Prevention of necrotic actions of nitrogen-containing bisphosphonates (NBPs) in mice by non-NBPs (clodronate and etidronate)

Abstract

Nitrogen-containing bisphosphonates (NBPs) have powerful antibone-resorptive effects (ABREs), but they induce unexpected side effect, osteonecrosis of jaw-bones (ONJ). The mechanism underlying NBP-associated ONJ is unclear. Zoledronate, the strongest NBP, exhibits the highest incidence of ONJ. We previously found that clodronate and etidronate (non-NBPs) inhibit NBP-induced inflammation. Here, we found the following. (a) Subcutaneous injection of zoledronate into ear-pinnas induced inflammation and then necrosis at these sites. These effects of zoledronate were strongest among NBPs tested, while non-NBPs lacked these effects. (b) Coinjection of clodronate or etidronate reduced the amount of zoledronate retained within the ear tissue and reduced the inflammatory and necrotic effects of zoledronate. (c) When zoledronate and clodronate were intraperitoneally injected, clodronate little affected the ABRE of zoledronate, as well as those of other NBPs. In contrast, etidronate markedly reduced the ABRE of zoledronate. Notably, etidronate reduced the ABRE of zoledronate even when it was injected 16 h after the injection of zoledronate. These results suggest that (a) clodronate and etidronate may inhibit the entry of NBPs into cells related to inflammation and/or necrosis and prevent NBPs’ side effects, (b) clodronate could be useful as a combination drug with NBPs for preventing their side effects while retaining their ABREs, (c) etidronate (but not clodronate) may competitively inhibit the binding of NBPs to bone hydroxyapatite (BHA), and this reagent may reduce NBPs that have already accumulated within bones, and (d) etidronate, if used as a substitution drug for NBPs, may be effective at treating or preventing NBP-associated ONJ.