Search Results (71)

Bone metastases represent a critical complication in oncology, frequently indicating advanced malignancy and substantially reducing patient quality of life. This review provides a comprehensive analysis of the complex interactions between tumor cells and the bone microenvironment, emphasizing the relevance of the “seed and soil” hypothesis, the RANK/RANKL/OPG signaling axis, and Wnt signaling pathways that collectively drive metastatic progression. The molecular and cellular mechanisms underlying the formation of osteolytic and osteoblastic lesions are examined in detail, with a particular focus on their implications for bone metastases associated with breast, prostate, lung, and other cancers. A central component of this review is the categorization of pathological biomarkers into four types: diagnostic, prognostic, predictive, and monitoring. We provide a comprehensive evaluation of circulating tumor cells (CTCs), bone turnover markers (such as TRACP-5b and CTX), advanced imaging biomarkers (including PET/CT and MRI), and novel genomic signatures. These biomarkers offer valuable insights for early detection, enhanced risk stratification, and optimized therapeutic decision-making. Furthermore, emerging strategies in immunotherapy and bone-targeted treatments are discussed, highlighting the potential of biomarker-guided precision medicine to enhance personalized patient care. The distinctiveness of this review lies in its integrative approach, combining fundamental pathophysiological insights with the latest developments in biomarker discovery and therapeutic innovation. By synthesizing evidence across various cancer types and biomarker categories, we provide a cohesive framework aimed at advancing both the scientific understanding and clinical management of bone metastases. Full article

Biodentine, a tricalcium silicate cement, has emerged as a retrograde root-end filling material to promote periapical lesion (PL) healing after apicoectomy. However, its underlying mechanisms remain unclear. This study tested the hypothesis that Biodentine stimulates the osteogenic differentiation of mesenchymal stromal cells (MSCs) derived from PLs. The Biodentine extract (B-Ex) was prepared by incubating polymerized Biodentine in RPMI medium (0.2 g/mL) for three days at 37 °C. B-Ex, containing both released microparticles and soluble components, was incubated with PL-MSCs cultured in either a basal MSC medium or suboptimal osteogenic medium. Osteogenic differentiation was assessed by Alizarin Red staining and the expression of 20 osteoblastogenesis-related genes. Non-cytotoxic concentrations of B-Ex stimulated the proliferation of PL-MSCs and induced their osteogenic differentiation in a dose-dependent manner, with a significantly enhanced effect in suboptimal osteogenic medium. B-Ex upregulated most early and late osteoblastic genes. However, the differentiation process was prolonged, as indicated by the delayed expression of wingless-type MMTV integration site family member 2 (WNT2), bone gamma-carboxyglutamate protein (BGLAP), bone morphogenic protein-2 (BMP-2), growth hormone receptor (GHR), and FOS-like 2, AP-1 transcription factor subunit (FOSL2), compared with their expression under optimal osteogenic conditions. The stimulatory effect of B-Ex was primarily calcium dependent, as it was reduced by 85% when B-Ex was treated with the calcium-chelating agent EGTA. In conclusion, Biodentine promotes the osteogenic differentiation of PL-MSCs in a calcium-dependent manner, supporting its stimulatory role in periapical healing. Full article

Objectives: The integration of machine learning and radiomics in medical imaging has significantly advanced diagnostic and prognostic capabilities in healthcare. This study focuses on developing and validating an artificial intelligence (AI) model using U-Net architectures for the accurate detection and segmentation of spinal metastases from computed tomography (CT) images, addressing both osteolytic and osteoblastic lesions. Methods: Our methodology employs multiple variations of the U-Net architecture and utilizes two distinct datasets: one consisting of 115 polytrauma patients for vertebra segmentation and another comprising 38 patients with documented spinal metastases for lesion detection. Results: The model demonstrated strong performance in vertebra segmentation, achieving Dice Similarity Coefficient (DSC) values between 0.87 and 0.96. For metastasis segmentation, the model achieved a DSC of 0.71 and an F-beta score of 0.68 for lytic lesions but struggled with sclerotic lesions, obtaining a DSC of 0.61 and an F-beta score of 0.57, reflecting challenges in detecting dense, subtle bone alterations. Despite these limitations, the model successfully identified isolated metastatic lesions beyond the spine, such as in the sternum, indicating potential for broader skeletal metastasis detection. Conclusions: The study concludes that AI-based models can augment radiologists’ capabilities by providing reliable second-opinion tools, though further refinements and diverse training data are needed for optimal performance, particularly for sclerotic lesion segmentation. The annotated CT dataset produced and shared in this research serves as a valuable resource for future advancements. Full article

