Atorvastatin exerts a preventive effect against steroid-induced necrosis of the femoral head by modulating Wnt5a release.

Steroid-induced osteonecrosis of the femoral head (SONFH) is a prevalent form of osteonecrosis in young individuals. More efficacious clinical strategies must be used to prevent and treat this condition. One of the mechanisms through which SONFH operates is the disruption of normal differentiation in bone marrow adipocytes and osteoblasts due to prolonged and extensive use of glucocorticoids (GCs). In vitro, it was observed that atorvastatin (ATO) effectively suppressed the impact of dexamethasone (DEX) on bone marrow mesenchymal stem cells (BMSCs), specifically by augmenting their lipogenic differentiation while impeding their osteogenic differentiation. To investigate the underlying mechanisms further, we conducted transcriptome sequencing of BMSCs subjected to different treatments, leading to the identification of Wnt5a as a crucial gene regulated by ATO. The analyses showed that ATO exhibited the ability to enhance the expression of Wnt5a and modulate the MAPK pathway while regulating the Wnt canonical signaling pathway via the WNT5A/LRP5 pathway. Our experimental findings provide further evidence that the combined treatment of ATO and DEX effectively mitigates the effects of DEX, resulting in the upregulation of osteogenic genes (Runx2, Alpl, Tnfrsf11b, Ctnnb1, Col1a) and the downregulation of adipogenic genes (Pparg, Cebpb, Lpl), meanwhile leading to the upregulation of Wnt5a expression. So, this study offers valuable insights into the potential mechanism by which ATO can be utilized in the prevention of SONFH, thereby holding significant implications for the prevention and treatment of SONFH in clinical settings.

Risk factor analysis of femoral avascular necrosis after operation for Tönnis grade IV developmental dysplasia of the hip.

PURPOSE: We explored the risk factors for avascular necrosis (AVN) after surgery using open reduction, pelvic osteotomy, and femoral osteotomy for Tönnis grade IV developmental dysplasia of the hip (DDH). METHODS: In this retrospective study, we collected data of patients with Tönnis grade IV DDH treated with open reduction and pelvic osteotomy combined with femoral osteotomy from January 2012 to May 2020. The patients were divided into the AVN group and non-AVN group using the Kalamchi-MacEwen classification system. The clinical and imaging data of the two groups were collected, and the possible risk factors were included in the analysis. Univariate and multivariate logistic regression analyses were used to identify the independent risk factors and odds ratios of AVN. RESULTS: In all, 254 patients (mean age; 2.6±0.9 years, 278 hips) were included. The mean follow-up time was 3.8±1.5 years. A total of 89 hips (32%) were finally classified as AVN (Kalamchi-MacEwen II-IV). Univariate analysis showed significant associations with AVN for age (p=0.006), preoperative femoral neck anteversion (FAV) (p<0.001), femoral osteotomy length to dislocation height ratio (FDR) <1 (p<0.001), and the epiphyseal ossific nucleus diameter to the neck diameter ratio (ENR) <50% (p=0.009). Multivariate logistic regression analysis showed that only excessive preoperative FAV (OR: 1.04; 95% CI: 1.02-1.05; p<0.001) and FDR<1 (OR: 3.58; 95% CI: 2.03-6.31; p<0.001) were independent risk factors for femoral head necrosis. CONCLUSION: Excessive preoperative FAV and FDR<1 are important risk factors for femoral AVN after open reduction, pelvic osteotomy, and femoral osteotomy for Tönnis grade IV DDH. For children with DDH with high dislocation and excessive FAV, clinicians should fully evaluate their condition and design more personalized treatment programs to prevent AVN.

Protective effect of modified lange "second position" for developing avascular necrosis following closed reduction for developmental dysplasia of the hip.

BACKGROUND: Developmental Dysplasia of the Hip (DDH) is a condition affecting hip joint development in children, presenting multiple manifestations. Immobilization methods to ensure hip concentricity, such as the human position and modified Lange position, vary in effectiveness and risks, especially avascular necrosis. The purpose of this study was to identify whether closed reduction (CR), with two different immobilization techniques, is effective in avoiding complications such as residual hip dysplasia (RHD), re-dislocation, and Avascular Necrosis (AVN). METHODS: A total of 66 patients with DDH (84 hips) were treated with two different techniques of immobilization (groups A and B); the mean age at the time of reduction was 8 (6-13) months. The rates of RHD, Re-dislocation, and AVN were determined with a minimum follow-up of 48 months in both techniques. RESULTS: The Chi-square analysis conducted across the study groups unveiled that patients in Group B demonstrated a protective effect against AVN compared to those in Group A (OR: 0.248, 95% CI: 0.072-0.847, p = 0.026). However, no statistically significant differences were found between the groups concerning RHD (p = 0.563) and re-dislocation (p = 0.909). CONCLUSIONS: After the initial Human Position immobilization, the second cast with the modified Lange "second position" demonstrated a protective effect compared with maintaining the Human Position immobilization throughout the immobilization period, reducing the likelihood of AVN development in patients undergoing closed reduction for developmental dysplasia of the hip.

