Clinical efficacy of Osteoking in knee osteoarthritis therapy: a prospective, multicenter, non-randomized controlled study in China.

Background: Osteoking has been extensively used for the treatment of knee osteoarthritis (KOA). However, it is lack of high-quality evidence on the clinical efficacy of Osteoking against KOA and the comparison with that of nonsteroidal anti-inflammatory drugs (NSAIDs). Aims: To evaluate the efficacy and safety of Osteoking in treating KOA. Methods: In the current study, a total of 501 subjects were recruited from 20 medical centers, and were divided into the Osteoking treatment group (n = 428) and the NSAIDs treatment group (n = 73). The Propensity Score Matching method was used to balance baseline data of different groups. Then, the therapeutic effects of Osteoking and NSAIDs against KOA were evaluated using VAS score, WOMAC score, EQ-5D-3L and EQ-VAS, while the safety of the two treatment were both assessed based on dry mouth, dizziness, diarrhea, etc. Results: After 8 weeks of treatment, the Osteoking group was compared with the NSAIDs group, the VAS score [2.00 (1.00, 3.00) vs. 3.00 (2.00, 4.00)], WOMAC pain score [10.00 (8.00, 13.00) vs. 11.00 (8.00, 16.00) ], WOMAC physical function score [32.00 (23.00, 39.00) vs. 39.07 ± 16.45], WOMAC total score [44.00 (31.00, 55.00) vs. 53.31 ± 22.47) ], EQ-5D-3L score [0.91 (0.73, 0.91) vs. 0.73 (0.63, 0.83) ] and EQ-VAS score [80.00 (79.00, 90.00) vs. 80.00 (70.00, 84.00) ] were improved by the treatment of Osteoking for 8 weeks more effectively than that by the treatment of NSAIDs. After 8 weeks of treatment with Osteoking, the VAS scores of KOA patients with the treatment of Osteoking for 8 weeks were reduced from 6.00 (5.00, 7.00) to 2.00 (1.00, 3.00) (p < 0.05), which was better than those with the treatment of NSAIDs starting from 2 weeks during this clinical observation. Importantly, further subgroup analysis revealed that the treatment of Osteoking was more suitable for alleviating various clinical symptoms of KOA patients over 65 years old, with female, KL II-III grade and VAS 4-7 scores, while the clinical efficacy of NSAIDs was better in KOA patients under 65 years old and with VAS 8-10 scores. Of note, there were no differences in adverse events and adverse reactions between the treatment groups of the two drugs. Conclusion: Osteoking may exert a satisfying efficacy in relieving joint pain and improving life quality of KOA patients without any adverse reactions, especially for patients with KL II-III grades and VAS 4-7 scores. Clinical Trial Registration: https://www.chictr.org.cn/showproj.html?proj=55387, Identifier ChiCTR2000034475.

Topical Chinese patent medicines for chronic musculoskeletal pain: systematic review and trial sequential analysis.

PURPOSE: Chronic musculoskeletal pain (CMP) is defined as persistent or recurrent pain that occurs in the joints, musculo-soft tissue, spine or bones for more than three months and is not completely curable. Although topical Chinese patent medicine (CPM) is the most extensively utilized medication in Asia and is widely used for pain management, its efficacy remains controversial. This article presents a systematic review of clinical studies on the therapeutic properties of topical CPM for CMP patients to better inform clinical decision-making and provide additional and safer treatment options for patients with CMP. METHOD: We performed a comprehensive search on PubMed, Cochrane Library, web of science and Chinese databases (CNKI and WanFang data) from 2010 to 2022. In all the studies, knee osteoarthritis, cervical spondylosis, low back pain, and periarthritis of shoulder met the International Pain Association definition of chronic musculoskeletal pain. We included only randomized controlled trials (RCTs) using topical CPM primarily for chronic musculoskeletal pain in adults. To determine the effect of topical CPM on clinical symptoms, we extracted the Visual Analog Scale (VAS, range 0-10) and the Western Ontario and McMaster Universities Arthritis Index pain scores (WOMAC pain, range 0-20), in which the lower the score, the better the results. We also accepted the comprehensive outcome criteria developed by the Chinese National Institute of Rheumatology as an endpoint (total effectiveness rate, range 0-100%, higher score = better outcome), which assesses the overall pain, physical function and wellness. Finally, trial sequential analysis of VAS pain score and total effectiveness rate was performed using TSA software. RESULTS: Twenty-six randomized controlled trials (n = 3180 participants) compared topical CPM with oral Nonsteroidal Anti-inflammatory Drugs (NSAIDs) (n = 15), topical NSAIDs (n = 9), physiotherapy (n = 5), exercise therapy (n = 4), and intra-articular Sodium hyaluronate injection (n = 2). Sixteen studies found that topical CPM was statistically significant in improving CMP pain (measured by VAS pain and Womac pain scores)(p < 0.05), and 12 studies found topical CPMs to be more clinically effective (assessed by ≥ 30% reduction in symptom severity) in treating patients with CMP (p < 0.05). Trial sequential analysis indicates that the current available evidence is robust, and further studies cannot reverse this result. In most of the studies, randomisation, allocation concealment and blinding were not sufficiently described, and no placebo-controlled trials were identified. CONCLUSION: Most studies showed superior analgesic effects of topical CPM over various control treatments, suggesting that topical CPM may be effective for CMP and is an additional, safe and reasonable treatment option. These reported benefits should be validated in higher-quality RCTs.

