Impact of fixation method on femoral bone loss: a retrospective evaluation of stem loosening in first-time revision total hip arthroplasty among two hundred and fifty five patients.

PURPOSE: Implant loosening represent the most common indication for stem revision in hip revision arthroplasty. This study compares femoral bone loss and the risk of initial revisions between cemented and uncemented loosened primary stems, investigating the impact of fixation method at primary implantation on femoral bone defects. METHODS: This retrospective study reviewed 255 patients who underwent their first revision for stem loosening from 2010 to 2022, receiving either cemented or uncemented stem implants. Femoral bone loss was preoperatively measured using the Paprosky classification through radiographic evaluations. Kaplan-Meier analysis estimated the survival probability of the original stem, and the hazard ratio assessed the relative risk of revision for uncemented versus cemented stems in the first postoperative year and the following two to ten years. RESULTS: Cemented stems showed a higher prevalence of significant bone loss (type 3b and 4 defects: 32.39% vs. 2.72%, p < .001) compared to uncemented stems, which more commonly had type 1 and 2 defects (82.07% vs. 47.89%, p < .001). In our analysis of revision cases, primary uncemented stems demonstrated a 20% lower incidence of stem loosening in the first year post-implantation compared to cemented stems (HR 0.8; 95%-CI 0.3-2.0). However, the incidence in uncemented stems increased by 20% during the subsequent years two to ten (HR 1.2; 95%-CI 0.7-1.8). Septic loosening was more common in cemented stems (28.17% vs. 10.87% in uncemented stems, p = .001). Kaplan-Meier analysis indicated a modestly longer revision-free period for cemented stems within the first ten years post-implantation (p < .022). CONCLUSION: During first-time revision, cemented stems show significantly larger femoral bone defects than uncemented stems. Septic stem loosening occurred 17.30% more in cemented stems.

Comparative analysis of femoral bone loss: uncemented vs. cemented aseptic stem loosening in first-time revision surgery-a retrospective evaluation of 215 patients.

INTRODUCTION: The integrity of the femoral bone is crucial when considering reconstructive options for the first-time revision of a total hip arthroplasty (THA). Aseptic loosening of primary stems, whether cemented or uncemented, significantly affects the volume and quality of resultant femoral bone loss. This study evaluates the impact of the initial fixation method on femoral bone defect patterns by comparing the extent of bone loss. MATERIALS AND METHODS: A retrospective cohort of 215 patients with either cemented or uncemented stems, indicated for aseptic stem loosening, and undergoing first-time stem revision from 2010 to 2022 at our institution was analyzed. Femoral bone loss extent at first-time revision was preoperatively gauged using radiographs and categorized by the Paprosky classification. Survival probabilities pre-first-time revision for both stem types were calculated using Kaplan-Meier methods. Hazard ratios were applied to compare the risk of initial revision for uncemented versus cemented stems within the first and subsequent 2nd to 10th years post-primary implantation. RESULTS: Cemented stems were associated with a higher occurrence of significant bone defects of type 3a (23.53% vs. 14.02%, p = .108), 3b (39.22% vs. 1.22%, p < .001), and 4 (3.92% vs. 0.00%) compared to uncemented stems. Conversely, smaller defects of type 1 and 2 were more prevalent in uncemented stem loosening (84.76% vs. 33.33%, p < .001). Notably, cemented stems exhibited a significantly prolonged revision-free period over the complete decade following primary insertion (p < .001). The unadjusted risk of first-time revision due to stem loosening showed a tendency to an increase in uncemented stems within the initial postoperative year (HR 5.55, 95% CI 0.74; 41.67, p = .096), and an adjusted risk of 2.1 (95% CI 0.26; 16.53, p = .488). However, these differences did not reach statistical significance. In the subsequent 2nd-10th years, the risk was lower compared to cemented stems (HR 2.35, 95% CI 1.39; 3.99, p = .002). CONCLUSIONS: Uncemented primary stems necessitating first-time revision due to aseptic loosening demonstrated notably smaller femoral bone defects in comparison to primary cemented stems.