[Research progress on mechanism of traditional Chinese medicine intervention in angiogenesis in prevention and treatment of nontraumatic avascular necrosis of femoral head].

Nontraumatic avascular necrosis of the femoral head(NANFH) is a common and refractory femoral head disease that causes bone death due to interruption of blood supply. Early clinical symptoms are atypical, such as hip pain and limited joint function. In the late stage, severe pain, shortening of the affected limb, claudication, and other serious symptoms are common, which se-riously affects the quality of life of patients. Therefore, it is of great significance to actively improve the clinical symptoms of NANFH to enhance the quality of life of patients. The pathogenesis of NANFH is complex, such as traumatic vascular circulatory disorders, the use of hormones or other drugs, alcoholism, and diabetes mellitus. These factors directly or indirectly lead to femoral head vascular damage, thrombosis, and coagulation system disorders, which reduce the blood supply to the acetabulum and femoral head, thus causing ischaemic death of the femoral head or even femoral head collapse. NANFH is mainly categorized as "bone impotence" and "bone paralysis" in traditional Chinese medicine(TCM). The treatment of NANFH with TCM has the characteristics and advantages of a long history, stable and reliable therapeutic effect, fewer adverse reactions, good patient tolerance, and high acceptance. Previous studies have shown that the promotion of angiogenesis is a key initiative in the prevention and treatment of NANFH, and TCM can promote fe-moral head angiogenesis by interfering with the expression of angiogenesis-related factors, which in turn can help to restore the blood supply of the femoral head and thus improve clinical symptoms of NANFH and prevent and treat NANFH. This article described the roles of blood supply interruption and angiogenesis in NANFH and the accumulated knowledge and experience of TCM in NANFH and summarized the role of angiogenesis-related factors in NANFH and the research progress on TCM intervention, so as to provide an idea for the subsequent research and a new basis for the clinical application of TCM in the treatment of NANFH.

Effects of Puerarin-Loaded Tetrahedral Framework Nucleic Acids on Osteonecrosis of the Femoral Head.

Osteonecrosis of the femoral head (ONFH) is recognized as a common refractory orthopedic disease that causes severe pain and poor quality of life in patients. Puerarin (Pue), a natural isoflavone glycoside, can promote osteogenesis and inhibit apoptosis of bone mesenchymal stem cells (BMSCs), demonstrating its great potential in the treatment of osteonecrosis. However, its low aqueous solubility, fast degradation in vivo, and inadequate bioavailability, limit its clinical application and therapeutic efficacy. Tetrahedral framework nucleic acids (tFNAs) are promising novel DNA nanomaterials in drug delivery. In this study, tFNAs as Pue carriers is used and synthesized a tFNA/Pue complex (TPC) that exhibited better stability, biocompatibility, and tissue utilization than free Pue. A dexamethasone (DEX)-treated BMSC model in vitro and a methylprednisolone (MPS)-induced ONFH model in vivo is also established, to explore the regulatory effects of TPC on osteogenesis and apoptosis of BMSCs. This findings showed that TPC can restore osteogenesis dysfunction and attenuated BMSC apoptosis induced by high-dose glucocorticoids (GCs) through the hedgehog and Akt/Bcl-2 pathways, contributing to the prevention of GC-induced ONFH in rats. Thus, TPC is a promising drug for the treatment of ONFH and other osteogenesis-related diseases.

CircPVT1 up-regulation attenuates steroid-induced osteonecrosis of the femoral head through regulating miR-21-5p-mediated Smad7/TGFß signalling pathway.

