Treatment Of Metastatic Bone Disease Research Articles

Targeted Radionuclide Therapy for the Treatment of Metastatic Bone Disease: A Retrospective Analysis in Moscow, Russia

Introduction: Metastatic bone disease (MBD) is a common complication of advanced cancer, causing significant morbidity and negatively impacting patients' quality of life. Targeted radionuclide therapy (TRT) has emerged as a promising treatment modality for MBD, offering targeted delivery of therapeutic radiation to bone metastases while minimizing damage to healthy tissues. Methods: A retrospective cohort study was conducted at leading oncology centers in Moscow, Russia, between 2018 and 2023. Patients with MBD who received TRT with either Strontium-89 or Samarium-153 were included. Data on patient demographics, primary tumor type, number of bone metastases, pre-treatment pain scores, performance status, and survival outcomes were collected. Results: A total of 150 patients were included in the study (mean age 62 years, 55% female). The most common primary tumor types were prostate (35%), breast (25%), and lung (15%). The median number of bone metastases was 5 (range 1-20). Pre-treatment pain scores were high (median 7 on a 0-10 scale). A significant reduction in pain scores was observed post-TRT (median 3, p<0.001). Overall survival at 1 year was 75%, with a median survival of 18 months. Favorable prognostic factors included a lower number of bone metastases, good performance status, and absence of visceral metastases. Conclusion: TRT is a safe and effective treatment option for patients with MBD in Moscow, Russia, offering significant pain palliation and improved quality of life.

Life Expectancy After Treatment of Metastatic Bone Disease: An International Trend Analysis.

The decision to treat metastatic bone disease (MBD) surgically depends in part on patient life expectancy. We are unaware of an international analysis of how life expectancy among these patients has changed over time. Therefore, we asked (1) how has the life expectancy for patients treated for MBD changed over time, and (2) which, if any, of the common primary cancer types are associated with longer survival after treatment of MBD? We reviewed data collected from 2000 to 2022 in an international MBD database, as well as data used for survival model validation. We included 3,353 adults who underwent surgery and/or radiation. No patients were excluded. Patients were grouped by treatment date into period 1 (2000 to 2009), period 2 (2010 to 2019), and period 3 (2020 to 2022). Cumulative survival was portrayed using Kaplan-Meier curves; log-rank tests were used to determine significance at P < 0.05. Subgroup analyses by primary cancer diagnosis were performed. Median survival in period 2 was longer than in period 1 ( P < 0.001). Median survival (at which point 50% of patients survived) had not been reached for period 3. Median survival was longer in period 2 for all cancer types ( P < 0.001) except thyroid. Only lung cancer reached median survival in period 3, which was longer compared with periods 1 and 2 ( P < 0.001). Slow-growth, moderate-growth, and rapid-growth tumors all demonstrated longer median survival from period 1 to period 2; only rapid-growth tumors reached median survival for period 3, which was longer compared with periods 1 and 2 ( P < 0.001). Median duration of survival after treatment of MBD has increased, which was a consistent finding in nearly all cancer types. Longer survival is likely attributable to improvements in both medical and surgical treatments. As life expectancy for patients with MBD increases, surgical methods should be selected with this in mind. VI.

Scintigraphie osseuse monophotonique : quelle place dans la prise en charge du cancer de la prostate ?

Bone scintigraphy (SO) with bisphosphate labeled with 99mTc remains indicated in the guidelines for the detection of bone metastases before treatment of intermediate risk and high risks of recurrence prostate cancers (PC). SO remains also indicated in the evaluation of response to treatment of metastatic bone disease. Its main advantages are its availability, as it is performed routinely in all nuclear medicine centers in France, and very high performances, since whole-body Single Photon Emission Computed Tomography/Computed Tomography (SPECT/CT) hybrid tomoscintigraphy almost systematically completes whole-body scanning. We propose in this article to review this technique at all clinical stages of CP.

Occlusive wound closure prevents prolonged wound discharge-A randomised controlled trial in patients undergoing tumour resection and endoprosthetic reconstruction of the proximal femur because of metastatic bone disease.

