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Recently, more and more studies have shown that guanylate cyclase, an enzyme that synthesizes cyclic guanosine monophosphate (cGMP), plays an important role in bone metabolism. Vericiguat (VIT), a novel oral soluble guanylate cyclase stimulator, directly generates cyclic guanosine monophosphate and reduce the death incidence from cardio-vascular causes or hospitalization. Recent studies have shown beneficial effects of VIT in animal models of osteoporosis, but very little is currently known about the effects of VIT on bone defects in the osteoporotic states. Therefore, in this study, β-tricalcium phosphate (β-TCP) was used as a carrier to explore the effect of local VIT administration on the repair of femoral metaphyseal bone defects in ovariectomized (OVX) rats. When MC3T3-E1 was cultured in the presence of H2H2, VIT, similar to Melatonin (MT), therapy could increase the matrix mineralization and ALP, SOD2, SIRT1, and OPG expression, reduce ROS and Mito SOX production, RANKL expression, Promote the recovery of mitochondrial membrane potential. In the OVX rat model, VIT increases the osteogenic effect of β-TCP and better results were obtained at a dose of 5 mg. Local use of VIT can inhibit increased OC, BMP2 and RUNX2 expressions in bone tissue, while decreased SOST and TRAP expressions by RT-PCR and immunohistochemistry. Thereby, VIT stimulates bone regeneration and is a promising candidate for promoting bone repair in osteoporosis. [ABSTRACT FROM AUTHOR]

Probucol (PBC) is a potent cholesterol-lowering drug and has been studied extensively for its powerful antioxidative stress. The purpose of this study is to investigate the role of PBC in ovariectomized rat model and to explore the mechanism of osteogenic differentiation of MC3TE-E1 Cells. RT-qPCR and Immunofluorescence were used to measure the expression level of SOD2, SIRT1, intracellular oxidative stress levels and osteogenic markers proteins. Moreover, CCK-8 assay was conducted to detect cell viability. Alizarin red staining and alkaline phosphatase staining were applied to examine osteogenic function and calcium deposits. The ovariectomized rat model was set up successfully and HE staining were employed to examine femoral trabeculae tissue. Our results showed that PBC suppressed MC3TE-E1 resist oxidative stress to promote osteogenic differentiation. Additionally, it was confirmed that PBC promoted osteogenic differentiation of MC3TE-E1 through inhibiting oxidative stress. Further study indicated that PBC exerted its beneficial function by suppressing oxidative stress-mediated alter bone metabolism to alleviate osteoporosis in vivo. Our research suggested that the PBC-modulated oxidative stress inhibition is responsible for activation of the process of osteogenic differentiation, providing a novel insight into the treatment of osteoporosis. [ABSTRACT FROM AUTHOR]

• There fewer studies that have compared the impact of Cyclosporine A treatment on bone regeneration in osteoporotic condition. • The present study investigate the impact of CSA on bone mass and bone repair, revealing its detrimental effects on both aspects. • Overall, our experiments confirmed that CSA enhances osteogenic proliferation and differentiation while simultaneously accelerating bone resorption. Cyclosporine A (CSA) is an immunosuppressant that has been extensively studied for its side effects on inhibiting osseointegration of titanium implants. However, the impact of CSA on bone healing in postmenopausal osteoporosis remains unknown. Therefore, this study aimed to investigate the effect of CSA on bone repair in an ovariectomized (OVX) rat model through both in vitro and in vivo experiments. We examined the interventions of CSA on osteoblast progenitor cells MC3T3-E1 and assessed their effects on biological function using RT-qPCR, CCK-8 assay, alizarin red staining, and alkaline phosphatase staining. Furthermore, we evaluated the effects of CSA on bone regeneration and bone mass in both OVX rat models and femoral diaphysis bone defect models. The results from the CCK-8 experiment indicated a positive influence of experimental doses of CSA on osteogenic differentiation of MC3T3-E1 cells. ALP expression levels and calcified nodules were also evaluated, suggesting that CSA intervention promoted osteogenic differentiation in MC3T3-E1 cells. Additionally, specific gene expressions including OPN, Runx-2, OC, and Col1a1 were up-regulated after CSA intervention. Biomechanical parameters aligned with histological analysis as well as micro-CT scans confirmed worse bone microstructure and strength following CSA intervention. Our findings preliminarily suggest that whether it is normal or osteoporotic bones, CSA has adverse effects on bone health which are associated with elevated-bone turnover. [ABSTRACT FROM AUTHOR]

