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Objective Recent evidence supports that leukocyte telomere length (LTL) may be positively associated with healthy living and inversely correlated with the risk of age‐related diseases, including osteoporosis. Furthermore, it is important to note that sex hormone‐binding globulin (SHBG) levels play a crucial role in the regulation of osteoporosis by influencing the availability of sex hormones. Hence, this study holds significant importance as it aims to unravel the roles of LTL and SHBG levels and determine which one acts as a predominant intermediary factor in influencing osteoporosis. Using Mendelian randomization (MR), we can gain valuable insights into the intricate relationships between aging, sex hormones, and bone health. Methods Univariable and multivariable and MR analyses were employed in this study. First, we used genetic variants associated with both LTL, as determined from a study involving 472,174 European participants by Codd et al., and SHBG levels, as identified in a study conducted by Ruth et al. with 370,125 participants, as instrumental variables (IVs). Then we aimed to establish a causal relationship between LTL and SHBG levels and their potential impact on osteoporosis using univariable MR. Finally, we conducted multivariable MR to provide insights into the independent and combined effects of LTL, SHBG levels on osteoporosis risk. We used various MR methods, with the primary analysis employing the inverse‐variance weighted (IVW) model. Results Univariable MR analysis reveals a potential causal effect of longer LTL on reduced risk of osteoporosis [odds ratio (OR): 0.85; 95% confidence interval (CI): 0.73–0.99; p = 0.03]. Conversely, higher genetically determined SHBG levels affect the risk of osteoporosis positively. (OR: 1.38; 95% CI: 1.09–1.75; p

Objective Prior observational studies have reported that levels of sex hormones constitute a risk factor for the fracture. The aim of this study was to ascertain whether there is a causal relationship between the levels of sex hormones and the risk of fracture through Mendelian randomization (MR). Methods Single‐nucleotide polymorphisms (SNPs) associated with two indicators of sex hormone levels, circulating sex hormone‐binding globulin (SHBG) and bioavailable testosterone levels, as exposures were selected from a large genome‐wide association study (GWAS) from UK Biobank. The summary statistics for 11 different types of fracture as outcomes from the FinnGen consortium. This study employed the two‐sample MR approach. For the main analysis, the inverse‐variance‐weighted (IVW) method was utilized. To assess the heterogeneity of MR results, the IVW method and MR–Egger method were utilized. To evaluate potential pleiotropy, MR–Egger regression was conducted. Additionally, a leave‐one‐SNP‐out test was performed to assess the robustness of MR results to the exclusion of any individual SNP. Results The MR analyses demonstrated a conspicuous impact of SHBG on the risk of pathological fracture with osteoporosis (OP). We found that an increase of one standard deviation (SD) in SHBG correspondingly increased the risk of pathological fracture with OP [odds ratio (OR) 2.42, 95% confidence interval (CI), 1.52–3.85; p = 1.93 × 10−4]. The bioavailable testosterone showed the negative casual genetic associations with fractures of foot and forearm. An increase of one SD in the genetically predetermined bioavailable testosterone was associated with a reduction of 37% in the risk of fracture of foot (OR 0.63, 95% Cl 0.49 to 0.81; p = 3.37 × 10−4), as well as a 39% decrease in the risk of fracture of forearm (OR 0.61, 95% Cl 0.50 to 0.76; p = 5.40 × 10−6). Conclusions Our study confirms that individuals experiencing elevated SHBG concentrations showed a major causal effect on pathological fracture with OP. High bioavailable testosterone levels play an important role in preventing the fractures of foot and forearm. Although increasing bioavailable testosterone and decreasing SHBG levels had no casual effect on most fractures in the general population, they are likely to have the most clinically relevant effect on certain fracture risk reduction.

Abstract 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.

Objective In numerous observational studies, there has been an indication that educational attainment (EA) can impact the intensity of pain and disability resulting from chronic musculoskeletal disorders. Nonetheless, the association observed in these studies is not entirely conclusive. The aim of this study was to investigate the genetic causal relationship between educational attainment and 12 musculoskeletal disorders using Mendelian randomization (MR). Methods The meta‐analysis of genome‐wide association studies (GWAS) identified 3952 single‐nucleotide polymorphisms (SNPs) associated with educational attainment (EA) from the Social Science Genetic Association Consortium (SSGAC). Genetic data for 12 musculoskeletal disorders, including osteonecrosis, osteoporosis, osteomyelitis, low back pain, gout, spinal stenosis, rheumatoid arthritis, meniscus derangement, rotator cuff syndrome, ankylosing spondylitis, cervicobrachial syndrome, and lateral epicondylitis, were obtained from the FinnGen consortium. We conducted a two‐sample Mendelian randomization analysis to examine the causal effect of EA on the risk of these musculoskeletal disorders using the TwoSampleMR package in R. Results Based on the inverse‐variance weighted (IVW) method, we found that a genetically predicted per standard deviation (SD) increase in EA was inversely associated with low back pain [odds ratio (OR) 0.46, 95% confidence interval (Cl) 0.51–0.61, p

Abstract. Background:. Despite the advent of innovative knee prosthesis design, a consistent first-option knee implant design in total knee arthroplasty (TKA) remained unsettled. This study aimed to compare the clinical effects among posterior-stabilized (PS), cruciate-retaining (CR), bi-cruciate substituting (BCS), and bi-cruciate retaining designs for primary TKA. Methods:. Electronic databases were systematically searched to identify eligible randomized controlled trials (RCTs) and cohort studies from inception up to July 30, 2021. The primary outcomes were the range of knee motion (ROM), and the secondary outcomes were the patient-reported outcome measures (PROMs) and complication and revision rates. Confidence in evidence was assessed using Confidence in Network Meta-Analysis. The Bayesian network meta-analysis was performed for synthesis. Results:. A total of 15 RCTs and 18 cohort studies involving 3520 knees were included. The heterogeneity and inconsistency were acceptable. There was a significant difference in ROM at the early follow-up when PS was compared with CR (mean difference [MD] = 3.17, 95% confidence interval [CI] 0.07, 7.18) and BCS was compared with CR (MD = 9.69, 95% CI 2.18, 17.51). But at the long-term follow-up, there was no significant difference in ROM in any one knee implant compared with the others. No significant increase was found in the PROMs and complication and revision rates at the final follow-up time. Conclusions:. At early follow-up after TKA, PS and BCS knee implants significantly outperform the CR knee implant in ROM. But in the long run, the available evidence suggests different knee prostheses could make no difference in clinical outcomes after TKA with extended follow-up.

