Corticosteroid-associated Osteonecrosis Research Articles

Corticosteroid-associated osteonecrosis of the femoral head in young adolescents post-COVID 19 era - Two case reports

Corticosteroid-associated osteonecrosis of the femoral head in young adolescents post-COVID 19 era - Two case reports

Corticosteroid-associated osteonecrosis of the femoral head in an 87-year-old patient following treatment for COVID-19-associated pneumonia: A case report.

Coronavirus disease 2019 is known to cause severe acute respiratory syndrome, and serious cases need to be treated with corticosteroids. Herein, we report an 87-year-old woman who developed bilateral osteonecrosis of the femoral head after corticosteroid treatment for coronavirus disease 2019-related pneumonia. Sixteen months after treatment, she developed right hip pain without any evidence of trauma. A diagnosis of bilateral osteonecrosis of the femoral head was made based on sclerotic bands on plain radiographs and low-signal bands on T1-weighted magnetic resonance images. The patient underwent right total hip arthroplasty 4months after symptom onset. Histological examination of the resected femoral head revealed pathological evidence of osteonecrosis. The postoperative course was good, and the patient can now walk unassisted. To the best of our knowledge, this is the first report of histologically proven osteonecrosis after corticosteroid therapy for coronavirus disease 2019-related disease.

Etiology and Pathogenesis of Corticosteroid-Associated Osteonecrosis of the Femoral Head

Osteonecrosis of the femoral head (ONFH) is an intractable disease occurring at a relatively young age. The characteristic finding of ONFH – the femoral head collapse with severe hip pain – is observed in many cases, which frequently leads to further joint destruction, requiring surgical treatment. Among the associated factors of ONFH, majority of patients who require high-dose corticosteroid are still challenging due to inevitable therapeutic option regardless of poor prognosis. As a pathological mechanism, ONFH is defined as tissue necrosis in the femoral head region due to occlusion of the nutrient vessels; but the detailed micro-level processes leading to blood flow failure remains unclear. The elucidation of ONFH and the establishment of preventive therapy is desirable for these patients. Here, we discuss the etiology and pathogenesis of corticosteroid-associated ONFH by reviewing current literature.

The efficacy of lapine preconditioned or genetically modified IL4 over-expressing bone marrow-derived mesenchymal stromal cells in corticosteroid-associated osteonecrosis of the femoral head in rabbits

Cell-based therapy for augmentation of core decompression (CD) using mesenchymal stromal cells (MSCs) is a promising treatment for early stage osteonecrosis of the femoral head (ONFH). Recently, the therapeutic potential for immunomodulation of osteogenesis using preconditioned (with pro-inflammatory cytokines) MSCs (pMSCs), or by the timely resolution of inflammation using MSCs that over-express anti-inflammatory cytokines has been described. Here, pMSCs exposed to tumor necrosis factor-alpha and lipopolysaccharide for 3 days accelerated osteogenic differentiation in vitro. Furthermore, injection of pMSCs encapsulated with injectable hydrogels into the bone tunnel facilitated angiogenesis and osteogenesis in the femoral head in vivo, using rabbit bone marrow-derived MSCs and a model of corticosteroid-associated ONFH in rabbits. In contrast, in vitro and in vivo studies demonstrated that genetically-modified MSCs that over-express IL4 (IL4-MSCs), established by using a lentiviral vector carrying the rabbit IL4 gene under the cytomegalovirus promoter, accelerated proliferation of MSCs and decreased the percentage of empty lacunae in the femoral head. Therefore, adjunctive cell-based therapy of CD using pMSCs and IL4-MSCs may hold promise to heal osteonecrotic lesions in the early stage ONFH. These interventions must be applied in a temporally sensitive fashion, without interfering with the mandatory acute inflammatory phase of bone healing.

Effect of porosity of a functionally-graded scaffold for the treatment of corticosteroid-associated osteonecrosis of the femoral head in rabbits.

