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The incidence of bone metastases in hepatocellular carcinoma (HCC) has increased prominently over the past decade owing to the prolonged overall survival of HCC patients. However, the mechanisms underlying HCC bone‐metastasis remain largely unknown. In the current study, HCC‐secreted lectin galactoside‐binding soluble 3 (LGALS3) is found to be significantly upregulated and correlates with shorter bone‐metastasis‐free survival of HCC patients. Overexpression of LGALS3 enhances the metastatic capability of HCC cells to bone and induces skeletal‐related events by forming a bone pre‐metastatic niche via promoting osteoclast fusion and podosome formation. Mechanically, ubiquitin ligaseRNF219‐meidated α‐catenin degradation prompts YAP1/β‐catenin complex‐dependent epigenetic modifications of LGALS3 promoter, resulting in LGALS3 upregulation and metastatic bone diseases. Importantly, treatment with verteporfin, a clinical drug for macular degeneration, decreases LGALS3 expression and effectively inhibits skeletal complications of HCC. These findings unveil a plausible role for HCC‐secreted LGALS3 in pre‐metastatic niche and can suggest a promising strategy for clinical intervention in HCC bone‐metastasis. Hepatocellular carcinoma (HCC)‐secreted LGALS3 induces osteolytic bone metastasis (BM) via promoting osteoclast fusion and podosome formation. Mechanistically, RNF219‐mediated α‐catenin degradation results in YAP1/β‐catenin‐dependent epigenetic modifications on LGALS3 promoter, eliciting in LGALS3 upregulation in HCC. Blocking YAP1/β‐catenin complex formation on LGALS3 promoter via verteporfin reduces LGALS3 expression and effectively inhibits HCC bone‐metastasis (HCC‐BM), which represents a potential strategy for HCC‐BM clinical treatment.

Background Triple‐negative breast cancer (TNBC) with bone metastasis is associated with poor prognosis and limited treatment options. Denosumab has shown efficacy in preventing skeletal‐related events, while PARP inhibitors have demonstrated promising activity in patients with homologous recombination deficiency. Case We report a patient with TNBC and bone metastasis who received a combination treatment including denosumab, PARP inhibitors, and chemoradiotherapy. The treatment resulted in effective disease control and improvement of clinical symptoms. Imaging evaluation showed stabilization of bone lesions, and the patient tolerated the treatment well without severe adverse events. Conclusion This case suggests that the combination of denosumab with PARP inhibitors and chemoradiotherapy may provide a potential therapeutic strategy for TNBC patients with bone metastasis. Further studies are warranted to validate the efficacy and safety of this combined treatment approach.

Background Bone metastasis (BoM) is common in advanced cancer, but its incidence in pleural mesothelioma (PM) remains unclear. This study aimed to determine the incidence of BoM in PM patients and assess its prognosis and risk factors to clarify its clinical significance. Methods A retrospective analysis was conducted on 515 histologically confirmed PM patients enrolled between January 2011 and December 2020. The cumulative incidence of BoM was calculated using the Kaplan–Meier method, with group differences assessed via log‐rank tests. Risk factors for BoM were evaluated using multivariate logistic regression. Results The median follow‐up was 13.3 months (range: 0.2–106.7 months). BoM was detected in 59 patients (11.5%) at diagnosis or during disease progression. Multivariate analysis identified non‐epithelial histology (odds ratio [OR]: 2.189, 95% confidence interval [CI]: 1.179–4.065, p = 0.013) as an independent risk factor for developing BoM. Patients with BoM had worse overall survival (OS) compared to those without BoM (median OS: 18.6 months vs. 21.7 months, p = 0.03). Conclusions BoM in PM occurs less frequently than in primary lung cancer, with non‐epithelial histology being more commonly associated with BoM. Patients with BoM had a poor prognosis, particularly when BoM was present at diagnosis. This study is limited by its retrospective design, which may introduce biases related to data collection and patient selection. Future prospective studies are needed to validate these findings. Bone metastasis (BoM) was observed in 11.5% of pleural mesothelioma (PM) patients, with non‐epithelial histology being an independent risk factor for developing BoM. Patients with BoM had significantly worse survival outcomes compared to those without BoM.

