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Multiple myeloma frequently leads to bone complications characterized by the presence of lytic defects with high incidence of pathologic fractures, hypercalcemia and osteoporosis. The basic cause of this effect lies in the ability of malignant plasmatic cells to stimulate osteoclasts which are cells participating in the process of resorption of osseous tissue. Increased resorption of osseous matrix by means of osteoclasts activation runs concurrently with the process of decrease of activity of osteoblasts which are cells synthesizing osseous matrix of the bones. It has been a long time since the efforts to cope with consequences of unfavorable influence of myeloma cells on osseous tissue has been under way mainly by symptomatic means: local radiotherapy, surgical reconstruction of the bone, especially in cases of vertebral involvement, and anesthesia. Recently new weapon has been added to the arsenal for treatment of bone complications: bisphosphonates which are agents inhibiting the activity of osteoclasts and thus promoting the consolidation of the bones. Results of controlled clinical trials showed that such a medications as clodronate, pamidronate and zoledronate considerably decrease the incidence of bone complications in patients with multiple myelomas. Pamidronate and xoledronate turned out to be more active, at the same time long term usage of zoledronic acid can lead to development of such an adverse complication as osteonecrosis of jaw. The ASCO recommendations indicates the appropriateness of long term use of pamidronate or zoledronate in patients with multiple myelomas and bone complications.

The interplay between bone and glucose metabolism has highlighted hyperglycemia as a potential risk factor for bone diseases. With the increasing prevalence of diabetes mellitus worldwide and its subsequent socioeconomic burden, there is a pressing need to develop a better understanding of the molecular mechanisms involved in hyperglycemia-mediated bone metabolism. The mammalian target of rapamycin (mTOR) is a serine/threonine protein kinase that senses extracellular and intracellular signals to regulate numerous biological processes, including cell growth, proliferation, and differentiation. As mounting evidence suggests the involvement of mTOR in diabetic bone disease, we provide a comprehensive review of its effects on bone diseases associated with hyperglycemia. This review summarizes key findings from basic and clinical studies regarding mTOR's roles in regulating bone formation, bone resorption, inflammatory responses, and bone vascularity in hyperglycemia. It also provides valuable insights into future research directions aimed at developing mTOR-targeted therapies for combating diabetic bone diseases. [ABSTRACT FROM AUTHOR]

Abstract Background Bone complications (pathologic fracture, spinal cord compression, surgery to bone and radiation to bone) are a common problem in patients with multiple myeloma (MM). We set out to provide insights into the real-world burden of bone complications in patients with newly diagnosed MM (NDMM). Methods We conducted a retrospective review of medical charts of patients with NDMM whose disease had progressed following first-line treatment in the 3 months before data collection in 2016 in five European countries (France, Germany, Italy, Spain and the United Kingdom). Results The aggregated study population included 813 patients. Bone pain commonly led to MM diagnosis (63%) and 74% of all patients had two or more bone lesions at initiation of first-line treatment. Furthermore, 26% of patients experienced a new bone complication between MM diagnosis and disease progression following first-line treatment, despite 75% of individuals receiving bisphosphonates. Most bone complications (52%) occurred in the period before initiation of first-line treatment (mean duration: 2.3 months) and more than half of patients (56%) who experienced a new bone complication were hospitalised. Analgesics were used more frequently in patients with bone complications than in those without them (76% vs 50%, respectively). Furthermore, 51% of patients had renal impairment by the time first-line treatment was started. Overall, 25% of patients did not receive bisphosphonates for prevention of bone complications and one in four of those with renal impairment at initiation of first-line treatment did not receive bisphosphonates. Conclusions Bone complications are common in patients with NDMM. They are frequently associated with hospitalization and analgesic use. Data from this study, conducted in the era of novel anti-myeloma therapies and before the approval of denosumab for use in patients with MM, suggest that although most patients (75%) received bisphosphonates, use of anti-resorptive therapy for prevention of bone complications may be suboptimal in patients with NDMM, irrespective of renal function.

Background: Bone complications (pathologic fracture, spinal cord compression, surgery to bone and radiation to bone) are a common problem in patients with multiple myeloma (MM). We set out to provide insights into the real-world burden of bone complications in patients with newly diagnosed MM (NDMM).Methods: We conducted a retrospective review of medical charts of patients with NDMM whose disease had progressed following first-line treatment in the 3 months before data collection in 2016 in five European countries (France, Germany, Italy, Spain and the United Kingdom).Results: The aggregated study population included 813 patients. Bone pain commonly led to MM diagnosis (63%) and 74% of all patients had two or more bone lesions at initiation of first-line treatment. Furthermore, 26% of patients experienced a new bone complication between MM diagnosis and disease progression following first-line treatment, despite 75% of individuals receiving bisphosphonates. Most bone complications (52%) occurred in the period before initiation of first-line treatment (mean duration: 2.3 months) and more than half of patients (56%) who experienced a new bone complication were hospitalised. Analgesics were used more frequently in patients with bone complications than in those without them (76% vs 50%, respectively). Furthermore, 51% of patients had renal impairment by the time first-line treatment was started. Overall, 25% of patients did not receive bisphosphonates for prevention of bone complications and one in four of those with renal impairment at initiation of first-line treatment did not receive bisphosphonates.Conclusions: Bone complications are common in patients with NDMM. They are frequently associated with hospitalization and analgesic use. Data from this study, conducted in the era of novel anti-myeloma therapies and before the approval of denosumab for use in patients with MM, suggest that although most patients (75%) received bisphosphonates, use of anti-resorptive therapy for prevention of bone complications may be suboptimal in patients with NDMM, irrespective of renal function. [ABSTRACT FROM AUTHOR]

