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.

Connexin43 overexpression promotes bone regeneration by osteogenesis and angiogenesis in rat glucocorticoid-induced osteonecrosis of the femoral head.

Glucocorticoids induced osteonecrosis of the femoral head (GIONFH) is a devastating orthopedic disease. Previous studies suggested that connexin43 is involved in the process of osteogenesis and angiogenesis. However, the role of Cx43 potentiates in the osteogenesis and angiogenesis of bone marrow-derived stromal stem cells (BMSCs) in GIONFH is still not investigated. In this study, BMSCs were isolated and transfected with green fluorescent protein or the fusion gene encoding GFP and Cx43. The osteogenic differentiation of BMSCs were detected after transfected with Cx43. In addition, the migration abilities and angiogenesis of human umbilical vein endothelial cells (HUVECs) were been detected after induced by transfected BMSCs supernatants in vitro. Finally, we established GC-ONFH rat model, then, a certain amount of transfected or controlled BMSCs were injected into the tibia of the rats. Immunohistological staining and micro-CT scanning results showed that the transplanted experiment group had significantly promoted more bone regeneration and vessel volume when compared with the effects of the negative or control groups. This study demonstrated for the first time that the Cx43 overexpression in BMSCs could promote bone regeneration as seen in the osteogenesis and angiogenesis process, suggesting that Cx43 may serve as a therapeutic gene target for GIONFH treatment.

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.

miR-486-5p Attenuates Steroid-Induced Adipogenesis and Osteonecrosis of the Femoral Head Via TBX2/P21 Axis.

Enhanced adipogenic differentiation of mesenchymal stem cells (MSCs) is considered as a major risk factor for steroid-induced osteonecrosis of the femoral head (SOFNH). The role of microRNAs during this process has sparked interest. miR-486-5p expression was down-regulated significantly in femoral head bone tissues of both SONFH patients and rat models. The purpose of this study was to reveal the role of miR-486-5p on MSCs adipogenesis and SONFH progression. The present study showed that miR-486-5p could significantly inhibit adipogenesis of 3T3-L1 cells by suppressing mitotic clonal expansion (MCE). And upregulated expression of P21, which was caused by miR-486-5p mediated TBX2 decrease, was responsible for inhibited MCE. Further, miR-486-5p was demonstrated to effectively inhibit steroid-induced fat formation in the femoral head and prevented SONFH progression in a rat model. Considering the potent effects of miR-486-5p on attenuating adipogenesis, it seems to be a promising target for the treatment of SONFH.

Microarchitecture Alternations of Osteochondral Junction in Patients with Osteonecrosis of the Femoral Head.

The study was aimed to investigate microarchitecture of osteochondral junction in patients with osteonecrosis of the femoral head (ONFH). We hypothesis that there were microarchitecture alternations in osteochondral junction and regional differences between the necrotic region (NR) and adjacent non-necrotic region(ANR) in patients with ONFH. Femoral heads with ONFH or femoral neck fracture were included in ONFH group (n = 11) and control group (n = 11). Cylindrical specimens were drilled on the NR/ANR of femoral heads in ONFH group and matched positions in control group (CO.NR/ CO.ANR). Histology, micro-CT, and scanning electron microscope were used to investigate microarchitecture of osteochondral junction. Layered analysis of subchondral bone plate was underwent. Mankin scores on NR were higher than that on ANR or CO.NR, respectively (P < 0.001, P < 0.001). Calcified cartilage zone on the NR and ANR was thinner than that on the CO.NR and CO.ANR, respectively (P = 0.002, P = 0.002). Tidemark roughness on the NR was larger than that on the ANR (P = 0.002). Subchondral bone plate of NR and ANR was thicker than that on the CON.NR and CON.ANR, respectively (P = 0.002, P = 0.009). Bone volume fraction of subchondral bone plate on the NR was significantly decreasing compared to ANR and CON.NR, respectively (P = 0.015, P = 0.002). Subchondral bone plate on the NR had larger area percentages and more numbers of micropores than ANR and CON.NR (P = 0.002/0.002, P = 0.002/0.002). Layered analysis showed that bone mass loss and hypomineralization were mainly on the cartilage side of subchondral bone plate in ONFH. There were microarchitecture alternations of osteochondral junction in ONFH, including thinned calcified cartilage zone, thickened subchondral bone plate, decreased bone mass, altered micropores, and hypomineralization of subchondral bone plate. Regional differences in microarchitecture of osteochondral junction were found between necrotic regions and adjacent non-necrotic regions. Subchondral bone plate in ONFH had uneven distribution of bone volume fraction and bone mineral density, which might aggravate cartilage degeneration by affecting the transmission of mechanical stresses.

