Aims. Long non-coding RNAs (lncRNAs) act as crucial regulators in osteoporosis (OP). Nonetheless, the effects and potential molecular mechanism of lncRNA PCBP1 Antisense RNA 1 (PCBP1-AS1) on OP remain largely unclear. The aim of this study was to explore the role of lncRNA PCBP1-AS1 in the pathogenesis of OP. Methods. Using quantitative real-time polymerase chain reaction (qRT-PCR), osteogenesis-related genes (alkaline phosphatase (ALP), osteocalcin (OCN), osteopontin (OPN), and Runt-related transcription factor 2 (RUNX2)), PCBP1-AS1, microRNA (miR)-126-5p, group I Pak family member p21-activated kinase 2 (PAK2), and their relative expression levels were determined. Western blotting was used to examine the expression of PAK2 protein. Cell Counting Kit-8 (CCK-8) assay was used to measure cell proliferation. To examine the osteogenic differentiation, Alizarin red along with ALP staining was used. RNA immunoprecipitation assay and bioinformatics analysis, as well as a dual-luciferase reporter, were used to study the association between PCBP1-AS1, PAK2, and miR-126-5p. Results. The expression of PCBP1-AS1 was pre-eminent in OP tissues and decreased throughout the development of human bone marrow-derived mesenchymal stem cells (hBMSCs) into osteoblasts. PCBP1-AS1 knockdown and overexpression respectively promoted and suppressed hBMSC proliferation and osteogenic differentiation capacity. Mechanistically, PCBP1-AS1 sponged miR-126-5p and consequently targeted PAK2. Inhibiting miR-126-5p significantly counteracted the beneficial effects of PCBP1-AS1 or PAK2 knockdown on hBMSCs’ ability to differentiate into osteoblasts. Conclusion. PCBP1-AS1 is responsible for the development of OP and promotes its progression by inducing PAK2 expression via competitively binding to miR-126-5p. PCBP1-AS1 may therefore be a new therapeutic target for OP patients. Cite this article: Bone Joint Res 2023;12(6):375–386

Aims. Osteoporosis (OP) is a metabolic bone disease, characterized by a decrease in bone mineral density (BMD). However, the research of regulatory variants has been limited for BMD. In this study, we aimed to explore novel regulatory genetic variants associated with BMD. Methods. We conducted an integrative analysis of BMD genome-wide association study (GWAS) and regulatory single nucleotide polymorphism (rSNP) annotation information. Firstly, the discovery GWAS dataset and replication GWAS dataset were integrated with rSNP annotation database to obtain BMD associated SNP regulatory elements and SNP regulatory element-target gene (E-G) pairs, respectively. Then, the common genes were further subjected to HumanNet v2 to explore the biological effects. Results. Through discovery and replication integrative analysis for BMD GWAS and rSNP annotation database, we identified 36 common BMD-associated genes for BMD irrespective of regulatory elements, such as FAM3C (p. discovery GWAS. = 1.21 × 10. -25. , p. replication GWAS. = 1.80 × 10. -12. ), CCDC170 (p. discovery GWAS. = 1.23 × 10. -11. , p. replication GWAS. = 3.22 × 10. -9. ), and SOX6 (p. discovery GWAS. = 4.41 × 10. -15. , p. replication GWAS. = 6.57 × 10. -14. ). Then, for the 36 common target genes, multiple gene ontology (GO) terms were detected for BMD such as positive regulation of cartilage development (p = 9.27 × 10. -3. ) and positive regulation of chondrocyte differentiation (p = 9.27 × 10. -3. ). Conclusion. We explored the potential roles of rSNP in the genetic mechanisms of BMD and identified multiple candidate genes. Our study results support the implication of regulatory genetic variants in the development of OP. Cite this article: Bone Joint Res 2023;12(2):147–154

