Role and mechanism of macrophage-mediated osteoimmune in osteonecrosis of the femoral head / 中国修复重建外科杂志

OBJECTIVE@#To summarize the research progress on the role of macrophage-mediated osteoimmune in osteonecrosis of the femoral head (ONFH) and its mechanisms.@*METHODS@#Recent studies on the role and mechanism of macrophage-mediated osteoimmune in ONFH at home and abroad were extensively reviewed. The classification and function of macrophages were summarized, the osteoimmune regulation of macrophages on chronic inflammation in ONFH was summarized, and the pathophysiological mechanism of osteonecrosis was expounded from the perspective of osteoimmune, which provided new ideas for the treatment of ONFH.@*RESULTS@#Macrophages are important immune cells involved in inflammatory response, which can differentiate into classically activated type (M1) and alternatively activated type (M2), and play specific functions to participate in and regulate the physiological and pathological processes of the body. Studies have shown that bone immune imbalance mediated by macrophages can cause local chronic inflammation and lead to the occurrence and development of ONFH. Therefore, regulating macrophage polarization is a potential ONFH treatment strategy. In chronic inflammatory microenvironment, inhibiting macrophage polarization to M1 can promote local inflammatory dissipation and effectively delay the progression of ONFH; regulating macrophage polarization to M2 can build a local osteoimmune microenvironment conducive to bone repair, which is helpful to necrotic tissue regeneration and repair to a certain extent.@*CONCLUSION@#At present, it has been confirmed that macrophage-mediated chronic inflammatory immune microenvironment is an important mechanism for the occurrence and development of ONFH. It is necessary to study the subtypes of immune cells in ONFH, the interaction between immune cells and macrophages, and the interaction between various immune cells and macrophages, which is beneficial to the development of potential therapeutic methods for ONFH.

Repair Mechanism of Jianpi Huogu Prescription on Vascular Injury in Alcohol-induced Osteonecrosis of Femoral Head Based on VEGF/VEGFR2/PI3K/Akt Signaling Pathway / 中国实验方剂学杂志

MethodIn the experiment， 46% vol Red Star Erguotou （10 mL·kg·d-1） was used to establish the AONFH rat model， and the intervention effect of JPHGP at different doses （2.5， 5.0， 10.0 g·kg-1） was observed. Jiangusheng pill （JGS， 1.53 g·kg-1） was selected as the positive control. After 8 weeks of administration， the bone histomorphometry of the femoral head was analyzed by Micro-CT imaging， and the area of medullary microvessels in the femoral head was detected by ink perfusion. The pathological change was observed by hematoxylin and eosin （HE） staining. The protein expressions of Platelet endothelial cell adhesion molecule-1 （CD31）， VEGF， VEGFR2， PI3K， phosphor-Akt （p-Akt） and phosphatase and Tensin homologue deleted on chromosome 10 （PTEN） in the femoral head were determined by immunohistochemistry and Western blot. ResultCompared with normal group， the model group presented the fracture and thinning of trabeculae in the femoral head， increased empty bone lacunae， and elevated number and diameter of adipocytes （P<0.01）. Micro-CT imaging revealed a decrease in bone mineral density （BMD）， bone volume fraction （BV/TV）， trabecular thickness （Tb.Th） and trabecular number （Tb.N） （P<0.05， P<0.01） while an increase in bone surface-to-volume ratio （BS/BV） and trabecular separation （Tb.Sp） （P<0.01）. The results of ink perfusion showed that the area of medullary microvessels in the femoral head was reduced （P<0.01）. Compared with model group， JPHGP lowered the empty bone lacunae rate as well as the number and diameter of adipocytes in the femoral head of AONFH rats. Micro-CT imaging indicated that JPHGP low-dose group had elevated BV/TV， Tb.Th and Tb.N （P<0.05， P<0.01） while decreased BS/BV （P<0.01）， and there was an upward trend in BMD while a downward trend in Tb.Sp， but without statistical difference. In addition， JPHGP medium- and high-dose groups had a rise in BMD， BV/TV， Tb.Th and Tb.N （P<0.05， P<0.01）， a decrease in BS/BV and Tb.Sp （P<0.05， P<0.01） and enlarged area of medullary microvessels in the femoral head （P<0.05， P<0.01）. The expressions of CD31， VEGF， VEGFR2， PI3K， p-Akt in the model group were lower than those in the normal group （P<0.01）， and after medium and high doses of JPHGP treatment， the expressions of CD31， PI3K and p-Akt in the femoral head of rats were up-regulated （P<0.01） while the protein expression of PTEN was down-regulated （P<0.01）. Moreover， JPHGP up-regulated the expressions of VEGF and VEGFR2 （P<0.05， P<0.01）. ConclusionJPHGP can repair the vascular injury in AONFH， and its mechanism may be related to the activation of VEGF/VEGFR2/PI3K/Akt signaling pathway. This study provides certain scientific basis and reference for the clinical application of JPHGP. ObjecctiveTo observe the repair effect of Jianpi Huogu prescription （JPHGP） on vascular injury in experimental alcohol-induced osteonecrosis of femoral head （AONFH）， and to explore its mechanism based on vascular endothelial growth factor （VEGF）/VEGFR2/phosphoinositide 3-kinase （PI3K）/protein kinase B （Akt） signaling pathway.

