Application of Machine Learning and Mendelian Randomization Analysis to Identify the Cuproptosis-Related Biomarker and Its Related Regulation in Osteonecrosis of the Femoral Head

Mesenchymal stem cells (MSCs) with multipotential differentiation capacity can differentiate into bone cells under specific conditions and can be used to treat osteonecrosis (ON) of the femoral head (ONFH) through cell transplantation. The current study aims to explore the role of bone marrow (BM) MSCs (BMSCs)-derived exosomes carrying microRNA-122-5p (miR-122-5p) in ONFH rabbit models.First, rabbit models with ONFH were established. ONFH-related miRNAs were screened using the Gene Expression Omnibus (GEO) database. A gain-of-function study was performed to investigate the effect of miR-122-5p on osteoblasts and BMSCs and effects of exosomes carrying miR-122-5p on ONFH. Co-culture experiments for osteoblasts and BMSCs were performed to examine the role of exosomal miR-122-5p in osteoblast proliferation and osteogenesis. The target relationship between miR-122-5p and Sprouty2 (SPRY2) was tested.MiR-122, significantly decreased in ONFH in the GSE89587 expression profile, was screened. MiR-122-5p negatively regulated SPRY2 and elevated the activity of receptor tyrosine kinase (RTK), thereby promoting the proliferation and differentiation of osteoblasts. In vivo experiments indicated that bone mineral density (BMD), trabecular bone volume (TBV), and mean trabecular plate thickness (MTPT) of femoral head were increased after over-expressing miR-122-5p in exosomes. Significant healing of necrotic femoral head was also observed.Exosomes carrying over-expressed miR-122-5p attenuated ONFH development by down-regulating SPRY2 via the RTK/Ras/mitogen-activated protein kinase (MAPK) signaling pathway. Findings in the present study may provide miR-122-5p as a novel biomarker for ONFH treatment.

Treatment with senolytic drugs ameliorates steroid-induced osteonecrosis of the femoral head by inhibiting osteoclastogenesis.

