Exosomes from bone marrow mesenchymal stem cells ameliorate glucocorticoid-induced osteonecrosis of femoral head by transferring microRNA-210 into bone microvascular endothelial cells.

OBJECTIVES: Bone microvascular endothelial cells (BMECs) played an important role in the pathogenesis of glucocorticoid-induced osteonecrosis of femoral head (GCS-ONFH), and exosomes derived from bone marrow mesenchymal stem cells (BMSC-Exos) may provide an effective treatment. This study aimed to evaluate the effects of BMSC-Exos and internal microRNA-210-3p (miRNA-210) on GCS-ONFH in an in vitro hydrocortisone-induced BMECs injury model and an in vivo rat GCS-ONFH model. METHODS: BMECs, BMSCs and BMSC-Exos were isolated and validated. BMECs after the treatment of hydrocortisone were cocultured with different concentrations of BMSC-Exos, then proliferation, migration, apoptosis and angiogenesis of BMECs were evaluated by CCK-8, Annexin V-FITC/PI, cell scratch and tube formation assays. BMSCs were transfected with miRNA-210 mimics and miRNA-210 inhibitors, then BMSC-ExosmiRNA-210 mimic and BMSC-ExosmiRNA-210 inhibitor secreted from such cells were collected. The differences between BMSC-Exos, BMSC-ExosmiRNA-210 mimic and BMSC-ExosmiRNA-210 inhibitor in protecting BMECs against GCS treatment were analyzed by methods mentioned above. Intramuscular injections of methylprednisolone were performed on Sprague-Dawley rats to establish an animal model of GCS-ONFH, then tail intravenous injections of BMSC-Exos, BMSC-ExosmiRNA-210 mimic or BMSC-ExosmiRNA-210 inhibitor were conducted after methylprednisolone injection. Histological and immunofluorescence staining and micro-CT were performed to evaluate the effects of BMSC-Exos and internal miRNA-210 on the in vivo GCS-ONFH model. RESULTS: Different concentrations of BMSC-Exos, especially high concentration of BMSC-Exos, could enhance the proliferation, migration and angiogenesis ability and reduce the apoptosis rates of BMECs treated with GCS. Compared with BMSC-Exos, BMSC-ExosmiRNA-210 mimic could further enhance the proliferation, migration and angiogenesis ability and reduce the apoptosis rates of BMECs, while BMECs in the GCS + BMSC-ExosmiRNA-210 inhibitor group showed reduced proliferation, migration and angiogenesis ability and higher apoptosis rates. In the rat GCS-ONFH model, BMSC-Exos, especially BMSC-ExosmiRNA-210 mimic, could increase microvascular density and enhance bone remodeling of femoral heads. CONCLUSIONS: BMSC-Exos containing miRNA-210 could serve as potential therapeutics for protecting BMECs and ameliorating the progression of GCS-ONFH.

The Optimal Dose, Efficacy and Safety of Tranexamic Acid and Epsilon-Aminocaproic Acid to Reduce Bleeding in TKA: A Systematic Review and Bayesian Network Meta-analysis.

OBJECTIVE: The optimal dose and efficacy of tranexamic acid (TXA) and epsilon-aminocaproic acid (EACA) in total knee arthroplasty (TKA) were under controversial, and we aimed to make comparisons between different doses of TXA and EACA in intravenous (IV) or intra-articular (IA) applications in patients undergoing TKA. METHODS: This network meta-analysis was guided by the Priority Reporting Initiative for Systematic Assessment and Meta-Analysis (PRISMA). According to the administrations of antifibrinolytic agents, patients in eligible studies were divided into three subgroups: (i) IA applications of TXA and EACA; (ii) IV applications (g) of TXA and EACA; (iii) IV applications (mg/kg) of TXA and EACA. Total blood loss (TBL), hemoglobin (HB) drops and transfusion rates were the primary outcomes, while drainage volume, pulmonary embolism (PE) or deep vein thrombosis (DVT) risk were the secondary outcomes. A multivariate Bayesian random-effects model was adopted in the network analysis. RESULTS: A total of 38 eligible trials with different regimens were assessed. Overall inconsistency and heterogeneity were acceptable. Taking all primary outcomes into account, 1.0-3.0 g TXA were most effective in IA applications, 1-6 g TXA and 10-14 g EACA were most effective in IV applications (g), while 30 mg/kg TXA and 150 mg/kg EACA were most effective in IV applications (mg/kg). None of the regimens showed increasing risk for pulmonary embolism (PE) or deep vein thrombosis (DVT) compared with placebo. CONCLUSION: 0 g IA TXA, 1.0 g IV TXA or 10.0 g IV EACA, as well as 30 mg/kg IV TXA or 150 mg/kg IV EACA were most effective and enough to control bleeding for patients after TKA. TXA was at least 5 times more potent than EACA.

