Biologic alternatives to bone graft can be classified into cell based or molecule based. Bone Morphogenetic Proteins (BMPs) are a group of molecules that works by inducing the mesenchymal stem cells to differentiate into bone forming cell lines that form new bone. BMPs are involved in many physiological and pathological processes such as inflammatory response, bone formation and resorption, growth signaling pathways, oncogenesis and immune response. The purity, local effects, systemic effects, immunogenicity, and biocompatibility influence the safety and efficacy of BMP as a bone graft substitute. The two commercially available forms of BMP,; rhBMP-2 and rhBMP-7 result in endochondral ossification.
Formation of bone (ossification) occurs by both intramembranous ossification and endochondral ossification. In intramembranous ossification, the primitive mesenchymal cells are first transformed to osteoprogenitor cells and then into osteoblasts which lays down osteoid. Intramembranous ossification is seen in the skull, mandible, and the clavicle. Endochondral ossification is seen in the long bones; here the primitive mesenchymal cells transform into chondroblasts which lays down cartilage, the cartilage matures then degenerates. Degenerated cartilage is invaded by blood vessels and also by osteoblasts which forms bone.
The cellular events of both endochondral and intramembranous ossification involve the mesenchymal stem cells (MSCs). MSCs may be bone marrow derived or periosteum derived. MSCs are pluripotent progenitors that can differentiate into osteoblast, chondroblast and other connective tissue cell lines. Differentiation of MSCs is regulated by signaling pathways and molecules such as bone morphogenetic proteins (BMP), Wnt, Notch, Hedgehog, and Fibroblast growth factor (FGF).
The cellular and molecular events that govern the bone formation during development and fracture healing are similar. The process of fracture healing is similar to endochondral ossification. Healing of fracture needs appropriate cellular environment, adequate growth factors, sufficient bone matrix and mechanical stability. In some situations, the process of fracture healing may fail, leading to nonunion or delayed union. Such conditions as well as traumatic bone loss and spinal fusion surgery need stimulation of the process of bone formation. This can be achieved by biophysical methods such as ultrasound or biological interventions such as bone graft, bone marrow or biologically active molecules. Autogenous bone graft is capable of stimulation of bone formation by the process of osteogenesis, osteoconduction and osteoinduction. Osteogenesis is the direct formation of bone by the living osteoblasts in the graft. Osteoconduction is the ability to promote bone growth by allowing bone formation on its surface. Osteoinduction is the ability to induce the cells of recipient area to form new bone. Autogenous iliac crest bone graft (AICBG) is considered the gold standard for stimulation of bone formation in the treatment of bone defects and nonunions. However, limited availability of bone graft, morbidity of graft harvest, and the variable success rate of union highlights the need for a better option.
One of the solutions to avoid the problems of autologous bone graft is the use of the parathyroid hormone (PTH), hypoxia-inducible factor 1α (HIF-1α), modulators of the Wnt signalling pathway and the BMPs as a bone graft substitutes as they are capable of osteoinduction. It was hoped that equal or better results can be achieved without the morbidity of graft harvest.