title: Phosphonocarboxylates Can Protect Mice against the Inflammatory and Necrotic Side Effects of Nitrogen-Containing Bisphosphonates by Inhibiting Their Entry into Cells via Phosphate Transporters.
abstract: Bisphosphonates (BPs) are used against diseases involving increased bone-resorption. Among BPs, nitrogen-containing 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 of (3)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.
authors.affiliation: Division of Oral Molecular Regulation, Graduate School of Dentistry, Tohoku University.
authors.forename: Tomomi
authors.initials: T
authors.lastname: Kiyama
authors.forename: Masahiro
authors.initials: M
authors.lastname: Tsuchiya
authors.forename: Satoru
authors.initials: S
authors.lastname: Okada
authors.forename: Takefumi
authors.initials: T
authors.lastname: Oizumi
authors.forename: Kouji
authors.initials: K
authors.lastname: Yamaguchi
authors.forename: Keiichi
authors.initials: K
authors.lastname: Sasaki
authors.forename: Shunji
authors.initials: S
authors.lastname: Sugawara
authors.forename: Yasuo
authors.initials: Y
authors.lastname: Endo
mesh_terms: D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology*; D050071:Bone Density Conservation Agents / Q000009:adverse effects / Q000494:pharmacology; D002264:Carboxylic Acids / Q000494:pharmacology*; D004164:Diphosphonates / Q000009:adverse effects / Q000494:pharmacology; D004423:Ear / Q000473:pathology; D005260:Female; D008807:Mice, Inbred BALB C; D009336:Necrosis / Q000139:chemically induced / Q000517:prevention & control; D009584:Nitrogen; D063065:Organophosphonates / Q000494:pharmacology*; D028061:Phosphate Transport Proteins / Q000378:metabolism*; D020011:Protective Agents / Q000494:pharmacology
chemical_list: D000893:Anti-Inflammatory Agents; D050071:Bone Density Conservation Agents; D002264:Carboxylic Acids; D004164:Diphosphonates; D063065:Organophosphonates; D028061:Phosphate Transport Proteins; D020011:Protective Agents; D009584:Nitrogen