Exploring the MEN1 dependent modulation of caspase 8 and caspase 3 in human pancreatic and murine embryo fibroblast cells.

MEN1 mutation causes pancreatic neuroendocrine neoplasia and benign malignancies of the parathyroid, the adrenal cortex and pituitary gland. The transcriptional activity of its product menin promotes the expression of genes deputed to several cellular mechanism including cell death. Here, we focused on its implication in the activation of the initiator and executioner caspases after staurosporine mediated cell death in 2D and 3D human and murine cell models. The administration of staurosporine, a well-known inducer of apoptotic cell death, caused a significant reduction of BON1, QGP1 and HPSC2.2 cell viability. The transient knockdown of MEN1, performed by using a specific siRNA, caused a significant down-regulation of CDKN1A and TP53 transcripts. The treatment with 1 µM of staurosporine caused also a significant down-regulation of MEN1 and was able to restore the basal expression of TP53 only in QGP1 cells. Transient or permanent MEN1 inactivation caused a decrease of caspase 8 activity in BON1, HPSC2.2 cells and MEN1-/- MEFs treated with staurosporine. Caspase 3/7 activity was suppressed after administration of staurosporine in MEN1 knocked down HPSC2.2 and MEN1-/- MEFs as well. The cleaved caspase 8 and caspase 3 decreased in human cells after MEN1 knockdown and in MEN1-/- MEFs. The treatment with staurosporine caused a reduction of the size of MEN1+/+ MEFs spheroids. Instead, MEN1-/- MEFs spheroids did not show any significant reduction of their size. In conclusion, MEN1 controls the activity of the initiator caspase 8 and the executioner caspase 3 in human and murine cells. Restoring of a functional MEN1 and interfering with the apoptotic mechanism could represent a future strategy for the treatment of MEN1-related malignancies.

Psychostimulants Modafinil, Atomoxetine and Guanfacine Impair Bone Cell Differentiation and MSC Migration.

Attention deficit hyperactivity disorder (ADHD) is one of the most common worldwide mental disorders in children, young and adults. If left untreated, the disorder can continue into adulthood. The abuse of ADHD-related drugs to improve mental performance for studying, working and everyday life is also rising. The potentially high number of subjects with controlled or uncontrolled use of such substances increases the impact of possible side effects. It has been shown before that the early ADHD drug methylphenidate influences bone metabolism negatively. This study focused on the influence of three more recent cognitive enhancers, modafinil, atomoxetine and guanfacine, on the differentiation of mesenchymal stem cells to osteoblasts and on their cell functions, including migration. Human mesenchymal stem cells (hMSCs) were incubated with a therapeutic plasma dosage of modafinil, atomoxetine and guanfacine. Gene expression analyses revealed a high beta-2 adrenoreceptor expression in hMSC, suggesting it as a possible pathway to stimulate action. In bone formation assays, all three cognitive enhancers caused a significant decrease in the mineralized matrix and an early slight reduction of cell viability without triggering apoptosis or necrosis. While there was no effect of the three substances on early differentiation, they showed differing effects on the expression of osterix (OSX), receptor activator of NF-κB ligand (RANKL) and osteoprotegerin (OPG) in the later stages of osteoblast development, suggesting alternative modes of action. All three substances significantly inhibited hMSC migration. This effect could be rescued by a selective beta-blocker (Imperial Chemical Industries ICI-118,551) in modafinil and atomoxetine, suggesting mediation via beta-2 receptor stimulation. In conclusion, modafinil, atomoxetine and guanfacine negatively influence hMSC differentiation to bone-forming osteoblasts and cell migration through different intracellular pathways.

Knee Arthrodesis Affects Gait Kinematics More in the Ankle Than in the Hip Joint.

