Analysis of the Potential Angiogenic Mechanisms of BuShenHuoXue Decoction against Osteonecrosis of the Femoral Head Based on Network Pharmacology and Experimental Validation.

OBJECTIVE: Osteonecrosis of the femoral head (ONFH) is a common orthopedic disease with a high disability rate. The clinical effect of BuShenHuoXue decoction (BSHX) for ONFH is satisfactory. We aimed to elucidate the potential angiogenic mechanisms of BSHX in a rat femoral osteonecrosis model and bone marrow mesenchymal stem cells (BMSCs). METHODS: With in vivo experiments, we established the steroid-induced osteonecrosis of the femoral head (SONFH) model using Sprague-Dawley (SD) rats (8-week-old). The rats were randomly divided into five group of 12 rats each and given the corresponding interventions: control, model (gavaged with 0.9% saline), BSHX low-, medium- and high-dose groups (0.132 3, 0.264 6, and 0.529 2 g/mL BSHX solution by gavage). After 12 weeks, haematoxylin and eosin (H&E) staining was preformed to evaluate rat osteonecrosis. the expression of angiogenic factors (CD31, VEGFA, KDR, VWF) in rat femoral head was detected by immunohistochemistry, qPCR and western blotting. In cell experiment, BMSCs were isolated and cultured in the femoral bone marrow cavity of 4-week-old SD rats. BMSCs were randomly divided into eight groups and intervened with different doses of BSHX-containing serum and glucocorticoids: control group (CG); BSHX low-, medium-, and high-dose groups (CG + 0.661 5, 1.323, and 2.646 g/kg BSHX gavage rat serum); dexamethasone (Dex) group; and Dex + BSHX low-, medium-, and high-dose groups (Dex + 0.661 5, 1.323, and 2.646 g/kg BSHX gavaged rat serum), the effects of BSHX-containing serum on the angiogenic capacity of BMSCs were examined by qPCR and Western blotting. A co-culture system of rat aortic endothelial cells (RAOECs) and BMSCs was then established. Migration and angiogenesis of RAOECs were observed using angiogenesis and transwell assay. Identification of potential targets of BSHX against ONFH was obtained using network pharmacology. RESULTS: BSHX upregulated the expression of CD31, VEGFA, KDR, and VWF in rat femoral head samples and BMSCs (p < 0.05, vs. control group or model group). Different concentrations of BSHX-containing serum significantly ameliorated the inhibition of CD31, VEGFA, KDR and VWF expression by high concentrations of Dex. BSHX-containing serum-induced BMSCs promoted the migration and angiogenesis of RAOECs, reversed to some extent the adverse effect of Dex on microangiogenesis in RAOECs, and increased the number of microangiogenic vessels. Furthermore, we identified VEGFA, COL1A1, COL3A1, and SPP1 as important targets of BSHX against ONFH. CONCLUSION: BSHX upregulated the expression of angiogenic factors in the femoral head tissue of ONFH model rats and promoted the angiogenic capacity of rat RAOECs and BMSCs. This study provides an important basis for the use of BSHX for ONFH prevention and treatment.

Return to work status of patients under 65 years of age with osteonecrosis of the femoral head after total hip arthroplasty.

OBJECTIVE: This aimed to evaluate the status of return to work (RTW) in patients with osteonecrosis of the femoral head (ONFH) after total hip arthroplasty (THA). METHODS: The baseline characteristics of all patients in this retrospective study were obtained from the hospital patient database. The relevant changes in patients' working conditions, as well as the numerical rating scale (NRS), Harris Hip Score (HHS), self-assessment of work ability, and Likert scale satisfaction assessment were obtained through video call follow-ups. RESULTS: 118 patients (response rate: 83%) were ultimately included in this study. The average length of time for the patients to stop working preoperatively was 20.7 weeks. Ninety-four patients (24 women and 70 men) who underwent THA had RTW status, with a mean RTW time of 21.0 weeks. Men had a significantly higher proportion of final RTW and a significantly faster RTW than women. Significant differences in smoking, drinking, cardiovascular diseases, changes in working levels, variations in the types of physical work, changes in working hours, and pain symptoms were observed between the RTW and Non-RTW populations. The patients with a positive RTW status had higher postoperative HHS scores, lower postoperative NRS scores, and higher self-assessment of work ability than patients who had a negative RTW status. CONCLUSION: Ultimately, 80% of patients achieved RTW status. Drinking, sex, change in working level, variation in the type of physical work, change in working hours, post-surgery HHS score and self-assessment of work ability can serve as predictive factors for RTW.