Prolonged wound discharge is a common postoperative complication of orthopaedic procedures and a risk factor for implant-related infection. Occlusive wound closure methods have previously been suggested to reduce or even prevent this complication. We performed a randomised controlled trial on 70 patients who underwent surgical treatment for metastatic bone disease involving the proximal femur at our centre between January 2017 and August 2018. At conclusion of the tumour resection and endoprosthetic reconstruction procedure, patients were randomised to either occlusive wound closure (n=35), using the Dermabond Prineo-22 skin closure system, or routine wound closure with conventional skin staples (n=35). Skin closure with occlusive wound closure resulted in a lesser degree (P < .0001) and shorter duration of postoperative wound discharge (HR 2.89 [95% CI 1.6-5.05], P < .0018). Compared with staples, surgical wounds were already dry after a mean of 3.5 days [95% CI 3.2-3.9] versus 6.1 days [95% CI 4.8-7.3] (P < .0001). Prolonged wound discharge for 7 days or more was observed in 23% of patients (n=8) in the Staples-group but was entirely absent in the occlusive wound closure group (P < .003). This study provides strong evidence that occlusive wound closure reduces frequency, degree, and duration of wound discharge in a patient population at particularly high risk for this complication.

Fully constrained acetabular liner vs. dual mobility hip joint in the surgical treatment of metastatic bone disease of the hip: study protocol for a randomized, open-label, two-arm, non-inferiority trial evaluating the post-operative hip dislocation rate

BackgroundPatients receiving total hip arthroplasty (THA) due to metastatic bone disease of the hip (MBD) are at an increased risk of post-operative joint dislocation compared to other populations. Different joint solutions have been developed with the purpose of reducing the dislocation risk compared to regular THAs. One of these solutions, the constrained liner (CL), has been used increasingly at our department in recent years. This design, however, is prone to polyethylene wear and higher revision rates. An alternative is the dual mobility cup (DM), which has been shown to reduce the risk of dislocation in other high-risk populations. Few studies have investigated DM for THA due to MBD, and no studies have directly compared these two treatments in this population. We therefore decided to conduct a trial to investigate whether DM is non-inferior to CL regarding the post-operative joint dislocation risk in patients receiving THA due to MBD.Materials and methodsThis study is a single-center, randomized, open-label, two-arm, non-inferiority trial. We will include 146 patients with MBD of the hip who are planned for THA at the Department of Orthopedic Surgery, Rigshospitalet. Patients with previous osteosynthesis or endoprosthetic surgery of the afflicted hip, or who are planned to receive partial pelvic reconstruction or total femoral replacement, will be excluded. Patients will be stratified by whether subtrochanteric bone resection will be performed and allocated to either CL or DM in a 1:1 ratio. The primary outcome is the 6 months post-operative joint dislocation rate. Secondary outcomes include overall survival, implant survival, the rate of other surgical- and post-operative complications, and quality of life and functional outcome scores.DiscussionThis study is designed to investigate whether DM is non-inferior to CL regarding the risk of post-operative dislocation in patients receiving THA due to MBD. To our knowledge, this trial is the first of its kind. Knowledge gained from this trial will help guide surgeons in choosing a joint solution that minimizes the risk of dislocation and, ultimately, reduces the need for repeat surgeries in this patient population.Trial registrationClinicalTrials.gov Identifier: NCT05461313. Registered on July 15 2022. This trial is reported according to the items in the WHO Trial Registration Data Set (Version 1.3.1).

Abstract 270: The novel control mechanism of the tubulin code and vesicular trafficking in breast cancer bone metastatic cells

