Aims. The modern prevalence of primary tumours causing metastatic bone disease is ill-defined in the oncological literature. Therefore, the purpose of this study is to identify the prevalence of primary tumours in the setting of metastatic bone disease, as well as reported rates of pathological fracture, postoperative complications, 90-day mortality, and 360-day mortality for each primary tumour subtype. Methods. The Premier Healthcare Database was queried to identify all patients who were diagnosed with metastatic bone disease from January 2015 to December 2020. The prevalence of all primary tumour subtypes was tabulated. Rates of long bone pathological fracture, 90-day mortality, and 360-day mortality following surgical treatment of pathological fracture were assessed for each primary tumour subtype. Patient characteristics and postoperative outcomes were analyzed based upon whether patients had impending fractures treated prophylactically versus treated completed fractures. Results. In total, 407,893 unique patients with metastatic bone disease were identified. Of the 14 primary tumours assessed, metastatic bone disease most frequently originated from lung (24.8%), prostatic (19.4%), breast (19.3%), gastrointestinal (9.4%), and urological (6.5%) malignancies. The top five malignant tumours resulting in long bone pathological fracture were renal (5.8%), myeloma (3.4%), female reproductive (3.2%), lung (2.8%), and breast (2.7%). Following treatment of pathological fractures of long bones, 90-day mortality rates were greatest for lung (12.1%), central nervous system (10.5%), lymphoma (10.4%), gastrointestinal (10.1%), and non-renal urinary (10.0%) malignancies. Finally, our study demonstrates improved 90-day and 360-day survival in patients treated for impending pathological fracture compared to completed fracture, as well as significantly lower rates of deep vein thrombosis, pulmonary embolism, urinary tract infection, and blood transfusion. Conclusion. This study defines the contemporary characteristics of primary malignancies resulting in metastatic bone disease. These data should be considered by surgeons when prognosticating patient outcomes during treatment of their metastatic bone disease. Cite this article: Bone Jt Open 2023;4(6):424–431

Aims. Bone metastasis ultimately occurs due to a complex multistep process, during which the interactions between cancer cells and bone microenvironment play important roles. Prior to colonization of the bone, cancer cells must succeed through a series of steps that will allow them to gain migratory and invasive properties; epithelial-to-mesenchymal transition (EMT) is known to be integral here. The aim of this study was to determine the effects of G protein subunit alpha Q (GNAQ) on the mechanisms underlying bone metastasis through EMT pathway. Methods. A total of 80 tissue samples from patients who were surgically treated during January 2012 to December 2014 were used in the present study. Comparative gene analysis revealed that the GNAQ was more frequently altered in metastatic bone lesions than in primary tumour sites in lung cancer patients. We investigated the effects of GNAQ on cell proliferation, migration, EMT, and stem cell transformation using lung cancer cells with GNAQ-knockdown. A xenograft mouse model tested the effect of GNAQ using micro-CT analyses and histological analyses. Results. GNAQ-knockdown showed down-regulation of tumour growth through mitogen-activated protein kinase (MAPK) signalling in lung cancer cells, but not increased apoptosis. We found that GNAQ-knockdown induced EMT and promoted invasiveness. GNAQ-knockdown cells injected into the bone marrow of murine tibia induced tumour growth and bone-to-lung metastasis, whereas it did not in control mice. Moreover, the knockdown of GNAQ enhanced cancer stem cell-like properties in lung cancer cells, which resulted in the development of resistance to chemotherapy. Conclusion. The present study reveals that the GNAQ-knockdown induced cancer stem cell-like properties. Cite this article: Bone Joint Res 2021;10(5):310–320

Aims. The incidence of bone metastases is between 20% to 75% depending on the type of cancer. As treatment improves, the number of patients who need surgical intervention is increasing. Identifying patients with a shorter life expectancy would allow surgical intervention with more durable reconstructions to be targeted to those most likely to benefit. While previous scoring systems have focused on surgical and oncological factors, there is a need to consider comorbidities and the physiological state of the patient, as these will also affect outcome. The primary aim of this study was to create a scoring system to estimate survival time in patients with bony metastases and to determine which factors may adversely affect this. Methods. This was a retrospective study which included all patients who had presented for surgery with metastatic bone disease. The data collected included patient, surgical, and oncological variables. Univariable and multivariable analysis identified which factors were associated with a survival time of less than six months and less than one year. A model to predict survival based on these factors was developed using Cox regression. Results. A total of 164 patients were included with a median survival time of 1.6 years (interquartile range 0.5 to 3.1) after surgery. On multivariable analysis, a higher American Society of Anesthesiologists grade (p < 0.001), a high white cell count (p = 0.002), hyponatraemia (p = 0.001), a preoperative resting heart rate of > 100 bpm (p = 0.052), and the type of primary cancer (p = 0.026) remained significant predictors of reduced survival time. The predictive model developed showed good discrimination and calibration to predict both six- and 12-month survival in patients with metastatic bone disease. Conclusion. In addition to surgical and oncological factors, the level of comorbidity and physiological state of the patient has a significant impact on survival in patients with metastatic bone disease. These factors should be considered when assessing the appropriateness of surgical intervention. This is the first study to examine other patient factors alongside surgical and oncological data to identify a relationship between these and survival. Cite this article: Bone Joint J 2021;103-B(11):1725–1730

Objectives. In this prospective cohort study, we investigated whether patient-specific finite element (FE) models can identify patients at risk of a pathological femoral fracture resulting from metastatic bone disease, and compared these FE predictions with clinical assessments by experienced clinicians. Methods. A total of 39 patients with non-fractured femoral metastatic lesions who were irradiated for pain were included from three radiotherapy institutes. During follow-up, nine pathological fractures occurred in seven patients. Quantitative CT-based FE models were generated for all patients. Femoral failure load was calculated and compared between the fractured and non-fractured femurs. Due to inter-scanner differences, patients were analyzed separately for the three institutes. In addition, the FE-based predictions were compared with fracture risk assessments by experienced clinicians. Results. In institute 1, median failure load was significantly lower for patients who sustained a fracture than for patients with no fractures. In institutes 2 and 3, the number of patients with a fracture was too low to make a clear distinction. Fracture locations were well predicted by the FE model when compared with post-fracture radiographs. The FE model was more accurate in identifying patients with a high fracture risk compared with experienced clinicians, with a sensitivity of 89% versus 0% to 33% for clinical assessments. Specificity was 79% for the FE models versus 84% to 95% for clinical assessments. Conclusion. FE models can be a valuable tool to improve clinical fracture risk predictions in metastatic bone disease. Future work in a larger patient population should confirm the higher predictive power of FE models compared with current clinical guidelines. Cite this article: F. Eggermont, L. C. Derikx, N. Verdonschot, I. C. M. van der Geest, M. A. A. de Jong, A. Snyers, Y. M. van der Linden, E. Tanck. Can patient-specific finite element models better predict fractures in metastatic bone disease than experienced clinicians? Towards computational modelling in daily clinical practice. Bone Joint Res 2018;7:430–439. DOI: 10.1302/2046-3758.76.BJR-2017-0325.R2

Advances in cancer therapy have prolonged cancer patient survival even in the presence of disseminated disease and an increasing number of cancer patients are living with metastatic bone disease (MBD). The proximal femur is the most common long bone involved in MBD and pathologic fractures of the femur are associated with significant morbidity, mortality and loss of quality of life (QoL). Successful prophylactic surgery for an impending fracture of the proximal femur has been shown in multiple cohort studies to result in patients more likely to walk after surgery, longer survival, lower transfusion rates and shorter post-operative hospital stays. However, there is currently no optimal method to predict a pathologic fracture. The most well-known tool is Mirel's criteria, established in 1989 and is limited from guiding clinical practice due to poor specificity and sensitivity. The goal of our study is to train a convolutional neural network (CNN) to predict fracture risk when metastatic bone disease is present in the proximal femur. Our fracture risk prediction tool was developed by analysis of prospectively collected data for MBD patients (2009–2016) in order to determine which features are most commonly associated with fracture. Patients with primary bone tumors, pathologic fractures at initial presentation, and hematologic malignancies were excluded. A total of 1146 patients comprising 224 pathologic fractures were included. Every patient had at least one Anterior-Posterior X-ray. The clinical data includes patient demographics, tumor biology, all previous radiation and chemotherapy received, multiple pain and function scores, medications and time to fracture or time to death. Each of Mirel's criteria has been further subdivided and recorded for each lesion. We have trained a convolutional neural network (CNN) with X-ray images of 1146 patients with metastatic bone disease of the proximal femur. The digital X-ray data is converted into a matrix representing the color information at each pixel. Our CNN contains five convolutional layers, a fully connected layers of 512 units and a final output layer. As the information passes through successive levels of the network, higher level features are abstracted from the data. This model converges on two fully connected deep neural network layers that output the fracture risk. This prediction is compared to the true outcome, and any errors are back-propagated through the network to accordingly adjust the weights between connections. Methods to improve learning included using stochastic gradient descent with a learning rate of 0.01 and a momentum rate of 0.9. We used average classification accuracy and the average F1 score across test sets to measure model performance. We compute F1 = 2 x (precision x recall)/(precision + recall). F1 is a measure of a test's accuracy in binary classification, in our case, whether a lesion would result in pathologic fracture or not. Five-fold cross validation testing of our fully trained model revealed accurate classification for 88.2% of patients with metastatic bone disease of the proximal femur. The F1 statistic is 0.87. This represents a 24% error reduction from using Mirel's criteria alone to classify the risk of fracture in this cohort. This is the first reported application of convolutional neural networks, a machine learning algorithm, to an important Orthopaedic problem. Our neural network model was able to achieve impressive accuracy in classifying fracture risk of metastatic proximal femur lesions from analysis of X-rays and clinical information. Our future work will aim to validate this algorithm on an external cohort