Background and Objectives: There have been numerous advances in spine surgery for metastatic spinal tumors, and minimally invasive spine stabilization (MISt) is becoming increasingly popular in Japan. MISt is a minimally invasive fixation procedure that temporarily stabilizes the spine, thereby reducing pain, preventing pathological fractures, and improving activities of daily living at an early stage. MISt may be useful given the recent shift toward outpatient cancer treatment. Materials and Methods: This study enrolled 51 patients with metastatic spinal tumors who underwent surgery using MISt between December 2013 and October 2020. The Spinal Instability Neoplastic Score, an assessment of spinal instability, was used to determine the indication for surgery, and the Epidural Spinal Cord Compression scale was used for additional decompression. Results: The patients comprised 34 men and 17 women, and the mean age at surgery was 68.9 years. The mean postoperative follow-up period was 20.8 months, and 35 of 51 patients (67%) had died by the last survey. The mean operative time was 159.8 min, mean blood loss was 115.7 mL, and mean time to ambulation was 3.2 days. No perioperative complications were observed, although two patients required refixation surgery. Preoperatively, 37 patients (72.5%) were classified as Frankel grade E. There were no cases of postoperative exacerbation, and six patients showed improvement of one or more Frankel grades after surgery. The median duration of patient survival was about 22.0 months. Patients with breast, prostate, renal, and thyroid cancers had a good prognosis, whereas those with gastrointestinal and head and neck cancers had a poor prognosis. Conclusions: MISt can benefit patients who are ineligible for conventional, highly invasive surgery and is also suitable because cancer treatment is increasingly performed on an outpatient basis. Furthermore, choosing the right surgery for the right patient at the right time can significantly affect life expectancy.

Background Skeletal‐related events (SREs), including the pathological fracture, surgical treatment or radiation of bone lesions, malignant spinal cord compression, hypercalcemia, are important considerations when managing metastatic bone tumors; however, owing to their rarity, the incidence of SREs in patients with Ewing sarcoma remains unknown. Methods We retrospectively reviewed the clinical data from 146 patients with Ewing sarcoma treated at a single institution from 2005 to 2019. The median age at diagnosis was 22.7 years. Fifty patients (34.2%) had metastatic disease at diagnosis. The primary outcome was the SRE‐free rate among patients with Ewing sarcoma. Moreover, we identified the risk factors for SREs using univariate or multivariate analyses. Results During the observational period (median, 2.6 years), SREs occurred in 23 patients. Radiation to the bone, malignant spinal cord compression, and hypercalcemia were documented as the initial SREs in 12 patients (52.2%), 10 patients (43.5%), and one patient (4.3%), respectively. The SRE‐free rate was 94.2 ± 2.0, 87.3 ± 3.0, and 79.6 ± 3.8% at 1, 2, and 3 years after the initial visit, respectively. Multivariate analysis revealed bone metastasis at diagnosis (hazard ratio [HR] = 4.41, p = 0.007), bone marrow invasion (HR = 34.08, p < 0.001), and local progression or recurrence after definitive treatment (HR = 3.98, p = 0.012) as independent risk factors for SREs. Conclusions SREs are non‐rare events that can occur during the treatment course for Ewing sarcoma, with an especially high incidence of malignant spinal cord compression. Patients with metastatic disease at diagnosis, especially in the bone or bone marrow, or with local progression or recurrence after definitive treatment, should be carefully monitored for the occurrence of SREs. The most effective methods to monitor the occurrence of SREs and new preventative therapies for SREs should be investigated in the future.