Abstract. Background:. Patellofemoral joint (PFJ) degeneration has traditionally been regarded as a contraindication to unicompartmental knee arthroplasty (UKA). More recently, some researchers have proposed that PFJ degeneration can be ignored in medial UKA, and others have proposed that this change should be reviewed in PFJ degenerative facets and severity. This study aimed to systematically evaluate the effect of PFJ degeneration on patient-reported outcome measures (PROMs) and revision rates after medial UKA. Methods:. Electronic databases (PubMed, Embase, Web of Science, etc.) were searched for studies assessing the influence of PFJ degeneration on medial UKA. A random-effects meta-analysis was conducted for the Oxford knee score (OKS), Knee society score (KSS), and revision rates and stratified by PFJ degenerative facets (medial/lateral/trochlear/unspecified), severe PFJ degeneration (bone exposed), and bearing type (mobile/fixed). Heterogeneity was assessed by the Cochran Q test statistic and chi-squared tests with the I-squared statistic. Results:. A total of 34 articles with 7007 knees (2267 with PFJ degeneration) were included (5762 mobile-bearing and 1145 fixed-bearing and 100 unspecified). Slight to moderate degenerative changes in the medial and trochlear facets did not decrease the OKS and KSS, and only lateral facets significantly decreased the OKS (mean difference [MD] = −2.18, P

Aims: Lumbar spinal stenosis (LSS) is a common skeletal system disease that has been partly attributed to genetic variation. However, the correlation between genetic variation and pathological changes in LSS is insufficient, and it is difficult to provide a reference for the early diagnosis and treatment of the disease. Methods: We conducted a transcriptome-wide association study (TWAS) of spinal canal stenosis by integrating genome-wide association study summary statistics (including 661 cases and 178,065 controls) derived from Biobank Japan, and pre-computed gene expression weights of skeletal muscle and whole blood implemented in FUSION software. To verify the TWAS results, the candidate genes were furthered compared with messenger RNA (mRNA) expression profiles of LSS to screen for common genes. Finally, Metascape software was used to perform enrichment analysis of the candidate genes and common genes. Results: TWAS identified 295 genes with permutation p-values < 0.05 for skeletal muscle and 79 genes associated for the whole blood, such as RCHY1 (PTWAS = 0.001). Those genes were enriched in 112 gene ontology (GO) terms and five Kyoto Encyclopedia of Genes and Genomes pathways, such as ‘chemical carcinogenesis - reactive oxygen species’ (LogP value = −2.139). Further comparing the TWAS significant genes with the differentially expressed genes identified by mRNA expression profiles of LSS found 18 overlapped genes, such as interleukin 15 receptor subunit alpha (IL15RA) (PTWAS = 0.040, PmRNA = 0.010). Moreover, 71 common GO terms were detected for the enrichment results of TWAS and mRNA expression profiles, such as negative regulation of cell differentiation (LogP value = −2.811). Conclusion: This study revealed the genetic mechanism behind the pathological changes in LSS, and may provide novel insights for the early diagnosis and intervention of LSS. Cite this article: Bone Joint Res 2023;12(6):387–396.

Objectives Perioperative enhanced recovery after surgery (ERAS) protocols can improve the quality of healthcare and reduce hospitalization for patients who underwent total hip arthroplasty (THA). The interval of staged bilateral THA under ERAS is still unclear. We attempt to ascertain the optimal interval of staged bilateral THA for reducing the perioperative complications and the cost of hospitalization. Methods We retrospectively reviewed patients who received staged bilateral THA under ERAS performed at West China Hospital of Sichuan University from 2018 to 2021. The staged time was divided into two groups using four different cutoff points: (1) ≤3 months versus >3 months, (2) ≤4 months versus >4 months, (3) ≤5 months versus >5 months and (4) ≤6 months versus >6 months. Primary outcomes included the rate of perioperative complications and the cost of hospitalization. The secondary outcomes were the length of hospital stay (LOS), the rates of transfusion and albumin (Alb) administration, hemoglobin (Hb) decrease and serum Alb decrease. The categorical variables were compared using chi‐squared and/or two‐tailed Fisher's exact tests, whereas continuous variables were compared using two‐tailed independent t‐tests, the continuous variables which were asymmetrical distributions used a Kruskal–Wallis test. Results With the application of ERAS, the rate of perioperative complications in the >5 months group was significantly lower than that in the ≤5 months group (13/195 vs. 45/307, p 5 monthly intervals spent significantly less than the ≤5 monthly intervals ($ 8695.91 vs. $ 8919.71, p

Objective The implications of the interval of staged bilateral total knee arthroplasty (TKA) procedures for postoperative complications and costs are not clear. We aimed to determine the optimal time interval between the two stages of bilateral TKA procedures under the enhanced recovery after surgery (ERAS) protocol. Methods This retrospective study of collected data included bilateral TKA cases under the ERAS protocol performed between 2018 and 2021 at the West China Hospital of Sichuan University. The staged time was subdivided into three groups according to the interval between the first TKA and second contralateral TKA: group 1: 2‐ to 6‐month, group 2: 6‐ to 12‐month, and group 3: >12 months. The primary outcome was the incidence of postoperative complications. The secondary outcomes were the length of hospital stay (LOS), hemoglobin (Hb) decrease, hematocrit (Hct) decrease, and albumin (Alb) decrease. Results We analyzed 281 patients who underwent staged bilateral TKAs between 2018 and 2021 at the West China Hospital of Sichuan University. Regarding postoperative complications, there were no statistically significant differences among the three groups (P = 0.21). For the mean LOS, the 6‐ to 12‐month group had a significantly shorter LOS compared with the 2‐ to 6‐month group (P 12 months group (P = 0.02; P

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.

