Effects of local simvastatin-alendronate conjugate in preventing periodontitis bone loss

U. Price, H. O T Le, S. E. Powell, M. J. Schmid, D. B. Marx, Y. Zhang, Dong Wang, Nagamani Narayana, Richard A Reinhardt

Research output: Contribution to journalArticle

22 Citations (Scopus)

Abstract

Background and 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. Material and 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 H2O; (ii) H2O 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). Conclusion: The primary conclusion of this study was that locally applied SIM-ALN-CD has the potential to prevent episodes of periodontitis bone loss.

Original languageEnglish (US)
Pages (from-to)541-548
Number of pages8
JournalJournal of Periodontal Research
Volume48
Issue number5
DOIs
StatePublished - Oct 1 2013

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Alendronate
Simvastatin
Periodontitis
Bone and Bones
Cyclodextrins
Injections
Lipopolysaccharides
Phosphates
Osteoclasts
Therapeutics
Inflammation
X-Ray Microtomography
Palate
Gingiva
Hematoxylin
Eosine Yellowish-(YS)
Sprague Dawley Rats
Disease Progression
Analysis of Variance

Keywords

  • Bisphosphonate
  • Bone
  • Periodontitis
  • Statin

ASJC Scopus subject areas

  • Periodontics

Cite this

Effects of local simvastatin-alendronate conjugate in preventing periodontitis bone loss. / Price, U.; Le, H. O T; Powell, S. E.; Schmid, M. J.; Marx, D. B.; Zhang, Y.; Wang, Dong; Narayana, Nagamani; Reinhardt, Richard A.

In: Journal of Periodontal Research, Vol. 48, No. 5, 01.10.2013, p. 541-548.

Research output: Contribution to journalArticle

Price, U. ; Le, H. O T ; Powell, S. E. ; Schmid, M. J. ; Marx, D. B. ; Zhang, Y. ; Wang, Dong ; Narayana, Nagamani ; Reinhardt, Richard A. / Effects of local simvastatin-alendronate conjugate in preventing periodontitis bone loss. In: Journal of Periodontal Research. 2013 ; Vol. 48, No. 5. pp. 541-548.
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AU - Price, U.

AU - Le, H. O T

AU - Powell, S. E.

AU - Schmid, M. J.

AU - Marx, D. B.

AU - Zhang, Y.

AU - Wang, Dong

AU - Narayana, Nagamani

AU - Reinhardt, Richard A

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N2 - Background and 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. Material and 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 H2O; (ii) H2O 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). Conclusion: The primary conclusion of this study was that locally applied SIM-ALN-CD has the potential to prevent episodes of periodontitis bone loss.

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KW - Bisphosphonate

KW - Bone

KW - Periodontitis

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