Abstract Metastasis of breast cancer (BC) to bone results in severe bone loss, fractures, and death. The crosstalk between BC cells and bone resident cells dramatically increases osteoclast activity, resulting in the release of growth factors from the bone matrix that causes aggressive tumor growth and bone loss. A potentially important aspect of this process is vesicular trafficking on microtubules (MTs) which can affect the output of signaling pathways and secretory activity of metastatic bone cells. MTs are cytoskeletal filaments composed of heterodimers, α- and β-tubulin. The tubulin isotypes and their variety of post-translational modifications (PTMs) control the properties and functions of MT filaments, a concept known as the ‘tubulin code’. Recent studies show an emerging link between alterations of the tubulin code with poor prognosis of breast cancer. However, the regulation of the code in metastatic bone cells is currently unknown. Tubulin acetylation occurs via α-tubulin N-acetyl transferase-1 (αTAT1) and can be reversed by histone deacetylase-6 (HDAC6). MTs lacking acetylation lose flexural rigidity and are prone to breaks following repetitive bending during vesicular trafficking. We found that HDAC6 interaction with α-tubulin is inhibited by a Runt-related factor (Runx2). Our biochemical, mass spectrometry and IPs analyses of MTs revealed that loss of Runx2 can reduce (i) acetylation and stability of MTs, (ii) interaction of HSP90 with α-tubulin, and (iii) levels of β 2a-tubulin. Our studies with Runx2 mutants indicate that the C-terminal of Runx2 serves a scaffolding function by interacting with MTs and HDAC6. Confocal microscopy revealed reduced puncta and altered distribution of endosomal vesicles and autophagosomes with Runx2 silencing. As MT targeting agents are often used as chemotherapeutics, we found that loss of Runx2 sensitizes breast cancer cells to docetaxel and vinblastine and reduces the secretion of IL-6. We found MDA-MB-231 cells metastasized to the bone show significant differences in microtubule isotype expression, with 10 of 19 studied showing 1.3 to 4.1 fold increases. Further analysis of whether Runx2 knockdown affects isotype expression, we found the majority of the 19 studied remain unchanged. Immunohistochemistry for Ac-α-Tub levels in bone metastatic patient samples shows significantly more Ac-α-Tub positive cells in metastatic bone tumors than primary tumors. These findings suggest a novel control mechanism of MTs stability via Runx2-HDAC6 interactions that can impact trafficking and cellular activity. Our results indicate that inhibition of Runx2 may sensitize metastatic tumors to MT targeting agents, and Runx2/HDAC6/Ac-α-Tub levels may serve as markers for metastatic tumors to help stratify patients for optimal treatment for metastatic bone disease. Citation Format: Shreya Patel, Marcus Winogradzki, Ahmad Othman, Waddell Holmes, Jitesh Pratap. The novel control mechanism of the tubulin code and vesicular trafficking in breast cancer bone metastatic cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 270.

Surgical Treatment of Metastatic Bone Disease in the Appendicular Skeleton: A Population-Based Study.

Simple SummaryPatients with bone metastases in the appendicular skeleton (aBM) can experience impending or pathological fractures requiring surgery. Few population-based studies exist and the aim of our retrospective population-based study was to describe a large population of patients surgically treated for aBM, examine changes in incidence of surgery, contrasts between patients at different centers, and the value of tumor biopsies and follow-up imaging. No change in incidence of surgery or absent of sufficient biopsy was found. Significant differences were found between patients treated at different centers. The study enhances the generalizability of our finding to other populations and it is hereby favorable for external validity.Background: Population-based studies of patients with bone metastases in the appendicular skeleton (aBM) requiring surgery for complete or impending fracture are rare. In this epidemiologically-based observational study we created a large population-based cohort of patients treated for aBM, aiming to: (1) monitor possible time-related changes of the incidence of surgical treatment of aBM-lesions, (2) examine differences in the population and care of patients treated at different treatment centers and (3) examine if findings from a previous pilot study regarding absence of a suitable biopsy of the lesions representing debut of cancer or a relapse has improved the awareness of aBM and hereby increased the focus on regular tumor biopsies and follow-up imaging of cancer patients. Methods: We examined a population-based cohort consisting of all patients treated for aBM 2014–2019. Procedures were performed at five secondary surgical centers (SSC) or one tertiary referral Musculoskeletal Tumor Center (MTC). Patients were followed until end of study (30 September 2021) or death. No patients were lost to follow-up. Results: Four-hundred-fifty-seven patients (493 primary aBM-lesions, 482 procedures) were included. Annual incidence of aBM-surgery was 46 aBM-lesions/million. MTC-patients had a significant better preoperative status than SSC-patients considering factors known for survival. Patients with complete fracture experienced longer surgical delay when treated at MTC compared to SSC: 4 (1–9) and 1 (1–3) days (p < 0.001), respectively. Overall survival for the entire cohort was 37% and 11% at 1 and 5 years (MTC and SSC 1 and 5 year respectively: 44% and 15% vs. 29% and 5%, p < 0.001). In patients with debut or relapse of cancer, 8% and 9% had insufficient biopsies, and 21% and 12% had no biopsy, respectively. Comparison showed no change over time. Conclusions: The current study highlights the low awareness on treating aBM at SSC and emphasizes the importance of caution in interpretation of studies not representing an entire population, thus introducing selection bias.