Visual and quantitative assessment of the effectiveness of non-vascularized bone grafting in osteonecrosis of the femoral head via CT-based radiomics and clinical data / 中国修复重建外科杂志

OBJECTIVE@#To investigate the value of CT-based radiomics and clinical data in predicting the efficacy of non-vascularized bone grafting (NVBG) in hip preservation, and to construct a visual, quantifiable, and effective method for decision-making of hip preservation.@*METHODS@#Between June 2009 and June 2019, 153 patients (182 hips) with osteonecrosis of the femoral head (ONFH) who underwent NVBG for hip preservation were included, and the training and testing sets were divided in a 7∶3 ratio to define hip preservation success or failure according to the 3-year postoperative follow-up. The radiomic features of the region of interest in the CT images were extracted, and the radiomics-scores were calculated by the linear weighting and coefficients of the radiomic features after dimensionality reduction. The clinical predictors were screened using univariate and multivariate Cox regression analysis. The radiomics model, clinical model, and clinical-radiomics (C-R) model were constructed respectively. Their predictive performance for the efficacy of hip preservation was compared in the training and testing sets, with evaluation indexes including area under the curve, C-Index, sensitivity, specificity, and calibration curve, etc. The best model was visualised using nomogram, and its clinical utility was assessed by decision curves.@*RESULTS@#At the 3-year postoperative follow-up, the cumulative survival rate of hip preservation was 70.33%. Continued exposure to risk factors postoperative and Japanese Investigation Committee (JIC) staging were clinical predictors of the efficacy of hip preservation, and 13 radiomic features derived from least absolute shrinkage and selection operator downscaling were used to calculate Rad-scores. The C-R model outperformed both the clinical and radiomics models in predicting the efficacy of hip preservation 1, 2, 3 years postoperative in both the training and testing sets ( P<0.05), with good agreement between the predicted and observed values. A nomogram constructed based on the C-R model showed that patients with lower Rad-scores, no further postoperative exposure to risk factors, and B or C1 types of JIC staging had a higher probability of femoral survival at 1, 2, 3 years postoperatively. The decision curve analysis showed that the C-R model had a higher total net benefit than both the clinical and radiomics models with a single predictor, and it could bring more net benefit to patients within a larger probability threshold.@*CONCLUSION@#The prediction model and nomogram constructed by CT-based radiomics combined with clinical data is a visual, quantifiable, and effective method for decision-making of hip preservation, which can predict the efficacy of NVBG before surgery and has a high value of clinical application.

Analysis of incidence and clinical characteristics of osteonecrosis of femoral head in patients with systemic lupus erythematosus treated with glucocorticoid: A descriptive study based on a prospective cohort / 中国修复重建外科杂志

OBJECTIVE@#To describe the disease characteristics of osteonecrosis of the femoral head (ONFH) in patients with systemic lupus erythematosus (SLE) who experiencing prolonged glucocorticoid (GC) exposure.@*METHODS@#Between January 2016 and June 2019, 449 SLE patients meeting the criteria were recruited from multiple centers. Hip MRI examinations were performed during screening and regular follow-up to determine the occurrence of ONFH. The cohort was divided into ONFH and non-ONFH groups, and the differences in demographic baseline characteristics, general clinical characteristics, GC medication information, combined medication, and hip clinical features were compared and comprehensively described.@*RESULTS@#The age at SLE diagnosis was 29.8 (23.2, 40.9) years, with 93.1% (418 cases) being female. The duration of GC exposure was 5.3 (2.0, 10.5) years, and the cumulative incidence of SLE-ONFH was 9.1%. Significant differences ( P<0.05) between ONFH and non-ONFH groups were observed in the following clinical characteristics: ① Demographic baseline characteristics: ONFH group had a higher proportion of patients with body mass index (BMI)<20 kg/m 2 compared to non-ONFH group. ② General clinical characteristics: ONFH group showed a higher proportion of patients with cutaneous and renal manifestations, positive antiphospholipid antibodies (aPLs) and anticardiolipin antibodies, severe SLE patients [baseline SLE Disease Activity Index 2000 (SLEDAI-2K) score ≥15], and secondary hypertension. Fasting blood glucose in ONFH group was also higher. ③ GC medication information: ONFH group had higher initial intravenous GC exposure rates, duration, cumulative doses, higher cumulative GC doses in the first month and the first 3 months, higher average daily doses in the first 3 months, and higher proportions of average daily doses ≥15.0 mg/d and ≥30.0 mg/d, as well as higher full-course average daily doses and proportion of full-course daily doses ≥30.0 mg/d compared to non-ONFH group. ④ Combined medications: ONFH group had a significantly higher rate of antiplatelet drug use than non-ONFH group. ⑤ Hip clinical features: ONFH group had a higher proportion of hip discomfort or pain and a higher incidence of hip joint effusion before MRI screening than non-ONFH group.@*CONCLUSION@#The incidence of ONFH after GC exposure in China's SLE population remains high (9.1%), with short-term (first 3 months), medium-to-high dose (average daily dose ≥15 mg/d) GC being closely associated with ONFH. Severe SLE, low BMI, certain clinical phenotypes, positive aPLs, and secondary hypertension may also be related to ONFH.

A novel lateral classification of osteonecrosis of femoral head based on CT recons-truction of necrotic area and its clinical verification / 中国修复重建外科杂志

