Effects of the combination with alpha-tricalcium phosphate and simvastatin on bone regeneration.
BACKGROUND
Although local application of statins stimulates bone formation, high dose of simvastatin induces inflammation.


OBJECTIVE
A study was conducted to test the hypothesis that maximum bone regeneration with less inflammation would be achieved by combining an optimal dose of simvastatin with alpha-tricalcium phosphate (alpha-TCP), which is an osteoconductive biomaterial capable of releasing the drug gradually.


METHODS
Bilateral 5-mm-diameter calvarial defects were created in adult Wistar rats and filled with preparations of different doses of simvastatin (0, 0.01, 0.1, 0.25 and 0.5 mg) combined with alpha-TCP particles or left empty. The animals were sacrificed at 2, 4 and 8 weeks and analyzed radiologically and histologically. Half of the animals of 4 and 8 weeks were labeled with fluorescence dyes and histomorphometrically analyzed.


RESULTS
Simvastatin doses of 0.25 and 0.5 mg caused inflammation of the soft tissue at the graft site whereas control and other doses did not. The micro-CT analysis revealed that the alpha-TCP with 0.1 mg simvastatin (TCP-0.1) group yielded significantly higher bone volumes than untreated control group at all three time points (249%, 227% and 266% at 2, 4 and 8 weeks, respectively). The percentage of defect closure, bone mineral content and bone mineral density were also higher in the TCP-0.1 group than in the other groups.


CONCLUSIONS
When combined with alpha-TCP particles, 0.1 mg simvastatin is the optimal dose for stimulation of the maximum bone regeneration in rat calvarial defects without inducing inflammation and it could be applied as an effective bone graft material.
Nyan
Myat
M
Oral Implantology and Regenerative Dental Medicine, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyo-ku, Tokyo 113-8549, Japan. myatnyan@gmail.com
Sato
Daisuke
D
Kihara
Hidemichi
H
Machida
Tetsu
T
Ohya
Keiichi
K
Kasugai
Shohei
S
D000704:Analysis of Variance; D000818:Animals; D000924:Anticholesteremic Agents / Q000494:pharmacology*; D001672:Biocompatible Materials / Q000494:pharmacology*; D001861:Bone Regeneration / Q000187:drug effects*; D002130:Calcium Phosphates / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D004337:Drug Carriers / Q000494:pharmacology; D004338:Drug Combinations; D010012:Osteogenesis / Q000187:drug effects; D051381:Rats; D017208:Rats, Wistar; D019821:Simvastatin / Q000494:pharmacology*; D012886:Skull / Q000187:drug effects / Q000601:surgery
D000924:Anticholesteremic Agents; D001672:Biocompatible Materials; D002130:Calcium Phosphates; D004337:Drug Carriers; D004338:Drug Combinations; C485828:alpha-tricalcium phosphate; D019821:Simvastatin