Aims. Surgery is often indicated in patients with metastatic bone disease (MBD) to improve pain and maximize function. Few studies are available which report on clinically meaningful outcomes such as quality of life, function, and pain relief after surgery for MBD. This is the published protocol for the Bone Metastasis Audit — Patient Reported Outcomes (BoMA-PRO) multicentre MBD study. The primary objective is to ascertain patient-reported quality of life at three to 24 months post-surgery for MBD. Methods. This will be a prospective, longitudinal study across six UK orthopaedic centres powered to identify the influence of ten patient variables on quality of life at three months after surgery for MBD. Adult patients managed for bone metastases will be screened by their treating consultant and posted out participant materials. If they opt in to participate, they will receive questionnaire packs at regular intervals from three to 24 months post-surgery and their electronic records will be screened until death or five years from recruitment. The primary outcome is quality of life as measured by the European Organisation for Research and the Treatment of Cancer Quality of Life questionnaire (EORTC-QLQ) C30 questionnaire. The protocol has been approved by the Newcastle & North Tyneside 2 Research Ethics Committee (REC ref 19/NE/0303) and the study is funded by the Royal College of Physicians and Surgeons of Glasgow (RCPSG) and the Association for Cancer Surgery (BASO-ACS). Discussion. This will be the first powered study internationally to investigate patient-reported outcomes after orthopaedic treatment for bone metastases. We will assess quality of life, function, and pain relief at three to 24 months post-surgery and identify which patient variables are significantly associated with a good outcome after MBD treatment. Cite this article: Bone Jt Open 2021;2(2):79–85

Advances in cancer therapy have prolonged patient survival even in the presence of disseminated disease and an increasing number of cancer patients are living with metastatic bone disease (MBD). The proximal femur is the most common long bone involved in MBD and pathologic fractures of the femur are associated with significant morbidity, mortality and loss of quality of life (QoL). Successful prophylactic surgery for an impending fracture of the proximal femur has been shown in multiple cohort studies to result in longer survival, preserved mobility, lower transfusion rates and shorter post-operative hospital stays. However, there is currently no optimal method to predict a pathologic fracture. The most well-known tool is Mirel's criteria, established in 1989 and is limited from guiding clinical practice due to poor specificity and sensitivity. The ideal clinical decision support tool will be of the highest sensitivity and specificity, non-invasive, generalizable to all patients, and not a burden on hospital resources or the patient's time. Our research uses novel machine learning techniques to develop a model to fill this considerable gap in the treatment pathway of MBD of the femur. The goal of our study is to train a convolutional neural network (CNN) to predict fracture risk when metastatic bone disease is present in the proximal femur. Our fracture risk prediction tool was developed by analysis of prospectively collected data of consecutive MBD patients presenting from 2009–2016. Patients with primary bone tumors, pathologic fractures at initial presentation, and hematologic malignancies were excluded. A total of 546 patients comprising 114 pathologic fractures were included. Every patient had at least one Anterior-Posterior X-ray and clinical data including patient demographics, Mirel's criteria, tumor biology, all previous radiation and chemotherapy received, multiple pain and function scores, medications and time to fracture or time to death. We have trained a convolutional neural network (CNN) with AP X-ray images of 546 patients with metastatic bone disease of the proximal femur. The digital X-ray data is converted into a matrix representing the color information at each pixel. Our CNN contains five convolutional layers, a fully connected layers of 512 units and a final output layer. As the information passes through successive levels of the network, higher level features are abstracted from the data. The model converges on two fully connected deep neural network layers that output the risk of fracture. This prediction is compared to the true outcome, and any errors are back-propagated through the network to accordingly adjust the weights between connections, until overall prediction accuracy is optimized. Methods to improve learning included using stochastic gradient descent with a learning rate of 0.01 and a momentum rate of 0.9. We used average classification accuracy and the average F1 score across five test sets to measure model performance. We compute F1 = 2 x (precision x recall)/(precision + recall). F1 is a measure of a model's accuracy in binary classification, in our case, whether a lesion would result in pathologic fracture or not. Our model achieved 88.2% accuracy in predicting fracture risk across five-fold cross validation testing. The F1 statistic is 0.87. This is the first reported application of convolutional neural networks, a machine learning algorithm, to this important Orthopaedic problem. Our neural network model was able to achieve reasonable accuracy in classifying fracture risk of metastatic proximal femur lesions from analysis of X-rays and clinical information. Our future work will aim to externally validate this algorithm on an international cohort

Surgical management for acute or impending pathologic fractures in metastatic bone disease (MBD) places patients at high-risk for post-operative venous thromboembolism (VTE). Due to the combination of malignancy, systemic cancer treatment, and surgical treatment, VTE-risk is increased 7-fold in patients with MBD compared to non-cancer patients undergoing the same procedure. The extent and duration of post-operative hypercoagulability in patients with MBD remains unknown and thromboprophylaxis guidelines were developed for non-cancer patients, limiting their applicability to address the elevated VTE-risk in cancer patients. Thrombelastography (TEG) analysis is a point-of-care test that measures clot formation, stabilization, and lysis in whole blood samples. The TEG parameter, maximal amplitude (MA), indicates clot strength and the threshold of ≥65 mm has been used to define hypercoagulability and predict VTE events in non-cancer patients requiring orthopaedic surgery. Therefore, this study aims to quantify the extent and duration of post-operative hypercoagulability in patients with MBD using serial TEG analysis. Consecutive adults (≥18 years) with MBD who required orthopaedic surgery for acute or impending pathologic fractures were enrolled into this single-centre, prospective cohort study. Serial TEG analysis was performed onsite using a TEG®6s haemostasis analyzer (Haemonetics Corporation, Boston, MA) on whole blood samples collected at seven timepoints: pre-operatively; on post-operative day (POD) 1, 3, and 5; and at 2-, 6-, and 12-weeks post-operatively. Hypercoagulability was defined as MA ≥65 mm. Participants received standardized thromboprophylaxis for four weeks and patient-reported compliance with thromboprophylaxis was recorded. VTE was defined as symptomatic DVT or PE, or asymptomatic proximal DVT, and all participants underwent a screening post-operative lower extremity Doppler ultrasound on POD3. Descriptive statistics were performed and difference between pre-operative MA values of participants with VTE versus no VTE was evaluated using Student's t-test (p≤0.05). Twenty-one participants (10 female; 47.6%) with a mean age of 70 ± 12 years were enrolled. Nine different primary cancers were identified amongst participants, with breast (23.8%), colorectal (19.0%), and lung cancer (14.3%) most frequently reported. Most participants (57.1%) were hypercoagulable pre-operatively, and nearly half remained hypercoagulable at 6- and 12-weeks post-operatively (47.1 and 46.7%, respectively). VTE occurred in 5 patients (23.8%) and mean MA was 68.1 ± 4.6 mm at the time of diagnosis. Mean pre-operative MA values were significantly higher (p=0.02) in patients who experienced VTE (68.9 ± 3.5 mm) compared to those who did not (62.7 ± 6.5 mm). VTE incidence was highest in the first week post-operatively, during which time four VTE events (80%) occurred. The proportion of patients in a hypercoagulable state increased at three consecutive timepoints, beginning on POD3 (85.0%), increasing on POD5 (87.5%), and peaking at 2-weeks post-operatively (88.9%). Current thromboprophylaxis guidelines do not consider cancer-associated risk factors that contribute to increased VTE incidence and prescription duration may be inadequate to address prolonged post-operative hypercoagulability in patients with MBD. The high rate of VTE events observed and sustained hypercoagulable state indicate that thromboprophylaxis may be prematurely terminated while patients remain at high risk for VTE. Therefore, extending thromboprophylaxis duration beyond 4-weeks post-operatively in patients with MBD warrants further investigation

Due to advances in the assessment and treatment of patients with metastatic bone disease, the survival has improved in recent years. It was the aim of this met-analysis to assess the outcome of patients with metastatic bone disease across Europe. Five major bone tumour treatment centres participated in the met-analyses. Data had been collected prospectively and was retrieved from the databases for the purpose of this study. All patients were referred to the bone tumour centre for assessment and possible surgical treatment. The data of almost 2500 patients were analysed. The average age at diagnosis was 60 years and the male to female ratio was 1:1.07. The overall 5-year survival was 35%, but this was significantly better in metastatic disease of the thyroid and breast as well as multiple myeloma. The number and site of metastases or the presence of a pathological fracture were not prognostic factors in terms of survival. Patients who were female or younger than 50 years of age at time of diagnosis had a better outcome. This registry will be expanded and more information analysed to try and provide useful information about prognostic factors and outcome for patients with meta-static bone disease

