Effects of locally administered bisphosphonate and rhBMP-2 on bone regeneration in the rat fibula

Abstract

The mechanism of bone formation involves osteogenesis, osteoinduction, and osteoconduction. Autogenous bone is the most useful graft material because of its osteogenic and osteoinductive features. For large defects caused by tumors or trauma, which are commonly encountered in oral and maxillofacial surgery, xenografting or allografting is required. However, these methods may not be sufficient because they only facilitate osteoconduction. In addition to studies of bone graft material, osteoinductive factors, such as recombinant human bone morphogenetic protein-2 (rhBMP-2), have also been investigated. For new bone formation, bone forming factors and carriers are both important; however, no studies have investigated appropriate carriers for rhBMP-2. Importantly, recent studies have demonstrated the anabolic effects of locally administered bisphosphonate, which affects both osteoclasts and osteoblasts. Thus, in this study, we evaluated the ability of CollaOss (xenogenic bone) and Rapiderm Pad (absorbable collagen sponge) to function as an rhBMP-2 carrier. Furthermore, the osteoinductive ability of bisphosphonate was studied by comparison with rhBMP-2. Thirty-two Sprague-Dawley male rats were divided into two groups to study the bone-forming ability of bisphosphonate and to identify an appropriate carrier for rhBMP-2. Segmental ostectomy of both fibulae (7 mm) was performed, and the defect area was then grafted with xenogenic bone with different bisphosphonate concentrations. Alternatively, the left and right fibulae were treated with absorbable collagen sponges or xenogenic bone with application of rhBMP-2. After 4 or 8 weeks, animals were sacrificed, and radiographic, histological, histomorphometrical, and immunohistochemical analyses were performed. The results showed that higher concentrations of bisphosphonate were associated with greater bone formation than lower concentrations of bisphosphonate. Moreover, rhBMP-2 promoted bone formation, regardless of the carrier; fibula grafted with collagen sponges or xenogenic bone exhibited continuity between the graft material and defect area. Additionally, the newly formed cortical layer was similar in appearance to the original fibula cortex, particularly after 8 weeks. A comparison of high-concentration bisphosphonate and rhBMP-2 revealed that these treatments had similar osteoinductive abilities, with slightly less bone formation observed for bisphosphonate. In conclusion, the locally application of bisphosphonate promoted new bone formation, particularly when used at high concentrations. Absorbable collagen sponges were advantageous in that there was no remaining graft material and that the bone was remodeled to resemble the existing fibula. In order to use these materials as a substitute for original bone, further studies regarding stability and mechanical strength are needed.