Treatment Of Bone Metastases Research Articles

Evaluation of Safety and Dosimetry of 177Lu-DOTA-ZOL for Therapy of Bone Metastases.

Palliative treatment of bone metastasis using radiolabeled bisphosphonates is a well-known concept proven to be safe and effective. A new therapeutic radiopharmaceutical for bone metastasis is 177Lu-DOTA-zoledronic acid (177Lu-DOTA-ZOL). In this study, the safety and dosimetry of a single therapeutic dose of 177Lu-DOTA-ZOL were evaluated on the basis of a series of SPECT/CT images and blood samples. Methods: Nine patients with exclusive bone metastases from metastatic castration-resistant prostate cancer (mCRPC) (70.8 ± 8.4 y) and progression under conventional therapies participated in this prospective study. After receiving 5,780 ± 329 MBq 177Lu-DOTA-ZOL, patients underwent 3-dimensional whole-body SPECT/CT imaging and venous blood sampling over 7 d. Dosimetric evaluation was performed for main organs and tumor lesions. Safety was assessed by blood biomarkers. Results:177Lu-DOTA-ZOL showed fast uptake and high retention in bone lesions and fast clearance from the bloodstream in all patients. The average retention in tumor lesions was 0.02% injected activity per gram at 6 h after injection and approximately 0.01% at 170 h after injection. In this cohort, the average absorbed doses in bone tumor lesions, kidneys, red bone marrow, and bone surfaces were 4.21, 0.17, 0.36, and 1.19 Gy/GBq, respectively. The red marrow was found to be the dose-limiting organ for all patients. A median maximum tolerated injected activity of 6.0 GBq may exceed the defined threshold of 2 Gy for the red bone marrow in individual patients (4/8). Conclusion:177Lu-DOTA-ZOL is safe and has a favorable therapeutic index compared with other radiopharmaceuticals used in the treatment of osteoblastic bone metastases. Personalized dosimetry, however, should be considered to avoid severe hematotoxicity for individual patients.

Ibandronate-Loaded Carbon Nanohorns Fabricated Using Calcium Phosphates as Mediators and Their Effects on Macrophages and Osteoclasts.

Carbon nanohorns (CNHs), a type of nanocarbon, have been studied for the application of drug delivery systems (DDSs) because they are easily functionalized, support bone regeneration, can be used to perform photohyperthermia, have low toxicity, and are easily phagocytosed by macrophages. To take advantage of these features of CNHs, we developed a DDS for the local treatment of bone metastasis by loading the antibone resorption drug ibandronate (IBN) onto CNHs. The poor adsorption of IBN onto CNHs due to the weak hydrophilic-hydrophobic interaction was overcome by using calcium phosphates (CaPs) as mediators. In the fabrication process, we used oxidized CNH (OxCNH), which is less hydrophobic, onto which IBN was coprecipitated with CaP from a labile supersaturated CaP solution. OxCNH-CaP-IBN composite nanoparticles exerted stronger cell-suppressive effects than OxCNH and IBN in both murine macrophages (RAW264.7 cells) and osteoclasts (differentiated from RAW264.7 cells). OxCNH-CaP-IBN composite nanoparticles were efficiently phagocytosed by macrophage cells, where they specifically accumulated in lysosomes. The stronger cell-suppressive effects were likely due to intracellular delivery of IBN, i.e., the release of IBN from OxCNH-CaP-IBN composite nanoparticles via dissociation of CaP in the acidic environment of lysosomes. Our findings suggest that OxCNH-CaP-IBN composite nanoparticles are potentially useful for the local treatment of metastatic bone destruction.

Systemic Radiotherapy of Bone Metastases With Radionuclides

Treatments of bone metastases using radionuclides are now well established in oncology. It is also a field that continues to develop. This article reviews the evidence base that led to the approval of strontium-89 and samarium-153 ethylenediaminetetramethylene phophanate (EDTMP) for the palliation of pain from bone metastases, as well as the evidence for the use of radium-223 in metastatic castrate-resistant prostate cancer. Efforts to optimise treatments and improve response rates, either by safely increasing the radiation dose to bone metastases or by combining treatment with non-radiation-based therapies, are discussed. In addition, the development of both alpha- and beta-particle-emitting radiopharmaceuticals designed to target prostate-specific membrane antigen are reviewed.

