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

Tomomi Kiyama, Masahiro Tsuchiya, Satoru Okada, Takefumi Oizumi, Kouji Yamaguchi, Keiichi Sasaki, Shunji Sugawara, Yasuo Endo

Research output: Contribution to journalArticle

8 Citations (Scopus)

Abstract

Bisphosphonates (BPs) are used against diseases involving increased bone-resorption. Among BPs, nitrogencontaining BPs (N-BPs) have much stronger anti-bone-resorptive effects than non-nitrogen-containing BPs (non-N-BPs). However, N-BPs carry the risk of inflammatory/necrotic effects, including osteonecrosis of jawbones. When injected into mouse ear-pinnas, N-BPs induce inflammatory/necrotic effects within the ear-pinna. We previously found that (a) the non-N-BPs clodronate and etidronate can reduce such side effects of N-BPs, and (b) phosphonoformate (an inhibitor of the phosphate transporters SLC20 and SLC34) can reduce the inflammatory/necrotic effects of zoledronate (the N-BP with the highest reported risk of side effects). However, it is not clear (i) whether phosphonoformate can reduce the side effects of other N-BPs, too, and (ii) whether other phosphonocarboxylates have such inhibitory effects. Here, using the mouse ear-pinna model, we compared the effects of etidronate, clodronate, and four phosphonocarboxylates on the inflammatory/necrotic effects of N-BPs of the alkyl type (alendronate) or cyclic type (zoledronate and minodronate). Like phosphonoformate, the other three phosphonocarboxylates protected against the inflammatory/necrotic effects of all the N-BPs. The protective potencies were clodronate>etidronate>phosphonoacetate>phosphonoformate> phosphonopropionate>phosphonobutyrate. With a similar order of potencies, these agents reduced the amount of3 H-alendronate retained within the ear-pinna after its injection therein. The mRNAs of SLC20 and SLC34 were detected in untreated ear-pinnas. These findings suggest that the inhibition of phosphate transporters by phosphonocarboxylates, as well as by etidronate and clodronate, might be a useful preventive strategy against the side effects of both alkyl- and cyclic-type N-BPs.

Original languageEnglish
Pages (from-to)712-720
Number of pages9
JournalBiological and Pharmaceutical Bulletin
Volume39
Issue number5
DOIs
Publication statusPublished - 2016 May 1

Keywords

  • Bisphosphonate side effect
  • Phosphate transporter
  • Phosphonoacetate
  • Phosphonocarboxylate
  • Phosphonoformate

ASJC Scopus subject areas

  • Pharmacology
  • Pharmaceutical Science

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