Objectives Red blood cell distribution width (RDW) with prognosis in various infectious diseases. For fractured patients admitted to the intensive care units (ICU), an accurate and fast appraisal is essential. To investigate the association between RDW and prognosis in fractured patients admitted to the ICU utilizing the MIMIC‐III database. Methods A retrospective cohort from the MIMIC III database from 2001 and 2012 was constructed. RDW and other information were collected with in‐hospital mortality as the primary outcome and 90‐day mortality and hospital and intensive care unit (ICU) length of stay (LOS) as secondary outcomes. Univariate and multivariate logistic regression models with propensity score inverse probability of treatment weighting (IPTW) were used to investigate the prognostic value of RDW. A nomogram was built with significant prognostic factors to predict in‐hospital mortality, and the performance of the nomogram was evaluated and compared with other severity assessment scores. Subgroup analysis was also conducted. Results A total of 2721 fracture patients admitted to the ICU were identified. After IPTW, the group with higher RDW was significantly associated with elevated in‐hospital mortality (odds ratio [OR]: 1.68, 95% confidence interval [CI]: 1.19–2.37), 90‐day mortality (OR: 1.39, 95% CI: 1.04–1.86), prolonged hospital LOS (OR: 1.25, 95% CI: 1.03–1.50), and ICU LOS significantly (OR: 1.26, 95% CI: 1.05–1.53) in the multivariate logistics model. The nomogram showed optimal discriminative ability and predictive accuracy with an area under the receiver operating characteristic curve of 0.77. Conclusion RDW independently predicted in‐hospital mortality, 90‐day mortality, and hospital and ICU LOS in fractured patients admitted to ICU. The nomogram including RDW could also be a promising tool with potential clinical benefits.

AimsDegenerative cervical spondylosis (DCS) is a common musculoskeletal disease that encompasses a wide range of progressive degenerative changes and affects all components of the cervical spine. DCS imposes very large social and economic burdens. However, its genetic basis remains elusive.MethodsPredicted whole-blood and skeletal muscle gene expression and genome-wide association study (GWAS) data from a DCS database were integrated, and functional summary-based imputation (FUSION) software was used on the integrated data. A transcriptome-wide association study (TWAS) was conducted using FUSION software to assess the association between predicted gene expression and DCS risk. The TWAS-identified genes were verified via comparison with differentially expressed genes (DEGs) in DCS RNA expression profiles in the Gene Expression Omnibus (GEO) (Accession Number: GSE153761). The Functional Mapping and Annotation (FUMA) tool for genome-wide association studies and Meta tools were used for gene functional enrichment and annotation analysis.ResultsThe TWAS detected 420 DCS genes with p < 0.05 in skeletal muscle, such as ribosomal protein S15A (RPS15A) (PTWAS = 0.001), and 110 genes in whole blood, such as selectin L (SELL) (PTWAS = 0.001). Comparison with the DCS RNA expression profile identified 12 common genes, including Apelin Receptor (APLNR) (PTWAS = 0.001, PDEG = 0.025). In total, 148 DCS-enriched Gene Ontology (GO) terms were identified, such as mast cell degranulation (GO:0043303); 15 DCS-enriched Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways were identified, such as the sphingolipid signalling pathway (ko04071). Nine terms, such as degradation of the extracellular matrix (R-HSA-1474228), were common to the TWAS enrichment results and the RNA expression profile.ConclusionOur results identify putative susceptibility genes; these findings provide new ideas for exploration of the genetic mechanism of DCS development and new targets for preclinical intervention and clinical treatment.Cite this article: Bone Joint Res 2023;12(1):80–90.

Abstract Osteoarthritis (OA) is mainly characterized by the progressive destruction of articular cartilage. Mounting studies have revealed that disruption of extracellular matrix (ECM) homeostasis, aberrant chondrocyte metabolism, an increase in the number of senescent chondrocytes and abnormal activation of cell death such as chondrocyte apoptosis and autophagy, are the crucial steps in OA development. Additionally, mitochondrial dysfunction also participates in the abovementioned processes and is the key element of OA pathogenesis. Sirtuin (SIRT) is a family of nicotinamide adenine dinucleotide (NAD+)-dependent protein deacetylases that can actively participate and primarily regulate chondrocyte function in OA pathophysiological processes. Some members of the SIRT family located in mitochondria can regulate mitochondrial function and mediate mitochondrial homeostasis via deacetylation to protect chondrocytes. In addition, SIRT can maintain ECM homeostasis, regulate chondrocyte metabolism, inhibit chondrocyte apoptosis and autophagy, and prevent chondrocyte senescence in cartilage by exerting its deacetylation activity. However, the molecular mechanism of the SIRT family against the onset and development of OA remains poorly elucidated. In this review, we will discuss the potential protective role of SIRT in the progression of OA and summarize several sirtuin-activating molecules as well as their potential therapeutic applications for OA.