Aims. Advances in treatment have extended the life expectancy of patients with metastatic bone disease (MBD). Patients could experience more skeletal-related events (SREs) as a result of this progress. Those who have already experienced a SRE could encounter another local management for a subsequent SRE, which is not part of the treatment for the initial SRE. However, there is a noted gap in research on the rate and characteristics of subsequent SREs requiring further localized treatment, obligating clinicians to extrapolate from experiences with initial SREs when confronting subsequent ones. This study aimed to investigate the proportion of MBD patients developing subsequent SREs requiring local treatment, examine if there are prognostic differences at the initial treatment between those with single versus subsequent SREs, and determine if clinical, oncological, and prognostic features differ between initial and subsequent SRE treatments. Methods. This retrospective study included 3,814 adult patients who received local treatment – surgery and/or radiotherapy – for bone metastasis between 1 January 2010 and 31 December 2019. All included patients had at least one SRE requiring local treatment. A subsequent SRE was defined as a second SRE requiring local treatment. Clinical, oncological, and prognostic features were compared between single SREs and subsequent SREs using Mann-Whitney U test, Fisher’s exact test, and Kaplan–Meier curve. Results. Of the 3,814 patients with SREs, 3,159 (83%) patients had a single SRE and 655 (17%) patients developed a subsequent SRE. Patients who developed subsequent SREs generally had characteristics that favoured longer survival, such as higher BMI, higher albumin levels, fewer comorbidities, or lower neutrophil count. Once the patient got to the point of subsequent SRE, their clinical and oncological characteristics and one-year survival (28%) were not as good as those with only a single SRE (35%; p < 0.001), indicating that clinicians’ experiences when treating the initial SRE are not similar when treating a subsequent SRE. Conclusion. This study found that 17% of patients required treatments for a second, subsequent SRE, and the current clinical guideline did not provide a specific approach to this clinical condition. We observed that referencing the initial treatment, patients in the subsequent SRE group had longer six-week, 90-day, and one-year median survival than patients in the single SRE group. Once patients develop a subsequent SRE, they have a worse one-year survival rate than those who receive treatment for a single SRE. Future research should identify prognostic factors and assess the applicability of existing survival prediction models for better management of subsequent SREs. Cite this article: Bone Joint Res 2024;13(9):497–506

The presence of metastatic bone disease (MBD) often necessitates major orthopaedic surgery. Patients will enter surgical care either through emergent or electively scheduled care pathways. Patients in a pain crisis or with an acute fracture are generally admitted via emergent care pathways whereas patients with identified high-risk bone lesions are often booked for urgent yet scheduled elective procedures. The purpose of this study is to compare the post-operative outcomes of patients who present through emergent or electively scheduled care pathways in patients in a Canadian health care system. We have conducted a retrospective, multicenter cohort study of all patients presenting for surgery for MBD of the femur, humerus, tibia or pelvis in southern Alberta between 2006 and 2021. Patients were identified by a search query of all patients with a diagnosis of metastatic cancer who underwent surgery for an impending or actual pathologic fracture in the Calgary, South and Central Alberta Zones. Subsequent chart reviews were performed. Emergent surgeries were defined by patients admitted to hospital via urgent care mechanisms and managed via unscheduled surgical bookings (“on call list”). Elective surgeries were defined by patients seen by an orthopaedic surgeon at least once prior to surgery, and booked for a scheduled urgent, yet elective procedure. Outcomes include overall survival from the time of surgery, hospital length of stay, and 30-day hospital readmission rate. We have identified 402 patients to date for inclusion. 273 patients (67.9%) underwent surgery through emergent pathways and 129 patients (32.1%) were treated through urgent, electively scheduled pathways. Lung, prostate, renal cell, and breast cancer were the most common primary malignancies and there was no significant difference in these primaries amongst the groups (p=0.06). Not surprisingly, emergent patients were more likely to be treated for a pathologic fracture (p<0.001) whereas elective patients were more likely to be treated for an impending fracture (p<0.001). Overall survival was significantly shorter in the emergent group (5.0 months, 95%CI: 4.0-6.1) compared to the elective group (14.9 months 95%CI: 10.4-24.6) [p<0.001]. Hospital length of stay was significantly longer in the emergent group (13 days, 95%CI: 12-16 versus 5 days, 95%CI: 5-7 days). There was a significantly greater rate of 30-day hospital readmission in the emergent group (13.3% versus 7.8%) [p=0.01]. Electively managed MBD has multiple benefits including longer post-operative survival, shorter length of hospital stay, and a lower rate of 30-day hospital readmission. These findings from a Canadian healthcare system demonstrate clinical value in providing elective orthopaedic care when possible for patients with MBD. Furthermore, care delivery interventions capable of decreasing the footprint of emergent surgery through enhanced screening or follow-up of patients with MBD has the potential to significantly improve clinical outcomes in this population. This is an ongoing study that will justify refinements to the current surgical care pathways for MBD in order to identify patients prior to emergent presentation. Future directions will evaluate the costs associated with each care delivery method to provide opportunity for health economic efficiencies

Cite this article: Bone Joint J 2024;106-B(1):6–8.

Aims. Accurate estimations of the risk of fracture due to metastatic bone disease in the femur is essential in order to avoid both under-treatment and over-treatment of patients with an impending pathological fracture. The purpose of the current retrospective in vivo study was to use CT-based finite element analyses (CTFEA) to identify a clear quantitative differentiating factor between patients who are at imminent risk of fracturing their femur and those who are not, and to identify the exact location of maximal weakness where the fracture is most likely to occur. Methods. Data were collected on 82 patients with femoral metastatic bone disease, 41 of whom did not undergo prophylactic fixation. A total of 15 had a pathological fracture within six months following the CT scan, and 26 were fracture-free during the five months following the scan. The Mirels score and strain fold ratio (SFR) based on CTFEA was computed for all patients. A SFR value of 1.48 was used as the threshold for a pathological fracture. The sensitivity, specificity, positive, and negative predicted values for Mirels score and SFR predictions were computed for nine patients who fractured and 24 who did not, as well as a comparison of areas under the receiver operating characteristic curves (AUC of the ROC curves). Results. The sensitivity of SFR was 100% compared with 88% for the Mirels score, and the specificity of SFR was 67% compared with 38% for the Mirels score. The AUC was 0.905 for SFR compared with 0.578 for the Mirels score (p = 0.008). Conclusion. All the patients who sustained a pathological fracture of the femur had an SFR of > 1.48. CTFEA was far better at predicting the risk of fracture and its location accurately compared with the Mirels score. CTFEA is quick and automated and can be incorporated into the protocol of CT scanners. Cite this article: Bone Joint J 2020;102-B(5):638–645

Metastatic bone disease resulting in acetabular destruction can provide the orthopaedic surgeon with the difficult challenge of achieving a stable reconstruction of the hip to provide pain relief and restoration of mobility. We review of twenty patients with metastatic disease requiring major acetabular reconstruction presenting to our orthopaedic oncology unit over a five year period was undertaken. This yielded 15 female and 5 male patients with mean age 59 years. The primary lesion was breast (8 cases), renal (3) prostate (2), myeloma (2) and others (5) with a solitary acetabular metastasis in 75% of cases. Eight patients had received radiotherapy to the region pre-operatively. In all cases, diseased bone was macroscopically cleared from the pelvis and reconstruction performed by means of a Harrington procedure with threaded pins passed antegrade from the iliac crest 915 cases) or mesh and screws (5 cases), all reinforced with cement around which a total hip arthroplasty was performed. Mean follow-up was 16 months. Complications were broken pin (1 case), dislocation of femoral prosthesis (1) and deep venous thrombosis (1). Three patients died of their disease at a mean of 12 months from surgery. The remaining 17 patients continue to function at a satisfactory level with no patients having required revision surgery for loosening or deep infection. We believe that surgical reconstruction of the acetabulum is worthwhile and can provide these deserving patients with improvement in quality of life

The aim of the study is to review the results of prophylactic reconstruction of subtrochanteric metastatic bone disease of femur using a Long Gamma Nail. Metastasis in the subtrochanteric region of femur can be challenging to treat not only due to peculiarities in biomechanics and anatomy, but also due to weak and deficient bone stock due to metastasis. Between 1996 and 2002, 28 subtrochanteric metastatic lesions of femur in 25 patients (3 bilateral) were treated with Long Gamma Nail. The outcome measures used in this study were pain relief, postoperative mobilization, and medical and implant related complications rate. There were 16 female and 9 male patients with an average age of 64 years. All patients reported marked pain relief. All but one regained pre-operative mobilization status. There were no intra-operative deaths including 3 bilateral nailings. Significant surgical and implant related complications were seen in 3(12%) patients. Postoperative medical complications were seen in 3 (12%) patients. There were no implant failures and reoperations. At the time of study 14 patients died with an average survival of 9 months and 11 patients were alive with an average survival of 16.5 months. Long Gamma Nail is valuable reconstruction device for the prophylactic treatment of subtrochanteric metastatic bone disease of femur. It is strong, versatile and biomechanically superior to extramedullary devises and compares favourably with other intramedullary devices. In our experience Long Gamma Nail allows immediate unrestricted mobilization with marked pain relief

