Aims. The involvement of long non-coding RNA (lncRNA) in bone marrow mesenchymal stem cell (MSC) osteogenic differentiation during osteoporosis (OP) development has attracted much attention. In this study, we aimed to disclose how LINC01089 functions in human mesenchymal stem cell (hMSC) osteogenic differentiation, and to study the mechanism by which LINC01089 regulates MSC osteogenesis. Methods. Quantitative reverse transcription polymerase chain reaction (RT-qPCR) and western blotting were performed to analyze LINC01089, miR-1287-5p, and heat shock protein family A (HSP70) member 4 (HSPA4) expression. The osteogenic differentiation of MSCs was assessed through alkaline phosphatase (ALP) activity, alizarin red S (ARS) staining, and by measuring the levels of osteogenic gene marker expressions using commercial kits and RT-qPCR analysis. Cell proliferative capacity was evaluated via the Cell Counting Kit-8 (CCK-8) assay. The binding of miR-1287-5p with LINC01089 and HSPA4 was verified by performing dual-luciferase reporter and RNA immunoprecipitation (RIP) experiments. Results. LINC01089 expression was reinforced in serum samples of OP patients, but it gradually diminished while hMSCs underwent osteogenic differentiation. LINC01089 knockdown facilitated hMSC osteogenic differentiation. This was substantiated by: the increase in ALP activity; ALP, runt-related transcription factor 2 (RUNX2), osteocalcin (OCN), and osteopontin (OPN) messenger RNA (mRNA) levels; and level of ARS staining. Meanwhile, LINC01089 upregulation resulted in the opposite effects. LINC01089 targeted miR-1287-5p, and the LINC01089 knockdown-induced hMSC osteogenic differentiation was repressed by miR-1287-5p depletion. HSPA4 is a downstream function molecule of the LINC01089/miR-1287-5p pathway; miR-1287-5p negatively modulated HSPA4 levels and attenuated its functional effects. Conclusion. LINC01089 negatively regulated hMSC osteogenic differentiation, at least in part, via governing miR-1287-5p/HSPA4 signalling. These findings provide new insights into hMSC osteogenesis and bone metabolism. Cite this article: Bone Joint Res 2024;13(12):779–789

Aims

This meta-analysis and systematic review aimed to comprehensively investigate the effects of vitamin K supplementation on bone mineral density (BMD) at various sites and bone metabolism in middle-aged and older adults.

Addressing bone defects is a complex medical challenge that involves dealing with various skeletal conditions, including fractures, osteoporosis (OP), bone tumours, and bone infection defects. Despite the availability of multiple conventional treatments for these skeletal conditions, numerous limitations and unresolved issues persist. As a solution, advancements in biomedical materials have recently resulted in novel therapeutic concepts. As an emerging biomaterial for bone defect treatment, graphene oxide (GO) in particular has gained substantial attention from researchers due to its potential applications and prospects. In other words, GO scaffolds have demonstrated remarkable potential for bone defect treatment. Furthermore, GO-loaded biomaterials can promote osteoblast adhesion, proliferation, and differentiation while stimulating bone matrix deposition and formation. Given their favourable biocompatibility and osteoinductive capabilities, these materials offer a novel therapeutic avenue for bone tissue regeneration and repair. This comprehensive review systematically outlines GO scaffolds’ diverse roles and potential applications in bone defect treatment. Cite this article: Bone Joint Res 2024;13(12):725–740

Aims

Extracellular matrix (ECM) is a critical determinant of tissue mechanobiology, yet remains poorly characterized in joint tissues beyond cartilage in osteoarthritis (OA). This review aimed to define the composition and architecture of non-cartilage soft joint tissue structural ECM in human OA, and to compare the changes observed in humans with those seen in animal models of the disease.

