Curculigoside Protects against Titanium Particle-Induced Osteolysis through the Enhancement of Osteoblast Differentiation and Reduction of Osteoclast Formation.

Wear particle-induced periprosthetic osteolysis is mainly responsible for joint replacement failure and revision surgery. Curculigoside is reported to have bone-protective potential, but whether curculigoside attenuates wear particle-induced osteolysis remains unclear. In this study, titanium particles (Ti) were used to stimulate osteoblastic MC3T3-E1 cells in the presence or absence of curculigoside, to determine their effect on osteoblast differentiation. Rat osteoclastic bone marrow stromal cells (BMSCs) were cocultured with Ti in the presence or absence of curculigoside, to evaluate its effect on osteoclast formation in vitro. Ti was also used to stimulate mouse calvaria to induce an osteolysis model, and curculigoside was administrated to evaluate its effect in the osteolysis model by micro-CT imaging and histopathological analyses. As the results indicated, in MC3T3-E1 cells, curculigoside treatment attenuated the Ti-induced inhibition on cell differentiation and apoptosis, increased alkaline phosphatase activity (ALP) and cell mineralization, and inhibited TNF-α, IL-1ß, and IL-6 production and ROS generation. In BMSCs, curculigoside treatment suppressed the Ti-induced cell formation and suppressed the TNF-α, IL-1ß, and IL-6 production and F-actin ring formation. In vivo, curculigoside attenuated Ti-induced bone loss and histological damage in murine calvaria. Curculigoside treatment also reversed the RANK/RANKL/OPG and NF-κB signaling pathways, by suppressing the RANKL and NF-κB expression, while activating the OPG expression. Our study demonstrated that curculigoside treatment was able to attenuate wear particle-induced periprosthetic osteolysis in in vivo and in vitro experiments, promoted osteoblastic MC3T3-E1 cell differentiation, and inhibited osteoclast BMSC formation. It suggests that curculigoside may be a potential pharmaceutical agent for wear particle-stimulated osteolysis therapy.

Does potassium citrate administration change the type and composition of encrusted material on Double-J stent compared to primary stone?

PURPOSE: To evaluate the effect of potassium citrate administration on the composition of encrusted material on the ureteral stent after Double-J insertion. METHODS: We designed a randomized clinical trial for our study; 65 patients that underwent transurethral lithotripsy and Double-J stent insertion were included in the study after informed consent and divided into two groups. In the first group (33 patients) potassium citrate was prescribed after surgery till stent removal and the second group (32 patients) followed without prescribing this medication. After stent removal, encrusted materials on removed stents were analyzed then the type and composition of encrusted material compared with the primary stone that was removed. RESULTS: Our results revealed that the type and composition of primary stone and encrusted stone were similar in patients that do not receive potassium citrate (p-value of 0.073, 0.251 and 0.944 for calcium oxalate, uric acid, and calcium phosphate respectively). In patients that taking potassium citrate rate of calcium oxalate (p-value < 0.001) and uric acid (p-value < 0.001) material on encrusted stent significantly decreased compared with the non-intervention group. CONCLUSION: Results of this study revealed that taking of potassium citrate after ureteral stent insertion significantly decreases the formation of calcium oxalate and uric acid encrusted material on Double-J stent so it could be recommended for prevention of stent encrustation in patients that primary stone analysis are calcium oxalate and uric acid stone.

Elimination of macrophages reduces glutaraldehyde-fixed porcine heart valve degeneration in mice subdermal model.

Glutaraldehyde-fixed porcine heart valve (GPHV) calcify and deteriorate over time. The aim of this study was to explore the roles macrophages play in mediating calcification and degeneration of the valve's connective tissue matrix. GPHV were implanted subcutaneously in the abdomens of C57BL/6 mice. The mice were equally divided into two study groups: (a) GPHV +phosphate buffered saline (PBS) liposomes, and (b) GPHV +clodronate liposomes. GPHV were collected for further analyses at 4 weeks post implant. Macrophages were almost depleted from the spleens of mice injected with clodronate liposomes as indicated by immunohistochemical staining. Furthermore, the expression of matrix metalloproteinase-2 (MMP-2), MMP-9, and proinflammatory cytokines like IL-1ß, IL-6, MCP-1, MIP-1a, MIP-1b, were downregulated in the GPHV +Clodronate liposomal group compared with the GPHV+PBS liposomal group. Clodronate liposomal treatment led to significant decreases in the expression of RUNX2, ALP and OPN as well as less calcium deposits in GPHVs compared with PBS liposomal treatment. This finding indicated that infiltrating macrophages are critically involved in the development of calcification and deterioration in GPHVs. Macrophage depletion by clodronate liposomes decreased the extent of GPHV's calcification and deterioration.

