P.153bis Treatment of bisphosphonate-associated osteonecrosis of the jaw. Less is more?

Abstract

Calcium phosphate cement (CPC) scaffolds have been widely used as bone graft substitutes, but their clinical application is restricted by the undesirable osteoinductivity and slow degradability. We developed new CPC microspheres loaded with bone morphogenetic protein-2 (BMP-2)-derived peptide P24 (P24/CPC). The BMP2-derived peptide P24 was evenly pasted with CPC microspheres, which maintained the bioactivity of BMP-2. We evaluated the effect of the P24/CPC microspheres on osteogenesis and examined the underlying mechanism in vitro and in vivo. The in vitro studies showed that the bioactivity of P24 was preserved in the P24/CPC microspheres and the P24 release duration lasted up to 39 days. The P24/CPC microspheres with different proportions of P24 (2% and 4%) induced high proliferation of bone marrow stromal cells (BMSCs) and well supported cell adhesion on the sphere surfaces. Furthermore, the cells exhibited higher alkaline phosphatase activity and higher expression of osteogenic-specific genes (OCN and Runx2) in 4% P24/CPC than in the CPC and control groups (P<0.05). Therefore, these findings indicated the enhanced osteoblastic differentiation of BMSCs on P24/CPC microspheres. In vivo osteoinductive studies revealed that the degrees of ectopic osteogenesis in the dorsal muscle pocket of rat were significantly higher in the P24/CPC microspheres than in the CPC microspheres. Finally, the CPC or P24/CPC microspheres were implanted into rabbit femoral condyle defects and P24/CPC serial groups were observed for 4, 8, and 12 weeks. Computed tomography (CT) and histological and histomorphological studies proved that P24/CPC microspheres were biocompatible, bioabsorbable, and osteoinductive. In conclusion, this study demonstrated that P24/CPC microspheres can enhance osteogenesis in vitro and promote bone regeneration in vivo. Furthermore, our results confirmed that BMP2-derived peptide P24 can have a beneficial effect on the bone-generating properties of CPC microspheres, suggesting that P24/CPC microspheres are strong potential bone graft substitutes in bone tissue engineering.