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Radiographic findings of the staging system for ONFH. a. Stage 1. No specific findings on plain radiographs, but a low-intensity band pattern was observed on T1-weighted MRI. b. Stage 2. Demarcation of sclerosis observed in the femoral head (arrows). c. Stage 3A. d. Stage 3B. e. Stage 4.
Source publication
Background:
Steroid (glucocorticoid)-induced osteonecrosis of the femoral head (ONFH) in young adults has been a challenging disorder due to frequent incidence of collapse of the femoral head and resulting dysfunction of the hip joint and impairing quality of life. In Japan, the working group on ONFH in the Specific Disease Investigation Committee...
Context in source publication
Context 1
... of the ONFH hips without femoral head collapse in respective groups was already reported [21]. Poor prognosis was consistently shown in type C (C1 and C2) group. Identification of stage of destructive changes in ONFH also would be important step to find optimal surgical option. And the Com- mittee has presented a grading system (Table 2, Fig. 4), based on the occurrence of the femoral head collapse and osteoarthritic changes [5]. The Committee recommends deciding optimal surgical treat- ment by considering type and stage of the ONFH as described ...
Similar publications
Background
Intertrochanteric curved varus osteotomy (CVO) has been widely used to remove the necrotic bone away from the weight-bearing portion in the treatment of osteonecrosis of the femoral head (ONFH). However, whether all types of necrosis will benefit from CVO, in terms of the stress level, the effect of different center-edge (CE) angles of a...
Citations
... Although the pathogenesis of ONFH is marked by the presence of empty lacunae in osteocytes, its etiology remains incompletely understood. Systemic corticosteroid therapy is a major risk factor for ONFH, involving oxidative stress, vascular endothelial damage, fat embolism, apoptosis, decreased osteoblast production, and increased osteoclast activity [1,2]. In a previous study involving 505 ONFH hips, it was found that 85% of hips with large extensive types developed radiological collapse within 5 years. ...
Background
Osteonecrosis of the femoral head (ONFH) primarily affects young individuals and is a leading cause of total hip arthroplasty in this population. Joint-preserving regenerative therapies involving core decompression (CD), enhanced with cells, growth factors, and bone substitutes, have been developed but lack extensive validation. Exosomes are emerging as a promising regenerative therapy. Human adipose stem cell (hADSC)-derived exosomes exhibit angiogenic and wound-healing effects on damaged and diseased tissues, suggesting their potential efficacy in treating early-stage ONFH. We aimed to investigate the efficacy of hADSC-derived exosomes based on CD in a medium-sized animal model (rabbit).
Methods
Exosomes were extracted using the ultrafiltration filter technique from the culture supernatants of two types of hADSCs. Characterization of exosomes was performed through nanoparticle tracking analysis, transmission electron microscopy, and the detection of specific biomarkers (CD9, CD63, and CD81) by western blotting. Eighteen rabbits underwent surgical vascular occlusion and intramuscular corticosteroid injections to induce ONFH. Concurrently, CD treatment with local administration of hADSC-derived exosomes (exosome group) or saline (control group) was performed. Femoral heads were harvested at 4, 8, and 12 weeks postoperatively and evaluated using micro-computed tomography and tissue staining to assess the protective effects on osteonecrosis, angiogenesis, and osteogenesis.
Results
Exosomes had average particle concentrations of 1.8 × 10¹² or 1.8 × 10⁹ particles/mL, with particle size distributions averaging 61.2 ± 14.7 or 123.1 ± 46.3 nm, and were confirmed by specific biomarkers. The exosome group exhibited a significant reduction in the severe progression of ONFH to stages 3 or 4 of the modified Ficat and Arlet classification, compared to the control group, which had four cases of stages 3 or 4. The exosome group showed significantly fewer empty lacunae in the subchondral bone area (p < 0.05) and significantly less articular cartilage injury (p < 0.05) compared to the corresponding in the control group. There were no significant differences in the microvessel number, bone trabecular structure, or volume of new bone in the medial region of the CD.
Conclusions
hADSC-derived exosomes can prevent the progression of ONFH by inhibiting osteonecrosis and cartilage damage. The ultrafiltration filter technique is effective for exosome extraction, indicating that exosomes hold potential as a therapeutic agent for ONFH.
... A prevalent complication arising from glucocorticoid treatment is steroid-induced osteonecrosis of the femoral head (SONFH). Studies from China and Japan underscore glucocorticoids as a significant risk factor for nontraumatic SONFH [3,4]. Without intervention, SONFH typically progresses, leading to hip joint degeneration and compromised function, significantly reducing patients' quality of life. ...