Repeat reteplase therapy in a patient with recurrent prosthetic tricuspid valve thrombosis after trido multiple valve replacement.

Prosthetic valve thrombosis (PVT) is a rare but life-threatening complication. It has an incidence of 6.1% in developing countries and 0.3%-1.3% in developed countries. The first-line treatment for the right-sided PVT is fibrinolytic therapy with streptokinase or recombinant tissue plasminogen activators, but there are limited cases that were treated with recombinant plasminogen activators. A 57-year-old female with a history of Trido valve surgery and persistent atrial fibrillation rhythm was hospitalized for recurrent tricuspid mechanical valve thrombosis multiple times. The patient was treated with fibrinolytics successfully three times. We report a rare case of recurrent tricuspid mechanical valve thrombosis that is treated with IV reteplase twice.

Enalapril inhibits inflammatory osteolysis induced by wear debris in a mouse model.

OBJECTIVE: Aseptic loosening, the most frequent complication after total joint replacement, is probably caused by an inflammatory response to the shedding of wear debris from the implant. The only effective treatment is surgical revision. Using a mouse model, we investigated whether enalapril inhibits wear debris-induced inflammatory osteolysis. METHODS: Titanium (Ti) alloy particles were introduced, and calvarial bone from syngeneic mice was implanted into air pouches established in BALB/c mice. Histological and molecular analyses were performed with inflammatory tissue samples obtained from mice treated with and without enalapril. RESULTS: Enalapril inhibited tissue inflammation and inflammatory osteolysis induced by Ti particles, reducing pouch membrane thickness and decreasing inflammatory cell infiltration. In addition, enalapril inhibited the expression of the inflammatory cytokines vascular endothelial growth factor and tumor necrosis factor-α. CONCLUSIONS: Our study provides evidence that enalapril inhibits Ti particle-induced inflammatory osteolysis, and it may be a potentially useful treatment for aseptic loosening.

Aspirin for metal stent in malignant distal common bile duct obstruction (AIMS): study protocol for a multicenter randomized controlled trial.

BACKGROUND: Endoscopic retrograde biliary drainage (ERBD) is the treatment of choice for patients with malignant distal common bile duct (CBD) obstruction. Self-expandable metal stents (SEMS), which are commonly used in unresectable cases, have many clinical advantages, including longer stent patency. Although the expected patency of SEMS is around 8 months, it has recently been reported that the duration of SEMS' patency in patients using aspirin is prolonged. Our study, therefore, aims to investigate the effect of aspirin on SEMS' patency. METHODS/DESIGN: This is an investigator-initiated, prospective, multicenter, double-blind, randomized placebo-controlled trial that will be conducted from November 2017 in four tertiary centers in South Korea. We intend to include in our study 184 adult (aged ≥ 20 years) patients with malignant distal CBD obstruction for whom ERBD with SEMS was successfully performed. The patients will be randomly allocated to two groups, which will comprise patients who have either taken 100 mg aspirin or a placebo for 6 months after index ERBD. The primary outcome will be the rate of stent dysfunction, and the secondary outcomes will be the duration of patency, the rate of reintervention, and the occurrence of adverse events. DISCUSSION: The aspirin for metal stents in malignant distal common bile duct obstruction (AIMS) study should determine the efficacy of aspirin in maintaining metal-stent patency in patients with malignant distal CBD obstructive. TRIAL REGISTRATION: ClinicalTrials.gov, ID: NCT03279809. Registered on 5 September 2017.

Cepharanthine ameliorates titanium particle-induced osteolysis by inhibiting osteoclastogenesis and modulating OPG/RANKL ratio in a murine model.

