Dexamethasone Induced Osteocyte Apoptosis in Steroid-Induced Femoral Head Osteonecrosis through ROS-Mediated Oxidative Stress.

OBJECTIVE: Glucocorticoid (GC) overuse is strongly associated with steroid-induced osteonecrosis of the femoral head (SINFH). However, the underlying mechanism of SINFH remains unclear. This study aims to investigate the effect of dexamethasone (Dex)-induced oxidative stress on osteocyte apoptosis and the underlying mechanisms. METHODS: Ten patients with SINFH and 10 patients with developmental dysplasia of the hips (DDH) were enrolled in our study. Sixty rats were randomly assigned to the Control, Dex, Dex + N-Acetyl-L-cysteine (NAC), Dex + Dibenziodolium chloride (DPI), NAC, and DPI groups. Magnetic resonance imaging (MRI) was used to examine edema in the femoral head of rats. Histopathological staining was performed to assess osteonecrosis. Immunofluorescence staining with TUNEL and 8-OHdG was conducted to evaluate osteocyte apoptosis and oxidative damage. Immunohistochemical staining was carried out to detect the expression of NOX1, NOX2, and NOX4. Viability and apoptosis of MLO-Y4 cells were measured using the CCK-8 assay and TUNEL staining. 8-OHdG staining was conducted to detect oxidative stress. 2',7'-Dichlorodihydrofluorescein diacetate (DCFH-DA) staining was performed to measure reactive oxygen species (ROS). The expression of NOX1, NOX2, and NOX4 in MLO-Y4 cells was analyzed by Western blotting. Multiple comparisons were performed using one-way analysis of variance (ANOVA). RESULTS: In patients and the rat model, hematoxylin-eosin (HE) staining revealed a significantly higher rate of empty lacunae in the SINFH group than in the DDH group. Immunofluorescence staining indicated a significant increase in TUNEL-positive cells and 8-OHdG-positive cells in the SINFH group compared to the DDH group. Immunohistochemical staining demonstrated a significant increase in the expression of NOX1, NOX2, and NOX4 proteins in SINFH patients compared to DDH patients. Moreover, immunohistochemical staining showed a significant increase in the proportion of NOX2-positive cells compared to the Control group in the femoral head of rats. In vitro, Dex significantly inhibited the viability of osteocyte cells and induced apoptosis. After Dex treatment, the intracellular ROS level increased. However, Dex treatment did not alter the expression of NOX proteins in vitro. Additionally, NAC and DPI inhibited the generation of intracellular ROS and partially alleviated osteocyte apoptosis in vivo and in vitro. CONCLUSION: This study demonstrates that GC promotes apoptosis of osteocyte cells through ROS-induced oxidative stress. Furthermore, we found that the increased expression of NOXs induced by GC serves as an important source of ROS generation.

Is there still an indication for the Birmingham Hip Resurfacing in femoral head osteonecrosis?

PURPOSE: Osteonecrosis of the femoral head (ONFH) is a progressive hip disease. Hip resurfacing arthroplasty (HRA) is a preferred surgical procedure among hip arthroplasty performed in young patients. The aim of this study is to show the long-term clinical and radiological results of HRA procedures performed for patients suffering from ONFH. METHODS: Forty-five patients who underwent hip resurfacing with the diagnosis of femoral head osteonecrosis were included in the study. The Harris Hip Score (HHS) was used for clinical scoring of the patients. The blood chromium, cobalt, white blood cell (WBC) count, and CRP levels of patients were checked. Ultrasonography (USG) was performed for all patients at mid-term control checked for pseudo-tumours. For the radiological evaluation, acetabular inclination, stem shaft angle, prothesis-to-neck ratio, osteolysis zones, and heterotopic ossification were used. RESULTS: The mean age of the patients was 46.6 ± 9.3 years, and the mean follow-up period was 11.83 ± 2.9 years. The mean HHS was 90.3 ± 12.8 for final follow-up. The mean WBC value was 8.2 109/L, mean CRP value was 6.3 mg/L, mean chromium value was 4.9 µg/L, and mean cobalt value was 1.8 µg/L. Inclination changing 0.2°(p = 0.788), stem shaft angle changing 0.7°(p = 0.424), and neck-to-prosthesis ratio changing 0.01°(p = 0.075). No pseudo-tumours were detected in any patients in USG examination. CONCLUSION: HRA provides long-term implant survival and excellent clinical outcomes for end-stage ONFH patients with low complication rates.