Introduction. The rising incidence of metastatic bone disease (MBD) in the UK poses a significant management problem. Poorly defined levels of service provision have meant that improvements in patient prognosis have been mediocre at best. For that reason the British Orthopaedic Association (BOA) in conjunction with the British Orthopaedic Oncology Society (BOOS) issued guidelines in 2002 on good practice in the management of MBD. Despite the availability of these standards, there is very little robust data available for audit. The aim of this study was to conduct a regional survey of how these guidelines are being used in the management of MBD. Methods. A questionnaire was designed with 9 multiple choice questions representing the most common MBD scenarios. This was posted to 106 Consultant Orthopaedic Surgeons in 12 NHS Trusts in the South East of England. Results. The overall response rate to the questionnaire was 44%. There was considerable variation in the management of solitary femoral diaphyseal lesions, pathological subtrochanteric and intertrochanteric femoral neck fractures and vertebral metastases. Furthermore only 2 out of the 12 Trusts surveyed had a designated MBD lead as per the BOA/BOOS guidelines. Discussion. Our study reflects the variation in the management of MBD throughout the region, which may in turn be linked to poorer clinical outcomes. The results demonstrate the possibility of (i) inappropriate initial treatment, (ii) subsequent late tertiary referral and (iii) poor understanding of the biomechanical basis of orthopaedic implants, with the potential for inappropriate choice of prostheses and high failure rates. Streamlining cancer care will involve establishing regional MBD units within large centres where multidisciplinary services are available. Consequently all surrounding hospitals will need a designated MBD lead that can function as a conduit to this integrated care for selected patients

Introduction: Sending intramedullary reamings for histology in patients with metastaic bone disease (MBD) is routinely done in many centres. However, whether the results of these reamings help in the diagnosis of MBD remains unclear. Recent studies have shown that on the basis of biopsy of the metastases alone, only 35% of the primary tumours are detected. British Orthopaedic Oncology Society guidelines recommend further investigations and a bone biopsy if the primary disease is unknown. Aim:The aim of this study was to correlate clinical, radiological and histological findings for patients with metastatic bone disease and assess the diagnostic accuracy of the reamings in MBD. Method: Demographic details, clinical evaluation, radiological findings and the histology results of the bone biopsy or reamings were reviewed retrospectively for all patients admitted in the year 2003 with suspected MBD. Results:Records and x-rays were identified of 50 patients admitted in 2003 with suspected primary or MBD of a long bone and pain or pathological fracture. . 56% were male. Average age was 69.2years (range 10–98years). 6 patients had primary bone tumour and were referred to the tumour specialist. Of the remaining patients with suspected MBD all required fixation and in all cases intramedullary reamings were sent for histology. 18 patients had a known primary tumour of which 8 (44%) had no evidence of malignancy on histology. 22 patients had an unknown primary tumour of which 19 (86%) had no evidence of malignancy on histology. Conclusion: Reamings, are a poor method of diagnosis, even in cases where the primary is known the histology is still less than 50 % accurate in confirming malignancy. Therefore, in patients with MBD the diagnostic accuracy of reamings should be re-evaluated due to the high false negative results

The burden of metastatic bone disease (MBD) in our Canadian cancer population continues to increase. MBD has a significant effect on patient morbidity, mortality, and health-related quality of life (HRQOL). There are various technical options used to surgically stabilize MBD lesions, surgical decision-making is variable and largely dependent on anatomic and surgeon-based factors. There is a paucity of research examining how surgical decision-making for MBD can be modified or individualized to improve quality of life (QOL) and functional outcomes, while more accurately aligning with patient-reported goals and expectations. The objective of this study was tosurvey MBD patients, support persons, physicians, and allied health care providers (HCP) with the goal of identifying 1) important contributors to HRQOL, 2) discordance in peri-operative expectations, and 3) perceived measures of success in the surgical management of MBD. This project is a longitudinal patient-engaged research initiative in MBD. A survey was developed based on HRQOL themes in the literature and based on feedback from our patient research partners. Participants were asked to identify 1) important contributors to HRQOL and 2) perceived measures of success relevant to the surgical management of MBD. Participants were asked to rank themes from ‘extremely important’ to ‘not important at all’. Using open-ended questions, participants were asked to identify areas of improvement. Responses from the open-ended questions were analyzed by an experienced qualitative researcher using conventional content analysis. Participant's demographics were calculated using descriptive statistics. Concordance or discordance of perceived measure of success was assessed via a Chi-Square test of independence. All statistical analyses were performed using IBM SPSS® software. Nine patients, seven support persons, 23 orthopaedic surgeons, 11 medical oncologists, 16 radiation oncologists, 16 nurses, and eight physiotherapists completed the survey. Regarding perceived measures of success, increased life expectancy (p Two main themes emerged around the timeliness of surgical care and the coordination of multidisciplinary care from patients and support persons. Patients and support persons expressed a sense of urgency in progressing to surgery/treatment, and frustration at perceived delays in treatment. Within coordination of care, patients and support persons would like clearer communication from the health care team. There is discordance between patient/support person goals compared to physicians/HCP goals in the surgical management of MBD. Surgical decision-making and operative techniques that minimize disease progression and improve survival are important to MBD patients. Timely access to surgery/surgical consultation and improved multidisciplinary communication is important to patients. This data suggests improved peri-operative communication and education is needed for MBD patients. Furthermore, future research evaluating how modern orthopaedic surgical techniques influence survival and disease progression in MBD is highly relevant and important to patients with MBD

Introduction: The rising incidence of metastatic bone disease (MBD) in the UK poses a significant management problem. Poorly defined levels of service provision have meant that improvements in patient prognosis have been mediocre at best. For that reason the British Orthopaedic Association (BOA) in conjunction with the British Orthopaedic Oncology Society (BOOS) issued guidelines in 2002 on good practice in the management of MBD. Despite the availability of these standards, there is very little robust data available for audit. The aim of this study was to conduct a regional survey of how these guidelines are being used in the management of MBD. Methods: A questionnaire was designed with 9 multiple choice questions representing the most common MBD scenarios. This was posted to 106 Consultant Orthopaedic Surgeons in 12 NHS Trusts in the South East of England. Results: The overall response rate to the questionnaire was 44%. There was considerable variation in the management of solitary femoral diaphyseal lesions, pathological subtrochanteric and intertrochanteric femoral neck fractures and vertebral metastases. Furthermore only 2 out of the 12 Trusts surveyed had a designated MBD lead as per the BOA/BOOS guidelines. Discussion: Our study reflects the variation in the management of MBD throughout the region, which may in turn be linked to poorer clinical outcomes. The results demonstrate the possibility of. inappropriate initial treatment,. subsequent late tertiary referral and. poor understanding of the biomechanical basis of orthopaedic implants, with the potential for inappropriate choice of prostheses and high failure rates. Streamlining cancer care will involve establishing regional MBD units within large centres where multidisciplinary services are available. Consequently all surrounding hospitals will need a designated MBD lead that can function as a conduit to this integrated care for selected patients

The management of pathological fractures due to Metastatic Bone Disease (MBD) and Primary Bone Tumours (PBTs) has implications for the Trauma service due to the extra pressures on staff, service delivery and budgets. We undertook an analysis of a cohort of patients presenting with MBD and PBTs. A retrospective chart review of all cases with MBD and PBTs admitted to a 40-bed Trauma Unit between 2005 and 2009 was conducted. The study looked at frequency, primary pathology, and site of pathology/fracture, time from primary diagnosis to referral, subsequent interventions and others. The results identified 34 patients, 21 females (62%) and 13 males (38%) (mean age: 64.6 years) with MBD or PBTs. Metastases secondary to breast cancer (n=13, 38%) and Myeloma (n=5, 15%) were the most common with the majority being found in the femur (n=22, 65%) and the Humerus (n=6, 18%). The mean time from primary tumour diagnosis to fracture referral was 29.6 months with 27 (79%) patients undergoing definitive surgical management within the unit. The conclusions of the study demonstrate that a wide variety of pathology presented to the unit over a 5 year period. Considerable variation was noted in the time from primary tumour diagnosis to presentation with a fracture. This could be due to improvements in treatments of specific cancers or a lack of understanding of what an Orthopaedic surgeon can offer the cancer patient. No definitive increase in pathological fractures was seen. The consensus opinion is that prompt and appropriate management of pathological fractures in cancer patients is cost effective. Management of these injuries, in a Trauma Unit, represents a small, but significant part of the annual work-load. While no significant trend has been seen, with respect to an increased incidence, it is noted that a proportion of these patients were a number of years from their initial diagnosis. With improvements in the survivorship of cancer patients, close scrutiny will be required to determine whether this ultimately translates into an increased fracture burden

Objectives

Guidelines for the management of patients with metastatic bone disease (MBD) have been available to the orthopaedic community for more than a decade, with little improvement in service provision to this increasingly large patient group. Improvements in adjuvant and neo-adjuvant treatments have increased both the number and overall survival of patients living with MBD. As a consequence the incidence of complications of MBD presenting to surgeons has increased and is set to increase further. The British Orthopaedic Oncology Society (BOOS) are to publish more revised detailed guidelines on what represents ‘best practice’ in managing patients with MBD. This article is designed to coincide with and publicise new BOOS guidelines and once again champion the cause of patients with MBD.

Aims

Acridine orange (AO) demonstrates several biological activities. When exposed to low doses of X-ray radiation, AO increases the production of reactive radicals (radiodynamic therapy (AO-RDT)). We elucidated the efficacy of AO-RDT in breast and prostate cancer cell lines, which are likely to develop bone metastases.

Aims

This study aimed to compare the performance of survival prediction models for bone metastases of the extremities (BM-E) with pathological fractures in an Asian cohort, and investigate patient characteristics associated with survival.

To assess the referral system, clinical notes and radiographs of patients presenting with metastatic disease of long bones in a regional oncology unit.

Thirty questionnaires were sent to oncologists asking about reasons for referral to orthopaedics and use of scoring system to assess risk of pathological fracture.

