Inflammatory and Necrotic Effects of Minodronate, a Nitrogen-Containing Bisphosphonate, in Mice
Inflammatory and Necrotic Effects of Minodronate, a Nitrogen-Containing Bisphosphonate, in Mice
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DOI：
10.1620/tjem.230.141
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发表时间：
2013-07-01
影响因子：
2.2
通讯作者：
Endo, Yasuo
中科院分区：
文献类型：
--
作者：
Kiyama, Tomomi;Okada, Satoru;Endo, Yasuo
涉及骨吸收增强的疾病（例如，骨质疏松症）广泛用双膦酸盐（BP）治疗。BP有两种类型：含氮BP（N-BP）和不含氮BP（non-N-BP）。N-BPs具有比非N-BPs强得多的抗骨吸收作用，并且N-BPs可以发挥炎症和坏死作用，包括颌骨的骨坏死。米诺膦酸盐是一种N-BP，于2009年在日本获批用于治疗骨质疏松症。其抗骨吸收作用与唑来膦酸盐相当，唑来膦酸盐是迄今报道的具有最强抗骨吸收作用和最高副作用风险的N-BP。与其他N-BP不同，米诺膦酸盐具有镇痛作用，并且没有严重的副作用。在这里，为了检查米诺膦酸盐是否缺乏炎症和/或坏死作用，我们使用小鼠（因为迄今为止测试的N-BP在小鼠中诱导这种作用，其效力与人类中报道的效力相似）。为了便于与以前的研究进行比较，我们给一个单一的全身（腹腔内）或局部（耳廓）注射米诺膦酸盐（或另一种N-BP）。我们测量了全身反应（胸腔渗出物重量、腹腔炎性细胞数量和脾脏重量）或局部反应（发炎皮肤面积和坏死发生率）。通过腹膜内注射后胫骨的X射线分析来评价抗骨吸收作用。米诺膦酸盐的抗骨吸收作用及其炎症和坏死作用与唑来膦酸盐一样大，甚至更大。此外，在培养的人牙周膜细胞，米诺膦酸盐的细胞毒性显着大于唑来膦酸盐。这些结果表明，与其他N-BP一样，在临床使用米诺膦酸盐时可能需要谨慎。
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.