Steroid-induced osteonecrosis of the femoral head (SIONFH) has been a common disease following corticosteroid therapy. Presently, we aim to explore the functions of circular RNA (circ) PVT1 in SIONFH rats and the underlying mechanism. Glucocorticoid (GC) was used to treat SD rats and bone marrow-derived mesenchymal stem cells (BMSCs) to construct SIONFH model in vitro and in vivo, respectively. The pathological injury of the femoral head in the SIONFH rats was detected via haematoxylin-eosin (HE) staining and immunohistochemistry (IHC). The osteogenic differentiation, proliferation and apoptosis of BMSCs were detected. Western blot was used to detect Smad7, Bax, Bcl2 and Smad2/3. The potential targets of circPVT1 and miR-21-5p were validated through luciferase reporter gene assay and RNA pull-down assay, respectively. We found that CircPVT1 was decreased in the femoral head of SIONFH rats and GC-treated BMSCs, while miR-21-5p was markedly up-regulated. Overexpressed circPVT1 attenuated the apoptosis and cell viability inhibition of BMSCs induced by GC, while miR-21-5p up-regulation had the opposite effects. What's more, the in vivo experiments confirmed that up-regulating circPVT1 repressed osteonecrosis in SIONFH rats through repressing apoptosis. Mechanistically, circPVT1 functioned as a ceRNA of miR-21-5p, which targeted at the 3'untranslated region of Smad7. CircPVT1 enhancing Smad7 and mitigating GC activated TGFß/Smad2/3 pathway through inhibiting miR-21-5p. In conclusion, CircPVT1 exerts protective effects against SIONFH via modulating miR-21-5p-mediated Smad7/TGFß pathway.

Epiphyseal Translation as a Predictor of Avascular Necrosis in Unstable Slipped Capital Femoral Epiphysis.

BACKGROUND: Physeal instability has been shown to be associated with a higher risk of avascular necrosis (AVN) in patients with slipped capital femoral epiphysis (SCFE). The purpose of this study was to identify additional preoperative factors associated with AVN in patients with unstable SCFE. METHODS: Basic demographic information, chronicity of symptoms, and estimated duration of nonambulatory status were noted. Preoperative radiographs were used to measure the Southwick slip angle, slip severity by Wilson criteria, and epiphyseal translation. Translation was measured by 3 distinct radiographic parameters in the position demonstrating maximal displacement. Postoperative radiographs at the time of most recent follow-up were assessed for the presence of AVN. Translation measurements were tested for inter-rater reliability. Patients who developed AVN were compared with those that did not by Fisher exact test and Wilcoxon tests. Logistic regression assessed the effect of translation on the odds of developing AVN. Receiver operating characteristic curve was plotted to assess any threshold effect. RESULTS: Fifty-one patients (55 hips) out of 310 patients (16%) treated for SCFE were considered unstable. Seventeen hips' unstable SCFE (31%) showed radiographic evidence of AVN. Slip severity by Wilson grade (P=0.009) and epiphyseal translation by all measurements (P< 0.05) were statistically significantly greater among patients who developed AVN. Superior translation had the best inter-rater reliability (intraclass correlation coefficient=0.84). Average superior translation in hips that developed AVN was 17.2 mm compared with 12.9 mm in those that did not (P<0.02). Although the receiver operating characteristic curve did not demonstrate a threshold effect for AVN, it did effectively rule out AVN in cases with <1 cm of superior translation. Age, sex, laterality, chronicity of prodromal symptoms or inability to bear weight, Southwick slip angle, and method of treatment did not vary with the occurrence of AVN. CONCLUSIONS: Epiphyseal translation, either by Wilson Grade or measured directly, is associated with AVN in patients with an unstable SCFE. LEVEL OF EVIDENCE: Level II-development of diagnostic criteria.

The effectiveness of preliminary traction in the treatment of congenital dislocation of the hip.

BACKGROUND: Historical papers on the treatment of congenital dislocation of the hip suggest the use of preliminary traction to facilitate closed reduction or to decrease the risk of avascular necrosis (AVN) of the femoral head. In the 1980s, some authors questioned the role of preliminary traction and suspended its use, yielding satisfactory results. Since then, several studies called into question this method, and some authors have continued to recommend preliminary traction while other authors have discouraged its use. MATERIALS AND METHODS: We reanalysed the full set of radiographs of 71 hips (52 patients) surgically treated by a medial approach after 4 weeks of preoperative longitudinal traction. The mean age at operation was 16 months. Before and after traction, the height of the dislocation was graded according to the Gage and Winter method. The hips were divided into two groups: group 1, in which the traction was effective, and group 2, in which the traction was not effective. These two groups were statistically analysed regarding the severity of the dislocation, the age of the patient at surgery and the incidence of AVN. RESULTS: Preliminary traction was effective in 48 hips (68%, group 1), while it was not effective in the remaining 23 (32%, group 2). The effectiveness of preliminary traction was statistically related to the height of the dislocation and to the age of the patient at surgery, with traction being less effective in more severe dislocations and in older children. The incidence of AVN was statistically lower in group 1 than in group 2. CONCLUSIONS: In our study population, despite not having a control group, preliminary traction-when effective-seemed to reduce the incidence of AVN in patients surgically treated for congenital dislocation of the hip. The effectiveness of the traction was influenced by the severity of the dislocation and the age of the patient; it worked better for less severe dislocations and in younger children. To reduce hospital costs, traction should be applied at home. LEVEL OF EVIDENCE: 3.

microRNA-148a-3p in extracellular vesicles derived from bone marrow mesenchymal stem cells suppresses SMURF1 to prevent osteonecrosis of femoral head.

