Aucubin suppresses TLR4/NF-κB signalling to shift macrophages toward M2 phenotype in glucocorticoid-associated osteonecrosis of the femoral head.

In this study, we investigated whether the ability of aucubin to mitigate the pathology of GONFH involves suppression of TLR4/NF-κB signalling and promotion of macrophage polarization to an M2 phenotype. In necrotic bone tissues from GONFH patients, we compared levels of pro-inflammatory M1 macrophages and anti-inflammatory M2 macrophages as well as levels of TLR4/NF-κB signalling. In a rat model of GONFH, we examined the effects of aucubin on these parameters. We further explored its mechanism of action in a cell culture model of M1 macrophages. Necrotic bone tissues from GONFH patients contained a significantly increased macrophage M1/M2 ratio, and higher levels of TLR4, MYD88 and NF-κB p65 than bone tissues from patients with hip osteoarthritis. Treating GONFH rats with aucubin mitigated bone necrosis and demineralization as well as destruction of trabecular bone and marrow in a dose-dependent manner, based on micro-computed tomography. These therapeutic effects were associated with a decrease in the overall number of macrophages, decrease in the proportion of M1 macrophages, increase in the proportion of M2 macrophages, and downregulation of TLR4, MYD88 and NF-κB p65. These effects in vivo were confirmed by treating cultures of M1 macrophage-like cells with aucubin. Aucubin mitigates bone pathology in GONFH by suppressing TLR4/NF-κB signalling to shift macrophages from a pro- to anti-inflammatory phenotype.

Lithium prevents glucocorticoid-induced osteonecrosis of the femoral head by regulating autophagy.

Autophagy may play an important role in the occurrence and development of glucocorticoid-induced osteonecrosis of the femoral head (GC-ONFH). Lithium is a classical autophagy regulator, and lithium can also activate osteogenic pathways, making it a highly promising therapeutic agent for GC-ONFH. We aimed to evaluate the potential therapeutic effect of lithium on GC-ONFH. For in vitro experiments, primary osteoblasts of rats were used for investigating the underlying mechanism of lithium's protective effect on GC-induced autophagy levels and osteogenic activity dysfunction. For in vivo experiments, a rat model of GC-ONFH was used for evaluating the therapeutic effect of oral lithium on GC-ONFH and underlying mechanism. Findings demonstrated that GC over-activated the autophagy of osteoblasts and reduced their osteogenic activity. Lithium reduced the over-activated autophagy of GC-treated osteoblasts through PI3K/AKT/mTOR signalling pathway and increased their osteogenic activity. Oral lithium reduced the osteonecrosis rates in a rat model of GC-ONFH, and restrained the increased expression of autophagy related proteins in bone tissues through PI3K/AKT/mTOR signalling pathway. In conclusion, lithium can restrain over-activated autophagy by activating PI3K/AKT/mTOR signalling pathway and up-regulate the expression of genes for bone formation both in GC induced osteoblasts and in a rat model of GC-ONFH. Lithium may be a promising therapeutic agent for GC-ONFH. However, the role of autophagy in the pathogenesis of GC-ONFH remains controversial. Studies are still needed to further explore the role of autophagy in the pathogenesis of GC-ONFH, and the efficacy of lithium in the treatment of GC-ONFH and its underlying mechanisms.

HIF-1α in cartilage homeostasis, apoptosis, and glycolysis in mice with steroid-induced osteonecrosis of the femoral head.

With the prevalence of coronavirus disease 2019, the administration of glucocorticoids (GCs) has become more widespread. Treatment with high-dose GCs leads to a variety of problems, of which steroid-induced osteonecrosis of the femoral head (SONFH) is the most concerning. Since hypoxia-inducible factor 1α (HIF-1α) is a key factor in cartilage development and homeostasis, it may play an important role in the development of SONFH. In this study, SONFH models were established using methylprednisolone (MPS) in mouse and its proliferating chondrocytes to investigate the role of HIF-1α in cartilage differentiation, extracellular matrix (ECM) homeostasis, apoptosis and glycolysis in SONFH mice. The results showed that MPS successfully induced SONFH in vivo and vitro, and MPS-treated cartilage and chondrocytes demonstrated disturbed ECM homeostasis, significantly increased chondrocyte apoptosis rate and glycolysis level. However, compared with normal mice, not only the expression of genes related to collagens and glycolysis, but also chondrocyte apoptosis did not demonstrate significant differences in mice co-treated with MPS and HIF-1α inhibitor. And the effects observed in HIF-1α activator-treated chondrocytes were similar to those induced by MPS. And HIF-1α degraded collagens in cartilage by upregulating its downstream target genes matrix metalloproteinases. The results of activator/inhibitor of endoplasmic reticulum stress (ERS) pathway revealed that the high apoptosis rate induced by MPS was related to the ERS pathway, which was also affected by HIF-1α. Furthermore, HIF-1α affected glucose metabolism in cartilage by increasing the expression of glycolysis-related genes. In conclusion, HIF-1α plays a vital role in the pathogenesis of SONFH by regulating ECM homeostasis, chondrocyte apoptosis, and glycolysis.

