The 2021 Association Research Circulation Osseous Classification for Early-Stage Osteonecrosis of the Femoral Head to Computed Tomography-Based Study.

BACKGROUND: The Association Research Circulation Osseous developed a novel classification for early-stage (precollapse) osteonecrosis of the femoral head (ONFH). We hypothesized that the novel classification is more reliable and valid when compared to previous 3 classifications: Steinberg, modified Kerboul, and Japanese Investigation Committee classifications. METHODS: In the novel classification, necrotic lesions were classified into 3 types: type 1 is a small lesion, where the lateral necrotic margin is medial to the femoral head apex; type 2 is a medium-sized lesion, with the lateral necrotic margin being between the femoral head apex and the lateral acetabular edge; and type 3 is a large lesion, which extends outside the lateral acetabular edge. In a derivation cohort of 40 early-stage osteonecrotic hips based on computed tomography imaging, reliabilities were evaluated using kappa coefficients, and validities to predict future femoral head collapse by chi-squared tests and receiver operating characteristic curve analyses. The predictability for future collapse was also evaluated in a validation cohort of 104 early-stage ONFH. RESULTS: In the derivation cohort, interobserver reliability (k = 0.545) and intraobserver agreement (63%-100%) of the novel method were higher than the other 3 classifications. The novel classification system was best able to predict future collapse (P < .05) and had the best discrimination between non-progressors and progressors in both the derivation cohort (area under the curve = 0.692 [0.522-0.863], P < .05) and the validation cohort (area under the curve = 0.742 [0.644-0.841], P = 2.46 × 10-5). CONCLUSION: This novel classification is a highly reliable and valid method of those examined. Association Research Circulation Osseous recommends using this method as a unified classification for early-stage ONFH. LEVEL OF EVIDENCE: Level III, diagnostic study.

Osteonecrosis of the Femoral Head: an Updated Review of ARCO on Pathogenesis, Staging and Treatment.

Non-traumatic osteonecrosis of the femoral head (ONFH) usually affects adults younger than 50 years and frequently leads to femoral head collapse and subsequent arthritis of the hip. It is becoming more prevalent along with increasing use of corticosteroids for the adjuvant therapy of leukemia and other myelogenous diseases as well as management of organ transplantation. This review updated knowledge on the pathogenesis, classification criteria, staging system, and treatment of ONFH.

Diagnosis and Treatment of Femoral Head Osteonecrosis: A Protocol for Development of Evidence-Based Clinical Practice Guidelines.

INTRODUCTION: There are many treatment options for patients who have osteonecrosis of the femoral head (ONFH) and management strategies vary widely both among and within individual countries. Although many researchers have attempted to elucidate the optimal strategies for managing this disease, the lack of large-scale randomized control trials and the lack of agreement on disease staging have curtailed the development of clear-cut guidelines. MATERIALS AND METHODS: The Association Research Circulation Osseous (ARCO) group sought to address three questions for the management of patients who have ONFH: 1) What imaging studies are most sensitive and specific for the diagnostic evaluation of patients who have ONFH?; 2) What is the best treatment strategy for preventing disease progression in patients who have pre-collapse lesions?; and 3) What is the best treatment strategy for patients who have post-collapse disease? The Patient, Intervention, Comparison, and Outcome (PICO) format was used to formulate the search strategy for each research question. A systematic review will be performed according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. ARCO participants have been allocated to three groups, each representing one of the PICO questions. After qualitative and quantitative analysis of the data extracted from studies pertaining to each of the three research questions, a set of evidence-based clinical practice guidelines will be proposed for the management of patients who have ONFH. DISCUSSION: It is not always clear which treatment method is optimal for the management of ONFH. Thus, many surgeons have developed and performed various procedures based on patient-specific factors. As there is no consensus on the optimal treatment for various stages of disease, it was clear that developing evidence-based clinical practice guidelines would provide more structure and uniformity to management of these patients. Therefore, the results of this systematic review will lead to the development guidelines that may improve patient-care strategies and result in better outcomes for patients who have ONFH.

ARCO Consensus on the Pathogenesis of Non-traumatic Osteonecrosis of the Femoral Head.

Osteonecrosis of the femoral head (ONFH) is a devastating disease frequently leading to femoral head collapse and hip arthritis. Specifically, non-traumatic ONFH primarily affects young and middle-aged adults. Although compromised local circulation of the femoral head seems to be pathognomonic for the disease, the pathogenesis is perplexing and continues to be an area of scrutiny and research. Comprehension of the pathogenesis is of crucial importance for developing and guiding treatments for the disease. Therefore, we provide an up-to-date consensus on the pathogenesis of non-traumatic 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.