Although mesenchymal stem cells (MSCs) insertion has gained recent attention as a joint-preserving procedure, no study has conducted direct intralesional implantation of human umbilical cord-derived MSCs (hUCMSCs) in patients with ONFH. This is a protocol for a phase 1 clinical trial designed to assess the safety and exploratory efficacy of human umbilical cord-derived osteoblasts (hUC-Os), osteogenic differentiation-induced cells from hUCMSCs, in patients with early-stage ONFH. Nine patients with Association Research Circulation Osseous (ARCO) stage 1 or 2 will be assigned to a low-dose (1 × 10⁷ hUC-O cells, n = 3), medium-dose (2 × 10⁷ cells, n = 3), and high-dose group (4 × 10⁷ cells, n = 3) in the order of their arrival at the facility, and, depending on the occurrence of dose-limiting toxicity, up to 18 patients can be enrolled by applying the 3 + 3 escalation method. We will perform hUC-O (CF-M801) transplantation combined with core decompression and follow-up for 12 weeks according to the study protocol. Safety will be determined through adverse event assessment, laboratory tests including a panel reactive antibody test, vital sign assessment, physical examination, and electrocardiogram. Efficacy will be explored through the change in pain visual analog scale, Harris hip score, Western Ontario and McMaster Universities Osteoarthritis Index, ARCO stage, and also size and location of necrotic lesion according to Japanese Investigation Committee classification before and after the procedure. Joint preservation is important, particularly in younger, active patients with ONFH. Confirmation of the safety and efficacy of hUC-Os will lead to a further strategy to preserve joints for those suffering from ONFH and improve our current knowledge of cell therapy. Full article

This interdisciplinary investigation of the human remains of Balduin Helm, one of the most important abbots of the Fürstenfeld monastery, provides novel information on this historic individual. This is particularly interesting since Balduin, during the early 18th century, was involved in the renovation of this large Bavarian monastery. Metastatic prostate cancer was found as evidenced by multiple mixed osteolytic–osteoblastic bone lesions in all available vertebral bodies, fragments of both os coxae, and isolated metastases in skull bones. Distribution, radio- and histomorphology, and especially the immunohistochemical detection of prostate-specific antigens in those metastases definitively confirm this diagnosis. Further investigation, especially by stable isotope analysis, showed a balanced high-level diet with considerable contribution from animal protein and significant freshwater fish. These additional findings suggest a significant radiocarbon reservoir effect as an explanation for a “too old” radiocarbon date. Finally, the obviously high-level protein diet may have contributed to the tumorigenesis which caused the death of the abbot at an advanced age. Full article

Prostate cancer accounts for 29% of malignant diagnoses among men in the United States and is the second leading cause of death from cancer. Effective screening methods and improved treatment have decreased the mortality rate significantly. This decreased mortality rate, however, does not apply to all histologic variants. Adenosquamous carcinoma of the prostate is an extremely aggressive neoplasm with no current known curative therapy. It is often diagnosed after chemotherapy, radiation, or androgen deprivation therapy for traditional prostatic adenocarcinomas. Primary carcinomas of the prostate with squamous features include, but are not limited to, pure squamous cell carcinoma and adenocarcinoma mixed with squamous cell carcinoma (SCC). Important distinguishable clinical features of adenosquamous carcinoma include normal prostate-specific antigen (PSA) levels, even with advanced disease and osteolytic versus osteoblastic metastatic lesions in adenocarcinoma. Additional entities to consider in the differential diagnosis are squamous metaplasia of the prostate, secondary involvement of pure SCC, and urothelial carcinoma with squamous differentiation. Here, we present a de novo case of adenosquamous carcinoma in a 48-year-old man who rapidly developed extensive metastatic disease. Full article

Osteonecrosis of the jaw is the progressive loss and destruction of bone affecting the maxilla or mandible in patients treated with antiresorptive and antiangiogenic agents without receiving prior radiation therapy. The pathogenesis involves the inflammatory pathway of receptor activator of nuclear factor NF-kB ligand and the macrophage colony-stimulating factor, essential for osteoclast precursors survival and proliferation and acting through its receptor c-Fms. Evidence has shown the role of non-coding RNAs in the pathogenesis of osteonecrosis of the jaw and this finding might be useful in diagnosis since these small RNAs could be considered as biomarkers of apoptotic activity in bone. Interestingly, it has been proved that miR-29 and miR-31-5p, acting on specific targets such as CALCR and RhoA, promote programmed-cell death and consequently the necrosis of bone tissue. Specific long non-coding RNAs, instead, have been detected both at reduced levels in patients with multiple myeloma and osteonecrosis, and associated with suppression of osteoblast differentiation, with consequences in the progression of mandible lesions. Among non-coding genic material, circular RNAs have the capability to modify the expression of specific mRNAs responsible for the inhibition of bisphosphonates activity on osteoclastogenesis. Full article