Abstract. Background:. Although various therapies have been developed to treat malalignment in osteoarthritic knees, the pattern of malalignment progression is still unclear. This study aimed to identify homogeneous subgroups with distinct trajectories of malalignment progression in subjects with symptomatic knee osteoarthritis (KOA) and to determine corresponding risk factors. Methods:. Eight-year follow-up (from 2004 to 2012) data on 1252 participants with symptomatic KOA from the Osteoarthritis Initiative were included. Varus/valgus angle progression was characterized by group-based trajectory models. Time-varying covariates were introduced into the model to investigate how they affected trajectories. Multinomial logistic regression for trajectory group membership was applied to ascertain risk factors. Results:. Five subgroups were identified. Participants in the varus worsening trajectory (n = 166) or valgus worsening trajectory (n = 118) proceeded to worsen malalignment over time. The neutral trajectory (n = 378), varus stable trajectory (n = 328), and valgus stable trajectory (n = 262) maintained close to the initial varus/valgus angle over 8 years. Higher baseline Kellgren and Lawrence grade (odds ratio [OR] = 4.35, P

Objective C‐reactive protein (CRP), erythrocyte sedimentation rate (ESR), plasma fibrinogen and D‐Dimer are used as diagnostic biomarkers of prosthetic joint infection (PJI) after total joint arthroplasty (TJA). The purpose of the study was to investigate the normal trajectory of CRP, ESR, plasma fibrinogen and D‐Dimer at different time points after two‐stage exchange arthroplasty for PJI. Methods We studied 53 patients undergoing two‐stage exchange for PJI at five time points: preoperatively (T0), duration of hospital stays (T1), 30 days (T2), 30–90 days (T3), and 90–180 days (T4) after surgery. The medical records of all patients were well documented and carefully reviewed. The Shapiro–Wilk test was utilized to compare the normal distribution for continuous variables, and the nonnormally distributed data were used for Friedmann's one‐way repeat measures analysis of variances. Post hoc Dunnett's test was used to compare each pair of data to find differences from baseline. Results Compare with T0 point, the levels of CRP and ESR increased significantly and reached peak values at T1 point (all P 0.05). Conclusions The study demonstrated the normal trajectory of CRP, ESR, plasma fibrinogen and D‐Dimer at five time points in patients who underwent two‐stage exchange for PJI. Thus, the results have the possibility of providing signs of infection after the patient receives two‐stage exchange arthroplasty for PJI, which can benefit from early treatment.

Abstract Osteoarthritis (OA) is a prevalent degenerative joint disease characterized by cartilage loss and accounts for a major source of pain and disability worldwide. However, effective strategies for cartilage repair are lacking, and patients with advanced OA usually need joint replacement. Better comprehending OA pathogenesis may lead to transformative therapeutics. Recently studies have reported that exosomes act as a new means of cell-to-cell communication by delivering multiple bioactive molecules to create a particular microenvironment that tunes cartilage behavior. Specifically, exosome cargos, such as noncoding RNAs (ncRNAs) and proteins, play a crucial role in OA progression by regulating the proliferation, apoptosis, autophagy, and inflammatory response of joint cells, rendering them promising candidates for OA monitoring and treatment. This review systematically summarizes the current insight regarding the biogenesis and function of exosomes and their potential as therapeutic tools targeting cell-to-cell communication in OA, suggesting new realms to improve OA management.

Abstract Background Osteoporosis is a common metabolic bone disease that is characterized by low bone mass. However, limited efforts have been made to explore the functional relevance of the blood proteome to bone mineral density across different life stages. Methods Using genome-wide association study summary data of the blood proteome and two independent studies of bone mineral density, we conducted a genetic correlation scan of bone mineral density and the blood proteome. Linkage disequilibrium score regression analysis was conducted to assess genetic correlations between each of the 3283 plasma proteins and bone mineral density. Results Linkage disequilibrium score regression identified 18 plasma proteins showing genetic correlation signals with bone mineral density in the TB-BMD cohort, such as MYOM2 (coefficient = 0.3755, P value = 0.0328) among subjects aged 0 ~ 15, POSTN (coefficient = − 0.5694, P value = 0.0192) among subjects aged 30 ~ 45 and PARK7 (coefficient = − 0.3613, P value = 0.0052) among subjects aged over 60. Conclusions Our results identified multiple plasma proteins associated with bone mineral density and provided novel clues for revealing the functional relevance of plasma proteins to bone mineral density.

Objective To verify whether an elevated preoperative international normalized ratio (INR) increases transfusion and complications independently in primary total hip arthroplasty (THA) with the management of an enhanced recovery after surgery (EARS) protocol. Methods We retrospectively reviewed the database of adults who underwent primary THA between 2014 and 2018 by the same surgeon. A total of 552 patients were assigned into three groups by preoperative INR class: INR ≤ 0.9, 0.9 0.05). Conclusions Elevated preoperative INR cannot increase transfusion or complication rates independently in primary THA with the management of the ERAS protocol. With the improvement in the ERAS protocol and the use of tranexamic acid (TXA), an INR

Abstract. Background:. Physical therapy is regarded as an essential aspect in achieving optimal outcomes following total knee arthroplasty (TKA). The coronavirus disease 2019 (COVID-19) pandemic has made face-to-face rehabilitation inaccessible. Virtual reality (VR) is increasingly regarded as a potentially effective option for offering health care interventions. This systematic review and meta-analysis investigate VR-based rehabilitation's effectiveness on outcomes following TKA. Methods:. From inception to May 22, 2021, PubMed/Medline, Embase, Web of Science, the Cochrane Central Register of Controlled Trials, Scopus, PsycINFO, Physiotherapy Evidence Database, China National Knowledge Infrastructure, and Wanfang were comprehensively searched to identify randomized controlled trials (RCTs) evaluating the effect of VR-based rehabilitation on patients following TKA according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses statement and the Cochrane Handbook for Systematic Reviews of Interventions. Results:. Eight studies were included in the systematic review, and seven studies were included in the meta-analysis. VR-based rehabilitation significantly improved visual analog scale (VAS) scores within 1 month (standardized mean difference [SMD]: −0.44; 95% confidence interval [CI]: −0.79 to −0.08, P = 0.02), the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) within 1 month (SMD: −0.71; 95% CI: −1.03 to −0.40, P

Abstract Hypertension was one common comorbidity of knee osteoarthritis (KOA), but the effect of different types of antihypertensive drugs on pain and joint space width (JSW) was unclear and not compared. Four hundred ninety KOA patients using one of the beta‐blockers, ACE inhibitors, angiotensin receptor blockers, Calcium channel blockers (CCBs), or thiazide diuretics were followed for four years. The blood pressure, cumulative knee replacement rate, Womac pain, and JSW were compared among groups. All data were from the Osteoarthritis Initiative project. The CCBs group has the highest systolic blood pressure, replacement rate, and pain score at most visit timepoints. At baseline, the CCBs group was with significantly higher pain score than the beta‐blockers group (3.3 vs 1.3, p

ObjectiveTo explore the genetic causal association between osteoporosis (OP) and iron status through Mendelian randomization (MR).MethodsPublicly 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.ResultsBased 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.ConclusionOur results demonstrate that there is no genetic causal association between OP and iron status, but the effects of other factors were not excluded.