OBJECTIVE@#To analyze the femoral head collapse and the operation of osteonecrosis of the femoral head (ONFH) in different Japanese Investigation Commitee (JIC) types, in order to summarize the prognostic rules of each type of ONFH, and explore the clinical significance of CT lateral subtypes based on reconstruction of necrotic area of C1 type and verify their clinical effect.@*METHODS@#A total of 119 patients (155 hips) with ONFH between May 2004 and December 2016 were enrolled in the study. The total hips consisted of 34 hips in type A, 33 in type B, 57 in type C1, and 31 in type C2, respectively. There was no significant difference in age, gender, affected side, or type of ONFH of the patients with differenct JIC types ( P>0.05). The 1-, 2-, and 5-year femoral head collapse and operation of different JIC types were analyzed, as well as the survival rate (with femoral head collapse as the end point) of hip joint between different JIC types, hormonal/non-hormonal ONFH, asymptomatic and symptomatic (pain duration >6 months or ≤6 months), and combined preserved angle (CPA) ≥118.725° and CPA<118.725°. JIC types with significant differences in subgroup surgery and collapse and with research value were selected. According to the location of the necrotic area on the surface of the femoral head, the JIC classification was divided into 5 subtypes in the lateral CT reconstruction, and the contour line of the necrotic area was extracted and matched to the standard femoral head model, and the necrosis of the five subtypes was presented by thermography. The 1-, 2-, and 5-year outcomes of femoral head collapse and operation in different lateral subtypes were analyzed, and the survival rates (with collapse of the femoral head as the end point) between CPA≥118.725° and CPA<118.725° hip in patients with this subtype were compared, as well as the survival rates of different lateral subtypes (with collapse and surgery as the end points, respectively).@*RESULTS@#The femoral head collapse rate and operation rate in the 1-, 2-, and 5-year were significantly higher in patients with JIC C2 type than in patients with other hip types ( P<0.05), while in patients with JIC C1 type than in patients with JIC types A and B ( P<0.05). The survival rate of patients with different JIC types was significantly different ( P<0.05), and the survival rate of patients with JIC types A, B, C1, and C2 decreased gradually. The survival rate of asymptomatic hip was significantly higher than that of symptomatic hip, and the survival rate of CPA≥118.725° was significantly higher than that of CPA<118.725° ( P<0.05). The lateral CT reconstruction of type C1 hip necrosis area was selected for further classification, including type 1 in 12 hips, type 2 in 20 hips, type 3 in 9 hips, type 4 in 9 hips, and type 5 in 7 hips. There were significant differences in the femoral head collapse rate and the operation rate among the subtypes after 5 years of follow-up ( P<0.05). The collapse rate and operation rate of types 4 and 5 were 0; the collapse rate and operation rate of type 3 were the highest; the collapse rate of type 2 was high, but the operation rate was lower than that of type 3; the collapse rate of type 1 was high, but the operation rate was 0. In JIC type C1 patients, the survival rate of the hip joint with CPA≥118.725° was significantly higher than that with CPA<118.725° ( P<0.05). In the follow-up with femoral head collapse as the end point, the survival rates of types 4 and 5 were all 100%, while the survival rates of types 1, 2, and 3 were all 0, and the difference was significant ( P<0.05). The survival rate of types 1, 4, and 5 was 100%, of type 3 was 0, and of type 2 was 60%, showing significant difference ( P<0.05).@*CONCLUSION@#JIC types A and B can be treated by non-surgical treatment, while type C2 can be treated by surgical treatment with hip preservation. Type C1 was classified into 5 subtypes by CT lateral classification, type 3 has the highest risk of femoral head collapse, types 4 and 5 have low risk of femoral head collapse and operation, type 1 has high femoral head collapse rate but low risk of operation; type 2 has high collapse rate, but the operation rate is close to the average of JIC type C1, which still needs to be further studied.

Traditional Chinese Medicine in Prevention and Treatment of Osteonecrosis of Femoral Head Based on OPG/RANK/RANKL Signaling Pathway： A Review / 中国实验方剂学杂志

Osteonecrosis of the femoral head （ONFH） is a painful and debilitating disease caused by impaired blood supply to the femoral head and cellular and tissue degeneration， leading to gradual destruction of the bone structure and progressive collapse of the femoral head. The main pathological mechanism of ONFH is the disruption of the balance between bone absorption and the reconstruction of new bone， resulting from microcirculation damage and decreased cellular tissue ability. This imbalance leads to biomechanical changes and accelerates the pathological progression of ONFH. In the early stages， clinical manifestations may not be obvious， mainly presenting as pain or discomfort in the hip or groin area， which can be relieved after rest. In the later stage of the disease， pain intensifies， and limb shortening， lower limb weakness， difficulty walking， or limping may occur. Currently， western medicine commonly uses osteogenic agents， anticoagulants， and artificial joint replacement for treatment， but there are also many issues such as prosthesis loosening and infection. Research has shown that traditional Chinese medicine （TCM） treatment of ONFH takes a holistic approach and employs multi-functional， multi-target， and multi-system Chinese medicine therapies， ensuring the safety and effectiveness of the treatment. The osteoprotegerin （OPG）/receptor activator of nuclear factor-κB （RANK）/RANK ligand （RANKL） signaling pathway plays a crucial role in maintaining the dynamic balance of bone remodeling. TCM treatments utilize this pathway to promote apoptosis of osteoclasts， reduce bone resorption， and accelerate bone formation， thereby playing an important role in the prevention and treatment of ONFH. This paper reviewed the role of OPG/RANK/RANKL signaling pathway and related cytokine expression in ONFH by reviewing relevant literature in China and abroad and research status of Chinese medicinal monomers， Chinese medicinal formulations， and combinations with physical therapy in increasing osteoblast secretion， promoting OPG expression， enhancing cytokine expression levels， and inhibiting osteoclast activity for the prevention and treatment of ONFH. This paper is expected to provide new ideas and directions for TCM in the prevention and treatment of ONFH.

Clinical application study of multiple small-diameter drilling combined with extracorporeal shock wave therapy (ESWT) under C-arm positioning in the treatment of early femoral head necrosis / 中国骨伤