Association of the Oncology Care Model With Value-Based Changes in Use of Radiation Therapy

Radiation utilization for breast cancer and metastatic bone disease varies in modality, fractionation, and cost, despite evidence demonstrating equal effectiveness and consensus recommendations such as Choosing Wisely that advocate for higher value care. We assessed whether the Oncology Care Model (OCM), an alternative payment model for practices providing chemotherapy to patients with cancer, affected the overall use and value of radiation therapy in terms of Choosing Wisely recommendations. We used Centers for Medicare & Medicaid Services administrative data to identify beneficiaries enrolled in traditional fee-for-service Medicare who initiated chemotherapy episodes at OCM and propensity-matched comparison practices. Difference-in-difference (DID) analyses evaluated the effect of OCM on overall use of postoperative radiation for breast cancer, use of intensity modulated radiation therapy and hypofractionation for breast cancer, and fractionation patterns for treatment of metastatic bone disease from breast or prostate cancer. We performed additional analyses stratified by the presence or absence of a radiation oncologist in the practice. Among 27,859 postoperative breast cancer episodes, OCM had no effect on overall use of radiation therapy after breast surgery (DID percentage point difference = 0.4%; 90% confidence interval [CI], -1.7%, 2.4%) or on use of intensity modulated radiation therapy in this setting (DID=-0.6; 90% CI, -3.1, 2.0). Among 19,366 metastatic bone disease episodes, OCM had no effect on fractionation patterns for palliation of bone metastases (DID for ≤10 fractions=-1.1%; 90% CI, -2.6%, 0.4% and DID for single fraction=-0.2%; 90% CI, -1.9%, 1.6%). Results were similar for practices with and without a radiation oncologist. We did not evaluate the effect of OCM on hypofractionated radiation after breast-conserving surgery owing to evidence of differential baseline trends. OCM had no effect on use of radiation therapy after breast-conserving surgery for breast cancer or on fractionation patterns for metastatic bone disease. Future payment models directly focused on radiation oncology providers may be better poised to improve the value of radiation oncology care.

Surgical management of bone metastasis located in the proximal femur-review of literature

Abstract Neoplasms are the second leading cause of death worldwide. The increase in diagnostic possibilities and development of new treatments has led to an increase in life expectancy among cancer patients. The proximal region of the femur is a favorite site for bone metastases, these lesions being accompanied by increased mortality and morbidity. The methods of treatment for metastatic bone disease can be surgical or non-surgical. Bone metastases and pathological bone fractures in the proximal femur are most commonly located in the intertrochanteric or subtrochanteric region. Patients with bone metastases at this level most often require osteosynthesis with a centromedullary nail, but also plates and screws or dynamic hip screw can be used. Bone metastases located in the femoral neck or femoral head can be treated surgically by hemiarthroplasty (HA) or total hip arthroplasty (THA). Both HA and THA have been shown to be successful surgeries in patients with bone metastases. In patients with multiple bone metastases located in the head or neck of the femur and trochanteric region, but with increased life expectancy, resection and reconstruction using endoprostheses is a viable solution. Given the complexity of oncological pathologies, the therapeutic decision in the case of a patient with secondary bone determinations must be established by a multidisciplinary team comprising the oncologist, orthopedic surgeon, pathologist, anesthetist, and radiotherapist. Surgical treatment of symptomatic bone metastases that cause pain and functional impotence with limited patient mobility increases survival and quality of life regardless of the type of surgery and the implant chosen.

Comparison between different prognostic models to be used for metastatic bone disease on appendicular skeleton in a Chilean population.

Several preoperation prognosis models used on the treatment of metastatic bone disease on appendicular skeleton have been devised. The purpose of this study was to compare the performance of different survival prognostic models on patients with metastatic bone disease in long bones in a Chilean population. This is a multicentric retrospective study. We retrospectively reviewed the medical records of 136 patients who were confirmed with metastatic bone disease of the appendicular skeleton and who were treated surgically from 2016 to 2019. The minimum follow-up time was 12months. All patients were assessed using four appendicular metastatic bone disease scoring systems. A preoperative predicted survival time for all 136 patients was retrospectively calculated making use of the revised Katagiri, PathFx, Optimodel and IOR score model. The PathFx model demonstrated an accuracy at predicting 3 (area under the curve [AUC] = 0.61) and 6-month (AUC = 0.65) survival time after surgical management. IOR score model demonstrated an accuracy at predicting 12-month survival time (AUC = 0.64). The survival rate reached the 44% in a year. The median survival time to death or last follow-up time was 14.9months (SD ± 15). PathFx score model demonstrated the highest accuracy at predicting a survival time of 3 and 6 months. IOR score model was the most accurate measure at predicting a survival time of 12-months. To our knowledge, this is the first study reporting a comparative analysis of metastatic bone disease with predicting models in a country located in Latin America. PathFx's and IOR score models are the ones to be used in the Chilean population as the predictive models in metastatic bone disease of the appendicular skeleton.