Osteonecrosis of the femoral head (ONFH), also called avascular necrosis of the femoral head (AVN), is a common and often refractory disease in the orthopaedic domain. ONFH can be caused by trauma or other factors (nontraumatic). Traumatic ONFH is caused mainly by trauma to the hip, such as femoral neck fracture or hip dislocation. In China, the causes of nontraumatic ONFH are mainly corticosteroid treatment and/or alcohol abuse. ONFH is progressive and about 80% of necrotic femoral heads will collapse within 1 to 4 years in the absence of effective treatment. Collapse of the femoral head (manifested as subchondral fracture and a positive crescent sign) can progress to severe osteoarthritis requiring prosthetic replacement. Nontraumatic ONFH mainly affects young and middle-aged people and bilateral hip involvement is common (approximately 80%). Because the long-term efficacy of total hip arthroplasty in young and middle-aged patients is unpredictable, it is important to perform joint-preserving procedures in the early stages. Based on the suggestions of the Association Research Circulation Osseous (ARCO) and American Academy of Orthopaedic Surgeons, ONFH can be defined as a disease involving the femoral head and characterized by structural change, collapse and joint dysfunction resulting from necrosis caused by interruption or impairment of the blood supply to the femoral head, and subsequent repair of the bone cells and marrow. Based on the diagnostic criteria of the Japanese Investigation Committee and Mont, we propose that the following diagnostic criteria for ONFH are appropriate for China. Clinical symptoms, signs and history which include hip joint pain involving the inguinal region, buttocks and upper leg; limited and painful internal rotation of the hip joint; a history of hip trauma, corticosteroid application and/or alcohol abuse. Radiographic findings: (i) femoral head collapse without joint space narrowing; (ii) calcification band(s) with clear borders inside the femoral head; and (iii) lucent band(s) in subchondral bone (subchondral fracture or positive crescent sign). Radionuclide bone scanning shows a cold area within the hot area of the femoral head. Magnetic resonance imaging of the femoral head shows a banded low signal shadow (banded type) in T1 weighted images or a double-line sign in T2 weighted images. Bone biopsy shows empty osteocytic lacuna with multiple trabecular involvement in >50% of trabeculae as well as necrotic bone marrow. Radiographic findings: (i) femoral head collapse with narrowed joint space; (ii) cystic changes or spotted calcification inside the femoral head; and (iii) flattening of the lateral superior aspect of the femoral head. Radionuclide bone scanning shows a cold or hot area inside the femoral head. Magnetic resonance imaging of the femoral head shows homogenous or heterogeneous low intensity signals with banded changes in T1 weighted images. Two or more positive primary criteria are sufficient for a diagnosis of ONFH. One positive primary criterion with three positive secondary criteria, including at least one positive radiographic sign, are sufficient for a diagnosis of possible ONFH. Clinical examination: a detailed case history, including any hip trauma, consumption of corticosteroids, alcohol abuse and/or anemia, should be taken and clinical features, such as the site and characteristics of any pain and the relationship between pain and weight bearing, should be collected. The physical examination should include assessment of the rotation of the involved hip joint. Radiography: ONFH in its early phases (phases 0 and I) is difficult to identify by radiography. Positive radiographic findings for phase II or greater phases of ONFH include calcification bands, radiotransparent cystic changes, spotty calcification, subchondral fracture and femoral head collapse. The recommended views on radiography include the anteroposterior and frog lateral views, the latter allowing clearer visualization of a necrotic femoral head. Magnetic resonance scan: MR scan is the most reliable method for the diagnosis of early ONFH with a sensitivity and specificity of up to 96%–99%. Typical MRI findings in ONFH include a spirally banded low signal and/or low signal surrounding a region of high or heterogeneous signal at the proximal end of, or across, the residual bone marrow line of the involved femoral head in T1 weighted images. T2 weighted images show a typical double-line sign. Combined T1 and T2 weighted imaging is recommended, supplemented with fat-suppression or short T1 inversion recovery sequencing for a suspected lesion. Sagittal scanning should be used to supplement the routine employment of coronal or transverse scanning, because it allows more precise estimation of the volume of necrosis and visualization of the lesion. Gadolinium-enhanced MRI is superior for the diagnosis of early ONFH. Radionuclide bone scanning: radionuclide bone scanning has high sensitivity and low specificity for diagnosing early ONFH. A cold area within a hot area in a scan for which 99mTC was used is a characteristic manifestation of ONFH, but the presence of pure radionuclide aggregation (hot area) should be differentiated from other joint diseases. This method of examination can be used for screening for the disease at an early phase or for involvement of multiple sites. Single photon emission computer tomography increases the sensitivity rather than the specificity. Computed tomography scanning: CT scanning can clearly display the borders, area, calcified bands, autologous repair and subchondral fractures of ONFH in phases II and III, but is useless for ONFH in phase I. CT scanning surpasses MRI and radiography in displaying any subchondral fracture. A supplemented two-dimensional reconstruction can display the overall femoral head from a coronal view. CT scanning is a useful method for determining the severity of the lesion and the appropriate therapeutic regimen. Other investigations: positron emission tomography, 67Ga or sulfur colloid labeled radioisotope scanning and T2 dynamic MRI blood flow perfusion determination for the diagnosis of early ONFH are currently being testing prior to their clinical application. Moderate/severe osteoarthritis. Typical osteoarthritis is not difficult to differentiate from ONFH, but a slightly narrow joint space and subchondral cystic changes may lead to a misdiagnosis. This disease typically shows calcification and cystic change on CT scanning, low signals on MRI and bony outgrowths at the medial lower margin of the femoral head. Osteoarthritis secondary to acetabular dysplasia. This is not difficult to differentiate from ONFH because it has characteristic radiographic findings including shallow acetabulum, narrowed or absent joint space in the superior lateral region of the femoral head, bony calcification, cystic changes and changes in the corresponding acetabular region similar to the weight-bearing region of the femoral head. Ankylosing spondylitis-related hip arthritis. This is not difficult to identify because of the following typical clinical properties: common in young male patients, bilateral sacroiliac joint involvement, HLA-B27 (+) and a narrowed or absent joint space (or even joint fusion), with a femoral head that is still round. However, patients with a history of long-term corticosteroid administration may develop concomitant ONFH, presenting with a mild to moderate femoral head collapse. Rheumatoid arthritis. This is not difficult to identify on the basis of the following characteristics: a common disease in female patients, narrowed or absent joint space with a round femoral head, frequent subchondral erosion of the femoral head, cystic changes and acetabular erosion. Idiopathic transient osteoporosis of the hip (ITOH). This is caused by transient painful bone marrow edemaand is common in middle-aged people. Its radiographic findings are bone mass reduction at the femoral head, neck and even the trochanter. MRI shows homogenous low signals on T1 weighted images and high signals on T2 weighted images, ranging from the neck to the trochanter of the femoral head, without the banded low signal changes that are seen in ONFH. ITOH can spontaneously resolve 3–6 months after onset. Subchondral incomplete fracture. Clinical features include: common in patients aged more than 60 years, absence of a trauma history, sudden onset of hip pain, walking difficulties and restricted joint movement. Radiography shows slight flattening of the superior lateral aspect of the femoral head. MRI shows subchondral low signals and edema of the surrounding bone marrow on T1 and T2 weighted images, and flaky high signals on T2 