Are leukocyte-poor or multiple injections of platelet-rich plasma more effective than hyaluronic acid for knee osteoarthritis? A systematic review and meta-analysis of randomized controlled trials.

INTRODUCTION: Platelet-rich plasma (PRP) has gained popularity as a treatment option for knee osteoarthritis; however, its efficacy remains controversial. The optimal leukocyte concentration and number of injections have not been well investigated. This study was, therefore, designed to provide clinical evidence on the leukocyte concentration and number of intra-articular injections of PRP via a meta-analysis of randomized controlled trials (RCTs). METHODS: The MEDLINE, Embase, Cochrane Library, CINAHL, and Scopus databases were searched and RCTs comparing PRP and hyaluronic acid (HA) for treating knee osteoarthritis were included. Clinical outcomes, including visual analog scale (VAS) score, Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC), and adverse reactions, were evaluated. RESULTS: A total of 138 studies were screened, of which 21 level 1 RCTs (2086 knees; 1077 PRP and 1009 HA) were included. PRPs showed significant improvement in pain according to the VAS score compared to HA at 6 and 12 months, regardless of leukocyte concentration. Both single and multiple injections of PRP improved pain better than HA at 12 months. Regarding function, both single and multiple injections of leukocyte-poor PRP and leukocyte-rich PRP led to significantly better improvement in total WOMAC score compared with HA at 6 months. There was no significant difference in procedure-related knee pain or swelling between the PRP and HA groups. Leukocyte-rich PRP had a significantly higher odds ratio for procedure-related knee pain or swelling compared to HA (odds ratio, 3.3 [95% confidence interval, 1.1-10.2], P = .037). CONCLUSION: Based on evidence from Level 1 studies, intra-articular injection of PRP improves pain and function in patients with knee osteoarthritis for up to 12 months and is superior to HA, regardless of leukocyte concentration or number of injections. The findings of this study support the routine clinical use of intra-articular injections of PRP for the treatment of knee osteoarthritis, regardless of the type and frequency of PRP injection. LEVEL OF EVIDENCE: Meta-analysis of level I studies.

A predictive model with radiographic signs can be a useful supplementary diagnostic tool for complete discoid lateral meniscus in adults.

PURPOSE: To investigate the diagnostic accuracy of radiographic signs for complete discoid lateral meniscus and whether a predictive model combining the radiographic signs can improve its diagnostic accuracy in adults. METHODS: A total of adult 119 knees with complete discoid lateral meniscus confirmed by arthroscopy and 119 age- and sex-matched knees with normal meniscus were included. The radiographic signs of lateral joint space, fibular head height, lateral tibial spine height, lateral tibial plateau obliquity, lateral femoral condyle squaring, lateral tibial plateau cupping, lateral femoral condyle notching, and the condylar cut-off sign were evaluated. The receiver-operating characteristic (ROC) curves and area under the curve (AUC) were evaluated for best accuracy. A prediction model was developed by multivariable regression with generalized estimating models, and was validated using data from 111 knees of children with complete discoid lateral meniscus and 111 normal controls. RESULTS: The fibular head height, lateral joint space, lateral tibial plateau obliquity, and the condylar cut-off sign were significantly different between the complete discoid lateral meniscus and the normal groups (p < 0.05). Among the four radiographic signs, the fibular head height showed the highest accuracy with 78.9% sensitivity and 57.3% specificity. The prediction models developed by logistic regression showed significantly improved accuracy for complete discoid lateral meniscus compared to the fibular head height (sensitivity: 69.8%, specificity: 82.9%, p = 0.001). For validation, the AUC of children seemed to be larger than that of adults, which indicated that the prediction models could be applied for children to detect complete discoid lateral meniscus. CONCLUSION: Among several radiographic signs, the fibular head height can be used as a screening tool for complete discoid lateral meniscus. The prediction models combined with lateral joint space, fibular head height, lateral tibial plateau obliquity, and/or the condylar cut-off sign yielded a much higher diagnostic value than each radiographic sign. Therefore, fibular head height and prediction models combined with radiographic signs can provide improved diagnostic value for complete discoid lateral meniscus. LEVEL OF EVIDENCE: III.

Associations between biomarkers and histological assessment in individual animals in a destabilization of the medial meniscus (DMM) model of osteoarthritis (OA).