Aims. Machine-learning (ML) prediction models in orthopaedic trauma hold great promise in assisting clinicians in various tasks, such as personalized risk stratification. However, an overview of current applications and critical appraisal to peer-reviewed guidelines is lacking. The objectives of this study are to 1) provide an overview of current ML prediction models in orthopaedic trauma; 2) evaluate the completeness of reporting following the Transparent Reporting of a multivariable prediction model for Individual Prognosis Or Diagnosis (TRIPOD) statement; and 3) assess the risk of bias following the Prediction model Risk Of Bias Assessment Tool (PROBAST) tool. Methods. A systematic search screening 3,252 studies identified 45 ML-based prediction models in orthopaedic trauma up to January 2023. The TRIPOD statement assessed transparent reporting and the PROBAST tool the risk of bias. Results. A total of 40 studies reported on training and internal validation; four studies performed both development and external validation, and one study performed only external validation. The most commonly reported outcomes were mortality (33%, 15/45) and length of hospital stay (9%, 4/45), and the majority of prediction models were developed in the hip fracture population (60%, 27/45). The overall median completeness for the TRIPOD statement was 62% (interquartile range 30 to 81%). The overall risk of bias in the PROBAST tool was low in 24% (11/45), high in 69% (31/45), and unclear in 7% (3/45) of the studies. High risk of bias was mainly due to analysis domain concerns including small datasets with low number of outcomes, complete-case analysis in case of missing data, and no reporting of performance measures. Conclusion. The results of this study showed that despite a myriad of potential clinically useful applications, a substantial part of ML studies in orthopaedic trauma lack transparent reporting, and are at high risk of bias. These problems must be resolved by following established guidelines to instil confidence in ML models among patients and clinicians. Otherwise, there will remain a sizeable gap between the development of ML prediction models and their clinical application in our day-to-day orthopaedic trauma practice. Cite this article: Bone Jt Open 2024;5(1):9–19

Aims. This study examined the relationship between obesity (OB) and osteoporosis (OP), aiming to identify shared genetic markers and molecular mechanisms to facilitate the development of therapies that target both conditions simultaneously. Methods. Using weighted gene co-expression network analysis (WGCNA), we analyzed datasets from the Gene Expression Omnibus (GEO) database to identify co-expressed gene modules in OB and OP. These modules underwent Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment and protein-protein interaction analysis to discover Hub genes. Machine learning refined the gene selection, with further validation using additional datasets. Single-cell analysis emphasized specific cell subpopulations, and enzyme-linked immunosorbent assay (ELISA), protein blotting, and cellular staining were used to investigate key genes. Results. WGCNA revealed critical gene modules for OB and OP, identifying the Toll-like receptor (TLR) signalling pathway as a common factor. TLR2 was the most significant gene, with a pronounced expression in macrophages. Elevated TLR2 expression correlated with increased adipose accumulation, inflammation, and osteoclast differentiation, linking it to OP development. Conclusion. Our study underscores the pivotal role of TLR2 in connecting OP and OB. It highlights the influence of TLR2 in macrophages, driving both diseases through a pro-inflammatory mechanism. These insights propose TLR2 as a potential dual therapeutic target for treating OP and OB. Cite this article: Bone Joint Res 2024;13(10):573–587

Aims. This study aimed to assess the risk of acute kidney injury (AKI) associated with combined intravenous (IV) and topical antibiotic therapy in patients undergoing treatment for periprosthetic joint infections (PJIs) following total knee arthroplasty (TKA), utilizing the Kidney Disease: Improving Global Outcomes (KDIGO) criteria for classification. Methods. We conducted a retrospective analysis of 162 knees (162 patients) that received treatment for PJI post-TKA with combined IV and topical antibiotic infusions at a single academic hospital from 1 January 2010 to 31 December 2022. The incidence of AKI was evaluated using the KDIGO criteria, focussing on the identification of significant predictors and the temporal pattern of AKI development. Results. AKI was identified in 9.26% (15/162) of the cohort, predominantly presenting as stage 1 AKI, which was transient in nature and resolved prior to discharge. The analysis highlighted moderate anaemia and lower baseline serum creatinine levels as significant predictors for the development of AKI. Notably, the study found no instances of severe complications such as wound dehiscence, skin erosion, or the need for haemodialysis following treatment. Conclusion. The findings suggest that the combined use of IV and topical antibiotic therapy in the management of PJIs post-TKA is associated with a low incidence of primarily transient stage 1 AKI. This indicates a potentially favourable renal safety profile, advocating for further research to confirm these outcomes and potentially influence treatment protocols in PJI management. Cite this article: Bone Joint Res 2024;13(10):525–534