The December 2024 Wrist & Hand Roundup³⁶⁰ looks at: Variability in thumb ulnar collateral ligament rupture management across the UK: survey insights; Identifying five distinct hand osteoarthritis pain phenotypes highlights the impact of biopsychosocial factors; Long-term outcomes of MAÏA TMC joint prosthesis for osteoarthritis: a possible alternative to trapeziectomy; Diagnostic and management strategies for malignant melanoma of the hand; Early versus delayed surgery for distal radius fractures: comparable outcomes but higher complications in delayed treatment; Perioperative anticoagulant and antiplatelet use does not increase complications in wide-awake hand surgery; Variability in treatment of metacarpal shaft fractures highlights need for standardized care; Low-intensity pulsed ultrasound ineffective in reducing time to union for scaphoid nonunion post-surgery.

Introduction. Promoting bone mass homeostasis keeps skeleton away from osteoporosis. a-Ketoglutarate (a-KG) is an indispensable intermediate of tricarboxylic acid cycle (TCA) process for cellular energy production. a-KG mitigates cellular senescence, tissue degeneration, and oxidative stress. We investigated whether a-KG affected osteoblast activity or osteoporosis development. Method. Serum and bone specimens were biopsied from 26 patients with osteoporosis or 24 patients without osteoporosis who required spinal surgery. Ovariectomized or aged mice were fed 0.25% or 0.75% a-KG in drinking water for 8 – 12 weeks ad libitum. Bone mineral density, trabecular/cortical bone microarchitecture, mechanical strength, bone formation, and osteoclastic erosion were investigated using mCT, material testing device, in vivo calcein labelling, and TRAP histochemical staining. Serum a-KG, osteocalcin, and TRAP5b levels were quantified using ELISA kits. Bone-marrow mesenchymal cells and macrophages were incubated osteogenic and osteoclastogenic media. Histone H3K27me3 levels and enrichment were investigated using immunoblotting and chromatin precipitation-PCR. Result. Serum a-KG levels in patients with osteoporosis were less than controls; and were correlated with T-scores of hips (R2 = 0.6471, P < 0.0001) and lumbar spine (R2 = 0.7235, P < 0.001) in osteoporosis (AUC = 0.9941, P < 0.001). a-KG supplement compromised a plethora of osteoporosis signs in ovariectomized or aged mice, including bone mass loss, trabecular bone microarchitecture deterioration, and mechanical strength loss. It elevated serum osteocalcin levels and decreased serum TRAP5b. a-KG preserved caclein-labelling bone formation and repressed osteoclast resorption. It reversed osteogenic differentiation of bone-marrow stromal cells and reduced osteoclast formation in ovariectomized mice. Mechanically, a-KG attenuated H3K27 hypermethylation and Runx2 transcription repression, improving mineralized matrix production in osteogenic cells. Conclusion. Decreased serum a-KG is correlated with human and murine osteoporosis. a-KG reverses bone loss by repressing histone methylation in osteoblasts. This study highlighted a-KG supplement as a new biochemical option for protecting osteoporosis

Introduction. The increased prevalence of osteoporosis in the patient population undergoing reverse shoulder arthroplasty (RSA) results in significantly increased complication rates. Mainly demographic and clinical predictors are currently taken into the preoperative assessment for risk stratification without quantification of preoperative computed tomography (CT) data (e.g. bone density). It was hypothesized that preoperative CT bone density measures would provide objective quantification with subsequent classification of the patients’ humeral bone quality. Methods. Thirteen bone density parameters from 345 preoperative CT scans of a clinical RSA cohort represented the data set in this study. The data set was divided into testing (30%) and training data (70%), latter included an 8-fold cross validation. Variable selection was performed by choosing the variables with the highest descriptive value for each correlation clustered variables. Machine learning models were used to improve the clustering (Hierarchical Ward) and classification (Support Vector Machine (SVM)) of bone densities at risk for complications and were compared to a conventional statistical model (Logistic Regression (LR)). Results. Clustering partitioned this cohort (training data set) into a high bone density subgroup consisting of 96 patients and a low bone density subgroup consisting of 146 patients. The optimal number of clusters (n = 2) was determined based on optimization metrics. Discrimination of the cross validated classification model showed comparable performance for the training (accuracy=91.2%; AUC=0.967) and testing data (accuracy=90.5 %; AUC=0.958) while outperforming the conventional statistical model (Logistic Regression (LR)). Local interpretable model-agnostic explanations (LIME) were created for each patient to explain how the predicted output was achieved. Conclusion. The trained and tested model provides preoperative information for surgeons treating patients with potentially poor bone quality. The use of machine learning and patient-specific calibration showed that multiple 3D bone density scores improved accuracy for objective preoperative bone quality assessment