fat-suppression images. This fracture is a fracture of tiny trabeculae secondary to osteoporosis. Pigmented villonodular synovitis. This involves the knee joints more often than the hip joints. The features of hip pigmented villonodular synovitis include common in young people, mild to moderate hip pain with claudication and mild restriction of joint movement in the early and middle stages and severe restriction of joint movement in the advanced stage. CT scanning and radiography show cortical erosion at the femoral head, neck and/or acetabulum and mild to moderate narrowing of the joint space. MRI shows extensive synovial hypertrophy involving the overall joint with well distributed low to moderate intensity signals. Femoral head bruise. This is characterized by a hip trauma history, hip pain and claudication. MRI shows moderate intensity signals inside the femoral head on T1 weighted images and high intensity signals on T2 weighted images, more often on the medial side of the femoral head. Synovial herniation pit. This is a benign disease characterized by invasion of hyperplastic synovial tissue into the cortex of the femoral neck. MRI shows low signals on T1 weighted images and small round lesions with high signals on T2 weighted images. It is commonly manifested as asymptomatic erosion of the the cortex in the superior region of the femoral neck. Once ONFH has been diagnosed, scientific staging should be undertaken. This is very helpful for selecting an appropriate treatment plan, accurately assessing the prognosis, and comparing the effects of treatment. We recommend the following staging methods: ARCO staging (Table 1), Steinberg staging (Table 2) and Ficat staging (Table 3). An appropriate treatment strategy should be selected according to the stage, volume of osteonecrosis, age, joint function and occupation of the patient. Currently, there is no single method for managing all variations of ONFH regardless of type, stage and necrotic volume. The treatment methods for ONFH are both non-surgical and surgical and each has its own indications. Whether weight bearing with protection can prevent collapse of the femoral head is controversial. Weight-bearing with crutches is recommended to reduce the pain, whereas use of a wheelchair is not recommended. This is suitable for the pre-collapse stage of ONFH (ARCO Stages 0, I, II) and includes non-steroidal anti-inflammatory analgesics, low molecular weight heparin, Chinese medicine for treating thrombophilia or hypofibrinolysis, alendronate for preventing collapse of the femoral head, vasodilator drugs and drugs for elimination of bone marrow edema. These include extracorporeal shock wave and high-frequency magnetic field therapy. All these methods are useful for alleviating pain and promoting recovery of necrotic bone. The procedures include joint-preservation and joint-replacement surgery. This utilizes the procedures of core decompression, bone grafting, and osteotomy and is suitable for ONFH in ARCO Stages I, II, and IIIA. If the procedure is selected appropriately, it is possible to avoid or delay joint replacement. Core decompression surgery has a long history and recognized benefits in the treatment of ONFH ARCO Stages I and II. It is recommended that a 3-mm wire be used to produce multiple holes under fluoroscopic control in combination with autologous bone marrow cell transplantation or bone morphogenetic protein. This is not recommended for advanced stages (ARCO Stages III and IV). Common methods used in the clinic include vascularized fibular grafting, vascularized iliac bone grafting, and bone grafting with preservation of muscle blood supply. These are suitable for young or middle-aged ONFH patients (ARCO Stages IIC, IIIA, and IIIB). When these surgical procedures are used appropriately, the mid- and long-term effects are good. However, the more severe surgical trauma, technical difficulty, and a certain percentage of complications at the donor site are disadvantages of these procedures. Currently, bone grafting with core decompression via the greater trochanter of the femur or via a femoral neck window is popular. Methods include support bone grafting and impaction bone grafting. Materials used for the bone graft include autologous bone, artificial substitutes, and allograft bone. These are suitable for young or middle-aged ONFH patients in ARCO Stages IIB and IIC with a necrotic volume >25%. Less surgical trauma, technical difficulty, and a small percentage of complications at the donor site are advantages of these procedures. The mid-term result is acceptable but the long-term results are still difficult to predict. The principle of osteotomy is to alter the weight-bearing surface of the femoral head, that is to say, shift the necrotic region out of the weight-bearing surface and make the non-necrotic region the weight-bearing surface. Methods include intertrochanteric varus/valgus osteotomy and transtrochanteric osteotomy. These are suitable for young or middle-aged ONFH patients with moderate Stage II and earlier stages, and middle stage III. When these surgical procedures are used appropriately the results are acceptable, but this surgery can create some technical difficulties for any future arthroplasty. This is still controversial. Some studies suggest that active treatment should be undertaken for large volume necrosis (>30%) and when the necrotic region is located on the weight-bearing surface of the femoral head, rather than waiting for symptoms to occur. Once collapse of the femoral head has progressed to the advanced stages of III, IV or V or there is joint dysfunction and severe pain, total hip replacement should be recommended. Surface replacement, metal-on-metal surface replacement, or the double-acting type of femoral head replacement should be suggested for young patients (<50 years old). These procedures are transitional surgery which preserves more bone quantity for future arthroplasty revision. The procedures above have their own variety of indications, technical requirements and corresponding complications and should be carefully chosen. Total hip arthroplasty for advanced ONFH has positive results. It is generally considered that the long-term efficacy of cementless or mixed-type prosthesis is superior to that of cement prosthesis. The surgical skills required, efficacy and complications of arthroplasty for ONFH vary according to the presence of other disorders. The surgeon should note that: For patients with a long-term history of taking steroids for an underlying disease or some other reason, postoperative infection rates may be increased. For some patients with secondary osteoporosis who have not been weight-bearing for a long time, care should be taken to avoid penetrating the acetabulum during hip replacement surgery. For some patients with failure of a previous preservation procedure, it can be difficult to insert a femoral prosthesis. An arthrodesis procedure can be suitable for younger patients with advanced unilateral ONFH who engage in a lot of physical work. Stage 0: patients with non-traumatic unilateral ONFH who have a definite diagnosis and in whom it is strongly suspected that the opposite hip may also be affected should be closely observed. Assessment by MRI is suggested at 6 monthly intervals. Stages I and II: those asymptomatic patients whose necrotic area is located in a non-weight-bearing region and whose necrotic lesion area <15%, should be closely observed and followed up regularly. Some patients who are symptomatic, or whose necrotic lesion area >15%, should be actively treated. Stages III A and B: a variety of surgical options, including bone grafting, osteotomy, and limited surface replacement, may be selected. Some patients with mild symptoms may be treated conservatively. Stages III C and IV: some younger patients with mild symptoms can be treated by joint-preservation surgery. Other options include surface replacement, total hip replacement and hip arthrodesis. Evaluation of the efficacy of ONFH treatment includes clinical results and radiographic evaluation. Hip function scores (such as the Harris score, the revised Merle d'Auligne score and SF36 evaluation) should be used for evaluation of clinical results. In evaluating imaging results, X-ray films with a template of concentric circles should be used to observe the femoral head shape, joint gap and acetabular changes. For lesions of Stages 0, I, II, MR scanning should be performed. For each patient, the clinical and radiological results are not the same, and should be assessed separately. The Chinese version of this guideline has been published in the Chinese Journal of Orthopaedics, Issue 2, Volume 27, pages 146–148.

