title: Simvastatin-doped pre-mixed calcium phosphate cement inhibits osteoclast differentiation and resorption.
abstract: Simvastatin, a cholesterol lowering drug, has been shown to have positive effects on fracture healing and bone regeneration based on its dual effect; bone anabolic and anti-resorptive. In this study the focus has been on the anti-resorptive effect of the drug and its impact on the degradation of acidic calcium phosphate cement. The drug was added to the pre-mixed acidic cement in three different doses (0.1, 0.25 and 0.5 mg/g cement) and the release was measured. Furthermore the effect of the loaded cements on osteoclast differentiation and resorption was evaluated by TRAP activity, number of multinucleated cells, gene expression and calcium ion concentration in vitro using murine bone marrow macrophages. The simvastatin did not affect the cell proliferation while it clearly inhibited osteoclastic differentiation at all three doses as shown by TRAP staining, TRAP activity and gene expression. Consistent with these results, simvastatin also impaired resorption of cements by osteoclasts as indicated by reduced calcium ion concentrations. In conclusion, our findings suggest that simvastatin-doped pre-mixed acidic calcium phosphate cement inhibits the osteoclastic mediated resorption of the cement thus slowing down the degradation rate. In addition with simvastatin's bone anabolic effect it makes the cement-drug combination a promising bone graft material, especially useful for sites with compromised bone formation.
authors.affiliation: Department of Engineering Sciences, Division of Applied Materials Science, Uppsala University, 751 21, Uppsala, Sweden. montazerolghaem5@hotmail.com.
authors.forename: M
authors.initials: M
authors.lastname: Montazerolghaem
authors.affiliation: Department of Medical Sciences, Section of Clinical Pharmacology, Uppsala University, 751 85, Uppsala, Sweden.
authors.forename: A
authors.initials: A
authors.lastname: Rasmusson
authors.affiliation: Department of Medical Sciences, Section of Clinical Pharmacology, Uppsala University, 751 85, Uppsala, Sweden.
authors.forename: H
authors.initials: H
authors.lastname: Melhus
authors.affiliation: Department of Engineering Sciences, Division of Applied Materials Science, Uppsala University, 751 21, Uppsala, Sweden.
authors.forename: H
authors.initials: H
authors.lastname: Engqvist
authors.affiliation: Department of Engineering Sciences, Division of Applied Materials Science, Uppsala University, 751 21, Uppsala, Sweden.
authors.forename: M
authors.initials: M
authors.lastname: Karlsson Ott
mesh_terms: D000818:Animals; D001843:Bone Cements / Q000737:chemistry*; D001854:Bone Marrow Cells / Q000187:drug effects* / Q000502:physiology; D001862:Bone Resorption / Q000517:prevention & control; D002118:Calcium / Q000737:chemistry / Q000378:metabolism; D002130:Calcium Phosphates / Q000737:chemistry*; D002454:Cell Differentiation / Q000187:drug effects*; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D065546:Drug Liberation; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000737:chemistry / Q000494:pharmacology; D008422:Materials Testing; D051379:Mice; D010010:Osteoclasts; D020133:Reverse Transcriptase Polymerase Chain Reaction; D019821:Simvastatin / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology*
chemical_list: D001843:Bone Cements; D002130:Calcium Phosphates; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; C020243:calcium phosphate; D019821:Simvastatin; D002118:Calcium