Biodegradable magnesium screw, titanium screw and direct embedding fixation in pedicled vascularized iliac bone graft transfer for osteonecrosis of the femoral head: a randomized controlled study.

BACKGROUND: The use of degradable magnesium screws to fix the bone flap implanted in the treatment of femoral head necrosis has achieved preliminary good therapeutic results. However, there is no conclusive evidence in the study to demonstrate whether biodegradable magnesium screws promote angiogenesis and no comparison has been made between degradable magnesium screws and traditional screws. OBJECTIVE: To investigate the clinical efficacy and safety of biodegradable magnesium screws in pedicled vascularized iliac bone graft transfer (PVIBGT) for osteonecrosis of the femoral head (ONFH). MATERIALS AND METHODS: A total of thirty-six patients (37 hips) with ONFH were recruited from March 2020 to July 2022. The study used a single-blind method, and patients who underwent PVIBGT were randomized into three groups: 12 patients (12 hips) were fixed with biodegradable magnesium screws (Group A), 12 patients (13 hips) were fixed with titanium screws (Group B), 12 patients (12 hips) were directly embedded (Group C). The operating time and the length of stay were recorded. Harris scores, radiological examinations (X-ray, CT, DCE-MRI), blood and serum tests were conducted before and after surgery. The gas yield and degradation rates of the magnesium screws were measured at the 3-months and 6-months post-operative follow-ups in Group A. RESULTS: There was no statistically significant difference among these three groups in terms of types, gender, age, course of disease, surgical side, operation time, the length of stay (P > 0.05). All patients were followed up for 6 months. The mean Harris scores were higher in all groups 6 months after surgery (P < 0.05). The rates of excellent and good outcomes were 66.7%, 46.2%, and 33.3% in Groups A, B, and C, respectively. PVIBGT and magnesium screws can improve the blood supply of the femoral head via DCE-MRI evaluation. Two patients with poor incision healing received prompt treatment and subsequently recovered well. No adverse events, such as hip infection or deep vein thrombosis, were reported in the patients. The patients had good biocompatibility of magnesium screws, and no fracture of the magnesium screws was observed in Group A. Liver and kidney functions (including serum magnesium) were within normal ranges. The area of the intermuscular air space was 0 cm2 in follow-ups. The degradation rate of the biodegradable magnesium screws was approximately 10.32% at the 3-months follow-up and 13.72% at the 6-months follow-up. CONCLUSIONS: PVIBGT has a positive effect, especially with regard to improving blood supply of the femoral head. The fixation of biodegradable magnesium screws is reliable and safe in PVIBGT, and promote angiogenesis.

The use of extracorporeal shock wave therapy (ESWT) in treating osteonecrosis of the femoral head (AVNFH): a retrospective study.

PURPOSE: As most of the cases of avascular necrosis (AVN) in Saudi Arabia is seen in young population and as literature showed good effect of extracorporeal shock wave therapy (ESWT) in reducing pain and oedema in avascular necrosis and delaying the need of surgical intervention. Our purpose of this study is to assess the effectiveness of ESWT in reducing pain, improving range of motion (ROM) and delaying the surgical intervention in patient with AVN of femoral head and compare our results to published literature. MATERIAL AND METHODS: We have treated 24 patients, 13 males and 11 females with a mean age of 29 years (range 14-48) with 34 hips affected. There were 14 unilateral and ten bilateral lesions. In our series 11 out of 24 patients (45.8%) were due to sickle cell disease. Other causes included idiopathic in five patients (20.8%), corticosteroids use and systemic lupus erythematous in three patients each (12.5% each) and post-traumatic AVN in two patients (8.3%). Extracorporeal shock wave therapy was implanted in FICAT stage I, II and III. All patients had two sessions of extracorporeal shock wave therapy, four to six weeks apart, each with 4000 impulses divided into four points. Radiological and MRI assessment were performed at regular time intervals with a minimum follow-up of two years. Clinical assessment was based on Visual Analog Scale and Harris Hip Score (HHS). The end point outcome measurement was the need for any operative intervention. RESULTS: Operative intervention was necessary in eight out of 34 hips (23.5%), within an average of 2.5 years (range 1 to 5 years). A hip salvage was achieved in 76.5%. Function was improved with the Harris Hip Score from a mean of 54.6 to 80.4 (P value using paired t test ≤ 0.05). Pain assessed with Visual Analog Scale improved from 5.73 to 2.75 (P value using paired t test ≤ 0.05). CONCLUSION: We do recommend the use of ESWT in treating AVN of bone whether of femoral head or other sites prior to the collapse of the articular surface. Further studies are needed to compare using two or more sessions as well as using four or six points for ESWT.

