BMP-2/beta-TCP Local Delivery for Bone Regeneration in MRONJ-Like Mouse Model

Medication-related osteonecrosis of the jaw (MRONJ) is a severe pathological condition associated mainly with the long-term administration of bone resorption inhibitors, which are known to induce suppression of osteoclast activity and bone remodeling. Bone Morphogenetic Protein (BMP)-2 is known to be a strong inducer of bone remodeling, by directly regulating osteoblast differentiation and osteoclast activity. This study aimed to evaluate the effects of BMP-2 adsorbed onto beta-tricalcium phosphate (beta-TCP), which is an osteoinductive bioceramic material and allows space retention, on the prevention and treatment of MRONJ in mice. Tooth extraction was performed after 3 weeks of zoledronate (ZA) and cyclophosphamide (CY) administration. For prevention studies, BMP-2/beta-TCP was transplanted immediately after tooth extraction, and the mice were administered ZA and CY for an additional 4 weeks. The results showed that while the tooth extraction socket was mainly filled with a sparse tissue in the control group, bone formation was observed at the apex of the tooth extraction socket and was filled with a dense connective tissue rich in cellular components in the BMP-2/beta-TCP transplanted group. For treatment studies, BMP-2/beta-TCP was transplanted 2 weeks after tooth extraction, and bone formation was followed up for the subsequent 4 weeks under ZA and CY suspension. The results showed that although the tooth extraction socket was mainly filled with soft tissue in the control group, transplantation of BMP-2/beta-TCP could significantly accelerate bone formation, as shown by immunohistochemical analysis for osteopontin, and reduce the bone necrosis in tooth extraction sockets. These data suggest that the combination of BMP-2/beta-TCP could become a suitable therapy for the management of MRONJ

The effect of growth factors for bone augmentation to enable dental implant placement: A systematic review

This systematic review assessed the potential benefits of growth factors for bone augmentation prior to the placement of dental implants in human. A systematic online review of the Medline database, using the PubMed search machine was performed between 1966 and November 2008 by entering the MeSH terms. The primary outcome of the included studies was bone regeneration of localized alveolar ridge defects. The initial search identified 119 papers from the electronic database. This review produced seven eligible papers that reported on bone augmentation with recombinant human Bone Morphogenetic Protein-2 (rhBMP-2), recombinant human Platelet-Derived Growth Factor (rhPDGF) and Plasma-Rich Growth Factor (PRGF). The rhBMP-2 affected local bone augmentation with increasing volume for higher doses. Both rhPDGF and PRGF showed a positive effect in favor of the growth factor. Differing levels and quantity of evidence were noted to be available for the growth factors evaluated, revealing that rhBMP-2, rhPDGF, and PRGF may stimulate local bone augmentation to various conditions. Especially the potential of rhBMP-2 is supportive. However, the confined number of investigators using these techniques and the low number of patient treatments reported in the literature, the generalizability of this approach is limited at this time

Suppression of Bone Necrosis around Tooth Extraction Socket in a MRONJ-like Mouse Model by E-rhBMP-2 Containing Artificial Bone Graft Administration

Medication-related osteonecrosis of the jaw (MRONJ) is related to impaired bone healing conditions in the maxillomandibular bone region as a complication of bisphosphonate intake. Although there are several hypotheses for the onset of MRONJ symptoms, one of the possible causes is the inhibition of bone turnover and blood supply leading to bone necrosis. The optimal treatment strategy for MRONJ has not been established either. BMP-2, a member of the TGF-beta superfamily, is well known for regulating bone remodeling and homeostasis prenatally and postnatally. Therefore, the objectives of this study were to evaluate whether cyclophosphamide/zoledronate (CY/ZA) induces necrosis of the bone surrounding the tooth extraction socket, and to examine the therapeutic potential of BMP-2 in combination with the hard osteoinductive biomaterial, beta-tricalcium phosphate (beta-TCP), in the prevention and treatment of alveolar bone loss around the tooth extraction socket in MRONJ-like mice models. First, CY/ZA was intraperitoneally administered for three weeks, and alveolar bone necrosis was evaluated before and after tooth extraction. Next, the effect of BMP-2/beta-TCP was investigated in both MRONJ-like prevention and treatment models. In the prevention model, CY/ZA was continuously administered for four weeks after BMP-2/beta-TCP transplantation. In the treatment model, CY/ZA administration was suspended after transplantation of BMP-2/beta-TCP. The results showed that CY/ZA induced a significant decrease in the number of empty lacunae, a sign of bone necrosis, in the alveolar bone around the tooth extraction socket after tooth extraction. Histological analysis showed a significant decrease in the necrotic alveolar bone around tooth extraction sockets in the BMP-2/beta-TCP transplantation group compared to the non-transplanted control group in both MRONJ-like prevention and treatment models. However, bone mineral density, determined by micro-CT analysis, was significantly higher in the BMP-2/beta-TCP transplanted group than in the control group in the prevention model only. These results clarified that alveolar bone necrosis around tooth extraction sockets can be induced after surgical intervention under CY/ZA administration. In addition, transplantation of BMP-2/beta-TCP reduced the necrotic alveolar bone around the tooth extraction socket. Therefore, a combination of BMP-2/beta-TCP could be an alternative approach for both prevention and treatment of MRONJ-like symptoms