Subcutaneous administration of lactone form of simvastatin stimulates ectopic osteoinduction by rhBMP-2.
OBJECTIVE
To evaluate the effects of various 3-hydroxy-3-methylglutaryl-coenzyme A reductase inhibitors (statins) on ectopic osteoinduction by recombinant human bone morphogenetic protein-2 (rhBMP-2) using different administration methods.


METHODS
Disks containing 5 mug of rhBMP-2 and type I collagen were implanted into the calf muscles of 6-week-old male rats (n = 64). Either the lactone form of simvastatin (SV), open hydroxy-acid form of simvastatin (SVA), cerivastatin (CVA), or vehicle (control) was then administered per orally (PO group) or subcutaneously (SC group) for 20 days. The disks were removed on day 21 after implantation, and ectopic induced bone formation was evaluated by radiographic, histologic, and biochemical analysis.


RESULTS
Both the projected and radiopaque area on X-ray film, and the calcium content of the SV group in the SC group (SV-SC group) were significantly greater than those in the other SC and PO groups. Alkaline phosphatase activity and tartrate-resistant acid phosphatase activity in the SV-SC group were significantly lower than those in the other SC and PO groups. Histologic examination revealed an increase of ectopic induced bone volume in the SV-SC group.


CONCLUSIONS
Subcutaneous administration of SV stimulates ectopic osteoinduction by rhBMP-2 through reduction of bone turnover.
Sugiyama
T
T
Division of Oral and Maxillofacial Surgery, Mie University Graduate School of Medicine, 2-174 Edobashi, Tsu, Mie 514-8507, Japan. takeou@clin.medic.mie-u.ac.jp
Nakagawa
T
T
Sato
C
C
Fujii
T
T
Mine
K
K
Shimizu
K
K
Murata
T
T
Tagawa
T
T
D000135:Acid Phosphatase / Q000032:analysis; D000284:Administration, Oral; D000469:Alkaline Phosphatase / Q000032:analysis; D000818:Animals; D000924:Anticholesteremic Agents / Q000494:pharmacology*; D055396:Bone Morphogenetic Protein 2; D019485:Bone Morphogenetic Proteins / Q000494:pharmacology*; D002118:Calcium / Q000032:analysis; D024042:Collagen Type I / Q000494:pharmacology; D006801:Humans; D006880:Hydroxy Acids; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology*; D007279:Injections, Subcutaneous; D007527:Isoenzymes / Q000032:analysis; D007783:Lactones; D008297:Male; D018482:Muscle, Skeletal / Q000000981:diagnostic imaging / Q000187:drug effects / Q000473:pathology; D009999:Ossification, Heterotopic / Q000139:chemically induced* / Q000000981:diagnostic imaging / Q000473:pathology; D014677:Pharmaceutical Vehicles; D011725:Pyridines / Q000494:pharmacology; D011859:Radiography; D051381:Rats; D017208:Rats, Wistar; D011994:Recombinant Proteins / Q000494:pharmacology*; D019821:Simvastatin / Q000494:pharmacology*; D013237:Stereoisomerism; D000071681:Tartrate-Resistant Acid Phosphatase; D016212:Transforming Growth Factor beta / Q000494:pharmacology*
D000924:Anticholesteremic Agents; D055396:Bone Morphogenetic Protein 2; D019485:Bone Morphogenetic Proteins; D024042:Collagen Type I; D006880:Hydroxy Acids; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D007527:Isoenzymes; D007783:Lactones; D014677:Pharmaceutical Vehicles; D011725:Pyridines; D011994:Recombinant Proteins; D016212:Transforming Growth Factor beta; C499469:recombinant human bone morphogenetic protein-2; D019821:Simvastatin; C086276:cerivastatin; D000469:Alkaline Phosphatase; D000135:Acid Phosphatase; D000071681:Tartrate-Resistant Acid Phosphatase; D002118:Calcium