An increased number of neutrophils (NEUs) has long been associated with infections in the knee joints; their contribution to knee osteoarthritis (KOA) pathophysiology remains largely unexplored. This study aimed to compare the phenotypic and functional characteristics of synovial fluid (SF)-derived NEUs in KOA and knee infection (INF). Flow cytometric analysis, protein level measurements (ELISA), NEU oxidative burst assays, detection of NEU phagocytosis (pHrodo. TM. Green Zymosan Biparticles. TM. Conjugate for Phagocytosis), morphological analysis of the SF-derived/synovial tissue NEUs, and cultivation of human umbilical vein endothelial cells (HUVECs) using SF supernatant were used to characterise NEUs functionally/morphologically. Results: Compared with INF NEUs, KOA NEUs were characterised by a lower expression of CD11b, CD54 and CD64, a higher expression of CD62L, TLR2 and TLR4, and lower production of inflammatory mediators and proteases, except CCL2. Functionally, KOA NEUs displayed an increased production of radical oxygen species and phagocytic activity compared with INF NEUs. Morphologically, KOA and INF cells displayed different cell sizes and morphology, histological characteristics of the surrounding synovial tissues and influence on endothelial cells. KOA NEUs were further subdivided into two groups: SF containing <10% and SF with 10%–60% of NEUs. Analyses of two KOA NEU subgroups revealed that NEUs with SF <10% were characterised by 1) higher CD54, CD64, TLR2 and TLR4 expression on their surface; 2) higher concentrations of TNF-α, sTREM-1, VILIP-1, IL-1RA and MMP-9 in SFs. Our findings reveal a key role for NEUs in the pathophysiology of KOA, indicating that these cells are morphologically and functionally different from INF NEUs. Further studies should explore the mechanisms that contribute to the increased number of NEUs and their crosstalk with other immune cells in KOA. This study was supported by the Ministry of Health of the Czech Republic (NU20-06-00269; NU21-06-00370)

Specific and rapid detection methods for spinal tuberculosis, with sufficient sensitivity in HIV-1 co-infected individuals, are needed, to ensure early initiation of appropriate treatment to prevent physical disability and neurological fallout. In addition, understanding the systemic and local pathophysiology of spinal tuberculosis, and its interaction with HIV-1 infection, is crucial to guide future therapeutic interventions. We prospectively enrolled adult patients presenting with signs and symptoms of suspected spinal tuberculosis, at Groote Schuur Hospital, between November 2020 and December 2021. TB diagnostic testing was performed on open and CT-guided spinal biopsies using Xpert MTB/RIF Ultra compared to gold standards TB culture and histology. A highly sensitive droplet digital PCR assay for detecting and quantifying Mycobacterium tuberculosis complex (MTBC) and HIV-1 DNA was tested. Plasma inflammatory proteins were measured to assess systemic inflammation. Xpert Ultra had a high sensitivity of 94.7% and specificity of 100% for STB against TB culture and histology in both open and CT-guided biopsy samples. The ddPCR assay confirmed TB detection in 94% of patients with positive Xpert Ultra results. Four patients with negative TB diagnostic results had MTBC DNA detected by ddPCR. HIV-1 DNA was detected in the spinal tissues from all HIV-1-infected patients. MTBC DNA levels were significantly higher in HIV-1-co-infected spinal tissue samples (p< 0.01). We identified four biomarkers significantly associated with higher bacterial burden at the disease site (p< 0.01). Xpert Ultra and MTBC ddPCR improve the detection of STB. DdPCR can be utilized as an additional, highly sensitive tool for detecting and quantifying Mtb, in pathological samples that may be paucibacillary. These findings provide novel diagnostic and pathophysiologic insight into STB, in the context of HIV-1 infection, and provide rationale to include these tests in hospital and research settings for patients from communities burdened by TB and HIV-1