Background/Objective: Core decompression (CD) with scaffold and cell-based therapies is a promising strategy for providing both mechanical support and regeneration of the osteonecrotic area for early stage osteonecrosis of the femoral head (ONFH). We designed a new 3D printed porous functionally-graded scaffold (FGS) with a central channel to facilitate delivery of transplanted cells in a hydrogel to the osteonecrotic area. However, the optimal porous structural design for the FGS for the engineering of bone in ONFH has not been elucidated. The aim of this study was to fabricate and evaluate two different porous structures (30% or 60% porosity) of the FGSs in corticosteroid-associated ONFH in rabbits.MethodsTwo different FGSs with 30% or 60% porosity containing a 1-mm central channel were 3D printed using polycaprolactone and β-tricalcium phosphate. The FGS was 3-mm diameter and 32-mm length and was composed of three segments: 1-mm in length for the non-porous proximal segment, 22-mm in length for the porous (30% versus 60%) middle segment, and 9-mm in length for the 15% porous distal segment. Eighteen male New Zealand White rabbits were given a single dose of 20 ​mg/kg methylprednisolone acetate intramuscularly. Four weeks later, rabbits were divided into three groups: the CD group, the 30% porosity FGS group, and the 60% porosity FGS group. In the CD group, a 3-mm diameter drill hole was created into the left femoral head. In the FGS groups, a 30% or 60% porosity implant was inserted into the bone tunnel. Eight weeks postoperatively, femurs were harvested and microCT, mechanical, and histological analyses were performed.ResultsThe actual porosity and pore size of the middle segments were 26.4% ​± ​2.3% and 699 ​± ​56 ​μm in the 30% porosity FGS, and 56.0% ​± ​4.5% and 999 ​± ​71 ​μm in the 60% porosity FGS, respectively using microCT analysis. Bone ingrowth ratio in the 30% porosity FGS group was 73.9% ​± ​15.8%, which was significantly higher than 39.5% ​± ​13.0% in the CD group on microCT (p ​< ​0.05). Bone ingrowth ratio in the 60% porosity FGS group (61.3% ​± ​30.1%) showed no significant differences compared to the other two groups. The stiffness at the bone tunnel site in the 30% porosity FGS group was 582.4 ​± ​192.3 ​N/mm3, which was significantly higher than 338.7 ​± ​164.6 ​N/mm3 in the 60% porosity FGS group during push-out testing (p ​< ​0.05). Hematoxylin and eosin staining exhibited thick and mature trabecular bone around the porous FGS in the 30% porosity FGS group, whereas thinner, more immature trabecular bone was seen around the porous FGS in the 60% porosity FGS group.ConclusionThese findings indicate that the 30% porosity FGS may enhance bone regeneration and have superior biomechanical properties in the bone tunnel after CD in ONFH, compared to the 60% porosity FGS.Translation potential statementThe translational potential of this article: This FGS implant holds promise for improving outcomes of CD for early stage ONFH.

Adverse Effects of Oxidative Stress on Bone and Vasculature in Corticosteroid-Associated Osteonecrosis: Potential Role of Nuclear Factor Erythroid 2-Related Factor 2 in Cytoprotection.

Significance: Osteonecrosis (ON) is characterized by bone tissue death due to disturbance of the nutrient artery. The detailed process leading to the necrotic changes has not been fully elucidated. Clinically, high-dose corticosteroid therapy is one of the main culprits behind osteonecrosis of the femoral head (ONFH). Recent Advances: Numerous studies have proposed that such ischemia concerns various intravascular mechanisms. Of all reported risk factors, the involvement of oxidative stress in the irreversible damage suffered by bone-related and vascular endothelial cells during ischemia simply cannot be overlooked. Several articles also have sought to elucidate oxidative stress in relation to ON using animal models or in vitro cell cultures. Critical Issues: However, as far as we know, antioxidant monotherapy has still not succeeded in preventing ONFH in humans. To provide this desideratum, we herein summarize the current knowledge about the influence of oxidative stress on ON, together with data about the preventive effects of administering antioxidants in corticosteroid-induced ON animal models. Moreover, oxidative stress is counteracted by nuclear factor erythroid 2-related factor 2 (Nrf2)-dependent cytoprotective network through regulating antioxidant expressions. Therefore, we also describe Nrf2 regulation and highlight its role in the pathology of ON. Future Directions: This is a review of all available literature to date aimed at developing a deeper understanding of the pathological mechanism behind ON from the perspective of oxidative stress. It may be hoped that this synthesis will spark the development of a prophylactic strategy to benefit corticosteroid-associated ONFH patients. Antioxid. Redox Signal. 35, 357-376.

