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Bisphosphonate Effects in Cancer and Inflammatory Diseases

In Vitro and In Vivo Modulation of Cytokine Activities

  • Drug Mechanisms and Targets
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Abstract

Bisphosphonates are endogenous pyrophosphate analogs in which a carbon atom replaces the central atom of oxygen. They are indicated in non-neoplastic diseases including osteoporosis, corticosteroid-induced bone loss, Paget disease, and in cancer-related diseases such as neoplastic hypercalcemia, multiple myeloma and bone metastases secondary to breast and prostate cancer. There is now extensive in vitro evidence suggesting a direct antitumor effect of bisphosphonates at different levels of action. Some new in vitro and in vivo studies support the cytostatic effects of bisphosphonates on tumor cells, and the effects on the regulation of cell growth, apoptosis, angiogenesis, cell adhesion, and invasion, with particular attention to biological properties. Well designed clinical trials are necessary to investigate whether the antitumor potential of bisphosphonates may be clinically relevant. On the basis of their effects on macrophages, we may divide bisphosphonates into two distinct categories: aminobisphosphonates, which sensitize macrophages to an inflammatory stimulus inducing an acute-phase response, and non-aminobisphosphonates that can be metabolized into macrophages and that may inhibit the inflammatory response of macrophages. There is evidence of aminobisphosphonate-induced pro-inflammatory response, in particular, related to modifications of the cytokine network. Several in vivo studies have demonstrated an acute-phase reaction after the first administration of aminobisphosphonates, with a significant increase in the main pro-inflammatory cytokines. However, a peculiar aspect concerning the action of non-aminobisphosphonates seems to be an anti-inflammatory activity caused by the inhibition of the release of inflammatory mediators from activated macrophages, such as interleukin (IL)-6, tumor necrosis factor-α and IL-1. The inhibition of inflammatory responses is demonstrated in both in vivo and in vitro models. This activity suggests the use of non-aminobisphosphonates in several inflammatory diseases characterized by macrophage-mediated production of acute-phase cytokines, as prevention of erosions in rheumatoid arthritis, and of loosening of joint prostheses, as well as possibly in osteoarthritis, ankylosing spondylitis, myelofibrosis, and hypertrophic pulmonary osteoarthropathy.

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Acknowledgments

We thank Futura-ONLUS for its continuous support. We also thank Prof. F. Dianzani for his methodological and scientific support.

No sources of funding were used to assist in the preparation of this review. The authors have no conflicts of interest that are directly relevant to the content of this review.

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  1. Oncology Department, Campus Bio-Medico University, Via Emilio Longoni 69, Rome, 00169, Italy

    Daniele Santini, Maria E. Fratto, Bruno Vincenzi, Annalisa La Cesa, Caterina Dianzani & Giuseppe Tonini

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  1. Daniele Santini
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  2. Maria E. Fratto
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Correspondence to Daniele Santini.

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Santini, D., Fratto, M.E., Vincenzi, B. et al. Bisphosphonate Effects in Cancer and Inflammatory Diseases. BioDrugs 18, 269–278 (2004). https://doi.org/10.2165/00063030-200418040-00004

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