Extracellular vesicle (EV)-associated microRNAs (miRNAs) have been found as the important biomarkers participating in the development of osteonecrosis of the femoral head (ONFH). Consequently, this study sought to examine the underlying mechanism of bone marrow mesenchymal stem cell (BMSC)-derived EVs containing miR-148a-3p in ONFH. The ONFH rat models were established. Reverse transcription quantitative polymerase chain reaction (RT-qPCR) and Western blot analysis were applied to detect miR-148a-3p, Smad ubiquitination regulatory factor 1 (SMURF1), SMAD7 and B-cell CLL/lymphoma 2 (BCL2) expression, followed by determination of relationship between miR-148a-3p and SMURF1. BMSCs were isolated from normal rats and ONFH rats, and EVs were extracted from BMSCs of normal rats. BMSCs from ONFH rats were treated with mimic, inhibitor, small interfering RNA or EVs from miR-148a-3p mimic-treated BMSCs from normal rats (BMSC-EV-miR-148a-3p mimic). Cell Counting Kit-8 and alizarin red staining were utilized to detect cell viability and osteogenic differentiation of BMSCs. ONFH rats were injected with BMSC-EV-miR-148a-3p mimic to explore the function of BMSC-EV-delivered miR-148a-3p in vivo. miR-148a-3p was down-regulated in BMSCs and EVs from ONFH rats following decreased BMSCs viability and osteogenic differentiation. SMURF1 was a target gene of miR-148a-3p, and resulted in ubiquitination and degradation of SMAD7 to decreased BCL2 expression. The proliferation and differentiation of BMSCs were promoted by BMSC-EV-miR-148a-3p mimic or SMURF1 silencing. Additionally, BMSC-EV-miR-148a-3p mimic increased cell proliferation and osteogenic response, diminished SMURF1 expression, and elevated SMAD7 and BCL2 expression in ONFH rats. Collectively, miR-148a-3p overexpressed in BMSC-EVs promoted SMAD7 and BCL2 expression by inhibiting SMURF1, thus alleviating ONFH.

Increased Hip Intracapsular Pressure Decreases Perfusion of the Capital Femoral Epiphysis in a Skeletally Immature Porcine Model.

BACKGROUND: Increased intracapsular hip pressure is thought to be one of the possible etiologies of femoral head avascular necrosis after intra-articular proximal femoral fractures or acute slipped capital femoral epiphysis. The purpose of this study was to evaluate the relationship between intra-articular hip pressure (IAP) and epiphyseal perfusion pressure (EPP), and its dependency on skeletal maturity using a porcine model. METHODS: Seven female Yorkshire-hybrid pigs were used to study the direct relationship between IAP and EPP. A needle inserted into the capsule provided both IAP monitoring and saline infiltration until IAP was above mean arterial pressure (MAP). Video simultaneously documented IAP, EPP, MAP. Parameters for all trials in each hip were averaged and compared between the 2 age groups. Significance was P<0.05. RESULTS: Four young hips (in pigs 10.3±1.0 wk, 27.4±2.0 kg) and 5 older hips (21.1±0.1 wk, 89.4±7.1 kg) were studied. There was no significant difference in the MAP (50.0±11.8 and 55.5±7.0 mm Hg respectively, P=0.411) between the 2 age groups. In the older hips, biphasic EPP persisted despite increasing IAP to an average of 177 mm Hg over MAP. In the young pigs, the biphasic EPP waveform ceased with increased IAP to an average of 28 mm Hg over MAP. Biphasic waveforms returned once IAP fell to an average of 5 mm Hg over MAP. CONCLUSIONS: Increased IAP resulted in tamponade of epiphyseal perfusion in the young, but not in the older hips. An intact physis may preclude intraosseous metaphyseal vessels from penetrating the epiphysis, leaving it vulnerable to retinacular artery tamponade. CLINICAL RELEVANCE: The IAP and EPP relationship has direct clinical practice implications. Hip capsulotomy and decompression in young patients with intra-articular proximal femoral fractures and increased intracapsular pressure may decrease avascular necrosis risk.

The proton pump inhibitor, lansoprazole, prevents the development of non-traumatic osteonecrosis of the femoral head: an experimental and prospective clinical trial.