Corticosteroid-associated osteonecrosis of the femoral head after orthotopic liver transplantation and the outcomes of subsequent total hip arthroplasty

BackgroundCorticosteroids are essential for immunosuppression after orthotopic liver transplantation (OLT), but also have many side effects. Osteonecrosis of the femoral head (ONFH) is one of the most serious complications requiring prostheses. However, few studies have investigated ONFH after OLT. The purpose of this study is to survey the incidence of corticosteroid-induced ONFH after OLT and the outcomes of total hip arthroplasty (THA). MethodsBetween January 2001 and December 2010, a series of 926 patients underwent OLT at our Hospital. A retrospective analysis was performed on a total of 738 patients who survived at least 2 years after OLT. The incidence of symptomatic ONFH, the interval from OLT to the initial diagnosis of ONFH, and the cumulative dose of corticosteroids were analyzed. The side effects related to OLT, such as other osteonecrosis lesions, osteoporotic fractures, and infection, were monitored. For patients who underwent THA, radiological findings and Japanese Orthopaedic Association (JOA) scores were evaluated. ResultsONFH occurred in 10 patients (13 hips) (6 men [7 hips], 4 women [6 hips]), with an incidence of 1.36%. The average age at OLT was 51.4 years (range, 31–61 years). The average interval from OLT to ONFH was 86.7 months (range, 22–155 months). The average cumulative dose of corticosteroids was 7274 mg (range, 1342–29,514 mg). Twenty patients suffered from side effects related to OLT. Seven patients (8 hips) underwent THA. No adverse events including infection arose during the perioperative process. One hip dislocated, and one femoral stem displayed a radiolucent line. The average JOA score improved from 45.4 (range, 25–76) preoperatively to 86.9 (range, 73–99) at final follow-up. No patients required revision surgery. ConclusionsThe incidence of symptomatic ONFH after OLT was 1.36%. Once the graft function becomes stable, THA can be a safe and effective treatment option for patients with ONFH after OLT.

Concentrated autologous bone marrow aspirate transplantation versus conservative treatment for corticosteroid-associated osteonecrosis of the femoral head in systemic lupus erythematosus.

Objective: To compare the outcomes of steroid-associated osteonecrosis of the femoral head in patients with systemic lupus erythematosus who underwent conservative treatment and concentrated autologous bone marrow aspirate transplantationMethods: Osteonecrosis of the femoral head was classified according to the Japanese Investigation Committee system. Concentrated autologous bone marrow aspirate transplantation was performed by aspirating the bone marrow from both iliac crests and then transplanting it to the necrotic area after the core decompression. Patients with >2-year follow-up after the concentrated autologous bone marrow aspirate transplantation in our institution (Group I) and those with >2-year follow-up after the first hospital visit in a cooperative institution (Group II) were included in this study. After a randomized matching based on age, sex, type, stage, and etiology, the collapse rate in pre-collapsed stages and total hip arthroplasty conversion rate in all stages were compared between the two groups.Results: After the matching adjustment, 33 pairs of hips were included. Preoperatively, 1, 2, 16, and 14 hips were classified as types A, B, C1, and C2, respectively, and 15, 13, 2, and 3 hips were classified as stages 1, 2, 3A, and 3B, respectively. The collapse rates in the pre-collapsed stages were 68% and 39% in Groups I and II, respectively. Total hip arthroplasty conversion rates were 33% and 45% in Groups I and II, respectively. However, Group I had significantly higher and lower conversion rates in stages 1 and 3, respectively (both P<0.05).Conclusion: Conservative treatment may be preferable in stage 1 hips. In addition, concentrated autologous bone marrow aspirate transplantation may prevent further collapse in stage 3.

Mid-term results of concentrated autologous bone marrow aspiratetransplantation for corticosteroid-associated osteonecrosis of the femoral head in systemic lupus erythematosus.