In approximately 20 years, surgical treatment of femoro-acetabular impingement (FAI) has been widely accepted, and its indications refined. However, the current approach of the disease prevents a good understanding of its pathophysiology, and numerous uncertainties remain. Comprehending inter-individual spine-hip relations (SHRs) can further clarify the pathophysiology of impingement, and explain occasional surprising mismatch between clinical assessment and imaging or intraoperative findings. The rational is simple, the more the spino-pelvic complex is mobile (sagittal ROM) and the more the hip is protected against hip impingement but would probably become at risk of spine-hip syndrome if the spino-pelvic complex comes to degenerate. Grouping patients based on their spine-hip relation can help predict and diagnose hip impingement, and assess the relevance of physiotherapy. With the proposed new classification of FAIs, every patient can be classified in homogeneous groups of complexity of treatment. The primary aim of this paper is to raise awareness of the potential impact that the spine-hip relations have on the hip impingement disease. Two new classifications are proposed, for FAIs and SHRs that can help surgeons in their comprehension, and could be beneficial in clinical and research areas

Aims. This study explored the shared genetic traits and molecular interactions between postmenopausal osteoporosis (POMP) and sarcopenia, both of which substantially degrade elderly health and quality of life. We hypothesized that these motor system diseases overlap in pathophysiology and regulatory mechanisms. Methods. We analyzed microarray data from the Gene Expression Omnibus (GEO) database using weighted gene co-expression network analysis (WGCNA), machine learning, and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis to identify common genetic factors between POMP and sarcopenia. Further validation was done via differential gene expression in a new cohort. Single-cell analysis identified high expression cell subsets, with mononuclear macrophages in osteoporosis and muscle stem cells in sarcopenia, among others. A competitive endogenous RNA network suggested regulatory elements for these genes. Results. Signal transducer and activator of transcription 3 (STAT3) was notably expressed in both conditions. Single-cell analysis pinpointed specific cells with high STAT3 expression, and microRNA (miRNA)-125a-5p emerged as a potential regulator. Experiments confirmed the crucial role of STAT3 in osteoclast differentiation and muscle proliferation. Conclusion. STAT3 has emerged as a key gene in both POMP and sarcopenia. This insight positions STAT3 as a potential common therapeutic target, possibly improving management strategies for these age-related diseases. Cite this article: Bone Joint Res 2024;13(8):411–426

Introduction and Objective

Intervertebral disc (IVD) degeneration is one of the major contributors to low back pain, the leading cause of disability worldwide. This multifactorial pathological process involves the degradation of the extracellular matrix, inflammation, and cell loss due to apoptosis and senescence. While the deterioration of the extracellular matrix and cell loss lead to structural collapse of the IVD, increased levels of inflammation result in innervation and the development of pain. Amongst the known regulators of inflammation, toll-like receptors (TLRs) and more specifically TLR-2 have been shown to be specifically relevant in IVD degeneration. As strong post-transcriptional regulators, microRNAs (miRNAs) and their dysregulation has been connected to multiple pathologies, including degenerative diseases such as osteoarthritis and IVD degeneration. However, the role of miRNAs in TLR signalling in the IVD is still poorly understood and was hence investigated in this study.

Total joint arthroplasty is the most significant advance in the treatment of end-stage arthritic disease of major joints. Despite the clinical success of this surgical procedure, however, some total joint prostheses fail, and although a failed prosthesis can be replaced, the results of revision arthroplasty are not as good as the first time. Studying the failed prosthesis and the associated bone and soft tissues provides insight into the causes of failure.

Most prosthetic failures are the result of structural limitations of the implant components. Although material failure may be sudden, a much more common cause is gradual aseptic loosening of the prostheses. Aseptic loosening is caused by both mechanical (gradual loss of material by wear) and biological (osteoclastic resorption of adjacent bone) factors. Wear particles induce a foreign body reaction characterized by a pseudomembrane composed of granulomatous tissues including macrophages, fibroblasts, giant cells, and osteoclasts in addition to debris particles. The extent of this response is driven by the number, size, composition, surface area, and types of particles present. Although there are differences in the relative local toxicity of each of these particles, the end result is the same. These mechanical and biological factors are unavoidable, and the success of a total joint prosthesis depends on the rate with which they occur. Polyethylene wear particles (1–200 ?) are the primary cause of loosening. They are strongly birefringent under polarized light microscopy. Smaller particles are phagocytized by histiocytes, whereas larger particles are surrounded by foreign body giant cells. Fragmentation of PMMA may also cause particulate debris. The presence of these particles (30–100 ?) may be deduced by empty spaces into the soft tissues, often bordered by foreign body giant cells, since PMMA is dissolved by xylene during routine histological techniques. Metal oxides form on the surface of chrome-cobalt or titanium alloys due to an electrolytic process, and stresses on the surface of the metal shear the oxides into the surrounding tissues, causing a black pigmentation of the tissues. Histologically, the black deposits of oxidized metals are seen extracellularly as well as in the cytoplasm of histiocytes. In addition to oxidation, metal undergoes corrosion and, as a result, metal ions enter the soft tissues and the bloodstream. A ceramic-on-ceramic coupling generates a significantly lower amount of debris as compared to the conventional metal-on polyethylene solution. When present, ceramic debris cause a mild histiocytic reaction without giant cells and virtually no osteoclastic bone resorption. There are various secretory proteins at the interfacial membrane that can affect bone turnover, including the cytokines IL-1, IL-6, Il-10, and TNF-a. Other factors involved with bone resorption include the enzymes responsible for catabolism of the organic component of bone, such as MMPs. Prostaglandins, in particular PGE2, are also known to be important intercellular messengers in the osteolytic cascade. More recently, several mediators known to be involved in stimulation or inhibition of osteoclast differentiation and maturation, such as RANKL and osteoprotegerin, have been suggested as key factors in the development and progression of osteolysis.

