title: Single-dose local simvastatin injection improves implant fixation via increased angiogenesis and bone formation in an ovariectomized rat model.
abstract: BACKGROUND
  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.
  
  
  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.
authors.affiliation: Department of Orthopaedic, Peking University Third Hospital, Beijing, China (mainland).
authors.forename: Jie
authors.initials: J
authors.lastname: Tan
authors.affiliation: Department of Orthopaedic, Peking University Third Hospital, Beijing, China (mainland).
authors.forename: Ning
authors.initials: N
authors.lastname: Yang
authors.affiliation: Department of Orthopaedic, Peking University Third Hospital, Beijing, China (mainland).
authors.forename: Xin
authors.initials: X
authors.lastname: Fu
authors.affiliation: Department of Orthopaedic, Peking University Third Hospital, Beijing, China (mainland).
authors.forename: Yueyi
authors.initials: Y
authors.lastname: Cui
authors.affiliation: Department of Neurology, Peking University Third Hospital, Beijing, China (mainland).
authors.forename: Qi
authors.initials: Q
authors.lastname: Guo
authors.affiliation: Department of Orthopaedic, Peking University Third Hospital, Beijing, China (mainland).
authors.forename: Teng
authors.initials: T
authors.lastname: Ma
authors.affiliation: Department of Orthopaedic, Peking University Third Hospital, Beijing, China (mainland).
authors.forename: Xiaoxue
authors.initials: X
authors.lastname: Yin
authors.affiliation: Department of Orthopaedic, Peking University Third Hospital, Beijing, China (mainland).
authors.forename: Huijie
authors.initials: H
authors.lastname: Leng
authors.affiliation: Department of Orthopaedic, Peking University Third Hospital, Beijing, China (mainland).
authors.forename: Chunli
authors.initials: C
authors.lastname: Song
mesh_terms: D015502:Absorptiometry, Photon; D000818:Animals; D001808:Blood Vessels / Q000187:drug effects / Q000648:ultrastructure; D015519:Bone Density / Q000187:drug effects*; D055396:Bone Morphogenetic Protein 2 / Q000096:biosynthesis; D001863:Bone Screws; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004353:Drug Evaluation, Preclinical; D005260:Female; D005269:Femur / Q000098:blood supply / Q000601:surgery; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D015552:Injections, Intralesional; D018919:Neovascularization, Physiologic / Q000187:drug effects*; D016348:Osseointegration / Q000187:drug effects*; D010012:Osteogenesis / Q000187:drug effects*; D015663:Osteoporosis, Postmenopausal / Q000188:drug therapy* / Q000503:physiopathology; D010052:Ovariectomy / Q000009:adverse effects; D019408:Platelet Endothelial Cell Adhesion Molecule-1 / Q000096:biosynthesis; D051381:Rats; D017207:Rats, Sprague-Dawley; D019821:Simvastatin / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D042461:Vascular Endothelial Growth Factor A / Q000096:biosynthesis; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000096:biosynthesis / Q000235:genetics; D014841:von Willebrand Factor / Q000096:biosynthesis
chemical_list: C525720:Bmp2 protein, rat; D055396:Bone Morphogenetic Protein 2; D019408:Platelet Endothelial Cell Adhesion Molecule-1; D042461:Vascular Endothelial Growth Factor A; C467498:vascular endothelial growth factor A, rat; D014841:von Willebrand Factor; D019821:Simvastatin; D040301:Vascular Endothelial Growth Factor Receptor-2