Inhibition of insulin degrading enzyme suppresses osteoclast hyperactivity via enhancing Nrf2-dependent antioxidant response in glucocorticoid-induced osteonecrosis of the femoral head.

BACKGROUND: Osteoclast hyperactivation due to the pathological overproduction of reactive oxygen species (ROS) stimulated by glucocorticoids (GCs) is one of the key drivers behind glucocorticoid-induced osteonecrosis of the femoral head (GIONFH). The insulin degrading enzyme (IDE), a conserved Zn2+ metallo-endopeptidase, facilitates the DNA binding of glucocorticoid receptor and plays a substantial role in steroid hormone-related signaling pathways. However, the potential role of IDE in the pathogenesis of GIONFH is yet undefined. METHODS: In this study, we employed network pharmacology and bioinformatics analysis to explore the impact of IDE inhibition on GIONFH with 6bK as an inhibitory agent. Further evidence was collected through in vitro osteoclastogenesis experiments and in vivo evaluations involving methylprednisolone (MPS)-induced GIONFH mouse model. RESULTS: Enrichment analysis indicated a potential role of 6bK in redox regulation amid GIONFH development. In vitro findings revealed that 6bK could attenuate GCs-stimulated overactivation of osteoclast differentiation by interfering with the transcription and expression of key osteoclastic genes (Traf6, Nfatc1, and Ctsk). The use of an H2DCFDA probe and subsequent WB assays introduced the inhibitory effects of 6bK on osteoclastogenesis, linked with the activation of the nuclear factor erythroid-derived 2-like 2 (Nrf2)-mediated antioxidant system. Furthermore, Micro-CT scans validated that 6bK could alleviate GIONFH in MPS-induced mouse models. CONCLUSIONS: Our findings suggest that 6bK suppresses osteoclast hyperactivity in GCs-rich environment. This is achieved by reducing the accumulation of intracellular ROS via promoting the Nrf2-mediated antioxidant system, thus implying that IDE could be a promising therapeutic target for GIONFH.

Palliative effect of rotating magnetic field on glucocorticoid-induced osteonecrosis of the femoral head in rats by regulating osteoblast differentiation.

With the substantial increase in the overuse of glucocorticoids (GCs) in clinical medicine, the prevalence of glucocorticoid-induced osteonecrosis of the femoral head (GC-ONFH) continues to rise in recent years. However, the optimal treatment for GC-ONFH remains elusive. Rotating magnetic field (RMF), considered as a non-invasive, safe and effective approach, has been proved to have multiple beneficial biological effects including improving bone diseases. To verify the effects of RMF on GC-ONFH, a lipopolysaccharide (LPS) and methylprednisolone (MPS)-induced invivo rat model, and an MPS-induced invitro cell model have been employed. The results demonstrate that RMF alleviated bone mineral loss and femoral head collapse in GC-ONFH rats. Meanwhile, RMF reduced serum lipid levels, attenuated cystic lesions, raised the expression of anti-apoptotic proteins and osteoprotegerin (OPG), while suppressed the expression of pro-apoptotic proteins and nuclear factor receptor activator-κB (RANK) in GC-ONFH rats. Besides, RMF also facilitated the generation of ALP, attenuated apoptosis and inhibits the expression of pro-apoptotic proteins, facilitated the expression of OPG, and inhibited the expression of RANK in MPS-stimulated MC3T3-E1 cells. Thus, this study indicates that RMF can improve GC-ONFH in rat and cell models, suggesting that RMF have the potential in the treatment of clinical GC-ONFH.

Omaveloxolone ameliorates glucocorticoid-induced osteonecrosis of the femoral head by promoting osteogenesis and angiogenesis.