Infection around a prosthesis also causes loosening in approximately 1–5% of cases. Total joint prostheses become infected by two mechanisms, wound contamination at the time of surgery by Staph. aureus or Staph.epidermidis, and late hematogenous spread of organisms (Staphylo- and Streptococci, E. Coli, Pseudomonas, and anaerobes). The following factors facilitate bacterial growth. First, reaming and sawing, as well as PMMA polymerization, cause necrosis of necrotize bone adjacent to the implant, and such nonvascularized area permits bacteria to grow, safe from circulating host defenses. Second, a highly hydrated matrix of extracellular polymeric substances (biofilm) is formed that defends bacteria from antibiotics and phagocytosis. Third, some metals, such as nickel or cobalt, may depress macrophage function. The distinguishing histologic features of an infected prosthesis is an acute inflammatory reaction: a finding of > 5 PMN or of > 50 lymphocytes/hp field are presumptive for infection. Because some low-grade infections fail to stimulate an acute inflammatory reaction, they go undiagnosed until postoperative period when microbacterial culture results are available. To date, no single routinely used clinical or laboratory test has been shown to achieve ideal sensitivity and specificity for the diagnosis of prosthetic joint infection, and in most cases the diagnosis depends on a combination of clinical features, radiographic findings, and laboratory results. Intra-operative tissue cultures may be falsely negative because of prior antimicrobial exposure, a low number of organisms, inappropriate culture media, or atypical organisms. Conversely, cultures may be falsely positive because of contamination in the operating room, during transport, or in the laboratory. If the implant is removed, the entire prosthesis can be cultured. Moreover, because prosthetic joint infection is a biofilm-mediated infection, techniques that sample bacteria in biofilm, such as sonication or enzymatic treatment, may improve the diagnosis of prosthetic joint infection. More recently, molecular techniques are being used to detect nucleic acid in samples from infected patients even when conventional techniques are negative because of unusual microbial growth requirements or failure to grow after antimicrobial exposure or due to unfavourable environmental conditions. A disadvantage of such approach is its extreme sensitivity, leading to the possibility of false positive results.

The clinical presentation of prosthetic joint infection may be indistinguishable from that of aseptic implant failure. In many cases, culture of granulomatous tissue around failed prostheses, preoperatively diagnosed as aseptically loosened, reveals the presence of bacteria that may per se significantly contribute to the recruitment, maturation and activation of osteoclasts and that superimpose to the foreign body reaction to wear debris. The presence of a smouldering infection in case of “aseptic” failure observed in revision arthroplasties. A systematic investigation on all retrieved implants is mandatory to define the precise role of each potential factor contributing to the pathogenesis of failure, in order to further improve the quality of care of patients having total joint arthroplasty.

