Bone metastases are common and severe complications of cancers. It is estimated to occur in 65–75% of breast and prostate cancer patients and cause 80% of breast cancer-related deaths. Metastasised cancer cells have devastating impacts on bone due to their ability to alter bone remodeling by interacting with osteoblasts and osteoclasts. Exercise, often used as an intervention for cancer patients, regulates bone remodeling via osteocytes. Therefore, we hypothesise that bone mechanical loading may regulate bone metastases via osteocytes. This provides novel insights into the impact of exercises on bone metastases. It will assist in designing cancer intervention programs that lowers the risk for bone metastases. Investigating the mechanisms for the observed effects may also identify potential drug targets. MLO-Y4 osteocyte-like cells (gift of Dr. Bonewald, University of Missouri-Kansas City) on glass slides were placed in flow chambers and subjected to oscillatory fluid flow (1Pa; 1Hz; 2 hours). Media were extracted (conditioned media; CM) post-flow. RAW264.7 osteoclast precursors were conditioned in MLO-Y4 CM for 7 days. Migration of MDA-MB-231 breast cancer cells and PC3 prostate cancer cells towards CM was assayed using Transwell. Viability, apoptosis, and proliferation of the cancer cells in the CM were measured with Fixable Viability Dye eFluor 450, APOPercentage, and BrDu, respectively. P-values were calculated using Student's t-test. Significantly more MDA-MB-231 and PC3 cells migrated towards the CM from MLO-Y4 cells with exposure to flow in comparison to CM from MLO-Y4 cells not exposed to flow. The preferential migration is abolished with anti-VEGF antibodies. MDA-MB-231 cells apoptosis rate was slightly lower in CM from MLO-Y4 cells exposed to flow, while proliferation rate was slightly higher. The current data showed no difference in cancer cells viability and adhesion to collagen between any two groups. On the other hand, it was observed that less MDA-MB-231 cells migrated towards CM from RAW264.7 cells conditioned in CM from MLO-Y4 cells stimulated with flow in comparison to those conditioned in CM from MLO-Y4 cells not stimulated with flow. TRAP staining results confirmed that there were less differentiated osteoclasts when RAW264.7 cells were cultured in CM from MLO-Y4 cells exposed to flow. Overall, this study suggests that when only osteocytes and cancer cells are involved, osteocytes subjected to mechanical loading can promote metastases due to the increased secretion of VEGF. However, with the incorporation of osteoclasts, mechanical loading on osteocytes seems to reduce MDA-MB-231 cell migration. This is likely because osteocytes reduce osteoclastogenesis in response to mechanical stimulation, and osteoclasts have been shown to support cancer cells. Animal studies will also be conducted to verify the pro- or anti-metastatic effect of mechanical loading that is observed in the in vitro part of this study

Background: About 60% of all cancer patients survive at least 5 years, and therefore have a risk to develop long-term effects after cancer treatment. Most research, the later years, on long-term effects after cancer treatment, has focused on cardiovascular side effects and side effects in the pelvic region. On the other hand, hardly any focus has been on possible side effects on the musclo-skeletal system, though there are multiple reasons that surviving cancer patients may develop such problems. Aim: To determine whether cancer patients have an increased risk for receiving a total hip replacement compared to the population of Norway. Analyses are based on a linkage between The Cancer Register of Norway and The Norwegian Arthroplasty Register. Materials and Methods: By linking these two registers we have connected all cancer diagnosis, all total hip arthroplasties and information about time of death for each patient. Data refers to 741,901 patients, divided into three groups; 652,197 patients with at least one cancer diagnose but none hip arthroplasties. 72,469 patients with at least one hip arthroplasty but no cancer diagnose. The last group of 17,235 patients have at least one cancer diagnose and at least one hip arthroplasty. From the last group 8,629 patients received a cancer diagnoses first and a total hip arthroplasty second. Statistical methods in this study were the Kaplan-Meier method, Cox regression and Standardized Incidence Ratio (SIR). Results: Cancer patients had a slight increased risk to receive a total hip arthroplasty compared to the Norwegian population (SIR=1.13 (95% CI, 1.10–1.15)). For cancer located proximal to the pelvic area there were no significant increase in risk for hip arthroplasty, except for breast cancer (SIR=1.12 (95% CI 1.07–1.17)). Cancer located to the pelvic area (SIR=1.18 (95% CI 1.14–1.22)), lymphoma (SIR=1.29 (95% CI 1.14–1.45)) and leukaemia (SIR=1.16 (95% CI 1.17–1.31)) had an increased risk for receiving a total hip arthroplasty. Conclusion: We found a small increase in risk for receiving total hip arthroplasty after cancer diagnose. Treatment type may affect these results. Radiation dose to the pelvic area may affect the bone structure and increase the need of arthroplasty. Future studies on effect of radiation doses and risk of receiving hip arthroplasty are planed

