Necrotic Actions of Nitrogen‐Containing Bisphosphonates and Their Inhibition by Clodronate, a Non‐Nitrogen‐Containing Bisphosphonate in Mice: Potential for Utilization of Clodronate as a Combination Drug with a Nitrogen‐Containing Bisphosphonate

Abstract

Nitrogen-containing bisphosphonates (NBPs) exhibit powerful anti-bone-resorptive effects (ABREs) via inhibition of farnesyl pyrophosphate synthase during cholesterol biosynthesis. Clinical applications have disclosed an unexpected side effect, namely osteonecrosis of jaw bones, and although thousands of cases have been documented in the last few years the mechanism remains unclear. Since NBPs accumulate in bone-hydroxyapatite, more jaw bone osteonecrosis cases may come to light if NBPs continue to be used as they are being used now. We have previously reported that in mice, systemic (intraperitoneal) injection of clodronate (a non-NBP) prevents the inflammatory effects of NBPs. Here, we examined in mice the local necrotic actions of various NBPs and the anti-necrotic effects of clodronate. A single subcutaneous injection of an NBP into the ear pinna induced necrosis at the injection site (relative potencies of necrotic actions of NBPs: zoledronate >> pamidronate ≥ alendronate > risedronate), while non-NBPs lacked this effect. Clodronate, when injected together with an NBP, reduced or prevented the necrosis induced by that NBP, but not its ABRE. Clodronate reduced the amount of each NBP retained within tissues. These results, together with those of previous studies, suggest that (i) clodronate inhibits the inflammatory and necrotic actions of NBPs by inhibiting their incorporation into cells related to inflammation and/or necrosis, (ii) clodronate could be useful as a combination drug with NBPs for preventing their necrotic actions while retaining their ABREs and (iii) clodronate could also be useful as a substitution drug for NBPs in patients at risk of osteonecrosis of jaw bones.

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

“…As described below, the inflammatory and necrotic actions of BPs were evaluated daily. 10) All experiments were terminated on day 7.…”

“…[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

“…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).…”

“…Further, it is thought that an N-BP that has accumulated within a jawbone may be released during and/or after injury or destruction of that bone (e.g., due to tooth extraction and/or infection), and that the released N-BP may directly injure the surrounding soft tissues . Indeed, (i) zoledronate can be detected in the saliva of patients who have been treated with zoledronate (Scheper et al 2009), (ii) as described above, N-BPs directly injure esophageal and gastric tissues, (iii) when injected topically in mice, N-BPs induce inflammation and necrosis at the injection site with potencies that nearly parallel those of their ABREs (Schenk et al 1986;Oizumi et al 2009), and (iv) the potencies with which N-BPs induce their inflammatory and necrotic side effects (INSEs) in mice seem to parallel those reported in human patients (Oizumi et al 2009). These findings suggest that for N-BPs, the potential to induce INSEs in animal experiments (see above) correlates with their clinical potential to cause INSEs (including ONJ).…”

“…On that basis, we proposed elsewhere that (i) clodronate could be valuable as a combination drug for use with N-BPs (to prevent their necrotic actions while retaining their ABREs) and (ii) clodronate could also be useful as a substitution drug for N-BPs in patients at high risk of osteonecrosis of the jawbones (Monma et al 2004;Oizumi et al 2009). …”