Parathyroid hormone (1–34) can reverse the negative effect of valproic acid on the osseointegration of titanium rods in ovariectomized rats

Objective The present work was aimed to evaluate the effect of valproic acid (VPA)，Parathyroid hormone (1–34) (PTH)+VPA on Ti rods osseointegration in ovariectomized rats and further investigation of the possible mechanism. Methods The MC3T3-E1 cells were co-cultured with VPA，PTH ​+ ​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 four groups: group OVX and VPA，PTH ​+ ​VPA, and all the rats received Ti implants and animals belong to group VPA，PTH ​+ ​VPA received valproic acid (300 ​mg/day), valproic acid (300 ​mg/day) plus Parathyroid hormone (1–34) every 3 days (60 ​μg/kg), 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 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 osteopenia 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 PTH treatment, the above indicators were significantly improved. Conclusions The present study suggests that systemic use of VPA may bring harm to the stability of titanium implants in osteoporosis, PTH can reverse the negative effect of VPA on the osseointegration of titanium rods in ovariectomized rats. Translational potential of this article According to our research, when patients with epilepsy have osteoporotic fractures, after joint replacement or internal fixation, continue to use sodium valproate for anti-epileptic therapy, the possibility of postoperative loosening increases, again on the basis of It can be reversed with the anti-osteoporosis drug parathyroid hormone (1-34).