Mf. Sciadini et Kd. Johnson, Evaluation of recombinant human bone morphogenetic protein-2 as a bone-graft substitute in a canine segmental defect model, J ORTHOP R, 18(2), 2000, pp. 289-302
A study was performed in dogs to evaluate the dose-response characteristics
and effectiveness of recombinant human bone morphogenetic protein-2 with a
collagen sponge carrier in a segmental defect model. Twenty-seven dogs und
erwent bilateral radial osteotomies with creation of a 2.5-cm diaphyseal de
fect. All received autogenous cancellous bone graft in one defect and a col
lagen implant in the other. These implants contained recombinant human bone
morphogenetic protein-2 at the following doses: group 1 at 0 mu g (three d
ogs, 0 mu g/ml total implant volume), group 2 at 150 mu g (three dogs, 50 m
u g/ml), group 3 at 600 mu g (three dogs, 200 mu g/ml), group 4 at 2,400 mu
g (three dogs, 800 mu g/ml), group 5 at 0 mu g (five dogs, 0 mu g/ml), gro
up 6 at 150 mu g (five dogs, 200 mu g/ml), and group 7 at 600 mu g (five do
gs, 50 mu g/ml). The defects were stabilized with external fixators. The do
gs in groups 1-4 were killed at 12 weeks postoperatively, and those in grou
ps 5-7 were killed at 24 weeks postoperatively except for one dog in group
7, which was killed at 48 weeks. Evaluation included monthly radiographs, b
iomechanical testing, and nondemineralized histology. All 27 radii with aut
ogenous cancellous bone graft and all 19 implants treated with recombinant
human bone morphogenetic protein-2 achieved radiographic and histologic uni
on and gross stability. The eight radii treated with collagen carrier alone
went on to radiographic and histologic nonunion and were grossly unstable
at death. A dose-dependent occurrence of cyst-like bone voids was noted rad
iographically and histologically. Biomechanical performance tended to be be
tter at the lowest dose studied at 12 weeks, and all three doses performed
better than the placebo (p < 0.05) at 12 and 24 weeks. By 24 weeks, radiolu
cent areas corresponding to histologic bone voids persisted radiographicall
y, although there was evidence of early bone remodeling. This remodeling pr
ogressed to 48 weeks in the single animal followed to this time point, alth
ough bone voids remained. These radiologic findings were confirmed histolog
ically. Recombinant human bone morphogenetic protein-2 in a collagen sponge
carrier has significant osteoinductive activity in this canine segmental d
efect model. A dose-response relationship is evident, with heterotopic bone
and cyst-like void formation at higher doses and a minimum effective dose
of 0-150 mu g. At 12 and 24 weeks postoperatively, biomechanical parameters
achieved by defects treated with recombinant human bone morphogenetic prot
ein-2 were comparable with those of autograft controls and were significant
ly stronger than those of the placebo (p < 0.05).