The optimal regimen, efficacy and safety of tranexamic acid and aminocaproic acid to reduce bleeding for patients after total hip arthroplasty: A systematic review and Bayesian network meta-analysis.

OBJECTIVES: We aimed to evaluate the optimal regimen, efficacy and safety of tranexamic acid (TXA) and aminocaproic acid (EACA) for patients after total hip arthroplasty (THA). METHODS: The network meta-analysis was guided by the Preferred Reporting Items for Systematic Reviews and Meta-analysis (PRISMA) guideline. The outcomes were total blood loss, transfusion rates, hemoglobin (HB) drop, and risk for pulmonary embolism (PE) or deep vein thrombosis (DVT). Subgroup analyses were performed among most effective regimens to determine the influences of timing and number of doses. RESULTS: A total of 56 eligible RCTs with different regimens were assessed. For reducing total blood loss, all high doses of TXA and EACA except high dose of intra-articular (IA) TXA, as well as medium dose of combination of intravenous and intra-articular (combined IV/IA) TXA were most effective. All high doses of TXA, as well as medium dose of combined IV/IA TXA did not show inferiority in reducing transfusion rates and HB drop compared with other regimens. No regimens showed higher risk for PE or DVT compared with placebo, and no statistical differences were seen among most effective regimens in subgroup analyses. CONCLUSIONS: As effective as high doses of EACA and TXA, medium dose (20-40 mg/kg or 1.5-3.0 g) of combined IV/IA TXA was enough to control bleeding for patients after THA without increasing risk for PE/DVT. TXA was at least 5 times more potent than EACA. Timing and number of doses had few influences on blood conserving efficacy. LEVEL OF EVIDENCE: Level I.

Combination of Intravenous and Intra-Articular Application of Tranexamic Acid and Epsilon-Aminocaproic Acid in Primary Total Knee Arthroplasty: A Prospective Randomized Controlled Trial.

OBJECTIVE: There were limited randomized controlled trials (RCTs) of epsilon-aminocaproic acid (EACA) versus tranexamic acid (TXA) in total knee arthroplasty (TKA). The aim of the study was to compare the efficacy and safety of TXA and EACA in the combination of intravenous (IV) and intra-articular (IA) administration on reducing blood loss in patients following primary TKA. METHODS: From January 2020 to January 2021, a total of 181 patients undergoing a primary unilateral TKA were enrolled in this prospective randomized controlled trial. Patients in the TXA group (n = 90) received 20 mg/kg of intravenous TXA preoperatively, 1 g of intra-articular TXA intraoperatively, and three doses of 20 mg/kg intravenous TXA at 0, 3, 6 h postoperatively. Patients in the EACA group (n = 91) received 120 mg/kg of intravenous EACA preoperatively, 2 g of intra-articular EACA intraoperatively, and three doses of 40 mg/kg intravenous EACA at 0, 3, 6 h postoperatively. The primary outcomes were total blood loss (TBL), transfusion rates and drop of hemoglobin (HB) level. The secondary outcomes included postoperative hospital stays and postoperative complications. The chi-square tests and Fisher's exact tests were utilized to compare categorical variables, while the independent-samples t-tests and Mann-Whitney tests were used to compare continuous variables. RESULTS: The patients who received TXA averaged less TBL than the patients who received EACA (831.83 ml vs 1065.49 ml, P = 0.015), and HB drop in TXA group was generally less than that of EACA group on postoperative day 1 and 3 (20.84 ± 9.48 g/L vs 24.99 ± 9.40 g/L, P = 0.004; 31.28 ± 11.19 vs 35.46 ± 12.26 g/L, P = 0.047). The length of postoperative stays in EACA group was 3.66 ± 0.81 day, which is longer than 2.62 ± 0.68 day in TXA group (P < 0.001). No transfusions were required in either group. The risk of nausea and vomiting in TXA group was significantly higher than that in EACA group (11/90 vs 0/91, P < 0.01). CONCLUSION: Although the TBL and HB drop were slightly greater in EACA group, these results were not clinically important, given that no transfusions were required. EACA could be an alternative to TXA, especially for patients with severe nausea and vomiting after using TXA postoperatively. Further studies are needed to adjust dosage of EACA to make better comparison of the two drugs.