Abstract   Objective: Maintaining the optimum bone health is one of the important concerns in patients with prostate cancer, but it usually remains neglected. Failure to screen these patients is detrimental to both the length and the quality of life. The estimation of bone mineral density (BMD) and more recently the World Health Organization’s fracture risk assessment (FRAX) algorithm in appropriate patients is recommended by several specialty organizations/associations at the time of instituting androgen deprivation therapy (ADT) for metastatic and high-risk individuals. It provides a 10-year risk evaluation of hip and major osteoporotic fractures (MOF). Using this web-based new investigating tool, candidates at high risk of fractures can be predicted more accurately according to clinical risk factors (CRF) alone or in combination with the femoral neck BMD. The FRAX application for senile osteoporosis has been studied and reviewed extensively, but no systematic review has ever been conducted for assessing the implication of FRAX in prostate cancer. This review article will give insight about the validity, role, and utility of this investigating tool in clinical practice for fracture risk assessment in these individuals.   Material and methods: This systematic review was carried out as per the Preferred Reporting Items for Systematic Reviews and Meta-analyses guidelines and Cochrane review principles. We searched the PubMed, Cochrane database of systematic reviews, and the EMBASE electronic database until December 2018 using the medical subject heading terms prostate cancer and FRAX.   Results: A total of nine studies meet the inclusion criteria and were included in the review. These studies enrolled a total of 3704 patients (sample size range, 78–1220) of localized, metastatic, castration resistant prostate cancer with or without ADT and/or on photon or radiotherapy. The factors that influenced FRAX included age, ethnicity, baseline BMD, duration of ADT, presence of CRF, and measurement methods (CRF, with/without BMD, computed tomography based). An advanced age and duration of ADT were the most robust risk factors. A 10-year MOF and hip fracture risk estimation was higher when the femoral neck BMD was not incorporated in the FRAX measurement. Despite several well-known strengths of using FRAX in the fracture risk assessment of suitable candidates with prostate cancer, several risk factors such as the mode/duration of ADT, mode of radiotherapy, Vitamin D levels, bone remodeling markers, and recent/recurrent fractures need to be incorporated in the FRAX calculator for improving the predictive ability. In contrast to senile osteoporosis with a longer life expectancy, the fracture risk in patients with prostate cancer need to be measured more frequently and for a shorter time. Therefore, models like Garvan calculator with both 5- and 10-year risk estimates have to be developed for these patients. Additionally, its utilization is of limited value in the presence of recurrent fractures or falls.   Conclusion: The FRAX algorithm is beneficial in identifying patients who require early intervention or bone-directed therapy as an early step to decrease skeletal-related events and other morbidity. Several risk factors need to be added for improving the FRAX predictive value. This model is still underutilized in the clinical practice and increasing the awareness among treating physicians will help in optimizing the bone health and the quality of life of this important population subgroup.     Cite this article as: Sharma A, Sinha RJ, Singh V, Garg G, Agarwal S, Pandey S. Implications of the Fracture Risk Assessment Algorithm for the assessment and improvement of bone health in patients with prostate cancer: A comprehensive review. Turk J Urol 2019; 45(4): 245-53.

Osteolytic bone disease, characterizedby bone pain, increased risk of pathologicfractures, tumor-induced hypercalcemiaknown as skeletal-related events (SREs), isa frequent complication of patients withmultiple myeloma (MM) and persists evenin the absence of active disease, resulting ina major cause of morbidity and mortality.The interaction between myeloma cells andtheir surrounding cells in the bone marrow(BM) microenvironment promotes bothmyeloma cell growth and bone destructionand forms the vicious cycle of MM bonedisease. Therefore, therapeutic strategiestargeting the interaction between myelomacells and cellular components includingosteoclasts (OCs), stromal cells andosteoblasts (OBs) in the BM is crucial notonly to attain tumor regression but also toprevent or delay the incidence of SREs, which leads to improve survival and qualityof life in affected patients. Recently, severalnovel targets which act on components ofthe cycle for treating MM-associated bonedisease have been identified in addition tocurrent treatments including nitrogen-con-taining bisphosphonates. This review focus-es on the overview of pathophysiology inMM-associated bone disease and summa-rizes its current clinical management. Several novel bone-targeted agents in pre-clinical setting will be also discussed

Wnt, a secreted glycoprotein, has an approximate molecular weight of 40 kDa, and it is a cytokine involved in various biological phenomena including ontogeny, morphogenesis, carcinogenesis, and maintenance of stem cells. The Wnt signaling pathway can be classified into two main pathways: canonical and non-canonical. Of these, the canonical Wnt signaling pathway promotes osteogenesis. Sclerostin produced by osteocytes is an inhibitor of this pathway, thereby inhibiting osteogenesis. Recently, osteoporosis treatment using an anti-sclerostin therapy has been introduced. In this review, the basics of Wnt signaling, its role in bone metabolism and its involvement in skeletal disorders have been covered. Furthermore, the clinical significance and future scopes of Wnt signaling in osteoporosis, osteoarthritis, rheumatoid arthritis and neoplasia are discussed.