To date, the use of biomarkers for assessing individual severity of osteoarthritis (OA) is limited, and the correlation of histological scores with biomarkers for individual animals in the destabilization of the medial meniscus (DMM) model of OA has not been well investigated. Accordingly, this study investigated how well representative biomarkers in the DMM model reflected specific changes in individual animals. Rats were randomly divided into the OA group and the sham group. OA model was established by destabilization of the medial meniscus (DMM). After 2,4,6,8,10 and 12 weeks (n=14, each week), the concentrations of CTXII, COMP, C2C, and OC in serum were measured, and cartilage degeneration, osteophytes, and synovial membrane inflammation, typical of OA, were scored using Osteoarthritis Research Society International (OARSI) scoring system. Additionally, the correlation between each biomarker and the specific changes in osteoarthritis was analyzed for individual animals using the Generalized Estimating Equation (GEE). Statistical analysis showed a low correlation between CTXII and osteophyte score of the medial femur (coefficient = -0.0088, p= 0.0103), COMP and osteophyte score of the medial tibia (coefficient = -0.0911, p= 0.0003), and C2C and synovial membrane inflammation scores of the medial femoral (coefficient = 0.054, p= 0.0131). These results suggest that representative OA bio- markers in individual animals in the DMM model did not reflect histological scores well.

Underestimation and undertreatment of osteoporosis in patients awaiting primary total knee arthroplasty.

INTRODUCTION: Osteoporosis is generally regarded as a risk factor for periprosthetic fracture during or after primary total knee arthroplasty (TKA). Despite this, little is known about osteoporosis in patients undergoing elective primary TKA Therefore, we sought to investigate the prevalence of osteoporosis and rates of pharmacologic osteoporosis treatment prior to primary TKA. We hypothesized that preoperative osteoporosis is underestimated and undertreated in the primary TKA population. MATERIALS AND METHODS: This retrospective study included consecutive 1972 patients scheduled for elective primary TKA at a single tertiary hospital (age, 50-89 years). Charts were reviewed for patient demographics, prior pharmacologic osteoporosis treatment and Knee Society (KS) scoring system and WOMAC score. Dual energy X-ray absorptiometry (DEXA) measurement of the lumbar vertebrae and proximal femur was performed in all patients on the day before surgery. The associations of BMD with age, sex, body mass index (BMI), and clinical outcome were analyzed. RESULTS: The prevalence of osteoporosis was 50.0% (53.4% in women and 7.0% in men). Among patients with osteoporosis, only 15.1% (149/986) of patients (15.0% in women and 30.0% in men) had pharmacological osteoporosis treatment prior to primary TKA. Age, sex and WOMAC stiffness showed association with osteoporosis. Sex (odds ratio (OR): 20.83, p < 0.001) was the most significant factor associated with osteoporosis. CONCLUSION: Osteoporosis was highly prevalent in patients awaiting TKA, but the rates of diagnosis and pharmacologic osteoporosis treatment were low. Therefore, more attention needs to estimate and treat osteoporosis in patients awaiting primary TKA, especially in female patients.

Common Repository of FBS Proteins (cRFP) To Be Added to a Search Database for Mass Spectrometric Analysis of Cell Secretome.

We propose to use cRFP (common Repository of FBS Proteins) in the MS (mass spectrometry) raw data search of cell secretomes. cRFP is a small supplementary sequence list of highly abundant fetal bovine serum proteins added to the reference database in use. The aim behind using cRFP is to prevent the contaminant FBS proteins from being misidentified as other proteins in the reference database, just as we would use cRAP (common Repository of Adventitious Proteins) to prevent contaminant proteins present either by accident or through unavoidable contacts from being misidentified as other proteins. We expect it to be widely used in experiments where the proteins are obtained from serum-free media after thorough washing of the cells, or from a complex media such as SILAC, or from extracellular vesicles directly.

Antibiotic-impregnated articulating cement spacer maintained for 7 years in situ for two-stage primary total knee arthroplasty: a case report.