Abstract Background Enhanced recovery after surgery (ERAS) program advocates implementation of perioperative goal-directed fluid therapy and reduced application of colloidal fluids. It should be used reasonably selectively in high-risk patients despite the clear efficacy of human albumin (HA). Therefore, it is vital to identify the risk factors for the use of HA. This study aims to determine the incidence and risk factors of HA administration in patients undergoing total hip or knee arthroplasty (THA, TKA). Methods We identified patients undergoing THA or TKA in multiple institutions from 2014 to 2016 and collected patient demographics and perioperative variables. The criterion of HA administration was defined as a postoperative albumin level < 32 g/L or 32 to 35 g/L for at-risk patients. We compared 14 variables between patients who received HA administration and those who did not after stratification by the preoperative albumin (pre-ALB) level. Multivariable regressions identified the independent risk factors associated with HA administration. Results In total, 958 (20.3%) of 4713 patients undergoing THA and 410 (9.7%) of 4248 patients undergoing TKA received HA administration. In addition to pre-ALB < 35 g/L, preoperative anemia (odds ratio [OR] 2.12, P = 0.001; OR 1.39, P < 0.001) and drain use (OR 3.33, P = 0.001; OR 4.25, P < 0.001) were also independent risk factors for HA administration after THA regardless pre-ALB < 35 g/L or not, and patients undergoing TKA diagnosed of rheumatoid arthritis or ankylosing spondylitis tended to receive HA administration regardless pre-ALB < 35 g/L or not (OR 3.67, P = 0.002; OR 2.06, P < 0.001). Conclusions The incidence of HA administration was high in patients undergoing THA or TKA, and several variables were risk factors for HA administration. This finding may aid surgeons in preoperatively identifying patients requiring HA administration and optimizing perioperative managements.

Abstract Background Although the high offset Tri-Lock bone preservation stem (BPS) was used widely, few studies explored the clinical and radiological results. The purpose of this study was to determine the clinical and radiological results of high offset Tri-Lock BPS in unilateral primary total hip arthroplasty (THA) at a minimum follow-up of 3 years. Methods 55 patients who underwent cementless THA with high offset Tri-lock BPS from 2017 to 2018 were followed for a minimum follow-up of 3 years. Patients were assessed clinically for complications, Harris hip score (HHS), Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC), and Oxford Hip Score (OHS). Femoral offset (FO), acetabular offset (AO), hip offset (HO), HO difference, and leg length discrepancy (LLD) were measured on the anteroposterior (AP) pelvic radiograph. Standard pelvic AP and lateral radiographs were used to evaluate for evidence of bone ingrowth, stem subsidence, stem alignment, radiolucent line around the stem, osteolysis, loosening, ectopic ossification, and femoral stress shielding. Results No patients reported complications during hospitalization nor the follow-up period. At a mean follow-up of 42.5 months, the mean HHS, WOMAC, and OHS scores showed a significant improvement from preoperative to the latest follow-up. No patients reported thigh pain. No revision nor sign of radiographic loosening had been detected. The high offset Tri-Lock BPS significantly improved the FO and HO postoperatively. HO difference and LLD were balanced postoperatively. No sign of stem subsidence, radiolucent line, osteolysis, loosening, ectopic ossification, nor severe stress shielding (more than grade 3–4) were observed at the latest follow-up. Conclusion The high offset Tri-Lock BPS demonstrated excellent clinical and radiographic outcomes at a minimum follow-up of 3 years. HO difference and LLD between legs decreased significantly and achieved balance postoperatively. Long-term follow-up is required for a definitive conclusion.

Abstract Background Current evidence does not recommend screening urine culture and curing asymptomatic bacteriuria (ASB) before joint arthroplasty. The bacteriuria count on pre-operative urinalysis is a more common clinical parameter. We aimed to investigate whether the bacteriuria count on preoperative urinalysis can increase postoperative wound complications in primary total hip arthroplasty (THA). Methods We conducted a retrospective study that included patients who underwent primary THA in our institution from 2012 to 2018. We obtained preoperative urinalysis results before THA during the same hospitalization and identified patients with abnormal urinalysis. Receiver operating characteristic (ROC) curves were first generated to evaluate the predicted value of leukocyte esterase (LE), nitrite, bacteriuria, and pyuria in the urinalysis for superficial wound infection. Then, all included patients were divided into two groups according to the preoperative urinalysis: a bacteriuria-positive group and a bacteriuria-negative group. The primary outcome was the superficial wound infection rate within 3 months postoperatively, and the secondary outcomes included wound leakage, prosthetic joint infection (PJI), pulmonary infection, urinary tract infection (UTI), readmission rate within 3 months postoperatively, and length of stay (LOS) during hospitalization. We utilized univariable analyses to compare the outcomes between the two groups. A multivariable logistic regression model was generated to explore the potential association between bacteriuria and the risk of superficial wound infection, wound leakage, and readmission rate controlling for baseline values. Results A total of 963 patients were included in the study. One hundred sixty patients had abnormal urinalysis. The AUCs for LE, nitrite, bacteriuria, and pyuria were 0.507 (95% confidence interval (CI), 0.315 to 0.698), 0.551 (0.347 to 0.756), 0.675 (0.467 to 0.882), and 0.529 (0.331 to 0.728), respectively. Bacteriuria was diagnostically superior to LE, nitrite, and pyuria. Among the 963 patients, 95 had a positive bacteriuria on preoperative urinalysis, and only 9 (9.5%) had a positive urine culture. Compared with the bacteriuria-negative group, the bacteriuria-positive group had a higher superficial wound infection rate (4.2% vs. 0.6%, P = 0.008), higher wound leakage rate (11.6% vs. 4.5%, P = 0.007), higher readmission rate (5.3% vs. 1.3%, P = 0.015) within 3 months postoperatively and longer LOS (6.19 ± 2.89 days vs. 5.58 ± 2.14 days, P = 0.011). After adjustment, the bacteriuria-positive group had a significantly increased risk of superficial wound infection (OR = 7.587, 95%CI: 2.002 to 28.755, P = 0.003), wound leakage (OR = 3.044, 95%CI: 1.461 to 6.342, P = 0.003), and readmission (OR = 4.410, 95%CI: 1.485 to 13.097, P = 0.008). Conclusion Preoperative bacteriuria positivity on urinalysis significantly increased the risk of postoperative wound complications, readmission, and LOS in primary THA regardless of the result of the urine culture. Urinalysis is a fast and cost-acceptable test whose advantages have been underestimated. Level of evidence Level III, observational study.

