1,721,170 research outputs found
Alterations of microenvironment in multiple myeloma patients: Interactions between myeloma cells and osteoprogenitor cells
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Role of bone density and biochemical markers of bone turn-over in the 'prediction' of bone loss and bone fracture
No full textSince risk factors for osteoporosis allow an estimation of the probability of future fractures, risk factors are said to have a 'predictive' ability for the occurrence of fractures. This terminology must be put in its proper probabilistic perspective. Risk factors for fracture predict the probability of fracture, but cannot identify individuals who will have a fracture. Nonetheless, even if a prediction does not come true in an individual patient, it will usually be borne out in many such cases. Therefore probabilities based on risk factors can guide clinical decision making. Bone density is considered the most important predictor of osteoporotic fragility fractures. Most measuring sites have virtually the same predictive ability for a decrease of 1 SD in bone density. However, measurement at the spine seems better for spine fractures, while measurement at hip appears better for predicting hip fracture. The role of ultrasonographic parameter of bone at calcaneous is promising, especially in elderly women, but needs to be further confirmed. Biochemical markers of bone turnover provide little value in the diagnosis of osteoporosis but some groups have shown in recent prospective studies that these indices may provide an estimate of fracture risk, independently of bone density, and that the combination of BMD measurements and biochemical markers might provide a better definition of the risk of fracture. The relationship between biochemical markers and rate of bone loss in early postmenopausal women is still controversial
Myeloma and osteoclast relationship
No full textMultiple myeloma (MM) is a plasma cell malignancy characterized by the high capacity to induce bone destruction. Osteolysis is the hallmark of bone lesions in MM patients due to a severe uncoupled and unbalanced bone remodeling with an increase of osteoclast (OC) formation and activity and the suppression of osteoblast formation and function. The biological mechanisms involved in MM-induced osteoclastogenesis have been elucidated in recent years, highlighting the critical role of the RANKL system. The activation of OCs by MM cells in turn stimulates MM cell survival and growth of MM cells. In vivo models also support the pro-survival critical role of OCs in MM patients. In this chapter we summarize the pathophysiological mechanisms involved in MM-induced activation of the OC formation and activity focusing on the reciprocal relationship between OCs and MM cells
The role of proteasome inhibitors in multiple myeloma bone disease and bone metastasis: Effects on osteoblasts and osteocytes
Full text linkThe alterations of bone remodeling are typical of multiple myeloma (MM) patients where the uncoupled and unbalanced bone remodeling caused the onset of osteolytic lesions. Moreover, bone metastasis occurs in the majority of patients with breast and prostate cancer. Skeletal-related events negatively impact on quality of life by increasing the vulnerability to fractures. Several bone-targeting treatments have been developed to control bone pain and pathological fractures, including bisphosphonates and Denosumab. Nevertheless, these agents act by inhibiting osteoclast activity but do not improve bone formation. Proteasome inhibitors (PIs) have shown bone anabolic effects and encouraging results in stimulating osteoblast differentiation and bone healing. Among these, the first-in-class bortezomib and the second-generation PIs, carfilzomib, and ixazomib regulate the bone remodeling process by controlling the degradation of several bone proteins. PIs have been recently proven to also be efficacious in blocking MM-induced osteocyte death providing new possible therapeutic use in the management of bone loss. PIs have significant side effects that limit their use as bone anabolic strategy. Multiple alternative approaches have been made. The conjugation of PIs with bisphosphonates, which can target them to bone, showed good results in terms of bone anabolic activity. However, the clinical implications of these effects require further investigations
Mechanistic insights into bone destruction in multiple myeloma: Cellular and molecular perspectives
No full textMultiple myeloma (MM) is a hematological malignancy that leads to significant bone destruction, resulting in debilitating pain and skeletal-related events. The pathophysiology of osteolytic bone destruction in MM involves complex interactions between malignant plasma cells (PCs) and the bone marrow (BM) microenvironment. This review aims to provide a comprehensive synthesis of the cellular and molecular pathways underlying MMassociated bone disease. We discuss the role of osteoclast (OC), osteoblast (OB), osteocytes, along with the complex interactions between immune cells and the BM microenvironment in shaping disease progression. Additionally, we explore the molecular signaling pathways involved in bone disease as well as the influence of inflammatory cytokines, and the role of the metabolic alterations that characterize the MM BM. We also explore novel therapeutic strategies targeting these pathways to improve clinical outcomes. Understanding these mechanisms is crucial for the development of more effective treatments to prevent bone damage in MM patients
Deciphering the bone marrow microenvironment’s role in multiple myeloma immunotherapy resistance
No full textMultiple Myeloma (MM) is a malignant monoclonal gammopathy characterized by the proliferation of plasma cells (PC) in the bone marrow (BM). The tight cross-talk between the BM microenvironment and PC is the hallmark of MM. The BM microenvironment comprises a cellular compartment, consisting of hematopoietic and non-hematopoietic cells. The first includes myeloid cells, T- and B-lymphocytes, natural killer (NK) cells, macrophages, and osteoclasts (OCs). In contrast, non-hematopoietic cell types include BM-derived mesenchymal stromal cells (MSCs), osteoblasts, adipocytes and endothelial cells. Besides the cellular compartment, there is a non-cellular compartment that includes extracellular matrix, growth factors, chemokines, and several cytokines. All these members play distinctive but interacting roles in the progression of MM and the drug response. MM remains an incurable disease, but in the last years immunotherapy has emerged as an important tool in the treatment of MM. The involvement of the BM microenvironment is a relevant barrier in the response to immunotherapy and in generating resistance. In this review, we provide an overview of the BM microenvironment perturbation in MM patients and how it can determine the possible resistance to immunotherapy, including monoclonal antibodies (mAbs), antibody-drug conjugates, chimeric antigen receptor T-cell (CAR-T), and bispecific T-cell engagers (BsAbs)
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