In situ metabolomic analysis of osteonecrosis of the femoral head (ONFH) using MALDI MSI.

Osteonecrosis of the femoral head (ONFH) is a common orthopedic disease characterized by disability and deformity. To better understand ONFH at molecular level and to explore the possibility of early diagnosis, instead of diagnosis based on macroscopic spatial characteristics, a matrix-assisted laser desorption/ionization mass spectrometry imaging (MALDI MSI) method was developed for ONFH disease for the first time. The most challenging step for ONFH MSI is to deal with human bone tissues which are much harder than the other biological samples studied by the reported MSI studies. In this work, the MSI sectioning method of hard bone tissues was established using tender acids and a series of test criteria. Small-molecule metabolites, such as lipids and amino acids, were detected in bone sections, realizing the in situ detection of spatial distribution of biometabolites. By comparing the distribution of metabolites from different regions of normal femoral head, ONFH bone tissue (ONBT), and adjacent ONFH bone tissue (ANBT), the whole process of femoral head from normal stage to necrosis was monitored and visualized at molecular level. Moreover, this developed MSI method was used for metabolomics study of ONFH. 72 differential metabolites were identified, suggesting that disturbances in energy metabolism and lipid metabolism affected the normal life activities of osteoblasts and osteoclasts. This study provides new perspectives for future pathological studies of ONFH.

MiR-601-induced BMSCs senescence accelerates steroid-induced osteonecrosis of the femoral head progression by targeting SIRT1.

BACKGROUND: The imbalance between osteogenic and adipogenic differentiation of bone marrow mesenchymal stem cells (BMSCs) is not only the primary pathological feature but also a major contributor to the pathogenesis of steroid-induced osteonecrosis of the femoral head (SONFH). Cellular senescence is one of the main causes of imbalanced BMSCs differentiation. The purpose of this study was to reveal whether cellular senescence could participate in the progression of SONFH and the related mechanisms. METHODS: The rat SONFH model was constructed, and rat BMSCs were extracted. Aging-related indicators were detected by SA-ß-Gal staining, qRT-PCR and Western Blot experiments. Using H2O2 to construct a senescent cell model, and overexpressing and knocking down miR-601 and SIRT1 in hBMSCs, the effect on BMSCs differentiation was explored by qRT-PCR, Western Blot experiment, oil red O staining (ORO), alizarin red staining (ARS), and luciferase reporter gene experiment. A rat SONFH model was established to test the effects of miR-601 and metformin in vivo. RESULTS: The current study showed that glucocorticoids (GCs)-induced BMSCs senescence, which caused imbalanced osteogenesis and adipogenesis of BMSCs, was responsible for the SONFH progression. Further, elevated miR-601 caused by GCs was demonstrated to contribute to BMSCs senescence through targeting SIRT1. In addition, the anti-aging drug metformin was shown to be able to alleviate GCs-induced BMSCs senescence and SONFH progression. CONCLUSIONS: Considering the role of BMSCs aging in the progression of SONFH, this provides a new idea for the prevention and treatment of SONFH.

Influence of avascular necrosis of the femoral head on hip prosthesis integration: a radiological analysis.

BACKGROUND: Avascular osteonecrosis of the femoral head (AVN) often results in total hip arthroplasty (THA). The cause for increased THA revision rates among patients with AVN is not yet fully understood. PURPOSE: To perform a comparative radiological analysis of implant integration between patients with AVN and osteoarthritis (OA). MATERIAL AND METHODS: After a matched pair analysis of 58 patients, 30 received THA due to OA, 28 due to AVN. X-ray images were evaluated after one week ("baseline") and on average 37.58 months postoperatively ("endline"). The prosthesis was grouped into 10 regions of interest (ROI): seven femoral and three acetabular. Incidence, width, and extent of "radiolucent lines" were measured within each zone. RESULTS: Between baseline and endline, width and extent progressed more noticeably in all femoral and acetabular zones among patients with AVN. In femoral ROI 1, the width increased in 40% of AVN cases compared to 6.7% of OA cases. For acetabular ROI 3, the width increased in 26.7% of AVN cases compared to no perceived changes in the OA group. No signs of prosthetic loosening were found in the AVN group. CONCLUSION: The increase of width and extent of radiolucent lines over time in patients with AVN could be a sign of lack of osteointegration. However, prosthetic loosening in absence of clinical symptoms cannot be deduced from radiological findings after medium-term postoperative follow-up. Further long-term studies are required to monitor how radiolucent lines develop in respect to long-term implant loosening. Dependent on bone quality, individually adapted reaming and broaching of the implant site are recommended.

