The Role of Bisphosphonates in Multiple Myeloma: Mechanisms, Side Effects, and the Future

Pozzi, Samantha; Raje, Noopur

doi:10.1634/theoncologist.2010-0225

Cited by 72 publications

(65 citation statements)

References 144 publications

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“…13,14 This is partially explained by functional and gene expression differences between MM-MSCs and normal donor (ND)-MSCs. 8,[15][16][17][18] However, mechanisms governing ineffectual MM-MSC osteogenesis remain unclear, and the roles of microRNAs (miRs) in this process are unknown.…”

Section: Introductionmentioning

confidence: 99%

Investigating osteogenic differentiation in multiple myeloma using a novel 3D bone marrow niche model

Reagan

Mishima

Glavey

et al. 2014

Blood

115

134

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Key Points• 3D bone marrow niche model recapitulates in vivo interactions of tumor and bone cells in a more biologically relevant system than in 2D.• Differential expression levels of miRs in MSCs provide novel insights into mechanisms of regulation of osteoblasts in multiple myeloma.Clonal proliferation of plasma cells within the bone marrow (BM) affects local cells, such as mesenchymal stromal cells (MSCs), leading to osteolysis and fatality in multiple myeloma (MM). Consequently, there is an urgent need to find better mechanisms of inhibiting myeloma growth and osteolytic lesion development. To meet this need and accelerate clinical translation, better models of myeloma within the BM are required.Herein we have developed a clinically relevant, three-dimensional (3D) myeloma BM coculture model that mimics bone cell/cancer cell interactions within the bone microenvironment. The coculture model and clinical samples were used to investigate myeloma growth, osteogenesis inhibition, and myeloma-induced abnormalities in MM-MSCs. This platform demonstrated myeloma support of capillarylike assembly of endothelial cells and cell adhesion-mediated drug resistance (CAM-DR). Also, distinct normal donor (ND)-and MM-MSC miRNA (miR) signatures were identified and used to uncover osteogenic miRs of interest for osteoblast differentiation. More broadly, our 3D platform provides a simple, clinically relevant tool to model cancer growth within the bone-useful for investigating skeletal cancer biology, screening compounds, and exploring osteogenesis. Our identification and efficacy validation of novel bone anabolic miRs in MM opens more opportunities for novel approaches to cancer therapy via stromal miR modulation. (Blood. 2014;124(22):3250-3259)

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Section: Introductionmentioning

confidence: 99%

Investigating osteogenic differentiation in multiple myeloma using a novel 3D bone marrow niche model

Reagan

Mishima

Glavey

et al. 2014

Blood

115

134

View full text Add to dashboard Cite

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“…For multiple myeloma, most recent consensus guidelines recommend monthly aBP treatment for a period of 2 years (3,4). However, it is unknown whether monthly dosing of aBPs is optimal, as there are consequences of long-term aBP therapy, such as osteonecrosis of the jaw (ONJ) and atypical stress fractures (3)(4)(5)(6)(7)(8)(9). Bisphosphonate-related ONJ is characterized by bone that is necrotic and exposed, located in the maxillofacial area, and present for at least 8 weeks in a patient with history of bisphosphonate treatment, but no history of prior radiation to that area (10).…”

Section: Introductionmentioning

confidence: 99%

Biomarkers of Bone Remodeling in Multiple Myeloma Patients to Tailor Bisphosphonate Therapy

Patel

Yee

Scullen

et al. 2014

Clinical Cancer Research

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Background: Patients with multiple myeloma may be susceptible to osteonecrosis of the jaw (ONJ) and stress fractures due to long-term aminobisphosphonate (aBP) therapy. However, it is unknown whether urinary N-telopeptide (NTX) or other bone biomarkers are predictive of skeletal-related events (SRE) or the impact of cessation of aBP therapy on bone remodeling.Methods: We studied markers of bone turnover over a 6-month period after a single dose of zoledronic acid in 29 patients with multiple myeloma in remission who previously received 8 to 12 doses of pamidronate or zoledronate (NCT00577642). Our primary objective was to determine the duration of time urinary NTX levels remain suppressed after a single dose of zoledronate. A secondary objective was to identify and correlate other markers of bone remodeling with NTX changes. Thirty cytokines, based on their possible role in bone remodeling, were tested using cytokine arrays. Candidates were confirmed by ELISA.Results: All patients had continued suppression of NTX levels, except 1 patient who had an increase in NTX levels associated with an SRE. GDF-15 and decorin were found to decrease, whereas bone-specific alkaline phosphatase (BSALP) increased. Although not significant in aggregate, osteopontin and osteoprotegerin levels increased in at least half of the patients.Conclusion: Our data show that NTX levels continue to be suppressed after aBP therapy, and suggest that suppressed NTX levels may be predictive of freedom from SRE in this patient population. Furthermore, osteoblast suppression by aBP may be reversible in myeloma. These data provide the basis for less frequent dosing of aBPs. Clin Cancer Res; 20(15); 3955-61. Ó2014 AACR.

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“…33,34 Despite the initial response, prolonged use of aminobisphosphonates often results in osteonecrosis of the jaw and atypical stress fractures. [35][36][37][38][39][40][41] Although the classical pathways activating osteoclast functions are well known in myeloma bone lesions, testing of novel approaches is hampered by a lack of appropriate preclinical models exhibiting adequate window for disease progression with characteristics of disseminated disease in major bones. Toward advancing and testing a genetically engineered stem cell therapy by a systemic approach, targeting osteolytic pathology in myeloma, we first developed a mouse model using the human myeloma cell lines, overexpressing heparanase.…”

Section: Discussionmentioning

confidence: 99%

Mesenchymal stem cells expressing osteoprotegerin variants inhibit osteolysis in a murine model of multiple myeloma

Higgs¹,

Lee²,

Wang³

et al. 2017

Blood Advances

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The Role of Bisphosphonates in Multiple Myeloma: Mechanisms, Side Effects, and the Future

Abstract: ABSTRACT

Cited by 72 publications

References 144 publications

Investigating osteogenic differentiation in multiple myeloma using a novel 3D bone marrow niche model

Investigating osteogenic differentiation in multiple myeloma using a novel 3D bone marrow niche model

Biomarkers of Bone Remodeling in Multiple Myeloma Patients to Tailor Bisphosphonate Therapy

Mesenchymal stem cells expressing osteoprotegerin variants inhibit osteolysis in a murine model of multiple myeloma

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