The paramount importance of synovial fluid in lubrication and protection of articular joints has long been recognized. Synovial fluid, a dialysate of plasma, forms an interface with both the synovium and cartilage and plays a crucial role in joint lubrication and bearing functions. In an osteoarthritic joint, damage to the articular cartilage causes modifications in the rheological properties of synovial fluid and, reducing the viscoelasticity and increasing the friction between articular surfaces. Viscosupplementation is a treatment for osteoarthritis that uses hyaluronic acid as a (visco)supplement to the diseased joint. The aim of this treatment is to restore the rheological properties of synovial fluid. Osteoarthritis is the most common disease affecting the joints in human population and among the most important causes of pain, disability and economic loss. Therefore, innovative methods are needed to more effectively treat osteoarthritis, directly addressing the disease process. Among various locomotor mechanisms that could serve to illustrate the integrated nature of functional morphology, perhaps none is more complex than the equine locomotor system.

Confronting the need for evaluating the current methods to control joint disease, the horse provides an excellent animal model. As it suffers similar clinical manifestations to those seen in human, it may provide tentative biomedical extrapolations.

Cite this article: Bone Joint Res 2022;11(8):514–517.

Avascular necrosis is poorly understood. The etiological factors have not been fully delineated. This disease process had a huge cost impact on the health system due to surgical treatment. Patients with avascular necrosis seen at a single institution underwent DNA extraction and analysis, coagulation-related analysis and buccal smears with DNA analysis. In this patient group 60% tested positive for at least one thrombophilic or hypofibrinolysis factor. We make recommendations depending on the defect in the cascade, allowing for potential non-surgical management of osteonecrosis in patients undergoing therapy with known antagonistic medications (i.e. corticosteroids).

The etiology and pathogenesis of nontraumatic AVN need to be better elucidated.

Our study identifies the potential association of thrombophilic and hypofibrinolytic factors and osteonecrosis of the hip, particularly genetic markers as identified through DNA markers

The significance of this study:

Osteonecrosis is a devastating musculoskeletal condition;

60% of patients had at least one tested thrombophilic or hypofibrinolysis factor positive. Most patients never had a thrombotic event.

Genetic screening, multiple hematological paramteres were tested on patients with avascular necrosis.

hypercoagulability plays a role in the development of AVN of the hip, mainly at the microvascular level;

Vascular inflammation and activation of myofibroblasts are significant contributors to the progression of fibrosis, which can severely impair tissue function. In various tissues, including tendons, Transforming growth factor beta 1 (TGF-β1) has been identified as a critical driver of adhesion and scar formation. Nevertheless, the mechanisms that underlie fibrotic peritendinous adhesions are still not well comprehended, and human microphysiological systems to help identify effective therapies remain scarce. To address this issue, we developed a novel human Tendon-on-a-Chip (hToC), comprised of an endothelialized vascular compartment harboring circulating monocytes and separated by a 5 μm/100 nm dual-scale ultrathin porous membrane from a type I/III collagen hydrogel with primary tendon fibroblasts and tissue-resident macrophages, all under defined serum-free conditions. The hToC models the crosstalk of the various cells in the system leading to the induction of inflammatory and fibrotic pathways including the activation of mTOR signaling. Consistent with phenotypes observed in vivo in mouse models and clinical human samples, we observed myofibroblast differentiation and senescence, tissue contraction, excessive extracellular matrix deposition, and monocytes’ transmigration and macrophages’ secretion of inflammatory cytokines, which were dependent on the presence of the endothelial barrier. This model offers novel insights on the role of vasculature in the pathophysiology of adhesions, which were previously underappreciated. Moreover, in testing whether the hToC could be used to evaluate efficacy of therapeutics, we were able to capture donor-specific variability in the response to Rapamycin treatment, which reduced myofibroblast activation regardless. Thus, our findings demonstrate the value of the hToC as a human microphysiological system for investigating the pathophysiology of fibrotic conditions in the context of peritendinous injury and similar fibrotic conditions, providing an alternative to animal testing