Total joint replacement (TJR) was one of the most revolutionary breakthroughs in joint surgery. The majority studies had shown that most implants could last about 25 years, anyway, there is still variation in the longevity of implants. In US, for all the hip revisions from 2012 to 2017 in the United States, 12.0% of the patients were diagnosed as aseptic loosening. Variable studies have showed that any factor that could cause a systemic or partial bone loss, might be the risk of periprosthetic osteolysis and aseptic loosening. Breast cancer is the most frequent malignancy in women, more than 2.1 million women were newly diagnosed with breast cancer, 626,679 women with breast cancer died in 2018. It's been reported that the mean incidence of THA was 0.29% for medicare population with breast cancer in USA, of which the incidence was 3.46% in Norwegian. However, the effects of breast cancer chemotherapy and hormonotherapy, such as aromatase inhibitors (AI), significantly increased the risk of osteoporosis, and had been proved to become a great threat to hip implants survival. In this case, a 46-year-old female undertook chemotherapy and hormonotherapy of breast cancer 3 years after her primary THA, was diagnosed with aseptic loosening of the hip prosthesis. Her treatment was summarized and analyzed. Breast cancer chemotherapy and hormonotherapy might be a threat to the stability of THA prosthesis. More attention should be paid when a THA paitent occurred with breast cancer. More studies about the effect of breast cancer treatments on skeleton are required

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

Cancer is a major health problem for teenagers and young adults (TYA’s). However, many young people are often late to receive a cancer diagnosis. Young people may not recognize symptoms as serious and delay seeking help. Furthermore, there is evidence to suggest that once a young person does seek help from a general practitioner (GP), significant delay can still occur. During the annual Find Your Sense of Tumour (FYSOT) conference 2007; a group of 200 TYA’s with cancer participated in a survey regarding their diagnostic experience; the cohort included 22 patients with bone tumours. Following the onset of symptoms; nearly half of the TYA’s with a bone tumour (46%) reported 4 or more visits to their G.P before being referred to a specialist. However, 91% of bone tumour patients had multiple, ‘classic’ cancer symptoms and the majority (77%) sought help from the G.P within 4 weeks of noticing symptoms. The ‘Christie Crew’ (CC) are a group of TYA’s who have been treated for cancer and work on various projects to improve cancer services. The Christie Crew wanted to empower young people with the knowledge that TYA’s do get cancer and to raise awareness of the signs and symptoms of cancer and have produced a DVD and education pack that has been launched across 80 schools and throughout the North West. The DVD is highlights individual’s stories of diagnosis. There is also a poster campaign highlighting signs and symptoms of cancer being displayed in large public venues across the Manchester area. The aim is to roll out the project nationally as part of the health awareness (Healthy Schools) initiative. By highlighting that young people get cancer it is hoped that more young people will recognise the signs and symptoms and be empowered to go to their GP if they have persistent problems