BACKGROUND: Antibiotic-impregnated articulating cement spacers can maintain interim joint motion with the potential to enhance functional status and improve patient satisfaction. Articular surfaces with cement against cement have raised concerns regarding mechanical complications and cement debris during knee motion. However, long-term clinical conditions regarding these concerns are not well addressed. CASE PRESENTATION: We report a case in which articulating cement spacers were maintained in situ for 7 years. The patient had severe left knee pain with an ankylosing knee and severe tricompartmental arthritis due to tuberculous infection. We planned to perform one- or two-stage primary total knee arthroplasty (TKA), depending on the presence of infection. Persistent osteomyelitis was found intraoperatively. The second-stage TKA was delayed on the patient's request. As the patient was satisfied with the improved knee function and pain relief after using articulating cement spacers. No symptom or sign that suggested recurrent infection or systemic toxicity was found during the 7-year follow-up. However, it seemed that the bone loss progressed insidiously. At the 7-year follow-up, a broken articulating cement spacer and medial femoral condylar fracture were found. The second-stage TKA was performed, and a considerable amount of bone loss surrounded by dense granulation tissue was observed intraoperatively. Excisional biopsy of the tissue revealed chronic foreign body reaction with infiltration of giant cells and macrophages. CONCLUSION: Although the articular spacers were maintained for 7 years without major complications, regular observation of the development and progress of bone loss was required. Surgeons should take considerable bone loss into account during conversion TKA in patients with a prolonged retention of articulating cement spacers.

Editorial Commentary: Considering Clinical Application of Bone Marrow Aspirate Concentrate for Restoration of Cartilage Defects in the Knee? Is It a Kind of Stem Cell Therapy?

The role of bone marrow aspirate concentrate (BMAC) is still inconclusive for restoration of chondral defects in lesions of the knee. More investigation is needed; thus, clinical application of BMAC for chondral defects should be considered cautiously. Correct nomenclature of the entity of cells used in various stem cell therapies for the treatment of cartilage lesions is critical to properly assess the efficacy and safety of various stem cell therapies. Constant effort is needed to prove the therapeutic potential of various novel therapeutic options such as BMAC or stem cell therapy under correct terminology for cartilage restoration before routine clinical application.

Intra-articular Mesenchymal Stem Cells in Osteoarthritis of the Knee: A Systematic Review of Clinical Outcomes and Evidence of Cartilage Repair.

PURPOSE: To provide a systematic review of the clinical literature reporting the efficacy of mesenchymal stem cells (MSCs) in terms of clinical outcomes including pain and function and cartilage repair in patients with osteoarthritis. METHODS: We systematically reviewed any studies investigating clinical outcomes and cartilage repair after the clinical application of cell populations containing MSCs in human subjects with knee osteoarthritis through MEDLINE, EMBASE, the Cochrane Library, CINAHL, Web of Science, and Scopus. Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines were followed. Studies with a level of evidence of IV or V were excluded. Methodological quality was assessed using the Modified Coleman Methodology Score. Clinical outcomes were assessed using clinical scores, and cartilage repair was assessed using magnetic resonance imaging and second-look arthroscopy findings. RESULTS: A total of 17 studies that met the criteria of 50 full-text studies were included in this review, with 6 randomized controlled trials, 8 prospective observational studies, and 3 retrospective case-control studies. Among 17 studies, 8 studies used bone marrow-derived MSCs, 6 used adipose tissue-derived stromal vascular fraction, 2 used adipose tissue-derived MSCs, and 1 used umbilical cord blood-derived MSCs. All studies except 2 reported significantly better clinical outcomes in the MSC group or improved clinical outcomes at final follow-up. In terms of cartilage repair, 9 of 11 studies reported improvement of the cartilage state on magnetic resonance imaging, and 6 of 7 studies reported repaired tissue on second-look arthroscopy. The mean Modified Coleman Methodology Score was 55.5 ± 15.5 (range, 28-74). CONCLUSIONS: Intra-articular MSCs provide improvements in pain and function in knee osteoarthritis at short-term follow-up (<28 months) in many cases. Some efficacy has been shown of MSCs for cartilage repair in osteoarthritis; however, the evidence of efficacy of intra-articular MSCs on both clinical outcomes and cartilage repair remains limited. LEVEL OF EVIDENCE: Level III; systematic review of level I, II, and III studies.

Variability of the Composition of Growth Factors and Cytokines in Platelet-Rich Plasma From the Knee With Osteoarthritis.