Probucol (PBC) is a potent cholesterol-lowering drug and has been studied extensively for its powerful antioxidative stress. The purpose of this study is to investigate the role of PBC in ovariectomized rat model and to explore the mechanism of osteogenic differentiation of MC3TE-E1 Cells. RT-qPCR and Immunofluorescence were used to measure the expression level of SOD2, SIRT1, intracellular oxidative stress levels and osteogenic markers proteins. Moreover, CCK-8 assay was conducted to detect cell viability. Alizarin red staining and alkaline phosphatase staining were applied to examine osteogenic function and calcium deposits. The ovariectomized rat model was set up successfully and HE staining were employed to examine femoral trabeculae tissue. Our results showed that PBC suppressed MC3TE-E1 resist oxidative stress to promote osteogenic differentiation. Additionally, it was confirmed that PBC promoted osteogenic differentiation of MC3TE-E1 through inhibiting oxidative stress. Further study indicated that PBC exerted its beneficial function by suppressing oxidative stress-mediated alter bone metabolism to alleviate osteoporosis in vivo. Our research suggested that the PBC-modulated oxidative stress inhibition is responsible for activation of the process of osteogenic differentiation, providing a novel insight into the treatment of osteoporosis. [ABSTRACT FROM AUTHOR]

Objective: The purpose is to observe whether local administration with selenium (Se) can enhance the efficacy of calcium phosphate cement (CPC) in the treatment of osteoporotic bone defects. Methods: Thirty ovariectomized (OVX) rats with two defects were generated and randomly allocated into the following graft study groups: (1) OVX group (n = 10), (2) CPC group (n = 10); and (3) Se-CPC group (n = 10). Then, these selenium-modified calcium phosphate cement (Se-CPC) scaffolds were implanted into the femoral epiphysis bone defect model of OVX rats for 12 weeks. Micro-CT, history, western blot and reverse transcription–quantitative polymerase chain reaction (RT-qPCR) analysis were used to observe the therapeutic effect and to explore the possible mechanism. Result: Micro-CT and histological analysis evaluation showed that the Se-CPC group presented the strongest effect on bone regeneration and bone mineralization when compared with the CPC group and the OVX group. Protein expressions showed that the oxidative stress protein expressions, such as SOD2 and GPX1 of the Se-CPC group, are significantly higher than those of the OVX group and the CPC group, while Se-CPC remarkably reduced the expression of CAT. RT-qPCR analysis showed that the Se-CPC group displayed more OPG than the OVX and CPC groups (p < 0.05), while Se-CPC exhibited less RANKL than the OVX and CPC groups (p < 0.05). Conclusion: Our current study demonstrated that Se-CPC is a scheme for rapid repair of femoral condylar defects, and these effects may be achieved by inhibiting local oxidative stress and through OPG/RANKL signaling pathway. [ABSTRACT FROM AUTHOR]

Despite advances in the pathogenesis of Tauroursodeoxycholic acid (TUDCA) on bone, the understanding of the effects and mechanisms of bone osseointegration in TUDCA-associated Hydroxyapatite (HA)-coated titanium implants remains poor. Therefore, the present work was aimed to evaluate the effect of local administration with TUDCA on HA-coated titanium implants osseointegration in ovariectomized(OVX) rats and further investigation of the possible mechanism. Twelve weeks after bilateral ovariectomy, all animals were randomly divided into three groups: sham operation(Sham) group, OVX group and TUDCA group, and all the rats from Sham group and OVX group received HA implants and animals belonging to group TUDCA received TUDCA-HA implants until death at 12 weeks. The bilateral femurs of rats were harvested for evaluation. TUDCA increased 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 systemic TUDCA showed positive effects than OVX group on bone formation in osteopenic rats, with beneficial effect on via activation OPG/RANKL pathway and BMP-2/Smad1 pathway and microarchitecture as well as by reducing protein expression of TNF-α and IFN-γ. The present study suggests that local use of TUDCA may bring benefits to the osseointegration of HA-coated titanium implants in patients with osteoporosis, and this effect may be related to the inhibition of inflammatory reaction and promotion of osteogenesis. [ABSTRACT FROM AUTHOR]

