Novel insights into actions of bisphosphonates on bone: Differences in interactions with hydroxyapatite
Novel insights into actions of bisphosphonates on bone: Differences in interactions with hydroxyapatite
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DOI：
10.1016/j.bone.2005.05.003
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发表时间：
2006-05-01
期刊：
影响因子：
4.1
通讯作者：
Ebetino, F. H.
中科院分区：
文献类型：
--
作者：
Nancollas, G. H.;Tang, R.;Ebetino, F. H.
双膦酸盐现在是治疗骨质疏松症等骨吸收增加相关疾病最广泛使用的药物。虽然双膦酸盐直接作用于破骨细胞，并干扰特定的生化过程，例如蛋白质异戊二烯化，但它们吸附骨矿物质的能力也有助于其效力和作用持续时间。本研究的目的是比较目前临床使用的 6 种双膦酸盐对羟基磷灰石 (HAP) 的结合亲和力，并确定这些双膦酸盐对其他矿物表面性质（包括 Zeta 电位和界面张力）的影响。双膦酸盐吸附常数 (K-L) 是通过在 37 摄氏度和生理离子强度 (0.15 M) 下使用恒定组成方法对 HAP 晶体生长的动力学研究计算得出的。在可能模拟双膦酸盐结合到骨上的条件下，HAP 生长（pH 7.4）的双膦酸盐之间的 K-L 存在显着差异，排序顺序为唑来膦酸盐 > 阿仑膦酸盐 > 伊班膦酸盐 > 利塞膦酸盐 > 依替膦酸盐 > 氯膦酸盐。 Zeta 电位的测量表明，晶体表面通过双膦酸盐的吸附进行了改性，其方式最好通过与侧链部分质子化相关的分子电荷来解释，其中利塞膦酸盐与阿仑膦酸盐、伊班膦酸盐和唑来膦酸盐表现出显着差异。固/液界面性质的研究表明，双膦酸盐之间存在额外的差异，这可能会影响它们结合和抑制晶体生长和溶解的机制。观察到的动力学结合亲和力、HAP zeta 电位和界面张力的差异可能会影响各种双膦酸盐的生物学特性。特别是，这些结合特性可能会导致骨吸收和持久性的差异以及作用的可逆性。因此，这些特性具有潜在的临床意义，对于理解强效双膦酸盐之间的差异可能很重要，例如与依替膦酸盐和利塞膦酸盐更容易可逆的作用相比，阿仑膦酸盐和唑来膦酸盐的作用持续时间明显更长。 (c) 2005 Elsevier Inc. 保留所有权利。
Bisphosphonates are now the most widely used drugs for diseases associated with increased bone resorption, such as osteoporosis. Although bisphosphonates act directly on osteoclasts, and interfere with specific biochemical processes such as protein prenylation, their ability to adsorb to bone mineral also contributes to their potency and duration of action.The aim of the present study was to compare the binding affinities for hydroxyapatite (HAP) of 6 bisphosphonates currently used clinically and to determine the effects of these bisphosphonates on other mineral surface properties including zeta potential and interfacial tension.Affinity constants (K-L) for the adsorption of bisphosphonates were calculated from kinetic studies on HAP crystal growth using a constant composition method at 37 degrees C and at physiological ionic strength (0.15 M). Under conditions likely to simulate bisphosphonate binding onto bone, there were significant differences in K-L among the bisphosphonates for HAP growth (pH 7.4) with a rank order of zoledronate > alendronate > ibandronate > risedronate > etidronate > clodronate. The measurements of zeta potential show that the crystal surface is modified by the adsorption of bisphosphonates in a manner best explained by molecular charges related to the protonation of their side-chain moieties, with risedronate showing substantial differences from alendronate, ibandronate, and zoledronate. The studies of the solid/liquid interfacial properties show additional differences among the bisphosphonates that may influence their mechanisms for binding and inhibiting crystal growth and dissolution. The observed differences in kinetic binding affinities, HAP zeta potentials, and interfacial tension are likely to contribute to the biological properties of the various bisphosphonates. In particular, these binding properties may contribute to differences in uptake and persistence in bone and the reversibility of effects. These properties, therefore, have potential clinical implications that may be important in understanding differences among potent bisphosphonates, such as the apparently more prolonged duration of action of alendronate and zoledronate compared with the more readily reversible effects of etidronate and risedronate. (c) 2005 Elsevier Inc. All rights reserved.