In multiple myeloma (MM), specific cytokines produced by plasma cells disrupt the equilibrium between osteoblasts and osteoclasts. As a result, MM patients experience an increase in osteoclast activity and a decrease in osteoblast activity. This disparity is fundamental to the development of myeloma bone disease. Lytic lesions, which are a feature of MM, can result in pathologic fractures and excruciating pain. For many years, whole-body X-ray radiography has been the standard imaging method for identifying lytic lesions. However, its sensitivity is limited because it can only detect lesions once the bone mass has been reduced by 30% to 50%. Hence, utilizing advanced and sensitive imaging modalities, such as positron emission tomography (PET) fused with computed tomography (CT), is crucial for the early detection of osteolytic lesions. Among radiotracers used in PET imaging, ¹⁸F-fluorodeoxyglucose ([¹⁸F]FDG) is the most commonly employed in the field of oncology. Currently, most guidelines include [¹⁸F]FDG PET/CT in the assessment of myeloma patients, particularly for detecting osteolytic lesions, evaluating treatment response, and assessing extramedullary and residual disease. Nonetheless, in recent years, new applications of PET/CT for evaluating myeloma have been investigated. These include assessing aspects such as bone turnover, dual-time-point imaging (early and delayed scans), the impact of chemotherapy on the brain (commonly known as ‘chemo brain’), innovative PET radiotracers, and the use of artificial intelligence technology. This article aims to provide a comprehensive review of both conventional and innovative uses of PET/CT in evaluating multiple myeloma. Full article

Despite the advancements in treatments for other cancers, the outcomes for osteosarcoma (OSA) patients have not improved in the past forty years, especially in metastatic patients. Moreover, the major cause of death in OSA patients is due to metastatic lesions. In the current study, we report on the establishment of three cell lines derived from metastatic canine OSA patients and their transcriptome as compared to normal canine osteoblasts. All the OSA cell lines displayed significant upregulation of genes in the epithelial mesenchymal transition (EMT) pathway, and upregulation of key cytokines such as CXCL8, CXCL10 and IL6. The two most upregulated genes are MX1 and ISG15. Interestingly, ISG15 has recently been identified as a potential therapeutic target for OSA. In addition, there is notable downregulation of cell cycle control genes, including CDKN2A, CDKN2B and THBS1. At the protein level, p16^INK4A, coded by CDKN2A, was undetectable in all the canine OSA cell lines, while expression of the tumor suppressor PTEN was variable, with one cell line showing complete absence and others showing low levels of expression. In addition, the cells express a variety of actionable genes, including KIT, ERBB2, VEGF and immune checkpoint genes. These findings, similar to those reported in human OSA, point to some genes that can be used for prognosis, targeted therapies and novel drug development for both canine and human OSA patients. Full article

Steroid hormone production via the adrenal cortex, gonads, and placenta (so-called glandular steroidogenesis) is responsible for the endocrine control of the body’s homeostasis and is organized by a feedback regulatory mechanism based on the hypothalamus–pituitary–steroidogenic gland axis. On the other hand, recently discovered extraglandular steroidogenesis occurring locally in different tissues is instead linked to paracrine or autocrine signaling, and it is independent of the control by the hypothalamus and pituitary glands. Bone cells, such as bone-forming osteoblasts, osteoblast-derived osteocytes, and bone-resorbing osteoclasts, respond to steroid hormones produced by both glandular and extraglandular steroidogenesis. Recently, new techniques to identify steroid hormones, as well as synthetic steroids and steroidogenesis inhibitors, have been introduced, which greatly empowered steroid hormone research. Based on recent literature and new advances in the field, here we review the local role of steroid hormones in regulating bone homeostasis and skeletal lesion formation. The novel idea of extraglandular steroidogenesis occurring within the skeletal system raises the possibility of the development of new therapies for the treatment of bone diseases. Full article

Bone metastases cause morbidity and mortality in several human cancer forms. Experimental models are used to unravel the mechanisms and identify possible treatment targets. The location inside the skeleton complicates accurate assessment. This study evaluates the performance of magnetic resonance imaging (MRI) of prostate cancer tumors growing intratibially in mice. MRI detected intratibial tumor lesions with a sensitivity and specificity of 100% and 89%, respectively, compared to histological evaluation. Location and some phenotypical features could also be readily detected with MRI. Regarding volume estimation, the correlation between MRI and histological assessment was high (p < 0.001, r = 0.936). In conclusion, this study finds MRI to be a reliable tool for in vivo, non-invasive, non-ionizing, real-time monitoring of intratibial tumor growth. Full article

