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-alpha 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.