Introduction. Osteoporosis accounts for a major risk factor of fracture-associated disability or premature death in the elderly. Enhancement of bone anabolism for slowing osteoporosis is highly demanding. Exerkine fibronectin type III domain containing 5 (FNDC5) regulates energy metabolism, inflammation, and aging. This study was aimed to investigate whether Fndc5 signaling in osteoblasts changed estrogen deficiency-mediated bone loss or microarchitecture deterioration. Method. Female osteoblast-specific Fndc5 transgenic mice (Fndc5Tg), which overexpressed Fndc5 under the control of key osteoblast marker osteocalcin promoter, were given bilateral ovariectomy to induce estrogen deficiency-mediated osteoporosis. Bone mass, microstructures, and biomechanical properties were quantified using μCT imaging and material testing. Dynamic bone formation was traced using fluorescence calcein. Osteogenic differentiation and adipocyte formation of bone-marrow mesenchymal cells were investigated using von Kossa staining and Nile red staining, respectively. Serum osteocalcin, CTX-1 and TRAP5b levels were quantified using designated ELISA kits. Mitochondrial respiration was investigated using Seahorse Extracellular Flux Analyzer. Result. Fndc5Tg mice developed relatively higher bone mass and microarchitecture than wild-type mice. Fndc5 overexpression attenuated the losses of bone mineral density and trabecular network, including trabecular volume, thickness, and trabecular number, and improved cortical thickness and porosity in ovariectomized mice. Gain of Fndc5 function preserved biomechanical characteristics (maximum load, breaking force, and energy), serum bone formation marker osteocalcin levels, and bone formation rate, whereas it reduced serum bone resorption makers CTX-1 and TRAP5b levels, osteoclast overburden, and marrow adiposis. In vitro, Fndc5 reversed the estrogen deficiency-mediated mineralized matrix underproduction and adipocyte formation of bone-marrow mesenchymal cells, and inhibited osteoclast formation in osteoporotic bone. Mechanistically, Fndc5 activated AMPK signaling, promoting mitochondrial respiration and ATP production to enhance osteoblastic activity. Conclusion. Fndc5 signaling exerted bone-protective actions delaying estrogen deficiency-mediated osteoporosis. This study highlighted a new molecular remedial option for osteoporosis development by manipulating Fndc5 functions

Introduction. The incidences of fragility fractures, often because of osteoporosis, are increasing. Research has moved towards bioresorbable scaffolds that provide temporary mechanical stability and promote osteogenesis. This research aims to fabricate a 3D printed composite Poly (l-lactic-co-glycolic acid)-strontium doped tricalcium phosphate (PLGA-SrTCP) scaffold and evaluate in an in vitro co culture study containing osteoporotic donor cells. Method. PLGA, PLGA TCP, and PLGA SrTCP scaffolds were produced using Fused Filament Fabrication (FFF). A four-group 35-day cell culture study was carried out using human bone marrow derived mesenchymal stem cells (hMSCs) from osteoporotic and control donors (monoculture) and hMSCs & human monocytes (hMCs) (Co culture). Outcome measures were biochemical assays, PCR, and cell imaging. Cells were cultured on scaffolds that had been pre-degraded for six weeks at 47°C prior to drying and gamma sterilisation. Result. 3D printed scaffolds were successfully produced by FFF. All groups in the study supported cell attachment onto the scaffolds, producing extracellular matrices as well as evidence of osteoclast cell structures. Osteoporotic cells increased CTSK activity and CAII activity and decreased ALP activity compared to controls. In control cultures, the addition of bTCP and bTCP/Sr to the PLGA reduced TRAP5b, CAII and ALP activity compared to PLGA alone. The addition of Sr did not show any differences between donors. Conclusion. This study details suitability of 3D printed polymer scaffolds for use in bone tissue applications. Both composite and pure polymer scaffolds promote osteogenesis in vitro. The introduction of ceramic filler and ion doping does not beneficially effect osteogenic potential and can reduce its ability compared to pure polymer. This study suggests the behaviour of control and osteoporotic cells are different and that osteoporotic cells are more prone to bone resorption. Therefore, it is important to design bone scaffolds that are specific to the patient as well as to the region of fracture

