Sir,
We read the interesting article by Morgan and Davies (2005) on the novel therapeutic strategies such as thalidomide and derivatives, proteasome inhibitors, and targeted therapy in the maintenance setting or in the induction phase of myeloma treatment prior to high-dose therapy (HDT). They emphasised the importance of the characterisation of the myeloma genome before selecting a treatment, the diagnosing of myeloma at an early stage to deliver the novel treatment in the natural history of their disease, and the establishment of the response rates and lengths of remission before novel combinations could be compared with HDT. However, there is no mention about the novel antitumour activity of bisphosphonates (BPs) besides its inhibiting effects on bone resorption in multiple myeloma (MM).
As is well known, BPs are used to treat osteoclast-mediated bone diseases, including osteoporosis, Paget's disease, hypercalcemia of malignancy, bone metastases, and bone disease associated with MM (Berenson et al, 1996; Jantunen, 2002). Current views suggest that BPs may affect differentiation and recruitment of osteoclast precursors (Hughes et al, 1989) or alter the capability of mature osteoclasts to resorb bone by altering the permeability of the osteoclast membranes to small ions (Sato et al, 1991). As a member, the more potent nitrogen-containing group of BPs, zoledronic acid, inhibits protein prenylation, thus affecting osteoclast function and survival. As protein prenylation is required by all cells, not just osteoclasts, the possibility that nitrogen-containing BPs could also affect the viability of tumour cells arises (Green, 2003). Several studies have clearly demonstrated that BPs are cytostatic to tumour cells in vitro, induce apoptosis, inhibit cell adhesion and interfere with the metastatic process (Aparicio et al, 1998). We have recently demonstrated that zoledronic acid induced antiproliferative and apoptotic effects on MM cell lines in vitro by activating protein kinase C and increasing extracellular calcium concentration, and these effects augmented with dexamethasone and thalidomide addition to zoledronic acid (Ural et al, 2003). Bisphosphonates may exert their antimyeloma effect by inhibiting release of bone marrow-derived growth factor, such as transforming growth factor β and insulin-like growth factor into marrow, by inducing apoptosis of MM cells, by downregulating production of interleukin 6 from bone marrow stroma, and by stimulating γδ T-cell-mediated antiplasma cell activity in the marrow (Mundy and Yoneda, 1998; Kunzmann et al, 2000). Therefore, zoledronic acid may augment in vivo the therapeutic action of dexamethasone and thalidomide through direct effects on myeloma cells as well as by inhibition of paracrine and autocrine signals by bone marrow stromal cells (Corral et al, 1996; Tassone et al, 2000). In this context, the results of clinical studies have suggested that BPs may reduce tumor burden and may improve survival of patients with MM (Berenson et al, 1998; Mundy and Yoneda, 1998). In addition, objective remission or inhibition of disease progression has been reported in patients with MM who underwent pamidronate treatment alone (Dhodapkar et al, 1998). In another study of ours, we demonstrated that zoledronic acid was able to increase disease-free survival in the pristane-induced plasmacytoma, a model with no direct bone involvement, in BALB/c mice model (Avcu et al, 2005). In this study, zoledronic acid treatment markedly impeded intraperitoneal plasmacytoma development. It also decreased tumour burden and extramedullary tumour growth in mice. Moreover, in contrast to many other animal tumours studied, which used high doses of BPs (Guenther et al, 2002; Croucher et al, 2003), the zoledronic acid dose of 20 μg kg−1 week−1 s.c., which was efficacious in the murine plasmacytoma model is approximately equivalent to the approved clinical dose for the treatment of the skeletal complications of MM (4 mg every 3–4 weeks i.v.). All these results raise the possibility that nitrogen-containing BPs, such as zolederonic acid, with their direct antitumour effects, may be valuable adjuncts to the novel therapeutic strategies in the treatment of MM.
