The Immobilized Patient: Functional Pathology and Management (Topics in bone and mineral disorders)

Notes Includes bibliographical references and index. View online Borrow Buy Freely available Show 0 more links Set up My libraries How do I set up "My libraries"? These 7 locations in All: Open to the public ; Flinders University Central Library. The University of Melbourne Library. University of Sydney Library. Open to the public. This single location in Australian Capital Territory: Open to the public Book; Illustrated English Show 0 more libraries This single location in New South Wales: This single location in Queensland: This single location in South Australia: This single location in Tasmania: This single location in Victoria: This single location in Western Australia: None of your libraries hold this item.

Found at these bookshops Searching - please wait We were unable to find this edition in any bookshop we are able to search. These online bookshops told us they have this item: Other suppliers National Library of Australia - Copies Direct The National Library may be able to supply you with a photocopy or electronic copy of all or part of this item, for a fee, depending on copyright restrictions. Tags What are tags? Denosumab, a human monoclonal antibody that binds to RANKL with high affinity and specificity, was approved by the FDA for prevention of SREs in patients with bone metastases from solid tumors in , and is currently under investigation for use in MM bone disease.

A recent clinical trial has demonstrated that denosumab inhibits bone resorption and prevents SREs in patients refractory to bisphosphonate therapy [] , []. Recent reports have demonstrated that denosumab treatment prevents bone loss and decreases fractures in patients with osteoporosis or receiving androgen deprivation therapy for prostate cancer [] , [] while also resulting in a statistically significant improvement in bone mineral density in patients with nonmetastatic prostate or breast cancer [] , [].

Efficacy advantages for denosumab over zoledronic acid in myeloma have not yet been demonstrated, though myeloma patients were included in a separate clinical trial evaluating the efficacy of denosumab in approximately patients with solid tumor bone metastasis and patients with myeloma.

In this study denosumab reduced skeletal related events and time to next skeletal related event as effectively as zoledronic acid []. In clinical trials thus far, denosumab has been well tolerated. Hypocalcemia occurs more frequently in denosumab-treated patients compared with patients treated with zoledronic acid, with an incidence ranging from 5. Reported rates of ONJ in patients treated with denosumab are similar to those for patients treated with zoledronic acid 1.

Bortezomib is a highly active agent for the treatment of MM. Clinical trials with bortezomib indicate that it may also increase OBL activity, induce new bone formation, and potentially repair lytic bone lesions. Bone marrow samples of patients responding to bortezomib had a significantly increased number of osteoblastic cells compared to non-responders.

These studies suggest that bortezomib can stimulate OBL in patients whose MM responded to bortezomib []. In all three trials, patients who had a partial response to bortezomib therapy had a transient increase in alkaline phosphatase level compared to non-responders. When compared to patients who responded to dexamethasone treatment, the bortezomib-treated group had higher serum levels of alkaline phosphatase than dexamethasone responders, suggesting that the increase in alkaline phosphatase was not merely a result of reduced tumor burden.

More recently, a prospective study of bortezomib-associated bone changes [] has been reported. Patients achieving stable disease were continued on the regimen and followed until evidence of disease progression. Histologic evaluation demonstrated a lack of OBL activity and osteoid formation at baseline compared to bortezomib treatment in patients who responded to therapy.

Alternatively, bortezomib's direct inhibition of myeloma cells in the bone marrow microenvironment might allow for normalization of OBL and OCL function, as these effects are only seen in patients whose disease is bortezomib responsive. IMiDs are highly active agents in the treatment of MM []. CC down-regulated the expression of PU. The down-regulation of PU. This inhibited OCL formation with a concomitant accumulation of immature granulocytes. Similarly, Breitkreutz et al. Parathyroid hormone has been tested in preclinical models for its capacity to repair bone lesions or inhibit bone destruction in patients with myeloma.

Yaccoby and coworkers have shown that PTH can stimulate bone formation in the SCID-RAB model of multiple myeloma [] , both in the implanted bone rudiment and normal mouse bones in this model, and resulted in decreased tumor burden.