Comparative analysis of surgical interventions for osteonecrosis of the femoral head: a network meta-analysis of randomized controlled trials.

BACKGROUND: Despite several surgical options, there remains no consensus regarding the optimal approach for osteonecrosis of the femoral head (ONFH), a prevalent and refractory disease. To determine the most suitable treatment modality, we compared randomized controlled trials (RCTs) that evaluated multiple surgical treatments for ONFH using a Bayesian network meta-analysis (NMA). METHODS: The outcomes of 11 different surgical treatments were assessed using NMA comparisons of the rate of progression of femoral head necrosis, the rate of conversion to total hip arthroplasty, and improvement of the Harris hip score (HHS). A random effects model was used to analyze the odds ratio (OR) or mean difference, and risk of bias was assessed using the Cochrane risk of bias assessment tool for randomized trials. The confidence of the results was assessed using the confidence in network meta-analysis tool. RESULTS: A total of 18 RCTs were included in the meta-analysis. Compared with core decompression (CD), the forest plot showed that autologous bone grafting (ABG), free fibula grafting (FFG), vascularized bone grafting (VBG), autologous bone grafting combined with bone marrow aspirate concentrate (ABG + BMAC), and biomaterial grafting combined with vascularized bone grafting (BMG + VBG) delayed ONFH progression. Among them, ABG + BMAC showed the most promising results (OR 0.019; 95% confidence interval [CI] 0.0012-0.25). However, upon comparing CD with different surgical modalities, no significant differences were found in preventing total hip arthroplasty. Furthermore, we cannot draw conclusions regarding the HHS due to attribution and high heterogeneity across the studies. CONCLUSION: Overall, ABG, VBG, FFG, ABG + BMAC, and BMG + VBG showed significant results in preventing ONFH progression compared with that shown by CD. Based on the surface under the cumulative ranking, ABG + BMAC was the most effective. Moreover, all treatments involving bone grafting were found to be effective, possibly indicating the necessity of its use in the treatment of ONFH.

Femoral neck fracture after femoral head necrosis: a case report and review of the literature.

INTRODUCTION: Pathological fractures of the femoral neck caused by necrosis of the femoral head are extremely rare. Here, we report a rare case of bilateral femoral head osteonecrosis extending to the femoral neck, with bilateral pathological fractures of the femoral neck occurring within a short period of time. CASE REPORT: A 65-year-old male with a 25-year history of daily consumption of 750 ml of liquor, presented with right hip pain after labor for 1 month. He subsequently sustained a right femoral neck fracture without trauma and underwent a right total hip arthroplasty. Two months later, he suffered a non-traumatic left femoral neck fracture and underwent a left total hip arthroplasty. Histopathological examination revealed osteonecrosis of the femoral head and neck, along with the presence of osteoclasts and granulomatous inflammation. Bone mineral density testing also showed osteoporosis. The bilateral femoral neck fractures were ruled out to be caused by any other pathological factors. DISCUSSION: This is the first report of pathological fractures of the bilateral femoral neck caused by femoral head necrosis. During the literature review process, we found that this case conforms to the histological characteristics of rapidly destructive hip disease and analyzed the etiology of femoral head necrosis and the pathogenesis of femoral neck fractures.

Hip-Spine Syndrome: A Focus on the Pelvic Incidence in Hip Disorders.