Steroid (glucocorticoid)-induced necrosis of the femoral head (SONFH) represents a prevalent, progressive, and challenging bone and joint disease characterized by diminished osteogenesis and angiogenesis. Omaveloxolone (OMA), a semi-synthetic oleanocarpane triterpenoid with antioxidant, anti-inflammatory, and osteogenic properties, emerges as a potential therapeutic agent for SONFH. This study investigates the therapeutic impact of OMA on SONFH and elucidates its underlying mechanism. The in vitro environment of SONFH cells was simulated by inducing human bone marrow mesenchymal stem cells (hBMSCs) and human umbilical vein endothelial cells (HUVECs) using dexamethasone (DEX).Various assays, including CCK-8, alizarin red staining, Western blot, qPCR, immunofluorescence, flow cytometry, and TUNNEL, were employed to assess cell viability, STING/NF-κB signaling pathway-related proteins, hBMSCs osteogenesis, HUVECs migration, angiogenesis, and apoptosis. The results demonstrate that OMA promotes DEX-induced osteogenesis, HUVECs migration, angiogenesis, and anti-apoptosis in hBMSCs by inhibiting the STING/NF-κB signaling pathway. This experimental evidence underscores the potential of OMA in regulating DEX-induced osteogenesis, HUVECs migration, angiogenesis, and anti-apoptosis in hBMSCs through the STING/NF-κB pathway, thereby offering a promising avenue for improving the progression of SONFH.

Identification of steroid-induced osteonecrosis of the femoral head biomarkers based on immunization and animal experiments.

BACKGROUND: Steroid-induced osteonecrosis of femoral head (SONFH) is a severe health risk, and this study aims to identify immune-related biomarkers and pathways associated with the disease through bioinformatics analysis and animal experiments. METHOD: Using SONFH-related datasets obtained from the GEO database, we performed differential expression analysis and weighted gene co-expression network analysis (WGCNA) to extract SONFH-related genes. A protein-protein interaction (PPI) network was then constructed, and core sub-network genes were identified. Immune cell infiltration and clustering analysis of SONFH samples were performed to assess differences in immune cell populations. WGCNA analysis was used to identify module genes associated with immune cells, and hub genes were identified using machine learning. Internal and external validation along with animal experiments were conducted to confirm the differential expression of hub genes and infiltration of immune cells in SONFH. RESULTS: Differential expression analysis revealed 502 DEGs. WGCNA analysis identified a blue module closely related to SONFH, containing 1928 module genes. Intersection analysis between DEGs and blue module genes resulted in 453 intersecting genes. The PPI network and MCODE module identified 15 key targets enriched in various signaling pathways. Analysis of immune cell infiltration showed statistically significant differences in CD8 + t cells, monocytes, macrophages M2 and neutrophils between SONFH and control samples. Unsupervised clustering classified SONFH samples into two clusters (C1 and C2), which also exhibited significant differences in immune cell infiltration. The hub genes (ICAM1, NR3C1, and IKBKB) were further identified using WGCNA and machine learning analysis. Based on these hub genes, a clinical prediction model was constructed and validated internally and externally. Animal experiments confirmed the upregulation of hub genes in SONFH, with an associated increase in immune cell infiltration. CONCLUSION: This study identified ICAM1, NR3C1, and IKBKB as potential immune-related biomarkers involved in immune cell infiltration of CD8 + t cells, monocytes, macrophages M2, neutrophils and other immune cells in the pathogenesis of SONFH. These biomarkers act through modulation of the chemokine signaling pathway, Toll-like receptor signaling pathway, and other pathways. These findings provide valuable insights into the disease mechanism of SONFH and may aid in future drug development efforts.

Comparison of clinical efficacy of robot-assisted and freehand core decompression in the treatment of osteonecrosis of the femoral head: a systematic review and meta-analysis.

OBJECTIVE: At present, the core decompression (CD) has become the main surgical procedure for the treatment of osteonecrosis of the femoral head (ONFH); however, the CD surgery requires high operator experience and repeated fluoroscopy increases the radiation damage to patients, and medical staff. This article compares the clinical efficacy of robot-assisted and freehand CD for ONFH by meta-analysis. METHODS: Computer searches of PubMed, Web of Science, Embase, Cochrane Library, Chinese National Knowledge Infrastructure, China Science and Technology Journal Database, WanFang, and Chinese BioMedical Literature Database were conducted from the time of database inception to November 15, 2023. The literature on the clinical efficacy of robot-assisted and freehand CD in the treatment of ONFH was collected. Two researchers independently screened the literature according to the inclusion and exclusion criteria, extracted data, and strictly evaluated the quality of the included literature. Outcome measures encompassed operative duration, intraoperative blood loss volume, frequency of intraoperative fluoroscopies, visual analog scale (VAS) score, Harris hip score (HHS), complications, and radiographic progression. Data synthesis was carried out using Review Manager 5.4.1 software. The quality of evidence was evaluated according to Grades of Recommendation Assessment Development and Evaluation (GRADE) standards. RESULTS: Seven retrospective cohort studies involving 355 patients were included in the study. The results of meta-analysis showed that in the robot-assisted group, the operative duration (MD = -17.60, 95% CI: -23.41 to -11.78, P < 0.001), intraoperative blood loss volume (MD = -19.98, 95% CI: -28.84 to -11.11, P < 0.001), frequency of intraoperative fluoroscopies (MD = -6.60, 95% CI: -9.01 to -4.20, P < 0.001), and ΔVAS score (MD = -0.45, 95% CI: -0.67 to -0.22, P < 0.001) were significantly better than those in the freehand group. The GRADE evidence evaluation showed ΔVAS score as low quality and other indicators as very low quality. There was no significant difference in the terms of ΔHHS (MD = 0.51, 95% CI: -1.34 to 2.35, P = 0.59), complications (RR = 0.30, 95% CI: 0.03 to 2.74, P = 0.29), and radiographic progression (RR = 0.50, 95% CI: 0.25 to 1.02, P = 0.06) between the two groups. CONCLUSION: There is limited evidence showing the benefit of robot-assisted therapy for treatment of ONFH patients, and much of it is of low quality. Therefore, caution should be exercised in interpreting these results. It is recommended that more high-quality studies be conducted to validate these findings in future studies. SYSTEMATIC REVIEW REGISTRATION: https://www.crd.york.ac.uk/prospero/ #recordDetails, CRD42023420593.