Multiple myeloma (MM) is a dyscrasia of plasma cells (PCs) characterized by abnormal immunoglobulin (Ig) production. The disease remains incurable due to a multitude of mutations and structural abnormalities in MM cells, coupled with a favorable microenvironment and immune suppression that eventually contribute to the development of drug resistance. The bone marrow microenvironment (BMME) is composed of a cellular component comprising stromal cells, endothelial cells, osteoclasts, osteoblasts, and immune cells, and a non-cellular component made of the extracellular matrix (ECM) and the liquid milieu, which contains cytokines, growth factors, and chemokines. The bone marrow stromal cells (BMSCs) are involved in the adhesion of MM cells, promote the growth, proliferation, invasion, and drug resistance of MM cells, and are also crucial in angiogenesis and the formation of lytic bone lesions. Classical immunophenotyping in combination with advanced immune profiling using single-cell sequencing technologies has enabled immune cell-specific gene expression analysis in MM to further elucidate the roles of specific immune cell fractions from peripheral blood and bone marrow (BM) in myelomagenesis and progression, immune evasion and exhaustion mechanisms, and development of drug resistance and relapse. The review describes the role of BMME components in MM development and ongoing clinical trials using immunotherapeutic approaches. Full article

Breast cancer is associated with phosphate toxicity, the toxic effect from dysregulated phosphate metabolism that can stimulate tumorigenesis. Phosphate toxicity and dysregulated phosphate metabolism are also associated with bone mineral abnormalities, including excessive bone mineral loss and deposition. Based on shared associations with dysregulated phosphate metabolism and phosphate toxicity, a hypothesis proposed in the present mixed methods–grounded theory study posits that middle-aged women with incidence of breast cancer had a greater magnitude of changes in bone mineral density over time compared with women who remained cancer-free. To test this hypothesis, a mixed-effects model was used to analyze the associations of breast cancer incidence with spinal bone mineral density changes in the U.S. Study of Women’s Health Across the Nation. Compared with women in the cohort who remained cancer-free, women who self-reported breast cancer had higher bone mineral density at baseline, but had more rapid losses in bone mineral density during follow-up visits. These findings agree with the hypothesis that a greater magnitude of changes in bone mineral density over time is associated with breast cancer in a cohort of middle-aged women. The findings also have implications for studies investigating dysregulated phosphate metabolism and phosphate toxicity as causative factors of bone metastasis in metastatic breast cancer. Additionally, the authors previously found increased breast cancer risk associated with high dietary phosphate intake in the same cohort of middle-aged women, and more studies should investigate a low-phosphorus diet to reduce bone mineral abnormalities and tumorigenesis in breast cancer patients. Full article

Osteochondral lesions, when not properly treated, may evolve into osteoarthritis (OA), especially in the elderly population, where altered joint function and quality are usual. To date, a collagen/collagen–magnesium–hydroxyapatite (Col/Col-Mg-HAp) scaffold (OC) has demonstrated good clinical results, although suboptimal subchondral bone regeneration still limits its efficacy. This study was aimed at evaluating the in vitro osteogenic potential of this scaffold, functionalized with two different strategies: the addition of Bone Morphogenetic Protein-2 (BMP-2) and the incorporation of strontium (Sr)-ion-enriched amorphous calcium phosphate (Sr-ACP) granules. Human osteoblasts were seeded on the functionalized scaffolds (OC+BMP-2 and OC+Sr-ACP, compared to OC) under stress conditions reproduced with the addition of H₂O₂ to the culture system, as well as in normal conditions, and evaluated in terms of morphology, metabolic activity, gene expression, and matrix synthesis. The OC+BMP-2 scaffold supported a better osteoblast morphology and stimulated scaffold colonization, cell activity, and extracellular matrix secretion, especially in the stressed culture environment but also in normal culture conditions, with increased expression of genes related to osteoblast differentiation. In conclusion, the incorporation of BMP-2 into the Col/Col-Mg-HAp scaffold also represents an improvement of the osteochondral scaffold in more challenging conditions, supporting further preclinical studies to optimize it for use in clinical practice. Full article

Endothelial-mesenchymal transition (EndMT) drives endothelium to contribute to atherosclerotic calcification. In a previous study, we showed that glycogen synthase kinase-3β (GSK3β) inhibition induced β-catenin and reduced mothers against DPP homolog 1 (SMAD1) in order to redirect osteoblast-like cells towards endothelial lineage, thereby reducing vascular calcification in Matrix Gla Protein (Mgp) deficiency and diabetic Ins2^Akita/wt mice. Here, we report that GSK3β inhibition or endothelial-specific deletion of GSK3β reduces atherosclerotic calcification. We also find that alterations in β-catenin and SMAD1 induced by GSK3β inhibition in the aortas of Apoe^−/− mice are similar to Mgp^−/− mice. Together, our results suggest that GSK3β inhibition reduces vascular calcification in atherosclerotic lesions through a similar mechanism to that in Mgp^−/− mice. Full article