OBJECTIVE@#To explore the therapeutic effect of multiple small diameter drilling combined with extracorporeal shock wave therapy (ESWT) under C-arm X-raylocalization in patients with early osteonecrosis of the femoral head (ONFH).@*METHODS@#A total of 106 cases of early ONFH patients admitted from May 2015 to May 2017 were retrospectively selected as the study subjects. According to different treatment methods, the patients were divided into observation group and control group, 53 cases in each group. The observation group was treated with multiple small-diameter drilling combined with ESWT under C-arm positioning in the observation group, including 41 males and 12 females with an age of (45.85±6.01) years old (22 to 70 years old);and the control group was treated with ESWT, including 34 males and 19 females with an age of (45.12±5.83) years old(20 to 68 years old) in the control group. The modified Harris hip scores(mHHS), visual analog scale(VAS), hip flexion range, hip abduction and adduction range, ONFH area ratio and clinical efficacy were compared between twe groups before and after treatment. Kaplan-Meier method was used to draw a survival curve to compare the femoral head survival rate between two groups during the 3-year follow-up period after treatment.@*RESULTS@#There were no complications such as poor wound healing and infection. All of 106 patients were followed up for 28 to 36 months with an average of (31.06±4.28) months. MHHS score, hip flexion range and hip abduction and adduction range in the observation group were increased from (63.85±5.42) scores, (23.79±2.21) °, (32.40±4.19) ° before treatment to (85.51±5.69) scores, (34.65±2.73)°, (43.32±5.71)° at 2 years after treatment, respectively(P<0.05). The above indicators in the control group increased from (64.73±5.64)°, (23.82±2.18)°, (32.45±4.13)° before treatment to (81.65±5.48) scores, (32.79±2.87)°, (39.75±5.68)°at two years after treatment, respectively(P<0.05). VAS score and ONFH area ratio in the observation group decreased from (5.76±1.41) scores and (35.07±4.96)% before treatment to (3.39±1.02) scores and (22.04±3.23)% at 2 years after treatment, respectively(P<0.05). The above indicatiors in control group decreased from (5.73±1.45) scores and (35.24±5.18)% before treatment to (4.43±1.21) scores and (28.32±3.76)% at 2 years after treatment, respectively(P<0.05), and the improvement in the observation group was significantly higher than that in the control group(P<0.05). At 3 years after treatment, the femoral head survival rate in the observation group was higher than that in the control group (P<0.05).@*CONCLUSION@#Multiple small diameter drilling combined with ESWT under C-arm positioning can significantly improve the clinical symptoms of patients with early ONFH, relieve pain and improve clinical efficacy.

Expert consensus on clinical drug prevention and treatment of osteonecrosis of the femoral head(2022) / 中国骨伤

With the in-depth understanding of osteonecrosis of femoral head (ONFH), and more and more patients seeking medical treatment in the early stage of the disease, surgical treatment of femoral head necrosis alone is no longer sufficient for the current treatment of patients' demand, how to rationally and effectively apply drugs to strengthen the early prevention and treatment of femoral head necrosis and delay the progression of disease is becoming more and more important. This article combines the latest expert consensus and evidence-based medical evidence on the principles of ONFH diagnosis and treatment in Chinese and Western medicine at home and abroad, combined with domestic actual clinical application experience, and is organized by experts from Association Related to Circulation Osseous Chinese Microcirculation Society (CSM-ARCO) to write this consensus, focusing on the types of ONFH drugs, the characteristics, safety, rationality and basic principles of drug use provide reference opinions for the safe, reasonable, standardized and effective drug use of medical institutions at all levels. This consensus is only an expert guideline based on literature and clinical experience, not as a requirement for mandatory implementation, let alone as a legal basis. The clinical practice could be tailored to the actual local conditions to develop appropriate prevention and treatment measures for patients.

Finite element analysis for predicting osteonecrosis of the femoral head collapse based on the preserved angles / 中国修复重建外科杂志

OBJECTIVE@#To establish finite element models of different preserved angles of osteonecrosis of the femoral head (ONFH) for the biomechanical analysis, and to provide mechanical evidence for predicting the risk of ONFH collapse with anterior preserved angle (APA) and lateral preserved angle (LPA).@*METHODS@#A healthy adult was selected as the study object, and the CT data of the left femoral head was acquired and imported into Mimics 21.0 software to reconstruct a complete proximal femur model and construct 3 models of necrotic area with equal volume and different morphology, all models were imported into Solidworks 2022 software to construct 21 finite element models of ONFH with LPA of 45°, 50°, 55°, 60°, 65°, 70°, and 75° when APA was 45°, respectively, and 21 finite element models of ONFH with APA of 45°, 50°, 55°, 60°, 65°, 70°, 75° when LPA was 45°, respectively. According to the physiological load condition of the femoral head, the distal femur was completely fixed, and a force with an angle of 25°, downward direction, and a magnitude of 3.5 times the subject's body mass was applied to the weight-bearing area of the femoral head surface. The maximum Von Mises stress of the surface of the femoral head and the necrotic area and the maximum displacement of the weight-bearing area of the femoral head were calculated and observed by Abaqus 2021 software.@*RESULTS@#The finite element models of ONFH were basically consistent with biomechanics of ONFH. Under the same loading condition, there was stress concentration around the necrotic area in the 42 ONFH models with different preserved angles composed of 3 necrotic areas with equal volume and different morphology. When APA was 60°, the maximum Von Mises stress of the surface of the femoral head and the necrotic area and the maximum displacement of the weight-bearing area of the femoral head of the ONFH models with LPA<60° were significantly higher than those of the models with LPA≥60° ( P<0.05); there was no significant difference in each index among the ONFH models with LPA≥60° ( P>0.05). When LPA was 60°, each index of the ONFH models with APA<60° were significantly higher than those of the models with APA≥60° ( P<0.05); there was no significant difference in each index among the ONFH models with APA≥60° ( P>0.05).@*CONCLUSION@#From the perspective of biomechanics, when a preserved angle of ONFH is less than its critical value, the stress concentration phenomenon in the femoral head is more pronounced, suggesting that the necrotic femoral head may have a higher risk of collapse in this state.