Engineered extracellular vesicles as therapeutics of degenerative orthopedic diseases.

Degenerative orthopedic diseases, as a global public health problem, have made serious negative impact on patients' quality of life and socio-economic burden. Traditional treatments, including chemical drugs and surgical treatments, have obvious side effects and unsatisfactory efficacy. Therefore, biological therapy has become the focus of researches on degenerative orthopedic diseases. Extracellular vesicles (EVs), with superior properties of immunoregulatory, growth support, and drug delivery capabilities, have emerged as a new cell-free strategy for the treatment of many diseases, including degenerative orthopedic diseases. An increasing number of studies have shown that EVs can be engineered through cargo loading, surface modification, and chemical synthesis to improve efficiency, specificity, and safety. Herein, a comprehensive overview of recent advances in engineering strategies and applications of engineered EVs as well as related researches in degenerative orthopedic diseases, including osteoarthritis (OA), osteoporosis (OP), intervertebral disc degeneration (IDD) and osteonecrosis of the femoral head (ONFH), is provided. In addition, we analyze the potential and challenges of applying engineered EVs to clinical practice.

Phase-contrast imaging with synchrotron hard X-ray reveals the effect of icariin on bone tissue morphology and microstructure in rabbits with early glucocorticoid-induced osteonecrosis of the femoral head.

Background: Phase-contrast imaging (PCI) with synchrotron hard X-ray was used to observe the changes in bone tissue morphology and microstructure in rabbit models of early glucocorticoid-induced osteonecrosis of the femoral head (ONFH), and to evaluate the intervention effect of Icariin. Methods: Fifty mature New Zealand rabbits (weighing 2.5-3.0 kg) were randomly divided into a control group (n = 10), a glucocorticoid group (n = 20), and an Icariin group (n = 20). The glucocorticoid group and the Icariin group were sequentially injected with lipopolysaccharide (LPS) and methylprednisolone (MPS) to establish a glucocorticoid-induced ONFH animal model. The Icariin group was given Icariin solution when methylprednisolone was injected for the first time, and the control group and glucocorticoid group were given the same amount of normal saline. Animals were sacrificed after 6 weeks, and bilateral femoral head specimens were taken for research. The right femoral head was observed by PCI with synchrotron hard X-ray technology, and the left femoral head was verified by Micro-CT scanning and HE staining. Results: Forty-three animals (nine in the control group, sixteen in the glucocorticoid group, and eighteen in the Icariin group) were included in the study. PCI with synchrotron hard X-ray revealed that the trabecular bone in the glucocorticoid group was thinned, broken, and structurally damaged, whereas the trabecular bone in the Icariin group had normal volume, thickness, and a relatively intact structure. Micro-CT scan reconstruction and HE staining were used to verify the reliability of this technique in identifying osteonecrosis. Conclusion: The effects of Icariin were observed in an early glucocorticoid-induced ONFH rabbit model using PCI with synchrotron hard X-ray. Icariin weakens the destructive effect of glucocorticoids on bone tissue structure, improves bone tissue morphology, and stabilizes bone microstructure. This technique may provide a definitive, non-invasive alternative to histological examination for the diagnosis of early ONFH.

Worldwide research trends on femur head necrosis (2000-2021): a bibliometrics analysis and suggestions for researchers.

Background: Osteonecrosis of the femoral head (ONFH) is a common and stubborn disease. The main causes are venous stasis of the femoral head, arterial blood supply damage, bone cell and bone marrow death, and bone tissue necrosis and subsequent repair obstacles. Over the past 22 years, the number of papers on ONFH has, overall, continued to increase. Methods: Using bibliometrics, we investigated the trends, frontiers, and hotspots of global scientific output in the past 22 years. We searched Science Citation Index Expanded (SCIE) of the Web of Science Core Collection (WoSCC) and retrieved information associated with papers and records published between 2000 and 2021. We used VOSviewer and CiteSpace to conduct bibliometric analysis and visual analysis on the overall distribution of annual output, major countries, active institutions, journals, authors, commonly cited literature, and keywords. The impact and quality of the papers were assessed using the global citation score (GCS). Results: We retrieved a total of 2006 articles and reviews. Over the past 22 years, the number of publications (NP) increased. China ranked first in terms of NP, while the United States had the highest h-index and the highest number of citations (NC). Shanghai Jiao Tong University and International Orthopaedics were the institution and periodical, respectively. The paper written by Mont et al. in 2006 had the highest total GCS score, at 379. The top three keywords were "ischemic necrosis", "osteonecrosis", and "hip joint". Although there was a fluctuation in publications associated with ONFH, overall, the NP increased. China was the most prolific in this area, while the United States was the most influential country. The top 3 authors in terms of NP were Zhang, Motomura, and Zhao. Areas of focus in ONFH over recent years include signal pathway, genetic differentiation, glucocorticoid-induced osteogenesis, induced ischemic necrosis and osteogenesis. Conclusions: Our bibliometrics analysis revealed the research hotspots and rapid development trends of ONFH research in the past 22 years. The most critical indicators [researchers, countries, research institutions, and journals publishing osteonecrosis of the femoral head (ONFH) research] relevant to the research hotspots in the field of ONFH research were analyzed.