Subtrochanteric fracture after core decompression for osteonecrosis of the femoral head: a case report and literature review.

BACKGROUND: Osteonecrosis of the femoral head (ONFH) is a common clinical disease. Improper treatment can lead to femoral head collapse and hip joint dysfunction. Core decompression is particularly important for early ONFH. However, subtrochanteric fractures after core decompression cause some clinical problems. CASE PRESENTATION: This article describes a 34-year-old male patient with early ONFH. After core decompression, he suffered a subtrochanteric fracture of the femur while bearing weight on the affected limb when going up stairs. He was subsequently treated with open reduction and intramedullary nail fixation. CONCLUSION: When core decompression is used to treat ONFH, the location or size of the drill hole, whether a tantalum rod or bone is inserted, and partial weight-bearing of the affected limb may directly affect whether a fracture occurs after surgery. It is hoped that this case report can provide a reference for clinical orthopedic surgeons in the treatment of early ONFH.

Risk factors for avascular necrosis of the femoral head after developmental hip dislocation reduction surgery and construction of Nomogram prediction model.

BACKGROUND: To analyze the risk factors for the development of avascular necrosis (AVN) of the femoral head after reduction surgery in children with developmental hip dysplasia (DDH), and to establish a prediction nomogram. METHODS: The clinical data of 134 children with DDH (169 hips) treated with closure reduction or open reduction from December 2016 to December 2019 were retrospectively analyzed. Independent risk factors for AVN after DDH reduction being combined with cast external immobilization were determined by univariate analysis and multivariate logistic regression and used to generate nomograms predicting the occurrence of AVN. RESULTS: A total of 169 hip joints in 134 children met the inclusion criteria, with a mean age at surgery of 10.7 ± 4.56 months (range: 4-22 months) and a mean follow-up duration of 38.32 ± 27.00 months (range: 12-94 months). AVN developed in 42 hip joints (24.9%); univariate analysis showed that the International Hip Dysplasia Institute (IHDI) grade, preoperative development of the femoral head ossification nucleus, cartilage acetabular index, femoral head to acetabular Y-shaped cartilage distance, residual acetabular dysplasia, acetabular abduction angle exceeding 60°, and the final follow-up acetabular index (AI) were associated with the development of AVN (P < 0.05). Multivariate logistic regression analysis showed that the preoperative IHDI grade, development of the femoral head ossification nucleus, acetabular abduction angle exceeding 60°, and the final follow-up AI were independent risk factors for AVN development (P < 0.05). Internal validation of the Nomogram prediction model showed a consistency index of 0.833. CONCLUSION: Preoperative IHDI grade, preoperative development of the femoral head ossification nucleus, final AI, and acetabular abduction angle exceeding 60° are risk factors for AVN development. This study successfully constructed a Nomogram prediction model for AVN after casting surgery for DDH that can predict the occurrence of AVN after casting surgery for DDH.

Risk factors of preoperative deep vein thrombosis in patients with non-traumatic osteonecrosis of the femoral head.