Aims

The incidence of limb fractures in patients living with HIV (PLWH) is increasing. However, due to their immunodeficiency status, the operation and rehabilitation of these patients present unique challenges. Currently, it is urgent to establish a standardized perioperative rehabilitation plan based on the concept of enhanced recovery after surgery (ERAS). This study aimed to validate the effectiveness of ERAS in the perioperative period of PLWH with limb fractures.

Aims

Lower limb fractures are common in low- and middle-income countries (LMICs) and represent a significant burden to the existing orthopaedic surgical infrastructure. In high income country (HIC) settings, internal fixation is the standard of care due to its superior outcomes. In LMICs, external fixation is often the surgical treatment of choice due to limited supplies, cost considerations, and its perceived lower complication rate. The aim of this systematic review protocol is identifying differences in rates of infection, nonunion, and malunion of extra-articular femoral and tibial shaft fractures in LMICs treated with either internal or external fixation.

Aims. The aim of this study was to investigate the impact of the level of upper instrumented vertebra (UIV) in frail patients undergoing surgery for adult spine deformity (ASD). Methods. Patients with adult spinal deformity who had undergone T9-to-pelvis fusion were stratified using the ASD-Modified Frailty Index into not frail, frail, and severely frail categories. ASD was defined as at least one of: scoliosis ≥ 20°, sagittal vertical axis (SVA) ≥ 5 cm, or pelvic tilt ≥ 25°. Means comparisons tests were used to assess differences between both groups. Logistic regression analyses were used to analyze associations between frailty categories, UIV, and outcomes. Results. A total of 477 patients were included (mean age 60.3 years (SD 14.9), mean BMI 27.5 kg/m. 2. (SD 5.8), mean Charlson Comorbidity Index (CCI) 1.67 (SD 1.66)). Overall, 74% of patients were female (n = 353), and 49.6% of patients were not frail (237), 35.4% frail (n = 169), and 15% severely frail (n = 71). At baseline, differences in age, BMI, CCI, and deformity were significant (all p = 0.001). Overall, 15.5% of patients (n = 74) had experienced mechanical complications by two years (8.1% not frail (n = 36), 15.1% frail (n = 26), and 16.3% severely frail (n = 12); p = 0.013). Reoperations also differed between groups (20.2% (n = 48) vs 23.3% (n = 39) vs 32.6% (n = 23); p = 0.011). Controlling for osteoporosis, baseline deformity, and degree of correction (by sagittal age-adjusted score (SAAS) matching), frail and severely frail patients were more likely to experience mechanical complications if they had heart failure (odds ratio (OR) 6.6 (95% CI 1.6 to 26.7); p = 0.008), depression (OR 5.1 (95% CI 1.1 to 25.7); p = 0.048), or cancer (OR 1.5 (95% CI 1.1 to 1.4); p = 0.004). Frail and severely frail patients experienced higher rates of mechanical complication than ‘not frail’ patients at two years (19% (n = 45) vs 11.9% (n = 29); p = 0.003). When controlling for baseline deformity and degree of correction in severely frail and frail patients, severely frail patients were less likely to experience clinically relevant proximal junctional kyphosis or failure or mechanical complications by two years, if they had a more proximal UIV. Conclusion. Frail patients are at risk of a poor outcome after surgery for adult spinal deformity due to their comorbidities. Although a definitively prescriptive upper instrumented vertebra remains elusive, these patients appear to be at greater risk for a poor outcome if the upper instrumented vertebra is sited more distally. Cite this article: Bone Joint J 2024;106-B(11):1342–1347

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We aimed to compare reoperations following distal radial fractures (DRFs) managed with early fixation versus delayed fixation following initial closed reduction (CR).

Aims

The aim of this study was to create artificial intelligence (AI) software with the purpose of providing a second opinion to physicians to support distal radius fracture (DRF) detection, and to compare the accuracy of fracture detection of physicians with and without software support.