Guidelines for clinical diagnosis and treatment of osteonecrosis of the femoral head in adults (2019 version).

Osteonecrosis of the femoral head (ONFH) is a common and refractory disease in orthopaedic clinics. The number of patients with ONFH is increasing worldwide every year. There are an estimated 8.12 million patients with nontraumatic osteonecrosis in China alone. Treatment of nontraumatic osteonecrosis has always been a clinical challenge for orthopaedic surgeons. To further standardize diagnosis and treatment of ONFH, these guidelines provide not only basic diagnosis, treatment, and evaluation systems for ONFH but also expert advice and standards in many aspects, including epidemiology, aetiology, diagnostic criteria, pathological staging, prevention and treatment options, and postoperative rehabilitation. The aetiological factors of ONFH can currently be divided into two major categories: traumatic and nontraumatic; however, the specific pathological mechanism of ONFH is not completely clear. Currently, the staging system of ONFH formulated by the Association Research Circulation Osseous is widely used in clinical practice. Based on the changes in the intraosseous blood supply at different stages, the corresponding nonsurgical and surgical treatments are recommended, and when there are risk factors for possible ONFH, certain preventive measures to avoid the occurrence of osteonecrosis are recommended. These guidelines provide brief classification criteria and treatment regimen for osteonecrosis. Specification of the aetiology, treatment plan based on comprehensive consideration of the different stages of osteonecrosis, hip function, age, and occupation of the patients are important steps in diagnosis and developing treatment strategies. TRANSLATIONAL POTENTIAL OF THIS ARTICLE: New advances in the epidemiology, etiology, pathophysiology, imaging, diagnosis and treatment of ONFH have been renewed in this revision. This guideline can be used for reference by orthopedic professionals and researchers, and for standardized diagnosis and treatment management under the clinical guidance, which is conducive to the prevention, treatment and further research of ONFH, improving the diagnosis and treatment level, making patients' symptoms under good control, and improving their quality of life.

Opposite hinge fractures in high tibial osteotomy: a displacement subtype is more critical than a fracture type.

PURPOSE: Analysis of the structure of the fractures of opposite hinge (FOH) after angle-stable closed-wedge (CW) and open-wedge (OW) high tibial osteotomy (HTO), and their influence on the development of tibial pseudarthrosis. METHODS: 187 CW and 94 OWHTOs were analyzed retrospectively. The FOHs in the OWHTO were classified according to Takeuchi, and in the CWHTO-according to the own classification with two types (depending on the direction of FOH). FOHs in both techniques were also subdivided into three subtypes according to displacement (A-non-displaced, B-primarily displaced, C-secondarily displaced). The statistical analysis included correlation analysis and logistic regression. RESULTS: FOHs were found in 81 (43.3%) CW and 39 (41.2%) OWHTOs. The stable type 1 fractures predominated in OWHTO (76.9 vs. 42%, p < 0.001), the unstable type 2 FOHs prevailed in CWHTO (58 vs. 17.9%, p < 0.001). The tibial pseudarthrosis rate was higher with type 1 (20 vs. 12.9%, n.s.) and subtype A (16.7 vs. 6.8%, p = 0.048) FOHs in OWHTO, and with type 2 (20 vs. 0%, p < 0.001) and subtypes B (25 vs. 0%, p < 0.001) and C (29.4 vs. 25%, n.s.) in CWHTO (without FOHs 0.9% in CW and 1.8% in OWHTO, n.s.). Relevant correlations were detected between the pseudarthrosis rate and fracture type only in CWHTO (ρs = 0.298, p < 0.001, OR 24.87 for type 2) and displacement subtype in both groups (for subtype C: ρs = 0.345, p < 0.001, OR 43.75 and ρs = 0.231, p = 0.02, OR 18.0, respectively). CONCLUSIONS: The unstable FOH types were more common in CWHTO. The displacement subtype was more predictive for the development of tibial pseudarthrosis than the fracture type, especially in OWHTO. The secondarily displaced FOHs (subtype C) represented the highest risk for the occurrence of pseudarthrosis in both techniques.

[Complication analysis after angle-stable CW and OW high tibial osteotomy]. / Komplikationsanalyse nach winkelstabiler CW- und OW-Tibiaumstellungsosteotomie.

