RAP‐011 augments callus formation in closed fractures in rats. Issue 2 (1st September 2015) - Morse, Alyson
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. © 2015 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 34:320–330, 2016.