BACKGROUND: An effective prevention strategy for osteonecrosis of the femoral head (ONFH) has yet to be established. We previously reported that the innate immune system via the toll-like receptor (TLR) response induced by corticosteroids leads to the development of ONFH and that repression of IRF7 activity by an inhibitor could interfere with the development of ONFH while maintaining the therapeutic effect of the corticosteroids. OBJECTIVE: In the present study, we hypothesize that lansoprazole has the potential to suppress IRF7 activity and prevent corticosteroid-induced ONFH in rats. Furthermore, we conducted a preliminary clinical trial to prevent corticosteroid-induced ONFH in autoimmune disease patients. METHODS: Male Wistar rats were randomly divided into four groups. On Day 1, each rat was injected with TLR4 ligand (LPS) or TLR7 ligand (imiquimod), followed by methylprednisolone with or without lansoprazole on Day 2. They were killed at 1 or 14 days after the last injection.We prospectively recruited 30 patients requiring primary high-dose corticosteroid treatment for immune diseases. All patients were administered lansoprazole, starting the night before corticosteroid treatment began. MRI was performed before corticosteroid treatment, and at 4, 12 and 24 weeks afterward. RESULTS: In rats, co-treatment of lansoprazole with corticosteroids significantly repressed both IRF7 activity and the development of ONFH. Moreover, in the human patients, the incidence of ONFH was significantly decreased from 53.4 to 13.3%. CONCLUSIONS: Although the present study is preliminary, the results show that co-treatment of lansoprazole with corticosteroids prevents ONFH development. Lansoprazole may be both safe and effective in preventing osteonecrosis of the femoral head in patients needing corticosteroid treatment.

Icariin promotes angiogenesis in glucocorticoid-induced osteonecrosis of femoral heads: In vitro and in vivo studies.

The injury and dysfunction of the femoral head microvascular endothelial cells are associated with the pathogenesis of glucocorticoid-induced osteonecrosis of the femoral head (ONFH). Reports indicate that icariin (ICA) can enhance vascular roles and also inhibit endothelial cell dysfunction. However, it still remains unclear whether ICA can promote angiogenesis in glucocorticoid-induced ONFH. In this study, we investigate this hypothesis through in vitro and in vivo experiments. Results showed that 0.1 mg/mL hydrocortisone significantly suppressed bone microvascular endothelial cells (BMECs) proliferation while ICA at 10-5  mol/L reversed this inhibition. ICA significantly promoted BMECs migration, tube formation, the angiogenesis-related cytokines expression and the activation of Akt. Furthermore, ICA enhanced Bcl-2 expression but diminished Bax expression. According to in vivo results, rats with ICA treatment exhibited a lower ratio of empty lacunae, higher volume of blood vessels and more CD31-positive cells. This study revealed that ICA promotes angiogenesis of BMECs in vitro and improves femoral head blood vessel volume of rats treated with glucocorticoid, suggesting the efficacy of ICA in the prevention of glucocorticoid-induced ONFH.

Early versus late treatment of paediatric femoral neck fractures: a systematic review and meta-analysis.

PURPOSE: Femoral neck fractures in children represent less than 1% of all paediatric fractures. Osteonecrosis of the femoral head is one of the devastating complications of this fracture. Time to treatment is one of the most important predictors of this outcome with no clear consensus in the literature. The aim of this study was to determine whether early treatment (< 24 hours) of pediatric femoral neck fractures is associated with a lower rate of osteonecrosis of the femoral head compared to late treatment (> 24 hours). METHODS: We searched several databases (PubMed, Embase, and Cochrane library), from January 1966 to November 2017 for any comparative studies that evaluated early (< 24 hours) versus late (> 24 hours) treatment of paediatric femoral neck fractures. We pooled the effect sizes using fixed effects model that compared the rate of osteonecrosis of the femoral head between children undergoing early versus late treatment, open versus closed reduction, displaced versus non-displaced and different Delbet type femoral neck fractures. Descriptive and qualitative data was also extracted. RESULTS: Of the 391 articles identified, six studies (prospective and retrospective cohort studies) were eligible for the meta-analysis, with a total of 231 paediatric femoral neck fractures. The pooled odds ratio (OR) for osteonecrosis of the femoral head did not show any statistically significant difference between early (< 24 hours) versus late (> 24 hours) treatment (OR = 1.19, 95% CI 0.56, 2.51, I2 = 23.6%), nor between open versus closed reduction of paediatric femoral neck fractures (OR = 1.62, 95% CI 0.82, 3.22, I2 = 19.57%). Displaced and Delbet type I/II femoral neck fractures were 3.8 (OR = 3.81, 95% CI 1.49, 9.78, I2 = 0.00%) and 2.4 (OR = 2.43, 95% CI 1.28, 4.61, I2 = 0.57%) times more associated with osteonecrosis of the femoral head compared to non-displaced and Delbet type III/IV fractures respectively. CONCLUSIONS: The cumulative evidence at present does not indicate an association between the time to treatment or method of reduction of femoral neck fractures in children and the risk of osteonecrosis of the femoral head. However, initial expedient treatment of femoral neck fractures in children should always remain the rule especially for displaced and Delbet type I/II femoral neck fractures. LEVEL OF EVIDENCE: II/III.