PURPOSE: This study aims to identify independent risk factors for preoperative lower extremity deep venous thrombosis (DVT) in patients with non-traumatic osteonecrosis of the femoral head (NONFH), and to develop a prediction nomogram. METHODS: Retrospective analysis of prospectively collected data on patients presenting with non-traumatic osteonecrosis of the femoral head between October 2014 and April 2019 was conducted. Duplex ultrasonography (DUS) was routinely used to screen for preoperative DVT of bilateral lower extremities. Data on demographics, chronic comorbidities, preoperative characteristics, and laboratory biomarkers were collected. Univariate analyses and multivariate logistic regression analyses were used to identify the independent risk factors associated with DVT which were combined and transformed into a nomogram model. RESULT: Among 2824 eligible patients included, 35 (1.24%) had preoperative DVT, including 15 cases of proximal thrombosis, and 20 cases of distal thrombosis. Six independent risk factors were identified to be associated with DVT, including Sodium ≤ 137 mmol/L (OR = 2.116, 95% confidence interval [CI]: 1.036-4.322; P = 0.040), AGE ≥ 49 years (OR = 7.598, 95%CI: 1.763-32.735; P = 0.008), D-Dimer > 0.18 mg/L (OR = 2.351, 95%CI: 1.070-5.163; P = 0.033), AT III ≤ 91.5% (OR = 2.796, 95%CI: 1.387-5.634; P = 0.006), PLT ≥ 220.4*109 /L (OR = 7.408, 95%CI: 3.434-15.981; P = 0.001) and ALB < 39 g/L (OR = 3.607, 95%CI: 1.084-12.696; P = 0.042). For the nomogram model, AUC was 0.845 (95%CI: 0.785-0.906), and C-index was 0.847 with the corrected value of 0.829 after 1000 bootstrapping validations. Moreover, the calibration curve and DCA exhibited the tool's good prediction consistency and clinical practicability. CONCLUSION: These epidemiologic data and the nomogram may be conducive to the individualized assessment, risk stratification, and development of targeted prevention programs for preoperative DVT in patients with NONFH.

Femoral neck system versus multiple cannulated screws for the fixation of Pauwels classification type II femoral neck fractures in older female patients with low bone mass.

BACKGROUND: Femoral neck fractures in older adult patients are a major concern and often necessitate surgical intervention. This study compared the clinical outcomes of 2 surgical techniques: the femoral neck system (FNS) and cannulated compression screws (CCSs). METHODS: A total of 40 female patients (mean age 73.50 ± 11.55 years) with femoral neck fractures of Pauwels classification type II and receiving surgical fixation between 2020 and 2022 were enrolled. The patients were categorized into an FNS group (n = 12) or a CCS group (n = 28), and surgical duration, intraoperative blood loss, length of hospital stay, and incidence of postoperative adverse events were analyzed. RESULTS: No significant intergroup differences in demographic characteristics were discovered. The mean surgical duration for all patients was 52.88 ± 22.19 min, with no significant difference between the groups. However, the FNS group experienced significantly higher intraoperative blood loss (P = 0.002) and longer hospital stay (P = 0.023) than did the CCS group. The incidence of osteonecrosis was higher in the CCS group, whereas the incidence of nonunion or malunion was higher in the FNS group. The surgical method did not appear to be a significant risk factor. The main risk factor for revision surgery was longer duration until the first adverse event (P = 0.015). CONCLUSION: The FNS does not appear to provide superior surgical outcomes compared with CCSs in older adult women with Pauwels classification type II femoral neck fractures. A longer duration between surgical fixation and the first adverse event before stabilization of the fracture site may be a risk factor for revision surgery.

Deep learning approach to femoral AVN detection in digital radiography: differentiating patients and pre-collapse stages.

OBJECTIVE: This study aimed to evaluate a new deep-learning model for diagnosing avascular necrosis of the femoral head (AVNFH) by analyzing pelvic anteroposterior digital radiography. METHODS: The study sample included 1167 hips. The radiographs were independently classified into 6 stages by a radiologist using their simultaneous MRIs. After that, the radiographs were given to train and test the deep learning models of the project including SVM and ANFIS layer using the Python programming language and TensorFlow library. In the last step, the test set of hip radiographs was provided to two independent radiologists with different work experiences to compare their diagnosis performance to the deep learning models' performance using the F1 score and Mcnemar test analysis. RESULTS: The performance of SVM for AVNFH detection (AUC = 82.88%) was slightly higher than less experienced radiologists (79.68%) and slightly lower than experienced radiologists (88.4%) without reaching significance (p-value > 0.05). Evaluation of the performance of SVM for pre-collapse AVNFH detection with an AUC of 73.58% showed significantly higher performance than less experienced radiologists (AUC = 60.70%, p-value < 0.001). On the other hand, no significant difference is noted between experienced radiologists and SVM for pre-collapse detection. ANFIS algorithm for AVNFH detection with an AUC of 86.60% showed significantly higher performance than less experienced radiologists (AUC = 79.68%, p-value = 0.04). Although reaching less performance compared to experienced radiologists statistically not significant (AUC = 88.40%, p-value = 0.20). CONCLUSIONS: Our study has shed light on the remarkable capabilities of SVM and ANFIS as diagnostic tools for AVNFH detection in radiography. Their ability to achieve high accuracy with remarkable efficiency makes them promising candidates for early detection and intervention, ultimately contributing to improved patient outcomes.