[Clinical study of intercondylar fossa formation to prevent intercondylar fossa impingement after high tibia osteotomy].

OBJECTIVE: To observe the clinical efficacy of intercondylar fossa plasty in preventing intercondylar fossa impingement syndrome after high tibial osteotomy. METHODS: From August 2018 to August 2020, 84 patients with inverted knee osteoarthritis were treated by arthroscopy combined with high tibial osteotomy, and were divided into two groups with 42 cases in each group according to different surgical methods. In the intercondylar fossa plasty group, there were 13 males and 29 females, age ranged from 52 to 67 years old with an average of(58.27±4.32) years old, and arthroscopic intercondylar fossa plasty was performed first, and then high tibial osteotomy. In the arthroscopic cleansing group, 16 males and 26 females, age ranged from 50 to 71 years old with an average of (59.02±5.14) years old, underwent arthroscopic cleansing and then high tibial osteotomy. Postoperative treatment was evaluated using visual analogue scale(VAS), hospital for special surgery (HSS) score for the knee, and the occurrence of intercondylar percussa impingement. RESULTS: All 84 patients were followed up, the duration ranged from 12 to 18 months with an average of (14.1±1.6) months. The VAS and HSS score of knee joint at 6, 12 and 18 months after surgery were significantly improved compared with preoperative period, and there was no significant difference between the two groups (P>0.05), but the incidence of intercondylar fossa index and intercondylar fossa impact between the two groups was significantly compared 18 months after surgery (P<0.05). CONCLUSION: Intercondylar fossa plasty can effectively prevent the incidence of intercondylar fossa impact after high tibial osteotomy, and has a more significant effect on postoperative knee pain and function improvement.

Cell-Permeable Stimuli-Responsive Ubiquitin Probe for Time-Resolved Monitoring of Substrate Ubiquitination in Live Cells.

Dynamic monitoring of intracellular ubiquitin (Ub) conjugates is instrumental to understanding the Ub regulatory machinery. Although many biochemical approaches have been developed to characterize protein ubiquitination, chemical tools capable of temporal resolution probing of ubiquitination events remain to be developed. Here, we report the development of the first cell-permeable and stimuli-responsive Ub probe and its application for the temporal resolution profiling of ubiquitinated substrates in live cells. The probe carrying the photolabile group N-(2-nitrobenzyl)-Gly (Nbg) on the amide bond between Ub Gly75 and Gly76 is readily prepared through chemical synthesis and can be delivered to live cells by conjugation via a disulfide bond with the cyclic cell-penetrating peptide cR10D (i.e., 4-((4-(dimethylamino)phenyl)-azo)-benzoic acid-modified cyclic deca-arginine). Both in vitro and in vivo experiments showed that Ub-modifying enzymes (E1, E2s, and E3s) could not install the Ub probe onto substrate proteins prior to removal of the nitrobenzyl group, which was easily accomplished via photoirradiation. The utility and practicality of this probe were exemplified by the time-resolved biochemical and proteomic investigation of ubiquitination events in live cells during a H2O2-mediated oxidative stress response. This work shows a conceptually new family of chemical Ub tools for the time-resolved studies on dynamic protein ubiquitination in different biological processes and highlights the utility of modern chemical protein synthesis in obtaining custom-designed tools for biological studies.

Chemical synthesis of on demand-activated SUMO-based probe by a photocaged glycine-assisted strategy.

The transiently-activated SUMO probes are conducive to understand the dynamic control of SENPs activity. Here, we developed a photocaged glycine-assisted strategy for the construction of on demand-activated SUMO-ABPs. The light-sensitive groups installed at G92 and G64 backbone of SUMO-2 can temporarily block probes activity and hamper aspartimide formation, respectively, which enabled the efficient synthesis of inert SUMO-2 propargylamide (PA). The probe could be activated to capture SENPs upon photo-irradiation not only in vitro but also in intact cells, providing opportunities to further perform intracellular time-resolved proteome-wide profiling of SUMO-related enzymes.