Background and Objectives: No gold standard exists for treating persistent periprosthetic knee infections. Knee arthrodesis represents one treatment concept for extensive bone defects and extensor system insufficiencies. It has already been shown that knee arthrodesis leads to a significant reduction in one's quality of life. The aim of this survey was to assess the influence of knee arthrodesis on the neighboring joints on the basis of gait analysis data. Our hypothesis is that the hip and ankle joints are negatively influenced by knee arthrodesis in the process of walking. Materials and methods: We performed six pedobarographic and four gait analytical measurements in six patients 2.4 ± 1.6 years after receiving knee arthrodesis at the operating ages of 69.1 ± 9.2 years. Gait analysis consisted of time-distance parameters/minute (number of steps, double support, cycle time, standing phase, step length, gait speed). A healthy group of test subjects (n = 52) was included as the control cohort. Gait analysis was conducted using a three-dimensional movement system and three force-measuring platforms to determine the ground reaction force. Foot pressure was measured using a pedography platform. Results: Five of six patients presented an incomplete rolling movement over the toes on the side that was operated on, presenting with a gait line ending in the forefoot area. All of the patients bore less weight on the side that was operated on. Three of six patients demonstrated a pathological gait line with a healthy opposite side ending in the forefoot area. All of the patients exhibited a reduction in gait speed and step length and a lower number of steps. All of the patients had a prolonged double support/cycle time. Conclusions: Isolated knee arthrodesis is associated with reduced forefoot repulsion, restricted movement on the side receiving the operation, and reduced movement in the ankle/knee joint. The hip showed norm deviations in the hip moment/angle. Knee arthrodesis causes reduced gait kinetics/kinematics. Our survey shows that the relative joint moments of the ankle joint and hip are often reduced. The ankle joint is more affected compared to the hip.

Cartilage Destruction by Hemophilic Arthropathy Can Be Prevented by Inhibition of the Ferroptosis Pathway in Human Chondrocytes.

(1) Background: Around 50% of hemophilia patients develop severe arthropathy, with even subclinical hemorrhage in childhood potentially leading to intra-articular iron deposition, synovia proliferation, neoangiogenesis, and eventual damage to articular cartilage and subchondral bone. Treatments typically include coagulation factor substitution, radiosynoviorthesis, and joint replacement for advanced cases. This study aims to elucidate programmed cell death mechanisms in hemophilic arthropathy (HA) to identify novel treatments. (2) Methods: Human chondrocytes were exposed to lysed/non-lysed erythrocytes, ferroptosis inducer ML-162, cytokines (IL-1ß, TNFα), and ferric citrate, then assessed for metabolic activity, DNA content, and cell death using Alamar Blue, cyQUANT, and Sytox assays. Three-dimensional spheroids served as a cartilage model to study the effects of erythrocytes and ML-162. (3) Results: Erythrocytes caused significant cell death in 2D cultures (p < 0.001) and damaged 3D chondrocyte spheroids. Iron citrate and erythrocytes reduced chondrocyte DNA content (p < 0.001). The ferroptosis pathway was implicated in cell death, with no effects from apoptosis and necroptosis inhibitors. (4) Conclusions: This study offers insights into HA's cell death pathway, suggesting ferroptosis inhibitors as potential therapies. Further studies are needed to evaluate their efficacy against the chronic effects of HA.

Psychological status affects postoperative quality of life, function, and pain after periacetabular osteotomy.

Aims: Psychological status may be an important predictor of outcome after periacetabular osteotomy (PAO). The aim of this study was to investigate the influence of psychological distress on postoperative health-related quality of life, joint function, self-assessed pain, and sports ability in patients undergoing PAO. Methods: In all, 202 consecutive patients who underwent PAO for developmental dysplasia of the hip (DDH) at our institution from 2015 to 2017 were included and followed up at 63 months (SD 10) postoperatively. Of these, 101 with complete data sets entered final analysis. Patients were assessed by questionnaire. Psychological status was measured by Brief Symptom Inventory (BSI-18), health-related quality of life was raised with 36-Item Short Form Survey (SF-36), hip functionality was measured by the short version 0f the International Hip Outcome Tool (iHOT-12), Subjective Hip Value (SHV), and Hip Disability and Outcome Score (HOS). Surgery satisfaction and pain were assessed. Dependent variables (endpoints) were postoperative quality of life (SF-36, HOS quality of life (QoL)), joint function (iHOT-12, SHV, HOS), patient satisfaction, and pain. Psychological distress was assessed by the Global Severity Index (GSI), somatization (BSI Soma), depression (BSI Depr), and anxiety (BSI Anx). Influence of psychological status was assessed by means of univariate and multiple multivariate regression analysis. Results: In multiple multivariate regression, postoperative GSI, BSI Soma, and BSI Depr had a negative effect on postoperative SF-36 (e -2.07, -3.05, and -2.67, respectively; p < 0.001), iHOT-12 (e -1.35 and -4.65, respectively; p < 0.001), SHV (e -1.20 and -2.71, respectively; p < 0.001), HOS QoL (e -2.09 and -4.79, respectively; p < 0.001), HOS Function (e -1.00 and -3.94, respectively; p < 0.001), and HOS Sport (e -1.44 and -5.29, respectively; p < 0.001), and had an effect on postoperative pain (e 0.13 and 0.37, respectively; p < 0.001). Conclusion: Psychological distress, depression, and somatization disorders affect health-related quality of life, perceived joint function, and sports ability. Pain perception is significantly increased by somatization. However, patient satisfaction with surgery is not affected.