Composite materials β-tricalcium phosphate (β-TCP) and poly-lactic-co-glycolic acid (PLGA) have achieved stable bone regeneration without cell transplantation in previous studies. Recent research shows that aspirin (ASP) has great potential in promoting bone regeneration. The objective of the present study was to incorporate PLGA into β-TCP combined with a lower single-dose local administration of ASP to enhance its in vivo biodegradation and bone tissue growth. After the creation of a rodent critical-sized femoral metaphyseal bone defect, PLGA -modified β-TCP (TP) was prepared by mixing sieved granules of β-TCP and PLGA (50:50, v/v) for medical use, then TP with dripped 50 µg/0.1 ml and 100 µg/0.1 ml aspirin solution was implanted into the defect of OVX rats until death at 8 weeks. The defected area in distal femurs of rats was harvested for evaluation by histology, micro-CT, biomechanics and real time RT-PCR. The results of our study show that a single-dose local administration of ASP combined with the local usage of TP can increase the healing of defects in OVX rats. Single-dose local administration of aspirin can improve the transcription of genes involved in the regulation of bone formation and vascularization in the defect area, and inhibits osteoclast activity. Furthermore, treatments with a higher single-dose local administration of ASP and TP showed a stronger effect on accelerating the local bone formation than while using a lower dose of ASP. The results from our study demonstrate that the combination of a single-dose local administration of ASP and β-TCP/PLGA had an additive effect on local bone formation in osteoporosis rats, and bone regeneration by PLGA/β-TCP/ASP occured in a dose-dependent manner. [ABSTRACT FROM AUTHOR]

As hydroxyapatite has good osteoconductive properties, it is used as coating material for the implants in cementless arthroplasty. However, its effect is not sufficient for osteoporotic bone. Silymarin promotes osteoblast proliferation and inhibits osteoclast proliferation, and positively affects bone regeneration. System administration of silymarin increases bone strength and both cancellous and cortical bone mass. The aim of this study was to confirm the effect of the local incorporation silymarin into hydroxyapatite-coated titanium implants in the osteoporotic and normal condition. Twelve-week-old female Sprague-Dawley rats were used for this study. Twelve weeks after bilateral ovariectomy, all animals were randomly divided into three groups: group sham, group ovariectomized and group silymarin, and the rats from ovariectomized and sham received hydroxyapatite implants and animals belong to group silymarin received silymarin-hydroxyapatite implants until death at 12 weeks, respectively. The bilateral femurs of rats were harvested for evaluation. All treatments increased new bone formation around the surface of titanium rods and push-out force other than group ovariectomized. Compared with group ovariectomized, group silymarin showed the strongest effects on new bone formation, biomechanical strength and regulation of osteogenesis and bone resorption-related gene expression, respectively. Additionally, these are significant difference in bone formation, gene expression and push-out force was observed among treatment groups. This finding suggests that local incorporation of silymarin is useful to improve the fixation of hydroxyapatite-coated implants in ovariectomized rats. [ABSTRACT FROM AUTHOR]

Parathyroid hormone (1-34, PTH) combined β-tricalcium phosphate (β-TCP) achieves stable bone regeneration without cell transplantation in previous studies. Recently, with the development of tissue engineering slow release technology, PTH used locally to promote bone defect healing become possible. This study by virtue of collagen with a combination of drugs and has a slow release properties, and investigated bone regeneration by β-TCP/collagen (β-TCP/COL) with the single local administration of PTH. After the creation of a rodent critical-sized femoral metaphyseal bone defect, β-TCP/COL was prepared by mixing sieved granules of β-TCP and atelocollagen for medical use, then β-TCP/COL with dripped PTH solution (1.0 µg) was implanted into the defect of OVX rats until death at 4 and 8 weeks. The defected area in distal femurs of rats was harvested for evaluation by histology, micro-CT, and biomechanics. The results of our study show that single-dose local administration of PTH combined local usage of β-TCP/COL can increase the healing of defects in OVX rats. Furthermore, treatments with single-dose local administration of PTH and β-TCP/COL showed a stronger effect on accelerating the local bone formation than β-TCP/COL used alone. The results from our study demonstrate that combination of single-dose local administration of PTH and β-TCP/COL had an additive effect on local bone formation in osteoporosis rats. [ABSTRACT FROM AUTHOR]

Surface modification techniques have been applied to generate titanium implant surfaces that promote osseointegration for the implants in cementless arthroplasty. However, its effect is not sufficient for osteoporotic bone. Strontium (Sr) promotes osteoblast proliferation and inhibits osteoclast proliferation and positively affects bone regeneration. The aim of this study was to confirm the effects of strontium-substituted hydroxyapatite (Sr-HA) coating via electrochemical deposition on implant's osseointegration in the osteoporotic condition. Female Sprague Dawley rats were used for this study. Twelve weeks after bilateral ovariectomy, all animals were randomly divided into four groups: group HA; group 5 % Sr-HA; group 10 % Sr-HA; and group 20 % Sr-HA. Afterward, all rats from groups HA, 5 % Sr-HA, 10 % Sr-HA, and 20 % Sr-HA received implants with hydroxyapatite coating containing 0, 5, 10, and 20 % Sr. Implants were inserted bilaterally in all animals until death at 12 weeks. The bilateral femurs of rats were harvested for evaluation. All treatment groups increased new bone formation around the surface of titanium rods and push-out force; group 20 % Sr-HA showed the strongest effects on new bone formation and biomechanical strength. Additionally, these are significant differences in bone formation and push-out force was observed between groups 5 % Sr-HA and 10 % Sr-HA. This finding suggests that Sr-HA coating can improve implant osseointegration, and the 20 % Sr coating exhibited the best properties for implant osseointegration among the tested coatings in osteoporosis rats. [ABSTRACT FROM AUTHOR]