Aims. 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. Methods. We investigated the specific role of GNAQ using GNAQ wild-type cell lines (non-small-cell lung cancer cell lines; A549 cell lines), GNAQ knockdown cell lines, and patient-derived cancer cells. We evaluated GNAQ, RANKL, macrophage colony-stimulating factor (M-CSF), nuclear transcription factor-κB (NF-κB), inhibitor of NF-κB (IκB), and protein kinase B (Akt) signalling in the GNAQ wild-type and the GNAQ-knockdown cells. Osteoclastogenesis was also evaluated in both cell lines. Results. In the GNAQ-knockdown cells, RANKL expression was significantly upregulated (p < 0.001). The expression levels of M-CSF were also significantly increased in the GNAQ-knockdown cells compared with control cells (p < 0.001). GNAQ knockdown cells were highly sensitive to tumour necrosis factor alpha (TNF-α) and showed significant activation of the NF-κB pathway. The expression levels of RANKL were markedly increased in GNAQ mutant compared with GNAQ wild-type in patient-derived tumour tissues. Conclusion. The present study reveals that the alterations of GNAQ activate NF-κB pathway in cancers, which increase RANKL and M-CSF expression and induce osteoclastogenesis in cancers. Cite this article:Bone Joint Res. 2020;9(1):29–35

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. Methods. We used the mouse osteosarcoma cell line LM8, the human breast cancer cell line MDA-MB-231, and the human prostate cancer cell line PC-3. Cultured cells were exposed to AO and radiation at various concentrations followed by various doses of irradiation. The cell viability was then measured. In vivo, each cell was inoculated subcutaneously into the backs of mice. In the AO-RDT group, AO (1.0 μg) was locally administered subcutaneously around the tumour followed by 5 Gy of irradiation. In the radiation group, 5 Gy of irradiation alone was administered after macroscopic tumour formation. The mice were killed on the 14th day after treatment. The change in tumour volume by AO-RDT was primarily evaluated. Results. The viability of LM8, MDA-MB-231, and PC-3 cells strongly decreased at AO concentration of 1.0 μg/ml and a radiation dose of 5 Gy. In xenograft mouse model, the AO-RDT also showed a strong cytocidal effect on tumour at the backside in osteosarcoma, breast cancer, and prostate cancer. AO-RDT treatment was more effective for tumour control than radiotherapy in breast cancer. Conclusion. AO-RDT was effective in preventing the proliferation of osteosarcoma, breast cancer, and prostate cancer cell lines in vitro. The reduction in tumour volume by AO-RDT was also confirmed in vivo. Cite this article: Bone Joint Res 2022;11(10):715–722

