Tohoku J. Exp. Med., 2013 July, 230(3)

Inflammatory and Necrotic Effects of Minodronate, a Nitrogen-Containing Bisphosphonate, in Mice

TOMOMI KIYAMA,^1,2 SATORU OKADA,^1,3 YUKINORI TANAKA,¹ SIYOUNG KIM,^1,4 KANAN BANDO,^1,4 MASAKAZU HASEGAWA,⁴ KOUJI YAMAGUCHI,^1,3 TERUKO TAKANO-YAMAMOTO,⁴ KEIICHI SASAKI,² SHUNJI SUGAWARA¹ and YASUO ENDO¹

¹Division of Oral Molecular Regulation, Graduate School of Dentistry, Tohoku University, Sendai, Miyagi, Japan
²Division of Advanced Prosthetic Dentistry, Graduate School of Dentistry, Tohoku University, Sendai, Miyagi, Japan
³Division of Oral and Maxillofacial Surgery, Graduate School of Dentistry, Tohoku University, Sendai, Miyagi, Japan
⁴Division of Orthodontics and Dentofacial Orthopedics, Graduate School of Dentistry, Tohoku University, Sendai, Miyagi, Japan

Diseases involving enhanced bone-resorption (e.g., osteoporosis) are widely treated with bisphosphonates (BPs). BPs are of two types: the nitrogen-containing BPs (N-BPs) and the non-nitrogen-containing BPs (non-N-BPs). N-BPs have much stronger anti-bone-resorptive effects than non-N-BPs, and N-BPs can exert inflammatory and necrotic effects, including osteonecrosis of jawbones. Minodronate, an N-BP, was approved in 2009 in Japan for osteoporosis. Its anti-bone-resorptive effect is comparable to that of zoledronate, the N-BP with the strongest anti- bone-resorptive effect and the highest risk of side effects yet reported. Unlike other N-BPs, minodronate has an analgesic effect, and no serious side effects have been documented. Here, to examine whether minodronate lacks inflammatory and/or necrotic effects, we used mice (since the N-BPs tested so far induce such effects in mice with potencies that parallel those reported in humans). To facilitate comparison with previous studies, we gave a single systemic (intraperitoneal) or local (ear pinna) injection of minodronate (or another N-BP). We measured the systemic responses (weight of thoracic exudate, number of inflammatory cells in the peritoneal cavity, and spleen weight) or local responses (area of inflamed skin and incidence of necrosis). Anti-bone-resorptive effects were evaluated by X-ray analysis of tibias following intraperitoneal injection. Minodronate's anti-bone-resorptive effect and its inflammatory and necrotic effects were as great as, or greater than those of zoledronate. Moreover, in cultured human periodontal ligament cells, the cytotoxicity of minodronate was significantly greater than that of zoledronate. These results suggest that caution may be needed with minodronate in clinical use, as with other N-BPs.

keywords —— bisphosphonates; inflammation; minodronate; osteonecrosis; osteoporosis

© 2013 Tohoku University Medical Press

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Tohoku J. Exp. Med., 2013, 230, 141-149

Correspondence: Yasuo Endo, Department of Oral Molecular Regulation, Graduate School of Dentistry, Tohoku University, 4-1 Seiryo-machi, Sendai, Miyagi 980-8575, Japan.

e-mail: endo@dent.tohoku.ac.jp