PURPOSE: To investigate the composition and concentration of growth factors and cytokines in platelet-rich plasma (PRP) with knee osteoarthritis and to explore the association of the concentration of growth factors and cytokines with the platelet count of PRPs. METHODS: Patients who visited outpatient clinic with symptomatic knee osteoarthritis (Kellgren-Lawrence grades 1 to 3) and had no blood dyscrasia were enrolled from October 2014 to March 2015. PRPs were obtained using a commercial system. Concentrations of growth factors and cytokines were measured with an enzyme-linked immunosorbent assay. Anabolic factors (platelet-derived growth factor [PDGF]-AA, -BB, and -AB, transforming growth factor-ß, vascular endothelial growth factor [VEGF], epidermal growth factor [EGF], basic fibroblast growth factor [bFGF], and insulin-like growth factor 1), catabolic factors (interleukin [IL]-1ß and matrix metalloproteinase 13), and catabolic blockers (IL-1 receptor antagonist) were included. The degree of variation was determined by coefficient of variation (CoV). RESULTS: 105 patients were included. Growth factors and cytokines showed wide variation. bFGF showed the highest variation (CoV 78.45), and transforming growth factor-ß1 showed the lowest variation (CoV 5.30). Platelet count in PRP showed a positive correlation with PDGF-BB and -AB, and VEGF (r = 0.270, P = .005; r = 0.231, P = .018; and r = 0.200, P = .041, respectively) and was negatively correlated with IL-1ß (r = -0.220, P = .025). CONCLUSION: Growth factors and cytokines in PRPs obtained from patients with knee osteoarthritis show a wide variation; the highest variation was shown in bFGF. Platelet counts associated positively with PDGF-AB and -BB and VEGF and negatively with IL-1ß. CLINICAL RELEVANCE: This information leads to the concept that variation and association of specific factors needs to be taken into consideration for future investigations of PRPs in clinical application in patients with knee osteoarthritis.

Comparable bone union progression after opening wedge high tibial osteotomy using allogenous bone chip or tri-calcium phosphate granule: a prospective randomized controlled trial.

PURPOSE: The purpose of this study is to compare the progression rate of bone union and clinical outcomes of opening wedge high tibial osteotomy (OWHTO) using allogenous bone chip or tri-calcium phosphate (TCP) granule as bone graft materials. The hypothesis was that the bone union progression in OWHTOs using TCP granule grafts would be comparable to that of OWHTOs using allogenous bone chip grafts. METHODS: Between 2011 and 2013, 54 patients who had undergone OWHTO for genu varum and osteoarthritis were randomized to one of the two groups at five centres. TCP granule was used to fill the defect in 27 patients and lyophilized allogenous bone chip was used in the other 27 patients. The degree of bone union was classified on a five-point scale and evaluated using plain radiographs of the knee at 6 weeks, 3 months, 6 months, and 12 months postoperatively. Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) score, pain Visual Analogue Scale (VAS) score and complications were also evaluated. RESULTS: The highest degree of bone union observed at 6 and 12 months postoperatively was grade 4, and the number of cases of union progression at each time-point was not significantly different between the two groups (p > 0.05). WOMAC and pain VAS scores also showed no differences between the two groups. No complications were observed during the 12-month period following OWHTO in either group. CONCLUSION: OWHTO using TCP granule bone substitute showed similar bone union rates and clinical outcomes compared to allogenous bone chip grafts. TCP granule can be used as bone substitutes instead of allogenous bone chip grafts in OWHTO. LEVEL OF EVIDENCE: Level 1.

Intra-articular injection of mesenchymal stem cells for clinical outcomes and cartilage repair in osteoarthritis of the knee: a meta-analysis of randomized controlled trials.