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

Lung cancer is the most common cancer diagnosed, the leading cause of cancer-related deaths, and bone metastases occurs in 20–40% of lung cancer patients. They often present symptomatically with pain or skeletal related events (SREs), which are independently associated with decreased survival. Bone modifying agents (BMAs) such as Denosumab or bisphosphonates are routinely used, however no specific guidelines exist from the National Comprehensive Cancer Center or the European Society of Medical Oncologists. Perhaps preventing the formation of guidelines is the lack of a high-quality quantitative synthesis of randomized controlled trial (RCT) data to determine the optimal treatment for the patient important outcomes of 1) Overall survival (OS), 2) Time to SRE, 3) SRE incidence, and 4) Pain Resolution. The objective of this study was to perform the first systematic review and network meta-analysis (NMA) to assess the best BMA for treatment of metastatic lung cancer to bone. We conducted our study in accordance to the PRISMA protocol. We performed a librarian assisted search of MEDLINE, PubMed, EMBASE, and Cochrane Library and Chinese databases including CNKI and Wanfang Data. We included studies that are RCTs reporting outcomes specifically for lung cancer patients treated with a bisphosphonate or Denosumab. Screening, data extraction, risk of bias and GRADE were performed in duplicate. The NMA was performed using a Bayesian probability model with R. Results are reported as relative risks, odds ratios or mean differences, and the I2 value is reported for heterogeneity. We assessed all included articles for risk of bias and applied the novel GRADE framework for NMAs to rate the quality of evidence supporting each outcome. We included 132 RCTs comprising 11,161 patients with skeletal metastases from lung cancer. For OS, denosumab was ranked above zoledronic acid (ZA) and estimated to confer an average of 3.7 months (95%CI: −0.5 – 7.6) increased survival compared to untreated patients. For time to SRE, denosumab was ranked first with an average of 9.1 additional SRE-free months (95%CI: 4.0 – 14.0) compared to untreated patients, while ZA conferred an additional 4.8 SRE-free months (2.4 – 7.0). Patients treated with the combination of Ibandronate and systemic therapy were 2.3 times (95%CI: 1.7 – 3.2) more likely to obtain successful pain resolution, compared to untreated. Meta-regression showed no effect of heterogeneity length of follow-up or pain scales on the observed treatment effects. Heterogeneity in the network was considered moderate for overall survival and time to SRE, mild for SRE incidence, and low for pain resolution. While a generally high risk of bias was observed across studies, whether they were from Western or Chinese databases. The overall GRADE for the evidence underlying our results is High for Pain control and SRE incidence, and Moderate for OS and time to SRE. This study represents the most comprehensive synthesis of the best available evidence guiding pharmacological treatment of bone metastases from lung cancer. Denosumab is ranked above ZA for both overall survival and time to SRE, but both treatments are superior to no treatment. ZA was first among all bisphosphonates assessed for odds of reducing SRE incidence, while the combination of Ibandronate and radionuclide therapy was most effective at significantly reducing pain from metastases. Clinicians and policy makers may use this synthesis of all available RCT data as support for the use of a BMA in MBD for lung cancer

The initiation and progression of malignant tumors are supported by their microenvironment: cancer cells per se cannot explain growth and formation of the primary or metastasis, and a combination of proliferating tumor cells, cancer stem cells, immune cells, mesenchymal stromal cells and/or cancer-associated fibroblasts all contribute to the tumor bulk. The interaction between these multiple players, under different microenvironmental conditions of biochemical and physical stimuli (i.e. oxygen tension, pH, matrix mechanics), regulates the production and biological activity of several soluble factors, extracellular matrix components, and extracellular vesicles that are needed for growth, maintenance, chemoresistance and metastatization of cancer. Both in osteosarcoma and bone metastases from carcinomas this aspect has been only recently explored. In this lecture, I will discuss the role of tumor microenvironment, with a particular focus on the mesenchymal stroma, contributing to bone tumor progression through inherent. The most recent advances in the molecular cues triggered by cytokines, soluble factors, and metabolites that are partially beginning to unravel the axis between stromal elements of mesenchymal origin and bone cancer cells, under different microenvironmental conditions, will be reviewed providing insights likely to be used for novel therapeutic approaches

Breast and other cancers commonly metastasize to bone to cause bone destruction, pain, fractures hypercalcemia and muscle weakness. Recently, we described a specific molecular mechanism by which bone-derived transforming growth factor (TGF)-beta, released as a consequence of tumor-induced bone destruction causes muscle dysfunction, before the loss of muscle mass. Circulating TGF-beta induces oxidation of the ryanodine receptor (RYR1) on the sarcoplasmic reticulum of skeletal muscle to induce calcium leak and muscle weakness. Blocking TGF-beta, or its release from bone (with bisphosphonates), preventing oxidation of or stabilizing RyR1 all prevented muscle weakness in mouse models of breast cancer bone metastases. In addition to these effects on skeletal muscle, circulating TGF-beta may act on beta cells of the pancreas to impair insulin secretion and result in glucose intolerance. These and other potential systemic effects of TGF-beta released from the tumor-bone microenvironment or from cancer treatment-induced bone destruction implicate bone as a major source of systemic effects of cancer and cancer treatment. Therapy to block the systemic effects of the bone microenvironment will improve morbidity associated with bone metastases and cancer treatment

