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Purpose The purpose of our study is to describe the rationale, the surgical technique and the early clinical and radiographic results of the treatment of patients with early stage osteonecrosis of the femoral head (ONFH) by performing: core decompression, injection of autologous bone marrow concentrate and the use of a new composite injectable bone substitute (PRO-DENSE ® ), as a mechanical supplementation associated with decompression. Methods The study included 37 hips (31 patients, 14 females, 17 males; mean age 43.9 years, range 24–56 years) with stages IC–IIIA ONFH. The outcome was determined by the changes in the Harris hip score (HHS), by progression in radiographic stages and by the need for hip replacement. The mean follow-up was 20.6 months (range 12–32 months). Results At final follow-up the mean HHS increased from 68 points pre-operatively to 86 points post-operatively. The radiological results showed that 29 hips (78.4  %) improved or had no further collapse. The overall clinical success rate of the procedure was 86.5 %, with three conversions to THA, and a failure rate of only 3.3 % in the pre-collapse group. Conclusions We are encouraged by these early results using core decompression, injection of the autologous bone marrow concentrate and backfilling the defect with an injectable bioceramic for the treatment of early stages of ONFH; as far as a conclusion can be drawn from the current data, this treatment seems to relieve hip pain and prevent the progression of ONFH in the majority of the cases.

ObjectivesTo observe the regulation of Chinese herbal medicine, Modifified Qing’e Pill (加味青娥丸, MQEP), on the expression of adiponectin, bone morphogenetic protein 2 (BMP2), osteoprotegerin (OPG) and other potentially relevant risk factors in patients with nontraumatic osteonecrosis of the femoral head (ONFH).MethodsA total of 96 patients with nontraumatic ONFH were unequal randomly divided into treatment group (60 cases) and control group (36 cases). The treatment group were treated with MQEP while the control group were treated with simulated pills. Both groups were given caltrate D. Six months were taken as a treatment course. Patients were followed up every 2 months. The levels of plasma adiponectin, BMP2, OPG, von Willebrand factor (vWF), von Willebrand factor cleaving protease (vWF-cp), plasminogen activator inhibitor 1 (PAI-1), tissue plasminogen activator (tPA), C-reactive protein (CRP), blood rheology, bone mineral density (BMD) of the femoral head and Harris Hip Score were measured before and after treatment.ResultsAfter 6 months of treatment, compared with the control group, patients in the treatment group had signifificantly higher adiponectin and BMP2 levels (P<0.01 and P=0.013, respectively), lower vWF, PAI-1 and CRP levels (P=0.019, P<0.01 and P<0.01, respectively), and lower blood rheology parameters. BMD of the femoral neck, triangle area and Harris Hip Score in the treatment group were signifificantly higher than those in the control group. Moreover, plasma adiponectin showed a positive association with BMP2 (r=0.231, P=0.003) and a negative association with PAI-1 (r=–0.159, P<0.05).ConclusionMQEP may play a protective role against nontraumatic ONFH by increasing the expression of adiponectin, regulating bone metabolism and improving the hypercoagulation state, which may provide an experimental base for its clinical effects.

The onset of osteonecrosis of the femoral head (ONFH) is intimately associated with the extensive administration of glucocorticoids (GCs). Long‐term stimulation of GCs can induce oxidative stress in both osteoclasts (OCs) and osteoblasts (OBs), resulting in the disturbance of bone remodelling. An alkaloid named crebanine (CN) demonstrates pharmacological properties including anti‐inflammation and reactive oxygen species (ROS) modulation. Our objective is to assess the therapeutic potential of CN in treating ONFH and elucidate the associated underlying mechanisms. The network pharmacology analysis uncovered that CN played a role in regulating ROS metabolism. In vitro, CN demonstrated its ability to reduce the dexamethasone (DEX)‐stimulated generation of OCs and suppress their resorptive function by downregulating the level of osteoclast marker genes. Concurrently, CN also mitigated DEX‐induced damage to OBs, facilitating the restoration of osteoblast marker gene expression, cellular differentiation and function. These effects were achieved by CN augmenting the antioxidant system to reduce intracellular ROS levels. Furthermore, in vitro results were corroborated by micro‐CT and histological data, which also showed that CN attenuated MPS‐induced ONFH in mice. This study highlights the therapeutic potential of CN in counteracting GCs‐induced ONFH.