Since Offierski and MacNab reported a close association between the hip and spine as hip-spine syndrome in 1983, many studies on spinal alignment in hip disorders have been conducted. Notably, the pelvic incidence angle (PI) is the most important parameter and is determined by the anatomical variations in the sacroiliac joint and hip. Studies on the association of the PI with hip disorders can help in understanding the pathophysiology of hip-spine syndrome. A PI increase has been observed during the evolution of bipedal locomotion in humans and in the acquisition of gait during child development. Although the PI is a fixed parameter that is stable and unaffected by posture from adulthood onwards, it has become clear that it increases in the standing position in older people. While it may be associated with a greater risk of developing or progressing to spinal disorders, the association between the PI and hip disorders remains controversial because of the multifactorial nature of hip osteoarthritis (HOA) and the wide range of PIs in HOA (18-96°), making the interpretation of results difficult. However, several hip disorders (i.e., femoroacetabular impingement and rapid destructive coxarthrosis) have been shown to be associated with the PI. Further investigation on this topic is, therefore, warranted.

Prognostic factors in the management of osteonecrosis of the femoral head: A systematic review.

BACKGROUND: Several hip preserving techniques have been described for the management of osteonecrosis of the femoral head (ONFH). This systematic review identified prognostic factors in the treatment of ONFH that are associated with treatment failure and conversion to total hip arthroplasty (THA). MATERIAL AND METHODS: This study followed the PRISMA guidelines. The literature search was conducted in November 2021. All clinical trials comparing two or more treatments for femoral head osteonecrosis were accessed. A multivariate analysis was performed to investigate the association between baseline characteristics and the surgical outcome. A multiple linear model regression analysis through the Pearson Product-Moment Correlation Coefficient (r) was used. RESULTS: Data from 88 articles (6112 procedures) were retrieved. Female gender was associated with increased time to THA (P = 0.03) and reduced rate of THA (P = 0.03). Longer symptom duration before treatment was associated with shorter time to failure (P = 0.03). Increased pre-treatment VAS was associated with reduced time to failure (P = 0.03) and time to THA (P = 0.04). Reduced pre-treatment hip function was associated with increased rate of THA (P = 0.02) and failure (P = 0.005). Patient age and BMI, aetiology, time from surgery to full weight bearing and the side did not show evidence of a statistically significant association with the surgical outcome. CONCLUSION: Male gender, longer symptom duration before treatment, higher VAS scores, and lower HHS scores were negative prognostic factors after treatment for osteonecrosis of the femoral head.

Complications of primary total hip arthroplasty in human immunodeficiency virus-positive patients with femoral head osteonecrosis.

BACKGROUND: Femoral head osteonecrosis (FHON) is a well-recognised complication in patients with human immunodeficiency virus (HIV) infection. Total hip arthroplasty (THA) is a reliable solution to FHON and has provided functional improvement and pain relief in these patients. Higher complication rates, in particular infections, have been reported in the series of THAs done in the HIV-positive patients. The purpose of this study was to evaluate the complication rate of THA for FHON in HIV-positive patients managed with the highly active antiretroviral therapy (HAART) protocols. METHODS: A retrospective review was performed of HIV-positive patients with FHON who underwent THAs over a 10-year period at a single institution. RESULTS: A total of 56 THAs (44 patients) met the inclusion criteria. The mean age at the time of THAs was 47 (range 34-60) years. Of the 44 patients, 39 (88.6%) were males. The mean follow-up was 6.6 (range 2.0-11.3) years. The overall complication rate was 12.5%, with 2 (3.6%) cases of deep periprosthetic infections. CONCLUSIONS: HIV-positive patients with FHON undergoing THAs do have a considerable complication rate (12.5%). The deep periprosthetic infection rate (3.6%) in these patients, however, has decreased with contemporary disease modification protocols.

Volume and location of bone regeneration after autologous expanded mesenchymal stromal cells in hip osteonecrosis : a pilot study.