76 BASIC FIBROBLAST GROWTH FACTOR INDUCES OSTEOGENESIS AND SUPPRESSES THE PROGRESSION OF SECONDARY OA IN A RABBIT MODEL OF OSTEONECROSIS OF THE FEMORAL HEAD

Background: Studies have shown that platelet lysate (PL) stimulates resting osteoblasts to resume proliferation, activates the angiogenesis induction pathway, secretes factors that promote angiogenesis, accelerates osteoblast differentiation and bone formation, and can treat Avascular necrosis. Glucocorticoids(GCs) can induce osteonecrosis of the femoral head(ONFH), which is avascular osteonecrosis, which is largely related to the increase of autophagy. Super active platelet lysate (sPL) has a variety of biologically active factors, high content and strong activity. It is an upgraded version of PL and can repair ONFH. However, the relationship between sPL and glucocorticoid-related rat ONFH is still It is not clear, therefore, the purpose of our study is whether sPL can prevent and treat ONFH through autophagy. In this study, we tried to explore the role of sPL in ONFH and explore its mechanism. Methods: Through scanning electron microscopy(SEM) and enzyme-linked immunosorbent assay (ELISA) to detect the characteristics of sPL. We used methylprednisolone (MPS)-induced in vitro osteoblast necrosis model, divided into control group, MPs group, 5% group, 10% group, 15% group and 20% group, cell counting kit-8 (CCK-8), cell cycle analysis, An-nexin V And PI staining was used to diagnose its effects on cell proliferation, apoptosis, angiogenesis and osteogenesis. Using RT-PCR and western-blotting technology to analyze its molecular mechanism. Using the rat ONFH model, divided into the control group, treatment-100 group, treatment-300 group, the prevention and treatment effects of sPL on it were verified by Micro-CT and histology. Results: Increased autophagy in the ONFH model. The characterization of sPL showed that the biologically active factor was higher than that of PRP. In vitro, the results of ccK-8 showed that sPL can significantly induce the proliferation of osteoblasts and endothelial cells. Flow cytometry results also proved that sPL can inhibit cell apoptosis and promote bone formation. In addition, in the body, sPL promotes the treatment of ONFH. In order to further verify the correlation between sPL prevention and treatment of ONFH and autophagy, we found that after sPL was used to treat hormone-induced ONFH, the effect of sPL on glucocorticoid-inducedONFH by stimulating autophagy was significantly inhibited. This study reported for the first time that sPL can improve ONFH caused by glucocorticoid-activated autophagy by inhibiting the mTOR signaling pathway. which provides a research basis for the clinical application of sPL and also provides a basis for conservative treatment of femoral head necrosis. Interpretation: sPL can inhibit GC-induced ONFH through autophagy. This simple treatment brings good news for patients with femoral head necrosis. Funding: This work is supported by the Postgraduate Research & Practice Innovation Program of Harbin Medical University (No. YJSKYCX2019- 39HYD). Declaration of Interests: The authors have declared that there are no competing interests. Ethics Approval Statement: All experimental and animal care procedures were approved by the Ethics Committee of Laboratory Animal Ethics Committee of the First Affiliated Hospital of Harbin Medical University and performed under the guidelines of the National Institutes of Health Guidelines for the Care and Use of Laboratory Animals.