The burden of metastatic disease presenting with axial skeleton lesions is exponentially rising predominantly due to advances in oncological therapies. A large proportion is these lesions are located in the proximal femora, which given its unique biomechanical architecture is problematic. These patients are frequently comorbid and require prompt and concise decision making regarding their orthopaedic care in line with recent British Orthopaedic Association guidelines. We present data detailing the outcomes for patients with proximal femoral metastatic disease referred and treated over a three year period in an Regional Cancer Centre. We retrospectively reviewed a prospectively maintained database of all patients referred for discussion at MDT with axial skeletal metastatic disease. From this we isolated patients with femoral disease. Demographic data along with primary tumour and metastatic disease site were assessed. Treatment regimens were analysed and compared. Finally predicted and actual mortality data was collated. 331 patients were referred over the analysed time period, of which 99 had femoral disease. 66% of patients were managed conservatively with serial monitoring while 34% underwent operative treatment. 65% of those received an intramedullary fixation while 35% had arthroplasty performed. There was a 51:49 split male to female with Prostate, Lung and Breast being the predominant primary tumours. Concurrent spinal metastatic disease was noted in 62% of patients while visceral mets were seen in 37%. Mortality rate was 65% with an average prognosis of 388 days (1.06years) while average mortality was noted within 291 days (0.8 years). Proximal femoral metastatic disease accounts for a large volume of the overall mets burden. There is an overall tendency towards conservative management and of those requiring surgery IM nailing was the treatment of choice. The data would indicate that outcomes for these patients are guarded and on average worse than those predicted

A recent French report suggested that cobalt metal ions released from total hip replacements (THRs) were associated with an increased risk of dilated cardiomyopathy and heart failure. If the association is causal the consequences would be significant given the millions of Orthopaedic procedures in which cobalt-chrome is used annually. We examined whether cobalt-chrome containing THRs were associated with an increased risk of all-cause mortality, heart failure, cancer, and neurodegenerative disorders. Data from the National Joint Registry was linked to NHS English hospital inpatient episodes for 375,067 primary THRs with up to 14·5 years follow-up. Implants were grouped as either containing cobalt-chrome or not containing cobalt-chrome. The association between implant construct and the risk of all-cause mortality and incident heart failure, cancer, and neurodegenerative disorders was examined. There were 132,119 individuals (35·2%) with an implant containing cobalt-chrome. There were 48,106 deaths, 27,406 heart outcomes, 35,823 cancers, and 22,097 neurodegenerative disorders. There was no evidence of an association that patients with cobalt-chrome implants had higher rates of any of the outcomes. For all-cause mortality there was a very small survival advantage for patients having a cobalt-chrome implant (restricted mean survival time 13·8=days, 95% CI=6·8-20·9). Cobalt-chrome containing THRs did not have an increased risk of all-cause mortality, heart failure, cancer, and neurodegenerative disorders into the second decade post-implantation. Our findings will reassure clinicians and patients that primary THR is not associated with systemic implant effects

Aims. 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. Methods. A retrospective, single-centre review was conducted of patients with spinal metastases from NSCLC who underwent surgery followed by systemic therapy at our institution from January 2018 to September 2022. Kaplan-Meier analysis and log-rank tests were used to compare the LC and OS between groups. Associated factors for LC and OS were assessed using Cox proportional hazards regression analysis. Results. Overall, 123 patients with 127 spinal metastases from NSCLC who underwent decompression surgery followed by postoperative systemic therapy were included. A total of 43 lesions were treated with stereotactic body radiotherapy (SBRT) after surgery and 84 lesions were not. Survival rate at one, two, and three years was 83.4%, 58.9%, and 48.2%, respectively, and LC rate was 87.8%, 78.8%, and 78.8%, respectively. Histological type was the only significant associated factor for both LC (p = 0.007) and OS (p < 0.001). Treatment with targeted therapy was significantly associated with longer survival (p = 0.039). The risk factors associated with worse survival were abnormal laboratory data (p = 0.021), lesions located in the thoracic spine (p = 0.047), and lumbar spine (p = 0.044). This study also revealed that postoperative radiotherapy had little effect in improving OS or LC. Conclusion. Tumour histological type was significantly associated with the prognosis in spinal NSCLC metastasis patients. In the presence of post-surgical systemic therapy, radiotherapy appeared to be less effective in improving LC, OS, or quality of life in spinal NSCLC metastasis patients. Cite this article: Bone Jt Open 2024;5(4):350–360