Periprosthetic asepteic loosening, caused by wear debris, is one of the most severe complications, generally resulting in implant failure. Extensive osteoclast formation and activation are considered as the cause for periprosthetic osteolysis. However, few approaches have been approved to be used for preventing early-stage periprosthetic osteolysis. In this study, we investigated the preventive effects of CEP on titanium particles-induced osteolysis in a murine calvaria model. This inhibitory effect was confirmed to be realized by attenuating osteoclastogenesis in vivo. In addition, CEP markedly reduced wear particles-induced elevation of receptor activator of nuclear factor kappa B ligand (RANKL)/Osteoprotegerin (OPG) ratio in vivo. In conclusion, these data concluded that CEP demonstrated a preventive effect of CEP on titanium particles induced osteolysis, suggesting that CEP might be a novel therapeutic for periprosthesis loosening.

Use of beta-blockers and risk of aseptic loosening in total hip and knee arthroplasty: a nested case - control study.

OBJECTIVES: To analyze the effect of beta-blockers on the risk of aseptic loosening (AL) in Total Hip (THA) or Knee (TKA) Arthroplasty. METHODS: A nested case-control study was conducted. Cases were patients who underwent revision surgery for THA or TKA due to AL. Controls were patients who sustained primary THA or TKA and were matched to cases in respect to age, sex, type of prostheses and follow-up in a 4:1 ratio. The use of beta-blockers was achieved. A logistic regression analysis adjusted to potential confounders was performed to determine the risk of AL. Analysis was also adjusted to cardioselectivity of the beta-blocker and the adherence to treatment, measured as Proportion of Days Covered (PDC). RESULTS: 24 cases and 96 controls were selected. Compared to non-users, any use of beta-blockers was associated with a reduced risk of AL [adjusted OR 0.141 (Confidence Interval (CI) 95% 0.04-0.86)]. Use of selective beta-blockers showed significant lower risk of AL [adjusted OR 0.112 (CI95% 0.01-0.91)]. PDC ≥50% was associated with reduced risk of AL compared to non-users [adjusted OR 0.083 (CI95% 0.01-0.66)]. CONCLUSION: The first clinical evidence showing an association between the use of beta-blockers and lower risk of aseptic loosening in THA and TKA is provided.

Protection Effect of Curcumin for Macrophage-Involved Polyethylene Wear Particle-Induced Inflammatory Osteolysis by Increasing the Cholesterol Efflux.

BACKGROUND Periprosthetic osteolysis, induced by wear particles and inflammation, is a common reason for failure of primary arthroplasty. Curcumin, a nature phenol from plants, has been reported to reduce the inflammation in macrophages. This study aimed to investigate the potential effect of curcumin on macrophage involved, wear particle-induced osteolysis and its mechanism. MATERIAL AND METHODS RAW264.7 macrophages were used to test the effects of polyethylene (PE) particles and curcumin on macrophage cholesterol efflux and phenotypic changes. A mouse model of PE particle-induced calvarial osteolysis was established to test the effects of curcumin in vivo. After 14 days of treatment, the bone quality of the affected areas was analyzed by micro-computed tomography (micro-CT) and histology, and the bone surrounding soft tissues were analyzed at the cellular and molecular levels. RESULTS We found that PE particles can stimulate osteoclastogenesis and produce an M1-like phenotype in macrophages in vitro. Curcumin enhanced the cholesterol efflux in macrophages, and maintained the M0-like phenotype under the influence of PE particles in vitro. Additionally, the cholesterol transmembrane regulators ABCA1, ABCG1, and CAV1 were enhanced by curcumin in vivo. We also found enhanced bone density, reduced osteoclastogenesis, and fewer inflammatory responses in the curcumin treated groups in our mouse osteolysis model. CONCLUSIONS Our study findings indicated that curcumin can inhibit macrophage involved osteolysis and inflammation via promoting cholesterol efflux. Maintaining the cholesterol efflux might be a potential strategy to prevent periprosthetic osteolysis after total joint arthroplasty surgery.

The use of bisphosphonates after joint arthroplasty is associated with lower implant revision rate.

