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

• Published in: Biological & pharmaceutical bulletin Vol. 39; no. 5; pp. 712 - 720
• Main Authors: Kiyama, Tomomi, Tsuchiya, Masahiro, Okada, Satoru, Oizumi, Takefumi, Yamaguchi, Kouji, Sasaki, Keiichi, Sugawara, Shunji, Endo, Yasuo
• Format: Journal Article
• Language: English
• Published: Japan The Pharmaceutical Society of Japan 01-05-2016; Japan Science and Technology Agency
• Subjects: Animals; Anti-Inflammatory Agents - pharmacology; bisphosphonate side effect; Bone Density Conservation Agents - adverse effects; Bone Density Conservation Agents - pharmacology; Carboxylic Acids - pharmacology; Diphosphonates - adverse effects; Diphosphonates - pharmacology; Ear - pathology; Female; Mice, Inbred BALB C; Necrosis - chemically induced; Necrosis - prevention & control; Nitrogen; Organophosphonates - pharmacology; Phosphate Transport Proteins - metabolism; phosphate transporter; phosphonoacetate; phosphonocarboxylate; phosphonoformate; Protective Agents - pharmacology
• ISSN: 0918-6158; 1347-5215
• DOI: 10.1248/bpb.b15-00770

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 3H-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.