Aims. Chronic osteomyelitis (COM) of the lower limb in adults can be surgically managed by either limb reconstruction or amputation. This scoping review aims to map the outcomes used in studies surgically managing COM in order to aid future development of a core outcome set. Methods. A total of 11 databases were searched. A subset of studies published between 1 October 2020 and 1 January 2011 from a larger review mapping research on limb reconstruction and limb amputation for the management of lower limb COM were eligible. All outcomes were extracted and recorded verbatim. Outcomes were grouped and categorized as per the revised Williamson and Clarke taxonomy. Results. A total of 3,303 records were screened, of which 99 studies were included. Most studies were case series (77/99; 78%) and assessed one method of reconstruction (68/99; 69%). A total of 511 outcomes were reported, which were grouped into 58 distinct outcomes. Overall, 143/511 of all outcomes (28%) were provided with a clear, in-text definition, and 231 outcomes (45%) had details reported of how and when they were measured. The most commonly reported outcome was ‘recurrence of osteomyelitis’ (62; 12%). The single-most patient-reported outcome measure was ‘pain’. Conclusion. This study has highlighted significant inconsistencies in the defining, reporting, and measuring of outcomes across studies investigating surgical management for chronic osteomyelitis of the lower limb in adults. Future studies should clearly report complete details of how outcomes are defined and measured, including timing. The development of a standardized core outcome set would be of significant benefit in order to allow evidence synthesis and comparison across studies. Cite this article: Bone Jt Open 2023;4(3):146–157

Aims. Several previously identified patient-, injury-, and treatment-related factors are associated with the development of nonunion in distal femur fractures. However, the predictive value of these factors is not well defined. We aimed to assess the predictive ability of previously identified risk factors in the development of nonunion leading to secondary surgery in distal femur fractures. Methods. We conducted a retrospective cohort study of adult patients with traumatic distal femur fracture treated with lateral locking plate between 2009 and 2018. The patients who underwent secondary surgery due to fracture healing problem or plate failure were considered having nonunion. Background knowledge of risk factors of distal femur fracture nonunion based on previous literature was used to form an initial set of variables. A logistic regression model was used with previously identified patient- and injury-related variables (age, sex, BMI, diabetes, smoking, periprosthetic fracture, open fracture, trauma energy, fracture zone length, fracture comminution, medial side comminution) in the first analysis and with treatment-related variables (different surgeon-controlled factors, e.g. plate length, screw placement, and proximal fixation) in the second analysis to predict the nonunion leading to secondary surgery in distal femur fractures. Results. We were able to include 299 fractures in 291 patients. Altogether, 31/299 fractures (10%) developed nonunion. In the first analysis, pseudo-R. 2. was 0.27 and area under the receiver operating characteristic curve (AUC) was 0.81. BMI was the most important variable in the prediction. In the second analysis, pseudo-R. 2. was 0.06 and AUC was 0.67. Plate length was the most important variable in the prediction. Conclusion. The model including patient- and injury-related factors had moderate fit and predictive ability in the prediction of distal femur fracture nonunion leading to secondary surgery. BMI was the most important variable in prediction of nonunion. Surgeon-controlled factors had a minor role in prediction of nonunion. Cite this article: Bone Jt Open 2023;4(8):584–593

Aims. There is a lack of biomaterial-based carriers for the local delivery of rifampicin (RIF), one of the cornerstone second defence antibiotics for bone infections. RIF is also known for causing rapid development of antibiotic resistance when given as monotherapy. This in vitro study evaluated a clinically used biphasic calcium sulphate/hydroxyapatite (CaS/HA) biomaterial as a carrier for dual delivery of RIF with vancomycin (VAN) or gentamicin (GEN). Methods. The CaS/HA composites containing RIF/GEN/VAN, either alone or in combination, were first prepared and their injectability, setting time, and antibiotic elution profiles were assessed. Using a continuous disk diffusion assay, the antibacterial behaviour of the material was tested on both planktonic and biofilm-embedded forms of standard and clinical strains of Staphylococcus aureus for 28 days. Development of bacterial resistance to RIF was determined by exposing the biofilm-embedded bacteria continuously to released fractions of antibiotics from CaS/HA-antibiotic composites. Results. Following the addition of RIF to CaS/HA-VAN/GEN, adequate injectability and setting of the CaS/HA composites were noted. Sustained release of RIF above the minimum inhibitory concentrations of S. aureus was observed until study endpoint (day 35). Only combinations of CaS/HA-VAN/GEN + RIF exhibited antibacterial and antibiofilm effects yielding no viable bacteria at study endpoint. The S. aureus strains developed resistance to RIF when biofilms were subjected to CaS/HA-RIF alone but not with CaS/HA-VAN/GEN + RIF. Conclusion. Our in vitro results indicate that biphasic CaS/HA loaded with VAN or GEN could be used as a carrier for RIF for local delivery in clinically demanding bone infections. Cite this article: Bone Joint Res 2022;11(11):787–802