Steroid-induced osteonecrosis of the femoral head (SONFH) is a serious bone disease commonly seen in patients on long-term glucocorticoid therapy. Although statins have shown some efficacy in improving lipid metabolism, their efficacy in the treatment of SONFH remains limited. PPARγ inhibitors may enhance the efficacy of statins through several mechanisms. This study aims to investigate how PPARγ inhibitors may enhance the effects of statins in the treatment of SONFH by directly inhibiting apoptosis and indirectly modulating lipoprotein subfractions. We first treated osteoblasts in vitro with high concentrations of hormones to simulate the SONFH environment. We then treated the cells with either the PPARγ inhibitor GW9662, the statin lovastatin, or a combination of both. We assessed cell proliferation and apoptosis using CCK-8, flow cytometry and Western blotting. We then established a SONFH rabbit model using high doses of methylprednisolone and lipopolysaccharide. The rabbits were randomly divided into four groups: control group, lovastatin group, GW9662 group and combination therapy group. We observed hip joint MRI before treatment, after 4 weeks of treatment, and 4 weeks after stopping treatment. We performed hematoxylin-eosin staining of the femoral head and analysed serum lipoprotein subfractions using VAP technology. In addition, we used quantitative polymerase chain reaction (qPCR) to analyse the expression of genes related to lipid metabolism at week 3. In vitro experiments showed that both GW9662 and lovastatin effectively inhibited hormone-induced apoptosis. In the animal studies, imaging and pathological results showed that the progression of SONFH was slower in the combination therapy group than in the other groups. VAP analysis showed that the lovastatin group had disturbed lipoprotein subfractions at the fourth week after stopping treatment, while the combination therapy group had more stable lipoprotein subfractions. PPARγ inhibitors significantly enhance the efficacy of statins in the treatment of SONFH by directly inhibiting apoptosis and indirectly modulating lipoprotein subfractions. These findings provide new insights into the clinical management of SONFH and suggest that combination therapy may be an effective strategy.

teroid-induced osteonecrosis of the femoral head (SONFH) is a severe bone disorder caused by long-term glucocorticoid administration and is characterized by osteoblast apoptosis. Oleuropein (OLP), a natural compound with anti-inflammatory and antioxidant properties, has demonstrated anti-apoptotic potential in bone-related diseases. However, its therapeutic role in SONFH has not yet been elucidated. This study aimed to investigate the therapeutic effects of OLP on SONFH and elucidate its underlying molecular mechanisms. In vitro, MC3T3-E1 osteoblasts treated with methylprednisolone (MPS) were co-incubated with OLP. Cell viability was assessed using a CCK-8 assay and live/dead cell staining. In vivo, a rat SONFH model was established with lipopolysaccharide and MPS, followed by OLP treatment. Bone microstructure was analyzed by micro-computed tomography and histopathological staining (H&E, Masson, Goldner). Network pharmacology and proteomics analyses were used to identify key targets and pathways related to the effects of OLP on SONFH. Apoptosis was examined with flow cytometry, TUNEL staining and ELISA. Protein and mRNA expression levels of relevant targets and pathways were examined with western blotting and quantitative real-time polymerase chain reaction. OLP significantly reversed MPS-induced osteoblast apoptosis and enhanced cell viability. In SONFH rats, OLP reduced empty lacunae, restored trabecular bone structure, and improved collagen organization. Molecular docking confirmed OLP’s binding to AKT and Bcl2. Network pharmacology and proteomics highlighted apoptosis regulation, PI3K-AKT signaling, and cell cycle control as key mechanisms. Furthermore, OLP activated the PI3K-AKT-Bcl2 pathway, increasing p-PI3K, p-AKT, and Bcl2 levels while decreasing Caspase3 and Caspase9. OLP also promoted osteogenesis (upregulated ALP and Runx2) and angiogenesis (increased vWF and CD31). OLP alleviates SONFH by inhibiting osteoblast apoptosis and promoting osteogenesis and angiogenesis through activation of the PI3K-AKT-Bcl2 pathway. These findings support OLP as a promising natural compound for early intervention in SONFH.