AIMS: Successful cell therapy in hip osteonecrosis (ON) may help to avoid ON progression or total hip arthroplasty (THA), but the achieved bone regeneration is unclear. The aim of this study was to evaluate amount and location of bone regeneration obtained after surgical injection of expanded autologous mesenchymal stromal cells from the bone marrow (BM-hMSCs). METHODS: A total of 20 patients with small and medium-size symptomatic stage II femoral head ON treated with 140 million BM-hMSCs through percutaneous forage in the EudraCT 2012-002010-39 clinical trial were retrospectively evaluated through preoperative and postoperative (three and 12 months) MRI. Then, 3D reconstruction of the original lesion and the observed postoperative residual damage after bone regeneration were analyzed and compared per group based on treatment efficacy. RESULTS: The mean preoperative lesion volume was 18.7% (SD 10.2%) of the femoral head. This reduced to 11.6% (SD 7.5%) after three months (p = 0.015) and 3.7% (SD 3%) after one year (p < 0.001). Bone regeneration in healed cases represented a mean 81.2% (SD 13.8%) of the initial lesion volume at one year. Non-healed cases (n = 1 stage progression; n = 3 THAs) still showed bone regeneration but this did not effectively decrease the ON volume. A lesion size under mean 10% (SD 6%) of the femoral head at three months predicted no ON stage progression at one year. Regeneration in the lateral femoral head (C2 under Japanese Investigation Committee (JCI) classification) and in the central and posterior regions of the head was predominant in cases without ON progression. CONCLUSION: Bone regeneration was observed in osteonecrotic femoral heads three months after expanded autologous BM-hMSC injection, and the volume and location of regeneration indicated the success of the therapy.Cite this article: Bone Joint Res 2022;11(12):881-889.

Effects of angiotensin II combined with asparaginase and dexamethasone on the femoral head in mice: A model of steroid-induced femoral head osteonecrosis.

Background: To study the pathogenesis of steroid-induced femoral head osteonecrosis, an ideal animal model is very important. As experimental animals, mice are beneficial for studying the pathogenesis of disease. However, there are currently few mouse models of steroid-induced femoral head osteonecrosis, and there are many questions that require further exploration and research. Purposes: The purpose of this study was to establish a new model of osteonecrosis in mice using angiotensin II (Ang II) combined with asparaginase (ASP) and dexamethasone (DEX) and to study the effects of this drug combination on femoral head osteonecrosis in mice. Methods: Male BALB/c mice (n = 60) were randomly divided into three groups. Group A (normal control, NC) was treated with physiological saline and given a normal diet. Group B (DEX + ASP, DA) was given free access to food and water (containing 2 mg/L DEX) and subjected to intraperitoneal injection of ASP (1200 IU/kg twice/week for 8 weeks). Group C (DEX + ASP + Ang II, DAA) was treated the same as group B, it was also given free access to food and water (containing 2 mg/L DEX) and subjected to intraperitoneal injection of ASP (1200 IU/kg twice/week for 8 weeks), but in the 4th and 8th weeks, subcutaneous implantation of a capsule osmotic pump (0.28 mg/kg/day Ang II) was performed. The mice were sacrificed in the 4th and 8th weeks, and the model success rate, mouse mortality rate, body weight, blood lipids, coagulation factors, histopathology, and number of local vessels in the femoral head were evaluated. Results: DAA increased the model success rate [4th week, 30% (DA) vs. 40% (DAA) vs. 0% (NC); 8th week, 40% (DA) vs. 70% (DAA) vs. 0% (NC)]. There was no significant difference in mortality rate between the groups [4th week, 0% (DA) vs. 0% (DAA) vs. 0% (NC); 8th week, 5% (DA) vs. 10% (DAA) vs. 0% (NC)]. DAA affected mouse body weight and significantly affected blood lipids and blood coagulation factors. DAA reduces the number of blood vessels in the femoral head and destroys the local blood supply. Conclusion: Angiotensin II combined with asparaginase and dexamethasone can obviously promote the necrosis of femoral head and provide a new idea for the model and treatment of osteonecrosis.

Management of femoral head fracture by Ganz surgical dislocation of the hip.