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 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.

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.

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.

Total hip arthroplasty after failed transtrochanteric rotational osteotomy for osteonecrosis of the femoral head: analysis of three-dimensional morphological features.

BACKGROUND: In total hip arthroplasty (THA) after failed transtrochanteric rotational osteotomy (TRO) for osteonecrosis of the femoral head (ONFH), deformity of the proximal femur has been reported to affect stem placement. The aims of this study were to evaluate the morphological changes in the proximal femur, muscle atrophy, and soft tissue thickening in THA after TRO and the clinical outcomes. METHODS: The TRO group included 17 patients (18 hips) who underwent THA after failed TRO. The control group included 21 patients (28 hips) who underwent primary THA for ONFH. To evaluate the deformity of the proximal femur before THA, we measured the anteroposterior and mediolateral diameters of the femur on computed tomographic slices 5 mm proximal to the lesser trochanter. To evaluate muscle atrophy and soft tissue thickening, we measured the thicknesses of the psoas major, iliac, and gluteus medius muscles and the anterior capsule of the hip joint. RESULTS: The ratio of the anteroposterior to mediolateral diameters of the proximal femur was significantly greater in the TRO group (p < 0.01). The thicknesses of the muscles did not differ between the two groups, whereas the anterior capsule was significantly thicker in the TRO group (p < 0.05). Varus or valgus stem alignment (> 3°) was frequent in the TRO group (p < 0.01). CONCLUSIONS: The round shape of the proximal femur was deformed after TRO compared with primary THA for ONFH, which may have caused malposition of the stem. In addition, we should pay attention to anterior protrusion of the proximal femur and thickening of the anterior capsule.

Corticosteroid-associated osteonecrosis of the femoral head in an 87-year-old patient following treatment for COVID-19-associated pneumonia: A case report.

Coronavirus disease 2019 is known to cause severe acute respiratory syndrome, and serious cases need to be treated with corticosteroids. Herein, we report an 87-year-old woman who developed bilateral osteonecrosis of the femoral head after corticosteroid treatment for coronavirus disease 2019-related pneumonia. Sixteen months after treatment, she developed right hip pain without any evidence of trauma. A diagnosis of bilateral osteonecrosis of the femoral head was made based on sclerotic bands on plain radiographs and low-signal bands on T1-weighted magnetic resonance images. The patient underwent right total hip arthroplasty 4 months after symptom onset. Histological examination of the resected femoral head revealed pathological evidence of osteonecrosis. The postoperative course was good, and the patient can now walk unassisted. To the best of our knowledge, this is the first report of histologically proven osteonecrosis after corticosteroid therapy for coronavirus disease 2019-related disease.

Taxifolin-mediated Nrf2 activation ameliorates oxidative stress and apoptosis for the treatment of glucocorticoid-induced osteonecrosis of the femoral head.

Glucocorticoid-induced osteonecrosis of the femoral head (GIONFH) is the main complication secondary to long-term or excessive use of glucocorticoids (GCs). Taxifolin (TAX) is a natural antioxidant with various pharmacological effects, such as antioxidative stress and antiapoptotic properties. The purpose of this study was to explore whether TAX could regulate oxidative stress and apoptosis in GIONFH by activating the nuclear factor erythroid 2-related factor 2 (Nrf2) pathway. We conducted qRT-PCR, Western blotting, TUNEL assays, flow cytometry, and other experiments in vitro. Microcomputed tomography analysis, hematoxylin-eosin staining, and immunohistochemical staining were performed to determine the therapeutic effect of TAX in vivo. TAX mitigated the overexpression of ROS and NOX gene expression induced by DEX, effectively reducing oxidative stress. Additionally, TAX could alleviate DEX-induced osteoblast apoptosis, as evidenced by qRT-PCR, Western blotting, and other experimental techniques. Our in vivo studies further demonstrated that TAX mitigates the progression of GIONFH in rats by combating oxidative stress and apoptosis. Mechanistic exploration revealed that TAX thwarts the progression of GIONFH through the activation of the Nrf2 pathway. Overall, our research herein reports that TAX-mediated Nrf2 activation ameliorates oxidative stress and apoptosis for the treatment of GIONFH.

Development and Validation of an Automated Classification System for Osteonecrosis of the Femoral Head Using Deep Learning Approach: A Multicenter Study.