One out of nine Canadian males would suffer prostate cancer (PC) during his lifetime. Life expectancy of males with PC has increased with modern therapy and 90% live >10 years. However, 20% of PC-affected males would develop incurable metastatic diseases. Bone metastases (BM) are present in ~80% of metastatic PC patients, and are the most severe complication of PC, generating severe pain, fractures, spinal cord compression, and death. Interestingly, PC-BMs are mostly osteoblastic. However, the structure of this newly formed bone and how it relates to pain and fracture are unknown. Due to androgen antagonist treatment, different PC phenotypes develop with differential dependency on androgen receptor (AR) signaling: androgen-dependent (AR+), double negative (AR-) and neuroendocrine. How these phenotypes are related to changes in bone structure has not been studied. Here we show a state-of-the-art structural characterization of PCBM and how PC phenotypes are associated to abnormal bone formation in PCBM. Cadaveric samples (n=14) obtained from metastases of PC in thoracic or lumbar vertebrae (mean age 74yo) were used to analyze bone structure. We used micro-computed tomography (mCT) to analyze the three-dimensional structure of the bone samples. After imaging, the samples were sectioned and one 3mm thick section was embedded in epoxy-resin, ground and polished. Scanning electron microscopy (SEM)/energy-dispersive X-ray spectroscopy (EDS) and quantitative backscattering electron (qBSE) imaging were used to determine mineral morphology and composition. Another section was used for histological analysis of the PC-affected bone. Collagen structure, fibril orientation and extracellular matrix composition were characterized using histochemistry. Additionally, we obtained biopsies of 3 PCBM patients undergoing emergency decompression surgery following vertebral fracture and used them for immunohistological characterization. By using mCT, we observed three dysmorphic bone patterns: osteolytic pattern with thinned trabecula of otherwise well-organized structures, osteoblastic pattern defined as accumulation of disorganized matrix deposited on pre-existing trabecula, and osteoblastic pattern with minimum residual trabecula and bone space dominated by accumulation of disorganized mineralized matrix. Comparing mCT data with patho/clinical parameters revealed a trend for higher bone density in males with larger PSA increase. Through histological sections, we observed that PC-affected bone, lacks collagen alignment structure, have a higher number of lacunae and increased amount of proteoglycans as decorin. Immunohistochemistry of biopsies revealed that PC-cells inside bone organize into two manners: i) glandular-like structures where cells maintain their polarization in the expression of prostate markers, ii) diffuse infiltrate that spreads along bone surfaces, with loss of cell polarity. These cells take direct contact with osteoblasts in the surface of trabecula. We define that PCBM are mostly composed by AR+ with some double negative cells. We did not observe neuroendocrine phenotype cells. PCBMs generate predominantly osteoblastic lesions that are characterized by high lacunar density, lack of collagen organization and elevated proteoglycan content. These structural changes are associated with the infiltration of PC cells that are mostly androgen-dependent but have lost their polarization and contact directly with osteoblasts, perhaps altering their function. These changes could be associated with lower mechanical properties that led to fracture and weakness of the PCBM affected bone