The objective of this study was to evaluate the effect of following combined treatment with parathyroid hormone (1-34) (PTH) and beta-tricalcium phosphate (β-TCP) on local bone formation in a rat 3-mm critical-size defect at distal femur. Twelve weeks after bilateral ovariectomy (OVX) and sham operation (sham), all animals were randomly divided into four groups: group OVX, group OVX + β-TCP, group sham, and group sham + β-TCP, then all rats underwent bone defect in the bilateral distal femurs, and β-TCP were implanted into critical-sized defects for group OVX + β-TCP and group sham + β-TCP. After defect operation, all animals were received following subcutaneous injections with PTH (60 μg/kg, three times a week) until death at 4 and 8 weeks. The defected area in distal femurs of rats was harvested for evaluation by histology, micro-CT, and biomechanics. The results of our study show that systemic usage of PTH or local usage of β-TCP can increase the healing of defects in OVX or sham rats. Furthermore, treatments with PTH and β-TCP showed a stronger effect on accelerating the local bone formation than used alone. Osteoporosis can limit the function of PTH and/or β-TCP. The results from our study demonstrate that combination of PTH and β-TCP had an additive effect on local bone formation in non-osteoporosis and/or osteoporosis rats. [ABSTRACT FROM AUTHOR]

Silibinin (SIL) has been used extensively for its hepatoprotective properties and antioxidant properties, including bone health. Iron overload can inhibit osteogenic proliferation and differentiation and promote bone loss. However, whether SIL can reverse the harmful effects of iron overload inovariectomized (OVX) rats and the mechanism is not clear. Therefore, this study intends to investigate the effect of SIL on bone mass and bone metabolism in iron overload rats and also explore the role of SIL on osteogenic differentiation of MC3T3-E1.RT-qPCR was used to measure the transcribe of target genes. Furthermore, alizarin red staining, alkaline phosphatase staining, immunofluorescence and CCK-8 assay were conducted to detect cell viability and target protein expression, osteogenic function. The OVX rat model with iron overload was set up to investigate bone reconstruction.Our results demonstrated that SIL promotes the proliferation and differentiation of osteoblasts, increases the ALP secretion and mineralization ability of osteoblasts, and enhances the transcribe and expression of target genes including OC, Runx-2, SOD2 and SIRT1 in an iron overload environment. In addition, it was confirmed that systemic SIL administration inhibits bone loss in OVX rats with iron overload and changes bone metabolism and oxidative stress status. Further study has shown that iron overload exerts its harmful function by accelerating bone turnover-mediated changes in higher bone metabolism to worsen osteoporosis. SIL can inhibit the unfriendly effects of iron overload, and by modifying bone metabolism and oxidative stress levels, the results contribute to clinical prevention and treatment of the progression of postmenopausal osteoporosis. • Iron overload accelerates ovariectomy-induced bone loss. • Iron overload mediated bone loss by promoting bone turnover and oxidative stress. • Silibinin can inhibit iron overload-induced oxidative stress and bone loss. [ABSTRACT FROM AUTHOR]

Surface modification techniques have been applied to generate titanium implant surfaces that promote osseointegration for the implants in cementless arthroplasty. However, its effect is not sufficient for osteoporotic bone. Zinc (Zn), magnesium (Mg), and strontium (Sr) present a beneficial effect on bone growth, and positively affect bone regeneration. The aim of this study was to confirm the different effects of the fixation strength of Zn, Mg, Sr-substituted hydroxyapatite-coated (Zn-HA-coated, Mg-HA-coated, Sr-HA-coated) titanium implants via electrochemical deposition in the osteoporotic condition. Female Sprague–Dawley rats were used for this study. Twelve weeks after bilateral ovariectomy, all animals were randomly divided into four groups: group HA; group Zn-HA; group Mg-HA and group Sr-HA. Afterwards, all rats from groups HA, Zn-HA, Mg-HA and Sr-HA received implants with hydroxyapatite containing 0%, 10% Zn ions, 10% Mg ions, and 10% Sr ions. Implants were inserted bilaterally in all animals until death at 12 weeks. The bilateral femurs of rats were harvested for evaluation. All treatment groups increased new bone formation around the surface of titanium rods and push-out force; group Sr-HA showed the strongest effects on new bone formation and biomechanical strength. Additionally, there are significant differences in bone formation and push-out force was observed between groups Zn-HA and Mg-HA. This finding suggests that Zn, Mg, Sr-substituted hydroxyapatite coatings can improve implant osseointegration, and the 10% Sr coating exhibited the best properties for implant osseointegration among the tested coatings in osteoporosis rats. [ABSTRACT FROM AUTHOR]