INTRODUCTION: Mesenchymal stem cells (MSCs) have gained popularity for articular cartilage repair. However, efficacy of intra-articular MSCs in osteoarthritis remains unclear. In the setting of a meta-analysis of randomized controlled trials (RCTs), we aimed to investigate the efficacy of intra-articular MSCs on clinical outcomes and cartilage repair in patients with knee osteoarthritis. MATERIALS AND METHODS: PubMed, EMBASE, Cochrane Library, CINAHL, and Scopus were searched from inception to March 31, 2017. This study included RCTs using cell population containing MSCs for treatment of knee osteoarthritis. The quality was assessed by Cochrane Collaboration`s risk of bias tool. For meta-analysis, data on clinical outcomes measured by visual analog scale (VAS), Lysholm score, WOMAC and data on cartilage repair measured by MOCART and WORMS were extracted. In studies with several cell concentrations, outcomes of recommended concentration were used mainly to ensure robustness. RESULTS: A total of five RCTs (220 patients) were included. Two studies were deemed to have low risk of bias. In pooled analysis, there was significant difference in VAS score (mean difference [MD], - 9.2; 95% CI: - 17.21, - 1.20) and Lysholm score (MD, 8.70; 95% CI 0.06, 17.34), but not WOMAC (MD, - 7.44; 95% CI - 20.38, 5.50). In cumulative functional analysis using Lysholm score and WOMAC in recommended concentration, there was a significant improvement (standard mean difference [SMD], 0.53; 95% CI 0.13, 0.94) after treatment. In cartilage repair assessed by MRI, there was no significant difference (SMD, 0.53; 95% CI- 0.28, 1.34). CONCLUSIONS: This meta-analysis demonstrated that intra-articular MSCs have a limited evidence in pain relief and functional improvement in knee osteoarthritis. While MSCs may result in favorable clinical outcomes with a recommended concentration, use of concomitant treatment should be considered. In addition, current evidence does not support the use of intra-articular MSCs for improving cartilage repair in knee osteoarthritis. LEVEL OF EVIDENCE: Systematic review of Level-II studies.

Prediction Models to Improve the Diagnostic Value of Plain Radiographs in Children With Complete Discoid Lateral Meniscus.

PURPOSE: To develop prediction models to improve the diagnostic utility of plain radiographs for the diagnosis of complete discoid lateral meniscus by combining previously reported radiographic findings. METHODS: Patients ages 5 to 16 years with complete discoid lateral meniscus confirmed by arthroscopy or magnetic resonance imaging were included. Patients with insufficient radiographs were excluded. Normal control subjects were randomly sampled by age and sex matching. Subjects were divided into 2 groups considering skeletal maturation (5-9 and 10-16 years). Radiographic variables included were lateral joint space, height of the fibular head, height of the lateral tibial spine, obliquity and cupping of the lateral tibial plateau, condylar cutoff sign, and squaring and notching of the lateral femoral condyle. Prediction models were developed by regression analyses. The cutoff value (COV) for best accuracy was determined with its sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV). RESULTS: A total of 162 knees (126 patients) with complete discoid lateral meniscus and 151 age- and sex-matched knees (151 subjects) with normal meniscus were included. In subjects 5 to 9 years old, the prediction model was risk score = [-20.08 * height of the fibular head/femoral interepicondylar distance (FIED)] + [-42.26 * height of the lateral tibial spine/FIED]. The COV of -8.47 showed the best accuracy (74.4%), with sensitivity of 85.9%; specificity, 60.4%; PPV, 72.4%; and NPV, 78.0%. In subjects 10 to 16 years old, the prediction model was risk score = [77.04 * lateral joint space/FIED] + [-34.55 * height of the fibular head/FIED] + [-56.58 * height of the lateral tibial spine/FIED] + [-16.44 * condylar cutoff sign]. The COV of -18.03 showed the best accuracy (85.4%), with sensitivity of 79.6%; specificity, 90.4%; PPV, 87.6%; and NPV, 83.9%. CONCLUSIONS: The prediction models combining the plain radiographic findings showed higher diagnostic values than the diagnostic values of the individual radiographic findings. The results of this study provide improved diagnostic utility of plain radiography for the detection of completed discoid lateral meniscus in children. LEVEL OF EVIDENCE: Level III, diagnostic study.

Inhibition of BATF/JUN transcriptional activity protects against osteoarthritic cartilage destruction.

OBJECTIVE: The basic leucine zipper transcription factor, ATF-like (BATF), a member of the Activator protein-1 family, promotes transcriptional activation or repression, depending on the interacting partners (JUN-B or C-JUN). Here, we investigated whether the BATF/JUN complex exerts regulatory effects on catabolic and anabolic gene expression in chondrocytes and contributes to the pathogenesis of osteoarthritis (OA). METHODS: Primary cultured mouse chondrocytes were treated with proinflammatory cytokines (interleukin-1ß, IL-6 or tumour necrosis factor-α) or infected with adenoviruses carrying the Batf gene (Ad-Batf). Expression of BATF and JUN was examined in human and mouse experimental OA cartilage samples. Experimental OA in mice was induced by destabilisation of the medial meniscus or intra-articular injection of Ad-Batf. The chromatin immunoprecipitation assay was used to examine the binding of BATF and JUN to the promoter regions of candidate genes. RESULTS: Overexpression of BATF, which forms a heterodimeric complex with JUN-B and C-JUN, induced upregulation of matrix-degrading enzymes and downregulation of cartilage matrix molecules in chondrocytes. BATF expression in mouse joint tissues promoted OA cartilage destruction, and conversely, knockout of Batf in mice suppressed experimental OA. Pharmacological inhibition of BATF/JUN transcriptional activity reduced the expression of matrix-degrading enzymes and protected against experimental OA in mice. CONCLUSIONS: BATF/JUN-B and BATF/C-JUN complexes play important roles in OA cartilage destruction through regulating anabolic and catabolic gene expression in chondrocytes. Our findings collectively support the utility of BATF as a therapeutic target for OA.