Background Steroid-induced osteonecrosis of the femoral head (SONFH) lacks effective early-stage interventions, and its systemic drivers remain incompletely defined. Luteolin (Lut) is reported to be protective, but the in vivo mechanism is unclear. We investigated whether Lut acts through a gut microbiota–metabolite–innate immunity axis in SONFH. Methods Male Sprague–Dawley rats underwent SONFH induction using lipopolysaccharide plus methylprednisolone and received oral Lut or L-Carnitine; gut microbiota dependence was examined using a four-antibiotic depletion regimen. Femoral heads were evaluated by histology and micro-computed tomography. Mechanisms were interrogated by integrated 16S rRNA profiling, untargeted serum Liquid Chromatography–Mass Spectrometry metabolomics, and femoral-head transcriptomics. Dexamethasone (Dex)-injuried ROS17/2.8 osteoblasts and HMEC-1 endothelial cells were used for functional validation, and IFIH1 was silenced by shRNA to test pathway necessity. Results Lut preserved trabecular microarchitecture and reduced empty osteocyte lacunae in vivo, yet minimally rescued Dex-injured osteoblasts and endothelial cells, indicating an indirect mechanism mediated by gut microbiota-derived metabolic changes. Microbiota depletion abolished Lut’s in vivo benefit, establishing microbiota dependence. Metabolomics identified an increase in circulating L-Carnitine that correlated with four bacterial genera. Exogenous L-Carnitine restored cell proliferation, reduced apoptosis, and improved endothelial tube formation, and in vivo improved trabecular indices while lowering inflammatory cytokines (IL-1β, IL-6, TNF-α). Integrated multi-omics highlighted an interferon-stimulated gene module (OAS1A, HERC6, IFIH1, IFI44), with IFIH1 most strongly associated with disease severity. L-Carnitine attenuated Dex-induced IFIH1 expression, and IFIH1 knockdown mimicked L-Carnitine and eliminated its additional anti-inflammatory effect. Conclusions Lut alleviates SONFH via gut microbiota-driven elevation of L-Carnitine, which constrains IFIH1 expression and inflammation to preserve femoral-head trabecular microarchitecture. Targeting the microbiota–L-Carnitine–IFIH1 axis may enable mechanism-based early intervention strategies for SONFH.

Autophagy may play an important role in the occurrence and development of glucocorticoid‐induced osteonecrosis of the femoral head (GC‐ONFH). Lithium is a classical autophagy regulator, and lithium can also activate osteogenic pathways, making it a highly promising therapeutic agent for GC‐ONFH. We aimed to evaluate the potential therapeutic effect of lithium on GC‐ONFH. For in vitro experiments, primary osteoblasts of rats were used for investigating the underlying mechanism of lithium's protective effect on GC‐induced autophagy levels and osteogenic activity dysfunction. For in vivo experiments, a rat model of GC‐ONFH was used for evaluating the therapeutic effect of oral lithium on GC‐ONFH and underlying mechanism. Findings demonstrated that GC over‐activated the autophagy of osteoblasts and reduced their osteogenic activity. Lithium reduced the over‐activated autophagy of GC‐treated osteoblasts through PI3K/AKT/mTOR signalling pathway and increased their osteogenic activity. Oral lithium reduced the osteonecrosis rates in a rat model of GC‐ONFH, and restrained the increased expression of autophagy related proteins in bone tissues through PI3K/AKT/mTOR signalling pathway. In conclusion, lithium can restrain over‐activated autophagy by activating PI3K/AKT/mTOR signalling pathway and up‐regulate the expression of genes for bone formation both in GC induced osteoblasts and in a rat model of GC‐ONFH. Lithium may be a promising therapeutic agent for GC‐ONFH. However, the role of autophagy in the pathogenesis of GC‐ONFH remains controversial. Studies are still needed to further explore the role of autophagy in the pathogenesis of GC‐ONFH, and the efficacy of lithium in the treatment of GC‐ONFH and its underlying mechanisms.