Aims. The primary aim of this study was to compare the migration of the femoral and tibial components of the cementless rotating platform Attune and Low Contact Stress (LCS) total knee arthroplasty (TKA) designs, two years postoperatively, using radiostereometric analysis (RSA) in order to assess the risk of the development of aseptic loosening. A secondary aim was to compare clinical and patient-reported outcome measures (PROMs) between the designs. Methods. A total of 61 TKAs were analyzed in this randomized clinical RSA trial. RSA examinations were performed one day and three, six, 12, and 24 months postoperatively. The maximal total point motion (MPTM), translations, and rotations of the components were analyzed. PROMs and clinical data were collected preoperatively and at six weeks and three, six, 12, and 24 months postoperatively. Linear mixed effect modelling was used for statistical analyses. Results. The mean MTPM two years postoperatively (95% confidence interval (CI)) of the Attune femoral component (0.92 mm (0.75 to 1.11)) differed significantly from that of the LCS TKA (1.72 mm (1.47 to 2.00), p < 0.001). The Attune femoral component subsided, tilted (anteroposteriorly), and rotated (internal-external) significantly less. The mean tibial MTPM two years postoperatively did not differ significantly, being 1.11 mm (0.94 to 1.30) and 1.17 mm (0.99 to 1.36, p = 0.447) for the Attune and LCS components, respectively. The rate of migration in the second postoperative year was negligible for the femoral and tibial components of both designs. The mean pain-at-rest (numerical rating scale (NRS)-rest) in the Attune group was significantly less compared with that in the LCS group during the entire follow-up period. At three months postoperatively, the Knee injury and Osteoarthritis Outcome Physical Function Shortform score, the Oxford Knee Score, and the NRS-activity scores were significantly better in the Attune group. Conclusion. The mean MTPM of the femoral components of the cementless rotating platform Attune was significantly less compared with that of the LCS design. This was reflected mainly in significantly less subsidence, posterior tilting, and internal rotation. The mean tibial MTPMs were not significantly different. During the second postoperative year, the components of both designs stabilized and low risks for the development of aseptic loosening are expected. Cite this article: Bone Joint J 2023;105-B(2):148–157

Despite the vast quantities of published artificial intelligence (AI) algorithms that target trauma and orthopaedic applications, very few progress to inform clinical practice. One key reason for this is the lack of a clear pathway from development to deployment. In order to assist with this process, we have developed the Clinical Practice Integration of Artificial Intelligence (CPI-AI) framework – a five-stage approach to the clinical practice adoption of AI in the setting of trauma and orthopaedics, based on the IDEAL principles (. https://www.ideal-collaboration.net/. ). Adherence to the framework would provide a robust evidence-based mechanism for developing trust in AI applications, where the underlying algorithms are unlikely to be fully understood by clinical teams. Cite this article: Bone Joint Res 2024;13(9):507–512

Osteoarthritis (OA) is a chronic degenerative joint disease characterized by progressive cartilage degradation, synovial membrane inflammation, osteophyte formation, and subchondral bone sclerosis. Pathological changes in cartilage and subchondral bone are the main processes in OA. In recent decades, many studies have demonstrated that activin-like kinase 3 (ALK3), a bone morphogenetic protein receptor, is essential for cartilage formation, osteogenesis, and postnatal skeletal development. Although the role of bone morphogenetic protein (BMP) signalling in articular cartilage and bone has been extensively studied, many new discoveries have been made in recent years around ALK3 targets in articular cartilage, subchondral bone, and the interaction between the two, broadening the original knowledge of the relationship between ALK3 and OA. In this review, we focus on the roles of ALK3 in OA, including cartilage and subchondral bone and related cells. It may be helpful to seek more efficient drugs or treatments for OA based on ALK3 signalling in future