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.
... ONFH impacts patients' mobility and quality of life and is an increasing global health problem [4][5][6]. The national epidemiologic survey in 2004 estimated that for ONFH, approximately 11,400 patients in Japan were treated annually, and 2200 patients per year were newly diagnosed with this disease [7]. The prevalence of ONFH in males is higher than that of females; the peak decades of age in the final diagnosis were young, the 40s in male patients, and the 30s in females [7]. ...
... The national epidemiologic survey in 2004 estimated that for ONFH, approximately 11,400 patients in Japan were treated annually, and 2200 patients per year were newly diagnosed with this disease [7]. The prevalence of ONFH in males is higher than that of females; the peak decades of age in the final diagnosis were young, the 40s in male patients, and the 30s in females [7]. Femoral head collapse induces severe hip pain, resulting in surgical treatment such as total hip arthroplasty or osteotomy [8,9]. ...
... The systematic review found that types A, B, and C of hip collapses occur in 9%, 19%, and 59% of ONFH patients, respectively [10]. In addition, cessation of collapse and improvement of symptoms without surgical intervention can occur in patients with type A and B hips once the femoral head has collapsed [7,12,34]. Most of the type-A hips survived without collapsing and progressive symptoms. ...
The acetabular coverage in osteonecrosis of the femoral head (ONFH) affects the need for surgical intervention, and the collapse of the femoral head remains unclear. This study aimed to evaluate the relation between the acetabular coverage and the need for surgical treatment and femoral head collapse.
The study included 158 patients with 252 hips with glucocorticoid administration and idiopathic ONHF without osteoarthritis changes. The mean age at the first visit was 45.2 years, and the mean follow-up period was 92.2 months. All ONFH hips were subsequently divided into two groups: those needing surgical intervention and those without surgery. Additionally, it divided 167 initially non-collapsed hips into those that either later collapsed or not. Radiographic parameters with the centre-edge angle, acetabular roof obliquity, sharp angle, and necrotic location, following the guidelines of the Japanese Investigation Committee, were evaluated.
There were no significant differences in radiographic parameters between the 106 hips that underwent surgery and the 146 hips without surgery. Among the 167 hips without initial collapse, 91 eventually collapsed while 76 did not; their radiographic findings have no significant differences. The necrotic locations were significantly larger in hips requiring surgical intervention or femoral head collapse. Furthermore, 21.8% (55 out of 252 hips) had acetabular dysplasia, which did not significantly correlate with the necessity for surgical treatment or the incidence of femoral head collapse.
Acetabular coverage has little effect on the necessity for surgical treatment and femoral head collapse in ONFH patients over a long-term follow-up.
... It is estimated that there are 8.12 million cases of non-traumatic osteonecrosis in China alone(6). The exact etiology of ONFH is unknown, and steroid use is a common causative factor, accounting for 51% of ONFH cases (7). ...
Background: Autophagy is closely associated with the onset and progression of steroid-induced osteonecrosis of the femoral head (SIONFH). SQSTM1/p62 is an important indicator of autophagic activity. The aim of this study was to investigate the role of SQSTM1/p62 in the development of SIONFH.
Methods: From May 2021 through November 2021, 36 patients diagnosed with SIONFH and 36 healthy controls were recruited for this study. Evaluations included imaging and pathologic assessment of clinical bone tissue, location and level of SQSTM1/p62 expression, plasma SQSTM1/p62 levels, and receiver operating characteristic (ROC) curves.
Results: We observed that the expression level of SQSTM1/p62 in bone samples decreased with the Association Research Circulation Osseous (ARCO) phase. Plasma SQSTM1/p62 levels were significantly higher in the SIONFH group compared to healthy controls. Plasma SQSTM1/p62 levels were higher in pre-crash patients than in post-crash patients, and lower plasma SQSTM1/p62 levels were associated with elevated ARCO stage.
Conclusion: Plasma SQSTM1/p62 may represent a potential biomarker for different stages during SIONFH. Lower plasma SQSTM1/p62 levels indicate an advanced stage of SIONFH. This study provides new clues for early diagnosis of SIONFH.
... Current treatments for SONFH are aimed at preventing femoral head collapse. Nevertheless, the optimal treatment is still unknown (Fu et al., 2019;Kubo et al., 2016). ...
... The disease's genesis can be split into the following two categories: traumatic and nontraumatic. The former is primarily caused by hip trauma, such as femoral neck fractures and hip dislocations; the latter is primarily caused by long-term corticosteroid usage or long-term drinking, smoking, and so on [1][2][3][4]. ...
