Bisphosphonates in multiple myeloma: an updated network meta-analysis

Mhaskar, Rahul; Kumar, Amit; Miladinović, Branko; Djulbegoviĉ, Benjamin

doi:10.1002/14651858.cd003188.pub4

Cited by 104 publications

(112 citation statements)

References 172 publications

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“…The effect of a common bisphosphonate, zoledronic acid, was evaluated in the localized 5GTM1 model. Bisphosphonate treatment is commonly used in the clinic to improve bone quality and decrease skeletal‐related events in myeloma patients, and systematic literature reviews have shown that it ameliorates pain However, the quality of the pain data has recently been questioned because of the different read‐outs used in different trials and the lack of clinically significant analgesic effect in double‐blinded clinical trials . In the localized 5TGM1 model, systemic treatment with zoledronic acid protected the myeloma‐bearing bones from developing osteolytic lesions.…”

Section: Discussionmentioning

confidence: 99%

“…Bisphosphonate treatment is commonly used in the clinic to improve bone quality and decrease skeletal-related events in myeloma patients, and systematic literature reviews have shown that it ameliorates pain (48,49) However, the quality of the pain data has recently been questioned because of the different read-outs used in different trials and the lack of clinically significant analgesic effect in double-blinded clinical trials. (50) In the localized 5TGM1 model, systemic treatment with zoledronic acid protected the myelomabearing bones from developing osteolytic lesions. Bisphosphonate treatment also led to increased survival and partly ameliorated the pain-like behavior over time, suggesting that osteolytic bone lesions may play a role in pain development, but not be entirely responsible for it.…”

Section: Discussionmentioning

confidence: 99%

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Differential Pain‐Related Behaviors and Bone Disease in Immunocompetent Mouse Models of Myeloma

et al. 2019

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Bone pain is a serious and debilitating symptom of multiple myeloma (MM) that impairs the quality of life of patients. The underlying mechanisms of the pain are unknown and understudied, and there is a need for immunocompetent preclinical models of myeloma‐induced bone pain. The aim of this study was to provide the first in‐depth behavioral characterization of an immunocompetent mouse model of MM presenting the clinical disease features: osteolytic bone disease and bone pain. We hypothesized that a widely used syngeneic model of MM, established by systemic inoculation of green fluorescent protein‐tagged myeloma cells (5TGM1‐GFP) in immunocompetent C57Bl/KaLwRijHsd (BKAL) mice, would present pain‐related behaviors. Disease phenotype was confirmed by splenomegaly, high serum paraprotein, and tumor infiltration in the bone marrow of the hind limbs; however, myeloma‐bearing mice did not present pain‐related behaviors or substantial bone disease. Thus, we investigated an alternative model in which 5TGM1‐GFP cells were directly inoculated into the intrafemoral medullary cavity. This localized myeloma model presented the hallmarks of the disease, including high serum paraprotein, tumor growth, and osteolytic bone lesions. Compared with control mice, myeloma‐bearing mice presented myeloma‐induced pain‐related behaviors, a phenotype that was reversed by systemic morphine treatment. Micro‐computed tomography analyses of the myeloma‐inoculated femurs showed bone disease in cortical and trabecular bone. Repeated systemic bisphosphonate treatment induced an amelioration of the nociceptive phenotype, but did not completely reverse it. Furthermore, intrafemorally injected mice presented a profound denervation of the myeloma‐bearing bones, a previously unknown feature of the disease. This study reports the intrafemoral inoculation of 5TGM1‐GFP cells as a robust immunocompetent model of myeloma‐induced bone pain, with consistent bone loss. Moreover, the data suggest that myeloma‐induced bone pain is caused by a combinatorial mechanism including osteolysis and bone marrow denervation. © 2019 The Authors. JBMR Plus published by Wiley Periodicals, Inc. on behalf of American Society for Bone and Mineral Research.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Differential Pain‐Related Behaviors and Bone Disease in Immunocompetent Mouse Models of Myeloma

et al. 2019

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“…multiple myeloma or breast cancer) and often in conjunction with other anti‐cancer agents such as anti‐angiogenesis agents and/or systemic glucocorticoids. In multiple myeloma, a meta‐analysis of 24 studies found that about 1 in 1000 patients in bisphosphonate myeloma studies developed ONJ . Though the incidence rates of ONJ in the dosing regimens used for osteoporosis has varied substantially between different observational studies, it has generally been found to be tenfold lower than for the cancer regimes .…”