The August 2023 Knee Roundup. 360. looks at: Curettage and cementation of giant cell tumour of bone: is arthritis a given?; Anterior knee pain following total knee arthroplasty: does the patellar cement-bone interface affect postoperative anterior knee pain?; Nickel allergy and total knee arthroplasty; The use of artificial intelligence for the prediction of periprosthetic joint infection following aseptic revision total knee arthroplasty; Ambulatory unicompartmental knee arthroplasty: development of a patient selection tool using machine learning; Femoral asymmetry: a missing piece in knee alignment; Needle arthroscopy – a benefit to patients in the outpatient setting; Can lateral unicompartmental knees be done in a day-case setting?

The December 2024 Children’s orthopaedics Roundup. 360. looks at: Establishing best practice for managing idiopathic toe walking in children: a UK consensus; Long-term outcomes of below-elbow casting in paediatric diaphyseal forearm fractures; Residual dysplasia risk persists in developmental dysplasia of the hip patients after Pavlik harness treatment; 3D printing in paediatricorthopaedics: enhancing surgical efficiency and patient outcomes; Pavlik harness treatment for hip dysplasia does not delay motor skill development in children; High prevalence of hip dysplasia found in adolescents with idiopathic scoliosis on routine spine radiographs; Minifragment plates as effective growth modulation for ulnar deformities of the distal radius in children; Long-term success of Chiari pelvic osteotomy in preserving hip function: 30-year follow-up study

The June 2024 Trauma Roundup. 360. looks at: Skin antisepsis before surgical fixation of limb fractures; Comparative analysis of intramedullary nail versus plate fixation for fibula fracture in supination external rotation type IV ankle injury; Early weightbearing versus late weightbearing after intramedullary nailing for distal femoral fracture (AO/OTA 33) in elderly patients: a multicentre propensity-matched study; Long-term outcomes with spinal versus general anaesthesia for hip fracture surgery; Operative versus nonoperative management of unstable medial malleolus fractures: a randomized clinical trial; Impact of smoking status on fracture-related infection characteristics and outcomes; Reassessing empirical antimicrobial choices in fracture-related infections; Development and validation of the Nottingham Trauma Frailty Index (NTFI) for older trauma patients

Musculoskeletal diseases are having a growing impact worldwide. It is therefore crucial to have an evidence base to most effectively and efficiently implement future health services across different healthcare systems. International trials are an opportunity to address these challenges and have many potential benefits. They are, however, complex to set up and deliver, which may impact on the efficient and timely delivery of a project. There are a number of models of how international trials are currently being delivered across a range of orthopaedic patient populations, which are discussed here. The examples given highlight that the key to overcoming these challenges is the development of trusted and equal partnerships with collaborators in each country. International trials have the potential to address a global burden of disease, and in turn optimize the benefit to patients in the collaborating countries and those with similar health services and care systems. Cite this article: Bone Joint J 2023;105-B(7):719–722

Aims. The present study investigated receptor activator of nuclear factor kappa-Β ligand (RANKL), osteoprotegerin (OPG), and Runt-related transcription factor 2 (RUNX2) gene expressions in giant cell tumour of bone (GCTB) patients in relationship with tumour recurrence. We also aimed to investigate the influence of CpG methylation on the transcriptional levels of RANKL and OPG. Methods. A total of 32 GCTB tissue samples were analyzed, and the expression of RANKL, OPG, and RUNX2 was evaluated by quantitative polymerase chain reaction (qPCR). The methylation status of RANKL and OPG was also evaluated by quantitative methylation-specific polymerase chain reaction (qMSP). Results. We found that RANKL and RUNX2 gene expression was upregulated more in recurrent than in non-recurrent GCTB tissues, while OPG gene expression was downregulated more in recurrent than in non-recurrent GCTB tissues. Additionally, we proved that changes in DNA methylation contribute to upregulating the expression of RANKL and downregulating the expression of OPG, which are critical for bone homeostasis and GCTB development. Conclusion. Our results suggest that the overexpression of RANKL/RUNX2 and the lower expression of OPG are associated with recurrence in GCTB patients. Cite this article: Bone Joint Res 2024;13(2):84–91