Chinese expert consensus statement on the clinical diagnosis and treatment of breast cancer bone metastasis and bone related disease

: Breast cancer is one of the most common malignancy in Chinese women. Up to 80% of patients with metastatic breast cancer develop bone metastasis resulting in local bone destruction and skeletal-related events such as pathological fracture and spinal cord compression. Skeletal-related events pose an enormous impact on patients' motor function and quality of life. Therefore, prevention of skeletal-related events is one of the treatment objectives of breast cancer bone metastasis, which often requires participation of multidisciplinary team to optimize therapeutic regimen for individual. Standard anti-tumor therapy includes chemotherapy, endocrine therapy, targeted therapy, immunotherapy, etc. Bone-modifying agents are the basic treatment after the occurrence of bone metastases in addition to anti-tumor therapy. As the disease progresses, patients may receive bone radiotherapy and orthopedic surgery. The purpose of this expert’s consensus is to standardize diagnosis and treatment of breast cancer bone metastasis and improve the quality of life of patients.

Simultaneous Use of Targeted Radiotherapy with External Beam Radiotherapy in the Treatment of Bone Metastasis

Simultaneous Use of Targeted Radiotherapy with External Beam Radiotherapy in the Treatment of Bone Metastasis

Systemic Treatment in Bone Metastases

Systemic Treatment in Bone Metastases

Radionuclide Therapy in the Treatment of Bone Metastases

Radionuclide Therapy in the Treatment of Bone Metastases

Breast cancer exosomes contribute to pre-metastatic niche formation and promote bone metastasis of tumor cells.

Rationale: Breast cancer preferentially develops osteolytic bone metastasis, which makes patients suffer from pain, fractures and spinal cord compression. Accumulating evidences have shown that exosomes play an irreplaceable role in pre-metastatic niche formation as a communication messenger. However, the function of exosomes secreted by breast cancer cells remains incompletely understood in bone metastasis of breast cancer.Methods: Mouse xenograft models and intravenous injection of exosomes were applied for analyzing the role of breast cancer cell-derived exosomes in vivo. Effects of exosomes secreted by the mildly metastatic MDA231 and its subline SCP28 with highly metastatic ability on osteoclasts formation were confirmed by TRAP staining, ELISA, microcomputed tomography, histomorphometric analyses, and pit formation assay. The candidate exosomal miRNAs for promoting osteoclastogenesis were globally screened by RNA-seq. qRT-PCR, western blot, confocal microscopy, and RNA interfering were performed to validate the function of exosomal miRNA.Results: Implantation of SCP28 tumor cells in situ leads to increased osteoclast activity and reduced bone density, which contributes to the formation of pre-metastatic niche for tumor cells. We found SCP28 cells-secreted exosomes are critical factors in promoting osteoclast differentiation and activation, which consequently accelerates bone lesion to reconstruct microenvironment for bone metastasis. Mechanistically, exosomal miR-21 derived from SCP28 cells facilitates osteoclastogenesis through regulating PDCD4 protein levels. Moreover, miR-21 level in serum exosomes of breast cancer patients with bone metastasis is significantly higher than that in other subpopulations.Conclusion: Our results indicate that breast cancer cell-derived exosomes play an important role in promoting breast cancer bone metastasis, which is associated with the formation of pre-metastatic niche via transferring miR-21 to osteoclasts. The data from patient samples further reflect the significance of miR-21 as a potential target for clinical diagnosis and treatment of breast cancer bone metastasis.

Bone targeting nano-aggregates prepared from self-assembled polyaspartamide graft copolymers for pH sensitive DOX delivery.