Tendinopathy can commonly occur around the foot and ankle resulting in isolated rupture, debilitating pain and degenerative foot deformity. The pathophysiology and key cells involved are not fully understood. This is partly because the dense collagen matrix that surrounds relatively few resident cells limits the ability of previous techniques to identify and target those cells of interest. In this study, we apply novel single cell RNA sequencing (CITE-Seq) techniques to healthy and tendinopathic foot/ankle tendons. For the first time we have identified multiple sub-populations of cells in human tendons. These findings challenge the view that there is a single principal tendon cell type and open new avenues for further study. Healthy tendon samples were obtained from patients undergoing tendon transfer procedures; including tibialis posterior and FHL. Diseased tendon samples were obtained during debridement of intractable Achilles and peroneal tendinopathy, and during fusion of degenerative joints. Single cell RNA sequencing with surface proteomic analysis identified 10 sub-populations of human tendon derived cells. These included groups expressing genes associated with fibro-adipogenic progenitors (FAPs) as well as ITGA7+VCAM1- recently described in mouse muscle but, as yet, not human tendon. In addition we have identified previously unrecognised sub-classes of collagen type 1 associated tendon cells. Each sub-class expresses a different set of extra-cellular matrix genes suggesting they each play a unique role in maintaining the structural integrity of normal tendon. Diseased tendon harboured a greater proportion of macrophages and cytotoxic lymphocytes than healthy tendon. This inflammatory response is potentially driven by resident tendon fibroblasts which show increased expression of pro-inflammatory cytokines. Finally, identification of a previously unknown sub-population of cells found predominantly in tendinopathic tissue offers new insight into the underlying pathophysiology. Further work aims to identify novel proteins targets for possible therapeutic pathways

Aims. Osteoarthritis (OA) is a common degenerative joint disease worldwide, which is characterized by articular cartilage lesions. With more understanding of the disease, OA is considered to be a disorder of the whole joint. However, molecular communication within and between tissues during the disease process is still unclear. In this study, we used transcriptome data to reveal crosstalk between different tissues in OA. Methods. We used four groups of transcription profiles acquired from the Gene Expression Omnibus database, including articular cartilage, meniscus, synovium, and subchondral bone, to screen differentially expressed genes during OA. Potential crosstalk between tissues was depicted by ligand-receptor pairs. Results. During OA, there were 626, 97, 1,060, and 2,330 differentially expressed genes in articular cartilage, meniscus, synovium, and subchondral bone, respectively. Gene Ontology enrichment revealed that these genes were enriched in extracellular matrix and structure organization, ossification, neutrophil degranulation, and activation at different degrees. Through ligand-receptor pairing and proteome of OA synovial fluid, we predicted ligand-receptor interactions and constructed a crosstalk atlas of the whole joint. Several interactions were reproduced by transwell experiment in chondrocytes and synovial cells, including TNC-NT5E, TNC-SDC4, FN1-ITGA5, and FN1-NT5E. After lipopolysaccharide (LPS) or interleukin (IL)-1β stimulation, the ligand expression of chondrocytes and synovial cells was upregulated, and corresponding receptors of co-culture cells were also upregulated. Conclusion. Each tissue displayed a different expression pattern in transcriptome, demonstrating their specific roles in OA. We highlighted tissue molecular crosstalk through ligand-receptor pairs in OA pathophysiology, and generated a crosstalk atlas. Strategies to interfere with these candidate ligands and receptors may help to discover molecular targets for future OA therapy. Cite this article: Bone Joint Res 2022;11(12):862–872

Imaging can provide valuable information about the function of tissues and organs. The capacity for detecting and measuring imaging biomarkers of biological activities, allows for a better understanding of the pathophysiology of any process in the human body, including the musculoskeletal system. This is of particular importance in oncologic, metabolic and rheumatologic diseases, but not limited to these. In the domain of the musculoskeletal system, functional imaging also means to be able to address biomechanical evaluations. Weight-bearing imaging and dynamic studies have a prominent role. All imaging techniques (X-rays, CT, MR, ultrasound) are in demand, and offer different applications, specific equipment and novel methods for addressing this. Functional imaging is also essential to drive minimally invasive treatments – i.e. interventional radiology, and new treatment approaches move together with the advances on imaging guidance methods. On both the diagnostic and the interventional side, the increasing availability of dedicated equipment and the development of specific imaging methods and protocols greatly helps the transition from research to clinical practice

