Experimental study on the effects of simvastatin in reversing the femoral metaphyseal defects induced by sodium valproate in normal and ovariectomized rats

Abstract

Introduction: Long-term treatment with antiepileptic drugs may cause secondary osteoporosis. The present study investigated the influence of simvastatin (SIM) in reversing the effects of valproate on bone defect healing in normal and ovariectomized (OVX) rats. Methods: Bone defects in femora were established in seven experimental groups of rats: control (vehicle), sodium valproate (SVP; 300 mg/kg/d), SVP plus SIM (25 mg/kg/d), sham control (sham), OVX, OVX SVP and OVX SVP plus SIM. All rats were euthanized at 8 weeks after bone defect creation. Results: Micro-CT, biomechanical and histological evaluations demonstrated lower bone strength and delayed bone healing in the SVP therapy group compared with the SVP plus SIM therapy group. Biochemical and immunohistochemical results showed that osteocalcin (OCN), collagen I (Col I) and procollagen type I N-terminal propeptide (P1NP) levels decreased, tartrate-resistant acid phosphatase type 5 precursor (TRACP-5b) expression increased, and Dickkopf-1 (DKK-1) and receptor activator of nuclear factor-κ B ligand (RANKL) expression were upregulated in the SVP therapy rats compared with the SVP plus SIM therapy group. Bone loss was exacerbated by OVX, but the effect of SIM in ameliorating bone loss was also more marked in the OVX rats. Conclusions: This study indicated lower bone strength and delayed healing of bone defects in rats given SVP therapy, especially the OVX SVP treatment group. In contrast, treatment with SIM was effective in enhancing bone strength and promoting bone defect repair and showed significant influence on promoting osteogenesis and inhibiting osteoclastogenesis.

Keywords

• Antiepileptic drugs
• Simvastatin
• Sodium valproate
• Osteoporosis
• Ovariectomized rats