Nanoparticles with bone targeting ability and pH-sensitivity were prepared with polyaspartamide (PASPAM) derivatives based on polysuccinimide (PSI) grafted with octadecylamine (C18), hydrazine (HYD) and polyethylene glycol (PEG, Mw: 5000). For the bone targeting, alendronate (ALN), which has bone affinity, was grafted to PEG and doxorubicin (DOX) was conjugated with linkers of acid sensitive hydrazone bonds, which can be cleaved most effectively in an intracellular acidic environment. At pH 5.0, ∼75% of the drug was released from ALN-PEG/C18/HYD-DOX-g-PASPAM due to the effective cleavage of HYD under the acidic condition. Also, ALN-PEG/C18/HYD-DOX-g-PASPAM particles were more effectively adsorbed on the surface of bone than PEG/C18/HYD-DOX-g-PASPAM. According to an in vivo antitumor activity test, the volume of tumor treated with ALN-PEG/C18/HYD-DOX-g-PASPAM decreased (1550 mm3) when compared with the PBS control sample (3850 mm3), proving that ALN-PEG/C18/HYD-DOX-g-PASPAM is an effective drug delivery system for the treatment of bone metastasis of breast cancer.

Current progress and mechanisms of bone metastasis in lung cancer: a narrative review.

Lung cancer is a kind of malignant tumor with rapid progression and poor prognosis. Distant metastasis has been the main cause of mortality among lung cancer patients. Bone is one of the most common sites. Among all lung cancer patients with bone metastasis, most of them are osteolytic metastasis. Some serious clinical consequences like bone pain, pathological fractures, spinal instability, spinal cord compression and hypercalcemia occur as well. Since the severity of bone metastasis in lung cancer, it is undoubtedly necessary to know how lung cancer spread to bone, how can we diagnose it and how can we treat it. Here, we reviewed the process, possible mechanisms, diagnosis methods and current treatment of bone metastasis in lung cancer. We divided the process of bone metastasis in lung cancer into three steps: tumor invasion, tumor cell migration and invasion in bone tissue. It may be influenced by genetic factors, microenvironment and other adhesion-related factors. Imaging examination, laboratory examination, and pathological examination are used to diagnose lung cancer metastasis to bone. Surgery, radiotherapy, targeted therapy, bisphosphonate, radiation therapy and chemotherapy are the common clinical treatment methods currently. We also found some problems remained to be solved. For example, drugs for skeletal related events mainly target on osteoclasts at present, which increase the ratio of patients in osteoporosis and fractures in the long term. In all, this review provides the direction for future research on bone metastasis in lung cancer.

Combinatorial Photothermal 3D‐Printing Scaffold and Checkpoint Blockade Inhibits Growth/Metastasis of Breast Cancer to Bone and Accelerates Osteogenesis

AbstractCancer metastases are the main causes for the high mortality of cancer. The current treatment modality for bone metastasis of breast cancer is dominantly destructive, which urges the engineering of multifunctional biomaterials, not only for eliminating primary/metastases tumors effectively but also for enhancing bone–tissue regeneration. Herein, an immune adjuvant (R837)‐loaded and niobium carbide (Nb2C) MXene‐modified 3D‐printing biodegradable scaffold (BG@NbSiR) is designed and constructed to effectively treat bone metastasis of breast cancer. The engineered BG@NbSiR scaffold can eradicate primary tumors, activate the immune response, suppress metastases, prevent tumor relapses (long‐term immunological memory) by synergizing with checkpoint blockade immunotherapy, and accelerate osteogenesis as evidenced by multiple in vivo murine models. In particular, single‐cell sequencing (scRNA‐seq) is employed to further determine the critical factors responding to BG@NbSiR scaffold‐based photothermia plus checkpoint blockade‐combined immunotherapy. Several gene functional terms are identified in both tumor biology (including copy number variation) and immune response, which further reveal the underlying therapeutic mechanisms from the perspective of single‐cell transcriptome. This work not only demonstrates the promising clinical application potentials of BG@NbSiR scaffold‐based therapy against bone metastasis of breast cancer, but also provides distinctive avenues to optimize the design and construction of multifunctional tissue‐engineering biomaterials based on single‐cell genomes.

Medication-Related Osteonecrosis of the Jaws and CDK4/6 Inhibitors: A Recent Association.