PURPOSE: This study hypothesized that the use of bisphosphonates (BPs) after total joint arthroplasty (TJA) is associated with a lower implant revision rate. This study aimed (1) to investigate the association between BP use and the revision rate of TJA and (2) to determine the relationship between the medication period and the revision rate of TJA. METHODS: National Health Insurance Service data on surgeries, medications, diagnoses, and screenings of 50 million Koreans were reviewed. People who underwent TJA in the period from 2002 to 2012 were identified and followed until 2016. During that period, 331,660 patients underwent total knee arthroplasty (TKA), and 56,043 patients underwent total hip arthroplasty (THA). Among them, 8447 knee patients (2.5%) and 2851 hip patients (5.0%) required revision surgery due to aseptic loosening. Demographic data, the duration of BP medication, and comorbidities were identified. The rate of revision surgery according to BP medication was investigated. The extended Cox proportional hazard model was used to evaluate the effect of the medication period. RESULTS: The rate of TKA revision was 1.4% for BP users and 2.9% for BP non-users (p < 0.001). The THA revision rate was 2.8% and 5.3% for BP users and non-users, respectively (p < 0.001). The hazard ratio (HR) of revision was significantly lower in patients who took BP medication for more than one year (TKA HR = 0.472, 95% CI [0.350-0.637]; THA HR = 0.490, 95% CI [0.247-0.972]) compared to that in short-term users (less than 1 year). CONCLUSIONS: The use of BPs after TJA was associated with a lower revision rate. The use of BPs for more than one year further reduced the risk of revision. Bisphosphonate use can be highly recommended to reduce the revision rate of TJA. LEVEL OF EVIDENCE: Retrospective cohort study, Level III.

Modification of Cysteine 179 in IKKß by Ursolic Acid Inhibits Titanium-Wear-Particle-Induced Inflammation, Osteoclastogenesis, and Hydroxylapatite Resorption.

Aseptic loosening of artificial joints mainly accounts for the failure of arthroplasty. We previously reported that ursolic acid (UA) inhibited osteolysis caused by titanium (Ti) wear particles via suppression of NF-kB signaling. In the present study, that the suppressive effect of UA on Ti-particle-induced inflammation and osteoclastogenesis targets on IKKß cys-179 was demonstrated. A retrovirus packaged IKKßC179A plasmid with a Cys-179 mutation replaced by Ala was constructed. qRT-PCR, immunoblot, and immunofluorescence were used to evaluate the gene expressions. Secreted inflammatory cytokines were detected by ELISA. Formation and function of osteoclastogenesis were evaluated by TRAP stain and hydroxylapatite resorption assays. As a result, a mutation of IKKßC179A rescued the therapeutic effect of UA on Ti-particle-induced inflammation, including morphological transforms, upregulation of iNOS and COX-2, increased secretions of TNF-α, IL-1ß, and IL-6, and decreased secretion of IL-10. Meanwhile, inhibition of osteoclastogenesis and hydroxylapatite resorptions were restored by transfection of IKKßC179A. Phosphorylations of p65 and the IKKα/ß complex and translocation of p65 into the nucleus were suppressed by UA but rescued by a mutation of IKKßC179A. Conclusively, UA inhibits Ti-wear-particle-induced inflammation, osteoclastogenesis, and hydroxylapatite resorption via modifying cysteine 179 of IKKß.

Effects of strontium ranelate on wear particle­induced aseptic loosening in female ovariectomized mice.

Aseptic loosening and menopause­induced osteoporosis are caused by an imbalance between bone formation and osteolysis. With an aging population, the probability of simultaneous occurrence of such conditions in an elderly individual is increasing. Strontium ranelate (SR) is an anti­osteoporosis drug that promotes bone formation and inhibits osteolysis. The present study compared the effects of SR with those of the traditional anti­osteoporosis drug alendronate (ALN) using an ovariectomized mouse model of osteolysis. The degree of firmness of the prosthesis and the surrounding tissue was examined, a micro­CT scan of the prosthesis and the surrounding tissue was performed, and the levels of inflammatory and osteogenic and osteoclast factors were examined. It was observed that treatment with SR and ALN improved the bond between the prosthesis and the surrounding bone tissue by reducing the degree of osteolysis, thus improving the quality of bone around the prosthesis. SR increased the secretion of osteocalcin, runt­related transcription factor 2 and osteoprotegerin (OPG). It additionally decreased the expression of the receptor activator of nuclear factor­κB ligand (RANKL) and consequently increased the protein ratio OPG/RANKL, whereas ALN exhibited the opposite effect. Furthermore, SR and ALN suppressed tumor necrosis factor­α and interleukin­1ß production, with SR exerting a more marked effect. The present results demonstrate that SR and ALN may stimulate bone formation and inhibit bone resorption in the ovariectomized mouse model of wear particle­mediated osteolysis, with SR demonstrating better effects compared with ALN.