Safety and efficacy of bi-annual intra-articular LBSA0103 injections in patients with knee osteoarthritis.

The objective of this study is to assess the safety and efficacy of repeated intra-articular injection of high molecular weight hyaluronic acid (LBSA0103) at a 26-week interval, in patients with osteoarthritis of the knee. The study was an open-label, single arm, multicentre prospective trial conducted in patients with symptomatic knee osteoarthritis. The intervention consisted of two intra-articular injections of LBSA0103, with the second injection performed 26 weeks after the first injection. The primary outcome was the incidence of adverse drug reactions related to each injection. Assessment of efficacy of repeated injections in terms of maintenance of pain relief was a secondary objective of this study. Of the 185 patients screened, 174 patients received the first injection and 153 patients received both injections of LBSA0103. Nine adverse drug reactions occurred in seven patients (4.02%) after the first injection, while only one adverse drug reaction occurred (0.65%) after the second injection. As a secondary outcome measure, the improvements in the efficacy parameters including total WOMAC score and weight-bearing pain were all significant at both week 13 and 39 compared to the baseline value (P < 0.001), and improvements after the second injection were consistent with those after the initial injection of LBSA0103 (between week 26 and week 39, P < 0.001). Repeated intra-articular injection of LBSA0103 at a 26-week interval is safe without increased risk of adverse drug reactions. Additionally, LBSA0103 is effective in reduction of osteoarthritis knee pain and in maintenance of pain reduction for a 39-week period when a second injection is administered.

Restoration of a large osteochondral defect of the knee using a composite of umbilical cord blood-derived mesenchymal stem cells and hyaluronic acid hydrogel: a case report with a 5-year follow-up.

BACKGROUND: The treatment of articular cartilage defects is a therapeutic challenge for orthopaedic surgeons. Furthermore, large osteochondral defects needs restoration of the underlying bone for sufficient biomechanical characteristics as well as the overlying cartilage. CASE PRESENTATION: A symptomatic large osteochondral defect in the knee joint was restored using a composite of umbilical cord blood-derived mesenchymal stem cells (UCB-MSCs) 0.5 x 107/ml and 4% hyaluronic acid (HA) hydrogel. Significant improvements in pain and function of the knee joint were identified by the evaluation at 12 months after surgery. A hyaline-like cartilage completely filled the defect and was congruent with the surrounding normal cartilage as revealed by magnetic resonance imaging (MRI), a second-look arthroscopy and histological assessment. The improved clinical outcomes maintained until 5.5 years. MRI also showed the maintenance of the restored bony and cartilaginous tissues. CONCLUSION: This case report suggests that the composite of allogeneic UCB-MSCs and HA hydrogel can be considered a safe and effective treatment option for large osteochondral defects of the knee.

Efficacy and safety of single injection of cross-linked sodium hyaluronate vs. three injections of high molecular weight sodium hyaluronate for osteoarthritis of the knee: a double-blind, randomized, multi-center, non-inferiority study.