The purpose of the present study was to estimate the prevalence of cyclin-dependent kinase (CDK) 4/6 inhibitors use among cancer patients from the medication-related osteonecrosis of the jaw (MRONJ) cohort of the University of Messina. We retrospectively reviewed the records of all patients with either intravenous bisphosphonates or denosumab-related MRONJ reported in the electronic health records of the Unit of Oral Surgery, School of Dentistry, University of Messina between the first quarter of 2018 and the first quarter 2020 to identify eligible patients. We observed six cases of MRONJ associated with CDK4/6 inhibitors concomitantly with intravenous bisphosphonates and/or denosumab in breast cancer patients. The CDK4/6 inhibitors registered were palbociclib (n = 5) and abemaciclib (n = 1). Data of cancer patients diagnosed with MRONJ in the same period (n = 10) were extracted for comparison. The comparative assessment with this group of patients showed a similar distribution of MRONJ stage ranged and clinical course after treatment. The degree of risk for osteonecrosis in patients taking these new classes of drugs is uncertain but warrants awareness and close monitoring. The role of premedication dental evaluation as a prevention strategy has been acknowledged for cancer patients about to initiate intravenous bisphosphonates and/or denosumab for treatment of bone metastasis, but additional attention should be paid to whom are assuming CDK4/6 inhibitors because of their oral adverse events.

Bone-Targeted Calcium Phosphate-Polymer Hybrid Nanoparticle Co-Deliver Zoledronate and Docetaxel to Treat Bone Metastasis of Prostate Cancer.

Prostate cancer is the most common malignant tumor with bone metastasis, and there is still no ideal treatment for bone metastasis of prostate cancer. In this study, a pH and GSH dual sensitive calcium phosphate-polymer hybrid nanoparticle (DTX@Cap/HP) was prepared to co-deliver zoledronate (ZOL) and docetaxel (DTX) to treat bone metastasis of prostate cancer. DTX@Cap/HP exhibited high bone binding affinity and released more DTX and ZOL in acidic and high GSH concentration environment. A large amount of DTX@Cap/HP was uptaken by PC-3cell in acidic medium than that in neutral medium. DTX@Cap/HP obviously reduced PC-3cell proliferation and bone lesion in in-vitro 3D model of bone metastases of prostate cancer. Besides, DTX@Cap/HP also exhibited stronger anti bone metastases of prostate cancer activity invivo as compared with the same dose of DTX+ZOL, which resulted from the co-delivery of DTX and ZOL to bone metastases of prostate cancer by DTX@Cap/HP and the synergistic effects of DTX and ZOL. DTX@Cap/HP has great potential in the treatment of bone metastases of prostate cancer.

A novel topical treatment for bone metastases using a gelatin hydrogel incorporating cisplatin as a sustained release system.

Management of bone metastasis is becoming increasingly important. Thus, local and systemic treatment options have been developed for control. Although systemic administration of anticancer agents is effective for bone metastasis, it is often stopped because of poor general conditions or side effects. Therefore, it is highly desirable to develop a more effective and safer local treatment for bone metastasis. The purpose of the current study was to investigate the antitumor effects and safety of gelatin hydrogel microspheres incorporating cisplatin (GM-CDDP), which we developed as a sustained release system without harmful substances. First, we assessed GM-CDDP for its in vitro degradability and potential for sustained release. Second, in vivo antitumor and side effects were evaluated using a murine bone metastasis model of MDA-MB-231 human breast cancer cells incorporating GFP. In vitro, initial bursts were observed within 2 h and CDDP was released gradually with gelatin hydrogel degradation, which reached 100% at 48 h. In vivo, local administration of GM-CDDP (2 mg/kg) significantly suppressed tumor growth and bone osteolysis compared with the control, and local and systemic administration of free CDDP (2 mg/kg; p < 0.05). Local administration of GM-CDDP significantly reduced loss of body weight and elevation of blood urea nitrogen compared with the systemic administration of free CDDP (p < .05). The current study suggests that local administration of GM-CDDP achieves higher antitumor effects with a potential for lesser side effects compared with local or systemic administration of free CDDP.