Hip Preservation or Total Hip Arthroplasty? A Retrospective Case-Control Study of Factors Influencing Arthroplasty Decision-Making for Patients with Osteonecrosis of the Femoral Head in China.

OBJECTIVE: At present, there is no consensus or guidance on indications for osteonecrosis of the femoral head (ONFH) patients to receive hip arthroplasty (THA) treatment. This study aims to explore the factors that influence the decision-making for THA in patients with ONFH, and to provide references for clinical decision for ONFH patients to be indicated for THA or hip preservation. METHODS: This retrospective case-control study involved data for ONFH patients from July 2016 to October 2021 from the China Osteonecrosis of the Femoral Head Database (CONFHD). The patients with ONFH, and unilateral hip affected at the first visit were divided into THA group and non-THA group according to if they had undergone THA treatment. The differences between the two groups of patients in terms of gender, age at the time of consultation, body mass index (BMI), etiology, onset side, association research circulation osseous (ARCO) stage, hip joint function, visual analog scale (VAS), etc. were analyzed. Multivariate binomial logistic regression analysis was then applied to evaluate the risk factors of ONFH patients who underwent THA during the first visit. RESULTS: A total of 640 patients were recruited for analysis, including 209 cases from the THA group and 431 cases from the non-THA group. The results of univariate analysis showed that the two groups of patients were significantly different in the following six indicators: age (59 vs. 46, Z = -9.58, p < 0.001), duration of disease (78 vs. 17, Z = -16.14, p < 0.001), gender composition (χ2  = 8.09, p = 0.004), disease etiology (χ2  = 33.04, p < 0.001), ARCO stage (χ2  = 334.86, p < 0.001), flexion of hip joint (χ2  = 172.33, p < 0.001). However, the comparison between the two groups on VAS (Z = -0.82, p = 0.41), BMI (Z = -1.35, p = 0.18), and onset side (χ2  = 1.53, p = 0.22) did not obviously differ. The results regression analysis showed that the age at the time of consultation, duration of disease, ARCO stage, and the hip joint function affected the decision making if the patients should undergo THA. The results of receiver operating characteristic curve (ROC) analysis showed that aforementioned indicators were satisfactory in predicting whether patients with ONFH would be treated with THA. The regression model using the above four indicators as comprehensive indicators has satisfactory performance in predicting whether to perform THA, and the area under the curve (AUC) is 93.94%. CONCLUSION: These factors such as age, duration of disease, ARCO stage, and hip flexion function should be considered comprehensively before making decisions to perform THA or not in our clinical practice.

Clinical Efficacy and Safety of Chondroitin Combined with Glucosamine in the Treatment of Knee Osteoarthritis: A Systematic Review and Meta-Analysis.

Objective: This analysis was aimed at providing evidence-based medicine basis for systematic evaluation of chondroitin combined with glucosamine in the treatment of knee osteoarthritis. Methods: The randomized controlled trials (RCTs) of chondroitin combined with glucosamine in the treatment of knee osteoarthritis (KOA) were searched in PubMed, EMBASE, ScienceDirect, Cochrane Library, China Knowledge Network Database (CNKI), China VIP Database, Wanfang Database, and China Biomedical Literature Database (CBM) online database. The retrieval time ranges from the database creation to the present. Two investigators gathered the information individually. The risk of bias was assessed using the criteria of the Cochrane back review group. RevMan5.4 statistical software analyzed the selected data. Results: A total of 6 RCT articles were obtained. Overall, 764 samples were evaluated by meta-analysis. The clinical efficacy of chondroitin combined with glucosamine was significantly better than that of routine treatment by meta-analysis. The confidence interval of 95% was (4.86, 17.08) (Z = 6.89, P < 0.00001). The scores of joint pain, tenderness, swelling, and dysfunction in patients with knee osteoarthritis treated with chondroitin combined with glucosamine were significantly lower than those treated with routine treatment. There was no significant difference in the incidence of adverse reactions between chondroitin combined with glucosamine and single treatment of KOA. Due to the small number of documents included in the analysis, it is not suitable to make a funnel chart, but there may be some publication deviation in the analysis. Conclusion: Chondroitin combined with glucosamine is more effective than chondroitin or glucosamine alone in the treatment of KOA and deserves clinical promotion. However, this conclusion still needs to be supported by multicenter, high-quality, double-blind, large-sample randomized controlled clinical trials due to the limitations of the six trials included.

Tongue Manifestation in Patients with Osteonecrosis of the Femoral Head: A Cross-sectional Study.