BackgroundIt has been well known that the degeneration of hip articular cartilage with osteonecrosis of the femoral head (ONFH) increases the instability of hip and accelerates the development process of ONFH. A better understanding of the expression of chondrogenesis-related and arthritis-related genes of cartilage along with the progression of ONFH seems to be essential for further insight into the molecular mechanisms of ONFH pathogenesis.MethodsWe analyzed the differentially expressed gene profile (GSE74089) of human hip articular cartilage with ONFH. The functions and pathway enrichments of differentially expressed genes (DEGs) were analyzed via GO and KEGG analysis. The expression of six selected critical chondrogenesis-related and four arthritis-related genes in eight human hip articular cartilage with femoral neck fracture (FNF) and 26 human hip articular cartilage with different stages ONFH (6 cases of Ficat stage II, 10 cases of Ficat stage III and 10 cases of Ficat stage IV) were detected.ResultsA total of 2,174 DEGs, including 1,482 up-regulated and 692 down-regulated ones, were obtained in the ONFH cartilage specimens compared to the control group. The GO and KEGG enrichment analysis indicated that the function of these DEGs mainly enriched in extracellular matrix, angiogenesis, antigen processing and presentation. The results showed a significant stepwise up-expression of chondrogenesis-related genes, including MMP13, ASPN, COL1A1, OGN, COL2A1 and BMP2, along with the progression of ONFH. The arthritis-related genes IL1β, IL6 and TNFα were only found up-expressed in Ficat IV stage which indicated that the arthritis-related molecular changes were not significant in the progression of ONFH before Ficat III stage. However, the arthritis-related gene PTGS2 was significant stepwise up-expression along with the progression of ONFH which makes it to be a sensitive arthritis-related biomarker of ONFH.ConclusionExpression changes of six chondrogenesis-related and four arthritis-related genes were found in hip articular cartilage specimens with different ONFH Ficat stages. These findings are expected to a get a further insight into the molecular mechanisms of ONFH progression.