The pathophysiological basis of alterations in trabecular bone of patients with osteonecrosis of the femoral head (ONFH) remains unclear. ONFH has classically been considered a vascular disease with secondary changes in the subchondral bone. However, there is increasing evidence suggesting that ONFH could be a bone disease, since alterations in the functionality of bone tissue distant from the necrotic lesion have been observed. We comparatively studied the transcriptomic profile of trabecular bone obtained from the intertrochanteric region of patients with ONFH without an obvious aetiological factor, and patients with osteoarthritis (OA) undergoing total hip replacement in our Institution. To explore the biological processes that could be affected by ONFH, we compared the transcriptomic profile of trabecular bone from the intertrochanteric region and the femoral head of patients affected by this condition. Differential gene expression was studied using an Affymetrix microarray platform. Transcriptome analysis showed a differential signature in trabecular bone from the intertrochanteric region between patients with ONFH and those with OA. The gene ontology analyses of the genes overexpressed in bone tissue of patients with ONFH revealed a range of enriched biological processes related to cell adhesion and migration and angiogenesis. In contrast, most downregulated transcripts were involved in cell division. Trabecular bone in the intertrochanteric region and in the femoral head also exhibited a differential expression profile. Among the genes differentially expressed, we highlighted those related with cytokine production and immune response. This study identified a set of differently expressed genes in trabecular bone of patients with idiopathic ONFH, which might underlie the pathophysiology of this condition. Acknowledgements: This work was supported by grants PI18/00643 and PI22/00939 from ISCIII-FEDER, Ministerio de Ciencia, Innovación y Universidades (MICINN)-AES

Introduction. Osteoarthritis (OA) is a prevalent joint disorder characterized by cartilage degeneration, inflammation, and pain. Current treatments provide only symptomatic relief, necessitating novel molecular targets. The caspase family, known for its roles in apoptosis and inflammation regulation, may additionally influence crucial processes for cartilage homeostasis such as differentiation and proliferation. However, the specific roles of individual caspases in OA pathogenesis remain unclear. This study aims to investigate the involvement of the caspase family in OA and as potential targets for therapy, with a focus on caspase-1 and -8. Method. Chondrocytes from both healthy and OA donors were cultured in 2D and 3D culture models and stimulated with TNF-α or IL-1β. The expression and activation of caspase-1 and -8 was assessed using RT-PCR, ELISA. Transcriptome analysis of OA and healthy cartilage samples, along with Mendelian randomization (MR) analysis were conducted to explore the involvement of caspase family in OA and to assess its potential as therapeutic targets. Result. Higher expression levels of caspase-1, -8 were observed in OA cartilage compared to healthy cartilage. TNF-α stimulation increased their expression in both healthy and OA chondrocytes, while IL-1β had limited impact. Caspase-8 expression was causally associated with knee OA in MR analysis, suggesting a potential therapeutic target. The caspase-1 inhibitor VX-765 mildly reduced chondrocyte viability, with no significant effect in the presence of TNF-α. While the caspase-8 inhibitor Z-IETD-FMK exhibited slight enhancements in cell viability, these improvements were not statistically significant. Nevertheless, its effectiveness significantly increased in the presence of TNF-α. Conclusion. This study highlights the involvement of caspase-1 and caspase-8 in OA pathology, with caspase-8 emerging as a potential therapeutic target for knee OA treatment. Further investigation into the roles of caspase-1 and -8 in OA pathophysiology, including the efficacy and potential side effects of their corresponding inhibitors, is warranted. Acknowledgements. Funding Inter-Action/Inter-Excellence project (BTHA-JC-2022-36/LUABA22019)

Introduction. The most frequent diagnosis in young adults undergoing total hip arthroplasty (THA) is osteonecrosis of the femoral head (ONFH), an evolving and disabling condition with an increasing prevalence worldwide. Treatment of ONFH remains a challenge mainly because of a lack of understanding of the disease's pathophysiological basis. This study investigated the biological processes that could be affected by ONFH by comparing the microstructure, histological characteristics and transcriptomic profile of trabecular bone from the femoral head (FH) and the intertrochanteric region (IT) of patients suffering from this condition. Method. A total of 18 patients with idiopathic ONFH undergoing THA in our institution were included. Trabecular bone explants were taken intraoperatively from the FH and the IT of patients. Bone microstructure was examined by micro-computed tomography (micro-CT). After bone sectioning, histological features were studied by hematoxylin and eosin staining. Differential gene expression was investigated using a microarray platform. Result. Micro-CT imaging showed higher trabecular separation and lower trabecular thickness and bone volume in trabecular bone from the FH than from the IT. Histological staining revealed that the number of osteoblasts on the bone surface and the percentage of empty lacunae were higher in trabecular bone from the FH. Transcriptome analysis identified a differential signature in trabecular bone from the FH compared to the IT. The gene ontology analyses of the genes overexpressed in trabecular bone from the FH revealed a range of enriched biological processes related to cell division and immune response. In contrast, most downregulated transcripts were involved in bone formation. Conclusion. This study identified changes in the microarchitecture, histological features and transcriptomic signature of trabecular bone from the FH of patients with idiopathic ONFH, which might underlie the pathophysiology of this condition. This work was supported by PI22/00939 grant from ISCIII-FEDER-MICINN-AES and Luis Alvarez grant from IdiPAZ