OBJECTIVE: Although tongue manifestation is a vital component of Traditional Chinese Medicine (TCM), relevant research on patients with osteonecrosis of the femoral head (ONFH) is still lacking. This study will explore the characteristic tongue manifestation of ONFH patients to inform future research and clinical practice. METHODS: This is a cross-sectional study. All ONFH patients meeting criteria and their clinical data were collected from the online China osteonecrosis of the femoral head database (CONFHD) since it was created. Organized tongue manifestations of eligible patients through the tongue manifestation acquisition instrument, including tongue shape, tongue color, tongue coating thickness, tongue coating color and tongue coating moisture. We used descriptive analysis for the general information while systematic clustering analysis for the better summary of tongue characteristics. RESULTS: A total of 375 ONFH patients were included with an average age of 46.3 years. Most patients appeared with enlarged tongue body (54.4%), and the proportions of pale and red tongue (62.4%) were higher than others. Tongue coating were mainly showed as thick (64.5%), white (57.6%) and moist (79.7%). Comparison of tongue shape between different causes of ONFH had a significant statistically difference (P = 0.000). Tongue manifestations could be cluster analyzed into three categories which were matched into four TCM syndromes. CONCLUSIONS: The tongue manifestation of ONFH patients has a significant change both in tongue body and coating, and different features may be related to the ONFH pathology. This study provides new and valuable tongue informations for a preliminary screening of ONFH patients.

Photocaging of Activity-Based Ubiquitin Probes via a C-Terminal Backbone Modification Strategy.

Photocaged, activity-based ubiquitin (Ub) probes (Ub-ABPs) have been developed for the time-resolved probing of deubiquitinating enzyme (DUB) activities, but many Ub-ABPs are still challenging to photocage because their warheads (e.g. propargylamide (PA) or dehydroalanine (Dha)) are difficult to temporally block and activate. Here, we describe a new C-terminal backbone modification strategy for the construction of photocaged Ub-ABPs in which a light-sensitive group is placed at the backbone amide bond of the Ub Gly75. This strategy enabled the facile generation of cell-permeable photocaged Ub-PA and Dha probes that could be activated to capture DUBs after photo-irradiation, and were used to profile DUBs in cells under specially designed conditions (e.g. in cells experiencing oxidative stress) or DUBs with isopeptide linkage selectivity. This backbone modification strategy is anticipated to provide a general solution for the development of photocaged Ub ABPs bearing any warheads for DUB profiling.

Chinese patent medicine for osteoporosis: a systematic review and meta-analysis.

Chinese patent medicine (CPM) has been widely used in China for patients with osteoporosis (OP) but a comprehensive literature review is still important. Therefore, we performed meta-analysis using six electronic databases prior to 30 April 2021 only randomized controlled trials (RCTs) using CPM as the first-line treatment in adults with OP were included. Thirty RCTs met the inclusion criteria with a total of 2723 patients, and seven types of CPM were included. Compared with the control group, 23 studies showed significantly improved bone mineral density (BMD) (lumbar spine) (mean difference [MD] = 0.08; confidence interval [CI], 0.03 to 0.13), 15 studies showed significantly improved BMD (femoral) (MD = 0.05; 95% CI, 0.02 to 0.07), 6 studies showed significantly improved BMD (radius) (MD = 0.06; 95% CI, 0.03 to 0.09), 2 trials showed significantly improvement of BMD (ulna) (MD = 0.02; 95% CI, 0.01 to 0.03), and 4 trials showed significantly improved BMD (MD = 0.09; 95% CI, 0.09 to 0.10). The meta-analysis also showed that CPM had superior pain improvement, a higher total effectiveness rate, and a lower risk of adverse events compared with standard western treatment. The findings of this study suggest that CPM therapy may be a safe and effective alternative treatment modality for OP, it has potential benefits in relieving symptoms and improving BMD compared to western medications or placebos.

Three-dimensional surgical planning and clinical evaluation of the efficacy of distal tibial tuberosity high tibial osteotomy in obese patients with varus knee osteoarthritis.