BACKGROUND: High tibial osteotomy (HTO) is a good joint-preserving alternative to joint replacement in the treatment of isolated medial varus gonarthrosis. It is, however, accompanied by a number of complications, which can compromise the outcome of the treatment. OBJECTIVES: Analysis and comparison of the complication structure after angle-stable navigated closed wedge (CW) HTO and conventional angle-stable open wedge (OW) HTO, as well as determination of influence factors. MATERIAL AND METHODS: 281 HTO (187 CW- and 94 OWHTO) were analyzed retrospectively. Age, sex, BMI, time of surgery and radiological parameters were included as possible influence factors. A statistical analysis was performed with binary logistic regression. RESULTS: An overall complication rate of 21.4% was revealed (25.1% after CW- and 13.8% after OWHTO, p = 0.02); the major complications occurred after 13.9% CW- and 10.6% OWHTO (p = 0.27); minor complications were observed after 11.2% CW- and 3.2% OWHTO (p = 0.03). This difference results from complications specific to CWHTO (peroneal lesions and pseudarthrosis fibulae). The incidence of pseudarthrosis tibiae was equal in both procedures (7.5%). Age ≥ 52 years and body mass index (BMI) ≥ 30 kg/m2 were the relevant predictors for mechanical complications after CWHTO; these were not relevant for OWHTO. CONCLUSION: The correct patient selection is essential to avoid postoperative complications after HTO. The overall complication rates are lower after OWHTO, mainly through the avoidance of complications typical for CWHTO. OWHTO offers a wider choice with respect to the selection of patients.

The 2019 Revised Version of Association Research Circulation Osseous Staging System of Osteonecrosis of the Femoral Head.

BACKGROUND: The Association Research Circulation Osseous (ARCO) presents the 2019 revised staging system of osteonecrosis of the femoral head (ONFH) based on the 1994 ARCO classification. METHODS: In October 2018, ARCO established a task force to revise the staging system of ONFH. The task force involved 29 experts who used a web-based survey for international collaboration. Content validity ratios for each answer were calculated to identify the levels of agreement. For the rating queries, a consensus was defined when more than 70% of the panel members scored a 4 or 5 rating on a 5-point scale. RESULTS: Response rates were 93.1%-100%, and through the 4-round Delphi study, the 1994 ARCO classification for ONFH was successfully revised. The final consensus resulted in the following 4-staged system: stage I-X-ray is normal, but either magnetic resonance imaging or bone scan is positive; stage II-X-ray is abnormal (subtle signs of osteosclerosis, focal osteoporosis, or cystic change in the femoral head) but without any evidence of subchondral fracture, fracture in the necrotic portion, or flattening of the femoral head; stage III-fracture in the subchondral or necrotic zone as seen on X-ray or computed tomography scans. This stage is further divided into stage IIIA (early, femoral head depression ≤2 mm) and stage IIIB (late, femoral head depression >2 mm); and stage IV-X-ray evidence of osteoarthritis with accompanying joint space narrowing, acetabular changes, and/or joint destruction. This revised staging system does not incorporate the previous subclassification or quantitation parameters, but the panels agreed on the future development of a separate grading system for predicting disease progression. CONCLUSION: A staging system has been developed to revise the 1994 ARCO classification for ONFH by an expert panel-based Delphi survey. ARCO approved and recommends this revised system as a universal staging of ONFH.

Opposite cortical fractures in closed-wedge HTO: New classification and treatment algorithm.

BACKGROUND: An intact opposite cortex (OC) is essential for HTO stability. For an appropriate prognosis of the role of opposite cortical fracture (OCF) in the development of mechanical complications, it is important to identify the type of OCF. This study seeks to establish an OCF classification in CWHTO with a treatment algorithm. METHODS: The clinical radiological results of 187 angle-stable navigated CWHTOs were retrospectively analyzed. Two OCF types (according the direction of fracture line) with three subtypes (A-nondisplaced, B-primarily, and C-secondarily displaced) were identified. RESULTS: A total of 67.6% of type 1 and 44.7% of type 2 OCFs were non-displaced (p = 0.041). Secondary displacement developed in 36.2% of type 2 OCFs and in none of the type 1 OCFs. The tibial pseudoarthrosis rate was significantly higher with displaced type 2B and 2C OCFs than with non-displaced 2A fractures (30.8% vs. 4.8%, p = 0.03). The regression analysis showed a relevant correlation between OCF types 1B, 2B, and 2C and the incidence of mechanical complications; the significance of type 2C fractures (OR 43.8) for the incidence of tibial pseudoarthrosis was more than twice as high than for type 1B fractures. CONCLUSION: Type 1 OCFs are considered to be stable and type 2 OCFs unstable with a tendency to become displaced. Only 57.4% of type 2 OCFs were recognizable intraoperatively; thus, increased attention must be focused on this event in postoperative repeat radiographs. The classification provides practice-relevant therapeutic approaches.

