title: Effects of local simvastatin-alendronate conjugate in preventing periodontitis bone loss.
abstract: OBJECTIVE
  Local host-modulation therapy is an emerging approach to prevent disease progression in sites with moderate periodontitis. The combination of simvastatin and alendronate would be an intriguing host-modulatory strategy because of the bone-anabolic properties of simvastatin and the antiresorptive/bone-targeting characteristics of alendronate. The objective of this study was to evaluate the effects of local administration of a simvastatin-alendronate-β-cyclodextrin (SIM-ALN-CD) conjugate for preventing experimental periodontitis bone loss.
  
  
  METHODS
  Twenty-four mature female Sprague-Dawley rats were treated with three, 12 μL injections, administered one week apart, bilaterally into the palatal/interproximal gingiva. The injections contained: (i) a conjugate of 0.5 mg of SIM and 3.75 mg of ALN-CD in H2 O; (ii) H2 O alone; or (iii) no treatment. One week later, the same sites were subjected to induction of experimental periodontitis by three injections (i.e. one injection administered every other day for five d) of 0.01 mg of Escherichia coli endotoxin [lipopolysaccharide (LPS)] in phosphate-buffered saline (PBS) or PBS alone. After an additional week, the rats were killed, the palates were harvested and interproximal bone volume and adjacent thickness were calculated using microcomputed tomography. Subsequently, specimens were decalcified, and interproximal histologic sections were stained with hematoxylin and eosin for evaluation of alveolar crest osteoclasts and surrounding inflammation. Values were compared among treatment groups using analysis of variance and the Kruskal-Wallis test.
  
  
  RESULTS
  Interproximal bone volume was reduced by LPS injections (p ≤ 0.04), yet when experimental periodontitis was preceded by treatment with SIM-ALN-CD, more bone was preserved than after treatment with carrier alone (p = 0.007). While LPS caused a significant loss in bone thickness over the palatal roots (p ≤ 0.04), the injection protocol (PBS) also caused a significant loss of palatal bone thickness (p ≤ 0.03). However, prophylactic SIM-ALN-CD injections resulted in no further loss of bone thickness during experimental periodontitis. LPS injections gave histologic evidence of increased osteoclasts and subsulcular inflammation, both of which were reduced when preceded by treatment with SIM-ALN-CD (p ≤ 0.0002).
  
  
  CONCLUSIONS
  The primary conclusion of this study was that locally applied SIM-ALN-CD has the potential to prevent episodes of periodontitis bone loss.
authors.affiliation: Department of Surgical Specialties, University of Nebraska Medical Center, College of Dentistry, Lincoln, NE, USA.
authors.forename: U
authors.initials: U
authors.lastname: Price
authors.forename: H-O T
authors.initials: HO
authors.lastname: Le
authors.forename: S E
authors.initials: SE
authors.lastname: Powell
authors.forename: M J
authors.initials: MJ
authors.lastname: Schmid
authors.forename: D B
authors.initials: DB
authors.lastname: Marx
authors.forename: Y
authors.initials: Y
authors.lastname: Zhang
authors.forename: D
authors.initials: D
authors.lastname: Wang
authors.forename: N
authors.initials: N
authors.lastname: Narayana
authors.forename: R A
authors.initials: RA
authors.lastname: Reinhardt
mesh_terms: D019386:Alendronate / Q000008:administration & dosage*; D016301:Alveolar Bone Loss / Q000382:microbiology / Q000517:prevention & control*; D000818:Animals; D050071:Bone Density Conservation Agents / Q000008:administration & dosage*; D004338:Drug Combinations; D004731:Endotoxins / Q000494:pharmacology; D004926:Escherichia coli; D005260:Female; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000008:administration & dosage*; D021621:Imaging, Three-Dimensional / Q000379:methods; D007267:Injections; D008070:Lipopolysaccharides / Q000494:pharmacology; D008439:Maxillary Diseases / Q000382:microbiology / Q000517:prevention & control; D008963:Molar / Q000382:microbiology / Q000473:pathology; D010010:Osteoclasts / Q000187:drug effects / Q000473:pathology; D010159:Palate / Q000382:microbiology / Q000473:pathology; D010518:Periodontitis / Q000382:microbiology / Q000517:prevention & control*; D011292:Premedication; D051381:Rats; D017207:Rats, Sprague-Dawley; D064449:Sequestering Agents / Q000008:administration & dosage; D019821:Simvastatin / Q000008:administration & dosage*; D055114:X-Ray Microtomography / Q000379:methods; D047392:beta-Cyclodextrins / Q000008:administration & dosage
chemical_list: D050071:Bone Density Conservation Agents; D004338:Drug Combinations; D004731:Endotoxins; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D008070:Lipopolysaccharides; D064449:Sequestering Agents; D047392:beta-Cyclodextrins; D019821:Simvastatin; C031215:betadex; D019386:Alendronate
keywords: bisphosphonate; bone; periodontitis; statin