PURPOSE: High tibial osteotomy (HTO) is an effective surgical treatment for varus knee osteoarthritis. However, obese patients require reinforced internal fixation materials to prevent internal fixation fractures and hardware failure after osteotomy. Therefore, the purpose of our study is to evaluate the clinical efficacy of distal tibial tuberosity high tibial osteotomy (DTT-HTO) using the new patented π-shaped plate in obese patients with varus knee osteoarthritis. METHOD: Thirty-four obese patients (39 knees) with varus knee osteoarthritis who underwent DTT-HTO with the π-shaped plate and second-look arthroscopy when implant removal occurred from September 2017 to June 2020 were retrospectively reviewed. Three-dimensional surgical planning using DTT-HTO on the knees is performed. There were 9 males and 25 females, with body mass index (BMI) values ranging from 30.3 to 38.5 kg/m2 and ages ranging from 50 to 75 years old. The radiological assessment was performed with the femora tibial angle (FTA) and the weight-bearing line ratio (WBLR). The clinical outcomes were evaluated by the Hospital for Special Surgery (HSS) knee score and the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC). The status of the cartilage was evaluated by the International Cartilage Repair Society (ICRS) grading system. RESULTS: All patients were followed up for 18-30 months. The FTA significantly changed from 181.68±1.68.preoperatively to171.29±1.51.at the last follow-up (P<0.001). The WBLR significantly increased from 16.85±2.20 to 55.41±2.46% from before surgery to the last follow-up after surgery (P<0.001). The HSS score significantly improved from 56.65±5.27 preoperatively to 68.79±2.61, 77.82±2.15, and 86.12±2.78 at the 6-month, 12-month, and last follow-up after surgery (P<0.001). The WOMAC score significantly decreased from 105.47±3.89 preoperatively to 80.50±4.20, 71.44±4.65, and 52.44±3.14 at the 6-month, 12-month, and last follow-up after surgery (P<0.001). During implant removal, no internal fixation fractures occurred in any patient. The articular cartilage grade in the medial compartment of the knee were significantly higher in the second arthroscopy than in the first arthroscopy, according to the ICRS grading system (P<0.001). The articular cartilage grade in the lateral compartment of the knee showed no statistical differences from the first- to the second-look arthroscopy (P>0.05). CONCLUSION: There are no correlation between BMI and postoperative outcomes. DTT-HTO shows yield excellent clinical results in obese patients with varus knee osteoarthritis. It can be recommended to be used for the heavy patients.

Epidemiological Study Based on China Osteonecrosis of the Femoral Head Database.

OBJECTIVE: The aim of the present study was to reveal the case characteristics of osteonecrosis of the femoral head (ONFH) in Mainland China. METHODS: This cross-sectional epidemiological study derived data for ONFH patients from July 2016 to December 2018 from the China Osteonecrosis of the Femoral Head Database (CONFHD). The derived data included gender, age, body mass index (BMI), height, occupation, region, and etiology of femoral head necrosis. A descriptive analysis was performed to summarize the epidemiological characteristics of the case data in the CONFHD. RESULTS: A total of 1844 ONFH patients (2945 hips) were included in this study, comprising 1302 men and 542 women. The age of patients ranged from 18 to 95 years, with a median of 50 years, and the male to female ratio was 2.4. Male patients are younger than female patients (48.26 ± 12.56 years old and 55.56 ± 14.94 years old, respectively). Among the 1844 patients (2945 hips), there were 528 (17.92%) hips at ARCO stage I, 941 (31.99%) hips at ARCO stage II, 873 (29.63%) hips at ARCO stage III, and 603 (20.46%) hips at ARCO stage IV. In the subclassification of ARCO stages I and II, the majority of cases were type C; type A comprised the majority in the subclassification of ARCO stage III. According to the Kellgren-Lawrence classification system, among the 603 ARCO stage IV hips, there were 178 (29.52%) grade 1 hips, 201 (33.34%) grade 2 hips, 176 (29.18%) grade 3 hips, and 48 (7.96%) grade 4 hips. Most were from three provinces: Henan (27.3%), Shanxi (13.9%), and Shandong (11.9%). Regarding BMI, 982 patients (53.25%) were overweight or obese. Among all patients, the largest proportion of patients engaged in level IV manual work. Of all the patients, there were 495 (26.84%) with steroid-induced ONFH, 685 (37.15%) were alcoholics, and 290 (15.73%) had traumatic ONFH. The 495 patients with steroid-induced ONFH included 278 men (56.16%) and 217 women (43.84 %), had a complete history of hormone use. Among the primary diseases, there were 195 cases (39.39%) of immune system diseases, followed by dermatological diseases, respiratory diseases, nephropathy, and other diseases. There were a total of 685 patients with alcoholic ONFH, 589 of these patients (85.99%) were men. A total of 188 (27.45%) patients had drunk alcohol for 6-10 years (comprising the highest proportion), and 280 patients (40.88%) consumed 3001-3500 mL of alcohol each week (the highest proportion). CONCLUSION: Osteonecrosis of the femoral head most commonly occurs after the age of 40. Male patients have an earlier onset than female patients, and the number of male patients is approximately twice that of female patients. The BMI of patients was mainly in the overweight and obese range, and half of these patients engaged in level IV manual work. From the imaging findings, the numbers of hips at ARCO stages II and III were greatest, and the number at stage I was relatively small. Among all the causes of disease, alcohol, steroid use and trauma were the three most common reasons for ONFH.