BACKGROUND: Accurate classification can facilitate the selection of appropriate interventions to delay the progression of osteonecrosis of the femoral head (ONFH). This study aimed to perform the classification of ONFH through a deep learning approach. METHODS: We retrospectively sampled 1,806 midcoronal magnetic resonance images (MRIs) of 1,337 hips from 4 institutions. Of these, 1,472 midcoronal MRIs of 1,155 hips were divided into training, validation, and test datasets with a ratio of 7:1:2 to develop a convolutional neural network model (CNN). An additional 334 midcoronal MRIs of 182 hips were used to perform external validation. The predictive performance of the CNN and the review panel was also compared. RESULTS: A multiclass CNN model was successfully developed. In internal validation, the overall accuracy of the CNN for predicting the severity of ONFH based on the Japanese Investigation Committee classification was 87.8%. The macroaverage values of area under the curve (AUC), precision, recall, and F-value were 0.90, 84.8, 84.8, and 84.6%, respectively. In external validation, the overall accuracy of the CNN was 83.8%. The macroaverage values of area under the curve, precision, recall, and F-value were 0.87, 79.5, 80.5, and 79.9%, respectively. In a human-machine comparison study, the CNN outperformed or was comparable to that of the deputy chief orthopaedic surgeons. CONCLUSION: The CNN is feasible and robust for classifying ONFH and correctly locating the necrotic area. These findings suggest that classifying ONFH using deep learning with high accuracy and generalizability may aid in predicting femoral head collapse and clinical decision-making.

Extension of the Antero-Posterior Necrotic Regions Associated With Collapse Cessation in Osteonecrosis of the Femoral Head.

BACKGROUND: Collapse cessation is of utmost importance following a long period of collapse due to osteonecrosis of the femoral head (ONFH). This study investigated the relationship between collapse cessation and the extent of the necrotic regions of ONFH. METHODS: Overall, 74 patients who had symptomatic ONFH (collapse < 3 mm) at the first visit with a minimum follow-up of 3 years were included in this study. Patients were categorized based on collapse progression or cessation into the progression and stable groups. The extent of the antero-posterior (AP) and medio-lateral necrotic regions between the groups was assessed using sagittal and coronal sections of T1-magnetic resonance imaging. Additionally, the most effective cutoff value was determined from the receiving operating characteristic curve where collapse cessation could be obtained, while the survival rates were determined with collapse progression as the endpoints were evaluated. RESULTS: Overall, 45 and 29 patients were in the progression and stable groups, respectively. The AP and medio-lateral necrotic regions were significantly different (P < .01 and P < .01, respectively) between the progression and stable groups. A cutoff value of 62.1% of the AP necrotic regions was determined from the receiving operating characteristic curve analysis. The 5-year survival rates with collapse progression as the endpoints were 5.4 and 77.8% in the AP necrotic regions of ≥62.1 and <62.1%, respectively (P < .01). CONCLUSIONS: Cases with AP necrotic regions of ≤62.1% can be expected to have collapse cessation, which could be a useful index for ONFH treatment strategies. LEVEL OF EVIDENCE: Level IV.

Effect of Corticosteroid Use on the Occurrence and Progression of Osteonecrosis of the Femoral Head: A Nationwide Nested Case-Control Study.

BACKGROUND: Although it is very well known that corticosteroids cause osteonecrosis of the femoral head (ONFH), it is unclear as to which patients develop ONFH. Additionally, there are no studies on the association between corticosteroid use and femoral head collapse in ONFH patients. We aimed to investigate the association between corticosteroid use and the risk of ONFH among the general population and what factors affect ONFH occurrence. Additionally, we aimed to demonstrate which factors affect femoral head collapse and total hip arthroplasty (THA) after ONFH occurrence. METHODS: A nationwide, nested case-control study was conducted with data from the National Health Insurance Service Physical Health Examination Cohort (2002 to 2019) in the Republic of Korea. We defined ONFH (N = 3,500) using diagnosis and treatment codes. Patients who had ONFH were matched 1:5 to form a control group based on the variables of birth year, sex, and follow-up duration. Additionally, in patients who have ONFH, we looked for risk factors for progression to THA. RESULTS: Compared with the control group, ONFH patients had a low household income and had more diabetes, hypertension, dyslipidemia, and heavy alcohol use (drinking more than 3 to 7 drinks per week). Systemic corticosteroid use (≥1,800 mg) was significantly associated with an increased risk of ONFH incidence. However, lipid profiles, corticosteroid prescription, and cumulative doses of corticosteroid did not affect the progression to THA. CONCLUSIONS: The ONFH risk increased rapidly when cumulative prednisolone use was ≥1,800 mg. However, oral or high-dose intravenous corticosteroid use and cumulative dose did not affect the prognosis of ONFH. Since the occurrence and prognosis of ONFH are complex and multifactorial processes, further study is needed.