SPHK-2 Promotes the Particle-Induced Inflammation of RAW264.7 by Maintaining Consistent Expression of TNF-α and IL-6.

Aseptic implant loosening is a devastating long-term complication of total joint arthroplasty. It is mainly initiated by the interaction of wear debris and macrophages. However, how does the chronic inflammation persist and how to stop it is poorly understood. Sphingosine kinases (SPHKs) are an essential feature of immunosuppressive M2 polarisation in macrophages and a promoter for chronic inflammation. In this study, RAW 264.7 macrophages were exposed to stimulation with titanium particles (0.1 mg/ml), and the subsequent expression of SPHKs and pro-inflammatory cytokines was evaluated. The effect of inhibitors of SPHKs (FTY720, PF543, and ABC294640) on titanium particle-challenged macrophages was analysed. As for results, the amount of sphingosine kinase (SPHK)-1 and SPHK-2 in RAW264.7 macrophages increased in the presence of titanium particles in a time-dependent manner. Two inhibitors of SPHKs (FTY720 and ABC294640) suppressed titanium particle-induced tumour necrosis factor (TNF)-α and interleukin (IL)-6 production in RAW264.7 macrophages. These findings suggest that persistent stimulation with titanium particles may lead to a consistent release of TNF-α and IL-6 via SPHK-2 activity, which may lead to aseptic implant loosening. Appropriate regulation of SPHK-2 may serve as a potential new strategy in the treatment of aseptic implant loosening.

Decreased migration with locally administered bisphosphonate in cemented cup revisions using impaction bone grafting technique.

Background and purpose - Impaction bone grafting (IBG) in revision hip surgery is an established method in restoring bone stock deficiencies. We hypothesized that local treatment of the morsellized allograft with a bisphosphonate in cemented revision would, in addition to increased bone density, also reduce the early migration of the cup as measured by radiostereometry (RSA). Patients and methods - 20 patients with aseptic cup loosening underwent revision using the IBG technique. The patients were randomized to either clodronate (10 patients) or saline (10 patients, control group) as local adjunct to the morsellized bone. The outcome was evaluated by dual-energy X-ray absorptiometry (DXA) during the first year regarding periacetabular bone density and with radiostereometric analysis (RSA) for the first 2 years regarding cup migration. Results - 2 patients were lost to follow-up: 9 patients remained in the clodronate and 9 in the control group. Less proximal migration was found in the clodronate group compared with the controls, measured both over time (mixed-models analysis, p = 0.02) as well as at the specified time points up to 2 years (0.22 mm and 0.59 mm respectively, p = 0.02). Both groups seemed to have stabilized at 1 year. We found similar bone mineral density measured by DXA, and similar RSA migration in the other directions. No cups were re-revised. Interpretation - Local treatment of the allograft bone with clodronate reduced early proximal migration of the revised cup but without any measurable difference in periacetabular bone density.

Strontium ranelate reduces the progression of titanium particle-induced osteolysis by increasing the ratio of osteoprotegerin to receptor activator of nuclear factor-κB ligand in vivo.

The present study aimed to investigate the effects of strontium ranelate (SR), an anti­osteoporotic drug, on osteolysis in an experimental mouse model of aseptic loosening. A total of 45 female C57BL/6J mice each received implantation of one titanium alloy pin into the tibia, followed by intraarticular injection of titanium particles. One week following surgery, mice were randomly divided into three groups: Control group (no additional treatment), SR625 group (treated with SR at a dose of 625 mg/kg/day), and SR1800 group (treated with SR at a dose of 1,800 mg/kg/day). SR was administered via oral gavage once every day for 12 weeks. Micro­computed tomography scanning and hematoxylin/eosin staining were used to assess osteolysis around the prosthesis. Immunohistochemistry and reverse transcription-quantitative polymerase chain reaction analysis were used to measure the expression of receptor activator of nuclear factor­κB ligand (RANKL) and osteoprotegerin (OPG). Compared with the control, the SR625 and SR1800 groups exhibited a significantly increased pulling force of the titanium alloy pin. Bone volume and the bone surface/volume ratio in the periprosthetic tissue were significantly increased in the SR­treated groups. Significant differences were observed between the SR1800 group and control group with respect to trabecular thickness and trabecular number. Mechanistically, SR downregulated the expression of RANKL and upregulated the expression of OPG in the periprosthetic tissue. In addition, SR was observed to inhibit wear particle­associated osteolysis in a dose­dependent manner. In conclusion, the present data illustrated that SR inhibited titanium particle­induced osteolysis in vivo.

