Augmentation of lipopolysaccharide-induced production of IL-1α and IL-1β in mice given intravenous zoledronate (a nitrogen-containing bisphosphonate) and its prevention by clodronate (a non-nitrogen-containing bisphosphonate)

Abstract

Bisphosphonates (BPs) bind strongly to bone and exhibit long-acting anti-bone-resorptive effects. Among BPs, nitrogen-containing BPs (N-BPs) have far stronger anti-bone-resorptive effects than non-N-BPs. However, N-BPs induce acute inflammatory reactions (fever, arthralgia and myalgia, etc.) after their first injection. The mechanisms underlying these side effects remain unclear. Zoledronate (one of the most potent N-BPs) is given intravenously to patients, and the side-effect incidence is reportedly the highest among N-BPs. Our murine experiments have clarified that (a) intraperitoneally injected N-BPs induce various inflammatory reactions, including a production of interleukin-1 (IL-1) (a typical inflammatory cytokine), and these inflammatory reactions are weak in IL-1-deficient mice, (b) subcutaneously injected N-BPs induce inflammation/necrosis at the injection site, (c) lipopolysaccharide (LPS; a cell-wall component of Gram-negative bacteria) and N-BPs mutually augment their inflammatory/necrotic effects, (d) the non-N-BP clodronate can reduce N-BPs’ inflammatory/necrotic effects. However, there are few animal studies on the side effects of intravenously injected N-BPs. Here, we found in mice that (i) intravenous zoledronate exhibited weaker inflammatory effects than intraperitoneal zoledronate, (ii) in mice given intravenous zoledronate, LPS-induced production of IL-1α and IL-1β was augmented in various tissues, including bone, resulting in them increasing in serum, and (iii) clodronate (given together with zoledronate) prevented such augmentation and enhanced, slightly but significantly, zoledronate’s anti-bone-resorptive effect. These results suggest that infection may be a factor promoting the acute inflammatory side effects of N-BPs via augmented production of IL-1 in various tissues (including bone), and that clodronate may be useful to reduce or prevent such side effects.