Previous studies have demonstrated the effect of human parathyroid hormone (1–34) (PTH) or strontium-doped hydroxyapatite coating (Sr-HA) on osteoporotic bone implantation. However, reports about effects of PTH plus Sr-HA on bone osseointegration of titanium implants in a state of osteoporosis were limited. This study was designed to investigate the effects of intermittent administration of human parathyroid hormone (1–34) on strontium-doped hydroxyapatite coating (Sr-HA) implant fixation in ovariectomized (OVX) rats. Twelve weeks after bilateral ovariectomy, all animals were randomly divided into four groups including control group, Sr group, PTH group and PTH+Sr group. Forty OVX rats accepted implant insertion in the distal femurs, control group, and PTH group with HA implants and the Sr group and PTH+Sr group with Sr-HA implants. Animals from PTH group and PTH+Sr group then randomly received PTH (60 µg/kg, 3 times a week) until death at 12 weeks. After 12-week healing period, implants from group PTH+Sr revealed improved osseointegration compared with other treatment groups, which is manifested by the exceeding increase of bone area ratio and bone-to-implant contact, the trabecular microarchitecture and the maximal push-out force displayed by tests like histomorphometry, micro-CT, and biomechanics evaluation. These results demonstrated that PTH+ Sr-HA coatings could enhance implant osseointegration in OVX rats, and suggested the feasibility of using this method to improve implant fixation in osteoporotic bone. [ABSTRACT FROM AUTHOR]

The objective of this study was to evaluate local bone formation following systemic administration of parathyroid hormone (1–34), a surgically implanted synthetic β-tricalcium phosphate bone biomaterial serving as a matrix to support new bone formation. Twelve weeks after bilateral ovariectomy, all rats underwent bone defect in the distal femurs, and β-tricalcium phosphate was implanted into critical sized defects. After defect operation, all animals were randomly divided into four groups and received following subcutaneous injections until death at four and eight weeks: sham rats (group ST); sham rats + parathyroid hormone, 30 µg/kg, three times a week (group SPT); OVX rats (group OT); and OVX rats + parathyroid hormone (group OPT). The distal femurs of rats were harvested for evaluation. The treatment group demonstrating the highest levels of new bone formation was the defects treated with parathyroid hormone as assessed by micro-computed tomography, biomechanical strength, and histological analysis for sham rats. Furthermore, parathyroid hormone showed a stronger effect on accelerating the degradation of β-tricalcium phosphate. Osteoporosis can limit the function of parathyroid hormone and/or β-tricalcium phosphate. The results from our study demonstrate that combination of parathyroid hormone and β-tricalcium phosphate brings better effect to bone tissue repair in non-osteoporosis and/or osteoporosis status. [ABSTRACT FROM AUTHOR]

The present work was aimed to evaluate the effect of different administration modes of sodium valproate (VPA) on bone strength, bone mass and bone mineral density in ovariectomized (OVX) rats and further investigation of the possible mechanism. 60 female SD rats were randomly divided into 4 groups: Sham group (Sham, n = 15), OVX group (OVX, n = 15), OVX rats received intermittent VPA treatment group (IVPA, n = 15) and OVX rats received daily VPA treatment group (EVPA, n = 15). After 12 weeks of treatment, the rats were sacrificed, and serum and femur samples were harvested. DEXA, Micro-CT, history, biomechanical testing, biochemical index and western blot analysis were used to observe the therapeutic effect and explore the possible mechanism. Micro-CT and DEXA analysis of bones revealed better BMD and higher BV/TV, Tb. Th, Tb. N, Conn. D and lower Tb. Sp at femoral metaphysis evaluated in IVPA when compared with OVX and EVPA group (P < 0.05). Histological, fluorescent analysis and biological strength revealed more trabecular bone and higher relative mineral apposition rate, maximal load, elastic modulus and energy at break with evaluated in IVPA when compared with OVX and EVPA group (P < 0.05). The levels of P1NP, estrogen, CTX, TRAP-5b and RANKL of the IVPA group showed a significant increase when compared with the OVX and EVPA group (P < 0.05). We confirm adverse effects on protein expressions including Notch1, Jagged1, HEY1, Wnt 1, β-catenin and RUNX2 following daily VPA treatment in OVX female rats. Our current study demonstrated that intermittent administration of sodium valproate has a protective effect on bone health in OVX rats and these effects may be achieved by activating Notch/Wnt/β-catenin/RUNX2 signal axis. [ABSTRACT FROM AUTHOR]