Osteogenic Effect of Pregabalin in Human Primary Mesenchymal Stem Cells, Osteoblasts, and Osteosarcoma Cells.

Seventy million patients worldwide are suffering from epilepsy. The long-term use of antiepileptic drugs causes the alteration of the bone tissue and its metabolism, thus increasing the risk of fractures. Clinical and pre-clinical studies have highlighted conflicting data on the influence of the relatively new antiepileptic drug pregabalin (Lyrica®). The objective of the present study was therefore to investigate its cytotoxicity in primary human osteoblasts (hOB). HOB and human mesenchymal stem cells (hMSC) were isolated from patients. The human osteosarcoma cells MG63 were included as established cell line. Cells were incubated with pregabalin at concentrations ranging from 0 to 40 µg/mL. Time-dependent cell proliferation was measured by automatic cell counting, and metabolism was determined by XTT assay and osseous differentiation by alkaline phosphatase (ALP) activity. Histological examinations of calcium deposit were performed with ALP, Alizarin Red, and von Kossa staining. A concentration-dependent increase in the proliferation of hOB and hMSC was observed after treatment with pregabalin. All cells showed a significant increase in cell metabolism. The osteogenic differentiation, confirmed by the increase of calcium deposit, was promoted by the administration of pregabalin. This effect was already significant at the therapeutic plasma concentration of pregabalin (10 µg/mL). In contrast to the other antiepileptic drugs, pregabalin showed no osteocatabolic effects. Conflicting in-vivo data must therefore be attributed to systemic effects of pregabalin.

Chondral/Desmal Osteogenesis in 3D Spheroids Sensitized by Psychostimulants.

Attention deficit hyperactivity disorder (ADHD) affects 6.4 million children in the United States of America. Children and adolescents, the main consumers of ADHD medication, are in the bone growth phase, which extends over a period of up to two decades. Thus, impaired proliferation and maturation of chondrocytes and osteoblasts can result in impaired bone formation. The aim of this study is to investigate, for the first time, the effects of the ADHD-medication modafinil, atomoxetine and guanfacine on bone growth and repair in vitro. Using two-dimensional and three-dimensional cell models, we investigated the chondrogenic/osteogenic differentiation, proliferation and viability of human mesenchymal progenitor cells. Real-time cell proliferation was measured by xCELLigence. Live/dead staining and size measurement of hMSC- and MG63 monolayer and spheroids were performed after administration of therapeutic plasma concentrations of modafinil, atomoxetine and guanfacine. Chondrogenic differentiation was quantified by RTqPCR. The chondrogenic and osteogenic differentiation was evaluated by histological cryo-sections. Modafinil, atomoxetine and guanfacine reduced chondrogenic and osteogenic differentiation terms of transcript expression and at the histological level. Cell viability of the MG63- and hMSC monolayer was not impeded by ADHD-medication. Our in vitro results indicate that modafinil, atomoxetine and guanfacine may impair chondrogenic and osteogenic differentiation in a 3D model reflecting the in vivo physiologic condition.