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Teriparatide, recombinant PTH, decreases the risk of vertebral and non-vertebral fractures in post menopausal women with a history of vertebral fractures [] , however no clinical trials have been reported that show that PTH is an effective treatment for myeloma bone disease. Although there has been a concern that PTH may stimulate tumor growth in patients with myeloma, to date PTH receptors have not been detected on myeloma cells.

Another novel anabolic agent that is in clinical trial for patients with myeloma is sotatercept ACE, Acceleron Pharm. Sotatercept is a chimeric fusion protein derived from the extracellular component of the activin A receptor and the Fc domain of human IgG1 that functions as an activin receptor inhibitor, thus blocking osteoblast suppression and osteoclast stimulation by activin. Raje and coworkers reported that activin levels are increased in patients with myeloma, and that OCL and OBL are the primary source of activin in these patients []. They further showed that blocking activin inhibits bone destruction in preclinical models of myeloma.

A clinical trial of the bone anabolic effects of sotatercept in MM patients with osteolytic lesions is in process.

Myeloma bone disease is responsible for some of the most devastating complications of the disease. Patients endure severe bone pain, pathologic fractures, hypercalcemia, and a markedly decreased quality of life. Understanding the pathogenesis of myeloma bone disease has allowed us to identify novel targets for treating the disease.

An important feature of myeloma bone disease is that the lytic lesions do not heal even when the patients are in prolonged remission, suggesting that bone repair does not occur at previous sites of bone destruction in patients with myeloma. The development of anabolic agents, which are safe for use in patients with myeloma, may reverse this process and reverse the loss of skeletal integrity in patients with myeloma. With the enhanced median survival in patients with myeloma that has occurred since the introduction of new therapies for treatment of myeloma, managing the bone disease and its complications will be evermore important for myeloma patients.

Thus, the future should be bright for patients with myeloma with new agents to block bone destruction as well as potentially build bone at sites of previous bone destruction. GDR is a consultant to Amgen and develops and presents continuing medical education material for Clinical Care Options. RS presents continuing medical education material for Clinical Care Options.

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1. Introduction

Journal List J Bone Oncol v. Published online Apr Author information Article notes Copyright and License information Disclaimer. This article has been cited by other articles in PMC. Abstract Multiple myeloma bone disease is marked by severe dysfunction of both bone formation and resorption and serves as a model for understanding the regulation of osteoblasts OBL and osteoclasts OCL in cancer. Open in a separate window. Pathogenesis of the increased osteoclast activity in myeloma Histologic studies of bone biopsies from patients with MM demonstrate that increased OCL activity occurs adjacent to MM cells, suggesting that bone destruction in MM is a local event.

Osteoblast suppression in myeloma OBL activity is suppressed in MM, with decreased bone formation and calcification despite increased bone resorption [17] , [89]. Treatment of myeloma bone disease Treatment of myeloma bone disease requires management of both the underlying malignancy and the increased bone destruction and suppressed new bone formation detailed above. Denosumab Denosumab, a human monoclonal antibody that binds to RANKL with high affinity and specificity, was approved by the FDA for prevention of SREs in patients with bone metastases from solid tumors in , and is currently under investigation for use in MM bone disease.

Bortezomib Bortezomib is a highly active agent for the treatment of MM. Other anabolic agents for myeloma Parathyroid hormone has been tested in preclinical models for its capacity to repair bone lesions or inhibit bone destruction in patients with myeloma. Conclusions Myeloma bone disease is responsible for some of the most devastating complications of the disease.

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Manipulating bone disease in inflammatory bowel disease patients

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Osteoclast-derived matrix metalloproteinase-9 directly affects angiogenesis in the prostate tumor-bone microenvironment.

Osteoclasts are important for bone angiogenesis. The hypoxia-inducible factor alpha pathway couples angiogenesis to osteogenesis during skeletal development. Journal of Clinical Investigation. Proteolysis of latent transforming growth factor-beta TGF-beta -binding protein-1 by osteoclasts. A cellular mechanism for release of TGF-beta from bone matrix. Journal of Biological Chemistry. Observations on the mechanism of bone resorption induced by multiple myeloma marrow culture fluids and partially purified osteoclast-activating factor.

