title: RAP-011 augments callus formation in closed fractures in rats.
abstract: ACE-011 is a bone anabolic agent generated by fusing the extracellular domain of the Activin Type 2A receptor (ActRIIA) to an IgG-Fc. The orthopedic utility of ACE-011 was investigated using a murine analogue, RAP-011. Initially, a rat closed fracture model was tested using bi-weekly (biw) 10 mg/kg RAP-011. RAP-011 significantly increased callus length and callus bone volume (BV, +43% at 6w, p < 0.01). The polar moment of inertia was calculated to be substantively increased (+80%, p < 0.01), however mechanical bending tests showed a more modest increase in maximum load to failure (+24%, p < 0.05). Histology indicated enhanced appositional bone growth, but it was hypothesized that reduced remodeling, evidenced by decreased serum CTX (-16% at 6w, p < 0.01), could be compromising bone quality in the callus. A second closed fracture study was performed to examine lower "pulse" [RAP-011(p)] and "sustained" [RAP-011(s)] regimens of biw 0.6mg/kg × 2, 0.35mg/kg × 3 and 0.18mg/kg × 2, 0.1mg/kg × 7 respectively, compared with PTH(1-34) (25 μg/kg/d) and vehicle controls. RAP-011 treatments gave modest increases in callus length and callus BV at 6w (p < 0.01), but did not achieve an increase in maximum load over vehicle. In summary, RAP-011 is effective in promoting bone formation during repair, but optimizing callus bone quality will require further investigation.
authors.affiliation: Orthopaedic Research and Biotechnology Unit, The Children's Hospital at Westmead, Sydney, 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 and Biotechnology Unit, The Children's Hospital at Westmead, Sydney, 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: Orthopaedic Research and Biotechnology Unit, The Children's Hospital at Westmead, Sydney, Australia.
authors.forename: Lauren
authors.initials: L
authors.lastname: Peacock
authors.affiliation: Orthopaedic Research and Biotechnology Unit, The Children's Hospital at Westmead, Sydney, Australia.
authors.forename: Kathy
authors.initials: K
authors.lastname: Mikulec
authors.affiliation: Orthopaedic Research and Biotechnology Unit, The Children's Hospital at Westmead, Sydney, Australia.|Discipline of Paediatrics and Child Health, Faculty of Medicine, University of Sydney, Sydney, Australia.
authors.forename: David G
authors.initials: DG
authors.lastname: Little
authors.affiliation: Orthopaedic Research and Biotechnology Unit, The Children's Hospital at Westmead, Sydney, Australia.|Discipline of Paediatrics and Child Health, Faculty of Medicine, University of Sydney, Sydney, Australia.
authors.forename: Aaron
authors.initials: A
authors.lastname: Schindeler
mesh_terms: D000818:Animals; D001696:Biomechanical Phenomena; D002146:Bony Callus / Q000187:drug effects; D004353:Drug Evaluation, Preclinical; D050723:Fractures, Bone / Q000188:drug therapy*; D008297:Male; D017208:Rats, Wistar; D011993:Recombinant Fusion Proteins / Q000494:pharmacology / Q000627:therapeutic use*
chemical_list: C000595663:ActRIIA-mIgG2aFc fusion protein; D011993:Recombinant Fusion Proteins
keywords: activin; bone; bone formation; fracture; orthopedics