Regenerative medicine for osteonecrosis of the femoral head : present and future.

Cite this article: Bone Joint Res 2023;12(1):5-8.

Aggressive Presentation and Rapid Progression of Osteonecrosis of the Femoral Head After COVID-19.

Background: We aim to report the consecutive patients diagnosed with osteonecrosis of femoral head (ONFH) following recovery from COVID-19 disease and elucidate the unique features of ONFH associated with COVID-19. Methods: Consecutive 22 patients (39 hips) recovered from COVID-19 and presented with ONFH from November 2020 to October 2021 were included. All the patients received corticosteroids as a supportive treatment during COVID-19. Patients were classified into two types based on the type of presentation, namely classic ONFH and rapidly destructive coxarthrosis (RDC) depending on radiographs, MRI, inflammatory markers and hip aspiration findings. Harris hip score was used to evaluate the functional outcome before and after treatment. Results: The mean time to diagnose of ONFH from the onset of hip symptoms was 39.3 days (range 10-90 days). The average duration of onset of hip symptoms after COVID 19 infection was 7.5 months (range 3 - 11 months). The average cumulative dose of methylprednisolone equivalent was 811 mg (range 200-2100 mg) and the average duration of steroid intake was 2.8 weeks. There was significant elevation in the inflammatory markers in RDC group compared to classic ONFH (p < 0.05). The Harris hip score improved from 63.6 ± 23.2 at presentation to 82.6 ± 9.6 after treatment (p < 0.05). Three patients had features of RDC. Among the three patients with RDC, two patients had rapid progression of ONFH and underwent total hip arthroplasty (THA). The third patient is awaiting a THA. Conclusion: ONFH after COVID-19 can have a varied presentation. While the most common presentation is like classical ONFH, some patients can have an acute and aggressive presentation with rapid destruction. They have features like elevated serological markers and extensive periarticular bone and soft tissue edema. A low cumulative dose of steroids in our patients suggests that the COVID-19-associated vasculitis may play a role in the pathogenesis of ONFH.

miR-122-5p targets GREM2 to protect against glucocorticoid-induced endothelial damage through the BMP signaling pathway.

Glucocorticoid (GC)-induced osteonecrosis of the femoral head (ONFH) accounts for a big portion of non-traumatic ONFH; nevertheless, the pathogenesis has not yet been fully understood. GC-induced endothelial dysfunction might be a major contributor to ONFH progression. The Gene Expression Omnibus (GEO) dataset was analyzed to identify deregulated miRNAs in ONFH; among deregulated miRNAs, the physiological functions of miR-122-5p on ONFH and endothelial dysfunction remain unclear. In the present study, miR-122-5p showed to be under-expressed within GC-induced ONFH femoral head tissues and GC-stimulated bone microvascular endothelial cells (BMECs). In human umbilical vein endothelial cells (HUVECs) and BMECs, GC stimulation significantly repressed cell viability, promoted cell apoptosis and increased the mRNA expression of proinflammatory cytokines, such as TNF-α, IL-1ß, and IFN-γ. After overexpressing miR-122-5p, GC-induced endothelial injuries were attenuated, as manifested by rescued cell viability, cell migration, and tube formation capacity. Regarding the BMP signaling, GC decreased the protein levels of BMP-2/6/7 and SMAD-1/5/8, whereas miR-122-5p overexpression significantly attenuated the inhibitory effects of GC on these proteins. Online tool and experimental analyses revealed the direct binding between miR-122-5p and GREM2, a specific antagonist of BMP-2. In contrast to miR-122-5p overexpression, GREM2 overexpression aggravated GC-induced endothelial injury; GREM2 silencing partially eliminated the effects of miR-122-5p inhibition on GC-stimulated HUVECs and BMECs. Finally, GREM2 silencing reversed the suppressive effects of GC on BMP-2/6/7 and SMAD-1/5/8, and attenuated the effects of miR-122-5p inhibition on these proteins upon GC stimulation. Conclusively, the present study demonstrates a miR-122-5p/GREM2 axis modulating the GC-induced endothelial damage via the BMP/SMAD signaling. Considering the critical role of endothelial function in ONFH pathogenesis, the in vivo role and clinical application of the miR-122-5p/GREM2 axis is worthy of further investigation.

