Single-Dose Local Simvastatin Injection Improves Implant Fixation via Increased Angiogenesis and Bone Formation in an Ovariectomized Rat Model
Jie Tan, Ning Yang, Xin Fu, Yueyi Cui, Qi Guo, Teng Ma, Xiaoxue Yin, Huijie Leng, Chunli Song
Department of Orthopaedic, Peking University Third Hospital, Beijing, China (mainland)
Med Sci Monit 2015; 21:1428-1439
Statins have been reported to promote bone formation. However, taken orally, their bioavailability is low to the bones. Implant therapies require a local repair response, topical application of osteoinductive agents, or biomaterials that promote implant fixation.
Material and Methods: The present study evaluated the effect of a single local injection of simvastatin on screw fixation in an ovariectomized rat model of osteoporosis.
Results: Dual-energy X-ray absorptiometry, micro-computed tomography, histology, and biomechanical tests revealed that 5 and 10 mg simvastatin significantly improved bone mineral density by 18.2% and 22.4%, respectively (P<0.05); increased bone volume fraction by 51.0% and 57.9%, trabecular thickness by 16.4% and 18.9%, trabeculae number by 112.0% and 107.1%, and percentage of osseointegration by 115.7% and 126.3%; and decreased trabeculae separation by 34.1% and 36.6%, respectively (all P<0.01). Bone mineral apposition rate was significantly increased (P<0.01). Furthermore, implant fixation was significantly increased (P<0.05), and bone morphogenetic protein 2 (BMP2) expression was markedly increased. Local injection of a single dose of simvastatin also promoted angiogenesis. Vessel number, volume, thickness, surface area, and vascular volume per tissue volume were significantly increased (all P<0.01). Vascular endothelial growth factor (VEGF), VEGF receptor-2, von Willebrand factor, and platelet endothelial cell adhesion molecule-1 expression were enhanced.
Conclusions: A single local injection of simvastatin significantly increased bone formation, promoted osseointegration, and enhanced implant fixation in ovariectomized rats. The underlying mechanism appears to involve enhanced BMP2 expression and angiogenesis in the target bone.
Keywords: Animals, Absorptiometry, Photon, Antigens, CD31 - biosynthesis, Blood Vessels - ultrastructure, Bone Density - drug effects, Bone Morphogenetic Protein 2 - biosynthesis, Bone Screws, Disease Models, Animal, Dose-Response Relationship, Drug, Drug Evaluation, Preclinical, Femur - surgery, Gene Expression Regulation - drug effects, Injections, Intralesional, Neovascularization, Physiologic - drug effects, Osseointegration - drug effects, Osteogenesis - drug effects, Osteoporosis, Postmenopausal - physiopathology, Ovariectomy - adverse effects, Rats, Rats, Sprague-Dawley, Simvastatin - therapeutic use, Vascular Endothelial Growth Factor A - biosynthesis, Vascular Endothelial Growth Factor Receptor-2 - genetics, von Willebrand Factor - biosynthesis