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Summary Based on this double-blind, placebo-controlled study, ibandronate has no beneficial effect on clinical and radiological outcome in patients with spontaneous osteonecrosis of the knee over and above anti-inflammatory medication. Introduction Observational studies suggest beneficial effects of bisphosphonates in spontaneous osteonecrosis (ON) of the knee. We investigated whether ibandronate would improve clinical and radiological outcome in newly diagnosed ON. Methods In this randomized, double-blind, placebo-controlled trial, 30 patients (mean age, 57.3 ± 10.7 years) with ON of the knee were assigned to receive either ibandronate (cumulative dose, 13.5 mg) or placebo intravenously (divided into five doses 12 weeks). All subjects received additional treatment with oral diclofenac (70 mg) and supplementation with calcium carbonate (500 mg) and vitamin D (400 IU) to be taken daily for 12 weeks. Patients were followed for 48 weeks. The primary outcome was the change in pain score after 12 weeks. Secondary endpoints included changes in pain score, mobility, and radiological outcome (MRI) after 48 weeks. Results At baseline, both treatment groups (IBN, n  = 14; placebo, n  = 16) were comparable in relation to pain score and radiological grading (bone marrow edema, ON). After 12 weeks, mean pain score was reduced in both ibandronate- (mean change, −2.98; 95 % CI, −4.34 to −1.62) and placebo- (−3.59; 95 % CI, −5.07 to −2.12) treated subjects (between-group comparison adjusted for age, sex, and osteonecrosis type, p  = ns). Except for significant decrease in bone resorption marker (CTX) in ibandronate-treated subjects ( p  < 0.01), adjusted mean changes in all functional and radiological outcome measures were comparable between treatment groups after 24 and 48 weeks. Conclusions In patients with spontaneous osteonecrosis of the knee, bisphosphonate treatment (i.e., IV ibandronate) has no beneficial effect over and above anti-inflammatory medication.

Background: Medication-related osteonecrosis of the jaw (MRONJ) is an adverse condition in patients receiving antiresorptive or antiangiogenic therapies. Standard treatments, including surgical debridement, often yield suboptimal outcomes. In this context, bone morphogenetic proteins (BMPs), have been explored for their ability to stimulate osteogenesis and enhance bone repair. Materials and methods: A systematic review of the literature was conducted, focusing on studies that applied rh-BMPs during surgeries to treat MRONJ. Databases were searched for relevant articles from inception to the present, using keywords such as \"MRONJ; 'BMP', and 'bone regeneration' Inclusion criteria involved studies with human participants who had been treated with rh-BMPs, along with the surgical elimination of bone sequestrum, MRONJ stages 2 and 3 according to the AAOMS staging system and a minimum follow-up period of 6 months. Two independent reviewers (L.H.C. and C.C.V.) systematically selected the articles independently. Results: The review included nine studies with a total of 217 patients treated with rh-BMP. Bone regeneration and osteonecrosis healing was reported in all the studies included using rh-BMP. However, the measurement methods were very different between the studies, using clinical examinations, different radiological tests and biomarkers and own scales. Moreover, there were inconsistencies in treatment protocols and follow-up periods, making it difficult to standardize conclusions. Discussion: While rh-BMPs show promising results for bone regeneration in MRONJ patients, the variability in study methodologies limits definitive conclusions. The biological potential of BMPs could be beneficial, but standardized protocols and longer-term studies are needed to establish their effectiveness. Conclusions: The application of rh-BMPs may promote bone regeneration in MRONJ patients, but further research with standardized methods is required to confirm these findings.

Osteonecrosis (ON), a significant complication following treatment of acute lymphoblastic leukemia (ALL), has a profound impact on quality of life of ALL survivors. We studied incidence and outcome of ON in patients treated on or according to Australian and New Zealand Children's Haematology/ Oncology Group (ANZCHOG) study 8 at The Children's Hospital at Westmead. The study involved retrospective chart review of the patients. ON was defined by development of symptoms and confirmed by magnetic resonance imaging. From 2002–2011, 251 patients (143M, 108F, 59 Standard Risk (SR), 159 Medium Risk (MR) 5 High Risk (HR), and 28 Very high risk (VHR)) were treated according to study 8. Eighteen (7M, 11F, 2 SR, 12 MR, 4 VHR) patients developed ON (7.2%). Median age at diagnosis was 13.05 years(4.3–16.7). Incidence of ON in patients > 10 years at diagnosis was 29%. Six out of 18 patients developed ON after allogeneic stem cell transplantation. Median time from diagnosis to the development of ON following chemotherapy for ALL was 1.15 years (range 0.25–2.12). Most patients were treated with intravenous Zoledronic acid. At last follow‐up, three patients had undergone arthroplasty, two patients were symptom free, and the remaining 13 patients reported persistent pain with activity. A majority of patients with ON of the hips had radiological progression. Overall, 7% of patients with ALL developed ON. Age >10 years was the most important risk factor. At last follow‐up, 70% of patients had persistent symptoms. Although Zoledronic acid improved pain, most patients with ON of the hips had radiological progression. Osteonecrosis is a severe complication of treatment for acute lymphoblastic leukemia , especially in patient older than 10 years at diagnosis. Treatment with Zoledronic acid improves pain, but most patients with hip joint involvement have radiological progression despite this treatment.

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.

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.