[Lipid metabolomic analysis in exosomes of osteonecrosis of the femoral head based on ultra performance liquid chromatography-tandem mass spectrometry].

Osteonecrosis of the femoral head (ONFH) can lead to its collapse which requires total hip arthroplasty. Exosomes, which are important for intercellular communication are involved in a series of physiological and pathological processes, and therefore play a unique role in disease diagnosis and treatment. In this study, untargeted metabolomics was used to investigate the metabolic characteristics of lipids in exosomes of femoral head tissue with osteonecrosis and to explain the metabolic changes that occur in the body during this disease. Ultracentrifugation was used to separate and enrich exosomes from femoral head tissue with osteonecrosis. Exosomes were identified using dynamic light scattering (DLS), Western blotting, and transmission electron microscopy (TEM). Gradient elution was performed with ultrapure water and acetonitrile as mobile phases using a Kinetex XB-C18 column (100 mm×2.1 mm, 2.6 µm). The column oven temperature, flow rate of the mobile phase, and duration were 30 ℃, 300 µL/min, and 15 min, respectively. A triple TOF 4600 high resolution mass spectrometry system was used, and the mass scan range of m/z was set at 100 -1000. Other conditions were as follows: sheath gas, 380 kPa; auxiliary gas, 380 kPa; curtain gas, 170 kPa; and atomization temperature, 600 ℃. Ultra performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) combined with multivariate statistical analysis was used to identify the lipid metabolic profile of ONFH-derived exosomes. The exosome metabolites were characterized in detail, which enables their identification and provided a reliable method for quality evaluation. After transforming the obtained original data using MarkView software, peak identification, peak alignment, subtraction of solvent peak, impurity peak, noise filtering, and other treatments, a three-dimensional matrix was obtained from the exported data table. Principal component analysis (PCA) and orthogonal partial least squares discrimination analysis (OPLS-DA) in the SIMCA-P14.1 software were used for multivariate statistical analysis of differentially expressed exosome lipid metabolites. This strategy was validated using lipid metabolites from patients with ONFH and healthy controls. The correlation distribution was shown according to the point dispersion of the PCA score plot, and lipid metabolites from the same disease showed ideal clustering. This result indicates a small difference between the groups. A good clustering effect is also obtained using OPLS-DA, and the statistical model has high reliability. A total of 18 significantly altered lipid metabolites were detected in the exosomes, including acrylolipids, fatty acid esters, glycerides, and their derivatives. The pathway analysis was conducted with MetaboAnalyst (https://www.metaboanalyst.ca/) via database source including the HMDB (http://www.hmdb.ca/) and MMCD (http://mmcd.nmrfam.wisc.edu/) for confirming the impacted metabolic pathways and visualization. Metabolic pathway analysis showed that glycerophospholipid and sphingolipid metabolism were the most significantly altered in exosomes. An imbalance between sphingolipids and glycerophospholipids leads to lipotoxic damage, which is implicated in the pathophysiology of common metabolic diseases. Furthermore, glycerophospholipids are correlated with cell proliferation, differentiation, and apoptosis, and the change in glycerophospholipid ratio can reflect the disturbance in lipid metabolism. The metabolic changes in exosomes may reflect the metabolic changes in ONFH. In this study, lipid metabolomics analysis based on UPLC-MS/MS was used to determine metabolic differences between exosomes extracted from ONFN and femoral neck fracture (FNF). Metabolomic analysis of necrotic femoral head tissue-derived exosomes can help explore the most relevant pathways for assessing the changes in exosome metabolism that affect exosome metabolism in necrotic bone tissue.

PCA-Assisted Raman Analysis of Osteonecrotic Human Femoral Heads.