Characteristic changes of blood stasis syndrome in rat model of steroid-induced femoral head necrosis based on the combination of disease, syndrome, and symptom / 中国中药杂志

The approach combining disease, syndrome, and symptom was employed to investigate the characteristic changes of blood stasis syndrome in a rat model of steroid-induced osteonecrosis of the femoral head(SONFH) during disease onset and progression. Seventy-two male SD rats were randomized into a healthy control group and a model group. The rat model of SONFH was established by injection of lipopolysaccharide(LPS) in the tail vein at a dose of 20 μg·kg~(-1)·d~(-1) on days 1 and 2 and gluteal intramuscular injection of methylprednisolone sodium succinate(MPS) at a dose of 40 mg·kg~(-1)·d~(-1) on days 3-5, while the healthy control group received an equal volume of saline. The mechanical pain test, tongue color RGB technique, gait detection, open field test, and inclined plane test were employed to assess hip pain, tongue color, limping, joint activity, and lower limb strength, respectively, at different time points within 21 weeks of modeling. At weeks 2, 4, 8, 12, 16, and 21 after modeling, histopathological changes of the femoral head were observed by hematoxylin-eosin(HE) staining and micro-CT scanning; four coagulation items were measured by rotational thromboelastometry; and enzyme-linked immunosorbent assay(ELISA) was employed to determine the levels of six blood lipids, vascular endothelial growth factor(VEGF), endothelin-1(ET-1), nitric oxide(NO), tissue-type plasminogen activator(t-PA), plasminogen activator inhibitor factor-1(PAI-1), bone gla protein(BGP), alkaline phosphatase(ALP), receptor activator of nuclear factor-κB(RANKL), osteoprotegerin(OPG), and tartrate-resistant acid phosphatase 5b(TRAP5b) in the serum, as well as the levels of 6-keto-prostaglandin 1α(6-keto-PGF1α) and thromboxane B2(TXB2) in the plasma. The results demonstrated that the pathological alterations in the SONFH rats were severer over time. The bone trabecular area ratio, adipocyte number, empty lacuna rate, bone mineral density(BMD), bone volume/tissue volume(BV/TV), trabecular thickness(Tb.Th), trabecular number(Tb.N), bone surface area/bone volume(BS/BV), and trabecular separation(Tb.Sp) all significantly increased or decreased over the modeling time after week 4. Compared with the healthy control group, the mechanical pain threshold, gait swing speed, stride, standing time, and walking cycle of SONFH rats changed significantly within 21 weeks after modeling, with the greatest difference observed 12 weeks after modeling. The time spent in the central zone, rearing score, and maximum tilt angle in the open field test of SONFH rats also changed significantly over the modeling time. Compared with the healthy control group, the R, G, and B values of the tongue color of the model rats decreased significantly, with the greatest difference observed 11 weeks after modeling. The levels of total cholesterol(TC), total triglycerides(TG), low-density lipoprotein-cholesterol(LDL-C), and apoprotein B(ApoB) in the SONFH rats changed significantly 4 and 8 weeks after modeling. The levels of VEGF, ET-1, NO, t-PA, PAI-1, 6-keto-PGF1α, TXB2, four coagulation items, and TXB2/6-keto-PGF1α ratio in the serum of SONFH rats changed significantly 4-16 weeks after modeling, with the greatest differences observed 12 weeks after modeling. The levels of BGP, TRAP5b, RANKL, OPG, and RANKL/OPG ratio in the serum of SONFH rats changed significantly 8-21 weeks after modeling. During the entire onset and progression of SONFH in rats, the blood stasis syndrome characteristics such as hyperalgesia, tongue color darkening, gait abnormalities, platelet, vascular, and coagulation dysfunctions were observed, which gradually worsened and then gradually alleviated in the disease course(2-21 weeks), with the most notable differences occurred around 12 weeks after modeling.

Prognostic prediction of the femoral head using osteonecrosis and contralateral regions based on CT images / 西安交通大学学报(医学版)

【Objective】 To develop a prognosis model based on CT images using radiomics method for patients with osteonecrosis of the femoral head (ONFH) and to investigate the additional prediction value of the imaging features of the contralateral normal femoral head regions for the prognosis prediction. 【Methods】 A total of 51 patients were included in this retrospective study. All the patients had preoperative CT images. For each patient, two regions of interest (ROIs) were involved, including the osteonecrosis region and the contralateral normal femoral head region. A total of 968 radiomics features were extracted for each patient. We made both the univariate and multivariable analyses. Three models were developed based on the features of osteonecrosis region, contralateral normal femoral head region, and both regions. The 10 times of repeated random experiments were used for model construction and validation. The average performance of the 10 times of experiments was reported as the results. 【Results】 For the features of osteonecrosis region, 37 features showed significant predictive value, with the mean AUC value of 0.708 2±0.029 9. The AUC of the constructed prediction model was 0.911 0±0.029 4 and 0.688 6±0.089 3 for the training set and validation set, respectively. For the features of contralateral normal femoral head region, 14 features showed significant predictive value, with the mean AUC value of 0.703 6±0.006 9. The AUC value of the constructed model for the training set and validation set was 0.867 2±0.039 5 and 0.669 0±0.072 6, respectively. For the models developed based on combined features, the AUC value was higher than that of the models developed based on osteonecrosis region features (training set: 0.935 8±0.016 6 vs. validation set: 0.737 9±0.090 8). 【Conclusion】 We developed a novel CT images-based radiomics method to predict postoperative prognosis in patients with ONFH. Furthermore, the features of contralateral normal femoral head region has additional prediction value. Combining the imaging features of osteonecrosis region and contralateral normal femoral head region can obtain more accurate prediction of prognosis in patients with ONFH.

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.

Clinical application of stem cells for bone injury / 中华创伤骨科杂志

Development and application of stem cells and their related technologies have paved new ways for prevention and treatment of orthopedic diseases. Application of stem cells for clinical treatment of bone defects is extremely promising, fracture, nonunion and osteonecrosis of the femoral head (ONFH) in particular. However, promotion of clinical stem cell therapy still faces difficulties and lacks corresponding standards. This article reviews clinical researches on stem cell therapy for bone injury and summarizes the injury types, cell types, cell numbers and their clinical efficacy, hoping to provide references for clinical treatment of bone injury with stem cells.