Steroid-induced osteonecrosis of the femoral head (SONFH) is a severe bone disease associated with long-term glucocorticoid use, characterized by impaired bone metabolism and vascular insufficiency. Bilobalide (BB), a natural sesquiterpene from Ginkgo biloba, exhibits anti-apoptotic, antioxidant, and pro-angiogenic properties, yet its role in SONFH remains unclear. We integrated network pharmacology and molecular docking to predict the targets and pathways of BB in SONFH. Key targets were validated using molecular docking software. For in vivo experiments, a rat SONFH model was established using methylprednisolone (MPS), and BB was administered orally. Micro-CT, H&E staining, TUNEL assay, and immunohistochemistry were employed to evaluate bone microstructure, apoptosis, and the expression of osteogenic and angiogenic markers. Immunofluorescence was used to assess HIF-1α expression in rat femoral head tissues. For in vitro experiments, MC3T3-E1 osteoblasts were treated with dexamethasone(DEX) and BB. Cell viability was detected using the CCK-8 assay, and the protein levels of the HIF-1α and ERK pathways were examined by Western blot. Network pharmacology identified 94 common targets between BB and SONFH, with enrichment in HIF-1 and ERK signaling pathways. Molecular docking confirmed strong binding affinities between BB and core targets. In MPS-induced rats, BB treatment significantly improved bone mineral density, trabecular microstructure, and reduced osteocyte apoptosis. BB also upregulated HIF-1α, Runx2, OCN, CD31, and VEGF expression, indicating enhanced osteogenesis and angiogenesis. In vitro, BB rescued dexamethasone-induced suppression of osteoblast viability and upregulated the ERK/HIF-1α pathway. Bilobalide attenuates SONFH progression by activating the ERK/HIF-1α signaling pathway, promoting osteogenesis and angiogenesis, and reducing osteocyte apoptosis. These findings highlight BB as a promising candidate for SONFH prevention and support the utility of network pharmacology in mechanistic natural product research.

Characteristic pathological changes in osteonecrosis of the femoral head (ONFH) include reduced osteogenic differentiation of bone mesenchymal stem cells (BMSCs), impaired osseous circulation and increased intramedullary adipocytes deposition. Osthole is a bioactive derivative from coumarin with a wide range of pharmacotherapeutic effects. The aim of this study was to unveil the potential protective role of osthole in alcohol‐induced ONFH. In vitro, ethanol (50 mmol/L) remarkably decreased the proliferation and osteogenic differentiation of BMSCs and impaired the proliferation and tube formation capacity of human umbilical vein endothelial cell (HUVECs), whereas it substantially promoted the adipogenic differentiation of BMSCs. However, osthole could reverse the effects of ethanol on osteogenesis via modulating Wnt/β‐catenin pathway, stimulate vasculogenesis and counteract adipogenesis. In vivo, the protective role of osthole was confirmed in the well‐constructed rat model of ethanol‐induced ONFH, demonstrated by a cascade of radiographical and pathological investigations including micro‐CT scanning, haematoxylin‐eosin staining, TdT‐mediated dUTP nick end labelling, immunohistochemical staining and fluorochrome labelling. Taken together, for the first time, osthole was demonstrated to rescue the ethanol‐induced ONFH via promoting bone formation, driving vascularization and retarding adipogenesis.

Glucocorticoid-induced osteonecrosis of the femoral head (SONFH) is the most prevalent form of secondary osteonecrosis affecting the femoral head. Glucocorticoids can cause damage to both vascular endothelial cells and osteoblasts. Previous studies have demonstrated that silicon can improve the resistance of vascular endothelial cells to oxidative stress and positively impact bone health. However, the impact of silicon on SONFH has yet to be investigated. We examined the influence of ortho-silicic acid (OSA, Si(OH)4) on the apoptosis and proliferation of vascular endothelial cells after glucocorticoid induction. Additionally, we evaluated the expression of apoptosis-related genes such as cleaved-caspase-3, Bcl-2 and Bax. The impact of glucocorticoids and OSA on the function of vascular endothelial cells was evaluated through wound healing, transwell and angiogenesis assays. Osteogenic function was subsequently evaluated through alizarin red staining, alkaline phosphatase staining and expression levels of osteogenic genes like RUNX2 and ALP. Moreover, we investigated the potential role of OSA in vivo using the SONFH animal model. At concentrations below 100 μM, OSA exhibits no toxicity on vascular endothelial cells and effectively reverses glucocorticoid-induced apoptosis in these cells. OSA increases the resilience of vascular endothelial cells against oxidative stress and enhances osteoblast differentiation. Our study revealed that glucocorticoids activate endoplasmic reticulum stress, a process that mediates the apoptosis of vascular endothelial cells. OSA ameliorated the endoplasmic reticulum stress associated with glucocorticoids through the increased expression of p-Akt levels. In vivo, OSA treatment effectively improved SONFH by enhancing vascular endothelial cell function and promoting osteogenic differentiation. OSA counteracted the adverse effects of glucocorticoids both in vitro and in vivo, demonstrating a beneficial therapeutic effect on SONFH.