title: Sclerostin Antibody Increases Callus Size and Strength but does not Improve Fracture Union in a Challenged Open Rat Fracture Model.
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.
authors.affiliation: Orthopaedic Research & Biotechnology Unit, The Children's Hospital at Westmead, Westmead, Australia.|Discipline of Paediatrics and Child Health, Faculty of Medicine, University of Sydney, Sydney, Australia.
authors.forename: Alyson
authors.initials: A
authors.lastname: Morse
authors.affiliation: Orthopaedic Research & Biotechnology Unit, The Children's Hospital at Westmead, Westmead, Australia.|Bone Biology Program, The Garvan Institute of Medical Research, Sydney, Australia.
authors.forename: Michelle M
authors.initials: MM
authors.lastname: McDonald
authors.affiliation: Orthopaedic Research & Biotechnology Unit, The Children's Hospital at Westmead, Westmead, Australia.|Discipline of Paediatrics and Child Health, Faculty of Medicine, University of Sydney, Sydney, Australia.
authors.forename: Aaron
authors.initials: A
authors.lastname: Schindeler
authors.affiliation: Orthopaedic Research & Biotechnology Unit, The Children's Hospital at Westmead, Westmead, Australia.
authors.forename: Lauren
authors.initials: L
authors.lastname: Peacock
authors.affiliation: Orthopaedic Research & Biotechnology Unit, The Children's Hospital at Westmead, Westmead, Australia.
authors.forename: Kathy
authors.initials: K
authors.lastname: Mikulec
authors.affiliation: Orthopaedic Research & Biotechnology Unit, The Children's Hospital at Westmead, Westmead, Australia.|Discipline of Paediatrics and Child Health, Faculty of Medicine, University of Sydney, Sydney, Australia.
authors.forename: Tegan L
authors.initials: TL
authors.lastname: Cheng
authors.affiliation: Amgen Inc, Thousand Oaks, USA.
authors.forename: Min
authors.initials: M
authors.lastname: Liu
authors.affiliation: UCB Pharma, Slough, UK.
authors.forename: Hua Zhu
authors.initials: HZ
authors.lastname: Ke
authors.affiliation: Orthopaedic Research & Biotechnology Unit, The Children's Hospital at Westmead, Westmead, Australia. david.little@health.nsw.gov.au.|Discipline of Paediatrics and Child Health, Faculty of Medicine, University of Sydney, Sydney, Australia. david.little@health.nsw.gov.au.
authors.forename: David G
authors.initials: DG
authors.lastname: Little
mesh_terms: D000818:Animals; D000906:Antibodies / Q000494:pharmacology*; D001696:Biomechanical Phenomena / Q000187:drug effects; D015519:Bone Density / Q000187:drug effects*; D019485:Bone Morphogenetic Proteins / Q000276:immunology*; D002146:Bony Callus / Q000473:pathology*; D004195:Disease Models, Animal; D005264:Femoral Fractures / Q000188:drug therapy / Q000473:pathology; D005269:Femur / Q000187:drug effects / Q000473:pathology; D017102:Fracture Healing / Q000187:drug effects; D005819:Genetic Markers / Q000276:immunology*; D008297:Male; D010012:Osteogenesis / Q000187:drug effects; D010027:Osteotomy / Q000379:methods; D051381:Rats
chemical_list: D000906:Antibodies; D019485:Bone Morphogenetic Proteins; D005819:Genetic Markers; C486031:Sost protein, rat
keywords: Delayed union; Open fracture; Osteotomy; Sclerostin; Sost