Osteonecrosis of the femoral head (ONFH) is a chronic and irreversible disease that has a risk of eventually developing into a joint collapse and resulting in joint dysfunction. Quyushengxin capsule (QYSXC) is an effective and safe traditional Chinese medicine used in the treatment of ONFH. In this present study, an integrated approach was used to investigate the mechanism of QYSXC in the treatment of ONFH, which contained systems pharmacology, molecular docking, and chip experiment. In the systems pharmacology, target fishing, protein-protein interaction (PPI), Kyoto encyclopedia of genes and genomes (KEGG) pathway enrichment analysis, and herbs-compounds-targets-pathways (H-C-T-P) network construction were performed to study the mechanism of QYSXC in the treatment of ONFH. The results showed that 15 key compounds, 8 key targets, and 8 key signaling pathways were found for QYSXC in the treatment with ONFH. Then, molecular docking was performed to further explore the interaction between some key compounds and key targets. After that, the chip experiment was performed to verify some target factors, including ICAM-1, IL-6, IL-1α, IL-1β, IL-2, IL-4, IL-10, and TNF-α. The results of this work may provide a theoretical basis for further research on the molecular mechanism of QYSXC in the treatment of ONFH.

Cell therapy has been proposed as part of the therapeutic arsenal to assist bone formation and remodeling in the early stages of osteonecrosis of the femoral head. The purpose of this study is to determine the effects of intraosseous inoculation of mesenchymal stem cells on bone formation and remodeling in an established experimental model of osteonecrosis of the femoral head in immature pigs. Thirty-one 4-week-old immature Yorkshire pigs were used. Experimental osteonecrosis of the femoral head was created in the right hip of all included animals (n = 31). The month after surgery, hip and pelvis radiographs were taken to confirm osteonecrosis of the femoral head. Four animals were excluded following surgery. Two groups were established: (A) mesenchymal stem cell-treated group (n = 13) and (B) saline-treated group (n = 14). One month after surgery the mesenchymal stem cell-group received an intraosseous injection of 10 × 106 mesenchymal stem cell (5 cc) and the saline-treated group of 5 cc of physiological saline solution. Osteonecrosis of the femoral head progression was assessed by monthly X-rays (1-, 2-, 3- and 4-months post-surgery). The animals were sacrificed 1 or 3 months following the intraosseous injection. Repair tissue and osteonecrosis of the femoral head were histologically evaluated immediately after sacrifice. At time of sacrifice, radiographic images showed evident osteonecrosis of the femoral head with associated severe femoral head deformity in 11 of the 14 animals (78%) in the saline group and in only 2 of the 13 animals (15%) in the mesenchymal stem cell group. Histologically, the mesenchymal stem cell group showed less osteonecrosis of the femoral head and less flattening. In the saline group, there was pronounced femoral head flattening and the damaged epiphyseal trabecular bone was largely replaced with fibrovascular tissue. Intraosseous mesenchymal stem cells inoculation improved bone healing and remodeling in our immature pig osteonecrosis of the femoral head model. This work supports further investigation to determine whether mesenchymal stem cells enhance the healing process in immature osteonecrosis of the femoral head.

Osteonecrosis of the femoral head (ONFH) typically affects relatively young, active patients and frequently follows an unrelenting course resulting in considerable loss of function. In human immunodeficiency virus-infected patients, ONFH is a growing problem. Etiology, pathogenesis, and treatment of ONFH in these patients remain controversial. We analyzed retrospectively patients with ONFH in a series of 815 patients followed in our AIDS reference center. Six patients out of the 815 were affected by ONFH (0.74%). The sex ratio was 1. Two of the six patients (33.3%) had no evidence of risk factor, whereas four patients (66.6%) had risk factors. One patient had three cumulated risk factors which were corticosteroids, chemotherapy, and radiotherapy. For this patient, the onset time for ONFH was shorter (36 months). It is difficult to attribute the effect to any single class of antiretroviral agents because combination therapy is standard of care, and a change in therapies is common. All classes of antiretroviral drugs have been used: protease inhibitors (mean use duration of 15.2 months before the ONFH onset), non-nucleoside reverse transcriptase inhibitors (12 months), and nucleoside reverse transcriptase inhibitors (40.5 months). ONFH was bilateral in four cases (66.6%) and unilateral in two cases (33.3%). One patient had other osteonecrosis location (both shoulders). ONFH was classified on plain radiography stage IV in five patients and stage III in one patient. All patients received initial medical treatment. It consisted of painkillers and non-weight bearing of the hip. All were finally operated on by total hip arthroplasty (THA). The average interval between ONFH diagnosis and the first THA was 10.3 months for the six patients. A controlateral THA was performed for three patients after a mean interval of 23.3 months after ONFH diagnosis. Of the nine implanted prostheses, four were cemented, four were cementless, and one was resurfacing prosthesis.