The purpose of this study was to estimate the risk of developing skeletal‐related events (SREs) based on site of metastasis at diagnosis and identify other predictors of developing SREs among metastatic prostate cancer patients. We conducted a retrospective cohort study using linked SEER (Surveillance, Epidemiology, and End Results) and Medicare data and identified men over the age of 65 with incident metastatic prostate cancer diagnosed during 2005–2009. SREs included radiation (RAD), pathological fractures (PF), bone surgery (BS), and spinal cord compression (SCC). The association between site of metastasis at diagnosis and SRE was examined using a Cox proportional hazards model that accounts for death as a competing risk. Among 4404 men (median age: 79 years) with incident metastatic prostate cancer, 44% experienced SREs at a median of 9.6 months post diagnosis. Compared to bone metastasis only, our model showed that patients were significantly less likely to develop SREs if they had LN‐only metastasis at diagnosis (Sub‐Hazard Ratio [SHR] 0.56; 95% Confidence Interval [CI]: 0.43–0.72) or unknown site of metastasis (SHR: 0.79; CI: 0.64–0.97). Other predictors of reduced SRE risk were age 80+ years (SHR: 0.83; CI: 0.75–0.91), non‐Hispanic Black (SHR: 0.77; CI: 0.65–0.90), or being diagnosed in year 2009 (SHR: 0.85; CI: 0.72–0.99). Patients were significantly more likely to develop SREs if they received androgen deprivation therapy (SHR: 1.73; CI: 1.48–2.02) or had Gleason score 8–10 disease (SHR: 0.79; CI: 0.64–0.97). Compared to patients who present with bone metastasis only at diagnosis, patients presenting with other metastatic sites have similar risk of developing SREs, with the exception of those presenting with lymph node only metastasis who have a significantly reduced risk of SREs. This study estimated the risk of developing SREs based on site of metastasis at diagnosis in prostate cancer patients. There is a risk of developing SREs regardless of the site of metastasis at diagnosis; however, the risk is lowest among patients with lymph node‐only metastasis at presentation.

BackgroundAntiresorptive drugs (ARD) are associated with a known serious adverse event, known as medication-related osteonecrosis of the jaws (MRONJ). Transition from one ARD to another has become common clinical practice with the advent of more potent or safer agents; however, the influence of sequential antiresorptive therapy as a risk factor for MRONJ has not been established.ObjectivesTo investigate the prevalence of MRONJ in oncology or osteoporosis patients treated with two or more sequential ARDs as opposed to a single antiresorptive drug.Material and methodsSystematic electronic literature searches were conducted using Ovid MEDLINE, Ovid EMBASE, and Cochrane Central Register of Controlled Trials. Two review authors retrieved studies using pre-determined eligibility criteria and conducted quality assessment and data extraction. Fixed or random-effects meta-analysis models were used to summarize relative estimates for prevalence of MRONJ.ResultsA total of 483 titles and abstracts were screened, and 18 full texts were retrieved for review. Twelve studies were included in the final qualitative and quantitative synthesis. Random effects meta-analysis models revealed a weighted pooled MRONJ prevalence of 19% (95% CI 10–27%) for sequential pamidronate-zoledronate therapy, 10% (95% CI 3–22%) for sequential ibandronate-zoledronate therapy. Pooled weighted prevalence of MRONJ was 13% (95% CI 3–22%) for sequential bisphosphonate-denosumab therapy while bisphosphonates only was 5% (95% CI 0–9%) and denosumab only was 4% (95% CI 3–5%).ConclusionsThe present systematic review suggests an increased prevalence of MRONJ associated with sequential ARD therapy for pamidronate-zoledronate and bisphosphonate-denosumab administration when compared to single ARD therapy.