Retreatment after Single Fraction Palliative Bone Metastasis Treatment in the Modern Era

Radiation therapy (RT) for bone metastases is effective for palliative care to reduce pain, prevent pathologic fractures, and improve patients’ quality of life. However, randomized studies of single fraction versus multiple fraction treatment in bone metastases remain limited in the current era of improved systemic therapy, with concerns regarding retreatment in older studies. In this study, we evaluated retreatment rates and time to retreatment in patients receiving single fraction RT in the modern era at a high-volume cancer center using our rapid access bone metastasis (RABC) clinic. Records of patients evaluated in the RABC at MDACC between April 2018 and December 2019 were reviewed. Patients who received 8 Gy in 1 fraction for bone metastases were included in the study; pre-op and post-op RT sites were excluded. Patients were followed closely by orthopedic surgery, radiation oncology and medical oncology, and retreatment was given at the clinician’s discretion but was generally for local failure with pain. Competing risks analysis was performed for time to any site retreatment and time to same site retreatment, with death treated as a censoring event. Retreatment included radiation or orthopedic surgery. 227 treatments were recorded in this study (RABC: n = 108, non-RABC: n = 119). Median overall survival for all patients was 9.7 months (95% CI: 7-11.8). In competing risk analysis, median retreatment-free survival (any site) was 6.7 months (95% CI 4.4-8.6). Median retreatment-free survival (same site) was not reached. For patients who were retreated to the same site, median time to retreatment was 3.9 months (range 0.7-11). One-year retreatment for surviving patients was 18% (9/49) of sites were retreated at the same location; 1 of these sites received surgery alone and 7 sites received RT alone. One site received both RT and surgery at retreatment. Post-8Gy retreatment rates were in line with historic studies. In a diverse patient population of patients with long life expectancy and close follow up receiving single fraction palliative RT, this study suggests that higher dose could be considered in patients with a longer than a 12-month life expectancy, as these patients have a retreatment rate of nearly 20%.

Bone metastases.

Bone is the most frequent site for metastasis for many cancers, notably for tumours originating in the breast and the prostate. Tumour cells can escape from the primary tumour site and colonize the bone microenvironment. Within the bone, these disseminated tumour cells, as well as those arising in the context of multiple myeloma, may assume a state of dormancy, remaining quiescent for years before resuming proliferation and causing overt metastasis, which causes bone destruction via activation of osteoclast-mediated osteolysis. This structural damage can lead to considerable morbidity, including pain, fractures and impaired quality of life. Although treatment of bone metastases and myeloma bone disease is rarely curative, disease control is often possible for many years through the use of systemic anticancer treatments on a background of multidisciplinary supportive care. This care should include bone-targeted agents to inhibit tumour-associated osteolysis and prevent skeletal morbidity as well as use of appropriate local treatments such as radiation therapy, orthopaedic surgery and specialist palliative care to minimize the impact of metastatic bone disease on physical functioning. In this Primer, we provide an overview of the clinical features, the pathophysiology and the specific treatment approaches to prevent and treat bone metastases from solid tumours as well as myeloma bone disease.

Dendrimer-based micelles with highly potent targeting to sites of active bone turnover for the treatment of bone metastasis

Bone-drug targeting therapies using nanoparticles based on targeting ligands remain challenging due to their uptake clearance at non-target sites such as the liver, kidney, and spleen. Furthermore, the distribution sites of nanoparticles in bones have not been fully investigated, thus halting the development of more effective bone metastasis treatment strategies. In this study, we developed nanoparticles self-assembled from cholesterol-terminated, polyethylene glycol-conjugated, aspartic acid (Asp)-modified polyamidoamine dendrimer (Asp-PAMAM-Micelles) with targeting to active bone turnover sites associated with bone metastasis pathogenesis. On analysis through whole-body single photon emission computed tomography/computed tomography (SPECT/CT) imaging, 111In-Asp-PAMAM-Micelles showed high specificity to active bone turnover sites (especially the joints in the lower limbs, shoulder, and pelvis) after intravenous injection in mice. The lower limb bone uptake clearance for 111In-Asp-PAMAM-Micelles encapsulating paclitaxel (PTX) was 3.5-fold higher than that for 111In-unmodified PAMAM-Micelles (PTX). 3H-PTX encapsulated Asp-PAMAM-Micelles effectively accumulated in the lower limb bones in a similar manner as the 111In-Asp-PAMAM-Micelles (PTX). In a bone metastatic tumor mouse model, the tumor growth in the lower limb bones was significantly inhibited by injection of Asp-PAMAM-Micelles (PTX) compared to unmodified PAMAM-Micelles (PTX). Our results demonstrate that Asp-PAMAM-Micelles are sophisticated drug delivery systems for highly potent targeting to active bone turnover sites.