Role of Nrf2 in Fracture Healing: Clinical Aspects of Oxidative Stress.

Fracture healing is a natural process that recapitulates embryonic skeletal development. In the early phase after fracture, reactive oxygen species (ROS) are produced under inflammatory and ischemic conditions due to vessel injury and soft tissue damage, leading to cell death. Usually, such damage during the course of fracture healing can be largely prevented by protective mechanisms and functions of antioxidant enzymes. However, intrinsic oxidative stress can cause excessive toxic radicals, resulting in irreversible damage to cells associated with bone repair during the fracture healing process. Clinically, patients with type-2 diabetes mellitus, osteoporosis, habitual drinkers, or heavy smokers are at risk of impaired fracture healing due to elevated oxidative stress. Although increased levels of oxidative stress markers upon fracture and effects of antioxidants on fracture healing have been reported, a detailed understanding of what causes impaired fracture healing under intrinsic conditions of oxidative stress is lacking. Nuclear factor erythroid 2-related factor 2 (Nrf2) has been identified as a key transcriptional regulator of the expression of antioxidants and detoxifying enzymes. It further not only plays a crucial role in preventing degenerative diseases in multiple organs, but also during fracture healing. This narrative review evaluates the influence of intrinsic oxidative stress on fracture healing and sheds new light on the intriguing role of Nrf2 during bone regeneration in pathological fractures.

Etiologic Classification Criteria of ARCO on Femoral Head Osteonecrosis Part 1: Glucocorticoid-Associated Osteonecrosis.

BACKGROUND: Glucocorticoid usage, a leading cause of osteonecrosis of the femoral head (ONFH), and its prevalence was reported in 25%-50% of non-traumatic ONFH patients. Nevertheless, there have been no unified criteria to classify glucocorticoid-associated ONFH (GA-ONFH). In 2015, the Association Research Circulation Osseous addressed the issue of developing a classification scheme. METHODS: In June 2017, a task force was set up to conduct a Delphi survey concerning ONFH. The task force invited 28 experts in osteonecrosis/bone circulation from 8 countries. Each round of the Delphi survey consists of questionnaires, analysis of replies, and feedback reports to the panel. After 3 rounds of the survey, the panel reached a consensus on the classification criteria. The response rates were 100% (Round 1), 96% (Round 2), and 100% (Round 3), respectively. RESULTS: The consensus on the classification criteria of GA-ONFH included the following: (1) patients should have a history of glucocorticoid use >2 g of prednisolone or its equivalent within a 3-month period; (2) osteonecrosis should be diagnosed within 2 years after glucocorticoid usage, and (3) patients should not have other risk factor(s) besides glucocorticoids. CONCLUSION: Association Research Circulation Osseous established classification criteria to standardize clinical studies concerning GA-ONFH.

Etiologic Classification Criteria of ARCO on Femoral Head Osteonecrosis Part 2: Alcohol-Associated Osteonecrosis.

BACKGROUND: Although alcohol is a leading risk factor for osteonecrosis of the femoral head (ONFH) and its prevalence reportedly ranges from 20% to 45%, there are no unified classification criteria for this subpopulation. In 2015, Association Research Circulation Osseous decided to develop classification criteria for alcohol-associated ONFH. METHODS: In June of 2017, Association Research Circulation Osseous formed a task force to conduct a Delphi survey. The task force invited 28 experts in osteonecrosis/bone circulation from 8 countries. Each round of the Delphi survey included questionnaires, analysis of replies, and feedback reports to the panel. After 3 rounds of the survey, consensus was reached on the classification criteria. The response rates for the 3 Delphi rounds were 100% (round 1), 96% (round 2), and 100% (round 3). RESULTS: The consensus on the classification criteria of alcohol-associated ONFH included the following: (1) patients should have a history of alcohol intake >400 mL/wk (320 g/wk, any type of alcoholic beverage) of pure ethanol for more than 6 months; (2) ONFH should be diagnosed within 1 year after alcohol intake of this dose; and (3) patients should not have other risk factor(s). CONCLUSION: ARCO-established classification criteria to standardize clinical studies concerning AA-ONFH.

Expansion of functional personalized cells with specific transgene combinations.