Shoulder injury related to vaccine administration (SIRVA) is a prolonged episode of shoulder dysfunction that commences within 24 to 48 hours of a vaccination. Symptoms include a combination of shoulder pain, stiffness, and weakness. There has been a recent rapid increase in reported cases of SIRVA within the literature, particularly in adults, and is likely related to the mass vaccination programmes associated with COVID-19 and influenza. The pathophysiology is not certain, but placement of the vaccination in the subdeltoid bursa or other pericapsular tissue has been suggested to result in an inflammatory capsular process. It has been hypothesized that this is associated with a vaccine injection site that is “too high” and predisposes to the development of SIRVA. Nerve conduction studies are routinely normal, but further imaging can reveal deep-deltoid collections, rotator cuff tendinopathy and tears, or subacromial subdeltoid bursitis. However, all of these are common findings within a general asymptomatic population. Medicolegal claims in the UK, based on an incorrect injection site, are unlikely to meet the legal threshold to determine liability. Cite this article: Bone Joint J 2023;105-B(8):839–842

Aims. The aim of this investigation was to compare risk of infection in both cemented and uncemented hemiarthroplasty (HA) as well as in total hip arthroplasty (THA) following femoral neck fracture. Methods. Data collection was performed using the German Arthroplasty Registry (EPRD). In HA and THA following femoral neck fracture, fixation method was divided into cemented and uncemented prostheses and paired according to age, sex, BMI, and the Elixhauser Comorbidity Index using Mahalanobis distance matching. Results. Overall in 13,612 cases of intracapsular femoral neck fracture, 9,110 (66.9%) HAs and 4,502 (33.1%) THAs were analyzed. Infection rate in HA was significantly reduced in cases with use of antibiotic-loaded cement compared with uncemented fixated prosthesis (p = 0.013). In patients with THA no statistical difference between cemented and uncemented prosthesis was registered, however after one year 2.4% of infections were detected in uncemented and 2.1% in cemented THA. In the subpopulation of HA after one year, 1.9% of infections were registered in cemented and 2.8% in uncemented HA. BMI (p = 0.001) and Elixhauser Comorbidity Index (p < 0.003) were identified as risk factors of periprosthetic joint infection (PJI), while in THA cemented prosthesis also demonstrated an increased risk within the first 30 days (hazard ratio (HR) = 2.73; p = 0.010). Conclusion. The rate of infection after intracapsular femoral neck fracture was statistically significantly reduced in patients treated by antibiotic-loaded cemented HA. Particularly for patients with multiple risk factors for the development of a PJI, the usage of antibiotic-loaded bone cement seems to be a reasonable procedure for prevention of infection. Cite this article: Bone Joint Res 2023;12(5):331–338

Aims. To report the development of the technique for minimally invasive lumbar decompression using robotic-assisted navigation. Methods. Robotic planning software was used to map out bone removal for a laminar decompression after registration of CT scan images of one cadaveric specimen. A specialized acorn-shaped bone removal robotic drill was used to complete a robotic lumbar laminectomy. Post-procedure advanced imaging was obtained to compare actual bony decompression to the surgical plan. After confirming accuracy of the technique, a minimally invasive robotic-assisted laminectomy was performed on one 72-year-old female patient with lumbar spinal stenosis. Postoperative advanced imaging was obtained to confirm the decompression. Results. A workflow for robotic-assisted lumbar laminectomy was successfully developed in a human cadaveric specimen, as excellent decompression was confirmed by postoperative CT imaging. Subsequently, the workflow was applied clinically in a patient with severe spinal stenosis. Excellent decompression was achieved intraoperatively and preservation of the dorsal midline structures was confirmed on postoperative MRI. The patient experienced improvement in symptoms postoperatively and was discharged within 24 hours. Conclusion. Minimally invasive robotic-assisted lumbar decompression utilizing a specialized robotic bone removal instrument was shown to be accurate and effective both in vitro and in vivo. The robotic bone removal technique has the potential for less invasive removal of laminar bone for spinal decompression, all the while preserving the spinous process and the posterior ligamentous complex. Spinal robotic surgery has previously been limited to the insertion of screws and, more recently, cages; however, recent innovations have expanded robotic capabilities to decompression of neurological structures. Cite this article: Bone Jt Open 2024;5(9):809–817