The Journal of Clinical Investigation. A crosstalk between myeloma cells and marrow stromal cells stimulates production of DKK1 and interleukin New insight in the mechanism of osteoclast activation and formation in multiple myeloma: Macrophage inflammatory protein 1-alpha is a potential osteoclast stimulatory factor in multiple myeloma. IL-3 expression by myeloma cells increases both osteoclast formation and growth of myeloma cells.

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Osteoclasts enhance myeloma cell growth and survival via cell—cell contact: Fibroblast activation protein FAP is upregulated in myelomatous bone and supports myeloma cell survival. Tumor necrosis factor receptor family member RANK mediates osteoclast differentiation and activation induced by osteoprotegerin ligand.

RANK is the essential signaling receptor for osteoclast differentiation factor in osteoclastogenesis. Biochemical and Biophysical Research Communications. Osteoclast differentiation and activation. Osteoprotegerin and its cognate ligand: European Journal of Endocrinology.

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Myeloma bone disease: Pathophysiology and management

Critical Reviews in Eukaryotic Gene Expression. Soluble receptor activator of nuclear factor kappaB ligand—osteoprotegerin ratio predicts survival in multiple myeloma: Myeloma interacts with the bone marrow microenvironment to induce osteoclastogenesis and is dependent on osteoclast activity. Osteoprotegerin inhibits the development of osteolytic bone disease in multiple myeloma.

Stem Cells and Development. The role of the bone microenvironment in the pathophysiology and therapeutic management of multiple myeloma: European Journal of Cancer. Production of interleukin 1 beta, a potent bone resorbing cytokine, by cultured human myeloma cells. TNF-alpha induces osteoclastogenesis by direct stimulation of macrophages exposed to permissive levels of RANK ligand.

Osteoblast function in myeloma.

A novel role for CCL3 MIP-1alpha in myeloma-induced bone disease via osteocalcin downregulation and inhibition of osteoblast function. Role for macrophage inflammatory protein MIP -1alpha and MIP-1beta in the development of osteolytic lesions in multiple myeloma. Antisense inhibition of macrophage inflammatory protein 1-alpha blocks bone destruction in a model of myeloma bone disease. Dual effects of macrophage inflammatory protein-1alpha on osteolysis and tumor burden in the murine 5TGM1 model of myeloma bone disease.

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Macrophage inflammatory protein-1alpha is an osteoclastogenic factor in myeloma that is independent of receptor activator of nuclear factor kappaB ligand. Macrophage inflammatory protein 1-alpha MIP-1 alpha triggers migration and signaling cascades mediating survival and proliferation in multiple myeloma MM cells.

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Activin A promotes multiple myeloma-induced osteolysis and is a promising target for myeloma bone disease. Elevated levels of circulating activin-A correlate with features of advanced disease, extensive bone involvement and inferior survival in patients with multiple myeloma. IL-3 is a potential inhibitor of osteoblast differentiation in multiple myeloma. Inhibiting activin-A signaling stimulates bone formation and prevents cancer-induced bone destruction in vivo. Journal of bone and mineral research: A molecular compendium of genes expressed in multiple myeloma.

Overexpression of Annexin II affects the proliferation, apoptosis, invasion and production of proangiogenic factors in multiple myeloma. International Journal of Hematology. Bidirectional ephrinB2-EphB4 signaling controls bone homeostasis. Normalizing the bone marrow microenvironment with p38 inhibitor reduces multiple myeloma cell proliferation and adhesion and suppresses osteoclast formation.

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Wnt signalling in osteoblasts regulates expression of the receptor activator of NFkappaB ligand and inhibits osteoclastogenesis in vitro. Journal of Cell Science. Sclerostin is overexpressed by plasma cells from multiple myeloma patients. Annals of the New York Academy of Sciences. Elevated circulating sclerostin correlates with advanced disease features and abnormal bone remodeling in symptomatic myeloma: Increased osteocyte death in multiple myeloma patients: Tgf-Beta inhibition restores terminal osteoblast differentiation to suppress myeloma growth.

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