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• It is confirmed for the first time that valproic acid has a harmful effect on the stability of titanium implant under the condition of osteoporosis. • Studies have confirmed that simvastatin can reverse the osseointegration of titanium implants treated with valproic acid in the state of osteoporosis. • It is confirmed that valproic acid can inhibit the proliferation and differentiation of osteoblasts, while simvastatin can reverse the harmful effect of valproic acid on osteoblasts. The present work was aimed to evaluate the effect of valproic acid(VPA), simvastatin (SIM)+VPA on Ti(titanium) rods osseointegration in ovariectomized(OVX) rats and further investigation of the possible mechanism. The MC3T3-E1 cells were co-cultured with VPA, SIM + VPA and induced to osteogenesis, and the cell viability, mineralization ability were observed by MTT and ALP staining, Alizarin Red staining and Western blotting. Twelve weeks after bilateral ovariectomy, all animals were randomly divided into three groups: group OVX and VPA, SIM + VPA, and all the rats received Ti implants and animals belong to group VPA, SIM + VPA received valproic acid(300 mg/kg/day), valproic acid(300 mg/kg/day) plus SIM (25 mg/kg/day), respectively, treatment until death at 12 weeks. Micro-CT, histology, biomechanical testing, bone metabolism index and Reverse transcription-quantitative polymerase chain reaction (RT-qPCR) analysis were used to observe the therapeutic effect and explore the possible mechanism. Results shown that VPA decreased new bone formation around the surface of titanium rods and push-out force other than group OVX. Histology, Micro-CT and biochemical analysis results showed combined application of systemic VPA showed harmful effects than OVX group on bone formation in osteopenic rats, with the worse effects on CTX-1, P1NP and microarchitecture as well as biomechanical parameters by down-regulated gene expression of Runx2, OCN, Smad1, BMP-2 and OPG, while up-regulated RANKL. However, after SIM treatment, the above indicators were significantly improved. The present study suggests that systemic use of VPA may bring harm to the stability of titanium implants in osteoporosis, SIM can reverse the negative effect of VPA on the osseointegration of titanium rods in ovariectomized rats. [ABSTRACT FROM AUTHOR]