We had previously established concentrated autologous bone marrow aspirate transplantation (CABMAT), a one-step, low-invasive, joint-preserving surgical technique for treating osteonecrosis of the femoral head (ONFH). This study aimed to evaluate the effects of CABMAT as a hip-preserving surgical approach, preventing conversion to total hip arthroplasty (THA) and femoral head collapse in patients with systemic lupus erythematosus (SLE). Since 2003, 52 SLE patients (8 male, 44 female, 92 hips, mean age 35.3 (16-77) (years) were treated with CABMAT. The mean follow-up period was 5.5 (0.7-14) years. Conversion rate to THA and its predicting factors were analyzed. The overall conversion rate to THA was 29% (27/92). Conversion rate to THA was 0% (0/3), 0% (0/4), 22% (9/41), and 41% (18/44) in types A, B, C1, and C2, respectively. Conversion rate to THA was 26% (5/19), 26% (6/23), 28% (11/39), 44% (4/9), and 50% (1/2) in stages 1, 2, 3A, 3B, and 4, respectively. In multivariate logistic regression analysis, sex, body mass index (BMI), pre-operative type, and pre-operative stage were significantly correlated with conversion to THA. The conversion rate to THA was lower than that in the natural course and core decompression, but was higher than that seen in other bone marrow transplantation and osteotomy. Since sex, pre-operative type, and pre-operative stage were significantly correlated with conversion to THA, it is suggested that the higher proportion of women, advanced stage (stage 3A or above), and advanced type (type C or above) in this study affected the THA conversion rate.

Articular collapse and surgical frequency in corticosteroid-associated osteonecrosis of the femoral head and the knee: an MRI-based prospective study

The purpose of this magnetic resonance imaging (MRI)-based prospective study was to clarify the frequency of articular collapse in, and to define the frequency with which surgical interventions are performed for, osteonecrosis of the femoral head and the knee. MRI screening for osteonecrosis of the femoral head and the knee was prospectively performed within 1 year after corticosteroid administration. Those patients with osteonecrosis were conservatively followed with MRI to detect articular collapse by bone marrow edema. Several surgical interventions were considered after articular collapse. The frequencies of collapse and of surgical intervention were compared using the Kaplan–Meier method and the log-rank test. Of 1,239 joints (623 hips and 616 knees) surveyed in the study, osteonecrosis was identified in 370 (191 hips and 179 knees) by MRI. Thus, the incidence of osteonecrosis was 30 % (31 % in hip and 29 % in knee). Of 155 hips and 154 knees followed for more than 2 years, the frequency of articular collapse was significantly higher in osteonecrosis of the femoral head than in osteonecrosis of the knee (p < 0.05, 38 % [59 hips] versus 5 % [7 knees]). After articular collapse, surgery was performed significantly more often for osteonecrosis of the femoral head than for osteonecrosis of the knee (p = 0.024, 63 % [37 femoral heads] versus 29 % [2 knees]). Osteonecrosis of the femoral head can result in clinically more severe sequelae than osteonecrosis of the knee, and surgery is more often performed for osteonecrosis of the femoral head.

Corticosteroid-associated Osteonecrosis: A Rare, but Serious, Complication in Uveitis

Purpose: To examine the incidence and prevalence of osteonecrosis in uveitis patients.Methods: An electronic medical record database search was conducted to identify uveitis patients with osteonecrosis and the number at risk for corticosteroid-related osteonecrosis from 2003 to 2012. The clinical and ophthalmologic features of the uveitis patients with osteonecrosis were assessed with retrospective chart reviews.Results: Six uveitis patients with osteonecrosis were identified, comprising a prevalence of 1.5%. The incidence density was 0.19 per 100 person-years of follow-up. The uveitides included sarcoidosis, sympathetic ophthalmia, idiopathic retinal vasculitis, idiopathic chronic anterior and intermediate uveitis, Vogt-Koyanagi Harada disease, and Cogan syndrome. The duration of systemic corticosteroid treatment ranged from 6 weeks to 6 years. The potential systemic risk factors were Raynaud phenomenon, antiphospholipid and autoantibodies, sickle cell trait, and thalassemia.Conclusions: Although osteonecrosis appears to be a rare complication among uveitis patients, physicians should strive to minimize systemic corticosteroid use when appropriate. A higher level of suspicion for osteonecrosis may be warranted in patients with additional systemic risk factors.

