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)

• Published in: Biological & pharmaceutical bulletin Vol. 42; no. 2; pp. 164 - 172
• Main Authors: Suzuki, Hikari, Bando, Kanan, Tada, Hiroyuki, Kiyama, Tomomi, Oizumi, Takefumi, Funayama, Hiromi, Sugawara, Shunji, Takahashi, Tetsu, Endo, Yasuo
• Format: Journal Article
• Language: English
• Published: Japan The Pharmaceutical Society of Japan 01-02-2019; Japan Science and Technology Agency
• Subjects: Animals; Arthralgia; bisphosphonate; Bisphosphonates; Bone Density Conservation Agents - therapeutic use; clodronate; Clodronic acid; Clodronic Acid - pharmacology; Drug Synergism; Fever; Gram-negative bacteria; IL-1β; Inflammation; Inflammation - blood; Inflammation - chemically induced; Inflammation - drug therapy; Injection; Interleukin 1; interleukin-1 (IL-1); Interleukin-1beta - biosynthesis; Interleukin-1beta - blood; Intravenous administration; lipopolysaccharide (LPS); Lipopolysaccharides; Lipopolysaccharides - pharmacology; Liver - drug effects; Liver - metabolism; Long bone; Male; Mice; Myalgia; Nitrogen; Pectoralis Muscles - drug effects; Pectoralis Muscles - metabolism; side effect; Side effects; Spleen - drug effects; Spleen - metabolism; zoledronate; Zoledronic acid; Zoledronic Acid - pharmacology; clodronate; bisphosphonate; lipopolysaccharide (LPS); side effect; interleukin-1 (IL-1); zoledronate
• ISSN: 0918-6158; 1347-5215
• DOI: 10.1248/bpb.b18-00408

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.