Surgical treatment of metastatic bone disease of the distal extremities.

Metastatic bone disease of the distal extremities, also known as acrometastasis, is very rare. Thus, there is very limited information regarding the clinical manifestations and methods of surgical treatment. The current available literature shows that acrometastases are often encountered in the context of advanced disease and are thus associated with poor patient survival. As metastatic bone disease is generally uncurable, the goal of surgical treatment is to provide the patient with good function with as few complications as possible. In this article, we discuss the clinical manifestation of acrometastases, the methods of surgical intervention, and the expected clinical outcome. Non-surgically managed pathological fractures generally remain ununited; therefore, conservative treatment is reserved for patients with poor general condition or dismal prognosis. The current evidence suggests that in lesions of the lower arm and leg, osteosynthesis (plate and screw fixation or intramedullary nail) is the most common method of reconstruction, whereas local excision or amputation are more commonly used in cases of more distal lesions (such as ankle, foot and hand). Following surgery most patients receive adjuvant radiotherapy, even though its role is poorly documented. Close collaboration between orthopedic surgeons and medical oncologists is necessary to improve patient care and treatment outcome. Further studies are needed in order to provide stronger clinical evidence and improve decision-making, in an effort to optimize the patients’ quality of life and avoid the need for revision surgery.

Outcome of surgical treatment for bone metastases caused by colorectal cancer.

Cancer of the lower intestinal tract, although relatively common, rarely metastasizes to the skeleton. The treatment of metastatic bone disease due to colorectal cancer has thus been poorly described and treatment decisions are therefore difficult. The aim of this study was to describe the outcome of orthopedic surgery in patients with pathological fractures from colorectal cancer and investigate factors that correlate with patient survival, since it influences treatment decisions. Retrospective review of data collected in a prospectively collected database. 36 patients (38 fractures) who underwent surgery between 2000 and 2019 for metastatic bone disease caused by colorectal cancer were included. Most metastases were localized in the axial skeleton and 33/36 patients already had visceral metastases. Patients with pathological fractures from colorectal cancer had poor prognosis, with only 5/36 surviving more than 1 year, median survival being 3 months. Patients presenting with a single skeletal metastasis had a superior overall survival (P≤0.001). Post-operative complications were common, noted in 11 patients, and the surgical failure rate was considerable. Although relatively rare, bone metastases should be suspected in patients with colorectal cancer presenting with signs and symptoms of spinal cord compression or skeletal pain. In this case, the presence of a solitary skeletal lesion is a favorable prognostic sign. Awareness for local complications after surgery should be high.

Rehabilitation Principles in Bone Metastasis

Metastatic bone disease is often associated with a decline in function and overall quality of life. Pain and musculoskeletal events are contributors to decrease mobility and independence.4, 5, 6, 7 In cases where there is neurological involvement, such as in patients with cord compression syndrome, it can be associated with neurogenic bowel and bladder. The role of cancer rehabilitation providers is to improve the overall health-related quality of life and their function and independence. Rehabilitation interventions, including aerobic and resistant exercise prescription, are associated with positive physical and self-reported outcomes with a low rate of adverse events.4 Low impact aerobic activity has been wildly studied in patients with bone metastasis and has been found to be safe.4,9 Rehabilitation physicians focus on designing a rehabilitation and exercise plan that improves the patient's physical function while keeping in mind the necessary precautions to prevent musculoskeletal events. Activity modification and physical activity that prevents the axial loading of the spine can improve the core musculature of patients with spine involvement while decreasing the risk of compression fractures of the vertebral bodies.21 Furthermore, patients who have undergone surgical interventions as part of the treatment of metastatic bone disease frequently present an acute functional decline. Rehabilitation providers are vital in evaluating these functional impairments and developing a comprehensive rehabilitation plan in the appropriate setting (inpatient vs home vs outpatient).26 Overall, patients with metastatic bone disease present with functional impairments that put them at risk for immobility-related complications. Rehabilitation interventions, such as exercise, are safe and effective in improving immobility complications, decreasing caregiver burden, and improving overall quality of life.4,7,9,26

Current Overview of Treatment for Metastatic Bone Disease.