Aims. Socioeconomic and racial disparities have been recognized as impacting the care of patients with cancer, however there are a lack of data examining the impact of these disparities on patients with bone sarcoma. The purpose of this study was to examine socioeconomic and racial disparities that impact the oncological outcomes of patients with bone sarcoma. Methods. We reviewed 4,739 patients diagnosed with primary bone sarcomas from the Surveillance, Epidemiology and End Results (SEER) registry between 2007 and 2015. We examined the impact of race and insurance status associated with the presence of metastatic disease at diagnosis, treatment outcome, and overall survival (OS). Results. Patients with Medicaid (odds ratio (OR) 1.41; 95% confidence interval (CI) 1.15 to 1.72) and uninsured patients (OR 1.90; 95% CI 1.26 to 2.86) had higher risks of metastatic disease at diagnosis compared to patients with health insurance. Compared to White patients, Black (OR 0.63, 95% CI 0.47 to 0.85) and Asian/Pacific Islander (OR 0.65, 95% CI 0.46 to 0.91) were less likely to undergo surgery. In addition, Black patients were less likely to receive chemotherapy (OR 0.67, 95% CI 0.49 to 0.91) compared to White patients. In patients with chondrosarcoma, those with Medicaid had worse OS compared to patients with insurance (hazard ratio (HR) 1.65, 95% CI 1.06 to 2.56). Conclusion. In patients with a bone sarcoma, the cancer stage at diagnosis varied based on insurance status, and racial disparities were identified in treatment. Further studies are needed to identify modifiable factors which can mitigate socioeconomic and racial disparities found in patients with bone sarcomas. Cite this article: Bone Joint Res 2022;11(5):278–291

Purpose of study: Osteonecrosis is a potentially devastating condition which requires early diagnosis before articular collapse occurs. We have become aware of an increase in the number of childhood cancer survivors presenting to us with osteonecrosis. This is recognised in the literature among leukaemia survivors, particularly those treated in adolescence. In the majority of cases the hips have been affected, but shoulders, knees and ankles also appear susceptible. The presentation to orthopaedics is often late with subchondral fracture or collapse of the articular surface, which precludes any salvage of the joint. We wished to assess the extent of the problem throughout Britain. Method: A postal questionnaire was sent to all BSCOS members. Members were asked to note their unit’s experience of childhood cancer survivors with osteonecrosis, current management strategies and if they were willing to participate in a detailed national survey of cases. Results: 58% of respondents work in units where children with childhood cancer are treated. 37% of respondents, or their colleagues, had seen survivors of childhood cancer with osteonecrosis in the last twelve months. Most units had seen less than 5 cases per year. Of the respondents who had treated cases of osteonecrosis (n =30), management included restricted weight-bearing (29), core decompression (9) and bisphosphonates (6). Other treatment modalities used were joint distraction (2), fibular grafting (2), bone marrow injection (1), fusion (1) and arthroplasty (4). Conclusions: We have shown that a large number of units are each seeing small numbers of cases of osteonecrosis in childhood cancer survivors. The study establishes an estimate of the problem nationally and a network of centres to continue a more detailed analysis of cases

Introduction: Within a study group of 102 consecutive patients diagnosed with chondrosarcoma of the femur, tibia or humerus, an association with previously treated breast cancer was noted. We researched this proposed relationship. Methods: We retrospectively reviewed the records of all patients diagnosed histologically with chondrosarcoma of the femur, tibia or humerus over a six-year period at a supra-regional bone tumour unit. We identified those patients who had previously been treated for breast cancer. Results: There were 58 female and 44 male patients. The study group contained six females (10%, mean age 53 years) who had previously been treated for breast cancer, a higher proportion than would be expected. They were referred following identification of a solitary area of increased activity on routine screening with isotope bone scan, presumed to be a solitary bony metastasis. Most (86%) of this breast carcinoma sub-group had developed low-grade bone chondrosarcoma (Trojani grade 0.5-I) and only one case (14%) had developed high-grade chondrosarcoma (Trojani grade II–III). Discussion: A suspicious long bone lesion on bone scan in a patient with a past medical history of breast cancer must, therefore, not be assumed to be a metastasis without further investigation; the possibility of a chondral lesion should be considered. It is important that patients receive a full multidisciplinary team investigation prior to treatment in order to obtain the correct tissue diagnosis, as the management of these conditions is often different. Our study suggests there may be a relationship between patients previously treated for breast cancer and the development of subsequent chondrosarcoma

