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.

Poly 2-methacryloyloxyethyl Phosphorylcholine Protects Corneal Cells and Contact Lenses from Desiccation Damage.

SIGNIFICANCE: Contact lens (CL) wearing may cause discomfort and eye dryness. We describe here the efficacy of a synthetic polymer in protecting both the corneal epithelial cells and the CL from desiccation damage. Artificial tears containing this polymer might be helpful to treat or prevent ocular surface damage in CL wearers. PURPOSE: We aimed to investigate the protective effects of the synthetic polymer 2-methacryloyloxyethyl phosphorylcholine (poly-MPC) on corneal epithelial cells and CLs subjected to desiccation damage. METHODS: The interaction of poly-MPC with the cell membrane was evaluated on human primary corneal epithelial cells (HCE-F) by the sodium dodecyl sulfate damage protection assay or the displacement of the cell-binding lectin concanavalin A (ConA). Survival in vitro of HCE-F cells and ex vivo of porcine corneas exposed to desiccating conditions after pre-treatment with poly-MPC or hyaluronic acid (HA), hypromellose (HPMC), and trehalose was evaluated by a colorimetric assay. Soft CLs were soaked overnight in a solution of poly-MPC/HPMC and then let dry in ambient air. Contact lens weight, morphology, and transparency were periodically registered until complete dryness. RESULTS: Polymer 2-methacryloyloxyethyl phosphorylcholine and HPMC were retained on the HCE-F cell membrane more than trehalose or HA. Polymer 2-methacryloyloxyethyl phosphorylcholine, HA, and HPMC either alone or in association protected corneal cells from desiccation significantly better than did trehalose alone or in association with HA. Contact lens permeation by poly-MPC/HPMC preserved better their shape and transparency than did saline. CONCLUSIONS: Polymer 2-methacryloyloxyethyl phosphorylcholine coats and protects corneal epithelial cells and CLs from desiccation damage more efficiently compared with trehalose and as good as other reference compounds.

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.

Propofol Safety in Anticoagulated and Nonanticoagulated Patients During Extracorporeal Membrane Oxygenation.

Sedation management during extracorporeal membrane oxygenation(ECMO) is a common challenge encountered by treating intensivists. Data about the safety of propofol use during ECMO has been contradictory. We aimed to investigate associated risks of propofol use on oxygenator lifespan and to explore the effect of propofol use on oxygenator membranes when therapeutic anticoagulation was omitted. Adult respiratory ECMO patients who received propofol were retrospectively compared with those who did not, and outcomes were assessed by means of duration of oxygenator functionality before requiring an exchange, and number of exchanges during propofol use and/or ECMO support. Out of the 63patients included in the analysis, 46%received propofol during ECMO as part of sedation regimen. The use of propofol was not found to be associated with an increased incidence of oxygenator failure when compared with cohorts who did not receive propofol (21% propofol arm vs. 6% control, p = 0.13). When analyzed for anticoagulation omission effects, propofol did not increase the risk of oxygenator failure (p = 0.63). The only predictor that statistically predicted the risk of oxygenator failure was development of heparin-induced thrombocytopenia (HIT) during ECMO. The results of this study further support the previously reported safety of propofol utilization during respiratory ECMO even in the absence of anticoagulation.

Changes in Symptoms of Midday Fogging with a Novel Scleral Contact Lens Filling Solution.

