BMP implants in bone formation. Studies in rabbits and rats

Abstract: Bone morphogenic proteins, BMPs, are a group endogenous proteins that are highly conserved through evolution. The amino acid sequences of about 15 different BMPs are now known and recombinant human BMPs are commercially available. Implantation of an individual BMP protein is sufficient to induce bone formation even at a subcutaneous site. Our initial studies discovered inhibition of bone formation by BMP-2 implanted in a titanium chamber model in rabbit tibia. This paradoxical effect was previously unknown, and lead to studies trying to elucidate the required conditions for BMPs to induce bone formation. Inhibition of bone formation was still found, despite testing different doses of BMP-2, another BMP (OP-1), a different carrier, and altered microenvironment. Stimulation of bone formation by BMP-2 was finally shown in a similar titanium chamber model by adding micromotion. The used titanium model induces minimal fracture surfaces when implanting the BMP and thus a minimal trauma unless micromotion was added. Therefore, we conclude that a certain amount of trauma probably is a prerequisite for BMP induction of bone formation. Impaction of morselized allografts in rat titanium chamber models slowed down new bone ingrowth. This delay was overcome by adding OP-1 to the impacted graft. A marrow-like cavity forms by resorption behind the bone ingrowth frontier in impacted bone allografts. In situations where the graft must resist deformation during remodeling, this resorption might compromise the final result. Bisphosphonates bind to the mineral phase of bone and induce cell death to osteoclasts resorbing the bone. By treating impacted allografts in rats with a bisphosphonate we increased the bone density (both new bone and remaining graft) after 6 weeks. When treating allograft with both a bishosphonate and a BMP (OP-1) the previous increase in new bone ingrowth by OP-1 was lost, suggesting that, at least in some grafting situations, resorption may be a prerequisite for stimulation of bone ingrowth by a BMP.