To summarize the current progress of vascularized bone grafting in the treatment of osteonecrosis of the femoral head (ONFH), and to provide reference for treatment of ONFH. The literature at home and abroad on the treatment of ONFH with vascularized bone grafting was reviewed, and the mechanism, operating methods and effectiveness, indications, and complications were summarized. Vascularized bone grafting is a commonly used clinical hip-preserving operation. By replacing necrotic bone tissue with vascularized bone, it can rebuild the blood circulation system, promote the healing of the necrotic area, and provide biomechanical support for the necrotic area of the femoral head, prevent the joint surface collapse. The main operations include the vascularized iliac bone flap grafting, the vascularized greater trochanter bone flap grafting, and the vascularized fibular grafting. The clinical application has achieved certain effectiveness, and the different procedures are suitable for different types of patients. The procedures need to be selected based on the patient's overall condition, the cause of ONFH, the necrosis stage, and the degree of the evaluation. Vascularized bone grafting has a definite effectiveness in the treatment of ONFH in the young and middle-aged. It can significantly improve hip joint function, control the further development of the disease to a great extent, effectively delay or even avoid hip arthroplasty. It is a reliable hip-preserving operation worthy of promotion.

Objective: To analyze the risk factors of deep vein thrombosis (DVT) after core decompression in patients with osteonecrosis of the femoral head (ONFH) and construct a predictive model. Method: A retrospective analysis was conducted on the clinical data of 244 patients with ONFH who underwent core decompression and were hospitalized in Guizhou Hospital of Jishuitan, Beijing from January 2020 to May 2025. There were 143 males and 101 females, with an age of (62.2±4.2) years. According to whether DVT occurred within 3 months after the operation, the patients were divided into the non-DVT group (n=167) and the DVT group (n=77), and the differences in various clinical indicators between the two groups were analyzed. After screening for variables through least absolute shrinkage and selection operator (LASSO) regression, a multivariate logistic regression model was conducted to analyze the risk factors of DVT after core decompression in patients with ONFH, and a nomogram of the DVT prediction model was drawn. The predictive ability, accuracy and clinical applicability of the model were evaluated respectively by the area under the receiver operating characteristic curve (AUC), calibration curve and decision analysis curve. Result: The age, ONFH volume, proportion of diabetes, postoperative bed rest time, fibrinogen (FIB), D-dimer, complement C3, complement C4, matrix metalloproteinase-1 (MMP-1), matrix metalloproteinase-2 (MMP-2), and Caprini score of patients in the DVT group were greater than those in the non-DVT group (all P<0.05). LASSO regression screened out 10 variables for analysis, namely age, ONFH volume, postoperative bed rest time, FIB, D-dimer, complement C3, complement C4, MMP-1, MMP-2, and Caprini score. The analysis of the multi-factor logistic regression model showed that large ONFH volume (OR=1.90, 95%CI:1.34-2.68), postoperative bed rest time≥3 d (OR=11.22, 95%CI:1.46-16.04), elevated FIB (OR=2.83, 95%CI:1.29-6.21), elevated D-dimer (OR=2.17, 95%CI:1.11-4.25), elevated complement C3 (OR=5.28, 95%CI:4.22-8.08), elevated MMP-1 (OR=18.78, 95%CI:15.90-27.37) and a higher Caprini score (OR=4.44, 95%CI:1.74-11.35) were risk factors for DVT in patients with ONFH after core decompression. Based on the above parameters, a prediction model for DVT after core decompression in patients with ONFH was drawn. The predictive model predicted that the AUC of DVT after core decompression in patients with ONFH was 0.82 (95%CI: 0.77-0.88).The sensitivity was 78.3%, and specificity was 81.2%. The calibration curve has a high degree of fit with the standard model curve (P=0.521) and has good clinical applicability. Conclusions: Large ONFH volume, postoperative bed rest time≥3 d, elevated FIB, elevated D-dimer, elevated complement C3, elevated MMP-1, and high Caprini score are risk factors for DVT after core decompression in patients with ONFH. The nomogram prediction model constructed based on the above parameters has good clinical applicability.