Icariin Protects against Glucocorticoid-Induced Osteonecrosis of the Femoral Head in Rats.

BACKGROUND/AIMS: Glucocorticoid (GC)-related osteonecrosis of the femoral head (ONFH) is a common complication following administration of steroids to treat many diseases. Our previous study demonstrated that icariin (ICA) might have a beneficial effect on the bone marrow mesenchymal stem cells (BMSCs) of patients with steroid-associated osteonecrosis. In this study, we investigated the underlying mechanisms of ICA associated with the potential enhancement of osteogenesis and anti-adipogenesis in GC-related ONFH. METHODS: In vitro cell proliferation was evaluated by CCK-8 assay. Alizarin red S and alkaline phosphatase (ALP) activity were used to measure osteogenic differentiation, while adipogenic differentiation was revealed by oil red O staining and TG content assay. The expression level of osteogenesis-associated genes and PPARγ was evaluated by RT-qPCR, western blotting and immunofluorescence. A total of 30 female SD rats were randomly separated into three groups: a control group, a methylprednisolone (MPS) group and a MPS + ICA group. Serum ALP and TG (triglyceride), micro-CT scanning, histological and immunohistochemical analyses were performed in the animal model. RESULTS: In the in vitro study, ICA promoted proliferation, improved osteogenic differentiation and suppressed adipogenic differentiation of BMSCs treated with MPS. The group treated with MPS and 10-6 M ICA expressed higher levels of Runx2, ALP, bone morphogenetic protein (BMP) 2, and OC and lower expression of PPARγ than the MPS group. In the in vivo study, ICA prevented bone loss in a rat model of GC-related ONFH as shown by micro-CT scanning, histological and immunohistochemical analyses. CONCLUSIONS: ICA is an effective compound for promoting bone repair and preventing or delaying the progression of GC-associated ONFH in rats. This effect can be explained by its ability to improve the balance between adipogenesis and osteogenesis, indicating that ICA is an effective candidate for management of GC-associated ONFH.

Pharmacological interventions for the prevention of insufficiency fractures and avascular necrosis associated with pelvic radiotherapy in adults.

BACKGROUND: Pelvic radiotherapy is a treatment delivered to an estimated 150,000 to 300,000 people annually across high-income countries. Fractures due to normal stresses on weakened bone due to radiotherapy are termed insufficiency fractures. Pelvic radiotherapy-related interruption of the blood supply to the hip is termed avascular necrosis and is another recognised complication. The reported incidences of insufficiency fractures are 2.7% to 89% and risk of developing avascular necrosis is 0.5%. These complications lead to significant morbidity in terms of pain, immobility and consequently risk of infections, pressure sores and mortality. OBJECTIVES: To assess the effects of pharmacological interventions for preventing insufficiency fractures and avascular necrosis in adults over 18 years of age undergoing pelvic radiotherapy. SEARCH METHODS: We performed electronic literature searches in the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, Embase and DARE to 19 April 2017. We also searched trial registries. Further relevant studies were identified through handsearching of citation lists of included studies. SELECTION CRITERIA: Randomised controlled trials (RCTs) or non RCTs with concurrent comparison groups including quasi-RCTs, cluster RCTs, prospective cohort studies and case series of 30 or more participants were screened. We included studies assessing the effect of pharmacological interventions in adults over 18 years of age undergoing radical pelvic radiotherapy as part of anticancer treatment for a primary pelvic malignancy. We excluded studies involving radiotherapy for bone metastases. We assessed use of pharmacological interventions at any stage before or during pelvic radiotherapy. Interventions included calcium or vitamin D (or both) supplementation, bisphosphonates, selective oestrogen receptor modulators, hormone replacement therapy (oestrogen or testosterone), denosumab and calcitonin. DATA COLLECTION AND ANALYSIS: Two review authors independently assessed trial quality and extracted data. We contacted study authors to obtain missing data. Data were to be pooled using the random-effects model if study comparisons were similar, otherwise results were to be reported narratively. MAIN RESULTS: We included two RCTs (1167 participants). The first RCT compared zoledronic acid with placebo in 96 men undergoing pelvic radiotherapy for non-metastatic prostate cancer.The second RCT had four treatment arms, two of which evaluated zoledronic acid plus adjuvant androgen suppression compared with androgen suppression only in 1071 men undergoing pelvic radiotherapy for non-metastatic prostate cancer.Both studies were at a moderate to high risk of bias and all evidence was judged to be of very low certainty.The studies provided no evidence on the primary outcomes of the review and provided limited data in relation to secondary outcomes, such that meta-analyses were not possible. Both studies focused on interventions to improve bone health in relation to androgen deprivation rather than radiation-related insufficiency fractures and avascular necrosis. Few fractures were described in each study and those described were not specific to insufficiency fractures secondary to radiotherapy. Both studies reported that zoledronic acid in addition to androgen deprivation and pelvic radiotherapy led to improvements in BMD; however, the changes in BMD were measured and reported differently. There was no available evidence regarding adverse effects. AUTHORS' CONCLUSIONS: The evidence relating to interventions to prevent insufficiency fractures and avascular necrosis associated with pelvic radiotherapy in adults is of very low certainty. This review highlights the need for prospective clinical trials using interventions prior to and during radiotherapy to prevent radiation-related bone morbidity, insufficiency fractures and avascular necrosis. Future trials could involve prospective assessment of bone health including BMD and bone turnover markers prior to pelvic radiotherapy. The interventions for investigation could begin as radiotherapy commences and remain ongoing for 12 to 24 months. Bone turnover markers and BMD could be used as surrogate markers for bone health in addition to radiographic imaging to report on presence of insufficiency fractures and development of avascular necrosis. Clinical assessments and patient reported outcomes would help to identify any associated adverse effects of treatment and quality of life outcomes.