Ninety three percent of oncologists did not use a reliable scoring system to assess risk of pathological fracture. The majority referred in respect to pain on mobilising and the presence of a lytic lesion. Sixty percent felt an improvement in communication between the departments was required.

The notes and radiographs were reviewed of thirty-seven patients presenting with femoral metastatic lesions to the oncology department.

Sixteen patients had a Mirels score of greater than eight. Four patients were referred for an Orthopaedic opinion. All patients underwent prophylactic fixation. Twelve patients with a score of greater than eight were not referred. Seven of theses patients suffered a pathological fracture within three months.

Five patients had a Mirels score of 8. One patient had prophylactic fixation. No fractures occurred.

Sixteen patients had a Mirels score of less than 8. None of these patients were referred for an orthopaedic opinion. None of these patients had a pathological fracture within three months.

In conclusion, we presently do not offer a multidisciplinary approach to metastatic disease affecting the appendicular skeleton.

The majority of patients’ who score eight or above in the Mirels scoring system are at risk of fracture and do require prophylactic surgery.

In keeping with the BOA guidelines, “Metastatic Bone Disease: A Guide to Good Practice”, we would recommend that the introduction of a multidisciplinary approach and the use of a recognised scoring system is essential to improve patient care.

Aims

The aim of this study is to evaluate the clinical results of operative intervention for femoral metastases which were selected based on expected survival and to discuss appropriate surgical strategies.

Aims

The aims of this study were to evaluate the long-term outcome of surgery for bone or soft-tissue metastases from renal cell carcinoma (RCC) and to determine factors that affect prognosis.

Aims

The purpose of the study was to investigate whether closed intramedullary (IM) nailing with percutaneous cement augmentation is better than conventional closed nailing at relieving pain and suppressing tumours in patients with metastases of the femur and humerus.

Breast cancer is the most frequent malignancy in women with an estimation of 2.1 million new diagnoses in 2018. Even though primary tumours are usually efficiently removed by surgery, 20–40% of patients will develop metastases in distant organs. Bone is one of the most frequent site of metastases from advanced breast cancer, accounting from 55 to 58% of all metastases. Currently, none of the therapeutic strategies used to manage breast cancer bone metastasis are really curative. Tailoring a suitable model to study and evaluate the disease pathophysiology and novel advanced therapies is one of the major challenges that will predict more effectively and efficiently the clinical response. Preclinical traditional models have been largely used as they can provide standardization and simplicity, moreover, further advancements have been made with 3D cultures, by spheroids and artificial matrices, patient derived xenografts and microfluidics. Despite these models recapitulate numerous aspects of tumour complexity, they do not completely mimic the clinical native microenvironment. Thus, to fulfil this need, in our study we developed a new, advanced and alternative model of human breast cancer bone metastasis as potential biologic assay for cancer research. The study involved breast cancer bone metastasis samples obtained from three female patients undergoing wide spinal decompression and stabilization through a posterior approach. Samples were cultured in a TubeSpin Bioreactor on a rolling apparatus under hypoxic conditions at time 0 and for up to 40 days and evaluated for viability by the Alamar Blue test, gene expression profile, histology and immunohistochemistry. Results showed the maintenance and preservation, at time 0 and after 40 days of culture, of the tissue viability, biological activity, as well as molecular markers, i.e. several key genes involved in the complex interactions between the tumour cells and bone able to drive cancer progression, cancer aggressiveness and metastasis to bone. A good tis sue morphological and microarchitectural preservation with the presence of lacunar osteolysis, fragmented trabeculae locally surrounded by osteoclast cells and malignant cells and an intense infiltration by tumour cells in bone marrow compartment in all examined samples. Histomorphometrical data on the levels of bone resorption and bone apposition parameters remained constant between T0 and T40 for all analysed patients. Additionally, immunohistochemistry showed homogeneous expression and location of CDH1, CDH2, KRT8, KRT18, Ki67, CASP3, ESR1, CD8 and CD68 between T0 and T40, thus further confirming the invasive behaviour of breast cancer cells and indicating the maintaining of the metastatic microenvironment. The novel tissue culture, set-up in this study, has significant advantages in comparison to the pre-existent 3D models: the tumour environment is the same of the clinical scenario, including all cell types as well as the native extracellular matrix; it can be quickly set-up employing only small samples of breast cancer bone metastasis tissue in a simple, ethically correct and cost-effective manner; it bypasses and/or decreases the necessity to use more complex preclinical model, thus reducing the ethical burden following the guiding principles aimed at replacing/reducing/refining (3R) animal use and their suffering for scientific purposes; it can allow the study of the interactions within the breast cancer bone metastasis tissue over a relatively long period of up to 40 days, preserving the tumour morphology and architecture and allowing also the evaluation of different biological factors, parameters and activities. Therefore, the study provides for the first time the feasibility and rationale for the use of a human-derived advanced alternative model for cancer research and testing of drugs and innovative strategies, taking into account patient individual characteristics and specific tumour subtypes so predicting patient specific responses

Aims. Proximal femoral endoprosthetic replacements (PFEPRs) are the most common reconstruction option for osseous defects following primary and metastatic tumour resection. This study aimed to compare the rate of implant failure between PFEPRs with monopolar and bipolar hemiarthroplasties and acetabular arthroplasties, and determine the optimum articulation for revision PFEPRs. Methods. This is a retrospective review of 233 patients who underwent PFEPR. The mean age was 54.7 years (SD 18.2), and 99 (42.5%) were male. There were 90 patients with primary bone tumours (38.6%), 122 with metastatic bone disease (52.4%), and 21 with haematological malignancy (9.0%). A total of 128 patients had monopolar (54.9%), 74 had bipolar hemiarthroplasty heads (31.8%), and 31 underwent acetabular arthroplasty (13.3%). Results. At a mean 74.4 months follow-up, the overall revision rate was 15.0%. Primary malignancy (p < 0.001) and age < 50 years (p < 0.001) were risk factors for revision. The risks of death and implant failure were similar in patients with primary disease (p = 0.872), but the risk of death was significantly greater for patients who had metastatic bone disease (p < 0.001). Acetabular-related implant failures comprised 74.3% of revisions; however, no difference between hemiarthroplasty or arthroplasty groups (p = 0.209), or between monopolar or bipolar hemiarthroplasties (p = 0.307), was observed. There was greater radiological wear in patients with longer follow-up and primary bone malignancy. Re-revision rates following a revision PFEPR was 34.3%, with dual-mobility bearings having the lowest rate of instability and re-revision (15.4%). Conclusion. Hemiarthroplasty and arthroplasty PFEPRs carry the same risk of revision in the medium term, and is primarily due to acetabular complications. There is no difference in revision rates or erosion between monopolar and bipolar hemiarthroplasties. The main causes of failure were acetabular wear in the hemiarthroplasty group and instability in the arthroplasty group. These risks should be balanced and patient prognosis considered when contemplating the bearing choice. Dual-mobility, constrained bearings, or large diameter heads (> 32 mm) are recommended in all revision PFEPRs. Cite this article: Bone Joint J 2021;103-B(10):1633–1640

The August 2024 Research Roundup. 360. looks at: Effect of vitamin D deficiency on periprosthetic joint infection and complications after primary total joint replacement; Postoperative angiotensin receptor blocker use associated with decreased rates of manipulation under anaesthesia in patients undergoing total knee arthroplasty; Central sensitization: the missing link between psychological distress and poor outcome following primary total knee arthroplasty; Thromboprophylaxis for the trauma and orthopaedic surgeon; Life expectancy after treatment of metastatic bone disease: an international trend analysis

Aims. Most patients with advanced malignancy suffer bone metastases, which pose a significant challenge to orthopaedic services and burden to the health economy. This study aimed to assess adherence to the British Orthopaedic Oncology Society (BOOS)/British Orthopaedic Association (BOA) guidelines on patients with metastatic bone disease (MBD) in the UK. Methods. A prospective, multicentre, national collaborative audit was designed and delivered by a trainee-led collaborative group. Data were collected over three months (1 April 2021 to 30 June 2021) for all patients presenting with MBD. A data collection tool allowed investigators at each hospital to compare practice against guidelines. Data were collated and analyzed centrally to quantify compliance from 84 hospitals in the UK for a total of 1,137 patients who were eligible for inclusion. Results. A total of 846 patients with pelvic and appendicular MBD were analyzed, after excluding those with only spinal metastatic disease. A designated MBD lead was not present in 39% of centres (33/84). Adequate radiographs were not performed in 19% of patients (160/846), and 29% (247/846) did not have an up-to-date CT of thorax, abdomen, and pelvis to stage their disease. Compliance was low obtaining an oncological opinion (69%; 584/846) and prognosis estimations (38%; 223/846). Surgery was performed in 38% of patients (319/846), with the rates of up-to-date radiological investigations and oncology input with prognosis below the expected standard. Of the 25% (215/846) presenting with a solitary metastasis, a tertiary opinion from a MBD centre and biopsy was sought in 60% (130/215). Conclusion. Current practice in the UK does not comply with national guidelines, especially regarding investigations prior to surgery and for patients with solitary metastases. This study highlights the need for investment and improvement in care. The recent publication of British Orthopaedic Association Standards for Trauma (BOAST) defines auditable standards to drive these improvements for this vulnerable patient group. Cite this article: Bone Joint J 2023;105-B(10):1115–1122