BackgroundJuvenile idiopathic arthritis (JIA) is the most common rheumatic disease in children, and its pathogenesis is still unclear. Genome-wide association studies (GWASs) of JIA have identified hundreds of risk factors, but few of them implicated specific biological mechanisms.MethodsA cross-tissue transcriptome-wide association study (TWAS) was performed with the functional summary-based imputation software (FUSION) tool based on GWAS summary datasets (898 JIA patients and 346,102 controls from BioBank Japan (BBJ)/FinnGen). The gene expression reference weights of skeletal muscle and the whole blood were obtained from the Genotype-Tissue Expression (GTExv8) project. JIA-related genes identified by TWAS findings genes were further compared with the differentially expressed genes (DEGs) identified by the mRNA expression profile of JIA from the Gene Expression Omnibus (GEO) database (accession number: GSE1402). Last, candidate genes were analyzed using functional enrichment and annotation analysis by Metascape to examine JIA-related gene sets.ResultsThe TWAS identified 535 significant genes with P

Abstract Exportin 5 (XPO5) is a shuttle protein that mediates precursor miRNA (pre‐miRNA) export from the nucleus to the cytoplasm, an important step in miRNA maturation. We previously demonstrated that XPO5 was phosphorylated by ERK kinase and subsequently underwent conformation change by the peptidyl‐prolyl isomerase Pin1, leading to the reduced miRNA expression in hepatocellular carcinoma (HCC). Protein phosphorylation modification serves as a reversible regulatory mechanism precisely governed by protein kinases and phosphatases. Here we identified that the phosphatase PP2A catalyzed XPO5 dephosphorylation. PP2A holoenzyme is a ternary complex composed of a catalytic subunit, a scaffold subunit, and a regulatory subunit that determines substrate specificity. In this study, we characterized the involvement of B55β subunit in XPO5 dephosphorylation that favored the distribution of XPO5 into the cytoplasm and promoted miRNA expression, leading to HCC inhibition in vitro and in vivo. Our study demonstrates the regulatory role of B55β‐containing PP2A in miRNA expression and may shed light on HCC pathogenesis.

Abstract Background Whether the cement should be used in the total knee arthroplasty (TKA) was still in controversy. This meta-analysis was performed to compare the efficacy of two kinds of fixation. Methods Randomized controlled trials (RCTs), prospective/retrospective observational studies from PubMed (on 2019 September), EMBASE (on 2019 September), and the Cochrane Central Register of Controlled Trials (CENTRAL) and Web of Science (on 2019 September) were searched. Only studies followed more than 2 years was included for the review. The PRISMA guidelines and Cochrane Handbook were adopted to assess the quality of the results reported in included studies to ensure that the results of our meta-analysis were reliable and veritable. The continuous and dichotomous outcomes were collected in a standard form, and the data were analyzed by Review Manager 5.3 software. Finally, the results were presented in the Forest plots. Results Twenty-six studies involving 2369 patients in cementless TKA and 2654 patients in cemented TKA were included. The rate of revision was not significantly different in two groups (p = 0.55). More than eight reasons caused revision were found in our study, the aseptic loosing was the most common, followed by the periprosthetic joint infection (PJI), neither was significantly different (p = 0.88 and 0.45, respectively). While significantly better long-term functional recovery was found in cementless TKA in terms of Knee Society Function Score (p = 0.004) and manipulation under anesthesia (p = 0.007). Conclusion Cementless fixation did not decrease the rate of revision after the total knee arthroplasty compared with the cemented fixation, while the long-term functional recovery was significantly better in the cementless group.

Abstract Background The purpose of this systematic review and meta-analysis was to compare the direct anterior approach and posterior approach for primary total hip arthroplasty in terms of the clinical, functional and radiographic outcomes. Methods We searched the PubMed and EMBASE databases and Cochrane Library from their inception to November 1, 2019. We searched for previously published articles and meta-analyses of randomized controlled trials. Results A total of 7 randomized controlled trials with 600 participants met the inclusion criteria. Among these patients, 301 and 299 were included in the DAA and PA groups, respectively. The DAA was associated with a longer surgery by a mean duration of 13.74 min (95% CI 6.88 to 20.61, p