Effects of erythropoietin for precaution of steroid-induced femoral head necrosis in rats.

BACKGROUND: Steroids such as glucocorticoid have been widely used for their excellent anti-inflammatory, anti-immune, and anti-shock properties. However, the long-term use in high doses has been found to cause necrosis of femoral head and other serious adverse reactions. Thus, it is of great importance to safely use these medications on patients without inducing bone necrosis. METHODS: In this preclinical study, we examined the effects of erythropoietin (EPO) to attenuate the induction of steroid-induced femoral bone necrosis using rats to build up the in-vivo models. Rats were randomly divided into three groups: negative control group (group A), disease group (group B), and EPO group (group C). 20 mg/kg methylprednisolone was administrated into group B and group C for 6 weeks with two intramuscular injections per week per rat. Group C was further given daily intraperitoneal injections of rHuEPO during this period. Group A received only injection of saline at the same schedule. 12 weeks after the initial drug administration, the rats' femoral tissues were harvested for HE staining, immunohistochemistry studies for PECAM-1(also CD31) expression and Western Blotting for VEGF expression. RESULTS: Histology studies showed that compared with the disease group, EPO group had significant improvement and bone morphology being much closer to the negative control group. Immunohistochemical studies revealed that EPO group had statistically much more expression of PECAM-1 than the other groups did. Western Blot demonstrated that the EPO group had significantly higher VEGF expression than the disease group. CONCLUSION: Results suggested that simultaneous injection of EPO could partially prevent steroid-induced ANFH.

Restoration of Blood Flow to the Proximal Femoral Epiphysis in Unstable Slipped Capital Femoral Epiphysis by Modified Dunn Procedure: A Preliminary Angiographic and Intracranial Pressure Monitoring Study.

BACKGROUND: The major complication of unstable slipped capital femoral epiphysis (SCFE) is avascular necrosis (AVN) of the femoral head. The purpose of this study was to document by angiography the preoperative and postoperative perfusion to the proximal femoral epiphysis following an unstable SCFE. A specific aim was to determine whether blood flow could be restored. A secondary aim was to determine the efficacy of an intracranial pressure (ICP) monitor to assess blood flow within the femoral head intraoperatively. METHODS: Nine patients with an unstable SCFE underwent superselective angiogram of the medial circumflex femoral artery preoperatively, followed by operative fixation with an open reduction using a modified Dunn approach. Femoral head blood flow was evaluated with an ICP monitor. Angiography was repeated postoperatively. Patients were followed radiographically to assess for AVN. RESULTS: Follow-up averaged 22 months. Six patients did not have arterial flow to the femoral head on the preoperative angiogram. Flow was restored postoperatively on angiogram in 4 of the 6 patients. Two patients developed AVN. One had no flow to the femoral head preoperatively or postoperatively on angiogram and complete tearing of the periosteum was noted. In 1 patient, there was no ICP waveform after the initial reduction. After removing more callous and repeating reduction, the waveform returned. Of the 2 patients with AVN, 1 had an ICP waveform after reduction. CONCLUSIONS: This study documents that some patients with unstable SCFE present with reduced femoral head blood supply due to SCFE. It also demonstrates blood flow restoration in 4 patients by angiogram and 5 by ICP monitor after surgical treatment. No patient immediately lost blood flow due to surgery. ICP monitor is a safe intraoperative tool for real-time assessment of femoral head blood flow during open reduction of unstable SCFE. Presence of flow by ICP is not a guarantee that AVN will not develop, but absence of flow was predictive of AVN. LEVEL OF EVIDENCE: Therapeutic level I-prognostic. See Instructions for Authors for a complete description of levels of evidence.