Common cancer metastases in bone include those derived from the breast or prostate. Associated with such metastases is considerable pain for the patient, a high incidence of pathological fractures (breast cancer metastases), and complications of spinal cord compression and paraplegia. Attention has focussed on the properties of breast or prostate cancer cells that permit them to migrate from their primary site and to invade and grow in bone. Both breast and prostate cancer cell lines and primary cancers exhibit a number of phenotypic properties in common with bone cells, and it has been proposed that these properties may contribute to a breast cancer’s capacity to establish and grow in bone. Once established in bone, these cancers may induce an osteosceloritic or osteolytic lesion. Osteolysis is also noted in the establishment of an osteosclerotic lesion that is frequently associated with prostate cancers. Thus, paramount for a cancer to establish in bone is the requirement for limited bone destruction, and the magnitude of associated bone destruction is a function of the cancer cell. Although it has been postulated that bone destruction by cancer cells is mediated directly by tumor cells, evidence indicates that breast cancer-induced bone destruction is mediated by the osteoclast. Support for the latter include: 1) breast cancers express cytokines [such as IL-1, IL-6, LIF, prostaglandin tumor necrosis factor and parathyroid hormone-related protein (PTHrP)] which can influence osteoclast formation; 2) histologic analyses of osteolytic lesions reveal tumor adjacent to osteoclasts resorbing bone; 3) and use of bisphosphonates, potent inhibitors of osteoclastic bone resorption, in women with breast cancer metastases to bone results in reduced skeletal morbidity. The interaction of cytokines expressed by cancer cells in the bone microenvironment and their action on osteoblast/stromal cells to induce differentiation of haematopoietic cells of the macrophage / monocyte lineage into osteoclasts is now understood. The mechanisms involved in cancer metastasis, osteoclast formation, and ultimately bone destruction will be discussed, along with the potential new therapies to limit bone destruction

Over 80% of patients with advanced breast cancer will develop bone metastases for which there is no cure. Although thought to involve a complex cascade of cell-cell interactions, the factors controlling the development of bone metastases are still poorly understood. Osteoblasts may have an important role in mediating homing and proliferation of breast cancer cells to the bony environment. This study aimed to examine the potential role osteoblasts have in the migration of circulating tumour cells to bone and the factors involved in this attraction. Culture of osteoblasts and MDA-MB-231 breast cancer cells was performed. Breast cancer cell migration in response to osteoblasts was measured using Transwell Migration Inserts. Potential mediators of cell migration were detected using ChemiArray & ELISA assays. A luminometer based Vialight assay was used to measure breast cancer cell proliferation in response to factors secreted by osteoblasts. There was a 3-4 fold increase of MDA-MB-231 migration in response to osteoblasts. ChemiArray analysis of osteoblast-conditioned medium revealed a range of secreted chemokines including IL-6 & 8, TIMP 1 & 2 and MCP-1. Initially, MCP-1 was quantified at 282 pg/ml, but rose to over 9000 pg/ml when osteoprogenitor cells were differentiated into mature osteoblasts. Inclusion of a monoclonal antibody to MCP-1 in osteoblast-conditioned medium resulted in a significant decrease in breast cancer cell migration to osteoblasts. There was no significant change in proliferation of MDA-MB 231 cells when exposed to osteoblast-conditioned medium. Osteoblasts are capable of inducing breast cancer cell migration mediated at least in part by chemokine secretion. MCP-1 produced by the osteoblasts was shown to play a central role in mediating homing of the breast cancer cells. Increased understanding of the pathways involved in the development of bone metastases may provide new targets for therapeutic intervention