Even in cases of bilateral osteonecrosis of the femoral head (ONFH), only one side often collapses and the contralateral side is often asymptomatic at the time of initial diagnosis. This study aimed to evaluate the presence of asymptomatic ONFH based on the radiographic necrotic area on the symptomatic side. The study included 89 hips of patients with ONFH who were divided into two groups: unilateral ONFH and bilateral ONFH groups, with a minimum follow-up of 3 years. The extent of the necrotic area in the anteroposterior (ANA) and lateral (LNA) radiographic hip joint views on the symptomatic side in the groups was assessed using plain radiography. The most effective cut-off value was extracted from the receiver operating characteristic (ROC) curve of the radiographic necrosis area of symptomatic ONFH in the absence of contralateral ONFH. The unilateral ONFH and bilateral ONFH groups included 36 and 53 patients, respectively. There was a significant difference in ANA and LNA between the unilateral ONFH and bilateral ONFH groups (ANA: 66.5 ± 16.3% vs. 77.2 ± 16.4%, p < 0.01; LNA: 62.2 ± 17.7% vs. 72.9 ± 17.6%, p <0.01). Multivariate analysis revealed that only LNA of the symptomatic side was a predictor of contralateral ONFH (odds ratio 1.052, 95% confidence interval 1.01-1.12, p = 0.028). A cut-off value of 67% of the LNA was extracted from the ROC curve analysis. The 4-year survival rates with the collapse progression as the endpoint were 30.6% in LNA ⩾67% and 80.0% in LNA <67% (p <0.01 and p <0.01, respectively). The LNA of ONFH on the symptomatic side is a useful indicator of the presence and prognosis of contralateral ONFH. The findings of this study provide useful information for planning treatment strategies and predicting the prognosis of patients with ONFH.

The Epidemiology of Osteonecrosis of the Femoral Head in South Korea: An Update in the COVID-19 Era.

BackgroundsThe humeral head is the second most common site of osteonecrosis, after the femoral head. However, compared to osteonecrosis of the femoral head (ONFH), epidemiological information on osteonecrosis of the humeral head (ONHH) is scarce. We hypothesised that different biomechanical properties of the shoulder from the hip joint might present different epidemiological characteristics of ONHH from those of the ONFH. To evaluate epidemiological differences, we compared trends in the surgical treatment of ONHH and ONFH using the nationwide medical claims database of the Republic of Korea (ROK).MethodsWe analysed epidemiological data from the Health Insurance Review and Assessment (HIRA) database of the ROK between 2008 and 2018. HIRA database contains almost all medical information in an anonymised form, including demographics, diagnoses, and types of surgical procedures, generated through healthcare practices in ROK. The annual incidence rates of ONHH and ONFH were calculated based on the total number of the general population. Demographics, annual incidence, and the proportion of post-traumatic osteonecrosis and surgical procedures were compared according to the anatomical site and the affected year.ResultsThe total number of patients treated for ONHH and ONFH during the study period was 1,028 and 66,260, respectively. Although the incidence of ONHH increased, it is a relatively rare disease compared to ONFH. ONHH occurred more frequently in females, while ONFH occurred predominantly in male patients (p < 0.001). Surgical treatment for ONHH was most frequently performed in older patients (63.7%), whereas middle-aged patients had the largest proportion of ONFH (48.9%, p < 0.001). The proportion of post-traumatic osteonecrosis was significantly higher in the ONHH (5.1%) than in the ONFH (1.9%, p < 0.001). Arthroplasty was performed more frequently in the ONHH (96.0%) than in the ONFH (92.9%, p < 0.001).ConclusionDespite the anatomical similarities between the hip and shoulder joints, the different biomechanical properties, such as weight-bearing functions, might cause epidemiological differences between ONHH and ONFH.

CircHGF suppressed cell proliferation and osteogenic differentiation of BMSCs in ONFH via inhibiting miR-25-3p binding to SMAD7