Background: This systematic review and meta-analysis aimed to evaluate the effect of neuromuscular electrical stimulation (NMES) on quadriceps muscle strength, pain, and function outcomes following total knee arthroplasty (TKA).Methods: PubMed/Medline, Embase, Web of Science, CENTRAL, Scopus, PsycINFO, PEDro, CINAHL, CNKI, and Wanfang were systematically searched for randomized controlled trials (RCTs) from their inception to 18 June 2021.Results: Nine RCTs that involving 691 patients were included in the meta-analysis. Our pooled analysis showed that NMES improved quadriceps muscle strength after TKA within 1 months [standardized mean difference (SMD): 0.81; 95% CI: 0.51–1.11], 1–2 months (SMD: 0.55; 95% CI: 0.13–0.97), 3–4 months (SMD: 0.42; 95% CI: 0.18–0.66), and 12–13 months (SMD: 0.46; 95% CI: 0.18–0.74), pain between 1 and 2 months [mean difference (MD): −0.62; 95% CI: −1.04 to −0.19], pain between 3 and 6 months (MD: −0.44; 95% CI: −0.74 to −0.14) Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) between 3 and 4 months (MD: −0.43; 95% CI: −0.82 to −0.05), timed up and go test (TUG) within 1 month (MD: −2.23; 95% CI: −3.40 to −1.07), 3 minutes walk test between 3 and 6 months (MD: 28.35; 95% CI: 14.55–42.15), and SF-36 MCS between 3 and 6 months after TKA (MD: 4.20, 95% CI: 2.41–5.98).Conclusion: As a supplementary treatment after TKA, postoperative NMES could improve the short-term to long-term quadriceps muscle strength, mid-term pain, and mid-term function following TKA. However, many outcomes failed to achieve statistically meaningful changes and minimal clinically important difference (MCID), thus the clinical benefits remained to be confirmed.Level of Evidence: Therapeutic level I.Systematic Review Registration:https://www.crd.york.ac.uk/PROSPERO/, identifier CRD42021265609.

Bisphosphonate has great potential in KOA therapy, but whether the anti-resorption mechanism of bisphosphonate aggravates sclerosis of subchondral bone remains unclear. We found that bisphosphonate use did not increase sclerosis of subchondral bone in established KOA, perhaps resolving some concerns about bisphosphonate in patients with KOA.Introduction: Most studies have focused on the protective effect of bisphosphonate on early knee osteoarthritis (KOA) through its anti-resorption mechanism in osteoclasts. However, late KOA has a decreased rate of resorption, which is the opposite of early KOA. The risk of subchondral bone sclerosis in late KOA after using bisphosphonate has not been investigated using morphometry.Methods: Forty-five patients who had ever used bisphosphonate (or 33 patients with current use) were matched with controls through propensity matching methods, including age, body mass index (BMI), sex, health status (12-Item Short Form Survey physical health score), physical activity level (Physical Activity Scale for the Elderly score), vitamin D use, and calcium use. At the baseline and 12-month (or 18-month) follow-up, bone mineral density (BMD) of the tibia and hip was measured by dual-energy X-ray absorptiometry (DXA), and medial tibial subchondral bone morphometry: bone volume fraction (BV/TV), trabecular thickness (Tb.Th), trabecular number (Tb.N), and trabecular separation (Tb.Sp) were calculated based on 3-T trabecular MRI. Data were obtained from the Bone Ancillary Study in the Osteoarthritis Initiative (OAI) project.Results: The yearly percentage change in hip BMD of the current bisphosphonate-use group was significantly greater than that of the non-bisphosphonate-use group (0.7% vs. −1%, P = 0.02). The other outcomes (BV/TV, Tb.N, Tb.Sp, Tb.Th, tibia medial BMD, and tibia lateral BMD) between the two groups presented no significant difference. The non-bisphosphonate-use group experienced a significant increase in Tb.Th [2%, 95% CI = (1%, 4%), P = 0.01], while the bisphosphonate-use group presented no significant change [1%, 95% CI = (−2%, 4%), P = 0.54].Conclusions: Bisphosphonate use did not increase sclerosis of subchondral bone in established KOA. Bisphosphonate might have a stage-dependent effect on subchondral bone in KOA initiation and progression.

Objective: Observational studies have shown the association between iron status and osteoarthritis (OA). However, due to difficulties of determining sequential temporality, their causal association is still elusive. Based on the summary data of genome-wide association studies (GWASs) of a large-scale population, this study explored the genetic causal association between iron status and OA. Methods: First, we took a series of quality control steps to select eligible instrumental SNPs which were strongly associated with exposure. The genetic causal association between iron status and OA was analyzed using the two-sample Mendelian randomization (MR). Inverse-variance weighted (IVW), MR-Egger, weighted median, simple mode, and weighted mode methods were used for analysis. The results were mainly based on IVW (random effects), followed by sensitivity analysis. IVW and MR-Egger were used for heterogeneity testing. MR-Egger was also used for pleiotropy testing. Leave-one-SNP-out analysis was used to identify single nucleotide polymorphisms (SNPs) with potential impact. Maximum likelihood, penalized weighted median, and IVW (fixed effects) were performed to further validate the reliability of results. Results: IVW results showed that transferrin saturation had a positive causal association with knee osteoarthritis (KOA), hip osteoarthritis (HOA) and KOA or HOA (p < 0.05, OR > 1), and there was a negative causal association between transferrin and HOA and KOA or HOA (p < 0.05, OR < 1). The results of heterogeneity test showed that our IVW analysis results were basically free of heterogeneity (p > 0.05). The results of the pleiotropy test showed that there was no pleiotropy in our IVW analysis (p > 0.05). The analysis results of maximum likelihood, penalized weighted median and IVW (fixed effects) were consistent with our IVW results. No genetic causal association was found between serum iron and ferritin and OA. Conclusions: This study provides evidence of the causal association between iron status and OA, which provides novel insights to the genetic research of OA.

Ferroptosis, a recently discovered regulated cell death modality, is characterised by iron-dependent accumulation of lipid hydroperoxides, which can reach lethal levels but can be specifically reversed by ferroptosis inhibitors. Osteoarthritis (OA), the most common degenerative joint disease, is characterised by a complex pathogenesis involving mechanical overload, increased inflammatory mediator levels, metabolic alterations, and cell senescence and death. Since iron accumulation and oxidative stress are the universal pathological features of OA, the role played by ferroptosis in OA has been extensively explored. Increasing evidence has shown that iron dyshomeostasis and lipid peroxidation are closely associated with OA pathogenesis. Therefore, in this review, we summarize recent evidence by focusing on ferroptotic mechanisms and the role played by ferroptosis in OA pathogenesis from the perspectives of clinical findings, animal models, and cell research. By summarizing recent research advances that characterize the relationship between ferroptosis and OA, we highlight avenues for further research and potential therapeutic targets.