The role and significance of the transforming growth factor-β signaling pathway in the model of steroid-induced osteonecrosis of the femoral head in young rabbits / 中华实用儿科临床杂志

Objective:To explore the relationship between the transforming growth factor-β (TGF-β) signaling pathway and steroid-induced osteonecrosis of the femoral head in young rabbits.Methods:Sixty 8-week-old rabbits weighing 1.5-2.0 kg were randomly divided into steroid injection group (48 cases) and control group (12 cases). Rabbits in the former group were injected with Prednisolone Acetate 7.5 mg/kg into bilateral gluteal muscles twice a week for 8 weeks, and those with successful modeling were included in the disease group; otherwise, they were included in the non-disease group.Rabbits in control group were similarly injected with the same volume of 9 g/L saline.Penicillin sodium 50 000 U/rabbit was injected once a week for preventing infection.After 8 weeks of injection, CT was performed in all the experimental animals.They were then sacrificed for collecting bilateral femoral heads.Expression levels of TGF-β1, TGF-β2, Smad2 and Smad3 in the femoral head were detected by enzyme linked immunosorbent assay (ELISA), and the mRNA level of Runx2 in the femoral head was detected by quantitative real-time PCR (qPCR), the expression differences of related factors in each group were compared.Results:In steroid injection group (48 cases), 6 rabbits were sacrificed, and 32 survived, involving 6/32 cases (18.75%) experimental animals with positive avascular necrosis (disease group), and 26 negative ones (non-disease group). ELISA data showed that expression levels of TGF-β1 in control group, non-disease group and disease group were (77.12±14.62) ng/L, (90.17±11.90) ng/L and (126.14±25.66) ng/L, respectively ( t=3.35, 4.24, all P<0.05). The expression levels of TGF-β2 in control group, non-disease group and disease group were (74.54±7.63) ng/L, (89.24±9.51) ng/L and (109.74±16.45) ng/L, respectively ( t=4.12, 5.65, all P<0.01). The expression levels of Smad2 in control group, non-disease group and disease group were (17.74±2.72) μg/L, (23.82±3.58) μg/L and (31.28±3.88) μg/L, respectively ( t= 4.54, 7.99, all P<0.01). The expression levels of Smad3 in control group, non-disease group and disease group were (1.76±0.52) μg/L, (2.39±0.45) μg/L and (3.53±0.47) μg/L, respectively ( t=5.60, 6.71, all P<0.01). qPCR data showed that the mRNA levels of Runx2 in control group, non-disease group and disease group were 1.02±0.17, 1.27±0.14, and 1.72±0.11, respectively ( t=7.60, 8.91, all P<0.01). Conclusions:TGF-β is up-regulated in the model of steroid-induced osteonecrosis of the femoral head in young rabbits, which stimulates the proliferation and differentiation of osteoblasts and osteoclasts, and triggers the process of bone remodeling.The TGF-β signaling pathway involved in the repair of necrotic bone.

Research Advances of Traditional Chinese Medicine in Treating Osteonecrosis of Femoral Head by Regulating Bone MetabolismRelated Signaling Pathways / 中国实验方剂学杂志

Osteonecrosis of the femoral head （ONFH） is a serious orthopedic disease caused by many factors. It is difficult to cure clinically and has a poor prognosis， which poses a serious threat to human health. The pathogenesis of this disease is still unclear. The ONFH caused by different causes involves the disorder of a variety of metabolic pathways in vivo. Abnormal proliferation and differentiation of bone mesenchymal stem cells （BMSCs）， imbalance of bone metabolism， and increased destruction of bone trabeculae caused by abnormal transduction of bone metabolism-related signaling pathways may be the important causes of ONFH. BMSCs are pluripotent stem cells with self-renewal and multidirectional differentiation ability， which have good regeneration rate. Improving the osteogenic and differentiation ability of BMSCs is the key to inhibit bone absorption and promote bone matrix reconstruction， which plays an important role in bone remodeling. In recent years， there are many studies on the prevention and treatment of ONFH in traditional Chinese medicine（TCM）， and it has been found that a variety of single herbs， monomers and compounds can regulate the differentiation direction and process of BMSCs by targeting signal molecules， with great potential for bone defect repair and anti-femoral head necrosis activity. Nowadays， prevention and treatment of ONFH by regulating bone metabolism signaling pathways has become a hot research topic. In this paper， the mechanism and related signal transduction pathways of TCM in preventing and treating ONFH were reviewed to explore some mechanisms of alleviating the rate of bone loss， promoting bone formation， and repairing bone defects， so as to provide reference for further research on the prevention and treatment of ONFH by TCM. The related clinical application studies also provided specific targets for gene-assisted therapy of ONFH.

Concentrated autologous bone marrow aspirate transplantation versus conservative treatment for corticosteroid-associated osteonecrosis of the femoral head in systemic lupus erythematosus / Journal of Rural Medicine

Objective: To compare the outcomes of steroid-associated osteonecrosis of the femoral head in patients with systemic lupus erythematosus who underwent conservative treatment and concentrated autologous bone marrow aspirate transplantationMethods: Osteonecrosis of the femoral head was classified according to the Japanese Investigation Committee system. Concentrated autologous bone marrow aspirate transplantation was performed by aspirating the bone marrow from both iliac crests and then transplanting it to the necrotic area after the core decompression. Patients with >2-year follow-up after the concentrated autologous bone marrow aspirate transplantation in our institution (Group I) and those with >2-year follow-up after the first hospital visit in a cooperative institution (Group II) were included in this study. After a randomized matching based on age, sex, type, stage, and etiology, the collapse rate in pre-collapsed stages and total hip arthroplasty conversion rate in all stages were compared between the two groups.Results: After the matching adjustment, 33 pairs of hips were included. Preoperatively, 1, 2, 16, and 14 hips were classified as types A, B, C1, and C2, respectively, and 15, 13, 2, and 3 hips were classified as stages 1, 2, 3A, and 3B, respectively. The collapse rates in the pre-collapsed stages were 68% and 39% in Groups I and II, respectively. Total hip arthroplasty conversion rates were 33% and 45% in Groups I and II, respectively. However, Group I had significantly higher and lower conversion rates in stages 1 and 3, respectively (both P<0.05).Conclusion: Conservative treatment may be preferable in stage 1 hips. In addition, concentrated autologous bone marrow aspirate transplantation may prevent further collapse in stage 3.

