Release of nitrogen-containing bisphosphonates (nbps) from hydroxyapatite by non-nbps and by pyrophosphate

Kanan Bando, Takefumi Oizumi, Tetsu Takahashi, Itaru Mizoguchi, Shunji Sugawara, Yasuo Endo

Research output: Contribution to journalArticlepeer-review

Abstract

Bisphosphonates (BPs) are major anti-bone-resorptive drugs. Among them, the nitrogen-containing BPs (NBPs) exhibit much stronger anti-bone-resorptive activities than non-nitrogen-containing BPs (non-NBPs). However, BP-related osteonecrosis of the jaw (BRONJ) has been increasing without effective strategies for its prevention or treatment. The release of NBPs (but not non-NBPs) from NBP-accumulated jawbones has been supposed to cause BRONJ, even though non-NBPs (such as etidronate (Eti) and clodronate (Clo)) are given at very high doses because of their low anti-bone-resorptive activities. Our murine experiments have demonstrated that NBPs cause inflammation/necrosis at the injection site, and that Eti and Clo can reduce or prevent the inflammatory/necrotic effects of NBPs by inhibiting their entry into soft-tissue cells. In addition, our preliminary clinical studies suggest that Eti may be useful for treating BRONJ. Notably, Eti, when administered together with an NBP, reduces the latter's anti-bone-resorptive effect. Here, on the basis of the above background, we examined and compared in vitro interactions of NBPs, non-NBPs, and related substances with hydroxyapatite (HA), and obtained the following results. (i) NBPs bind rapidly to HA under pH-neutral conditions. (ii) At high concentrations, Eti and Clo inhibit NBP-binding to HA and rapidly expel HA-bound NBPs (potency Eti>>Clo). (iii) Pyrophosphate also inhibits NBP-binding to HA and expels HAbound NBPs. Based on these results and those reported previously, we discuss (i) possible anti-BRONJ strategies involving the use of Eti and/or Clo to reduce jawbone-accumulated NBPs, and (ii) a possible involvement of pyrophosphate-mediated release of NBPs as a cause of BRONJ.

Original languageEnglish
Pages (from-to)1670-1680
Number of pages11
JournalBiological and Pharmaceutical Bulletin
Volume44
Issue number11
DOIs
Publication statusPublished - 2021 Nov
Externally publishedYes

Keywords

  • Bisphosphonate
  • Clodronate
  • Etidronate
  • Hydroxyapatite
  • Osteonecrosis
  • Pyrophosphate

ASJC Scopus subject areas

  • Pharmacology
  • Pharmaceutical Science

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