Aims. Despite multiple trials and case series on hip hemiarthroplasty designs, guidance is still lacking on which implant to use. One particularly deficient area is long-term outcomes. We present over 1,000 consecutive cemented Thompson’s hemiarthroplasties over a ten-year period, recording all accessible patient and implant outcomes. Methods. Patient identifiers for a consecutive cohort treated between 1 January 2003 and 31 December 2011 were linked to radiographs, surgical notes, clinic letters, and mortality data from a national dataset. This allowed charting of their postoperative course, complications, readmissions, returns to theatre, revisions, and deaths. We also identified all postoperative attendances at the Emergency and Outpatient Departments, and recorded any subsequent skeletal injuries. Results. In total, 1,312 Thompson’s hemiarthroplasties were analyzed (mean age at surgery 82.8 years); 125 complications were recorded, necessitating 82 returns to theatre. These included 14 patients undergoing aspiration or manipulation under anaesthesia, 68 reoperations (5.2%) for debridement and implant retention (n = 12), haematoma evacuation (n = 2), open reduction for dislocation (n = 1), fixation of periprosthetic fracture (n = 5), and 48 revised stems (3.7%), for infection (n = 13), dislocation (n = 12), aseptic loosening (n = 9), persistent pain (n = 6), periprosthetic fracture (n = 4), acetabular erosion (n = 3), and metastatic bone disease (n = 1). Their status at ten years is summarized as follows: 1,180 (89.9%) dead without revision, 34 (2.6%) dead having had revision, 84 (6.6%) alive with the stem unrevised, and 14 (1.1%) alive having had revision. Cumulative implant survivorship was 90.3% at ten years; patient survivorship was 7.4%. Conclusion. The Thompson’s stem demonstrates very low rates of complications requiring reoperation and revision, up to ten years after the index procedure. Fewer than one in ten patients live for ten years after fracture. This study supports the use of a cemented Thompson’s implant as a cost-effective option for frail hip fracture patients. Cite this article: Bone Jt Open 2022;3(9):710–715

Osteoclasts (OCs) are multinucleated cells that play a pivotal role in skeletal development and bone remodeling. Abnormal activation of OCs contributes to the development of bone-related diseases, such as osteoporosis, bone metastasis and osteoarthritis. Restoring the normal function of OCs is crucial for bone homeostasis. Recently, RNA therapeutics emerged as a new field of research for osteoarticular diseases. The aim of this study is to use non-coding RNAs (ncRNAs) to molecularly engineer OCs and modulate their function. Specifically, we investigated the role of the microRNAs (namely miR-16) and long ncRNAs (namely DLEU1) in OCs differentiation and fusion. DLEU1/DLEU2 region, located at chromosome 13q14, also encodes miR-15 and miR-16. Our results show that levels of these ncRNA transcripts are differently expressed at distinct stages of the OCs differentiation. Specifically, silencing of DLEU1 by small interfering RNAs (siDLEU1) and overexpression of miR-16 by synthetic miRNA mimics (miR-16-mimics) led to a significant reduction in the number of OCs formed per field (OC/field), both at day 5 and 9 of the differentiation stage. Importantly, time-lapse analysis, used to track OCs behavior, revealed a significant decrease in fusion events after transfection with siDLEU1 or miR-16-mimics and an alteration in the fusion mode and partners. Next, we investigated the migration profile of these OCs, and the results show that only miR-16-mimics-OCs, but not siDLEU-OCs, have a lower percentage of immobile cells and an increase in cells with mobile regime, compared with controls. No differences in cell shape were found. Moreover, mass-spectrometry quantitative proteomic analysis revealed independent effects of siDLEU1 and miR-16-mimics at the protein levels. Importantly, DLEU1 and miR-16 act by distinct processes and pathways. Collectively, our findings support the ncRNAs DLEU1 and miR-16 as therapeutic targets to modulate early stages of OCs differentiation and, consequently, to impair OC fusion, advancing ncRNA-therapeutics for bone-related diseases. Acknowledgements: Authors would like to thank to AO CMF / AO Foundation (AOCMFS-21-23A). SRM and MIA are supported by FCT (SFRH/BD/147229/2019 and BiotechHealth Program; CEECINST/00091/2018/CP1500/CT0011, respectively)

The ageing population and an increase in both the incidence and prevalence of cancer pose a healthcare challenge, some of which is borne by the orthopaedic community in the form of osteoporotic fractures and metastatic bone disease. In recent years there has been an increasing understanding of the pathways involved in bone metabolism relevant to osteoporosis and metastases in bone. Newer therapies may aid the management of these problems. One group of drugs, the antibody mediated anti-resorptive therapies (AMARTs) use antibodies to block bone resorption pathways. This review seeks to present a synopsis of the guidelines, pharmacology and potential pathophysiology of AMARTs and other new anti-resorptive drugs. . We evaluate the literature relating to AMARTs and new anti-resorptives with special attention on those approved for use in clinical practice. Denosumab, a monoclonal antibody against Receptor Activator for Nuclear Factor Kappa-B Ligand. It is the first AMART approved by the National Institute for Health and Clinical Excellence and the US Food and Drug Administration. Other novel anti-resorptives awaiting approval for clinical use include Odanacatib. Denosumab is indicated for the treatment of osteoporosis and prevention of the complications of bone metastases. Recent evidence suggests, however, that denosumab may have an adverse event profile similar to bisphosphonates, including atypical femoral fractures. It is, therefore, essential that orthopaedic surgeons are conversant with these medications and their safe usage. . Take home message: Denosumab has important orthopaedic indications and has been shown to significantly reduce patient morbidity in osteoporosis and metastatic bone disease. Cite this article: Bone Joint J 2016;98-B:160–5

Metastatic bone disease (MBD) is a significant contributor to diminished quality of life in cancer patients, often leading to pathologic fractures, hypercalcaemia, intractable bone pain, and reduced functional independence. Standard of care management for MBD patients undergoing orthopaedic surgery is multi-disciplinary, includes regular surgical follow-up, case by case assessment for use of bone protective medications, and post-operative radiation therapy to the operative site. The number of patients in southern Alberta receiving standard of care post-operative management is currently unclear. Our aim is to develop a database of all patients in southern Alberta undergoing orthopaedic surgery for MBD and to assess for deficiencies and opportunities to ensure standard of care for this complex patient population. Patients were identified for database inclusion by a search query of the Alberta Cancer Registry of all patients with a diagnosis of metastatic cancer who underwent surgery for an impending or pathologic fracture in the Calgary, South and Central Alberta Zones. Demographic information, primary cancer history, previous local and systemic treatments, anatomical location of MBD event(s), surgical fixation techniques, and post-operative care details were collected. The rate of standard of care post-operative treatment was evaluated. A comparison of outcomes between tertiary urban centres and rural centres was also completed. Survival was calculated from time of first operation to date of death. Univariate and multivariate analyses were performed to identify the impact of post-operative care variables on survival amongst patients surviving longer than one month. We identified 402 patients who have undergone surgical treatment for MBD in southern Alberta from 2006-2018. Median age at time of surgery was 66.3 years and 52.7% of patients were female. Breast, lung, prostate, renal cell and multiple myeloma were the most common primary malignancies (n=328, 81.6%). Median post-operative survival was 6.8 months (95%CI: 5.7-8.3). 203 patients (52.5%) were treated with post-operative radiotherapy and 159 patients (50.8%) had post-operative surgical follow-up. Only 39 patients (11.3%) received bone protective agents in the peri-operative period. On multivariate survival analysis, post-operative surgical follow-up was associated with improved survival (p<0.001). Patients were treated at nine hospitals across southern Alberta with most patients treated in an urban center (65.9%). Post-operative survival was significantly longer amongst patients treated in an urban center (9.0 months, 95%CI: 6.9-12.3 versus 4.3 months, 95%CI: 3.4-5.6, p<0.001). The burden of MBD is significant and increasing. With treatment occurring at multiple provincial sites, there is a need for standardized, primary disease-specific peri- and post-operative protocols to ensure quality and efficacious patient care. To provide evidence informed treatment recommendations, we have developed a database of all patients in southern Alberta undergoing orthopaedic surgery for MBD. Our results demonstrate that many patients were not treated according to post-operative standard of care recommendations. Notably, half of the included patients did not have documented surgical follow-up, post-operative radiation treatment was low and only 11% were actively treated with bone protective agents. This data justifies the need for established surgical MBD care pathways and provides reference data to benchmark prospective QA and QI outcomes in this patient population

The aim of this study was to evaluate whether duration of surgery correlates with the survival and final outcome of the patient with metastatic bone disease. Between 1999 and 2002, 23 consecutive patients with impending or complete pathological fractures of the femur due to metastatic bone disease caused by variety of malignancies or an unknown primary were reviewed. These fractures were treated with intramedullary fixation in the form of long intramedullary hip screw, long Gamma nail or AO nail. These patients were followed up clinically and radiologically until death from the primary disease. The results obtained demonstrate a mean survival time between 9 days to 12 months. Pain relief was achieved in 90% patients. Ambulatory status was improved in 47% patients. The postoperative course was complicated by four technical and five systemic complications. Intramedullary nailing is a safe and effective method in the treatment of metastatic bone disease. It provides good functional result with pain relief and improved mobility. The operating time does not predictably correlate with the survival and final outcome of the patient