Recovery of the blood flow around the femoral head during early corticosteroid therapy: dynamic magnetic resonance imaging in systemic lupus erythematosus patients

Disturbance of blood supply to the femoral head is a risk factor for corticosteroid-associated osteonecrosis. The aim was to measure blood supply of the proximal femur during corticosteroid therapy in systemic lupus erythematosus (SLE) patients. We repeatedly performed 78 dynamic MRIs of 19 hip joints in 19 SLE patients after initiation of corticosteroid administration for one year. Blood supply of the femoral head (epiphysis, growth plate, and metaphysis), the femoral neck, and the medial circumflex femoral artery were measured in terms of peak percent enhancement. At the first month, blood supply of the growth plate was significantly higher in the pediatric group (<15 years old) than in the adolescent and adult group (>15 years old). At the fourth month, blood supply in every part of the femoral head (epiphysis, growth plate, and metaphysis) was significantly higher in the pediatric group than in the adolescent and adult group. Multiple regression analysis revealed that blood supply to the femoral head depended on the number of days after initiation of corticosteroid administration and the age at the time of dynamic MRI. Blood supply to the femoral head is abundant in pediatric patients and is a function of the number of days after initiation of corticosteroid administration.

Idiopathic and secondary osteonecrosis of the femoral head show different thrombophilic changes and normal or higher levels of platelet growth factors

Background and purpose Thrombophilia represents a risk factor both for idiopathic and secondary osteonecrosis (ON). We evaluated whether clotting changes in idiopathic ON were different from corticosteroid-associated ON. As platelet-rich plasma has been proposed as an adjuvant in surgery, we also assessed whether platelet and serum growth factors were similar to those in healthy subjects.Methods 18 patients with idiopathic ON and 18 with corticosteroid-associated ON were compared with 44 controls for acquired and inherited thrombophilia. Platelet factor 4 (PF4), transforming growth factor-β1, platelet-derived growth factor-BB (PDGF-BB), and vascular endothelial growth factor were assayed in the supernatants of thrombin-activated platelets, in platelet lysates, and in serum from 14 ON patients and 10 controls.Results Idiopathic ON patients had higher plasminogen levels (median 118%) than controls (101%) (p = 0.02). Those with corticosteroid-associated ON had significantly higher D-dimer (333 ng/mL) and lower protein C levels (129%) than controls (164 ng/mL, p = 0.004; 160%, p = 0.02). The frequency of inherited thrombophilia was not different from the controls. No statistically significant differences were found between idiopathic and corticosteroid-associated ON. 20 of the 36 ON patients were smokers. (The controls were selected from smokers because nicotine favors hypercoagulability). ON patients had significantly higher serum PF4 levels (7,383 IU/mL) and PDGF-BB levels (3.1 ng/mL) than controls (4,697 IU/mL, p = 0.005; 2.2 ng/mL, p = 0.02).Interpretation Acquired hypercoagulability was common in both ON types, but the specific changes varied. The release of GF from platelets was not affected, providing a biological basis for platelet-rich plasma being used as an adjuvant in surgical treatment.

Fresh Osteochondral Allografting for Steroid-associated Osteonecrosis of the Femoral Condyles

Osteonecrosis is a complication of corticosteroid therapy with limited treatment options in young, active patients. These options include debridement, core decompression, osteotomy, allografting, and partial or total knee replacement. Few studies exist regarding the use of osteochondral allografts for treatment of steroid-associated osteonecrosis. We asked if fresh osteochondral allografts would (1) heal to host bone in the presence of osteonecrosis, (2) provide a clinically meaningful decrease in pain and improvement in function, and (3) prevent or postpone the need for prosthetic arthroplasty. Twenty-two patients (28 knees) who underwent osteochondral allografting for high-grade, corticosteroid-associated osteonecrosis were evaluated. Their average age was 24.3 years (range, 16-44 years). The mean graft surface area was 10.8 cm(2) (range, 5.0-19.0 cm(2)). Evaluation included a modified (for the knee) D'Aubigné and Postel (18-point) score, International Knee Documentation Committee (IKDC), and Knee Society function scores. The minimum followup was 25 months (mean, 67 months; range, 25-235 months). Five knees failed. The graft survival rate was 89% (25 of 28). The mean D'Aubigné and Postel score improved from 11.3 to 15.8; 19 of 25 (76%) had a score greater than 15. The mean IKDC pain score improved from 7.1 to 2.0, mean IKDC function score from 3.5 to 8.3, and mean Knee Society function score from 60.0 to 85.7. Our data suggest osteochondral allografting is a reasonable salvage option for osteonecrosis of the femoral condyles. TKA was avoided in 27 of the 28 of knees at last followup. Level IV, case series. See Guidelines for Authors for a complete description of levels of evidence.