Dynamic evolution of osseous structure in osteonecrosis of the femoral head and dynamic collapse risks: a preliminary CT image study.

BACKGROUND: Collapse risk of osteonecrosis of the femoral head (ONFH) is estimated mainly based on static indicators, including lesion size and lesion location, but bone repairing is a dynamic process that lasts for years. The present study attempted to analyze the dynamic evolution of the osseous structure and its correlation with radiographic progression. METHODS: This retrospective study included 50 hips with ONFH from 50 patients. Participants were divided into the non-collapse group (n = 25) and the collapse group (n = 25). Original files of the initial computed tomography (CT) images were imported into imaging processing software for morphology analysis. The volume of sclerotic bone, the volume of soft tissue, and bone mineral density (BMD) were calculated. The linear correlations between the aforementioned indicators and the disease duration were estimated. The logistic regression analysis was conducted to evaluate the correlation of these indicators with the radiographic progression. Receiver operating characteristic (ROC) analysis was used to evaluate these indicators' prediction performance. RESULTS: The volume of sclerotic bone and the BMD grew with disease duration, but the volume of soft tissue decrease. The logistic regression analysis found that the volume of sclerotic bone and the BMD were statistically associated with radiographic progression. The ROC analysis found that the regression model, which integrated the volume of sclerotic bone and the BMD, had satisfactory performance in predicting radiographic progression. CONCLUSION: The present study suggested a dynamic evolution of the osseous structure and a dynamic variation trend of the collapse risk in ONFH. The volume of sclerotic bone and the BMD might serve as further prognostic indicators when estimating the collapse risk.

Acupotomy Therapy for Knee Osteoarthritis Pain: Systematic Review and Meta-Analysis.

METHODS: We performed a comprehensive search on PubMed, the Cochrane Library, EMBASE, and four Chinese databases for articles published prior to June 2020. We included only randomized controlled trials (RCTs) that used acupotomy therapy as the major intervention in adults with knee OA, were published in either Chinese and English, included more than 20 subjects in each group, and included pain and function in the outcome measures. Knee OA was defined by the American College of Rheumatology or Chinese Orthopedic Association criteria in all studies. We extracted the visual analogue scale (VAS) pain score, the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) pain score, the total effectiveness rate, the modified Japanese Orthopedic Association (JOA) activities of daily living score, and Lysholm's score. We calculated the mean difference (MD) or risk ratio (RR) for all relevant outcomes. Meta-analyses were conducted using random-effects models when appropriate. RESULTS: We identified 1317 potentially relevant studies, thirty-two of which met the eligibility criteria and were conducted in China between 2007 and 2020. A total of 3021 knee OA patients (62.96% female, median age: 57 years, and median disease duration: 33 months) were included. The treatment duration ranged from 1 week to 5 weeks (median: 3 weeks). The typical acupotomy treatment involved releasing soft tissue adhesions and was performed once a week for 1-5 weeks until the pain was relieved. The control group treatments included acupuncture (8 studies), electroacupuncture (10 studies), sodium hyaluronate (8 studies), radiofrequency electrotherapy (1 study), and nonsteroidal anti-inflammatory drugs (NSAIDs, 5 studies). The results from the meta-analysis showed that acupotomy led to superior improvements in the VAS pain score (MD = -1.11; 95% confidence interval (CI), -1.51 to -0.71; p < 0.00001) and WOMAC pain score (MD = -2.32; 95% CI, -2.94 to -1.69; p < 0.00001), a higher total effectiveness rate (RR = 1.15; 95% CI, 1.09-1.21; p < 0.00001), and superior improvements in the JOA score (MD = 6.39; 95% CI, 4.11-9.76; p < 0.00001) and Lysholm's score (MD = 12.75; 95% CI, 2.61-22.89; p = 0.01) for overall pain and function. No serious adverse events were reported. CONCLUSION: Chinese acupotomy therapy may relieve pain and improve function in patients with knee OA. Furthermore, rigorously designed and well-controlled RCTs are warranted.

Exploring the Risk Factors for the Misdiagnosis of Osteonecrosis of Femoral Head: A Case-Control Study.