BACKGROUND: This randomized, double-blind, multi-center, non-inferiority trial was conducted to assess the efficacy and safety of a cross-linked hyaluronate (XLHA, single injection form) compared with a linear high molecular hyaluronate (HMWHA, thrice injection form) in patients with symptomatic knee osteoarthritis. METHODS: Two hundred eighty seven patients with osteoarthritis (Kellgren-Lawrence grade I to III) were randomized to each group. Three weekly injections were given in both groups but two times of saline injections preceded XLHA injection to maintain double-blindness. Primary endpoint was the change of weight-bearing pain (WBP) at 12 weeks after the last injection. Secondary endpoints included Western Ontario and McMaster Universities Osteoarthritis index; patient's and investigator's global assessment; pain at rest, at night, or in motion; OMERACT-OARSI responder rate; proportion of patients achieving at least 20 mm or 40% decrease in WBP; and rate of rescue medicine use and its total consumption. RESULTS: Mean changes of WBP at 12 weeks after the last injection were -33.3 mm with XLHA and -29.2 mm with HMWHA, proving non-inferiority of XLHA to HMWHA as the lower bound of 95% CI (-1.9 mm, 10.1 mm) was well above the predefined margin (-10 mm). There were no significant between-group differences in all secondary endpoints. Injection site pain was the most common adverse event and no remarkable safety issue was identified. CONCLUSIONS: This study demonstrated that a single injection of XLHA was non-inferior to three weekly injections of HMWHA in terms of WBP reduction, and supports XLHA as an effective and safe treatment for knee osteoarthritis. TRIAL REGISTRATION: ClinicalTrials.gov ( NCT01510535 ). This trial was registered on January 6, 2012.

Preoperative prediction of anterior cruciate ligament tibial footprint size by anthropometric variables.

PURPOSE: The purpose of this study was to evaluate whether the ACL tibial footprint size can be predicted by anthropometric variables including height, weight, leg length, femur length, tibia length, and anteroposterior and mediolateral diameters of proximal tibia. METHODS: This study included 209 out of the 378 eligible patients. The inclusion criterion was ACL with normal gross appearance. Patients with conditions that could have affected the measurement were excluded: torn ACL, osteophyte formation around the ACL tibial attachment, presence of inflammatory arthritis, or history of knee joint infection. According to the above criteria, 169 patients were excluded from this study; 138 had torn ACL, 24 had osteophyte around the ACL footprint, 5 had history of rheumatoid arthritis, and 2 had history of previous knee joint infection. The ACL tibial footprint was carefully dissected and measured during total knee arthroplasty. Anthropometric variables regarding bone lengths were measured on radiography. The association of the ACL tibial footprint size (length and width) with anthropometric variables was analysed using simple and multiple linear regression analyses. RESULTS: The height, weight, leg length, femur length, tibia length, and the size of proximal tibia were associated with the ACL tibial footprint length and width. The ACL tibial footprint length could be predicted by the equation using tibia length: ACL tibial footprint length = -9.361 + 0.759 * (tibia length in cm) (R 2 = 0.44, P < 0.001) and width by the equation using weight and tibia length: ACL tibial footprint width = -0.5615 + 0.279 * (tibia length in cm) + 0.0333 * (weight in kgs) (R 2 = 0.17, P < 0.001). The concordance correlation coefficient for the measured and predicted values of ACL tibial footprint length and width showed moderate and low agreement, respectively (0.61, 95 % CI 0.53-0.68; 0.30, 95 % CI 0.21-0.38). CONCLUSION: The ACL tibial footprint length and width are associated with anthropometric variables, especially with tibial length. The predictive equation developed from this study can serve as supplementary guides to determine the surgical techniques and graft options in preoperative planning of an individual ACL reconstruction. LEVEL OF EVIDENCE: IV.

The utility of the radiographic condylar cut-off sign in children and adolescents with complete discoid lateral meniscus.

PURPOSE: The purpose of this study was to determine the utility of the radiographic 'condylar cut-off sign' to detect the presence of a complete discoid lateral meniscus in children and adolescents. METHODS: The radiographs of 166 subjects younger than 17 with complete discoid lateral meniscus as well as 153 age- and sex-matched subjects with normal meniscus were reviewed. The condylar cut-off sign, judged by the prominence ratio of the medial and lateral femoral condyles in tunnel view radiographs, was assessed. The prominence ratio was compared between the complete discoid and the normal group. Subgroup analysis was performed by dividing the subjects into two groups: those younger than 10 and those between 10 and 16. When a significant difference was identified between the discoid and the normal group, the sensitivity, specificity and positive and negative predictive values (PPV and NPV) according to the best cut-off value for the prominence ratio was determined. RESULTS: The prominence ratio was significantly different between the complete discoid and normal groups in children and adolescents as a whole (p < 0.001). The ratio was also different in the subgroup aged 10-16 (p < 0.001), but not in the subgroup younger than 10 (n.s.). In children and adolescents as a whole, the condylar cut-off sign showed 50.6 % sensitivity, 79.4 % specificity, 73 % PPV and 59.8 % NPV with a cut-off value of 0.8. In the subgroup aged 10-16, the values were higher, with 65.3 % sensitivity, 79.6 % specificity, 76.2 % PPV and 69.6 % NPV using the same cut-off value. CONCLUSION: The condylar cut-off sign has a moderate degree of diagnostic utility for complete discoid lateral meniscus in adolescents aged 10-16. Early screening of complete discoid lateral meniscus in children or adolescents is important due to its vulnerability to meniscal tearing or arthrosis. The radiographic condylar cut-off sign can be used as a screening or supplementary diagnostic tool to detect the presence of a complete discoid lateral meniscus in this age group. LEVEL OF EVIDENCE: II.