Osteonecrosis of the femoral head (ONFH) occurs frequently in adolescents and young adults and causes progressive deformation and destruction of the hip joint and impairs standing and walking, resulting in a significant decrease in the quality of life of patients. In addition, studies have shown that a history of corticosteroid administration and heavy alcohol consumption are closely related to the occurrence of ONFH. However, the detailed mechanism by which steroid administration and alcohol consumption are associated with the development of the disease is still unknown. With many researches still ongoing and without a clear biological pathway for osteonecrosis, effective preventive measures cannot be taken. Therefore, the current focus of ONFH treatment is to establish an early diagnosis and treatment strategy. We obtained the femoral heads of four patients with steroidal ONFH and three patients with alcoholic ONFH. We then compared the femoral heads of steroidal and alcoholic osteonecrosis by analyzing them at the molecular level by Raman spectroscopy. Crystallographic changes (deformations) in the mineral phase and fraction of organic material respect to the total mass were then plotted as a function. We found that changes in bone composition in ONFH were different in steroidal and alcoholic ONFH. We conclude that this suggests that the developmental mechanisms of steroidal and alcoholic ONFH may follow different paths. We also noticed that while steroid seem to lead to a more marked degradation of the tissue, alcohol seem to affect also the quality of the healthy tissue.

Human Umbilical Cord Mesenchymal Stem Cells Improve the Necrosis and Osteocyte Apoptosis in Glucocorticoid-Induced Osteonecrosis of the Femoral Head Model through Reducing the Macrophage Polarization.

Background and Objectives: Apoptosis is an outstanding determinant of glucocorticoid (GC)-induced osteonecrosis of the femoral head (ONFH). Human umbilical cord mesenchymal stem cells (hUC-MSCs) have been demonstrated to be associated with apoptosis in diseases models. However, the role of hUC-MSCs in GC-induced ONFH via regulating apoptosis still needs further study. Methods and Results: In the present study, a GC-induced ONFH model was built in vivo through a consecutive injection with lipopolysaccharide (LPS) and methylprednisolone. The necrosis and apoptosis of the femoral head was evaluated by histological and Terminal-deoxynucleoitidyl Transferase Mediated Nick End Labeling (TUNEL) assay. The level of collagen and TRAP positive cells were determined by Masson and TRAP staining, respectively. M1 macrophage polarization was assessed using immunofluorescence assay. The level of proinflammatory cytokines including tumor necrosis factor (TNF)-α, Interleukin (IL)-1ß and IL-6 of femoral head was determined by enzyme-linked immunosorbent assay (ELISA) kits. The protein expression of AKT, mTOR, p-AKT and p-mTOR was detected using western blot assay. The results showed that hUC-MSCs treatment prominently promoted the GC-induced the decrease of the collagen level and the increase of TRAP positive cells. Besides, hUC-MSCs treatment decreased necrosis and apoptosis, macrophage polarization, the level of TNF-α, IL-1ß and IL-6, the protein expression of p-AKT and p-mTOR, and the radio of p-AKT to AKT and p-mTOR to mTOR of femoral head in vivo. Conclusions: Therefore, the present study revealed that hUC-MSCs improved the necrosis and osteocyte apoptosis in GC-induced ONFH model through reducing the macrophage polarization, which was associated with the inhibition of AKT/mTOR signaling pathway.

Spatial Distribution of Biomechanical Characteristics for Trabecular Bone in the Femoral Head with Osteonecrosis / 医用生物力学

Objective To explore the spatial distribution of microstructural parameters and mechanical properties for trabecular bone in the femoral head with osteonecrosis. Methods Microstructural parameters and mechanical properties of trabecular bone in different regions were analyzed by combined use of imaging measurements and numerical simulation method, and the spatial distribution of biomechanical properties for trabecular bone along coronal, sagittal and vertical directions was investigated. Results Microstructural characteristics and mechanical properties of trabecular bone were Y-shaped distributed along coronal and sagittal directions, and mechanical properties of trabecular bone in Y-shaped region were higher than those in the other regions. Such distribution characteristics was consistent with the location of principle compressive group in the femoral head. Conclusions Necrotic lesions in Y-shaped region had a greater influence on stress distribution of the femoral head and might cause the deterioration of osteonecrosis. The spacial correlation between necrotic lesions and Y-shaped region should be fully considered during clinical diagnosis.

Efficacy of various core decompression techniques versus non-operative treatment for osteonecrosis of the femoral head: a systemic review and network meta-analysis of randomized controlled trials.