Bone turnover characteristics in patients with alcohol-induced osteonecrosis of the femoral head / 中国组织工程研究

BACKGROUND: The pathological changes of alcohol-induced osteonecrosis of the femoral head (ONFH) are the result of a combination of various factors, and its specific pathogenesis is inconclusive. Related studies have shown abnormal bone metabolism in patients with avascular necrosis of the femoral head. OBJECTIVE: To explore the bone turnover markers in patients with alcohol-induced ONFH and to explore the relationship between different stages of ONFH and bone metabolism. METHODS: This study retrospectively selected 193 male patients with alcohol-induced ONFH (necrosis group), including 35 cases of ARCO stage II, 131 cases of ARCO stage III and 27 cases of ARCO stage IV. Among them, there were 65 cases of a little drinking of alcohol 52 cases of moderate drinking, and 76 cases of heavy drinking. Another 182 healthy males undergoing physical examination with no history of drinking were taken as control group. The bone turnover markers [procollagen type 1 N-terminal propeptide (P1NP), C-terminal cross-linked telopeptides of type 1 collagen (β-CTX), molecular fragment of N-terminal osteocalcin (N-MID) and 25 hydroxyvitamin D (25OHD)] and biochemical indexes were tested and compared between two groups, followed by logistic regression analysis and correlation analysis. The study protocol was performed in line with the relevant ethic requirements of the First Affiliated Hospital of Guangzhou University of Chinese Medicine. All participants in the trial had been fully informed of the trial process. RESULTS AND CONCLUSION: In the necrosis group, P1NP, β-CTX, N-MID, 25OHD, serum calcium, uric acid, alkaline phosphatase, serum phosphorus levels were significantly higher than that of the control group (P < 0.05), and apolipoprotein A1 and high-density lipoprotein levels in the necrosis group were significantly lower than those in the control group (P < 0.05). Compared with patients with low level of alcohol, β-CTX and N-MID levels were significantly reduced in the patients with heavy drinking (P < 0.05). The P1NP level of patients with ARCO stage IV was significantly higher than that of patients with ARCO stage II and III (P < 0.05), and the β-CTX level of patients with ARCO stage IV was significantly higher than that of patients with ARCO stage III (P < 0.05). The correlation analysis results showed that alcohol intake levels were negatively correlated with β-CTX, alkaline phosphatase level was positively correlated with P1NP and β-CTX, and 25OHD was negatively correlated with low-density lipoprotein. Logistic regression analysis results showed that: P1NP (odds ratio=0.984, P=0.004), β-CTX (odds ratio=0.325, P=0.043), and high-density lipoprotein (odds ratio=2.622, P=0.014). To conclude, male patients with alcohol-induced ONFH have active bone formation and bone resorption, and obvious abnormalities in lipid metabolism. The progression of alcohol-induced ONFH can be predicted by these bone turnover markers.

Terapia con células madre en la osteonecrosis de la cabeza femoral / Stem Cell Therapy in Osteonecrosis of the Femoral Head

RESUMEN Objetivos: Describir el efecto terapéutico del uso de células madre en el manejo de la osteonecrosis de la cabeza femoral. Métodos: Se realizó una búsqueda en las distintas bases de datos como Pubmed/MEDLINE, BVS y Cochrane de los últimos 10 años, incluyéndose estudios relevantes de metaanálisis, ensayos clínicos y revisiones. Además, se revisó la página electrónica oficial de la Organización Mundial de la Salud para referencias adicionales. Las palabras de búsqueda fueron: "("Stem Cells" OR "Stem Cell Transplantation"[Mesh] OR "Mesenchymal Stem Cell Transplantation"[Mesh] OR Hematopoietic Stem Cell Transplantation"[Mesh] OR Cell-and Tissue-Based Therapy"[Mesh] "Multipotent Stem Cells"[Mesh] OR "Embryonic Stem Cells"[Mesh]) AND ("Osteonecrosis"[Mesh] OR "Femur Head Necrosis"[Mesh] "osteonecrosis of the femoral head" OR "Femoral head"). Incluimos un total de 7 estudios. 2 metaanálisis, 2 artículos de revisión, 2 ensayos clínicos controlados y aleatorizados y un estudio de evidencia. Resultados: Todos los estudios evidenciaron que la terapia con células madre en el manejo de la osteonecrosis de la cabeza femoral es segura y efectiva. El tratamiento combinado de descompresión central más implantación de células madre mostró mayor efectividad. Conclusiones: La terapia con células madre es una opción terapéutica para tratar la osteonecrosis de la cabeza femoral, sobre todo en etapas tempranas. La combinación de descompresión central más la infiltración de células madre en la zona necrótica produce mejoría de la sintomatología y contiene el progreso de la enfermedad(AU)

