Localized intermittent delivery of simvastatin hydroxyacid stimulates bone formation in rats.
BACKGROUND
The cholesterol-lowering drug simvastatin promotes bone formation in cell cultures and animal models. In previous studies, devices for the controlled, localized delivery of simvastatin hydroxyacid enhanced osteoblastic activity in vitro. The objective of this investigation was to determine bioactivity of the delivery system in vivo.


METHODS
Devices for sustained or intermittent release of simvastatin hydroxyacid were formed using a blend of cellulose acetate phthalate and a poly(ethylene oxide) and poly(propylene oxide) block copolymer, and they were implanted directly over the calvarium of young male rats. Drug-free devices were used as controls. After 9, 18, or 28 days, specimens were histologically evaluated for new bone formation.


RESULTS
All three groups showed some level of new bone formation, but the extent of osteogenesis depended on the type of implant. Devices delivering simvastatin hydroxyacid were associated with a 77.5% to 133% increase in new woven bone thickness compared to control devices without a drug (P<0.05). Furthermore, intermittent release stimulated a 32.3% greater response in bone thickness and a 74.1% greater bone area than did sustained delivery (P<0.05). Although a minimal thickness of woven bone was formed directly under the device (up to 36 microm), a significantly thicker layer was observed at the periphery (up to 205 microm), implying mechanical and/or chemical effects directly under the implant. The percentage of lamellar bone area for intermittent and sustained release was higher than that for the control group (P<0.05).


CONCLUSIONS
Based on the present results of enhanced bone formation, these devices for the intermittent delivery of simvastatin hydroxyacid merit further attention for localized osteogenesis.
Jeon
Ju Hyeong
JH
Center for Biomedical Engineering, University of Kentucky, Lexington, KY 40506-0070, USA.
Piepgrass
Ward T
WT
Lin
Yi-Ling
YL
Thomas
Mark V
MV
Puleo
David A
DA
D000287:Administration, Topical; D000818:Animals; D002482:Cellulose / Q000031:analogs & derivatives; D003692:Delayed-Action Preparations; D004337:Drug Carriers; D016503:Drug Delivery Systems; D006903:Hydroxymethylglutaryl CoA Reductases / Q000008:administration & dosage*; D019344:Lactic Acid; D008297:Male; D008863:Microspheres; D023421:Models, Animal; D010012:Osteogenesis / Q000187:drug effects*; D011092:Polyethylene Glycols; D011100:Polyglycolic Acid; D000077182:Polylactic Acid-Polyglycolic Acid Copolymer; D051381:Rats; D017207:Rats, Sprague-Dawley; D019821:Simvastatin / Q000008:administration & dosage* / Q000031:analogs & derivatives*; D012886:Skull / Q000187:drug effects / Q000473:pathology; D013997:Time Factors
D003692:Delayed-Action Preparations; D004337:Drug Carriers; C532833:simvastatin hydroxyacid; D000077182:Polylactic Acid-Polyglycolic Acid Copolymer; D011100:Polyglycolic Acid; D019344:Lactic Acid; D011092:Polyethylene Glycols; D002482:Cellulose; C011708:cellulose acetate phthalate; D019821:Simvastatin; D006903:Hydroxymethylglutaryl CoA Reductases