BACKGROUND: Various Joint-preserving therapy (JPT) methods have been performed and tried in recent decades, but their results and efficacy were inconsistent and controversial. The purpose of this study is to evaluate its effectiveness and whether there are statistical differences in treatment between different interventions based on published RCT studies. METHODS: Following the PRISMA-NMA checklist, Medline, EMBASE, Web of Science, and Cochrane Library databases were searched and collected related RCT studies. The sources were searched from inception up to October 30, 2020. The primary outcomes including the rate of radiographic progression and conversion to THA and the secondary outcome -Harris Hip Scores (HHS) were extracted and compared in a Network meta-analysis. RESULTS: Seventeen RCT studies involving 784 patients (918 hips) with seven interventions including CD (core decompression), CD + BG (bone graft), CD + TI (tantalum rod implantation), CD + CT (Cell therapy), CD + BG + CT, VBG (vascularized bone graft), and nonsurgical or conservative treatment for ONFH were evaluated. In the radiographic progression results, CD + CT showed a relatively better result than CD, CD + BG and non-surgical treatment, the surface under the cumulative ranking curve (SUCRA) plot displayed that CD + CT (96.4%) was the best, followed by CD (64.1%).In conversion to THA results, there were no significant differences between the JPT methods and non-surgical treatment. In HHS, there was also no significant difference, other than CD + BG showed a statistical difference than non-surgical treatment only in terms of Cis, but the SUCRA was highest in non-surgical treatment (80.5%) followed by CD + CT (72.8%). CONCLUSIONS: This Net-work meta-analysis demonstrated that there was no statistical difference in the outcome of radiographic progression and conversion to THA, also in HHS, other than CD + CT showed a relatively superior result in radiographic progression than nonsurgical treatment, namely, it's maybe an effective method for delaying disease progression or reducing disease development based on current evidence.

Osteoblast function in patients with idiopathic osteonecrosis of the femoral head : implications for a possible novel therapy.

AIMS: To investigate whether idiopathic osteonecrosis of the femoral head (ONFH) is related to impaired osteoblast activities. METHODS: We cultured osteoblasts isolated from trabecular bone explants taken from the femoral head and the intertrochanteric region of patients with idiopathic ONFH, or from the intertrochanteric region of patients with osteoarthritis (OA), and compared their viability, mineralization capacity, and secretion of paracrine factors. RESULTS: Osteoblasts from the intertrochanteric region of patients with ONFH showed lower alkaline phosphatase (ALP) activity and mineralization capacity than osteoblasts from the same skeletal site in age-matched patients with OA, as well as lower messenger RNA (mRNA) levels of genes encoding osteocalcin and bone sialoprotein and higher osteopontin expression. In addition, osteoblasts from patients with ONFH secreted lower osteoprotegerin (OPG) levels than those from patients with OA, resulting in a higher receptor activator of nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) ligand (RANKL)-to-OPG ratio. In patients with ONFH, osteoblasts from the femoral head showed reduced viability and mineralized nodule formation compared with osteoblasts from the intertrochanteric region. Notably, the secretion of the pro-resorptive factors interleukin-6 and prostaglandin E2 as well as the RANKL-to-OPG ratio were markedly higher in osteoblast cultures from the femoral head than in those from the intertrochanteric region. CONCLUSION: Idiopathic ONFH is associated with a reduced mineralization capacity of osteoblasts and increased secretion of pro-resorptive factors. Cite this article: Bone Joint Res 2021;10(9):619-628.

Hsa_circ_0066523 promotes the proliferation and osteogenic differentiation of bone mesenchymal stem cells by repressing PTEN.

AIMS: Circular RNAs (circRNAs) are a novel type of non-coding RNA that plays major roles in the development of diverse diseases including osteonecrosis of the femoral head (ONFH). Here, we explored the impact of hsa_circ_0066523 derived from forkhead box P1 (FOXP1) (also called circFOXP1) on bone mesenchymal stem cells (BMSCs), which is important for ONFH development. METHODS: RNA or protein expression in BMSCs was analyzed by quantitative real-time polymerase chain reaction (qRT-PCR) or western blot, respectively. Cell Counting Kit 8 (CCK8) and 5-ethynyl-2'-deoxyuridine (EdU) were used to analyze cell proliferation. Alkaline phosphatase (ALP) activity, ALP staining, and Alizarin Red S staining were employed to evaluate the osteoblastic differentiation. Chromatin immunoprecipitation (ChIP), luciferase reporter, RNA pull down, and RNA immunoprecipitation (RIP) assays were combined for exploring molecular associations. RESULTS: Circ_0066523 was upregulated in osteogenic induction process of BMSCs. Silencing circ_0066523 restrained the proliferation and osteogenic differentiation of BMSCs. Mechanistically, circ_0066523 activated phosphatidylinositol-4,5-bisphosphate 3-kinase / AKT serine/threonine kinase 1 (PI3K/AKT) pathway via recruiting lysine demethylase 5B (KDM5B) to epigenetically repress the transcription of phosphatase and tensin homolog (PTEN). Functionally, AKT signalling pathway agonist or PTEN knockdown counteracted the effects of silenced circ_0066523 on BMSC proliferation and differentiation. CONCLUSION: Circ_0066523 promotes the proliferation and differentiation of BMSCs by epigenetically repressing PTEN and therefore activating AKT pathway. This finding might open new avenues for the identification of therapeutic targets for osteoblast differentiation related diseases such as ONFH. Cite this article: Bone Joint Res 2021;10(8):526-535.