Comparisons of Different Bearing Surfaces in Cementless Total Hip Arthroplasty: A Systematic Review and Bayesian Network Analysis.

BACKGROUND: We aimed to make comparisons of different bearing surfaces in patients after cementless total hip arthroplasty. METHODS: The network meta-analysis was guided by the Preferred Reporting Items for Systematic Reviews and Meta-analysis (PRISMA) guideline. The primary outcomes were implant survival and Harris hip score (HHS). Secondary outcomes included linear wear rates and serum level of metal ions. Subgroup analyses were performed by: (1) classifying head sizes as small and large; (2) femoral heads as ceramic and metal; and (3) liners as metal, ceramic, polyethylene, highly cross-linked polyethylene (HXP), or vitamin E-infused highly cross-linked polyethylene (HXPE). A total of 64 eligible RCTs with different bearings were assessed. Overall inconsistency and heterogeneity were acceptable. RESULTS: In the 10 years follow-up, metal-on-polythene and ceramic-on-polythene bearings with small heads showed higher risk for revisions compared with metal-on-HXP and ceramic-on-HXP bearings with small heads. Similarly, only metal or ceramic-on-polythene bearings with small heads showed inferiority in HHS compared with other bearings. Conventional polyethylene liners showed higher linear wear rates compared with HXP, HXPE, and ceramic liners at 5 and 10 years after surgery, while metal-on-metal and ceramic-on-metal bearings showed higher serum level of cobalt and chromium. CONCLUSION: Bearings containing HXP, HXPE, and ceramic liners showed comparable survivorship and hip function at follow-up of 5 and 10 years. Hard-on-hard bearings containing metal had higher serum level of metal ions than others. Bearings containing conventional polyethylene had worse performance in terms of implant survival, hip function, and wear rates. LEVEL OF EVIDENCE: Level I.

No genetic causal association between iron status and osteoporosis: A two-sample Mendelian randomization.

Objective: To explore the genetic causal association between osteoporosis (OP) and iron status through Mendelian randomization (MR). Methods: Publicly available genome-wide association study (GWAS) summary data were used for MR analysis with four iron status-related indicators (ferritin, iron, total iron binding capacity, and transferrin saturation) as exposures and three different types of OP (OP, OP with pathological fracture, and postmenopausal OP with pathological fracture) as outcomes. The inverse-variance weighted (IVW) method was used to analyze the genetic causal association between the four indicators of iron status and OP. The heterogeneity of MR results was determined using IVW and MR-Egger methods. The pleiotropy of MR results was determined using MR-Egger regression. A leave-one-SNP-out test was performed to determine whether the MR results were affected by a single nucleotide polymorphism (SNP). The weighted median method was conducted to further validate our results. Results: Based on IVW, MR-Egger and weighted median models, we found no causal association between iron status (ferritin, iron, total iron binding capacity, or transferrin saturation) and OP (Pbeta > 0.05 in all models). IVW and MR-Egger analysis of OP with pathological fracture and iron status indicators showed no potential genetic causal association (Pbeta> 0.05 in the two analyses). The results of the weighted median were consistent with those of IVW (Pbeta> 0.05 in all analyses). There was no potential genetic causal association between iron status and postmenopausal OP with pathological fracture based on serum iron (Pbeta>0.05 in all models). No heterogeneity or horizontal pleiotropy was found in any of the analyses. None of the leave-one-out tests in the analyses found any SNP that could affect the results of MR. Conclusion: Our results demonstrate that there is no genetic causal association between OP and iron status, but the effects of other factors were not excluded.