The use of bisphosphonates in multiple myeloma: recommendations of an expert panel on behalf of the European Myeloma Network

Terpos, Evangelos; Sezer, Orhan; Croucher, Peter I.; García‐Sanz, Ramón; Boccadoro, Mario; Miguel, Jesús F. San; Ashcroft, John; Bladé, Joan; Cavo, Michèle; Delforge, Michel; Dimopoulos, Meletios Α.; Façon, Thierry; Macro, Margaret; Waage, Anders; Sonneveld, Pieter

doi:10.1093/annonc/mdn796

Cited by 207 publications

(154 citation statements)

References 170 publications

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“…In this sense, it is important to note that the bisphosphonates, which are widely used to treat MM bone disease, 54,55 can block osteocyte apoptosis in vitro and in vivo in mouse models. 30,56 Although the difference in osteocyte viability between MM patients who had or had not previously received bisphosphonates did not reach a statistical significance, the possibility that they may have a positive effect on osteocyte viability cannot be excluded and it should be explored in future studies.…”

Section: Discussionmentioning

confidence: 99%

Increased osteocyte death in multiple myeloma patients: role in myeloma-induced osteoclast formation

et al. 2012

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The involvement of osteocytes in multiple myeloma (MM)-induced osteoclast (OCL) formation and bone lesions is still unknown. Osteocytes regulate bone remodelling at least partially, as a result of their cell death triggering OCL recruitment. In this study, we found that the number of viable osteocytes was significantly smaller in MM patients than in healthy controls, and negatively correlated with the number of OCLs. Moreover, the MM patients with bone lesions had a significantly smaller number of viable osteocytes than those without, partly because of increased apoptosis. These findings were further confirmed by ultrastructural in vitro analyses of human preosteocyte cells cocultured with MM cells, which showed that MM cells increased preosteocyte death and apoptosis. A micro-array analysis showed that MM cells affect the transcriptional profiles of preosteocytes by upregulating the production of osteoclastogenic cytokines such as interleukin (IL)-11, and increasing their pro-osteoclastogenic properties. Finally, the osteocyte expression of IL-11 was higher in the MM patients with than in those without bone lesions. Our data suggest that MM patients are characterized by a reduced number of viable osteocytes related to the presence of bone lesions, and that this is involved in MM-induced OCL formation.Leukemia ( Keywords: multiple myeloma; osteocytes; bone disease; osteoclasts INTRODUCTIONThe presence of osteolytic bone lesions or osteoporosis is the hallmark of multiple myeloma (MM), and leads to bone fragility and fractures in MM patients. The bone lesions are characterized by severely unbalanced and uncoupled bone remodelling in the area of plasma cell infiltration due to increased osteoclast (OCL) formation and activity, and osteoblast (OB) suppression. 1 --3 Local factors produced by MM cells and the bone marrow microenvironment are involved in the MM-induced increase in osteoclastogenesis, and include an imbalance in the receptor activator of nuclear factor kappa-B ligand (RANKL)/osteoprotegerin (OPG) ratio that favours RANKL, 2,4 and the MM cell production of osteoclastogenic factors such as Chemokine (C --C motif) ligand 3 (CCL3)/macrophage inflammatory proteins (MIP)-1a. 5 --7 OB exhaustion is mainly due to a reduction in OB differentiation and formation, from mesenchymal stem cells and OB progenitors, that is induced by MM cells as a result of cell-to-cell contacts and the release of soluble factors. 3,8 --11 Osteocytes are differentiated cells of osteogenic lineage 12 located in the lacuno-canalicular system of the bone (see the review by Bonewald). 13 There is increasing evidence that they regulate physiological local bone remodelling, 13 --16 partly as a result of the cell death and apoptosis that triggers OCL formation and bone resorption, 15 --19 and partly by secreting sclerostin, a molecule that is specifically produced by osteocytes that inhibits bone formation. 20,21 Interestingly, an apoptosis-related reduction in osteocyte viability has recently been demonstrated in

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Section: Discussionmentioning

confidence: 99%

Increased osteocyte death in multiple myeloma patients: role in myeloma-induced osteoclast formation

et al. 2012

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“…88 Therapy with bisphosphonates should last approximately 2 years to limit the risk of osteonecrosis of the jaw. 89 Bone pain can be managed both pharmacologically and with local, fractioned radiotherapy. Analgesia should be firstly provided with non-opiod drugs (avoiding nonsteroidal antiinflammatory drugs); if pain persists, opiod drugs should be used.…”

Section: Bone Diseasementioning

confidence: 99%

Management of older adults with multiple myeloma

Palumbo¹,

Mina²

2013

Blood Reviews

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Two-thirds of patients with multiple myeloma are aged 65 years or more and the prevalence of multiple myeloma in elderly patients is expected to rise in the next future. Patients older than 65 years are usually considered ineligible for transplantation. The introduction of novel agents, such as the immunomodulatory drugs thalidomide and lenalidomide and the proteasome inhibitor bortezomib, combined with conventional chemotherapy, has radically changed the treatment paradigm of elderly patients and improved outcome. A sequential approach, consisting of an induction regimen associated with a high rate of complete response, followed by consolidation/maintenance therapy, induces a profound cytoreduction and delays relapse, thus improving survival. Novel agents associated with reduced-intensity autologous transplant showed to be safe and effective in fit elderly patients. Patients older than 75 years or vulnerable ones are more susceptible to adverse events that negatively affect treatment adherence and outcome. In this setting, less toxic regimens and appropriate dose reductions should be adopted. Here we provide an overview of novel agent-based treatment strategies for elderly patients with multiple myeloma.

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“…Bisphosphonates such as zoledronic acid (zol), clodronate, and pamidronate inhibit osteoclast-mediated osteolysis and, by minimizing skeletal complications, provide significant benefit to patients with bone metastases from solid tumours or bone lesions from multiple myeloma 6,7 . Current clinical guidelines for the treatment of multiple myeloma recommend bisphosphonate therapy for all patients regardless of…”

Section: Introductionmentioning

confidence: 99%

Randomized Clinical Trial of Zoledronic Acid in Multiple Myeloma Patients Undergoing High-Dose Chemotherapy and Stem-Cell Transplantation

et al. 2013

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The use of bisphosphonates in multiple myeloma: recommendations of an expert panel on behalf of the European Myeloma Network

Abstract: BPs are an essential component of MM therapy for minimizing skeletal morbidity. Recent retrospective data indicate that a modified dosing regimen and preventive measures can greatly reduce the incidence of ONJ.

Cited by 207 publications

References 170 publications

Increased osteocyte death in multiple myeloma patients: role in myeloma-induced osteoclast formation

Increased osteocyte death in multiple myeloma patients: role in myeloma-induced osteoclast formation

Management of older adults with multiple myeloma

Randomized Clinical Trial of Zoledronic Acid in Multiple Myeloma Patients Undergoing High-Dose Chemotherapy and Stem-Cell Transplantation

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