• Our current study demonstrated that co-modification of β-tricalcium phosphate by strontium and aspirin is a scheme for rapid repair of femoral condylar defects. • Aspirin-strontium/β-tricalcium phosphate can promote bone repair by inhibiting local inflammation and promoting osteogenic activity through BMP-2/Smad1 and OPG/RANKL signaling pathway. • Aspirin-strontium/β-tricalcium phosphate is a very promising treatment plan for the treatment of osteoporotic bone defects. The purpose was to observe whether local administration Strontium (Sr) and Aspirin (Asp) can enhance the efficacy of β-Tricalcium phosphate(β-TCP) in the treatment of osteoporotic bone defect. The MC3T3-E1 cells were co-cultured with β-TCP, Sr/β-TCP, Asp-Sr/β-TCP scaffold and induced to osteogenesis, and the cell viability, mineralization ability were observed by MTT, Alizarin Red staining(ARS) and Western blotting(WB). Then this scaffolds were implanted into the femoral epiphysis bone defect model of ovariectomized(OVX) rats for 8 weeks. X-ray, Micro-CT, histology and Reverse transcription-quantitative polymerase chain reaction (RT-qPCR) analysis were used to observe the therapeutic effect and explore the possible mechanism. MTT, ARS results show that the cell mineralization and viability of Asp-Sr/β-TCP group is significantly higher than Control group, β-TCP group and Sr/β-TCP group. Protein expression show that the osteogenic protein expression such as ALP、OP、RUNX-2、OC and COL-1 of Asp-Sr/β-TCP group is significantly higher than Control group, β-TCP group and Sr/β-TCP group. X-ray images, Micro-CT and Histological analysis evaluation show that, group Asp-Sr/β-TCP presented the strongest effect on bone regeneration and bone mineralization, when compared with β-TCP group and Sr/β-TCP group. RT-qPCR analysis show that Asp-Sr/β-TCP, β-TCP group and Sr/β-TCP group showed increased BMP2, Smad1, OPG than the OVX group(p < 0.05), while Asp-Sr/β-TCP exhibited decreased TNF-α、IFN-γ and RANKL than the OVX group(p < 0.05). Our current study demonstrated that Asp-Sr/ β-TCP is a scheme for rapid repair of femoral condylar defects, and these effects may be achieved by inhibiting local inflammation and through BMP-2/Smad1 and OPG/RANKL signaling pathway. [ABSTRACT FROM AUTHOR]

• 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]

Introduction: Several techniques have been described to treat tibial fractures, which respectively remains defects. This article presents a novel intra- and extramedullary fixation technique: percutaneous external fixator combined with titanium elastic nails (EF-TENs system). The purpose of this study is to introduce this new minimally invasive surgical technique and selective treatment of tibial fractures, particularly in segmental fractures, diaphysis fractures accompanied with distal or proximal bone subfissure, or fractures with poor soft-tissue problems.Methods: Following ethical approval, thirty-two patients with tibial fractures were treated by the EF-TENs system between January 2010 and December 2012. The follow-up studies included clinical and radiographic examinations. All relevant outcomes were recorded during follow-up.Results: All thirty-two patients were achieved follow-ups. According to the AO classification, 3 Type A, 9 Type B and 20 Type C fractures were included respectively. According to the Anderson-Gustilo classification, there were 5 Type Grade II, 3 Type Grade IIIA and 2 Type Grade IIIB. Among 32 patients, 8 of them were segmental fractures. 12 fractures accompanied with bone subfissure. Results showed no nonunion case, with an average time of 23.7 weeks (range, 14-32 weeks). Among them, there were 3/32 delayed union patients and 0/32 malunion case. 4/32 patients developed a pin track infection and no patient suffered deep infection. The external fixator was removed with a mean time of 16.7 weeks (range, 10-26 weeks). Moreover, only 1/32 patient suffered with the restricted ROM of ankle, none with the restricted ROM of knee.Conclusion: This preliminary study indicated that the EF-TENs system, as a novel intra- and extramedullary fixation technique, had substantial effects on selective treatment of tibial fractures. [ABSTRACT FROM AUTHOR]

