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

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Radiotherapy is a well-known local treatment for spinal metastases. However, in the presence of postoperative systemic therapy, the efficacy of radiotherapy on local control (LC) and overall survival (OS) in patients with spinal metastases remains unknown. This study aimed to evaluate the clinical outcomes of post-surgical radiotherapy for spinal metastatic non-small-cell lung cancer (NSCLC) patients, and to identify factors correlated with LC and OS.

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The present study investigated receptor activator of nuclear factor kappa-Β ligand (RANKL), osteoprotegerin (OPG), and Runt-related transcription factor 2 (RUNX2) gene expressions in giant cell tumour of bone (GCTB) patients in relationship with tumour recurrence. We also aimed to investigate the influence of CpG methylation on the transcriptional levels of RANKL and OPG.

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

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The involvement of cyclin D1 in the proliferation of microglia, and the generation and maintenance of bone cancer pain (BCP), have not yet been clarified. We investigated the expression of microglia and cyclin D1, and the influences of cyclin D1 on pain threshold.

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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.

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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).

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

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Due to their radiolucency and favourable mechanical properties, carbon fibre nails may be a preferable alternative to titanium nails for oncology patients. We aim to compare the surgical characteristics and short-term results of patients who underwent intramedullary fixation with either a titanium or carbon fibre nail for pathological long-bone fracture.

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

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LY3023414 is a novel oral phosphatidylinositol 3-kinase (PI3K)/mammalian target of rapamycin (mTOR) dual inhibitor designed for advanced cancers, for which a phase II clinical study was completed in March 2020; however, little is known about its effect on bone modelling/remodelling. In this study, we aimed to explore the function of LY3023414 in bone modelling/remodelling.

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

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The aticularis genu (AG) is the least substantial and deepest muscle of the anterior compartment of the thigh and of uncertain significance. The aim of the study was to describe the anatomy of AG in cadaveric specimens, to characterize the relevance of AG in pathological distal femur specimens, and to correlate the anatomy and pathology with preoperative magnetic resonance imaging (MRI) of AG.

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Receptor activator of nuclear factor-κB ligand (RANKL) is a key molecule that is expressed in bone stromal cells and is associated with metastasis and poor prognosis in many cancers. However, cancer cells that directly express RANKL have yet to be unveiled. The current study sought to evaluate how a single subunit of G protein, guanine nucleotide-binding protein G(q) subunit alpha (GNAQ), transforms cancer cells into RANKL-expressing cancer cells.

During the last decades, several research groups have used bisphosphonates for local application to counteract secondary bone resorption after bone grafting, to improve implant fixation or to control bone resorption caused by bone morphogenetic proteins (BMPs). We focused on zoledronate (a bisphosphonate) due to its greater antiresorptive potential over other bisphosphonates. Recently, it has become obvious that the carrier is of importance to modulate the concentration and elution profile of the zoledronic acid locally. Incorporating one fifth of the recommended systemic dose of zoledronate with different apatite matrices and types of bone defects has been shown to enhance bone regeneration significantly in vivo. We expect the local delivery of zoledronate to overcome the limitations and side effects associated with systemic usage; however, we need to know more about the bioavailability and the biological effects. The local use of BMP-2 and zoledronate as a combination has a proven additional effect on bone regeneration. This review focuses primarily on the local use of zoledronate alone, or in combination with bone anabolic factors, in various preclinical models mimicking different orthopaedic conditions.

Cite this article: I. Qayoom, D. B. Raina, A. Širka, Š. Tarasevičius, M. Tägil, A. Kumar, L. Lidgren. Anabolic and antiresorptive actions of locally delivered bisphosphonates for bone repair: A review. Bone Joint Res 2018;7:548–560. DOI: 10.1302/2046-3758.710.BJR-2018-0015.R2.

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