The number of patients with bone metastasis increases as medical management and surgery improve the overall survival of patients with cancer. Bone metastasis can cause skeletal complications, including bone pain, pathological fractures, spinal cord or nerve root compression, and hypercalcemia. Before initiation of treatment for bone metastasis, it is important to exclude primary bone malignancy, which would require a completely different therapeutic approach. It is essential to select surgical methods considering the patient’s prognosis, quality of life, postoperative function, and risk of postoperative complications. Therefore, bone metastasis treatment requires a multidisciplinary team approach, including radiologists, oncologists, and orthopedic surgeons. Recently, many novel palliative treatment options have emerged for bone metastases, such as stereotactic body radiation therapy, radiopharmaceuticals, vertebroplasty, minimally invasive spine stabilization with percutaneous pedicle screws, acetabuloplasty, embolization, thermal ablation techniques, electrochemotherapy, and high-intensity focused ultrasound. These techniques are beneficial for patients who may not benefit from surgery or radiotherapy.

Operating procedures for electrochemotherapy in bone metastases: Results from a multicenter prospective study on 102 patients

IntroductionBone metastases are frequent in patients with cancer. Electrochemotherapy (ECT) is a minimally invasive treatment. Preclinical and clinical studies supported the use of ECT in patients with metastatic bone disease (MBD). The purposes of this multicentre study are to confirm the safety and efficacy of ECT, and to identify appropriate operating procedures in different MBD conditions. Materials and methods102 patients were treated in 11 Centres and recorded in the REINBONE registry (a shared database protected by security passwords): clinical and radiological information, ECT session, adverse events, response, quality of life indicators and duration of follow-up were registered. Results105 ECT sessions were performed (one ECT session in 99 patients, two ECT sessions in 3 patients). 24 patients (23.5%) received a programmed intramedullary nail after ECT, during the same surgical procedure. Mean follow-up was 5.9 ± 5.1 months (range 1.5–52). The response to treatment by RECIST criteria was 40.4% objective responses, 50.6% stable disease and 9% progressive disease. According to PERCIST criteria the response was: 31.4% OR; 51.7% SD, 16.9% PD with no significant differences between the 2 criteria. Diagnosis of breast cancer and ECOG values 0–1 were significantly associated to objective response. A significant decrease in pain intensity and significant better quality of life was observed after ECT session at follow-up. ConclusionThe results are encouraging on pain and tumour local control. ECT proved to be an effective and safe treatment for MBD and it should be considered as an alternative treatment as well as in combination with radiation therapy.

Which Bone-Modifying Agent is Associated with Better Outcomes in Patients with Skeletal Metastases from Lung Cancer? A Systematic Review and Network Meta-analysis.

