Inhibition of inflammatory actions of aminobisphosphonates by dichloromethylene bisphosphonate, a non‐aminobisphosphonate

Abstract

1 When injected intraperitoneally into mice in doses larger than those used clinically, all the amino derivatives of bisphosphonates (aminoBPs) tested induce a variety of in¯ammatory reactions such as induction of histidine decarboxylase (HDC, the histamine-forming enzyme), hypertrophy of the spleen, atrophy of the thymus, hypoglycaemia, ascites and accumulation of exudate in the thorax, and an increase in the number of macrophages and/or granulocytes in the peritoneal cavity of blood. On the other hand, dichloromethylene bisphosphonate (Cl 2 MBP) a typical non-aminoBP, has no such in¯ammatory actions. In the present study, we found that this agent can suppress the in¯ammatory actions of aminoBPs. 2 Cl 2 MBP, when injected into mice before or after injection of 4-amino-1-hydroxybutylidene-1,1-bisphosphonic acid (AHBuBP; a typical aminoBP), inhibited the induction of HDC activity by AHBuBP in a dose-and time-dependent manner. The increase in HDC activity induced by AHBuBP was largely suppressed by the injection of an equimolar dose of Cl 2 MBP. Cl 2 MBP also inhibited other AHBuBP-induced in¯ammatory reactions, as well as the in¯ammatory actions of two other aminoBPs. However, Cl 2 MBP did not inhibit the increase in HDC activity induced by lipopolysaccharide (LPS). 3 We have previously reported that AHBuBP augments the elevation of HDC activity and the production of interleukin-1b (IL-1b) that are induced by LPS. These actions of AHBuBP were also inhibited by Cl 2 MBP. 4 Based on these results and reported actions of bisphosphonates, the mechanisms underlying the contrasting eects of aminoBPs and Cl 2 MBP, a non-aminoBP are discussed. The results suggest that combined administration of Cl 2 MBP and an aminoBP in patients might be a useful way of suppressing the in¯ammatory side eects of aminoBPs.

Phosphonocarboxylates Can Protect Mice against the Inflammatory and Necrotic Side Effects of Nitrogen-Containing Bisphosphonates by Inhibiting Their Entry into Cells <i>via</i> Phosphate Transporters

“…[6][7][8][9][10] Actually, etidronate and clodronate are protective against the inflammatory/necrotic effects of N-BPs. 8,[10][11][12][13] Concerning the mechanism underlying this protective effect, we hypothesized that (i) N-BPs enter soft-tissue cells via phosphate transporters, and (ii) etidronate and clodronate can inhibit the entry of N-BPs into cells. These hypotheses were supported by our recent finding in mice that among various BP-related substances and inhibitors of various transporters, only etidronate, clodronate, and phosphonoformate (a well-known inhibitor of the phosphate-transporter families SLC34 and/or SLC20) dronate (a cyclic-type N-BP that has the highest reported risk of side effects among N-BPs).…”

Inflammatory and Necrotic Effects of Minodronate, a Nitrogen-Containing Bisphosphonate, in Mice

“…As reported previously, a single intraperitoneal injection of an N-BP (alendronate, incadronate, or ibandronate, each 40 µmol/kg) induces various inflammatory reactions, and the reactions are greatly reduced by co-administration of 160 µmol/kg of clodronate (Endo et al 1999). As shown in Fig.…”

“…Concerning the INSEs of N-BPs in mice, we have reported that clodronate and etidronate can reduce or prevent the systemic and local INSEs of various N-BPs (Endo et al 1999;Funayama et al 2005;Oizumi et al 2009Oizumi et al , 2010Shikama et al 2010). In the present study, clodronate prevented the INSEs of minodronate, too, suggesting that the protective effect of clodronate is widely exerted against the INSEs of various N-BPs.…”

“…Thus, it is questionable whether clodronate does indeed cause ONJ. In mice, not only is clodronate devoid of INSEs such as those described above, but its coadministration with an N-BP can reduce or prevent the INSEs of the N-BP without affecting the latter's ABRE (Endo et al 1999;Oizumi et al 2009;Shikama et al 2010).…”

“…N-BPs, when injected intraperitoneally into mice, induce a number of inflammatory reactions. These include prolonged induction of the histamine-forming enzyme histidine decarboxylase, pleural exudation, an increase in granulocytic cells in the peritoneal cavity, splenomegaly, hypoglycemia, and accumulation of IL-1β in various tissues (Endo et al 1993(Endo et al , 1999Deng et al 2006). Clodronate is a non-N-BP.…”