Topical zoledronic acid decreases micromotion induced bone resorption in a sheep arthroplasty model.

BACKGROUND: Initial micromotion of a total hip replacement is associated with aseptic loosening. The use of bisphosphonates could be one way to reduce peri-implant bone resorption induced by micromotion. Bisphosphonates compounds are inhibitors of bone resorption. The aim of this study was to investigate whether local treatment with bisphosphonate would reduce bone resorption and fibrous tissue around an experimental implant subjected to micromotion. METHODS: One micromotion implant were inserted into each medial femoral condyle in ten sheep. During each gait cycle the implant axially piston 0.5 mm. During surgery one of the femoral condyles were locally treated with 0.8 mg zoledronate. The other condyle served as control. Observation period was 12 weeks. RESULTS: Histological evaluation showed a fibrous capsule around both the control and bisphosphonate implants. Histomorphometrical analysis showed that 97% of the surface on both control and bisphosphonate implants were covered by fibrous tissue. However, the bisphosphonate was able to preserve bone in a 1 mm zone around the implants. CONCLUSION: This study indicates that local treatment with bisphosphonate cannot prevent the formation of a fibrous capsule around an implant subjected to micromotion, but bisphosphonate is able to reduce resorption of peri-prosthetic bone.

The impact of glucocorticosteroids administered for systemic diseases on the osseointegration and survival of dental implants placed without bone grafting-A retrospective study in 31 patients.

PURPOSE: To evaluate the impact of glucocorticosteroids, administered for the treatment of systemic diseases, on the osseointegration and survival of dental implants placed without bone grafting. MATERIALS AND METHODS: A retrospective study was conducted in search of patients treated with dental implants while receiving glucocorticosteroid therapy for various systemic diseases. In these cases, a conventional two-stage surgical protocol was used, without bone regeneration procedures. The osseointegration was clinically and radiographically tested at the uncovering of the implants. The follow-up after loading was set at a minimum of 3 years. RESULTS: A total of 31 patients were included in the study. Of the 105 dental implants placed, 104 were osseointegrated (99%). No bone absorption was radiographically noted at the uncovering of the osseointegrated implants. All of the osseointegrated implants were successfully loaded for the prosthetic restoration. The mean follow-up period after loading was 71 months, with an implant survival rate of 99%. CONCLUSIONS: Glucocorticosteroid intake for systemic diseases does not have a significant impact on the osseointegration and the 3-year survival of dental implants placed with a conventional two-stage surgical protocol and without bone grafting. Therefore, it should not be considered a contraindication for dental implant placement.

Denosumab reduces early migration in total knee replacement.

Background and purpose - Aseptic loosening is a main cause of late revision in total knee replacement (TKR). Migration of implants as measured by radiostereometric analysis (RSA) can predict future loosening. This migration is associated with bone resorption. Denosumab is a human monoclonal antibody that binds to receptors on osteoclast precursors and osteoclasts. This prevents osteoclast formation, resulting in less bone resorption in cortical and trabecular bone. We investigated whether denosumab can reduce migration of TKR, as measured with RSA. Patients and methods - In this 2-center, randomized, double-blind placebo-controlled trial, 50 patients with osteoarthritis of the knee were treated with an injection of either denosumab (60 mg) or placebo 1 day after knee replacement surgery and again after 6 months. RSA was performed postoperatively and after 6, 12, and 24 months. The primary effect variable was RSA maximal total point motion (MTPM) after 12 months. We also measured other RSA variables and the knee osteoarthritis outcome score (KOOS). Results - The primary effect variable, MTPM after 12 months, showed that migration in the denosumab group was statistically significantly less than in the controls. Denosumab MTPM 12 months was reduced by one-third (denosumab: median 0.24 mm, 10% and 90% percentiles: 0.15 and 0.41; placebo: median 0.36 mm, 10% and 90% percentiles: 0.20 and 0.62). The secondary MTPM variables (6 and 24 months) also showed a statistically significant reduction in migration. There was no significant difference in MTPM for the period 12-24 months. KOOS sub-variables were similiar between denosumab and placebo after 12 and 24 months. Interpretation - Denosumab reduces early migration in total knee replacement, as in previous trials using bisphosphonates. As migration is related to the risk of late loosening, denosumab may be beneficial for long-term results.