OPG/RANKL/RANK gene methylation among alcohol-induced femoral head necrosis in northern Chinese men.

BACKGROUND AND PURPOSE: Alcohol-induced osteonecrosis of the femoral head (ONFH) is a complex and heterogeneous disease. Genetic factors and epigenetic modifications are one of the pathogenesis of the disease. However, the influence of epigenetic factors on the disease has not been systematically studied. Our research aims to determine the methylation changes of alcohol-induced ONFH. METHODS: An analytical cross-sectional study of a Chinese male population (50 alcohol-induced ONFH patients and 50 controls). The EpiTYPER of the Sequenom MassARRAY platform was used to detect the DNA methylation status of 132 cytosine-phosphate-guanine (CpG) sites in the OPG/RANKL/RANK gene promoter region. RESULTS: In the whole study group, the chi-square test was used to analyze the methylation rate between the two groups, and six CpG sites were found to be different, among which OPG1_CpG_2, OPG3_CpG_4, RANK1_CpG_6, RANK3_CpG_10, RANKL2_CpG_21, and RANKL2_CpG_46 in the case group were higher than those in the control group, while OPG4_CpG_2 was lower than that in the control group. The results showed that in patients with alcohol-induced ONFH, 146 CpG sites were examined for differences in methylation levels compared with healthy controls, 32 of which were not detected, and 23 of the remaining 114 sites showed differences in methylation levels compared with alcohol-induced ONFH patients. Receiver operator characteristic (ROC) curve analysis demonstrated the methylation levels of OPG/RANKL/RANK could efficiently predict the existence of alcohol-induced ONFH. CONCLUSION: Our study of Chinese men suggests that several CpG sites in the OPG/RANKL/RANK gene in peripheral blood leukocytes of patients with alcohol-induced ONFH are in an abnormal methylation state (hypermethylation tended to be more frequent).

Development and validation of a predictive nomogram for postoperative osteonecrosis of the femoral head with cannulated screws fixation.

BACKGROUND: Osteonecrosis of the femoral head (ONFH) remains a major complication of femoral neck fractures. Early interventions require preliminary prediction and detection. In this study, we aimed to evaluate the perioperative variables of postoperative ONFH in femoral neck fracture patients with closed reduction and cannulated screw fixation. We also established and validated an individualized nomogram for the prediction of postoperative ONFH. METHODS: We included 470 patients with ONFH from two hospitals [First Affiliated Hospital of University of Science and Technology of China (n=360) and Southern Branch of the First Affiliated Hospital of the University of Science and Technology of China (n=110)]. We evaluated the prognostic value of multiple perioperative variables using a Cox regression model in the training cohort. We developed a nomogram for the prediction of ONFH using a logistic regression model. We assessed the performance of this nomogram in a validation cohort and evaluated its clinical value. RESULTS: Of the 470 patients who met the inclusion criteria, 141 (30.0%) developed postoperative ONFH. We found alcohol use [odds ratio (OR), 1.743, 95% confidence interval (CI), 1.042-2.901, P=0.033], cerebrovascular disease (OR, 5.357, 95% CI, 2.318-13.13, P<0.001), interval to surgery (OR, 5.273, 95% CI, 2.724-10.43, P<0.001), Garden classification (OR, 23.17, 95% CI, 6.812-145.3, P<0.001), Garden index (OR, 5.935, 95% CI, 2.670-14.184, P<0.001), interval to partial weight-bearing (OR, 0.053, 95% CI, 0.006-0.296, P=0.002), and six-month Harris hip score (OR, 0.856; 95% CI, 0.792-0.919, P<0.001) were independent predictors of postoperative development of ONFH. Based on these variables, we developed a nomogram that showed good discrimination in both the training [area under the curve (AUC) =0.865] and the validation cohort (AUC =0.877). The favorable performance of this nomogram was also confirmed in the validation cohort. CONCLUSIONS: We developed and validated an easy-to-use nomogram for predicting postoperative ONFH. This nomogram can aid decision-making of intraoperative interventions and postoperative rehabilitation plans for patients, surgeons, and osteo-rehabilitative physicians.