Pleiotropic roles of metallothioneins as regulators of chondrocyte apoptosis and catabolic and anabolic pathways during osteoarthritis pathogenesis.

OBJECTIVE: The zinc-ZIP8-MTF1 axis induces metallothionein (MT) expression and is a catabolic regulator of experimental osteoarthritis (OA) in mice. The main aim of the current study was to explore the roles and underlying molecular mechanisms of MTs in OA pathogenesis. METHODS: Experimental OA in mice was induced by destabilisation of the medial meniscus or intra-articular injection of adenovirus carrying a target gene (Ad-Zip8, Ad-Mtf1, Ad-Epas1, Ad-Nampt, Ad-Mt1 or Ad-Mt2) into wild type, Zip8fl/fl; Col2a1-Cre, Mtf1fl/fl; Col2a1-Cre and Mt1/Mt2 double knockout mice. Primary cultured mouse chondrocytes were infected with Ad-Mt1 or Ad-Mt2, and gene expression profiles analysed via microarray and reverse transcription-PCR. Proteins in human and mouse OA cartilage were identified via immunostaining. Chondrocyte apoptosis in OA cartilage was determined using terminal deoxynucleotidyl transferase (TdT)-mediated deoxyuridine triphosphate (dUTP) nick end labelling (TUNEL). RESULTS: MTs were highly expressed in human and mouse OA cartilage. Hypoxia-inducible factor 2α, nicotinamide phosphoribosyltransferase and several proinflammatory cytokine pathways, as well as the zinc-ZIP8-MTF1 axis were identified as upstream regulators of MT expression. Genetic deletion of Mt1 and Mt2 enhanced cartilage destruction through increasing chondrocyte apoptosis. Unexpectedly, aberrant overexpression of MT2, but not MT1, induced upregulation of matrix-degrading enzymes and downregulation of matrix molecules through nuclear factor-kappa B (NF-κB) and activator protein-1 (AP-1) activation, ultimately leading to OA. CONCLUSIONS: MTs play an antiapoptotic role in post-traumatic OA. However, aberrant and chronic upregulation of MT2 triggers an imbalance between chondrocyte anabolism and catabolism, consequently accelerating OA development. Our findings collectively highlight pleiotropic roles of MTs as regulators of chondrocyte apoptosis as well as catabolic and anabolic pathways during OA pathogenesis.

The Effects of Adherence to Non-Steroidal Anti-Inflammatory Drugs and Factors Influencing Drug Adherence in Patients with Knee Osteoarthritis.

We aimed to compare the clinical outcomes of knee osteoarthritis patients according to drug adherence; and to find out the factors the affecting those outcomes. We analyzed the drug adherence and clinical outcomes in 1,334 primary knee osteoarthritis patients who took non-steroidal anti-inflammatory drugs (NSAIDs) for 3 weeks. Clinical outcomes of Pain Numeric Rating Scale (NRS), Knee injury and Osteoarthritis Outcome Score (KOOS) and EQ-5D were compared at baseline and 3 weeks' follow-up between the two groups of adherent group and non-adherent group (1,167 vs. 167 patients). Logistic regression analysis was performed to examine the factors affecting the adherence, and the reasons for the non-adherence were asked. The follow-up clinical outcomes of NRS and KOOS symptom, pain and activity of daily life were significantly higher in the adherence group (P = 0.003, P = 0.048, P = 0.005, and P = 0.003, respectively). The adherence was better in the elderly and in the male group (P = 0.042 and P = 0.034, respectively) and the top reason for no strict adherence was "symptom improved" (21.5%) followed by side effects. In this study, the patients with better adherence to NSAIDs showed better outcomes compared to those with poor adherence. This study can contribute to the patient education for the pharmacological treatment in knee OA patients.