Scutellarin inhibits RANKL-mediated osteoclastogenesis and titanium particle-induced osteolysis via suppression of NF-κB and MAPK signaling pathway.

Aseptic prosthetic loosening is a major complication after hip joint replacement. Wear particle-induced periprosthetic osteolysis plays a key role in aseptic prosthetic loosening. Attempting to modulate receptor activator of nuclear factor-κB (RANKL) mediated signaling pathways is a promising strategy to prevent aseptic prosthetic loosening. In the present study, we determined the effect of scutellarin (SCU) on titanium (Ti) particle-induced osteolysis in a mouse calvarial model and RANKL-mediated osteoclastogenesis. We determined that SCU, the major effective constituent of breviscapine isolated from a Chinese herb, has potential effects on preventing Ti particle-caused osteolysis in calvarial model of mouse. In vitro, SCU could suppress RANKL-mediated osteoclastogenesis, the function of osteoclast bone resorption, and the expression levels of osteoclast-specific genes (tartrate-resistant acid phosphatase (TRAP), cathepsin K, c-Fos, NFATc1). Further investigation indicated that SCU could inhibit RANKL-mediated MAPK and NF-κB signaling pathway, including JNK1/2, p38, ERK1/2, and IκBα phosphorylation. Taken together, these results indicate that SCU could inhibit osteoclastogenesis and prevent Ti particle-induced osteolysis by suppressing RANKL-mediated MAPK and NF-κB signaling pathway. These results suggest that SCU is a promising therapeutic agent for preventing wear particle-induced periprosthetic osteolysis.

Association between Exposure to Benzodiazepines and Related Drugs and Survivorship of Total Hip Replacement in Arthritis: A Population-Based Cohort Study of 246,940 Patients.

BACKGROUND: Total hip replacement (THR) is successful in treating hip arthritis. Prosthetic survivorship may depend on the medications taken by the patient; particularly, the role of benzodiazepines and related drugs (Z-drugs) with THR revision has been poorly investigated. Our objective was to compare THR short-term survivorship according to level of exposure to benzodiazepine and Z-drugs. DESIGN, SETTING AND PARTICIPANTS: All French patients aged 40 years or older, having undergone primary THR from January 1, 2009, through December 31, 2012, for arthritis according to French national health insurance databases were included in the cohort. Outcome of interest was THR revision, including any surgical procedure in which the implant or any component was changed or removed. Follow-up started the day the primary THR was performed. Observations were right-censored on December 31, 2014, if neither revision nor death had yet occurred. Exposure of interest was the cumulative defined daily doses per day (cDDD/day) of benzodiazepines and Z-drugs dispensed within 6 months before or after inclusion. We defined four exposure groups; cDDD/d = 0: unexposed; <0.08: low exposure;] 0.08-0.38]: medium exposure; >0.38: high exposure. THR survivorship was assessed according to level of exposure to benzodiazepines and Z-drugs in univariate and multivariate Cox models adjusted for patient, THR and implanting center characteristics. RESULTS: The study cohort comprised 246,940 individuals: mean age at baseline, 69.9 years; women, 57.9%; unexposed: 51.7%; low exposure: 16.7%; medium exposure: 15.9%; and high exposure: 15.7%. During the median 45-month follow-up, 9043 individuals underwent prosthetic revision. Adjusted hazard ratios in low, medium and high exposed groups were 1.18 (95%CI, 1.12-1.26; P<0.001), 1.32 (95%CI, 1.24-1.40; P<0.001) and 1.37 (95%CI, 1.29-1.45; P<0.001), respectively, compared to unexposed. CONCLUSION AND RELEVANCE: Exposure to benzodiazepines and Z-drugs is associated with an increased risk of THR revision, with a dose-response relationship. Cautious prescribing might be needed as well as careful history examination and assessment of risk for patients with a hip prosthesis.