Osteonecrosis of the femoral head (ONFH) is a condition caused by a disruption or damage to the femoral head's blood supply, which causes the death of bone cells and bone marrow components and prevents future regeneration. Ferroptosis, a type of controlled cell death, is caused by iron‐dependent lipid peroxidation. Here, we identified ferroptosis‐related genes and infiltrating immune cells involved in ONFH and predicted the underlying molecular mechanisms. The GSE123568 dataset was subjected to differential expression analysis to identify genes related to ferroptosis. Subsequently, GO and KEGG pathway enrichment analyses, as well as protein–protein interaction (PPI) network analysis, were conducted. Hub genes involved in ferroptosis were identified using machine learning and other techniques. Additionally, immune infiltration analysis and lncRNA–miRNA‐mRNA network prediction analysis were performed. Finally, we determined whether ferroptosis occurred by measuring iron content. The hub genes were validated by ROC curve analysis and qRT–PCR. Four ferroptosis‐related hub genes (MAPK3, PTGS2, STK11, and SLC2A1) were identified. Additionally, immune infiltration analysis revealed a strong correlation among ONFH, hub genes, and various immune cells. Finally, we predicted the network relationship between differentially expressed lncRNAs and hub genes in the lncRNA–miRNA–mRNA network. MAPK3, PTGS2, STK11, and SLC2A1 have been identified as potential ferroptosis‐related biomarkers and drug targets for the diagnosis and prognosis of ONFH, while some immune cells, as well as the interaction between lncRNA, miRNA, and mRNA, have also been identified as potential pathogenesis markers and therapeutic targets.
... Alcohol abuse has been reported to account for approximatively 30 to 40% of patients who developed hip or femoral osteonecrosis. [13][14][15] There seems to be a dose response relationship between alcohol use and AVNHNF; however, the threshold for the threshold level of alcohol consumption associated with the development of avascular necrosis has not been clearly established. 16 Previous literature has reported multifactorial etiologies for the association between alcohol use and AVNHNF, such as genetic susceptibility, environmental factors, and medical comorbidities. ...
The association between bipolar disorder (BD) and avascular necrosis of the femoral head and neck (AVNHNF) remains unclear. We aimed to investigate the risk of AVNHNF among different polarity of BD. Between 2001 and 2010, patients with BD were selected from the Taiwan National Health Research Database. The controls were individuals without severe mental disorder who were matched for demographic, medical and psychiatric comorbidities. Cox regression analysis was used to estimate the risk of AVNHNF, with adjustments for demographics, comorbidities, exposure to corticosteroids, and all-cause clinical visits. A total of 84,721 patients with BD and 169,442 controls were included. Patients with BD demonstrated a 1.92-fold (95% of confidence interval: 1.21–3.04) higher risk of AVNHNF compared with the controls. The risk was increased to 7.91-fold (4.32–14.49) in patients with severe BD compared with the controls. Importantly, patients with severe bipolar depression were associated with a 14.23-fold higher risk of AVNHNF compared with the controls, while those with sever bipolar mania were associated with a 3.55-fold higher risk. Compared with the controls with alcohol use disorder (AUD), patients with BD and comorbid AUD were associated with a 2.0-fold higher risk of AVNHNF. Finally, long-term use of atypical antipsychotics was associated with a decreased risk of AVNHNF). Clinicians should be aware of the increased risk of AVNHNF among patients with BD. This increased risk was associated with disorder severity, polarity, and comorbidity with AUD, and attenuated by long-term atypical antipsychotic treatment.
... Nontraumatic ONFH is associated with many risk factors, including steroid use, alcohol consumption, and autoimmune diseases, such as systemic lupus erythematosus and rheumatoid arthritis [11][12][13]. In particular, steroid-induced ONFH (SIONFH) occurs frequently among young and middle-aged individuals [14]. Previous studies have found that high-dose corticosteroid use (> 20 mg prednisone equivalents per day) is related to ONFH [2,15]. ...
Background
Osteonecrosis of the femoral head (ONFH) is becoming a prevalent global health problem. 4-Hydroxynonenal (4-HNE) serves as a common marker of oxidative stress. This study aims to study the potential role of 4-HNE in the progression of steroid-induced osteonecrosis of the femoral head (SIONFH).
Method
Between April 2021 and December 2021, 64 subjects were enrolled in this cross-sectional case‒control study. Thirty-six patients were grouped based on the Association Research Circulation Osseous (ARCO) classification, and 28 healthy volunteers without hip pain or any lesions shown in anteroposterior and frog-leg lateral pelvic radiographs served as the normal control group. Bone hematoxylin–eosin (HE) staining, microcomputed tomography (micro-CT), immunohistochemistry, and levels of plasma 4-HNE were evaluated.