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

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This study intended to investigate the effect of vericiguat (VIT) on titanium rod osseointegration in aged rats with iron overload, and also explore the role of VIT in osteoblast and osteoclast differentiation.

Advanced 3D imaging and CT-based navigation have emerged as valuable tools to use in total knee arthroplasty (TKA), for both preoperative planning and the intraoperative execution of different philosophies of alignment. Preoperative planning using CT-based 3D imaging enables more accurate prediction of the size of components, enhancing surgical workflow and optimizing the precision of the positioning of components. Surgeons can assess alignment, osteophytes, and arthritic changes better. These scans provide improved insights into the patellofemoral joint and facilitate tibial sizing and the evaluation of implant-bone contact area in cementless TKA. Preoperative CT imaging is also required for the development of patient-specific instrumentation cutting guides, aiming to reduce intraoperative blood loss and improve the surgical technique in complex cases. Intraoperative CT-based navigation and haptic guidance facilitates precise execution of the preoperative plan, aiming for optimal positioning of the components and accurate alignment, as determined by the surgeon’s philosophy. It also helps reduce iatrogenic injury to the periarticular soft-tissue structures with subsequent reduction in the local and systemic inflammatory response, enhancing early outcomes. Despite the increased costs and radiation exposure associated with CT-based navigation, these many benefits have facilitated the adoption of imaged based robotic surgery into routine practice. Further research on ultra-low-dose CT scans and exploration of the possible translation of the use of 3D imaging into improved clinical outcomes are required to justify its broader implementation.

Cite this article: Bone Joint J 2024;106-B(9):892–897.

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

Background. Lateral lumbar spine statistical shape models (SSM) have been used previously to describe associations with osteoarthritis and back pain. However, associations with factors such as osteoporosis, menopause and parity have not been explored. Methods and Results. A 143-point SSM, describing L1 to the top of L5, was applied to lateral spine iDXA scans from UK Biobank. Associations with self-reported osteoporosis, menopause, parity and back pain and the first 10 modes of variation were examined using adjusted binary logistic regression or linear regression (adjusted for age, height, weight and total spine BMD). We report odds ratios with 95% confidence intervals for each standard deviation change in mode. Complete data were available for 2494 women. Mean age was 61.5 (± 7.4) years. 1369 women reported going through menopause, 96 women self-reported osteoporosis and 339 women reported chronic back pain. 80% of women reported at least 1 live birth. Lumbar spine shape was not associated with back pain in this cohort. Two modes were associated with menopause (modes 1 & 2), 1 mode with parity (mode 1) and 2 modes with osteoporosis (modes 3 & 5). Mode 1 (43.6% total variation), describing lumbar curvature was positively associated with both menopause [OR 1.15 95% CI 1.00–1.33, p=0.05] and parity [OR 1.058 95% CI 1.03–1.0, p=0.01]. Mode 3, describing decreased vertebral height was positively associated with osteoporosis [OR 1.40 95% CI 1.14–1.73, p=0.001]. Conclusion. Menopause and parity were associated with a curvier lumbar spine and osteoporosis with decreased vertebral height. Shape was not associated with back pain. No conflicts of interest.  . Sources of funding. Wellcome Trust collaborative award ref 209233

The August 2024 Shoulder & Elbow Roundup³⁶⁰ looks at: Comparing augmented and nonaugmented locking-plate fixation for proximal humeral fractures in the elderly; Elevated five-year mortality following shoulder arthroplasty for fracture; Total intravenous anaesthesia with propofol reduces discharge times compared with inhaled general anaesthesia in shoulder arthroscopy: a randomized controlled trial; The influence of obesity on outcomes following arthroscopic rotator cuff repair; Humeral component version has no effect on outcomes following reverse total shoulder arthroplasty: a prospective, double-blinded, randomized controlled trial; What is a meaningful improvement after total shoulder arthroplasty by implant type, preoperative diagnosis, and sex?; The safety of corticosteroid injection prior to shoulder arthroplasty: a systematic review; Mortality and subsequent fractures of patients with olecranon fractures compared to other upper limb osteoporotic fractures.