title: Inflammatory Effects of Nitrogen-Containing Bisphosphonates (N-BPs): Modulation by Non-N-BPs.
abstract: Bisphosphonates (BPs) are used against diseases with enhanced bone resorption. Those classed as nitrogen-containing BPs (N-BPs) exhibit much stronger anti-bone-resorptive effects than non-nitrogen-containing BPs (non-N-BPs). However, N-BPs carry the risk of inflammatory/necrotic side effects. Depending on their side-chains, BPs are divided structurally into cyclic and non-cyclic types. We previously found in mice that etidronate and clodronate (both non-cyclic non-N-BPs) could reduce the inflammatory effects of all three N-BPs tested (cyclic and non-cyclic types), possibly by inhibiting their entry into soft-tissue cells via SLC20 and/or SLC34 phosphate transporters. Tiludronate is the only available cyclic non-N-BP, but its effects on N-BPs' side effects have not been examined. Here, we compared the effects of etidronate, clodronate, and tiludronate on the inflammatory effects of six N-BPs used in Japan [three cyclic (risedronate, zoledronate, minodronate) and three non-cyclic (pamidronate, alendronate, ibandronate)]. Inflammatory effects were evaluated in mice by measuring the hind-paw-pad swelling induced by subcutaneous injection of an N-BP (either alone or mixed with a non-N-BP) into the hind-paw-pad. All of six N-BPs tested induced inflammation. Etidronate, clodronate, and the SLC20/34 inhibitor phosphonoformate inhibited this inflammation. Tiludronate inhibited the inflammatory effects of all N-BPs except ibandronate and minodronate, which have higher molecular weights than the other N-BPs. The mRNAs of SLC20a1, SLC20a2, and SLC34a2 (but not of SLC34a1 and SLC34a3) were detected in the soft-tissues of hind-paw-pads. These results suggest that etidronate, clodronate, and phosphonoformate may act non-selectively on phosphate transporter members, while tiludronate may not act on those transporting N-BPs of higher molecular weights.
authors.affiliation: Division of Orthodontics and Dentofacial Orthopedics, Graduate School of Dentistry, Tohoku University.
authors.forename: Kazuhiro
authors.initials: K
authors.lastname: Shima
authors.forename: Masahiro
authors.initials: M
authors.lastname: Tsuchiya
authors.forename: Takefumi
authors.initials: T
authors.lastname: Oizumi
authors.forename: Teruko
authors.initials: T
authors.lastname: Takano-Yamamoto
authors.forename: Shunji
authors.initials: S
authors.lastname: Sugawara
authors.forename: Yasuo
authors.initials: Y
authors.lastname: Endo
mesh_terms: D000818:Animals; D001862:Bone Resorption / Q000188:drug therapy; D004164:Diphosphonates / Q000009:adverse effects* / Q000494:pharmacology / Q000627:therapeutic use*; D004487:Edema / Q000139:chemically induced* / Q000188:drug therapy* / Q000378:metabolism; D008297:Male; D051379:Mice; D009584:Nitrogen; D012333:RNA, Messenger / Q000378:metabolism; D050608:Sodium-Phosphate Cotransporter Proteins / Q000235:genetics
chemical_list: D004164:Diphosphonates; D012333:RNA, Messenger; D050608:Sodium-Phosphate Cotransporter Proteins; D009584:Nitrogen