Local simvastatin effects on mandibular bone growth and inflammation.
BACKGROUND
Simvastatin has been shown to increase bone growth when applied topically to murine bone; however, it causes considerable soft tissue inflammation at high doses (2.2 mg), making future clinical use problematic. This study evaluated the effect of lower simvastatin doses and cyclooxygenase (COX) synthase inhibitors on tissue inflammation and bone growth in rats and gene expression in mice.


METHODS
Adult female rats were untreated or treated with a single dose of 0.1, 0.5, 1.0, 1.5, or 2.2 mg simvastatin in methylcellulose gel in a polylactic acid membrane (SIM) on the lateral aspect of the mandible. The contralateral mandible side was implanted with methylcellulose gel/polylactic acid membrane alone (GEL), and five rats in each dose pairing were evaluated histomorphometrically after 3, 7, and 24 days. Subsequent rats were similarly treated with 0.5 mg simvastatin (optimal dose) and daily intraperitoneal injections of COX-2 inhibitor (NS-398; 1 mg/kg x 7 days; N = 16), general COX inhibitor (indomethacin; 1 mg/kg x 7 days; N = 16), or no inhibitor (N = 10) and evaluated histomorphometrically after 7 or 24 days by analysis of variance (ANOVA). Gene arrays were also used to evaluate osteogenic gene expression from 0.5 mg simvastatin in murine calvaria (N = 12).


RESULTS
There was a 45% increase in bone area with 0.5 mg simvastatin versus gel control (P <0.001; similar to the 2.2-mg dose), and clinical swelling was reduced compared to the high simvastatin dose (P <0.05). The 0.1-mg simvastatin dose failed to stimulate significant bone growth. NS-398 and indomethacin reduced inflammation and bone growth. Simvastatin significantly upregulated procollagen, fibronectin, and matrix metalloproteinase-13 genes.


CONCLUSIONS
Reducing the simvastatin dose from 2.2 to 0.5 mg reduced inflammation to a more clinically acceptable level without sacrificing bone-growth potential, but COX-associated inflammation appears to be necessary for in vivo bone growth.
Stein
David
D
Department of Surgical Specialties, College of Dentistry, University of Nebraska Medical Center, Lincoln, NE 68583-0740, USA.
Lee
Yeonju
Y
Schmid
Marian J
MJ
Killpack
Byron
B
Genrich
Mikala A
MA
Narayana
Nagamani
N
Marx
David B
DB
Cullen
Diane M
DM
Reinhardt
Richard A
RA
D000818:Animals; D017364:Collagenases / Q000187:drug effects; D052246:Cyclooxygenase 2 Inhibitors / Q000494:pharmacology; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology; D005260:Female; D005353:Fibronectins / Q000187:drug effects; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000008:administration & dosage / Q000494:pharmacology*; D007213:Indomethacin / Q000494:pharmacology; D018836:Inflammation Mediators / Q000008:administration & dosage / Q000494:pharmacology*; D019344:Lactic Acid; D008334:Mandible / Q000187:drug effects* / Q000254:growth & development; D053509:Matrix Metalloproteinase 13; D008567:Membranes, Artificial; D008747:Methylcellulose; D051379:Mice; D009578:Nitrobenzenes / Q000494:pharmacology; D010012:Osteogenesis / Q000187:drug effects; D014677:Pharmaceutical Vehicles; D011091:Polyesters; D011108:Polymers; D011347:Procollagen / Q000187:drug effects; D051381:Rats; D019821:Simvastatin / Q000008:administration & dosage / Q000494:pharmacology*; D012886:Skull / Q000187:drug effects; D013449:Sulfonamides / Q000494:pharmacology; D015854:Up-Regulation
D052246:Cyclooxygenase 2 Inhibitors; D016861:Cyclooxygenase Inhibitors; D005353:Fibronectins; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D018836:Inflammation Mediators; D008567:Membranes, Artificial; D009578:Nitrobenzenes; D014677:Pharmaceutical Vehicles; D011091:Polyesters; D011108:Polymers; D011347:Procollagen; D013449:Sulfonamides; C080955:N-(2-cyclohexyloxy-4-nitrophenyl)methanesulfonamide; D019344:Lactic Acid; C033616:poly(lactide); D008747:Methylcellulose; D019821:Simvastatin; D017364:Collagenases; D053509:Matrix Metalloproteinase 13; C507081:Mmp13 protein, mouse; C507083:Mmp13 protein, rat; D007213:Indomethacin