Awareness of the need for prevention of glucocorticoid-induced fractures is growing, but glucocorticoid administration is often overlooked as the most common cause of nontraumatic osteonecrosis. Glucocorticoid-induced osteonecrosis develops in 9–40% of patients receiving long-term therapy although it may also occur with short-term exposure to high doses, after intra-articular injection, and without glucocorticoid-induced osteoporosis. The name, osteonecrosis, is misleading because the primary histopathological lesion is osteocyte apoptosis. Apoptotic osteocytes persist because they are anatomically unavailable for phagocytosis and, with glucocorticoid excess, decreased bone remodeling retards their replacement. Glucocorticoid-induced osteocyte apoptosis, a cumulative and unrepairable defect, uniquely disrupts the mechanosensory function of the osteocyte–lacunar–canalicular system and thus starts the inexorable sequence of events leading to collapse of the femoral head. Current evidence indicates that bisphosphonates may rapidly reduce pain, increase ambulation, and delay joint collapse in patients with osteonecrosis.

Dyslipidaemia has been implicated in osteonecrosis through some clinical studies. However, a direct causal relationship between hyperlipidaemia and osteonecrosis remains unconfirmed, and whether lipid‐lowering agents could be used to treat osteonecrosis remains unclear. This study aimed to investigate the causal role of lipid traits in osteonecrosis using Mendelian randomisation (MR) analysis, assess the potential effects and mechanisms of lipid‐lowering drug targets on osteonecrosis risk and validate these findings through experimental approaches. Genome‐wide association study (GWAS) data were used to analyse lipid traits, drug targets and FinnGen osteonecrosis. Statin effects were further studied in a rat model of steroid‐induced osteonecrosis and in vitro cell models. MR analysis revealed a significant association between LDL‐C and increased osteonecrosis risk. Genetic mimicry of HMGCR inhibitors was associated with reduced osteonecrosis risk, which was validated through colocalisation. Stem cell growth factor‐β (SCGF‐β) was identified as a mediator of 21.3% of HMGCR inhibitors' effect on osteonecrosis risk. Further studies confirmed simvastatin's alleviating effect on SONFH, suggesting that simvastatin promotes osteogenesis and inhibits adipogenesis of mesenchymal stem cells (MSCs), partly mediated by SCGF‐β upregulation, which activates the Wnt signalling pathway. Our findings supported dyslipidaemia as a causal factor for osteonecrosis, highlighting HMGCR as a promising therapeutic target.

SummaryWe studied the effectiveness of teriparatide (TPTD) for treating medication-related osteonecrosis of the jaw (MRONJ) in patients with osteoporosis and examined differences in the clinical outcomes following daily versus weekly TPTD. The outcomes were significantly improved in the entire patient series and the daily group.PurposeTeriparatide (TPTD) treatment for Stage II–III medication-related osteonecrosis of the jaw (MRONJ) in osteoporotic patients has yielded promising results in uncontrolled studies. The daily administration and the weekly administration of TPTD have been reported to improve outcomes in MRONJ. Herein, we sought to identify differences in the clinical outcomes of MRONJ patients treated with daily TPTD versus weekly TPTD.MethodsWe enrolled 13 patients and randomly assigned them to receive either of two treatments: 1×/week 56.5-μg TPTD injection for 6 months (weekly group; n = 6 patients after 1 dropout), or 20-μg TPTD injection daily for 6 months (daily group; n = 6 patients). Patients in both groups received conventional therapy plus intensive antibiotic therapy as necessary. We compared the changes in the patients’ clinical stage of MRONJ, bone metabolism, percentage of bone formation, and bone turnover markers between the weekly and daily groups.ResultsTPTD treatment with MRONJ led to partial remission or complete remission in 5 daily-group patients and 3 weekly-group patients. The MRONJ stage was significantly improved from baseline to 6 months of treatment in the entire series of 12 patients (p = 0.008); the weekly group did not show significant improvement, but the daily group did (p = 0.01).ConclusionsThis study provides the first comparison of clinical outcomes between MRONJ patients who received daily or weekly TPTD injections. Six months of treatment with TPTD realized a significant improvement of MRONJ stage in both the entire patient series and the daily group.

Aseptic loosening caused by wear particles is a common complication after total hip arthroplasty. We investigated the effect of the quercetin on wear particle‐mediated macrophage polarization, inflammatory response and osteolysis. In vitro, we verified that Ti particles promoted the differentiation of RAW264.7 cells into M1 macrophages through p‐38α/β signalling pathway by using flow cytometry, immunofluorescence assay and small interfering p‐38α/β RNA. We used enzyme‐linked immunosorbent assays to confirm that the protein expression of M1 macrophages increased in the presence of Ti particles and that these pro‐inflammatory factors further regulated the imbalance of OPG/RANKL and promoted the differentiation of osteoclasts. However, this could be suppressed, and the protein expression of M2 macrophages was increased by the presence of the quercetin. In vivo, we revealed similar results in the mouse skull by μ‐CT, H&E staining, immunohistochemistry and immunofluorescence assay. We obtained samples from patients with osteolytic tissue. Immunofluorescence analysis indicated that most of the macrophages surrounding the wear particles were M1 macrophages and that pro‐inflammatory factors were released. Titanium particle‐mediated M1 macrophage polarization, which caused the release of pro‐inflammatory factors through the p‐38α/β signalling pathway, regulated OPG/RANKL balance. Macrophage polarization is expected to become a new clinical drug therapeutic target.

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.