INTRODUCTION: Posterior hip dislocation is the commonest type of hip dislocation. It is associated with femoral head fracture in 7% of cases. Urgent and congruent hip reduction is mandatory to improve clinical outcomes and avoid irreversible complications. The purpose of this study is to assess the safety and functional and radiological outcomes of surgical hip dislocation by Ganz technique for treatment of femoral head fracture. PATIENTS AND METHODS: In this retrospective study, 18 cases of femoral head fracture were included. Six cases had Pipkin type I and 12 had Pipkin type II fracture. They were treated through surgical hip dislocation. All cases were followed up for at least 24 months. Matta's criteria were used for radiological evaluation (plain radiographs). Functional evaluation was done using Harris Hip Score and modified Merle d'Aubigne and Postel score at final follow-up. RESULTS: No patients were lost during the follow-up period. No signs of infection or wound dehiscence were noted in this study. There was one case of osteonecrosis. All cases had labral injury, which was debrided. None of our cases needed suture anchor repair of the labrum. Radiographical evaluation according to Matta's criteria yielded anatomic fracture reduction in 17 patients but imperfect in 1 patient. According to Harris Hip Score, four Pipkin type I cases were rated as excellent and two as good. Among cases of Pipkin type II fracture, six were rated as excellent, four as good, one as fair, and one as poor. According to modified Merle d'Aubigne and Postel score, 11 cases had excellent results, 5 cases were rated as good, one as fair, while one case had poor results. CONCLUSION: Open reduction and internal fixation of femoral head fracture using surgical hip dislocation through Ganz approach is a viable treatment option and provides satisfactory results with low complication rate.

Postacute sequelae of SARS-CoV-2 infection. Osteonecrosis must not be overlooked.

Recovery from COVID-19 is not always uneventful, especially in critically ill hospitalized patients. Persistent symptoms including fatigue/ weakness, shortness of breath, anxiety, and depression have been described at one-year follow-up. Furthermore, symptoms from the musculoskeletal system like joint pain or stiffness are underreported in studies with long-term follow-up of up to one year. Infection with SARS-CoV-2 itself has been associated with endothelial damage, and together with high-dose corticosteroid treatment, it is predisposed to the dissemination of microthrombi and the development of femoral head osteonecrosis (FHOn), as it has been shown during the previous (2003-2004) coronavirus outbreaks. A resurgence of FHOn cases is anticipated but this is not reflected in the existing studies with long-term follow-up. Prompt diagnosis is critical for early treatment and possibly for the hip joint preservation. Patients with COVID-19 treated with corticosteroids should be screened for avascular necrosis early after discharge from the hospital. Every healthcare worker involved in the management of these patients should maintain a high level of suspicion and should be alert when patients report symptoms such as vague aches at the buttocks, hip area, adductors, and/or above the knee. Studies are needed to identify risk factors for FHOn including disease severity, type of steroid, cumulative dose, and duration of treatment.

Integrative analyses of genes related to femoral head osteonecrosis: an umbrella review of systematic reviews and meta-analyses of observational studies.

BACKGROUND: Femoral head osteonecrosis (FHON) is a worldwide challenging clinical topic. Steroid use is one of the main etiologies of FHON. There are several genetic variants associated with FHON. Therefore, the purpose of this umbrella review was to provide a comprehensive summary of a meta-analysis and systematic review of genetic variations associated with nonsteroidal and steroid-induced FHON. METHODS: The eligible studies were selected from the PubMed and MEDLINE databases for the collection of diverse systematic meta-analyses and reviews. The genetic main effect score was assigned using the Human Genome Epidemiology Network's Venice criteria to assess the cumulative evidence on the effects of a single nucleotide polymorphism (SNP) on FHON. RESULTS: Eight articles reported the meta-analysis of candidate SNP-based studies covering eight genes and 13 genetic variants. In the nonsteroid-induced FHON genetic variants including rs2012390 and rs11225394 in MMP8, rs1800629 and rs361525 in tumor necrosis factor (TNF)-α, VNTR in intron 4, rs1799983 and rs2070744 in endothelial nitric oxide synthase (eNOS), rs2010963 in vascular endothelial growth factor (VEGF), and rs6025 in factor V showed significance in each reference. The steroid-induced FHON genetic variants including rs693 and rs1042031 in apolipoprotein (Apo)B, rs1045642 in ABCB1, and rs1799889 in PAI-1 showed significance in each reference. CONCLUSION: Based on the systematic review conducted in this study, we organized the genomes associated with FHON and looked at each contribution. Our results could give an integrative approach for understanding the mechanism of FHON etiology. It is expected that these results could contribute to the strategy of prediagnosis, evaluating the individual risk of nonsteroid-induced and steroid-induced FHON. LEVEL OF EVIDENCE: Level I.

Hidden osteonecrosis of the femoral head after healed femoral neck fractures: magnetic resonance imaging study of 58 consecutive patients.