Objective: Osteoporosis (OP) is the most common bone disease. The genetic and metabolic factors play important roles in OP development. However, the genetic basis of OP is still elusive. The study aimed to explore the relationships between OP and dietary habits. Methods: This study used large-scale genome-wide association study (GWAS) summary statistics from the UK Biobank to explore potential associations between OP and 143 dietary habits. The GWAS summary data of OP included 9434 self-reported OP cases and 444,941 controls, and the GWAS summary data of the dietary habits included 455,146 participants of European ancestry. Linkage disequilibrium score regression (LDSC) was used to detect the genetic correlations between OP and each of the 143 dietary habits, followed by Mendelian randomization (MR) analysis to further assess the causal relationship between OP and candidate dietary habits identified by LDSC. Results: The LDSC analysis identified seven candidate dietary habits that showed genetic associations with OP including cereal type such as biscuit cereal (coefficient = −0.1693, p value = 0.0183), servings of raw vegetables per day (coefficient = 0.0837, p value = 0.0379), and spirits measured per month (coefficient = 0.115, p value = 0.0353). MR analysis found that OP and PC17 (butter) (odds ratio [OR] = 0.974, 95% confidence interval [CI] = (0.973, 0.976), p value = 0.000970), PC35 (decaffeinated coffee) (OR = 0.985, 95% CI = (0.983, 0.987), p value = 0.00126), PC36 (overall processed meat intake) (OR = 1.035, 95% CI = (1.033, 1.037), p value = 0.000976), PC39 (spirits measured per month) (OR = 1.014, 95% CI = (1.011, 1.015), p value = 0.00153), and servings of raw vegetables per day (OR = 0.978, 95% CI = (0.977, 0.979), p value = 0.000563) were clearly causal. Conclusions: Our findings provide new clues for understanding the genetic mechanisms of OP, which focus on the possible role of dietary habits in OP pathogenesis.

Abstract Background The purpose of this study was to investigate the efficacy and safety of multiple low-dose dexamethasones in primary total knee arthroplasty (TKA). Methods One hundred fifty patients were equally randomized into 3 groups: Group A (n = 50) received 2 doses of normal saline only; Group B (n = 50) received with 1 dose of intravenous dexamethasone and 1 dose of normal saline; Group C (n = 50) received with 2 doses of intravenous dexamethasone. The clinical outcomes and complications were assessed. Results The CRP and IL-6 were significantly lower in Group C and B than Group A at 24, 48, and 72 h postoperatively (P

Background: Iron overload is drawing attention in the development of knee osteoarthritis (OA). To identify the modifiable risk factors for iron-related pathological conditions, we examined the association between iron intake and the risk of knee OA progression. Methods: A total of 1912 participants in the Osteoarthritis Initiative (OAI), aged 45–79 years and with at least one knee radiographic OA at baseline, were identified and were followed up to 6 years. The iron and other nutrient intake was measured by the validated Block Brief 2000 Food Frequency Questionnaire. The outcome measures were by radiographic progression on the basis of the Kellgren–Lawrence (KL) grade and the joint-space-narrowing (JSN) score. The association between the iron intake and the knee OA progression was examined by Cox proportional hazards models and restricted cubic spline (RCS) regression. Results: Among the study participants, 409 participants experienced KL-grade progression, and 684 participants experienced JSN-score progression within 6 years. Overall, the association between iron intake and the risk of KL-grade progression followed a U shape (p for nonlinearity < 0.001). The risk of KL-grade progression was significantly lower in participants with iron intakes of 23.3 mg/day: adjusted HR, 1.60; 95% CI, 1.19–2.16). Similar U-shaped relations were found for iron intake with the risk of JSN-score progression (p for nonlinearity = 0.035). Conclusions: There was a U-shaped association between the iron intake and the progression of knee OA, with an inflection point at about 16.5 mg/day, and minimal risk from 10.9 to 23.3 mg/day of iron intake. An appropriate iron intake was advisable for knee OA, whereas excessive or deficient iron intake increased the risk of knee OA progression.

Abstract Background The combined administration of intravenous (IV) and topical tranexamic acid (TXA) in primary total knee (TKA) knee remains controversial. The purpose of this meta-analysis was to assess the efficacy and safety of combined administration of IV and topical TXA in primary TKA. Methods PubMed, EMBASE, Cochrane Central Register of Controlled Trials, Web of Science, Google Search Engine and China National Knowledge Infrastructure databases were searched for randomized controlled trials (RCTs) were comparing the combined administration of IV and topical TXA following primary TKA. The primary outcomes were total blood loss, maximum hemoglobin drop, and deep venous thrombosis (DVT) and/or pulmonary embolism (PE). The second outcomes were drainage volume and transfusion requirements. Data were analyzed using RevMan 5.3. Results A total of 6 RCTs involving 701 patients were included in the meta-analysis. The combined group provided lower total blood loss (MD − 156.34 mL, 95% CI, − 241.51 to − 71.18; P = 0.0003), drainage volume (MD − 43.54 mL, 95% CI, − 67.59 to − 19.48; P = 0.0004), maximum hemoglobin drop (MD − 0.56 g/dl, 95% CI, − 0.93 to − 0.19; P = 0.003) than IV TXA alone. No significant difference were found in terms of transfusion requirements (RR 0.48, 95% CI, 0.16 to 1.44; P = 0.19), DVT (RR 1.01, 95% CI, 0.14 to 7.12; P = 0.99) and PE (RR 0.33, 95% CI, 0.01 to 7.91; P = 0.49) between the two group. Subgroup analyses shows that the combined group was less total blood loss in non-tourniquet (P = 0.0008), topical TXA dose > 1.5 g (P 1.5 g and number of IV TXA ≥ 2 doses of TXA. There was no increase the rates of DVT and PE.