callus size and bone mineral content in bimagrumab-treated animals compared with vehicle-treated animals at Day 29 (p < 0.05). There were, however, no differences in mature callus size, bone mineral density, or biomechanical competency. The aforementioned effects on immature callus size were not present when the treatment was initiated 4 weeks post osteotomy or when treating 6-month-old animals. In summary, these findings suggest that there is no major impact of ActRII blockade on overall fracture healing, and delayed treatment initiation can bypass the small and transient effect of the therapy on immature callus formation observed in younger animals. Verification of these findings in humans is the subject of an ongoing clinical trial on elderly hip fracture patients.
KeywordsFibular osteotomy Activin type II receptors Imaging Callus formation 4-Point bending test
The authors wish to thank Hardik Ashar (Scientific Writer, Novartis Healthcare Pvt. Ltd., India) for providing excellent support during the finalization of the manuscript including compilation of inputs from authors. This study was funded by Novartis Pharma AG, Basel, Switzerland.
Compliance with Ethical Standards
Conflict of Interest
Drs. László B. Tankó, Jörg Goldhahn and Andrew Pilling are employees of Novartis and may be eligible for Novartis stock and stock options. Aurore Varela, Elisabeth Lesage, and Susan Y. Smith are employees of Charles River, an organization that received support for conducting this study. Simon Chivers was employed with Novartis at the time of the study conduct and declares no conflict of interest related to this publication.
Human and Animal Rights and Informed Consent
All experimental protocols were reviewed and approved by the Novartis Animal Care and Use Committee (NACUC) of Novartis and the Institutional Animal Care and Use Committee (IACUC) of Charles River and were conducted in compliance with all regulatory, NACUC, and IACUC requirements.
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