Emergence of Cancer-Associated Fibroblasts as an Indispensable Cellular Player in Bone Metastasis Process.

Simple SummaryBone metastasis is frequently complicated in patients with advanced solid cancers such as breast, prostate and lung cancers, and impairs their prognosis. Bone metastasis proceeds through the interaction between cancer cells and resident cells in bone. Among resident cells, osteoclasts are commonly activated in bone metastasis, and therefore, the drugs targeting osteoclast activation are frequently used to treat bone metastasis. However, their ineffectiveness to inhibit cancer cell growth in bone marrow, raises the possibility of the involvement of additional types of resident cells in bone metastasis. Cancer-associated fibroblasts (CAFs) are fibroblasts that accumulate in cancer tissues as well as metastatic organs including bone. Hence, we will discuss the potential roles of CAFs, which are emerging as an important cellular player in bone metastasis.Bone metastasis is frequently complicated in patients with advanced solid cancers such as breast, prostate and lung cancers, and impairs patients’ quality of life and prognosis. At the first step of bone metastasis, cancer cells adhere to the endothelium in bone marrow and survive in a dormant state by utilizing hematopoietic niches present therein. Once a dormant stage is disturbed, cancer cells grow through the interaction with various bone marrow resident cells, particularly osteoclasts and osteoblasts. Consequently, osteoclast activation is a hallmark of bone metastasis. As a consequence, the drugs targeting osteoclast activation are frequently used to treat bone metastasis but are not effective to inhibit cancer cell growth in bone marrow. Thus, additional types of resident cells are presumed to contribute to cancer cell growth in bone metastasis sites. Cancer-associated fibroblasts (CAFs) are fibroblasts that accumulate in cancer tissues and can have diverse roles in cancer progression and metastasis. Given the presence of CAFs in bone metastasis sites, CAFs are emerging as an important cellular player in bone metastasis. Hence, in this review, we will discuss the potential roles of CAFs in tumor progression, particularly bone metastasis.

Innovative Options for Bone Metastasis Treatment: An Extensive Analysis on Biomaterials-Based Strategies for Orthopedic Surgeons.

Bone is the third most frequent site of metastasis, with a particular incidence in breast and prostate cancer patients. For example, almost 70% of breast cancer patients develop several bone metastases in the late stage of the disease. Bone metastases are a challenge for clinicians and a burden for patients because they frequently cause pain and can lead to fractures. Unfortunately, current therapeutic options are in most cases only palliative and, although not curative, surgery remains the gold standard for bone metastasis treatment. Surgical intervention mostly provides the replacement of the affected bone with a bioimplant, which can be made by materials of different origins and designed through several techniques that have evolved throughout the years simultaneously with clinical needs. Several scientists and clinicians have worked to develop biomaterials with potentially successful biological and mechanical features, however, only a few of them have actually reached the scope. In this review, we extensively analyze currently available biomaterials-based strategies focusing on the newest and most innovative ideas while aiming to highlight what should be considered both a reliable choice for orthopedic surgeons and a future definitive and curative option for bone metastasis and cancer patients.

New antibody therapeutics targeting connexin hemichannels in treatment of osteosarcoma and breast cancer bone metastasis

Background: The growth and migration of tumor cells is largely influenced by their microenvironment, and bone is the primary site for osteosarcoma and a preferred site for cancer metastasis. Connexin 43 (Cx43) hemichannels are highly expressed in osteocytes, the most abundant bone cell type, and have been shown to permit small molecules, such as ATP, to be released into the extracellular environment.