Lung cancer is one of the most commonly diagnosed cancers and is the leading cause of cancer-related deaths. Metastatic bone disease occurs in 20% to 40% of patients with lung cancer, and these patients often present with pain or skeletal-related events (SREs) that are associated with decreased survival. Bone-modifying agents such as denosumab or bisphosphonates are routinely used; however, to our knowledge, there has been no quantitative synthesis of randomized controlled trial data to determine the most effective pharmacologic treatment of metastatic bone disease because of lung cancer. We aimed to perform a network meta-analysis of randomized trials to identify the bone-modifying agent that is associated with the (1) highest overall survival, (2) longest time to SRE, (3) lowest SRE incidence, and (4) greatest likelihood of pain resolution. We conducted our study according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses protocol and pre-registered the analysis on PROSPERO (ID: CRD42019124364). We performed a librarian-assisted search of MEDLINE, PubMed, EMBASE, Cochrane Library, and Chinese databases including China National Knowledge Infrastructure and Wanfang Data. We included randomized controlled trials reporting outcomes specifically for patients with lung cancer treated with a bisphosphonate or denosumab. SREs included pathologic fractures, spinal cord compression, hypercalcemia of malignancy, or pain resulting in surgical intervention or radiation therapy. We excluded trials exclusively reporting surrogate outcomes such as changes in bone turnover markers. Screening, data extraction, risk of bias evaluation, and Grading of Recommendations Assessment, Development, and Evaluation evaluations were performed in duplicate. We included 131 randomized controlled trials that evaluated 11,105 patients with skeletal metastases from lung cancer. The network meta-analysis was performed using a frequentist model and the R statistical software. Results are reported as relative risks or mean differences, and the I2 value is reported for heterogeneity. The P-score, a measure of ranking certainty that accounts for standard error, is reported for each outcome. Heterogeneity in the network was considered moderate for overall survival and time to SRE, mild for the incidence of SRE, and low for pain resolution. For overall survival, denosumab was ranked above zoledronic acid and estimated to confer a mean of 3.3 months (95% CI 0.3-6.3) of increased overall survival compared with untreated patients (P-score = 89%). For the time to SRE, denosumab was ranked first with a mean of 9.1 additional SRE-free months (95% CI 6.7-11.5) compared with untreated patients (P-score = 99%), while zoledronic acid conferred an additional 4.8 SRE-free months (95% CI 3.6-6.1). Reduction in the incidence of SREs was not different between patients treated with denosumab (relative risk 0.54; 95% CI 0.33-0.87) and those treated with zoledronic acid (relative risk 0.56; 95% CI 0.46-0.67). Patients treated with the combination of ibandronate and systemic therapy were more likely to experience successful pain resolution than untreated patients (relative risk 2.4; 95% CI 1.8-3.2). In this comprehensive synthesis of all available randomized controlled trial evidence guiding the pharmacologic treatment of bone metastases from lung cancer, denosumab was ranked above zoledronic acid for overall survival and time to SRE and was not different for reducing the incidence of SRE. Both were superior to no treatment for each of these outcomes. Given this, we encourage physicians to consider the use of denosumab or zoledronic acid in treating this patient population. The combination of ibandronate and systemic therapy was the most effective at reducing pain because of metastases. No cost-effectiveness analysis has yet been performed for denosumab and zoledronic acid on patients with metastatic lung cancer, and this represents an avenue for future research. Level I, therapeutic study.

"The use of bisphosphonates to treat skeletal complications in solid tumours".

The skeleton is the most common site of secondary disease in breast cancer and prostate cancer, with up to 80% of patients with advanced disease developing bone metastases (BM). The proportion is also substantial in advanced lung cancer (20%-40%). Because of the high prevalence of cancers of the breast, prostate and lung, these cancers account for more than 80% of cases of metastatic bone disease occurring in solid tumours. Metastatic bone disease is associated with greatly increased bone resorption by osteoclasts, leading to moderate to severe pain and other skeletal complications, with major impact on quality of life (QoL). Skeletal Related Events (SREs) have been defined as: pathological long bone or vertebral fractures; spinal cord compression; need for radiation for pain relief or to prevent fracture/spinal cord compression, need for surgery to bone and hypercalcaemia. More recently, Symptomatic Skeletal Events (SSEs) have been defined to monitor QoL. Although there are currently no curative treatments for metastatic bone disease, patients with breast or prostate cancer and BM are now surviving for several years and sometimes longer, and prevention of SREs is the key aim to optimization of QoL. Since their discovery 50years ago and their introduction more than 30years ago into the field of metastatic bone disease, a range of oral and intravenous bisphosphonate drugs have made a major contribution to prevention of SREs. Large trials have clearly demonstrated the clinical value of different bisphosphonate-based drugs (including the oral drugs ibandronate and clodronate and intravenous agents such as zoledronate and pamidronate), in treatment of hypercalcaemia of malignancy and the reduction of SREs and SSEs in a range of cancers. Despite the success of denosumab in reducing osteolysis, bisphosphonates also remain mainstay drugs for treatment of metastatic bone disease. Recognizing the 50th Anniversary of the discovery of bisphosphonates, this review focuses on their continuing value in BM treatment and their future potential, for example in providing a bone-targeting vehicle for cytotoxic drugs.