INTRODUCTION: Several studies investigated the posttraumatic osteonecrosis of the femoral head (ONFH) after femoral neck fracture (FNF). However, no study has investigated the hidden ONFH after FNF, which is missed by simple radiographs, using magnetic resonance imaging (MRI). MATERIALS AND METHODS: This retrospective study involved 58 consecutive patients who underwent implant removal surgery after internal fixation due to FNF. MRI was used to investigate the incidence of hidden ONFHs, which were not initially revealed on plain radiographs. The comparisons between hidden ONFH and other groups were performed for patent demographics and clinical variables including ONFH location, lesion size, the progression rate of ONFH collapse, and end-stage arthroplasty conversion rate. RESULTS: Of the 58 patients, 38 exhibited no evidence of ONFH on plain radiograph screening. However, 13 of the 38 patients were confirmed of hidden ONFH via MRI. The collapse progressed in four of the 13 patients, and one of them underwent total hip arthroplasty surgery. No significant differences were found between the hidden and definite ONFH groups in demographics and clinical variables. However, a significant difference exists between the hidden ONFH and the normally healed FNF groups in terms of the Garden type (P < 0.001). CONCLUSIONS: A large number of cases with hidden ONFH were confirmed using MRI following healed FNF, and most of them were initially displaced FNF. Thus, the treatment method between internal fixation and hip arthroplasty should be carefully selected, particularly with displaced FNF.

Combination of hyperbaric oxygen and core decompression therapies improve outcomes in the treatment of hip osteonecrosis.

INTRODUCTION: To investigate whether combined treatment of hyperbaric oxygen (HBO) and core decompression (CD) result with better outcomes and have an additional influence on health quality scores when compared with HBO alone. METHODS: 63 consecutive patients' 80 hips (43 male, 20 female, 17 bilateral), diagnosed with Stage II Osteonecrosis of the femoral head were included in our study. The mean age at presentation in the HBO and CD + HBO groups were 39.9 years and 39.2 years, respectively. The mean follow-up was 39.8 months (24-56 months) for HBO group and 43.1 months (24-58 months) for the CD + HBO group. Standard radiographs and MRI were performed initially and during controls. Clinical outcomes were assessed using the modified Harris Hip Score (HHS), the visual analogue score (VAS) and SF-36 life quality score. RESULTS: 52 hips (65%) were Ficat Stage IIa and 28 hips (35%) were IIb. Totally, 46 hips (30 hips IIa, 16 hips IIb) were in HBO alone group and 34 hips (22 hips IIa, 12 hips IIb) were in CD + HBO group. Both VAS and HHSs were improved in each group after treatment (p < 0.001). When both groups were compared, this improvement was more distinct and evident in CD + HBO combination group than HBO alone group (p < 0.001). The physical function and pain components of SF-36 survey were found to be different in between two groups (p < 0.005). DISCUSSION: HBO treatment decreases pain, increases functional scores for Ficat Stage II patients. Addition of HBO treatment to decompression of the femoral head improves the results better than HBO alone. In particular, reduction of pain is more prevalent for Stage IIa patients than IIb with combination of HBO and CD therapies.

Damage associated molecular patterns in necrotic femoral head inhibit osteogenesis and promote fibrogenesis of mesenchymal stem cells.