Introduction: Breast cancer is the most frequently diagnosed cancer in western countries and bone metastases of breast cancer cause significant morbidity. Tumor growth and progression requires the formation of new blood vessels, a process called angiogenesis. Angiogenesis is a complex multifactorial process involving a variety of proangiogenic and proteolytic enzyme activators and inhibitors. The most important regulator of angiogenesis is vascular endothelial growth factor (VEGF), which is overexpressed in several tumor tissues. The single nucleotide polymorphism 1498 C/T of VEGF was associated with increased plasma levels of VEGF. In this case controlled study, we analyzed the role of this polymorphism in bone metastasis of breast cancer. Material and Methods: We genotyped 839 female breast cancer patients. The study was performed according to the Austrian Gene Technology Act and has been approved by the Ethical Committee of the Medical University Graz. According to breast cancer staging, patients were divided in three groups, representing patients without metastases (n = 708), those with metastases other than bone (n = 69), and those with bone metastasis (n = 62). Results: Frequency of the 1498 CC genotype of VEGF was significantly lower among patients with bone metastases (6.5%) than among those with other metastases (23.2%; p=0.005) or no metastases (23.4%; p=0.002). Odds ratio of the CC genotype for bone metastases was 0.22 (95% CI 0.08 – 0.61; p = 0.004). Conclusion: We conclude that the homozygous 1498 C genotype of VEGF may be protective against development of bone metastasis in breast cancer patients

Prophylactic treatment is advised for metastatic bone disease patients with a high risk of fracture. Clinicians face the task of identifying these patients with high fracture risk and determining the optimal surgical treatment method. Subject-specific finite element (FE) models can aid in this decision process by predicting the mechanical effect of surgical treatment. In this study, we specifically evaluated the potential of FE models to simulate femoroplasty, as uncertainty remains whether this prophylactic procedure provides sufficient mechanical strengthening to the weight-bearing femur. In eight pairs of human cadaveric femurs artificial metastatic lesions were created. In each pair, an identical defect was milled in the left and right femur. Four pairs received a spherical lesion in the neck and the other four an ellipsoidal lesion in the intertrochanteric region, each at the medial, superior/lateral, anterior and posterior side, respectively. One femur of each pair was augmented with polymethylmethacrylate (5–10 ml), while the contralateral femur was left untreated. CT scans were made at three different time points: from the unaffected intact femurs, the defect femurs with lesion and the augmented femurs. Bone strength was measured by mechanical testing until failure in eight defect and eight augmented femurs. Nonlinear CT-based FE models were developed and validated against the experimentally measured bone strength. Subsequently, the validated FE model was applied to the available CT scans for the three different cases: intact (16 scans), defect (16) and augmented (8). The FE predicted strength was compared for the three different cases. The FE models predicted the experimental bone strength with a strong correspondence, both for the defect (R. 2. = 0.97, RMSE= 0.75 kN) and the augmented femurs (R. 2. = 0.90, RMSE = 0.98 kN). Although all lesions had a “moderate” to “high” risk for fracture according to the Mirels’ scoring system (score 7 or 8), three defect femurs did not fracture through the lesion (intertrochanteric anterior, lateral and posterior), indicating that these lesions did not act as a critical weak spot. In accordance with the experimental findings, the FE models indicated almost no reduction in strength between the intact and defect state for these femurs (0.02 ± 0.1%). For the remaining “critical” lesions, bone strength was reduced with 15.7% (± 14.9%) on average. The largest reduction was observed for lesions on the medial side (up to 43.1%). For the femurs with critical lesions, augmentation increased bone strength with 29.5% (± 29.7%) as compared to the defect cases, reaching strength values that were 2.5% (± 3.7%) higher than the intact bone strength. Our findings demonstrate that FE models can accurately predict the experimental bone strength before and after augmentation, thereby enabling to quantify the mechanical benefit of femoroplasty. This way FE models could aid in identifying suitable patients for whom femoroplasty provides sufficient increase in strength. For all lesions evaluated in this study, femoroplasty effectively restored the initial bone strength. Yet, additional studies on larger datasets with a wide variation of lesion types are required to confirm these results

National guidelines recommend that trauma centres have a designated consultant for managing metastatic bone disease (MBD). No such system exists in Scotland. We compared MBD cases in a trauma hospital to a national bone tumour centre to characterise differences in management and outcome. Consecutive patients with metastatic proximal femoral lesions referred to a trauma unit and a national sarcoma centre were compared over a seven-year period (minimum follow-up one year). From Jan 2010-Dec 2016, 195 patients were referred to the trauma unit and 68 to the tumour centre. The trauma unit tended to see older patients (mean 72 vs. 65 years, p<0001) with cancers of poorer prognosis (e.g. 31% 61/195 vs. 13% 9/68 lung primary, p<0.001). Both units had similar operative rates but patients referred to the tumour centre were more likely to have endoprosthetic reconstruction (EPR 44% tumour vs. 3% trauma centre, p<0.001). Patients with an EPR survived longer than those with other types of fixation (81% 17/21 vs. 31% 35/112 one-year survival, p<0.001). Patients undergoing EPR were more likely to have an isolated metastasis (62% 13/21 vs. 17% 4/24, p<0.001). One patient from each centre had a revision for failed metalwork. There was a difference in caseload referred to both units, with the tumour centre seeing younger patients with a better prognosis. Patients suitable for endoprostheses were more likely to have isolated metastatic disease and a longer survival after surgery. An MBD pathway is required to ensure such patients are identified and referred for specialist management where appropriate

Vertebral fracture due to a metabolic bone disease or a neoplastic disease is a common and debilitating condition. It most often is associated with either osteoporosis or metastatic bone disease. Some of the patients suffering from such fractures continue to complain of back pain and deformity despite optimal medical therapy, including radiotherapy and biphosphonates. Vertebroplasty, i.e. transcutaneous injection of bone cement into the vertebral body can serve as an internal fixation device and allows restoration of mechanical strength and partial restoration of the vertebral height. During the year 2000, 17 vertebrae in 12 patients were injected. These were either lumbar or thoracic vertebrae. All patients reported decrease in pain and improved ambulation capacity. Two minor complications were encountered including headache lasting for 72 hours prior to spontaneously resolving. This possibly indicates a transarachnoidal approach, the other complication has been cement leak below the posterior longitudinal ligament. The patient reported pain amelioration. No emergency surgical interventions were necessary to date. Treatment of metastatic bone disease should be staged, with only a few vertebrae injected in each session, to prevent pulmonary embolization. Vertebroplasty appears to allow excellent palliative treatment in patients suffering from unresectable primary tumors of the vertebrae, or more commonly, metastatic bone tumors as well as osteoporotic fractures

Aims

This study aimed to analyze the accuracy and errors associated with 3D-printed, patient-specific resection guides (3DP-PSRGs) used for bone tumour resection.

Aims

We first sought to compare survival for patients treated surgically for solitary and multiple metastases in the appendicular skeleton, and second, to explore the role of complete and incomplete resection (R0 and R1/R2) in patients with a solitary bony metastasis in the appendicular skeleton.

Introduction: Current guidelines from the British Orthopaedic Oncology Society indicate that the role of the orthopaedic surgeon in the management of the meta-static bone disease (MBD) of the long bones falls into two principal categories; prophylactic fixation of meta-static deposits at risk of fracture and stabilisation following pathological fractures. Bone biopsy and MRI scan is advocated if the primary tumour is not identified. Aim: The aim of this study is to audit at the current practice in the South Trent region. Method: A postal questionnaire with three case scenarios was sent to all orthopaedic consultants and SpR’s in the South Trent region. They were asked how they would manage a patient with a fracture and; a single bone metastasis and a known primary tumour, a single bone metastasis and an unknown primary tumour, and multiple metastases of unknown origin. Results: 80 % of the questionnaires were completed and returned. In the presence of a known primary tumour and a single metastasis, 75 % would send intra-medullary reamings for histology at the time of fixation. In the presence of a single metastasis and an unknown primary tumour, 38 % would perform a biopsy prior to fracture fixation. In the event of multiple metastases with an unknown primary, 15 % would perform a biopsy. Conclusion: There is a lack of consensus among the orthopaedic surgeons sampled about the management of the MBD. Intramedullary reamings sent during fixation have a high rate of false negative results but are still preferred by many surgeons to aid diagnosis in MBD. Thorough clinical and radiological assessments are probably more useful in the diagnosis of the primary tumour