Age at time of corticosteroid administration is a risk factor for osteonecrosis in pediatric patients with systemic lupus erythematosus: A prospective magnetic resonance imaging study

To clarify whether age at the time of the initial administration of corticosteroids is a risk factor for corticosteroid-associated osteonecrosis in children with systemic lupus erythematosus (SLE), using magnetic resonance imaging (MRI). From 1986 to 2007, MRI was used to prospectively study 676 joints, including 72 joints (36 hips and 36 knees) in 18 pediatric patients with SLE (<15 years old), 100 joints (50 hips and 50 knees) in 25 adolescent patients with SLE (15-20 years old), and 504 joints (252 hips and 252 knees) in 126 adult patients with SLE (>20 years old), beginning just after corticosteroid administration, for at least 1 year. The followup rate was 100%. In pediatric patients, osteonecrosis developed in 4 joints (6%; all hips). In adolescent patients, osteonecrosis developed in 49 joints (49%; 18 hips and 31 knees). In adult patients, osteonecrosis developed in 207 joints (41%; 95 hips and 112 knees). The rate of osteonecrosis was significantly lower in pediatric patients than in adolescent or adult patients (P = 0.0001). Logistic regression analysis revealed that adolescent and adult patients had a significantly higher risk for osteonecrosis compared with pediatric patients, with an odds ratio of 10.3 (P < 0.0001). The youngest patients with osteonecrosis in the hip and knee were 14.9 years old and 15.5 years old, respectively. Osteonecrosis did not develop in patients younger than age 14 years. Our results suggest that age at the time of the initial administration of corticosteroids is associated with osteonecrosis in pediatric patients with SLE.

Bone Impaction Grafting for Corticosteroid-Associated Osteonecrosis of the Knee

Osteonecrosis of the distal portion of the femur produces a segment of dead bone in the weight-bearing portion of the femoral condyle, frequently associated with subchondral fracture and collapse and eventually resulting in secondary osteoarthritis. Treatment of these late stages of osteonecrosis in the knee can be problematic. The purpose of the present study was to evaluate a new surgical technique in which the subchondral osteonecrotic lesion is removed. The bone defect is then reconstructed with impacted bone grafts to prevent collapse and/or to regain distal femoral sphericity. In this prospective, one-surgeon study, nine consecutive knees in six patients were studied, all of which had extensive corticosteroid-associated osteonecrotic lesions of the femoral condyles. Six knees had collapsed lesions when they were initially treated. The mean age of the patients was thirty-one years. Both the clinical and radiographic outcomes were assessed at a minimal follow-up time of two years. At a mean follow-up time of fifty-one months, none of the reconstructed knees had been converted to a total knee prosthesis. The objective Knee Society score improved from a mean of 63 to 89 points. The functional Knee Society score improved from a mean of 19 to 81 points. During the follow-up period, there was no progression of collapse observed; however, three knees showed early signs of osteoarthritis. Clinical success was achieved in six of eight knees, and radiographic success was achieved in seven of nine knees. At the time of writing (at the time of midterm follow-up), this method appears attractive as a joint-preserving procedure. It is a relatively simple procedure that is not likely to interfere with future knee procedures. It appears that this technique can be effective in knees with collapse of the femoral condyle, and it may delay the need for a total knee arthroplasty. Therapeutic Level IV. See Instructions to Authors on jbjs.org for a complete description of levels of evidence.