ABSTRACT Objectives: To describe the therapeutic effect of the stem cell use in managing osteonecrosis of the femoral head. Methods: A search was carried out in the different databases as Pubmed / MEDLINE, BVS and Cochrane for the last 10 years, including relevant meta-analysis studies, clinical trials and reviews. In addition, the official website of the World Health Organization was checked for additional references. The search words were: "(" Stem Cells "OR" Stem Cell Transplantation "[Mesh] OR" Mesenchymal Stem Cell Transplantation "[Mesh] OR Hematopoietic Stem Cell Transplantation" [Mesh] OR Cell-and Tissue-Based Therapy "[ Mesh] "Multipotent Stem Cells" [Mesh] OR "Embryonic Stem Cells" [Mesh]) AND ("Osteonecrosis" [Mesh] OR "Femur Head Necrosis" [Mesh] "osteonecrosis of the femoral head" OR "Femoral head"). We include a total of 7 studies, 2 meta-analyzes, 2 review articles, 2 controlled and randomized clinical trials, and one evidence study. Findings: All the studies showed that stem cell therapy in managing osteonecrosis of the femoral head is safe and effective. The combined treatment of central decompression plus stem cell implantation showed greater effectiveness. Conclusions: Stem cell therapy is a therapeutic option to treat osteonecrosis of the femoral head, especially in the early stages. The combination of central decompression plus the infiltration of stem cells in the necrotic area produces an improvement in the symptoms and contains the progress of the disease(AU)

Exploration on Biological Basis Underling Different Syndromes of Nontraumatic Osteonecrosis of Femoral Head Based on Network Pharmacology / 中国实验方剂学杂志

Objective:To explore the biological basis underlying the different syndromes of nontraumatic osteonecrosis of the femoral head (NONFH) according to the molecular interaction network associated with syndromes and the corresponding prescriptions. Method:A total of 30 NONFH patients and 10 healthy controls were enrolled in the present study. The gene expression profiles associated with different syndromes of NONFH were detected by microarray analysis. Then, the molecular interaction networks of the differentially expressed genes of different syndromes were constructed to identify the crucial syndrome-related genes. After collecting the phenotype-related genes and the candidate targets of the corresponding prescriptions of different syndromes from Integrative Pharmacology-based Research Platform of Traditional Chinese Medicine (TCMIP) v2.0 (http://www.tcmip.cn/), the molecular interaction network associated with syndromes and the corresponding prescriptions were constructed and the biological basis of each syndrome was analyzed by functional enrichment analysis. Result:The crucial genes associated with the phlegm-stasis blocking collateral syndrome were mainly involved into the bone and lipid metabolism, and the regulation of immune-inflammation balance and circulation. Consistently, the candidate targets of the corresponding prescription-Jianpi Huogu prescription might play roles in the metabolism of osteogenesis, dissipating phlegm, activating circulation to remove blood stasis, relieving pain and inflammatory response. In addition, our data revealed that the stagnation of meridians syndrome-related genes could be mainly involved into the regulation of circulation and inflammatory response, as well as the metabolism of lipid and bone. Accordingly, the corresponding prescription of this syndrome-Huoxue Tongbi Formula could exert the regulatory effects on osteogenesis and inflammatory response, as well as the activation of the circulation and qi-invigorating. Moreover, the crucial genes associated with the liver and kidney deficiency syndrome played roles in various pathological processes during NONFH, such as the abnormal bone and lipid metabolisms, the immune-inflammation imbalance, and the blocked blood circulation, which were in line with our findings on the pharmacological mechanisms of the corresponding prescription of this syndrome-Bushen Zhuanggu formula. Conclusion:The current study indicated that the phlegm-stasis blocking collateral syndrome may be mainly associated with the abnormal bone and lipid metabolisms. The molecular mechanisms underlying the stagnation of meridians syndrome may be the imbalance of "immune-inflammation" and the blocking circulation. Furthermore, the liver and kidney deficiency syndrome may be not only associated with the abnormal bone and lipid metabolisms, but also implicated into various biological pathways-related to inflammation and circulation. Interestingly, the pharmacological mechanisms of the corresponding prescriptions may be in accord to the biological basis of each syndrome.

Clinical Analysis of "Different Diseases Saring Same Syndrome" Concept in End Stage of Different Hip Diseases / 中国实验方剂学杂志

The traditional Chinese medicine (TCM) concept that "different diseases may share the same TCM syndrome" is a unique theory explaining the relationship between diseases and TCM syndromes, which originally means that different diseases sharing the same TCM pathogenesis may develop the same syndrome. It accords with the theory of treatment based on syndrome differentiation. In clinical practices, this concept explains why the same herbal formula can be used to treat different diseases. With the development of a novel strategy to integrate the disease diagnosis and TCM syndrome differentiation, the meaning of "different diseases may share the same TCM syndrome" has also changed. It means that different diseases share the same TCM pathogenesis during their progression may show the same syndrome. Osteonecrosis of the femoral head （ONFH）, hip osteoarthritis (HOA), and hip rheumatoid arthritis (HRA) are three different diseases that occur in the bones, cartilage, and synovium of the hip joint, respectively. However, they share similar clinical symptoms and TCM symptoms if they had progressed to the end-stage. In the end-stage of the disease, hip pain, restricted activity, signs of waist and knee pain, and weakened walking function, whether it is symptoms or signs or TCM syndromes, all show their similarities, reflecting the concept of different diseases may share the same TCM syndrome. This article discusses the similarity of the three diseases from the aspects of syndrome characteristics, radiographic findings, syndrome differentiation, etiology and pathogenesis, as well as clinical treatments. We found that, in addition to similar clinical signs and symptoms, the three hip osteoarthropathies in the end-stage see articular cartilage degeneration, joint space stenosis, joint effusion, synovial thickening, bone hyperplasia, and subchondral bone cystic degeneration, etc. similar X-ray performance， kidney sperm, bone marrow, only kidney sufficiency, muscles and bones can be filled with bone marrow, liver blood, main muscles, liver and blood are sufficient to support the muscles and bones, and the disease is in the advanced stage， ONFH， HOA and HRA are closely related to liver and kidney dysfunction. Insufficient liver and kidney, meridian muscle, and bone malnutrition are three common pathological mechanisms of late hip bone disease. Deficiency, waist and knee weakness, and weakness in walking have also become common symptoms. It not only provides a theoretical basis for the "same syndrome",but also helps the differential diagnosis of "different diseases", improves the fracture level of hip diseases, and enriches the connotation of "different diseases sharing the same syndrome" in Chinese medicine.