Fundamental research and drug development for personalized medicine necessitates cell cultures from defined genetic backgrounds. However, providing sufficient numbers of authentic cells from individuals poses a challenge. Here, we present a new strategy for rapid cell expansion that overcomes current limitations. Using a small gene library, we expanded primary cells from different tissues, donors, and species. Cell-type-specific regimens that allow the reproducible creation of cell lines were identified. In depth characterization of a series of endothelial and hepatocytic cell lines confirmed phenotypic stability and functionality. Applying this technology enables rapid, efficient, and reliable production of unlimited numbers of personalized cells. As such, these cell systems support mechanistic studies, epidemiological research, and tailored drug development.

Bone-preserving total hip arthroplasty in avascular necrosis of the hip-a matched-pairs analysis.

PURPOSE: Short-stem hip arthroplasty has the potential advantage of femoral bone stock preservation, especially in view of the expected revisions in the often relatively young patients. Despite short-stem hip prosthesis are increasingly used for total hip arthroplasty, there are no sufficient mid- and long-term results especially for patients with avascular femoral head osteonecrosis. The present study investigates mid-term functional results as well as the revision rate following implantation of a short-stem prosthesis. METHODS: In the period 06/2005 until 12/2013, a total of 351 short-stem hip prostheses were implanted. The study included 331 complete data sets. A retrospective analysis was performed using the Oxford Hip Score. All revisions were registered. RESULTS: In a total of 331 prostheses, the Oxford Hip Score was "excellent" in 66.2%, "good" in 12.7%, "fair" in 13.0%, and "poor" in 8.2% with a mean follow-up of 57.4 months (SD ± 29.8; range 24-115). In 26 cases, aseptic osteonecrosis of the hip was the indication (7.9%). The Oxford Hip Score was "excellent" in 66.7%, "good" in 0.0%, "fair" in 20.8%, and "poor" in 12.5%. The cumulated five year survival rate was 96.7%. CONCLUSION: In mid-term observation, the Metha® short-stem prosthesis shows no disadvantage in functional outcome and in survival time compared to a standard hip stem. Providing a correct indication, the Metha® short stem is a valuable option in total hip arthroplasty for younger patients with avascular osteonecrosis of the femoral head. Evaluation has shown no significant differences between aseptic osteonecrosis and other indications.

The protective effect of platelet released growth factors and bone augmentation (Bio-Oss®) on ethanol impaired osteoblasts.

BACKGROUND: Chronic alcohol consumption is a known limiting factor for bone healing. One promising strategy to improve bone augmentation techniques with Bio-Oss® in oral and maxillofacial surgery might be the supportive application of platelet-concentrated biomaterials as platelet-released growth factor (PRGF). To address this matter, we performed an in vitro study investigating the protective effects of PRGF and Bio-Oss® in ethanol (EtOH) treated osteoblasts. METHODS: The SAOS-2 osteosarcoma cell line, with and without EtOH pretreatment was used. The cell viability, proliferation and alkali phosphatase activity (ALP) after application of 0%, 5% and 10% PRGF and Bio-Oss® were assessed. RESULTS: The application of PRGF and Bio-Oss® in EtOH impaired osteoblasts showed a significant beneficial influence increasing the viability of the osteoblasts in cell culture. The synergistic effect of Bio-Oss® and 5% PRGF on the proliferation of osteoblasts was also demonstrated. Bio-Oss® only in combination with PRGF increases the alkaline phosphatase (ALP) activity in EtOH pretreated cells. CONCLUSIONS: These results indicate that the simultaneous application of PRGF and Bio-Oss® inhibits EtOH induced bone healing impairment. Furthermore, in the cells, PRGF induced a protective mechanism which might promote bone regeneration.

Enoxaparin prevents steroid-related avascular necrosis of the femoral head.