Prostate cancer (PC) is one of the most urgent problems of modern oncourology. Morbidity and mortality from this disease in theRussian Federationin recent years has been steadily increasing. Including the number of patients with metastatic and refractory to castration therapy forms of the disease is increasing. Currently, the main method of treatment of patients with metastatic prostate cancer is palliative hormone therapy (HT). Patients who have progression of tumor process, with lingering castration levels of testosterone, transferred to the stage of so-called castrate-resistant prostate cancer (CRPC). The prognosis in this group of patients is extremely unfavorable, not only because of the progression of cancer, but of complications associated primarily with the presence of bone metastases. Prevention of development of serious complications such as pathological fractures, spinal cord compression is an extremely important issue. The article presents a review of studies, the sanctifying of the problem of prevention of development of bone complications in patients with CRPC. We resent the results of large studies, including those conducted in our country demonstrated the effectiveness zoedronic acid in patients with CRPC and the presence of bone metastases.

A balanced diet is crucial for healthy development and prevention of musculoskeletal related diseases. Diets high in fat content are known to cause obesity, diabetes and a number of other disease states. Our group and others have previously reported that activity of the urea cycle enzyme arginase is involved in diabetes-induced dysregulation of vascular function due to decreases in nitric oxide formation. We hypothesized that diabetes may also elevate arginase activity in bone and bone marrow, which could lead to bone-related complications. To test this we determined the effects of diabetes on expression and activity of arginase, in bone and bone marrow stromal cells (BMSCs). We demonstrated that arginase 1 is abundantly present in the bone and BMSCs. We also demonstrated that arginase activity and expression in bone and bone marrow is up-regulated in models of diabetes induced by HFHS diet and streptozotocin (STZ). HFHS diet down-regulated expression of healthy bone metabolism markers (BMP2, COL-1, ALP, and RUNX2) and reduced bone mineral density, bone volume and trabecular thickness. However, treatment with an arginase inhibitor (ABH) prevented these bone-related complications of diabetes. In-vitro study of BMSCs showed that high glucose treatment increased arginase activity and decreased nitric oxide production. These effects were reversed by treatment with an arginase inhibitor (ABH). Our study provides evidence that deregulation of l -arginine metabolism plays a vital role in HFHS diet-induced diabetic complications and that these complications can be prevented by treatment with arginase inhibitors. The modulation of l -arginine metabolism in disease could offer a novel therapeutic approach for osteoporosis and other musculoskeletal related diseases. [ABSTRACT FROM AUTHOR]

Purpose: The aim of this study was to assess patients' preferences for efficacy, safety, and mode of administration in relation to available bone-targeted agents (BTA) for the prevention of skeletal-related events (SREs) associated with bone metastases in Europe. Methods: Adults in France ( n = 159), Germany ( n = 166), and the United Kingdom (UK; n = 159) with a self-reported physician diagnosis of bone metastases secondary to a solid tumour completed an online discrete- choice experiment survey of ten questions, choosing between pairs of hypothetical BTA profiles. Profiles were defined by five treatment attributes: delay of first SRE, delay of worsening of pain, annual risk of osteonecrosis of the jaw (ONJ), annual risk of renal impairment, and mode of administration. Profiles were generated using an experimental design with known statistical properties. A main-effects random parameters logit (RPL) model was applied to relate participants' choices to the characteristics of the BTA profiles. Results: The most important treatment attributes for patients across all three countries were time until first SRE, annual risk of renal complications and time until pain worsening. For these attributes, better levels of outcomes were significantly preferred to worse levels ( p < 0.05). A 120-minutes infusion every 4 weeks was the least preferred mode of administration. Risk of ONJ was judged by patients in the UK and Germany to be the least important attribute. Conclusions: Patients consider delaying SREs, avoiding renal impairment and delaying pain worsening as the most important goals to consider when selecting treatment to prevent the bone complications commonly associated with bone metastases. [ABSTRACT FROM AUTHOR]