SIGNIFICANCE: Midday fogging of scleral contact lenses requires frequent lens removal and reapplication for a large portion of lens wearers. Using a lens filling solution that mimics the composition of tears is hypothesized to have an impact on the production of material trapped under a scleral lens. PURPOSE: The purposes of this open-label study were to assess the safety of a scleral lens filling solution, which closely approximates the ionic concentration and pH of human tears, and to assess signs and symptoms of midday fogging with this formulation and with subjects' habitual sodium chloride solutions. METHODS: Existing scleral lens wearers with midday fogging (N = 22) were examined and completed surveys of symptoms. Subjects filled the concavity of their current lenses with test solution and were assessed immediately and approximately 4 hours later for safety monitoring. Test solution was dispensed and used for 5 to 9 days when subjects were reexamined and repeated the surveys. Biomicroscopy and anterior optical coherence tomography images were used to assess midday fogging objectively. RESULTS: The median (interquartile range) Ocular Surface Disease Index score decreased from 27.1 (21.7) U when using habitual filling solution to 9.1 (20.1) U when using the test solution (P = .006). Current Symptoms Survey findings with the test solution compared with habitual solution resulted in statistically significant decreases in burning/stinging (P = .04), grittiness/foreign body sensation (P = .01), dryness (P = .002), blurry/fluctuating vision (P = .002), and overall pain/discomfort (P = .006). Objective assessment of corneal staining and fogging revealed decreases that were not statistically significant in this small sample size. CONCLUSIONS: This study establishes the safety and subject tolerance of a scleral lens filling solution that mimics the ionic composition of human tears. Significant improvements in subjective ratings, although likely biased in this unmasked trial, suggest that further studies of the effectiveness of this solution in reducing midday fogging are warranted.

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.

Misoprostol administration prior to intrauterine contraceptive device insertion: a systematic review and meta-analysis of randomised controlled trials.

Objectives: Misoprostol has been used before intrauterine contraceptive device (IUCD) insertion to prime the cervical os. As the literature about this topic is controversial, we aimed to evaluate IUCD insertion failure, women's pain perception, use of cervical dilators and prevalence of side effects following the administration of misoprostol.Methods: Trials published in MEDLINE, Scopus, the Cochrane Library and ClinicalTrials.gov were searched (last search on 23 October 2019). The primary outcome was IUCD insertion failure; secondary outcomes were women's pain perception, use of cervical dilators to facilitate insertion, and prevalence of side effects.Results: Fourteen studies were eligible for inclusion. Misoprostol premedication reduced IUCD insertion failure rates and the use of cervical dilators but significantly increased the prevalence of side effects. The risk of IUCD insertion failure with misoprostol premedication was reduced among women who had undergone previous caesarean section and among women who had experienced previous IUCD insertion failure. Nulliparas did not benefit from misoprostol premedication. Buccal misoprostol administration did not seem to be effective in reducing IUCD insertion failure. Visual analogue scale pain scores were increased with both sublingual and buccal misoprostol administration if IUCD insertion was performed ≤2.5 h after misoprostol premedication.Conclusion: Our data demonstrate reduced IUCD insertion failure among women with previous caesarean section and those with previous IUCD insertion failure, suggesting that misoprostol may be a reasonable choice in these groups of women. Although misoprostol premedication reduced insertion failures, it significantly increased side effects and had a heterogeneous pattern of efficacy; thus, its routine use is not supported by the evidence.

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.

Effects of sequential treatment with intermittent parathyroid hormone and zoledronic acid on particle-induced implant loosening: Evidence from a rat model.

Particle-induced implant loosening is a major challenge to long-term survival of joint prostheses. Administration of intermittent parathyroid hormone (PTH) has shown potential in the treatment of cases of early-stage periprosthetic osteolysis, while sequential administration of intermittent PTH (iPTH) and bisphosphonates (Bps) has achieved significant effects on treatment of postmenopausal osteoporosis. The objective of this study was to determine whether sequential treatment could preserve bone mass and implant fixation during a pathological course of peri-implant osteolysis in a rat model. Ninety male Sprague Dawley rats were randomly divided into nine groups, four of which were used for confirmation of establishment of the peri-implant osteolysis model at two time points, while the other five were used to determine the efficiency of the sequential treatment on peri-implant osteolysis. Implant fixation and peri-implant bone mass were evaluated using biomechanical testing, micro-CT analysis, and histology at 6 and 12 weeks postoperative. The biomechanical test demonstrated that the maximum loading force during a push-out test was significantly elevated in the sequential treatment group compared to the osteolysis group and iPTH withdrawal group at 12 weeks. Peri-implant bone morphology also indicated a robust increase in bone volume in the sequential treatment group. Sequential administration of iPTH and Bps was effective in preventing experimental peri-implant osteolysis, resulting in improved implant fixation and increased peri-implant bone volume. Clinical significance: The innovative application of sequential treatment in peri-implant osteolysis could be used clinically to improve the prognosis of patients with early-stage periprosthetic osteolysis. © 2019 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 37:1489-1497, 2019.

