High serum bone-specific alkaline phosphatase level after bortezomib-combined therapy in refractory multiple myeloma: possible role of bortezomib on osteoblast differentiation

Shimazaki, Chihiro; Uchida, Ryo; Nakano, Sonoko; Namura, Kenji; Si, Fuchida; Okano, Akira; Okamoto, Masashi; Inaba, Tohru

doi:10.1038/sj.leu.2403758

Cited by 50 publications

(38 citation statements)

References 7 publications

(10 reference statements)

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“…In support of these observations, Bortezemib has been demonstrated to reduce tumor burden and increase BMD in myeloma-bearing mice using the SCID-rab model of myeloma, an effect associated with an increase in osteoblasts and a reduction in osteoclasts (77). Clinical studies have demonstrated significant increases in markers of bone formation, including alkaline phosphatase and osteocalcin in those patients who responded to bortezomib treatment (78)(79)(80)(81). In addition to changes in markers of bone formation, bortezomib treatment has also been shown to result in a reduction in serum Dkk1 and RANKL (82).…”

Section: Proteasome Inhibitorsmentioning

confidence: 99%

The pathogenesis of the bone disease of multiple myeloma

Edwards

Zhuang

Mundy

2008

Bone

150

120

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Multiple myeloma is a fatal hematologic malignancy associated with clonal expansion of malignant plasma cells within the bone marrow and the development of a destructive osteolytic bone disease. The principal cellular mechanisms involved in the development of myeloma bone disease are an increase in osteoclastic bone resorption, and a reduction in bone formation. Myeloma cells are found in close association with sites of active bone resorption, and the interactions between myeloma cells, and other cells within the specialized bone marrow microenvironment are essential, both for tumor growth and the development of myeloma bone disease. This review discusses the many different factors which have been implicated in myeloma bone disease, including the evidence for their role in myeloma and subsequent therapeutic implications.

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Section: Proteasome Inhibitorsmentioning

confidence: 99%

The pathogenesis of the bone disease of multiple myeloma

Edwards

Zhuang

Mundy

2008

Bone

150

120

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“…Interestingly, some reports have shown high serum bone-specific alkaline phosphatase levels after bortezomib-combined therapy in MM patients (8,9), and administration of proteasome inhibitor induced bone formation accompanied with the expression of bone morphogenetic protein-2 (BMP-2) in mice (10). However, the effect of bortezomib on osteoclast differentiation and the effects of immunomodulatory compounds on osteoclast or osteoblast differentiation remain unknown.…”

Section: Introductionmentioning

confidence: 99%

Osteoprogenitor differentiation is not affected by immunomodulatory thalidomide analogs but is promoted by low bortezomib concentration, while both agents suppress osteoclast differentiation

Munemasa

Sakai²,

Kuroda³

et al. 2008

Int J Oncol

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Abstract.We investigated the effects of bortezomib (PS-341) and immunomodulatory thalidomide analogs (immunomodulatory compounds; CC-4047, CC-6032, and CC-5013, or lenalidomide) on osteoblast and osteoclast differentiation in vitro using human mesenchymal stem cells (hMSC) to commit to osteoprogenitor cells and peripheral blood mononuclear cells (PBMCs) isolated from healthy donors, respectively. First, the concentration of bortezomib for an anti-myeloma effect was more than 1.0 nM in myeloma cells of multiple myeloma (MM) patients and more than 2.5 nM in myeloma cell lines. In contrast, anti-myeloma effects of immunomodulatory compounds on myeloma cells differed among myeloma cells and these compounds themselves. Subsequently, these agents (bortezomib; 0.5-5.0 nM, immunomodulatory compounds; 10 μM) were added to the osteoprogenitor cell culture media or the media for osteoclast differentiation. Low bortezomib concentrations (0.5 and 1.0 nM) increased ALP activity, and the delayed addition of bortezomib further increased ALP activity. Mineralized nodular formation with <2.5 nM bortezomib was not impaired. BMP2 expression on osteoprogenitor cells was found to increase in a time-dependent manner irrespective of treatment with bortezomib. On the other hand, the antiosteoclast effect with low bortezomib concentration (≤2.5 nM) depended on MM patients. In contrast, immunomodulatory compounds at 10 μM showed an anti-osteoclast effect without cytotoxicity to osteoblast differentiation, at which dose myeloma cells underwent apoptosis. These findings might improve the treatment strategy for MM patients without damaging BM stromal cells by combining bortezomib with immunomodulatory compounds.

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“…This approach is based on the observation that the proteasome inhibitor bortezomib had bone forming effects in multiple myeloma patients (127). Proteasome inhibitors can promote osteoblast differentiation in MSC via increased BMP2 expression and stabilization of RUNX2 and proteasome inhibition (128)(129)(130).…”

Section: Other Potential Targets For Anabolic Therapiesmentioning

confidence: 99%

Osteoblasts in osteoporosis: past, emerging, and future anabolic targets

Marie¹,

Kassem²

2011

European Journal of Endocrinology

187

143

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Objective: Age-related bone loss is associated with significant changes in bone remodeling characterized by decreased trabecular and periosteal bone formation relative to bone resorption, resulting in bone fragility and increased risk of fractures. Prevention or reversal of age-related decrease in bone mass and increase in bone fragility has been based on inhibition of bone resorption using anticatabolic drugs. The current challenge is to promote osteoblastogenesis and bone formation to prevent age-related bone deterioration. Methods: A limited number of approved therapeutic molecules are available to activate bone formation. Therefore, there is a need for anabolic drugs that promote bone matrix apposition at the endosteal, endocortical, and periosteal envelopes by increasing the number of osteoblast precursor cells and/or the function of mature osteoblasts. In this study, we review current therapeutics promoting bone formation and anabolic molecules targeting signaling pathways involved in osteoblastogenesis, based on selected full-text articles searched on Medline search from 1990 to 2010. Results and discussion: We present current therapeutic approaches focused on intermittent parathyroid hormone and Wnt signaling agonists/antagonists. We also discuss novel approaches for prevention and treatment of defective bone formation and bone loss associated with aging and osteoporosis. These strategies targeting osteoblastic cell functions may prove to be useful in promoting bone formation and improving bone strength in the aging population.

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High serum bone-specific alkaline phosphatase level after bortezomib-combined therapy in refractory multiple myeloma: possible role of bortezomib on osteoblast differentiation

Cited by 50 publications

References 7 publications

The pathogenesis of the bone disease of multiple myeloma

The pathogenesis of the bone disease of multiple myeloma

Osteoprogenitor differentiation is not affected by immunomodulatory thalidomide analogs but is promoted by low bortezomib concentration, while both agents suppress osteoclast differentiation

Osteoblasts in osteoporosis: past, emerging, and future anabolic targets

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