Section: Antiresorptivesmentioning

confidence: 99%

Side effects of drugs for osteoporosis and metastatic bone disease

Skjødt

Frost

Abrahamsen

2018

Brit J Clinical Pharma

100

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Osteoporosis is a common condition that leads to substantial morbidity and mortality and affects an increasing number of persons worldwide. Several pharmacological therapies that inhibit bone resorption, promote bone formation, or both, are available for the treatment of osteoporosis. The osteoanabolic treatment spectrum was recently expanded by the introduction of a novel bone-forming agent in the United States, and clinical trials indicate that a new class of bone anabolic therapy may become available. Both antiresorptive and bone anabolic therapies are associated with common and rare adverse effects, which are particularly important to address as these drugs are used for long-term treatment in numerous patients with a large proportion being elderly and/or having multimorbidity. In addition, antiresorptive drugs are used to inhibit bone resorption in patients with malignant hypercalcaemia or to prevent skeletal events in cancer patients, and bisphosphonates have been repurposed as a cancer preventive therapy. However, therapeutic doses are generally higher when antiresorptive drugs are used in the oncological setting, which influence the prevalence of adverse effects significantly. This review highlights key issues and controversies regarding adverse effects of currently available and emerging drugs used for osteoporosis and metastatic bone diseases.

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“…34,35 In addition to this, bisphosphonates that are a well-established part of the treatment of MM patients, are known to reduce pathological vertebral fractures, skeletal-related events and pain. 36 Moreover, zoledronic acid, that was approved for MM in the latter calendar period of the study has shown a positive effect on overall survival. 13 In 2010, Swedish national guidelines recommended treatment with bisphosphonates from the time of MM diagnosis for all MM patients, irrespective of the presence of bone disease, and in the years 2008 to 2015, over 70% of MM patients received bisphosphonates as a part of their management.…”

Section: Our Analyses On Different Subgroups Of Fractures In MM Patiementioning

confidence: 97%

Fractures and survival in multiple myeloma: results from a population-based study

et al. 2019

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Multiple myeloma causes lytic bone lesions and fractures. The impact of fractures on multiple myeloma survival is unclear. The aim of this study was to evaluate the effect of fractures on survival in multiple myeloma using data from multiple myeloma patients diagnosed in Sweden in the years 1990-2013, identified from the Swedish Cancer Registry. Information on date of birth, multiple myeloma diagnosis, fractures, and death was collected from central registries.A Cox regression model was used to compare survival in patients with and without a fracture at multiple myeloma diagnosis and another Cox model was used with fracture as a timedependent variable to assess the effect of fracture on survival after multiple myeloma diagnosis. Results were adjusted for age, sex, year of diagnosis, and previous fractures. A total of 14,013 patients were diagnosed with multiple myeloma during the study, thereof 1,213 (8.7%) were diagnosed with a fracture at multiple myeloma diagnosis, and 3,235 (23.1%) after diagnosis. Patients with a fracture at diagnosis were at a significantly increased risk of death (hazard ratio=1.28; 95% confidence interval: 1.19-1.37). The risk of death was significantly increased in patients with a fracture after multiple myeloma diagnosis (2.00; 1.90-2.10). The impact of fractures on survival did not change significantly between the two calendar periods 1990-1999 and 2000-2013 (0.98; 0.89-1.08). Our large study shows that multiple myeloma patients with fractures are at a significantly increased risk of dying compared to those without fractures which stresses the importance of preventing bone disease in multiple myeloma.

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Bisphosphonates in multiple myeloma: an updated network meta-analysis

Abstract: Bisphosphonates in multiple myeloma: an updated network meta-analysis (Review)

Cited by 104 publications

References 172 publications

Differential Pain‐Related Behaviors and Bone Disease in Immunocompetent Mouse Models of Myeloma

Differential Pain‐Related Behaviors and Bone Disease in Immunocompetent Mouse Models of Myeloma

Side effects of drugs for osteoporosis and metastatic bone disease

Fractures and survival in multiple myeloma: results from a population-based study

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