Nontraumatic osteonecrosis of the femoral head is still a challenging problem in orthopedic surgery. It is responsible for 10% of the 500,000 hip replacement surgeries in the USA and affects relatively young, active patients in particular. Main reasons for nontraumatic osteonecrosis are glucocorticoid use, alcoholism, thrombophilia, and hypofibrinolysis (Glueck et al., 1997; Orth and Anagnostakos, 2013). One pathomechanism of steroid-induced osteonecrosis is thought to be impaired blood flow to the femoral head caused by increased thrombus formation and vasoconstriction. To investigate the preventive effect of enoxaparin on steroid-related osteonecrosis, we used male New Zealand white rabbits. Osteonecrosis was induced by methylprednisolone-injection (1 × 20 mg/kg body weight). Control animals were treated with phosphate-buffered saline. Treatment consisted of an injection of 11.7 mg/kg body weight of enoxaparin per day (Clexane) in addition to methylprednisolone. Four weeks after methylprednisolone-injection the animals were sacrificed. Histology (hematoxylin-eosin and Ladewig staining) was performed, and empty lacunae and histological signs of osteonecrosis were quantified. Histomorphometry revealed a significant increase in empty lacunae and necrotic changed osteocytes in glucocorticoid-treated animals as compared with the glucocorticoid- and Clexane-treated animals and with the control group. No significant difference was detected between the glucocorticoid and Clexane group and the control group. This finding suggests that cotreatment with enoxaparin has the potential to prevent steroid-associated osteonecrosis.

Rotationally stable screw-anchor versus sliding hip screw plate systems in stable trochanteric femur fractures: a biomechanical evaluation.

OBJECTIVES: The rotationally stable screw-anchor plate system (RoSA) is unique in using a novel screw-blade combination. This investigation tested the hypothesis whether RoSA is advantageous over the sliding hip screw plate system (SHS) with regard to stiffness, failure load, displacement, and migration in stable trochanteric femur fractures (OTA 31A1.1). METHODS: Thirteen femur pairs (mean age = 79 years; range, 64-92 years) received implants of either the RoSA or SHS (Koenigsee Implants, Allendorf, Germany). Beginning with 300 N and under consecutive 300 N load-increase steps (2000 cycles, 0.5 Hz) the femurs were cycled until failure. Specimens were evaluated for fragment displacement in both frontal and rotational planes and for migration. A survival analysis was carried out. RESULTS: With regard to stiffness (526 ± 195 N/mm vs 358 ± 143 N/mm; P = 0.006) and the failure load (2838 ± 781 N vs 2262 ± 863 N; P = 0.012), the RoSA proved superior to the SHS. Furthermore, RoSA demonstrated higher rotational stability in comparison to the SHS (1800 N: 0 ± 0 degrees vs 1.1 ± 1.3 degrees; P = 0.015; failure point: 0 ± 0 degrees vs 2.3 ± 2.6 degrees; P = 0.008), measuring rotation about femoral neck axis over time. Whereas cutout occurred only in the RoSA system (n = 3; P = 0.110), the SHS underwent plastic deformation in 7 cases (n = 7; P = 0.003). In one case (7%), the insertion of the RoSA blade resulted in iatrogenic cut-through caused by a jamming of the screw and the blade. CONCLUSIONS: The fixation of stable trochanteric femur fractures with RoSA in cadavers led to greater primary stability under cyclic load, with significant advantages with regard to stiffness, failure load, and rotational stability, compared with the SHS. A detrimental effect was its migration tendency, which began at 1800 N and occurred in the cranial direction. A meticulous insertion technique was a prerequisite to avoid iatrogenic perforation of the femoral head. Our results will have to be substantiated by further biomechanical and clinical trials using an optimized RoSA system.

Pluripotent stem cells escape from senescence-associated DNA methylation changes.

Pluripotent stem cells evade replicative senescence, whereas other primary cells lose their proliferation and differentiation potential after a limited number of cell divisions, and this is accompanied by specific senescence-associated DNA methylation (SA-DNAm) changes. Here, we investigate SA-DNAm changes in mesenchymal stromal cells (MSC) upon long-term culture, irradiation-induced senescence, immortalization, and reprogramming into induced pluripotent stem cells (iPSC) using high-density HumanMethylation450 BeadChips. SA-DNAm changes are highly reproducible and they are enriched in intergenic and nonpromoter regions of developmental genes. Furthermore, SA-hypomethylation in particular appears to be associated with H3K9me3, H3K27me3, and Polycomb-group 2 target genes. We demonstrate that ionizing irradiation, although associated with a senescence phenotype, does not affect SA-DNAm. Furthermore, overexpression of the catalytic subunit of the human telomerase (TERT) or conditional immortalization with a doxycycline-inducible system (TERT and SV40-TAg) result in telomere extension, but do not prevent SA-DNAm. In contrast, we demonstrate that reprogramming into iPSC prevents almost the entire set of SA-DNAm changes. Our results indicate that long-term culture is associated with an epigenetically controlled process that stalls cells in a particular functional state, whereas irradiation-induced senescence and immortalization are not causally related to this process. Absence of SA-DNAm in pluripotent cells may play a central role for their escape from cellular senescence.