Purpose. Versican is a member of the large aggregating chondroitin sulfate proteoglycan family. Structurally, it is made up of an N-terminal G1 domain, a glycosamingoglycan attachment region, and a C-terminus containing a selectin-like (G3) domain. Versican is highly expressed in the interstitial tissues at the invasive margins of breast carcinoma and predictive of relapse and overall survival. The purpose of the study to investigate the role of of versican G3 domain in breast cancer bone metastasis. Method. Mouse mammary tumor cell lines 66c14, 4T07 and 4T1, and human breast cancer cell lines MT-1, MDA-MB-468 and MDA-MB-231 were stably transfected with versican G3. Effects of expression of versican G3 on cell proliferation, migration, invasion, cell cycle progression, and EGFR signaling were observed. The effects of G3 on cell viability in the conditional media of serum free, apoptotic agent C2-ceramide, and chemotherapeutic agents, including Docetaxel, Doxorubicin, Epirubicin were investigated. Colony formation assay and mammosphere formation assay were performed. A syngeneic orthotopic animal model was used to do the in vivo study. Results. In vitro, G3 enhanced breast cancer cell proliferation and migration by up-regulating EGFR signaling, and enhanced cell motility through chemotactic mechanisms to bone stromal cells, which was prevented by inhibitor AG 1478. Experiments in a syngeneic orthotopic animal model demonstrated that G3 promoted tumor growth and bone metastasis in vivo. Versican G3 domain enhanced tumor cell resistance to apoptosis in serum free medium, Doxorubicin, or Epirubicin by up-regulating pERK and GSK-3β (S9P), and promoted cell apoptosis induced by C2-ceramide or Docetaxel by enhanced expression of pSAPK/JNK and decreased GSK-3β (S9P). Versican expresses highly in the breast cancer mammosphere progenitor cells. Expression of versican G3 enhanced breast cancer self-renewal in vitro and in vivo. Conclusion. The activity of G3 on mouse mammary tumor cell growth, migration and its effect on spontaneous metastasis to bone in an orthotopic model was modulated by up-regulating the EGFR-mediated signaling. The dual roles of G3 in modulating breast cancer cell resistance to chemotherapeutic agents indicate a potential mechanism for breast cancer cell sensitivity or resistance to chemotherapy and EGFR therapy. GSK-3β (S9P) works as a key check point for the balance of apoptosis and anti-apoptosis. Over-expression of versican G3 domain enhanced breast cancer self-renewal, and resistant to chemo-drug treatments. Strategies designed to target versican mediated breast cancer self-renewal or GSK-3β (S9P) may lead to an effective therapy benefiting advanced breast cancer patients

Purpose: To determine the surgical and functional outcome of an anatomically based approach to hip reconstruction for metastatic bone disease. Methods: Records of 123 consecutive patients who underwent hip arthroplasty for metastatic bone disease were reviewed. Sixty one patients (63 hips) had pelvic involvement that required periacetabular reconstruction. Sixty two patients (64 hips) had proximal femoral involvement but no acetabular disease. Operative technique was guided by the extent of column and dome disease in addition to the extent of involvement of the femur. Demographic variables, functional data (ECOG scores) and survival data were analyzed. Results: : The cohort included 94 females and 29 males, mean age 62 years (range, 39–85). Breast, lung and kidney were the most common primary sites. The average time from initial primary diagnosis to surgery was 42 months. The average time from initial primary diagnosis to surgery was significantly longer for those with breast cancer compared to those with other primary sites (65 vs. 21 months, P< 0.001). Average blood loss was 788 ml (range, 200–3800 ml) and average operative time was 2.3 hours (range, 2–6 hours). There were three perioperative deaths. Functional scores improved from an average of 2.7 preoperatively to 1.4 postoperatively (P< 0.05). Two patients required closed reduction, two required open trochanteric repair and one required ace-tabular revision. Median survival time was 15 months (range, 0–172 months). Patients with breast cancer enjoyed longer survival compared to patients with other primaries (21 vs. 9 months, P=0.02). Conclusions: Despite the moderate risk of operative complications, an anatomically based approach to reconstruction of metastatic hip disease is effective in improving functional outcome and quality of life in many patients

Purpose: We report a series of 58 patients with metastatic bone disease treated with resection and endoprosthetic reconstruction over a 5 year period at our institution. Introduction: The recent advances in adjuvant and neo-adjuvant therapy in cancer treatment has resulted in improved prognosis of patients with bone metastases. Most patients who have an actual or impending pathological fracture should have operative stabilisation or reconstruction. According to BOA guidelines patients should undergo a single procedure which allows early full weight bearing and lasts the expected lifespan of the patient. The use of modern modular endoprostheses allows these criteria to be met. Methods and Results: We retrospectively identified all patients diagnosed with metastatic disease to bone between 1999 to 2003. 171 patients were diagnosed with bone metastases. Metastatic breast and renal cancer accounted for 47% of the lesions. 58 patients with bone metastasis to the appendicular skeleton had an endo-prosthetic reconstruction. There were 28 males and 30 females. 11 patients had lesions in the upper extremity and 47 patients had lesions in the lower extremity. Mean age at presentation was 62 years (24 to 88 years). 19 patients are still alive, 34 patients had died and 5 were lost to follow-up. Patients died of disease at a mean of 22 months (2 to 51 months) from surgery. Mean follow-up was 55 months (24 to 78 months). There were 5 wound infections, 1 aseptic loosening, 3 dislocations, 1 subluxation and 1 prosthesis rotated requiring open repositioning. Patients were followed up and evaluated using the Musculoskeletal Society Tumour Score (MSTS) and the Toronto Extremity Salvage Score. The mean MSTS score was 73% (57 to 90%) and TESS was 71% (84 to 95%). Conclusions: We conclude that endoprosthetic replacement for the treatment of bone metastases in selected cases achieves the aims of restoring function, allowing early weight bearing and alleviating pain. The complication rate is low

The purpose of this study was to analyse the long-term results of prosthetic joint replacement in patients suffering from metastatic bone disease. The treatment was performed in order to prevent or treat pathological fractures, to control the pain and improve the functionality of the lower limb. 120 patients suffering from metastatic disease of the lower extremities were treated with prosthetic replacement between 1992 and 2004. The patients, 80 females and 40 males, having an age at the time of surgery ranging from 32 to 83 years, were treated by the same equipe in the San Raffaele Hospital in Milan. The primary tumor included breast carcinoma (66), lung carcinoma (19), kidney tumor (17), prostatic tumor (7), plasmocytoma (5), non identified tumor (5), melanoma (1). The metastasis was located in the proximal femur in 112 cases, in the distal femur in 3, in proximal tibia in 5. In 8 out of 120 patients, the metastatic lesion was the first sign of carcinoma, 25 patients had a pathological fracture and the bone metastases were detected from 6 mounth to 13 years after the diagnosis of the primary tumor. Knee: in our casuistry 8 patients with a metastasis in proximal tibia or distal femur were operated with modular prostheses: in 1 case of this group (single lesion of kidney tumor), we have implanted an allograft-prosthesis-composite. Proximal femur: for the treatment of this site, we have included also those patients having a life expectancy inferior to 1 month. In 30 cases the lesion was located in the epiphysis and neck and we have implanted 5 endoprosthesis, 5 total hip prostheses and 20 bipolar prostheses. In 82 patients with a metastasis located in the metaphysis we used a modular prosthesis with a femoral resection up to 16 cm. 69 patients are alive with a follow-up ranging from 6months to 12 years. 5 patients died in early post surgical period. 13 patients developed local recurrence. These latest have suffered from a pathological fracture, which had occurred before the first surgical treatment. Pain relief was achieved in all patients after surgery with acceptable functionality of the operated limb. We considered the risk of pathological fractures more important than life expectancy. Moreover, we believe that the surgery to these patients should be definitive. In fact, the use of prostheses allow for a wide resection of the lesion. This condition represents also an advantage in those cases where radio- or chemiotherapy can not be performed. Moreover, the prostheses permit an immediate weight bearing, a good functional recovery and also, in patients with critical general condition, a more easy assistance. In conclusion, for patients with metastatic bone disease, we consider a correct approach the radical excision of the lesion and the implant of a prosthesis

Introduction and Objectives: Half of primary tumors tend to disseminate to bones, and metastasis to bone is the third most common localisation for disseminated disease, after the lungs and liver. It is also the most common form of neoplasia in the skeleton. Treatment of bone metastasis is essentially palliative, and in select cases improves patient survival. We present results from the last 15 years in our centre. Materials and Methods: Between the years 1988–2003, our surgical oncology unit has treated 451 patients with bone metastasis. Of these, 49% were male, and 51% were female. Average age was 64 years (19–98). The most common causes were metastatic breast cancer (34%), unknown tumours (17%), multiple myeloma (9%), prostate cancer (9%), lung cancer (7%), bladder cancer (6%), and others (18%). Tumours localised to the following locations: femur (31%), spine (27%), multiple locations (13%), pelvis (11.5%), humerus (9%), and other locations (8.5%). In 69% of cases the first symptom was pain, in 28% pathologic fracture, and in the remaining 3% medullary compression. Of the 125 pathologic fractures, 71% were on the femur, 18% on the humerus, and the remaining 11% in other locations. Results: In 60% of cases (271 patients) conservative treatment was used, and in the remaining 40% (180 patients) surgical treatment was used. Of the 180 surgeries, 50.5% were for pathologic fractures, and 49.5% were prophylactic surgeries. Of the 125 pathologic fractures, 91 (73%) received surgical treatment, and the other 34 (27%) were treated conservatively. Intramedullary nailing was the most commonly used form of osteosynthesis (47%). Total resolution of pain was achieved in 86.5% of cases, and partial resolution in 13.5%. Mean time in bed from prophylactic surgery was 3 days. Mean time for recovery of function was 7 days for the arms and 11 days for the legs. Discussion and Conclusions: The fundamental goal is to offer short-term individualized treatment to control pain and avoid bedrest and hospitalization of these patients. Prophylactic surgery does not increase life expectancy of these patients. However, it does alleviate pain, avoids bedrest, and improves functionality. It should be kept in mind that the least aggressive surgical technique possible should be used

Aims

The proximal tibia (PT) is the anatomical site most frequently affected by primary bone tumours after the distal femur. Reconstruction of the PT remains challenging because of the poor soft-tissue cover and the need to reconstruct the extensor mechanism. Reconstructive techniques include implantation of massive endoprosthesis (megaprosthesis), osteoarticular allografts (OAs), or allograft-prosthesis composites (APCs).