In Legg-Calvé-Perthes disease (LCPD), a loss of blood supply to the juvenile femoral head leads to extensive cell death and release of damage-associated molecular patterns (DAMPs). Over time chronic inflammatory repair process is observed with impaired bone regeneration. Increased fibrous tissue and adipose tissue are seen in the marrow space with decreased osteogenesis in a piglet model of LCPD, suggesting inhibition of osteoblastic differentiation and stimulation of fibroblastic and adipogenic differentiation of mesenchymal stem cell (MSC) during the healing process. Little is known about the DAMPs present in the necrotic femoral head and their effects on MSC differentiation. The purpose of this study was to characterize the DAMPs present in the femoral head following ischemic osteonecrosis and to determine their effects on MSC differentiation. Necrotic femoral heads were flushed with saline at 48 h, 2 weeks and 4 weeks following the induction of ischemic osteonecrosis in piglets to obtain necrotic bone fluid (NBF). Western blot analysis of the NBF revealed the presence of prototypic DAMP, high mobility group box 1 (HMGB1), and other previously described DAMPs: biglycan, 4-hydroxynonenal (4-HNE), and receptor activator of NF-κB ligand (RANKL). ELISA of the NBF revealed increasing levels of inflammatory cytokines IL1ß, IL6 and TNFα with the temporal progression of osteonecrosis. To determine the effects of NBF on MSC differentiation, we cultured primary porcine MSCs with NBF obtained by in vivo necrotic bone flushing method. NBF inhibited osteoblastic differentiation of MSCs with significantly decreased OSX expression (p = 0.008) and Von Kossa/Alizarin Red staining for mineralization. NBF also significantly increased the expression of proliferation markers Ki67 (p = 0.03) and PCNA (p < 0.0001), and fibrogenic markers Vimentin (p = 0.02) and Fibronectin (p = 0.04). Additionally, NBF treated MSC cells showed significantly elevated RANKL/OPG secretion ratio (p = 0.003) and increased expression of inflammatory cytokines IL1ß (p = 0.006) and IL6 (p < 0.0001). To specifically assess the role of DAMPs in promoting the fibrogenesis, we treated porcine fibroblasts with artificial NBF produced by bone freeze-thaw method. We found increased fibroblastic cell proliferation in an NBF dose-dependent manner. Lastly, we studied the effect of HMGB1, a prototypic DAMP, and found that HMGB1 partially contributes to MSC proliferation and fibrogenesis. In summary, our findings show that DAMPs and the inflammatory cytokines present in the necrotic femoral head inhibit osteogenesis and promote fibrogenesis of MSCs, potentially contributing to impaired bone regeneration following ischemic osteonecrosis as observed in LCPD.

Simultaneous primary bilateral hip resection arthroplasty.

Hip resection arthroplasty is a useful procedure for the management of complex hip problems and in patients with high surgical and anesthetic risk factors. Unilateral procedures performed for failed total hip arthroplasty have been shown to be successful for pain relief with acceptable functional outcomes; however, to our knowledge, no research exists on simultaneous bilateral hip resection arthroplasty for femoral head osteonecrosis. We present two cases of single-stage bilateral hip resection arthroplasty performed under singular anesthetic procedures for femoral head osteonecrosis. The patients were each able to stand for transfers postoperatively and had no deterioration in pain or function. These two cases demonstrate that satisfactory pain control with preservation of function may be achievable with bilateral hip resection arthroplasty procedures in patients who are not a candidate for more advanced reconstructive procedures.

Delayed surgical diagnosis and treatment of severe sickle cell arthropathy: The need to raise clinicians' awareness.

OBJECTIVES: Sickle cell disease (SCD) is associated with femoral head osteonecrosis and is treated with hip arthroplasty 18 weeks after presentation. However, there is inadequate data regarding the timing of surgical management of severe hip arthropathy. This study explores the problem of delayed diagnosis and surgical management of severe SCD hip arthropathy by comparing the clinical outcomes of patients from Nigeria, Canada and Britain. METHODS: This is a prospective clinical audit of the routine care of 30 adult SCD patients who underwent hip arthroplasty for femoral head osteonecrosis. The clinical data are collected from five medical centers in Britain, Canada and Nigeria and compared. RESULTS: Hip arthroplasty was delayed beyond 18 weeks in 3 of 14 Nigerian patients (21%), 7 of 10 British patients (70%) and all 6 Canadian patients (100%). The majority of Nigerian patients (79%) and only 30% of British patients had diagnostic imaging and surgical management without delay. CONCLUSION: Inadequate physician awareness and delayed surgical management of SCD hip arthropathy can be mitigated by improving the education of physicians who manage patients with SCD. It is essential to recruit, train and support physicians with an interest in SCD. As this primarily affects young patients, it is necessary to set an international standard for the timing of surgical management of SCD hip arthropathy.

Bilateral femoral head osteonecrosis in a patient with metastatic breast cancer receiving long-term zoledronic acid treatment: A case report.