OBJECTIVE: The purpose of the present study was to evaluate the present situation and risk factors for the misdiagnosis of osteonecrosis of femoral head (ONFH), providing the basis for accurate diagnosis of ONFH. METHODS: For this retrospective study, 1471 patients with ONFH were selected from the China Osteonecrosis of Femoral Head Database (CONFHD). These patients had been recruited between July 2016 and December 2018. According to whether or not they were misdiagnosed, the patients were divided into two groups, with 1168 cases (22-84 years old) included in the diagnosis group and 303 cases (21-80 years old) in the misdiagnosis group. Misdiagnosis was measured using the following criteria: (i) the patient had the same symptoms and signs, and the second diagnosis was not consistent with the initial diagnosis within 6 months; and (ii) the patient was admitted to a hospital participating in CONFHD and the previous diagnosis was inconsistent with the diagnosis given by the expert group. Comparisons of age, visual analogue scale for pain, and body mass index between the two groups were performed using a t-test. Gender, causes of ONFH, primary diseases requiring corticosteroids, methods of corticosteroid use, corticosteroid species, type of trauma, onset side of the disease, pain side, whether symptoms are hidden, and type of imaging examination at the initial visit were compared using the χ2 -test. Years of alcohol consumption, weekly alcohol consumption, and physician title at the initial visit were compared using a Mann-Whitney U-test. Furthermore, the statistically significant factors were evaluated using multiple regression analysis to investigate the risk factors of misdiagnosis. RESULTS: A total of 303 patients (20.6%) were misdiagnosed: 118 cases were misdiagnosed as lumbar disc herniation, 86 cases as hip synovitis, 48 cases as hip osteoarthritis, 32 cases as rheumatoid arthritis, 11 cases as piriformis syndrome, 5 cases as sciatica, and 3 cases as soft-tissue injury. Whether symptoms are hidden (P = 0.038, odds ratio [OR] = 1.546, 95% confidence interval [CI] = 1.025-2.332), physician title at the initial visit (P < 0.001, OR = 3.324, 95% CI = 1.850-5.972), X-ray examination (P < 0.001, OR = 4.742, 95% CI = 3.159-7.118), corticosteroids (P < 0.001, OR = 0.295, 95% CI = 0.163-0.534), alcohol (P < 0.001, OR = 0.305, 95% CI = 0.171-0.546), and magnetic resonance imaging (MRI) examination (P = 0.042, OR = 0.649, 95% CI = 0.427-0.985) were each found to be associated with misdiagnosis. CONCLUSION: Osteonecrosis of the femoral head is easily misdiagnosed as lumbar disc herniation, hip synovitis, hip osteoarthritis, and rheumatoid arthritis. Patient history of corticosteroid use or alcohol abuse and MRI examination at the initial diagnosis may be protective factors for misdiagnosis. Hidden symptoms, physician title at the initial visit (as attending doctor or resident doctor), and only X-ray examination at the initial diagnosis may be risk factors for misdiagnosis.

Mechanisms and Molecular Targets of the Tao-Hong-Si-Wu-Tang Formula for Treatment of Osteonecrosis of Femoral Head: A Network Pharmacology Study.

The Tao-Hong-Si-Wu-Tang (THSWT) formula, a classic prescription of traditional Chinese medicine, has long been used for the treatment of osteonecrosis of femoral head (ONFH). However, its mechanisms of action and molecular targets are not comprehensively clear. In the present study, the Traditional Chinese Medicine System Pharmacology (TCMSP) database was employed to retrieve the active compounds of each herb included in the THSWT formula. After identifying the drug targets of active compounds and disease targets of ONFH, intersection analysis was conducted to screen out the shared targets. The protein-protein network of the shared targets was built for further topological analysis. Gene ontology and Kyoto Encyclopedia of Genes and Genomes pathway analysis were then carried out. A gene pathway network was constructed to screen the core target genes. We identified 61 active compounds, 155 drug targets, and 5443 disease targets. However, intersection analysis only screened out 37 shared targets. Kaempferol, luteolin, and baicalein regulated the greatest number of targets associated with ONFH. The THSWT formula may regulate osteocyte function through specific biological processes, including responses to toxic substances and oxidative stress. The regulated pathways included the relaxin, focal adhesion, nuclear factor-κB, toll-like receptor, and AGE/RAGE signaling pathways. RELA, VEGFA, and STAT1 were the important target genes in the gene network associated with the THSWT formula for the treatment of ONFH. Therefore, the present study suggested that the THSWT formula has an action mechanism involving multiple compounds and network targets for the treatment of ONFH.

Chinese herbal Huo-Gu formula for the treatment of steroid-associated osteonecrosis of femoral head: A 14-year follow-up of convalescent SARS patients.