Summary: This is the first study examining the impact of both clinical, biochemical, and genetic determinants in the occurrence of bone complications in patients with overt Cushing's syndrome (CS). It demonstrates that the degree and duration of hypercortisolism seem to play a major role in bone loss and fractures development in these patients. Introduction: Bone loss and fractures are a common complication of CS. We investigate the role of gender, disease etiology, duration, and degree of hypercortisolism as well as the impact of glucocorticoid receptor (GR) polymorphisms on the development of bone complications in CS. Methods: Fifty-two patients with active CS (38 Cushing's disease and 14 with cortisol-secreting adrenal adenoma) were genotyped for GR polymorphisms (BclI, N363S, ER22/23EK, and A3669G). In all patients, clinical, hormonal, and biochemical markers of bone turnover, densitometric parameters [lumbar spine and left femur bone mineral density (BMD), T-score, Z-score] as well as the prevalence of bone demineralization and both vertebral and peripheral fractures were assessed. Results: No differences were found in bone complications according to gender, disease etiology, and genetic variants distribution. Fractured patients compared to non-fractured ones showed increased levels of urinary free cortisol (UFC) and a more compromised densitometric profile. UFC levels correlated with the occurrence of vertebral fractures ( r = 0.43, p = 0.009) while midnight serum cortisol correlated with L1-L4 BMD values ( r = −0.35, p = 0.04). Disease duration correlated with the presence of peripheral fractures ( r = 0.36, p = 0.04). Conclusions: While GR gene variants as well as gender and disease etiology seem not to play a role, the degree and duration of hypercortisolism seem to be the major determinants of bone loss and fractures in this group of patients. More investigations are needed to understand the real impact of these determinants on the development of bone complications in patients with hypercortisolism. [ABSTRACT FROM AUTHOR]

The authors discuss the prevention of bone complications in prostate cancer which cause patients to be at risk for skeletal morbidities as pathologic fracture, compression of spinal cord, and pain. They focus on options to manage complications which include lifestyle modifications, selective estrogen-receptor modulators, and osteoclast-targeted therapy using bisphosphonates and denosumab. The authors also provide information on the pathophysiology of bone complications.

Abstract: Objective: Bone impairment is a well-known complication in childhood acute lymphoblastic leukemia (ALL) survivors but less is known about bone dynamics during ALL therapy. We longitudinally assessed by Quantitative Ultrasound (QUS) skeletal modifications during this treatment. Materials and methods: Forty-four newly diagnosed ALL children underwent bone measurement by QUS parameters BTT (Bone Transmission Time) and AD-SoS (Amplitude-Dependent Speed of Sound), mainly reliant on bone density and cortical thickness, respectively. Measurements were performed at diagnosis, and 6, 12, and 24 months thereafter. The occurrence of skeletal complications such as fractures, vertebral collapse, osteonecrosis, and osteopenia was related to measurement outcome. Results: A rapid deterioration of bone properties measured by BTT and AD-SoS was evident in the first semester of therapy (p <0.001). Subsequently, the next measurements were characterized by progressive uncoupling of the two QUS parameters (p <0.001). These were both significantly reduced at the end of therapy (p <0.001). Twelve subjects with in-treatment skeletal complications displayed an almost two-fold decrease of both parameters (p <0.001). BTT decreasing more than 1 Standard Deviation (SD) over 6 months of therapy was able to predict skeletal complication occurrence (p <0.001). Conclusion: This report represents the largest longitudinal cohort systematically submitted to bone condition assessment from the beginning to the end of therapy for childhood ALL. Bone deterioration occurs early and persists throughout therapy, consistent with bone properties uncoupling. This pattern possibly reflects an initial impairment of both mineral density and cortical thickness with a subsequent recovery of this latter. QUS permits an early detection of bone deterioration and related skeletal complications in childhood ALL. [Copyright &y& Elsevier]

Abstract: Gaucher''s disease was first described by Philippe Gaucher in 1882, who recognized that this was a systemic disease. The biochemical defect, genetic basis and molecular epidemiology have subsequently been characterized. Gaucher''s disease arises as a result of a deficiency of glucocerebrosidase and is the commonest of the lysosomal storage disorders. The overall incidence is approximately 1:40,000 individuals, but it is much commoner amongst individuals of Ashkenazi Jewish origin. A small number of genotypes are characteristically encountered amongst this population and the commonest of these (N370S) encodes an enzyme that has sufficient residual enzyme activity to ensure that significant neurologic disease does not occur. The main clinical features of adult Gaucher''s disease are organ enlargement (liver and spleen), bone marrow infiltration leading to anaemia, thrombocytopenia and leucopenia, and skeletal involvement leading to bone pain and pathological fracture. There is also an association with Parkinson''s disease, cancer and lymphoproliferative disease, illustrating that Gaucher''s disease is a multi-system disorder with manifestations in most organ systems. The underlying pathophysiology is imperfectly understood, but it is increasingly clear that inflammation mediated by cytokines is responsible for a significant part of the pathology. [Copyright &y& Elsevier]