An in-depth analysis of young adults with osteonecrosis secondary to developmental dysplasia of the hip who underwent total hip arthroplasty.

BACKGROUND: Patients with osteonecrosis of the femoral head secondary to DDH frequently require total hip arthroplasty (THA), but it is not well understood which factors necessitate this requirement. We determined the incidence of THA in patients who have osteonecrosis secondary to DDH and factors associated with need for THA. METHODS: We included patients who received closed or open reductions between 1995 and 2005 with subsequent development of osteonecrosis. We determined osteonecrosis according to Bucholz and Ogden; osteoarthritis severity (Kellgren-Lawrence), subluxation (Shenton's line); neck-shaft angle; and acetabular dysplasia (centre-edge and Sharp angles). We also recorded the number of operations of the hip in childhood and reviewed case notes of patients who received THA to describe clinical findings prior to THA. We assessed the association between radiographic variables and the need for THA using univariate logistic regression. RESULTS: Of 140 patients (169 hips), 22 patients received 24 THA (14%) at a mean age of 21.3 ± 3.7 years. Associated with the need for THA were grade III osteonecrosis (OR 4.25; 95% CI 1.70-10.77; p = 0.0019), grade IV osteoarthritis (21.8; 7.55-68.11; p < 0.0001) and subluxation (8.22; 2.91-29.53; p = 0.0003). All patients who required THA reported at least 2 of: severe pain including at night, stiffness, and reduced mobility. Acetabular dysplasia and number of previous operations were not associated with the need for THA. CONCLUSIONS: We identified a 14% incidence of THA by age 34 years in patients with osteonecrosis secondary to DDH. Grade III osteonecrosis (global involvement femoral head and neck) was strongly associated with THA, emphasising the importance to avoid osteonecrosis when treating DDH.

YTHDF2-Mediated m6A methylation inhibition by miR27a as a protective mechanism against hormonal osteonecrosis in BMSCs.

BACKGROUND: With the increasing incidence of steroid-induced necrosis of the femoral head (SNFH), numerous scholars have investigated its pathogenesis. Current evidence suggests that the imbalance between lipogenesis and osteoblast differentiation in bone marrow mesenchymal stem cells (BMSCs) is a key pathological feature of SNFH. MicroRNAs (miRNAs) have strong gene regulatory effects and can influence the direction of cell differentiation. N6-methyladenosine (m6A) is a prevalent epigenetic modification involved in diverse pathophysiological processes. However, knowledge of how miRNAs regulate m6A-related factors that affect BMSC differentiation is limited. OBJECTIVE: We aimed to investigate the role of miR27a in regulating the expression of YTHDF2 in BMSCs. METHODS: We compared miR27a, YTHDF2, and total m6A mRNA levels in SNFH-affected and control BMSCs. CCK-8 and TUNEL assays were used to assess BMSC proliferation and apoptosis. Western blotting and qRT‒PCR were used to measure the expression of osteogenic (ALP, RUNX2, and OCN) and lipogenic (PPARγ and C/EBPα) markers. Alizarin Red and Oil Red O staining were used to quantify osteogenic and lipogenic differentiation, respectively. miR27a was knocked down or overexpressed to evaluate its impact on BMSC differentiation and its relationship with YTHDF2. Bioinformatics analyses identified YTHDF2 as a differentially expressed gene in SNFH (ROC analysis) and revealed potential signaling pathways through GSEA. The effects of YTHDF2 silencing on the lipogenic and osteogenic functions of BMSCs were assessed. RESULTS: miR27a downregulation and YTHDF2 upregulation were observed in the SNFH BMSCs. miR27a knockdown/overexpression modulated YTHDF2 expression, impacting BMSC differentiation. miR27a silencing decreased m6A methylation and promoted osteogenic differentiation, while YTHDF2 silencing exerted similar effects. GSEA suggested potential signaling pathways associated with YTHDF2 in SNFH. CONCLUSION: miR27a regulates BMSC differentiation through YTHDF2, affecting m6A methylation and promoting osteogenesis. This finding suggests a potential therapeutic target for SNFH.

The Duration of Hardware Retention After Radiologic Union of Surgically Treated Femoral Neck Fractures in Children May Predict the Aggravation or Occurrence of Avascular Necrosis of the Femoral Head or Neck After Hardware Removal.