PURPOSE: The coronavirus disease 2019 (COVID-19) reminds us of the severe acute respiratory syndrome (SARS) outbreak in 2003, and up to date, corticosteroid is commonly administrated to severe patients with COVID-19. Osteonecrosis of the femoral head (ONFH) is a common disabling complication among convalescent SARS patients who received corticosteroid therapy. In China, a considerable number of convalescent SARS patients with steroid-associated ONFH had undergone conservative treatment by traditional Chinese medicine, and this study aims to evaluate the long-term results of a spleen-invigorating Huo-Gu formula (HGF) therapy in these patients. PARTICIPANTS AND METHODS: A total of 33 convalescent SARS patients (9 males and 24 females) with bilateral steroid-associated ONFH (66 hips) were enrolled in this study. All patients received oral HGF therapy for 6 months when they were confirmed the diagnosis of steroid-associated ONFH. They had been regularly followed up at an interval of 1 year. Harris hip score and medical imaging modalities, including plain radiography, computed tomography and magnetic resonance imaging, were performed to evaluate the outcomes. RESULTS: Based on average 14 years of follow-up of HGF therapy (ranging from 6 to 16 years), 38 hips (57%) among the 66 hips developed definite osteoarthritis, and 14 hips (26%) in 53 precollapse hips (Association Research Circulation Osseous [ARCO] Stage I or II) progressed to femoral head collapse (ARCO Stage III or IV). Only five patients (also 5 hips) underwent total hip arthroplasty, and the mean hip survival time was over 15 years by the Kaplan-Meier analysis. We observed a mean Harris hip score of 63 points, which represented the reserve of 55% in pain score and 70% in physical function score. The severity of groin pain was not correlated to the severity of osteoarthritis. CONCLUSION: Chinese herbal HGF therapy demonstrates beneficial effects on preventing femoral head collapse, delaying total hip arthroplasty, and maintaining physical function in the treatment of steroid-associated ONFH. HGF therapy might be therefore a good alternative for the treatment of steroid-associated ONFH secondary to rheumatologic and infection diseases. TRANSLATIONAL POTENTIAL OF THE ARTICLE: HGF therapy might be a good alternative for the treatment of steroid-associated ONFH secondary to rheumatologic and infectious diseases.

Discovery and validation an eight-biomarker serum gene signature for the diagnosis of steroid-induced osteonecrosis of the femoral head.

Steroid-induced osteonecrosis of the femoral head (SONFH) is difficult to be diagnosed at the early stages when it can be administrated effectively. Yet, to date no study has been performed to identify diagnostic biomarkers and to develop diagnostic models for SONFH. In the current study, a total of 60 SONFH patients with Association Research Circulation Osseous (ARCO) stages I-IV, and 20 controls were enrolled and divided into the discovery and validation cohorts. The serum samples were collected and the gene expression profiles were detected by microarray analysis based on the discovery cohort. Then, eight genes (BIRC3, CBL, CCR5, LYN, PAK1, PTEN, RAF1 and TLR4) were identified as the candidate serum biomarkers of SONFH due to the significant differential expression patterns and the topological importance in the interaction network of SONFH-related differentially expressed genes. Functionally, these candidate serum biomarkers were significantly involved into several pathological processes during SONFH progression, such as the immune regulation and inflammation, bone metabolism and angiogenesis. After that, a prediction model for the diagnosis of SONFH was constructed using Partial least squares regression based on the serum levels of the candidate biomarkers. Notably, both the 10-fold cross-validation and the independent dataset test demonstrated the good performance of this model. In conclusion, our study discovered eight promising serum biomarkers and developed the multi-biomarker-based prediction model as a new, potential and non-invasive diagnostic tool for the detection of SONFH, as well as benefit the administration of SONFH in a daily clinical setting.

Combining ultrasonic and computed tomography scanning to characterize mechanical properties of cancellous bone in necrotic human femoral heads.

Image-based finite element modelling has been commonly used to determine the biomechanical behaviours of human femora, particularly for the diagnosis of femoral head necrosis. One of the fundamental aspects of biomechanical modelling is the relationship between bone density, which is obtained from images, and elastic modulus. While there exist some empirical equations relating density with elastic modulus, the characterization of this relationship remains incomplete, especially for necrotic femoral heads. The objective of this study was to determine the relationship between density and elastic modulus by combining ultrasonic scanning and computed tomography (CT). Bone specimens were surgically removed from the femora of eight persons (seven females and one male in the age range of 55-68 years old) and underwent both ultrasonic and CT scanning. The images were processed with MATLAB scripts, and a bilinear interpolation algorithm was used to determine the relationship between the CT-measured densities and ultrasound-measured elastic moduli. The results showed different density-elastic modulus relations between the hardening strap of the necrotic region and non-hardening strap areas of the necrotic region. The uniqueness of this study is the characterization of mechanical properties (in the present study, the density-modulus relationship) from clinical images, which would be valuable in computational biomechanics used for the diagnosis and treatment evaluation of femoral head necrosis.