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.

Steroid-induced osteonecrosis of the femoral head (steroid-induced ONFH) presents great challenges due to the various effects of steroids on multi-system pathways involved into osteoblast differentiation, osteoblast and osteoclast apoptosis, lipid metabolism, calcium metabolism and coagulation. As one of the most frequently used herbs in Traditional Chinese Medicine formulas that are prescribed for the regulation of bone and mineral metabolism, the therapeutic effects of Achyranthes bidentata on steroid-induced ONFH remain unclear. Thus, the aim of the current study was to verify whether Achyranthes bidentata extract (ABE) can be used to prevent steroid-induced ONFH and to investigate its underlying pharmacological mechanisms. Steroid-induced ONFH rat models were established to evaluate the effects of ABE treatment on osteonecrotic changes and repair processes. Microfocal computed tomography (Micro-CT) was performed to assess the effects of ABE treatment on bone mass, microstructure, and vascularization. Then, the effects of ABE treatment on osteoclast differentiation and bone formation were also evaluated in vivo and in vitro. In addition, receptor activator of nuclear factor kappa B (RANK), RANK ligand (RANKL), and osteoprotegerin (OPG) expression in sera, femoral heads and bone marrow-derived mesenchymal stem cells (BMSCs) were detected at both protein and mRNA levels. The ratio of empty lacuna, adipose tissue area, and adipocyte perimeter in the bone marrow were markedly lower in the ABE treatment groups than in the model group. Micro-CT evaluation indicated that ABE treatment could improve the microstructure of the trabecular bone, increase bone mineral density and promote vascularization in steroid-induced ONFH rats. Moreover, ABE treatment inhibited osteoclast differentiation and activated bone formation markers. Interestingly, OPG downregulation, RANK and RANKL upregulation, and an increased ratio of RANKL to OPG in sera and necrotic femoral head could be reversed by ABE treatment, which also effectively inhibited RANKL-induced osteoclast differentiation and regulated RANKL and OPG expression of in vitro. ABE may prevent steroid-induced ONFH and alleviate steroid-induced bone deterioration by regulating the RANKL/RANK/OPG signaling pathway.

Coronavirus disease 2019 (COVID-19) is a disaster in human medical history and glucocorticoids remain the most promising therapy. Osteonecrosis is a disease caused by reduced intraosseous blood flow to bones in the joints, which will rapidly induce joint destruction. Approximately one-third patients with severe acute respiratory syndrome (SARS) who received high cumulative doses and long treatment durations of glucocorticoids occurred osteonecrosis. Considering the similarity of SARS and COVID-19 on their pathogen, clinical characteristics, and therapeutic strategies, it is particularly desirable to investigate whether osteonecrosis will become a common sequela among convalescent COVID-19 patients. This multi-strategy study was designed by integrating different research methods, such as meta-analysis, systematic review, and cross-sectional investigations to address above study objectives. At first, two meta-analyses were performed on the osteonecrosis incidence among SARS patients and the clinical data of glucocorticoid exposure among COVID-19 patients. Then, a systematic review of low-dosage glucocorticoid associated osteonecrosis and a cross-sectional investigation of glucocorticoid exposure of COVID-19 patients in Wuhan city of China were also conducted. Moreover, the pathogenesis, diagnosis, prevention, and treatment options for osteonecrosis patients with COVID-19 infection were further presented and discussed. Our meta-analysis showed that 32% of SARS patients had developed osteonecrosis after receiving glucocorticoid treatment with high dose, and our system review supported that low level glucocorticoid exposure might also lead to the occurrence of osteonecrosis. Similarly, 40% of COVID-19 patients had undergone glucocorticoid treatment according to our meta-analysis. The cross-sectional investigation in Wuhan city of China found that the average of cumulative glucocorticoid exposure level was 504 ​mg calculated by the dosage of methylprednisolone. Notably, a confirmed osteonecrosis case was identified from 1406 patients with COVID-19 during our cross-sectional investigation, implying that preventive management of osteonecrosis should be better started with regular clinical follow-up observation. Growing evidence of the glucocorticoid therapy for COVID-19 patients prompts us to establish risk-classification-based early screening and to introduce early prevention protocol of its associated osteonecrosis that will be of clinical significance in favor of improved prognosis of this disease. To establish risk-classification-based early screening and to introduce early prevention protocol of glucocorticoid-induced osteonecrosis will be of clinical significance in favor of improved prognosis of COVID-19.

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. Graphical Abstract

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. 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. 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. 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. HGF therapy might be a good alternative for the treatment of steroid-associated ONFH secondary to rheumatologic and infectious diseases.