Introduction: The objectives of the present study were to determine whether simvastatin (SIM) could reverse the harmful effects on titanium rod osseointegration in ovariectomized rats fed high-fat diet (HFD). Materials and Methods: Ovariectomized female Sprague–Dawley rats were randomly allocated to three groups and received SIM treatment plus HFD for 12 weeks. We then evaluated the microstructure parameters, histological parameters, biomechanical parameters, bone turnover, and blood lipid level. Results: After 12 weeks of treatment, SIM can significantly improve bone formation around the titanium rod and osseointegration including higher values of maximum push-out force, bone area ratio (BAR), bone-to-implant contact (BIC), bone mineral density (BMD), bone volume (BV/TV), trabecular number (Tb.N), trabecular thickness (Tb.Th), mean connective density (Conn.D) when compared with the HFD group. In addition, system administration of SIM showed positive effects on collagen type 1 cross-linked C-telopeptide (CTX-1), procollagen I N-terminal propeptide (PINP), total cholesterol (TC), triglycerides (TGL), low-density lipoprotein (LDL) cholesterol and high-density lipoprotein (HDL) cholesterol. Compared with the HFD group, lower values of CTX-1, P1NP, TC, TGL and LDL were observed in the SIM+HFD group (P < 0.05). Conclusion: Our findings revealed that HFD may have an adverse effect on osseointegration in osteoporotic conditions, and the harmful effect of HFD on osseointegration could be reversed by SIM. [ABSTRACT FROM AUTHOR]

Background: The use of antiepileptic drugs and estrogen deficiency put forward higher requirements for bone defect regeneration. The present study investigated the effects of alendronate (ALN) on femoral bone defect in ovariectomized (OVX) rats under the influence of carbamazepine (CBZ). Methods: One hundred female SD rats at 3 months of age were either sham-operated or OVX and divided into four groups: sham control (CON); OVX control (OVX); ovariectomized rats treated with CBZ via gavage (75 mg/kg/day; CBZ); ovariectomized rats treated with CBZ plus ALN (2 mg/kg/day; CBZ-ALN). A critical-sized femoral metaphyseal bone defect was established in all female SD rats. Animals from the CBZ and CBZ-ALN groups received drugs by gavage the day after bone defect surgery was performed. After the rats were sacrificed, the defected area located in the distal femur was harvested for evaluation by microcomputed tomography (micro-CT), hematoxylin and eosin (HE) staining, and Masson's trichrome staining. The samples were also analyzed by biomechanics and immunohistochemical evaluation (IHC). Besides, biochemical analysis evaluates all serum samples. Results: The present study showed that ovariectomy changed the microstructural parameters of bone. The use of CBZ further decreased femur bone mass while treatment with ALN prevented bone loss. Compared to OVX and CBZ groups, CBZ-ALN group promoted bone neoformation and enhanced the ultimate load of the femur bone. However, the group of CBZ-ALN did not return to normal levels compared with the CON group. Besides, we noticed that CBZ-ALN group reduced tartrate-resistant acid phosphatase-5b (Tracp-5b) expression and had no significant effect on the expression of osteocalcin (OCN) and type I collagen (Col-I) in IHC compared with CBZ group. Biochemical analysis results presented that systemic delivery of CBZ showed pernicious effects on bone formation and resorption in ovariectomized rats, with the worse effects on C-terminal crosslinked telopeptide of type I collagen (CTX-1). Besides, a significant decrease in CTX-1 levels was observed in CBZ-ALN group as compared to the group of CBZ. Conclusion: These results demonstrated that ALN can effectively reverse the effects of CBZ on the microarchitectural properties of bone, and thus can have a positive effect on local bone neoformation in rats with osteoporosis. Clinical relevance: The dose of 2 mg/kg ALN improves the negative effect of prescription of CBZ at 75 mg/kg and promotes bone neoformation of femoral bony deficits. [ABSTRACT FROM AUTHOR]