Association between the ossific nucleus and osteonecrosis in treating developmental dysplasia of the Hip: updated meta-analysis.

BACKGROUND: A meta-analysis concluded that there was no effect of the femoral head ossification and the incidence of osteonecrosis in the treatment of developmental dysplasia of the hip (DDH), unless only osteonecrosis grades II-IV were considered. The meta-analysis, limited due to the small number of studies available at that time, identified a need for an update as further research emerges. We observed a trend in recent years towards delaying treatment of DDH in the absence of an ossified nucleus. Numerous new publications on this topic encouraged us to update the 2009 meta-analysis. METHODS: We performed a systematic review of the literature from 1967 to 2016 and included studies that reported on the treatment of DDH, the ossific nucleus and osteonecrosis. Two independent reviewers evaluated all articles. We performed a meta-analysis with the main outcome defined as the development of osteonecrosis of the femoral head at least two years after closed or open reduction. RESULTS: Of four prospective and ten retrospective studies included in the systematic review, 11 studies (1,021 hips) met the inclusion criteria for the meta-analysis. There was no significant effect of the ossific nucleus on the development of all grades of osteonecrosis (relative risk, 0.88; 95% confidence interval, 0.56-1.41) or osteonecrosis grades II-IV (0.67; 0.41-1.08). In closed reductions, the ossific nucleus halved the risk for developing osteonecrosis grades II-IV (0.50; 0.26-0.94). CONCLUSIONS: Based on current evidence there does not appear to be a protective effect of the ossific nucleus on the development of osteonecrosis. In contrast to the previous meta-analysis, this update demonstrates that this remains the case irrespective of the grade of osteonecrosis considered relevant. This updated meta-analysis is based on twice as many studies with a higher quality of evidence.

Prevention of glucocorticoid-associated osteonecrosis by intravenous administration of mesenchymal stem cells in a rabbit model.

BACKGROUND: Glucocorticoid-associated osteonecrosis is an intractable condition, making the establishment of preventative strategies of particular importance. Recently various studies using mesenchymal stem cells (MSC) have been conducted. Using a rabbit glucocorticoid-associated osteonecrosis model we administered green fluorescent protein (GFP)-labeled MSC intravenously to investigate their effect on osteonecrosis. METHODS: A rabbit osteonecrosis model in which methylprednisolone (MP) 20 mg/kg was injected into the gluteus of a Japanese white rabbit was used. Simultaneously with MP, MSC labeled with GFP (GFP-labeled MSC) were injected intravenously. Fourteen days later the animals were killed (MSC(+)/MP(+)/14d), femurs were extracted, and the prevalence of osteonecrosis was determined histopathologically. Also, animals were killed 3 days after simultaneous administration of GFP-labeled MSC and MP (MSC(+)/MP(+)/3d), and western blotting (WB) for GFP was performed of the femur, liver, kidney, lung, blood vessel, and vertebra, in addition to immunohistochemical study of femur. As a control for the histopathological study, animals were killed 14 days after MP administration and intravenous vehicle injection (MSC(-)/MP(+)/14d). For WB, animals were killed 3 days after intravenous GFP-labeled MSC administration and vehicle injection into the gluteus (MSC(+)/MP(-)/3d). RESULTS: In MSC(-)/MP(+)/14d osteonecrosis was found in 7 of 10 rabbits (70%), while in MSC(+)/MP(+)/14d, partial bone marrow necrosis was found in only 1 rabbit (12.5%); osteonecrosis was not found in 7 of 8 rabbits (p < 0.05). WB showed expression of GFP in the femur, not in the liver, kidney, lung, blood vessel, or vertebra, of MSC(+)/MP(+)/3d; expression of GFP-labeled MSC was absent in the femur of MSC(+)/MP(-)/3d. In the immunohistochemical study of MSC(+)/MP(+)/3d, homing of GFP-labeled MSC was noted perivascularly in the femur, but not in MSC(+)/MP(-)/3d. CONCLUSIONS: With transvenous MSC administration a significant prophylactic effect against glucocorticoid-associated osteonecrosis was found. Direct administration of MSC to the site of tissue injury requires highly invasive surgery. In contrast, as shown here the simple and hardly invasive intravenous administration of MSC may succeed in preventing osteonecrosis.