Results
The 4-HNE level was higher in the SIONFH group than in the normal control group (P < 0.001), and 4-HNE levels were significantly higher in SIONFH patients in the early stage of disease (stage II). The 4-HNE level was negatively correlated with ARCO stage (r = − 0.6875, P < 0.001). Immunohistochemistry revealed the presence of 4-HNE in the trabecular bone, osteocytes, and bone marrow.
Conclusion
The 4-HNE level is negatively associated with ARCO stages. Lower levels of 4-HNE may serve as a critical biomarker for the progression of SIONFH.
... Osteonecrosis of the femoral head (ONFH) is a debilitating skeletal disorder that commonly occurs in young and middle-aged individuals [1,2]. Although many advances have been made in joint-preserving treatments, many patients still require surgery, usually total hip arthroplasty, while the durability of commonly used bone graft materials is unsatisfactory [3][4][5][6][7][8][9]. Steroids are known to be the most common cause of non-traumatic ONFH [10][11][12]. ...
Background
The impaired blood supply to the bones is an important pathological feature of steroid-induced osteonecrosis of the femoral head (SIONFH). Danshen is a Chinese herb that shows therapeutic effects on SIONFH, but the effects of one of its major bioactive constituents, Tanshinone I (TsI), on SIONFH remain unknown. Here, we evaluated the effects of TsI on SIONFH, particularly focusing on its effects on angiogenesis, in in vivo and in vitro research.
Methods
SIONFH was induced in Sprague–Dawley rats by an intramuscular injection of methylprednisolone (40 mg/kg) in combination with an intraperitoneal injection of lipopolysaccharide (20 μg/kg). Morphological alterations of the femoral head were observed by dual-energy X-ray absorptiometry and HE staining. Western blot, qRT-PCR, and immunohistochemical/immunofluorescence staining were used to determine gene expression.
Results
TsI (10 mg/kg) alleviated bone loss and rescued the expression of angiogenesis-related molecules (CD31, VWF, VEGF, and VEGFR2) in the femoral heads of SIONFH rats. Notably, TsI rescued the down-regulated expression of SRY-box transcription factor 11 (SOX11) in CD31⁺ endothelial cells in the femoral heads of SIONFH rats. In vitro studies showed that TsI preserved the dexamethasone-harmed angiogenic property (migration and tube formation) of human umbilical vein cells (EA.hy926), suppressed dexamethasone-induced cell apoptosis, reduced pro-apoptotic proteins (cytosolic cytochrome C, Bax, and caspase 3/9) and increased anti-apoptotic protein Bcl-2, whereas silencing of SOX11 reversed these beneficial effects.
Conclusions
This study demonstrates that TsI alleviates SIONFH and promotes angiogenesis by regulating SOX11 expression. Our work would provide new evidence for the application of TsI to treat SIONFH.
Graphical Abstract
... Recent surveys have indicated that ONFH afflicts more than 20 million people worldwide, 5-7.5 million in China (4). Excessive steroid use is the most common cause of osteonecrosis (ON) and makes up 24.4%-51% of total ONFH cases (5). The ON incidence in steroid users may reach 40%, depending on the duration, dose or underlying disease (6). ...
The excessive steroid may cause dyslipidaemia and oxidative insult during femoral head osteonecrosis, inducing bone loss and impairment of the intraosseous blood system. In contrast, bio-flavanone naringin has shown antioxidant, antiresorptive and lipid-lowering bioactivities. The present research is an effort to explore the anti-ON potential of naringin in vivo and in vitro. After a 6-week treatment, the femora were dissected for histological examination following bone mineral density assay by X-ray absorptiometry. Blood samples were examined for coagulation, oxidative stress, lipid transportation and endothelial injury. Marrow samples were cultured and assayed for adipogenic and osteogenic alterations by ALP activity, mineralization, RT-qPCR and western blot analysis. The results showed that naringin exerted a dose-dependent effect on reducing ON incidence, with inhibition of osteoporosis, oxidative stress and dyslipidaemia. The mechanism included the suppression of PPARγ2 for adipogenesis of bone marrow stem cells (BMSCs) and the prevention of oxidative stress in endothelium injury. Naringin may restore steroid-impaired osteogenesis by enhancing the mRNA and protein expression of osteogenic markers in a dose-ascending manner and new bone formation can be found in naringin groups. Taken together, our findings showed that naringin may serve as a prophylactic agent and selective PPARγ modulator for the early-stage ON.