Chitosan Oligosaccharide (COS) has been widely used for the systemic treatment of clinical diseases such as bone tissue engineering. However, its influence on osteoclast formation, which plays a critical role in bone homeostasis, has never been investigated. The aim of this study was to investigate the effect of chitosan oligosaccharide on differentiation of osteoclast. Using cell counting kit-8, tartrate-resistant acid phosphatase staining, reverse transcription‑quantitative polymerase chain reaction assay and western blot analysis, we demonstrated that chitosan oligosaccharide cannot inhibit RANKL-induced osteoclast precursor proliferation but does promote osteoclast differentiation by stimulating the activation of p38/mitogen-activated protein kinase (MAPK), c-Jun N-terminal kinase (JNK)/MAPK, extracellular signal-regulated kinase (ERK)/MAPK and protein kinase B (AKT) without affecting nuclear factor kappaB (NF-kB) signaling pathways. Based on the promoting effect of chitosan oligosaccharide on osteoclast differentiation, we suggest that this property of chitosan oligosaccharide may have potential detrimental effect on bone homeostasis. [ABSTRACT FROM AUTHOR]

Purpose: The aim of this study was to develop a novel method for observing the morphology of the blood vessels in the rabbit endplate.Methods: Twenty 6-month-old rabbits were used in this study. The blood vessels in the L5 endplate in Group A were injected with iohexol and Group B with barium sulfate. Group C was the control group with saline. To optimize the study, Group B was divided into two subgroups: Group B-1 was injected with 100% (w/v) barium sulfate and Group B-2 with 50% (w/v). After injection, the L4-L5 vertebral body was excised and the cranial endplate of L5 was scanned using a micro-CT scanner. Models of the vertebral endplate and vessels were reconstructed using the 3D reconstruction software (Mimics 16.0) by calculating a bone threshold value, and then merged these two models to create a superimposed model.Results: The 3D vessel models could not be created in Groups A and C, but they were clearly visualized in Group B. In the 3D model, the blood vessels extended from the subchondral bone to the endplate, and the density of the blood vessels in the area of the nucleus pulposus (NP) was higher than in the annulus fibrosus.Conclusions: The results of this study suggest that the blood vessels in the rabbit endplate can be clearly observed by the method described using barium sulfate [the 50% (w/v) gave better results compared with the 100% (w/v)]. The information from the 3D vessel structure could provide essential data to help us understand the nutrient pathways within the vertebral endplate. [ABSTRACT FROM AUTHOR]

The effect of human parathyroid hormone 1-34 (PTH) and simvastatin (SIM) alone could promote bone healing in osteoporotic osseous integration of the implant, but there are no reports about the combined use of PTH and SIM for promotion of bone healing around implant in osteoporotic settings still limited. This study aims to investigate effects of PTH+SIM on osseous integration of the implant in OVX rats. Female Sprague-Dawley rats were used for this study. Twelve weeks after bilateral ovariectomy, all animals were randomly divided into four groups: group control; group SIM; group PTH and group PTH+SIM. Afterwards, all OVX rats received hydroxyapatite (HA)-coated titanium rods (external diameter and length are 1.5mm and 20mm) in the femoral medullary canal. Subsequently, the animals from group SIM, group PTH and group PTH+SIM received human parathyroid hormone 1-34 (60μg/kg, three times a week), SIM (5mg/kg daily), or both for 12 weeks. Implants were inserted bilaterally in all animals until death at 12 weeks. The bilateral femurs of rats were harvested for evaluation. All groups increased new bone formation around the surface of titanium rods and push-out force; group PTH+SIM showed the strongest effects on new bone formation and biomechanical strength. Additionally, these are significant difference observed in bone formation and push-out force between groups SIM and PTH. This finding suggests that intermittent administration of PTH or SIM alone has an effect to increase new bone formation on the surface of HA-coated implants in the osteoporotic condition, and the additive effects of combination PTH and SIM on osseous integration of the implant in OVX rats. [ABSTRACT FROM AUTHOR]

In this study, we tested the effect of Teriparatide (PTH) in combination with β-tricalcium phosphate (β-TCP) as a bone void filler in an ovariectomised rat distal femoral metaphysis model.β-TCP is a completely resorbable synthetic calcium phosphate and the Teriparatide is a drug that can promote bone formation in the condition of osteoporosis. A critical size defect of 3mm in diameter, a through-hole bone defect, was drilled into each distal femur of the ovariectomised rats. The hole was filled with β-TCP and the rat was injected PTH Teriparatide (30μg/kg) in peritoneum 5 times per week. After 4and 8 weeks the animals were killed and the degree of bone healing analysed. In total, 60 animals were investigated. When the β-TCP and PTH were used, histological, biochemistry and histomor-phometric evaluations revealed significantly better bone healing in terms of quantity and quality of the newly formed bone. The Ovariectomised rats which suffer from femur metaphysis defect are cured by embedding β-tricalcuim phosphate and intermittently cured by parathyroid hormone (PTH). [ABSTRACT FROM AUTHOR]