The aim of this study was to examine the incidence of obesity in patients undergoing primary total shoulder replacement (TSR) (stemmed and reverse) for osteoarthritis (OA) in Australia compared to the incidence of obesity in the general population. A 2017–18 cohort of 2,621 patients from the Australian Orthopaedic Association National Joint Replacement Registry (AOANJRR) who underwent TSR, were compared with matched controls from the Australian Bureau of Statistics (ABS) National Health Survey from the same period. The two groups were analysed according to BMI category, sex and age. According to the 2017–18 National Health Survey, 35.6% of Australian adults are overweight and 31.3% are obese. Of the primary TSR cases performed, 34.2% were overweight and 28.6% were obese. The relative risk of requiring TSR for OA increased with increasing BMI category. Class-3 obese females, aged 55–64, were 8.9 times more likely to require TSR compared to normal weight counterparts. Males in the same age and BMI category were 2.5 times more likely. Class-3 obese patients underwent TSR 4 years (female) and 7 years (male) sooner than their normal weight counterparts. Our findings suggest that the obese population is at risk for early and more frequent TSR for OA. Previous studies demonstrate that obese patients undergoing TSR also exhibit increased risks of longer operative times, higher superficial infection rates, higher periprosthetic fracture rates, significantly reduced post-operative forward flexion range and greater revision rates. Obesity significantly increases the risk of requiring TSR. To our knowledge this is the first study to publish data pertaining to age and BMI stratification of TSR Societal efforts are vital to diminish the prevalence and burden of obesity related TSR. There may well be reversible pathophysiology in the obese population to address prior to surgery (adipokines, leptin, NMDA receptor upregulation). Surgery occurs due to recalcitrant or increased pain despite non-op Mx

Osteoporosis can cause significant disability and cost to health services globally. We aim to compare risk fractures for both osteoporosis and fractures at the L1-L4 vertebrae (LV) and the neck of femurs (NOFs) in patients referred for DEXA scan in the North-West of England. Data was obtained from 31546 patients referred for DEXA scan in the North-West of England between 2004 and 2011. Demographic data was retrospectively analysed using STATA, utilising chi-squared and t-tests. Logistical models were used to report odds ratios for risk factors included in the FRAX tool looking for differences between osteoporosis and fracture risk at the LV and NOFs. In a study involving 2530 cases of LV fractures and 1363 of NOF fractures, age was significantly linked to fractures and osteoporosis at both sites, with a higher risk of osteoporosis at NOFs compared to LV. Height provided protection against fractures and osteoporosis at both sites, with a more pronounced protective effect against osteoporosis at NOFs. Weight was more protective for NOF fractures, while smoking increased osteoporosis risk with no site-specific difference. Steroids were unexpectedly protective for fractures at both sites, with no significant difference, while alcohol consumption was protective against osteoporosis at both sites and associated with increased LV fracture risk. Rheumatoid arthritis increased osteoporosis risk in NOFs and implied a higher fracture risk, though not statistically significant compared to LV. Results summarised in Table 1. Our study reveals that established osteoporosis and fracture risk factors impact distinct bony sites differently. Age and rheumatoid arthritis increase osteoporosis risk more at NOFs than LV, while height and steroids provide greater protection at NOFs. Height significantly protects LV fractures, with alcohol predicting them. Further research is needed to explore risk factors’ impact on additional bony sites and understand the observed differences’ pathophysiology. For any figures or tables, please contact the authors directly