BACKGROUND: The incidence of aggravation or occurrence of avascular necrosis (AVN) following hardware removal in surgically treated pediatric femoral neck fractures who achieved radiologic consolidation is unknown. This study aimed to investigate the risk factors for this complication. METHODS: Seventy-one pediatric (mean age: 9.8±3.9 y) were retrospectively analyzed. Risk factors (age, sex, laterality, severity of initial displacement, type of fracture, time from trauma to reduction, reduction and fixation method, quality of reduction, time required to achieve radiologic union, duration of hardware retention, presence of AVN before hardware removal and follow-up time) were recorded. The severity of AVN was assessed based on radiographs with Ratliff's classification. RESULTS: Following hardware removal, the aggravation/occurrence of AVN was detected in 11 hips (15.5%). Among the 5 hips (7%) with aggravation of AVN, 1 (1.4%) with type II AVN and 3 (4.2%) with type III AVN exhibited aggravation of type I AVN, while the remaining hip (1.4%; type I) showed enlargement of the involved AVN area. Six hips (8.5%) developed AVN following hardware removal: 2 (2.8%) were classified as type I and 4 (5.6%) as type III. Receiver operating characteristic curve analysis indicated that hardware retention >7 months after union is associated with a decreased rate of aggravation or occurrence of AVN of the femoral neck or head following hardware removal. CONCLUSIONS: The incidence of aggravation or occurrence of AVN following hardware removal in surgically treated pediatric femoral neck fractures is 15.5%; hardware retention >7 months after radiologic union may reduce the risk of aggravation or occurrence of AVN of the femoral neck or head postimplant removal. LEVEL OF EVIDENCE: Level III.

Intraoperative Epiphyseal Perfusion Monitoring Does Not Reliably Predict Osteonecrosis Following Treatment of Unstable SCFE.

BACKGROUND: Avascular necrosis (AVN) remains the most dreaded complication of unstable slipped capital femoral epiphysis (SCFE) treatment. Newer closed reduction techniques (with perfusion monitoring) have emerged as a technically straightforward means to address residual SCFE deformity while still minimizing the risk of osteonecrosis. However, limited data exists regarding the reliability of intraoperative epiphyseal perfusion monitoring to predict the development of AVN. The purpose of this study was to evaluate its reliability. METHODS: We retrospectively reviewed all patients with unstable SCFE who underwent closed or open reduction with epiphyseal perfusion monitoring using an intracranial pressure (ICP) probe from 2015 to 2023 at a single institution with a minimum 6-month radiographic follow-up. Demographic, clinical, and radiographic data were recorded, including duration of symptoms, type of reduction, capsulotomy performed, presence of a waveform on ICP monitoring after epiphyseal fixation, and development of AVN on follow-up radiographs. RESULTS: Our cohort included 33 hips (32 patients), of which 60.6% (n=20) were male. The average age was 12.5±1.8 years, with a median follow-up of 15.8 months. Eleven hips were treated with open reduction using the modified Dunn technique (10 hips) or anterior approach (1 hip), and 22 hips were treated with inadvertent (5 hips) or purposeful closed reduction using the Leadbetter technique (17 hips). Overall, 8 of the 33 hips in our series (24.2%) developed AVN, 6 of which (20%) had a pulsatile waveform on intraoperative epiphyseal perfusion monitoring. The overall rate of AVN after closed reductions was 31.8% (7 of 22 hips); the incidence of AVN after closed reduction with a detectable waveform was 30% (6 of 20 hips). There was no significant association between time to surgery ( P =0.416) or type of reduction ( P =0.218) and the incidence of AVN. CONCLUSIONS: In this series, intraoperative epiphyseal perfusion monitoring did not reliably predict the development of osteonecrosis. To our knowledge, this is the first study to report AVN after demonstrable intraoperative epiphyseal perfusion following closed reduction of unstable slips. LEVEL OF EVIDENCE: Level IV: case series-therapeutic study.

Free Vascularized Proximal Fibular Epiphyseal Transfer For Hip Reconstruction Following Septic Necrosis In Children.

