title: Intraosseous Injection of Simvastatin in Poloxamer 407 Hydrogel Improves Pedicle-Screw Fixation in Ovariectomized Minipigs.
abstract: BACKGROUND
  Osteoporosis leads to poor osseointegration and reduces implant stability. Statins have been found to stimulate bone formation, but the bioavailability from oral administration is low. Local application may be more effective at augmenting bone formation and enhancing implant stability. This study was performed to evaluate the efficacy of an intraosseous injection of simvastatin in thermosensitive poloxamer 407 hydrogel to enhance pedicle-screw fixation in calcium-restricted ovariectomized minipigs.
  
  
  METHODS
  Nine mature female Guangxi Bama minipigs underwent bilateral ovariectomy and were fed a calcium-restricted diet for 18 months. Simvastatin (0, 0.5, or 1 mg) in thermosensitive poloxamer 407 hydrogel was injected into the lumbar vertebrae (L4-L6), and titanium alloy pedicle screws were implanted. Bone mineral density (BMD) measurements of the lumbar vertebrae were determined by dual x-ray absorptiometry (DXA) before and 3 months after treatment. The lumbar vertebrae were harvested and analyzed with use of microcomputed tomography, biomechanical pull-out testing, histological analysis, and Western blot analysis for bone morphogenetic protein (BMP)-2 and vascular endothelial growth factor (VEGF) expression.
  
  
  RESULTS
  Evaluation over a 3-month study period demonstrated that the BMD of the vertebrae injected with 0.5 and 1.0 mg of simvastatin had increased by 31.25% and 31.09%, respectively, compared with vehicle-only injection (p ≤ 0.00014 for both) and increased by 32.12% and 28.16%, respectively, compared with the pre-treatment levels (p < 0.0001 for both). A single injection of simvastatin in poloxamer 407 increased trabecular volume fraction, thickness, and number and decreased trabecular separation (p ≤ 0.002). The bone formation and mineral apposition rates significantly increased (p ≤ 0.023). The percentage of osseointegration in the simvastatin 0.5 and 1-mg groups was 46.54% and 42.63% greater, respectively, than that in the vehicle-only group (p ≤ 0.006), and the maximum pull-out strength was 45.75% and 51.53% greater, respectively, than in the vehicle-only group (p ≤ 0.0005). BMP-2 and VEGF expressions were higher than for the vehicle-only injection.
  
  
  CONCLUSIONS
  A single intraosseous injection of simvastatin in thermosensitive poloxamer 407 hydrogel stimulated bone formation, increased BMD, improved bone microstructure, promoted osseointegration, and significantly enhanced the stability of pedicle screws in calcium-restricted ovariectomized minipigs.
  
  
  CONCLUSIONS
  These results provide rationale for evaluating intraosseous injection of simvastatin in poloxamer 407 to enhance implant fixation in patients with osteoporosis.
authors.affiliation: Departments of Orthopedics (X.F., J.T., C.G.S., H.J.L., and C.L.S.) and Neurology (Y.S.X.), Peking University Third Hospital, Beijing, People's Republic of China.
authors.forename: X
authors.initials: X
authors.lastname: Fu
authors.affiliation: Departments of Orthopedics (X.F., J.T., C.G.S., H.J.L., and C.L.S.) and Neurology (Y.S.X.), Peking University Third Hospital, Beijing, People's Republic of China.
authors.forename: J
authors.initials: J
authors.lastname: Tan
authors.affiliation: Departments of Orthopedics (X.F., J.T., C.G.S., H.J.L., and C.L.S.) and Neurology (Y.S.X.), Peking University Third Hospital, Beijing, People's Republic of China.|Beijing Key Laboratory of Spinal Diseases, Beijing, People's Republic of China.
authors.forename: C G
authors.initials: CG
authors.lastname: Sun
authors.affiliation: Departments of Orthopedics (X.F., J.T., C.G.S., H.J.L., and C.L.S.) and Neurology (Y.S.X.), Peking University Third Hospital, Beijing, People's Republic of China.|Beijing Key Laboratory of Spinal Diseases, Beijing, People's Republic of China.
authors.forename: H J
authors.initials: HJ
authors.lastname: Leng
authors.affiliation: Departments of Orthopedics (X.F., J.T., C.G.S., H.J.L., and C.L.S.) and Neurology (Y.S.X.), Peking University Third Hospital, Beijing, People's Republic of China.
authors.forename: Y S
authors.initials: YS
authors.lastname: Xu
authors.affiliation: Departments of Orthopedics (X.F., J.T., C.G.S., H.J.L., and C.L.S.) and Neurology (Y.S.X.), Peking University Third Hospital, Beijing, People's Republic of China schl@bjmu.edu.cn.|Beijing Key Laboratory of Spinal Diseases, Beijing, People's Republic of China.
authors.forename: C L
authors.initials: CL
authors.lastname: Song
mesh_terms: D000818:Animals; D015519:Bone Density / Q000502:physiology*; D055396:Bone Morphogenetic Protein 2 / Q000378:metabolism; D005260:Female; D020100:Hydrogels / Q000627:therapeutic use*; D008159:Lumbar Vertebrae / Q000000981:diagnostic imaging / Q000378:metabolism / Q000601:surgery*; D019637:Orthopedic Procedures / Q000379:methods*; D010052:Ovariectomy; D065289:Pedicle Screws; D020442:Poloxamer / Q000627:therapeutic use*; D019821:Simvastatin / Q000627:therapeutic use*; D013552:Swine; D013556:Swine, Miniature; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism
chemical_list: D055396:Bone Morphogenetic Protein 2; D020100:Hydrogels; D042461:Vascular Endothelial Growth Factor A; D020442:Poloxamer; D019821:Simvastatin