ANALGESIC EFFECT OF VARIOUS RADIOPHARMACEUTICALS IN THE COMPLEX TREATMENT OF METASTATIC BONE DISEASE

The study objective was to investigate and compare the effectiveness of different radiopharmaceuticalsin the treatment of metastatic bone disease. Cancer patients (n = 150, average age (55 ± 11.6) years, 95 females, 55 males) having gotvarious primary tumors and metastatic bone disease were given medical treatment at the Department of NuclearMedicine of the National Institute of Cancer. The 153Sm, 32Р, and 89Sr radiopharmaceutical agents produced by the«Radiopreparats» enterprise (Republic of Uzbekistan) and Radioisotope Centre Polatom (National Centre for NuclearResearch, Poland) were administered to the patients. There were cases of breast cancer (n = 75), prostate cancer(n = 45), lung cancer (n = 10), kidney cancer (n = 4), cervical cancer (n = 5), and rectosigmoid cancer (n = 11) amongthe treated subjects. In 135 patients (90 %) the bone metastases were detected by osteoscintigraphy with 99мTc- mo-nodiphosphonate. In 15 cases the diagnosis of metastatic bone disease was verified by other radiology methods. The pain intensity rating scale (LACOMED) was used to assay the analgesic effect of various radiopharma-ceuticals in metastatic bone disease. Results of treatment with 32P, 89Sr, and 153Sm were included in a comparativeanalysis procedure. It was established that the level of pain syndrome ranged from 7-8 points on the LACOMED scalebefore treatment. Upon administration of radionuclide therapy the level of pain was reduced down to 3-5 points,namely with 32P therapy it has decreased by 30.7 %, with 89Sr by 33.2 %, and with 153Sm by 41.5 % respectively. Timepattern of 153Sm analgesic effectiveness was studied depending on the number of treatment sessions. The best valueof analgesic effect of 153Sm was registered after the first treatment session with a tendency to decrease after the sec-ond and significantly lower analgesic effects after the third session. Tolerance of 153Sm was rated on the CTCNCA (v)4.3 scale. The best tolerance was peculiar to 153Sm corresponding to the «good» level according to a point assess-ment. When using 89Sr the drug tolerance was lower, not requiring however the drug discontinuation. The 32P radio-pharmaceutical featured the lowest tolerance approaching the «satisfactory» rating. In 11 patients upon that theside effects were found significantly impairing the patient's status, accordingly some extra measures were required.No decision to cancel the drug administration was made. Radionuclide therapy with 153Sm-oxabiphor agent can be used in the complex treatment of metastat-ic bone disease in cancer patients having got tumors of different localization. 153Sm-oxabiphor is the most effectiveand best tolerable radiopharmaceutical agent in the pain treatment in metastatic bone disease in comparison with32P and 89Sr preparations (р < 0.05).

Systems for local, sustained release of zoledronic acid as a potential treatment for metastatic bone disease.

Bone pain is the leading cause of morbidity in patients with metastatic cancer. Systemic administration of zoledronic acid (ZA) decreases skeletally-related events in bone cancer patients but is associated with major side effects. This project investigated two biomaterials, poly(methyl methacrylate) (PMMA) bone cement and poly(lactic-co-glycolic acid) (PLGA), for local ZA delivery. Compressive properties of PMMA samples were tested with increased drug loading, and in vitro ZA release profiles from PMMA cylinders and PLGA films were measured over 8weeks. The activity of ZA eluted from both materials was evaluated on the RAW 264.7 macrophage cell line. PMMA samples released up to only 17% of incorporated drug, whereas PLGA films released over 95%. A burst profile was observed for PMMA, while ZA release from PLGA exhibited a typical triphasic profile. Drug bioactivity remained above 50% for both materials. Local ZA delivery from these materials may be useful in the treatment of metastatic bone cancer.

Current concepts in the surgical treatment of skeletal metastases.

Symptomatic metastatic bone disease affects a large proportion of patients with malignant tumours and significantly impairs patients’ quality of life. There are still controversies regarding both surgical indications and methods, mainly because of the relatively few high-quality studies in this field. Generally, prosthetic reconstruction has been shown to result in fewer implant failures and should be preferred in patients with a good prognosis. Survival estimation tools should be used as part of preoperative planning. Adjuvant treatment, which relies on radiotherapy and inhibition of osteoclast function may also offer symptomatic relief and prevent implant failure. In this review we discuss the epidemiology, indications for surgery, preoperative planning, surgical techniques and adjuvant treatment of metastatic bone disease.