BACKGROUND: Septic necrosis of the femoral head and neck in children represents a challenging problem. Several reconstructive techniques have been described but with disappointing long-term results. Vascularized epiphyseal transfer utilizing the proximal fibula have been successfully used for reconstruction of the proximal humerus and distal radius and only scarcely used for hip reconstruction. This cohort represents the largest reported series of epiphyseal transfer for hip reconstruction following septic necrosis in children. METHODS: A total of 18 patients with an average age at surgery of 5.4 years were included. The average follow-up was 3.6 years (range 2.3 to 6.8 y). RESULTS: Transient postoperative foot drop was observed in 4 patients. Radiographic resorption of the transferred fibula occurred in 2 cases. Longitudinal growth averaged 7.3 mm/year, and the physis width increased by an average of 2.7 mm/year. The rate of longitudinal growth was fastest after the age of 10 years (18.5 mm/y), which coincides with the pubertal growth spurt. All successful transfers had an open growth plate on final follow-up radiographs. Ten patients had limb length discrepancy of an average 2.8 cm (range 1 to 8 cm). Thirteen patients had satisfactory functional according to the criteria of Hunka et al. Three patients had unsatisfactory results; one had painful nonunion at the fibula-femur junction, and the other two had limited flexion range of 45 degrees. The average postoperative neck-shaft angle was 96.4 degrees which decreased by an average of 8 degrees at the final follow-up. Three patients underwent a valgus subtrochanteric osteotomy to correct a severe varus deformity. The final neck-shaft angle correlated significantly with the functional results where it averaged 96 degrees in the satisfactory group and 57 degrees in the unsatisfactory group. CONCLUSION: Vascularized epiphyseal transfer presents a promising treatment for children with septic necrosis of the femoral head and neck in whom other methods have failed to provide satisfactory long-term results. We recommend the procedure be done before the age of 5 years for optimum results. LEVEL OF EVIDENCE: Level-IV.

Total Hip Arthroplasty in Human Immunodeficiency Virus Positive Patients: A Systematic Review of Outcomes.

BACKGROUND: Total hip arthroplasty (THA) has become a common intervention for human immunodeficiency virus (HIV)-positive patients who have osteonecrosis of the femoral head. This paper provides a systematic review to assess survivorships, patient-reported outcomes (PROMs), infection rates, other complications, and immune competence for patients who had THAs who did and did not have HIV. METHODS: A comprehensive and systematic review of published studies investigating the outcomes of THA in HIV-positive patients (osteonecrosis and non-osteonecrosis patients) was performed adhering to Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. A total of 10 studies with 9,534 HIV-positive patients fulfilled the inclusion and exclusion criteria. Manuscript quality was assessed on 2 scales: the Coleman Methodology Score and the level of evidence derived from Center for Evidence-Based Medicine criteria. Data were extracted from studies in the 5 key areas of interest: survivorships, PROMs, infection rates, complications, and clusters of differentiation-4 (CD4+) counts and viral loads. RESULTS: Implant survivorship was between 95% and 100%. Postoperative Harris Hip Scores were significantly improved from preoperative values in HIV-positive patients. Postoperative PROMs and infections did not appear to be different between HIV-positive and HIV-negative patients. Many of the cohort studies demonstrate comparable complication rates to matched controls. Where described (7 reports), mean CD4+ counts ranged from 425 to 646 cells/mm3, with low viral loads (3 reports) and variations not found to influence outcomes. CONCLUSIONS: THA is an effective treatment for HIV-positive patients, many of whom suffer from osteonecrosis of the femoral head. The results demonstrate excellent implant survivorship, improved quality of life, and a low risk of infections and complications.

Effect of Patient Age on Total Hip Arthroplasty Outcomes in Patients Who Have Osteonecrosis of the Femoral Head Compared to Patients Who Have Hip Osteoarthritis.

BACKGROUND: Osteonecrosis of the femoral head (ONFH) affects both young and old patients. However, outcomes following total hip arthroplasty (THA) for these patients may vary with age. This study aimed to examine the effect of age on THA outcomes for non-traumatic ONFH patients, an area currently lacking research. METHODS: Patients who had non-traumatic ONFH undergoing THA with at least 2 years of follow-up were identified using a database and divided into four groups by age. Then, 4 matched control groups of patients who had hip osteoarthritis (OA) were created. Multivariate logistic regression analyses were used to evaluate the rates of medical and surgical complications. Additionally, cohorts with a minimum 5-year follow-up were filtered to obtain further data on surgical outcomes. The study analyzed 85,462 non-traumatic ONFH and 80,120 hip OA patients undergoing THA. RESULTS: Multiple medical complications in ONFH patients increased with age. Periprosthetic fracture within 2 years increased with age, while 90-day wound complications, 2-year periprosthetic joint infections, dislocations, and revisions decreased. The trends for complications continued at the 5-year follow-up. Compared to OA patients, those who had ONFH had higher risks of most complications, but this discrepancy decreased with age. CONCLUSIONS: In ONFH patients undergoing THA, medical complications generally rise with age, while most surgical complications, including revisions, decrease. It is notable that ONFH patients experienced more complications than those who had OA, but this difference diminished with age.