Change history
16 November 2011
This paper was modified 12 months after initial publication to switch to Creative Commons licence terms, as noted at publication
References
Aparicio A, Gardner A, Tu Y, Savage A, Berenson J, Lichtenstein A (1998) In vitro cytoreductive effects on multiple myeloma cells induced by bisphosphonates. Leukemia 12: 220–229
Avcu F, Ural AU, Yilmaz MI, Ozcan A, Ide T, Kurt B, Yalcin A (2005) The bisphosphonate zoledronic acid inhibits the development of plasmacytoma induced in BALB/c mice by intraperitoneal injection of pristane. Eur J Haematol 74: 496–500
Berenson JR, Lichtenstein A, Porter L, Dimopoulos MA, Bordoni R, George S, Lipton A, Keller A, Ballester O, Kovacs MJ, Blacklock HA, Bell R, Simeone J, Reitsma DJ, Heffernan M, Seaman J, Knight RD (1996) Efficacy of pamidronate in reducing skeletal events in patients with advanced multiple myeloma. Myeloma Aredia Study Group. N Engl J Med 334: 488–493
Berenson JR, Lichtenstein A, Porter L, Dimopoulos MA, Bordoni R, George S, Lipton A, Keller A, Ballester O, Kovacs M, Blacklock H, Bell R, Simeone JF, Reitsma DJ, Heffernan M, Seaman J, Knight RD (1998) Long-term pamidronate treatment of advanced multiple myeloma patients reduces skeletal events. Myeloma Aredia Study Group. J Clin Oncol 16: 593–602
Corral LG, Muller GW, Moreira AL, Chen Y, Wu M, Stirling D, Kaplan G (1996) Selection of novel analogs of thalidomide with enhanced tumor necrosis factor alpha inhibitory activity. Mol Med 2: 506–515
Croucher PI, De Hendrik R, Perry MJ, Hijzen A, Shipman CM, Lippitt J, Green J, Van Marck E, Van Camp B, Vanderkerken K (2003) Zoledronic acid treatment of 5T2MM-bearing mice inhibits the development of myeloma bone disease: evidence for decreased osteolysis, tumor burden and angiogenesis, and increased survival. J Bone Miner Res 18: 482–492
Dhodapkar MV, Singh J, Mehta J, Fassas A, Desikan KR, Perlman M, Munshi NC, Barlogie B (1998) Anti-myeloma activity of pamidronate in vivo. Br J Haematol 103: 530–532
Green JR (2003) Antitumor effects of bisphosphonates. Cancer 97 (Suppl 3): 840–847
Guenther A, Baum W, Burger R, Bakker F, Faller G, Gschaidmeier H, Green JR, Gramatzki M (2002) Zoledronic acid has direct in vivo anti-myeloma activity in the INA-6-SCID model. Blood 100(Suppl 11): 601a
Hughes DE, MacDonald BR, Russell RG, Gowen M (1989) Inhibition of osteoclast-like cell formation by bisphosphonates in long-term cultures of human bone marrow. J Clin Invest 83: 1930–1935
Jantunen E (2002) Bisphosphonate therapy in multiple myeloma: past, present, future. Eur J Haematol 69: 257–264
Kunzmann V, Bauer E, Feurle J, Weissinger F, Tony HP, Wilhelm M (2000) Stimulation of gammadelta T cells by aminobisphosphonates and induction of antiplasma cell activity in multiple myeloma. Blood 96: 384–392
Morgan GJ, Davies FE (2005) Evolving treatment strategies for myeloma. Br J Cancer 92: 217–221
Mundy GR, Yoneda T (1998) Bisphosphonates as anticancer drugs. N Engl J Med 339: 398–400
Sato M, Grasser W, Endo N, Akins R, Simmons H, Thompson DD, Golub E, Rodan GA (1991) Bisphosphonate action. Alendronate localization in rat bone and effects on osteoclast ultrastructure. J Clin Invest 88: 2095–2105
Tassone P, Forciniti S, Galea E, Morrone G, Turco MC, Martinelli V, Tagliaferri P, Venuta S (2000) Growth inhibition and synergistic induction of apoptosis by zoledronate and dexamethasone in human myeloma cell lines. Leukemia 14: 841–844
Ural AU, Yilmaz MI, Avcu F, Pekel A, Zerman M, Nevruz O, Sengul A, Yalcin A (2003) The bisphosphonate zoledronic acid induces cytotoxicity in human myeloma cell lines with enhancing effects of dexamethasone and thalidomide. Int J Hematol 78: 443–449
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
From twelve months after its original publication, this work is licensed under the Creative Commons Attribution-NonCommercial-Share Alike 3.0 Unported License. To view a copy of this license, visit http://creativecommons.org/licenses/by-nc-sa/3.0/
About this article
Cite this article
Ural, A., Avcu, F. Evolving therapeutic role of bisphosphonates in multiple myeloma. Br J Cancer 93, 267–268 (2005). https://doi.org/10.1038/sj.bjc.6602694
Published:
Issue Date:
DOI: https://doi.org/10.1038/sj.bjc.6602694
This article is cited by
-
Bisphosphonate treatment and radiotherapy in metastatic breast cancer
Medical Oncology (2008)
-
In vitrosynergistic cytoreductive effects of zoledronic acid and radiation on breast cancer cells
Breast Cancer Research (2006)
-
Recent advances in MMP inhibitor design
Cancer and Metastasis Reviews (2006)