Aim. The osteolytic process of osteomyelitis is, according to textbooks, caused by increased osteoclast activity due to RANKL production by osteoblasts. However, recent findings contradict this theory. Therefore, the aim was to investigate, in a porcine osteomyelitis model, how osteolysis is affected by massive inflammation and RANKL blocking, respectively. In parallel, patients with chronic osteomyelitis, diabetes, foot osteomyelitis, and fracture related infections (FRI) were included for advanced histological analysis of osteolysis. Methods. In pigs, a tibial implant cavity was created and inoculated with 10. 4. CFU of Staphylococcus aureus: Group A (n=7). Group B (n=7); + 1cm. 3. spongostan into the cavity. Group C (n=4); + systemic Denosumab treatment. Spongostan was used as an avascular material to support bacterial growth and thus increase the inflammatory response. Denosumab treatment was administrated to suppress osteoclast activity by RANKL inhibition (as in osteoporotic patients). The volume of osteolysis was accessed by CT scans. Immunohistochemistry with antibodies towards Cathepsin K was used to identify osteoclasts within the bone lesions. Briefly, the number of Cathepsin K positive cells, i.e., both precursors and bone resorbing osteoclasts, respectively, were counted in 10 high power fields (400x). In total, 50 bone infection patients were included (Herlev Hospital). From each patient five parried samples were taken for histology and microbiology, respectively. Histopathology, CT osteolysis volume estimation, and molecular expression of osteoclasts and inflammatory markers are ongoing. One FRI patient was osteoporotic and treated with Denosumab for 6 years. Results. All pigs were confirmed infected in the implant cavity. The volume (2.41 ± 1.29cm. 3. ) of osteolysis was significantly increased in the spongostan group in comparison to Group A (1.24 ± 0.59 cm. 3. ) (p=0.04). Thereby, the spongostan group had bacteria deeper into the bone from the inoculation point. Sufficient Denosumab treatment, i.e. reduced serum Ca was seen in 3 pigs. None of the Denosumab treated pigs showed reduced osteolysis in comparison to Group A (1.42 ± 0.63 cm. 3. ). The Cathepsin K score of Group C was 17 (15-23 IQR) of precursor osteoclasts and 2 (0-2 IQR) of osteoclasts in Howship lacunae. The Denosumab treated patient showed substantial osteolysis and histological analysis confirmed acute inflammatory. Conclusions. Application of spongostan, i.e., bacterial host optimization and massive inflammation promotes osteolysis and local bacterial dissemination. Osteoclast blocking with Denosumab showed no impact on osteolysis. Elucidation of the pathophysiology causing bone loss in osteomyelitis is fundamental. However, the widely accepted osteoclast-based theory might not be the only relevant

Aims. The increase in prescription opioid misuse and dependence is now a public health crisis in the UK. It is recognized as a whole-person problem that involves both the medical and the psychosocial needs of patients. Analyzing aspects of pathophysiology, emotional health, and social wellbeing associated with persistent opioid use after injury may inform safe and effective alleviation of pain while minimizing risk of misuse or dependence. Our objectives were to investigate patient factors associated with opioid use two to four weeks and six to nine months after an upper limb fracture. Methods. A total of 734 patients recovering from an isolated upper limb fracture were recruited in this study. Opioid prescription was documented retrospectively for the period preceding the injury, and prospectively at the two- to four-week post-injury visit and six- to nine-month post-injury visit. Bivariate and multivariate analysis sought factors associated with opioid prescription from demographics, injury-specific data, Patient Reported Outcome Measurement Instrumentation System (PROMIS), Depression computer adaptive test (CAT), PROMIS Anxiety CAT, PROMIS Instrumental Support CAT, the Pain Catastrophizing Scale (PCS), the Pain Self-efficacy Questionnaire (PSEQ-2), Tampa Scale for Kinesiophobia (TSK-11), and measures that investigate levels of social support. Results. A new prescription of opioids two to four weeks after injury was independently associated with less social support (odds ratio (OR) 0.26, p < 0.001), less instrumental support (OR 0.91, p < 0.001), and greater symptoms of anxiety (OR 1.1, p < 0.001). A new prescription of opioids six to nine months after injury was independently associated with less instrumental support (OR 0.9, p < 0.001) and greater symptoms of anxiety (OR 1.1, p < 0.001). Conclusion. This study demonstrates that potentially modifiable psychosocial factors are associated with increased acute and chronic opioid prescriptions following upper limb fracture. Surgeons prescribing opioids for upper limb fractures should be made aware of the screening and management of emotional and social health. Cite this article: Bone Jt Open 2021;2(2):119–124