Bone-modifying agents (BMAs), including bisphosphonate and anti-receptor activator of NF-κB ligand (RANKL) antibodies, are effective in treating bone metastases. The present study is a case report on the efficacy and side effects of long-term treatment with zoledronic acid, a BMA, in a 57-year-old woman. The patient was diagnosed with concurrent stage IV triple-negative breast cancer and stage II colon cancer. The patient experienced complete remission of both these cancers following chemotherapy, zoledronic acid treatment and irradiation for breast cancer and surgery for colon cancer. The patient received long-term zoledronic acid treatment and has survived >7 years after her initial diagnosis. The patient subsequently reported bilateral hip pain that was diagnosed as osteonecrosis of the femoral head, after the presence of bone metastases was ruled out using magnetic resonance imaging. The patient underwent bilateral artificial hip joint replacements. After orthopedic surgery, the multiple distant metastases, including a brain metastasis, remained in complete remission. It is well established that BMAs, such as zoledronic acid, increase the risk of osteonecrosis of the jaw, but it is not well understood if they can increase this risk in other anatomical locations. The findings of the present case study suggested that while long-term use of BMAs may be effective in managing bone metastases, it may increase the risk of osteonecrosis in anatomical locations other than the jaw.

Failure and progression to total hip arthroplasty among the treatments for femoral head osteonecrosis: a Bayesian network meta-analysis.

INTRODUCTION: Osteonecrosis of the femoral head (ONFH) often leads to secondary osteoarthritis and total hip arthroplasty. SOURCE OF DATA: Recent published literatures. AREAS OF AGREEMENT: There has been increasing focus on the early intervention in ONFH patients to preserve the native hip articulation, reduce pain and improve function. AREAS OF CONTROVERSY: Efficacy of surgical strategies for ONFH is debated. Several clinical studies showed controversial results, and the best treatment has not yet been clarified. GROWING POINTS: To provide an overview over current treatment options for ONFH compares their failure rates and conversion to total hip arthroplasty (THA) rates. AREAS TIMELY FOR DEVELOPING RESEARCH: Core decompression (CD) augmented with autologous bone grafting plus the implantation of bone marrow concentrate can decrease the rate of failure and progression to THA rates compared to CD alone.

Osteonecrosis of the Femoral Head Safely Healed with Autologous, Expanded, Bone Marrow-Derived Mesenchymal Stromal Cells in a Multicentric Trial with Minimum 5 Years Follow-Up.

Background: Osteonecrosis (ON) of the femoral head represents a potentially severe disease of the hip where the lack of bone regeneration may lead to femoral head collapse and secondary osteoarthritis, with serious pain and disability. The aim of this European, multicentric clinical trial was to prove safety and early efficacy to heal early femoral head ON in patients through minimally invasive surgical implantation of autologous mesenchymal stromal cells (MSC) expanded from bone marrow (BM) under good manufacturing practices (GMP). Methods: Twenty-two patients with femoral head ON (up to ARCO 2C) were recruited and surgically treated in France, Germany, Italy and Spain with BM-derived, expanded autologous MSC (total dose 140 million MSC in 7 mL). The investigational advanced therapy medicinal product (ATMP) was expanded from BM under the same protocol in all four countries and approved by each National Competent Authority. Patients were followed during two years for safety, based on adverse events, and for efficacy, based on clinical assessment (pain and hip score) and imaging (X-rays and MRIs). Patients were also reviewed after 5 to 6 years at latest follow-up for final outcome. Results: No severe adverse event was recalled as related to the ATMP. At 12 months, 16/20 per protocol and 16/22 under intention-to-treat (2 drop-out at 3 and 5 months) maintained head sphericity and showed bone regeneration. Of the 4 hips with ON progression, 3 required total hip replacement (THR). At 5 years, one patient (healed at 2 years visit) was not located, and 16/21 showed no progression or THR, 4/21 had received THR (all in the first year) and 1 had progressed one stage without THR. Conclusions: Expanded MSCs implantation was safe. Early efficacy was confirmed in 80% of cases under protocol at 2 years. At 5 years, the overall results were maintained and 19% converted to THR, all in the first year.