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.

Effects of vitamin E incorporation in polyethylene on oxidative degradation, wear rates, immune response, and infections in total joint arthroplasty: a review of the current literature.

Highly cross-linked ultrahigh molecular weight polyethylene (UHMWPE) was introduced to decrease wear debris and osteolysis. During cross-linking, free radicals are formed, making highly cross-linked polyethylene vulnerable to oxidative degradation. In order to reduce this process, anti-oxidant vitamin E can be incorporated in polyethylene. This review provides an overview of the effects of vitamin E incorporation on major complications in total joint arthroplasty: material failure due to oxidative degradation, wear debris and subsequent periprosthetic osteolysis, and prosthetic joint infections. Secondly, this review summarizes the first clinical results of total hip and knee arthroplasties with vitamin E incorporated highly cross-linked polyethylene. Based on in vitro studies, incorporation of vitamin E in polyethylene provides good oxidative protection and preserves low wear rates. Incorporation of vitamin E may have the beneficial effect of reduced inflammatory response to its wear particles. Some microorganisms showed reduced adherence to vitamin E-incorporated UHMWPE; however, clinical relevance is doubtful. Short-term clinical studies of total hip and knee arthroplasties with vitamin E-incorporated highly cross-linked UHMWPE reported good clinical results and wear rates similar to highly cross-linked UHMWPE without vitamin E.

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.

Bisphosphonates for the preservation of periprosthetic bone mineral density after total joint arthroplasty: a meta-analysis of 25 randomized controlled trials.

The present meta-analysis aimed to evaluate the long-term efficacy of bisphosphonates (BPs) on preservation of periprosthetic bone mineral density (BMD) after joint arthroplasty. It confirmed the protective effect of BPs in a long-term follow-up, and found the influence factors on this effect. INTRODUCTION: Periprosthetic bone loss is believed to cause aseptic loosening and failed prosthetic fixation in joint arthroplasty. This meta-analysis which included high-quality randomized controlled trials aimed to analyze the effect of bisphosphonates on maintaining periprosthetic bone mineral density after total joint arthroplasty. METHODS: Twenty-five RCTs were included and the total number of participants was 1163 by computerized searches of bibliographic databases. The weighted mean differences with 95% confidence interval were calculated to evaluate the efficacy of BPs on total periprosthetic BMD and the BMD of different Gruen zones. Subgroup analyses identified the potentially influencing factors such as surgical site, cement fixation, and generation of BPs. A descriptive review was conducted for BP-related adverse effects. RESULTS: The BPs group presented significantly higher total periprosthetic BMD in the BPs group than that in the control group at 3, 6, 12 months, 2-4 years, and 5-10 years after arthroplasty (P < 0.05). The BPs group presented significantly higher periprosthetic BMD in femoral Gruen Zone 1 and 7 than that in the control group at 3, 6, 12 months, 2-4 years, and 5-10 years (P < 0.05). The heterogeneity was minimized by dividing THA and TKA into two subgroups. Subgroup analyses revealed that the effect of BPs on preservation of BMD was significantly greater in arthroplasty with cemented component than in that with uncemented component at 12 months and 5-10 years (P < 0.05), and the administration of the second and third generation BPs was significantly more effective than the first-generation BPs at 6 and 12 months (P < 0.05). None of the included studies described severe or fatal adverse effects related to BPs. CONCLUSIONS: BPs have significantly long-term efficacy on the preservation of periprosthetic BMD after joint arthroplasty. To obtain a better efficacy, the cemented components and the second and third generation BPs are recommended.