Bisphosphonates - An update on mechanisms of action and how these relate to clinical efficacy
Bisphosphonates - An update on mechanisms of action and how these relate to clinical efficacy
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DOI：
10.1196/annals.1402.089
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发表时间：
2007-01-01
期刊：
影响因子：
--
通讯作者：
Ebetino, Frank H.
中科院分区：
文献类型：
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作者：
Russell, R. Graham G.;Xia, Zhidao;Ebetino, Frank H.
双膦酸盐（BPs）已被公认为过度骨吸收疾病的治疗选择，包括骨的佩吉特病、骨髓瘤和骨转移以及骨质疏松症。关于BP如何工作有相当多的新知识。它们的经典药理学作用似乎是由两个关键性质引起的：它们对骨矿物质的亲和力和它们对破骨细胞的抑制作用。临床使用的BP之间的矿物质结合亲和力不同，并可能影响其在骨内的差异分布，其生物学效价和作用持续时间。含氮BP（包括阿仑膦酸盐、利塞膦酸盐、伊班膦酸盐和唑来膦酸盐）对破骨细胞的抑制作用似乎是由于它们抑制甲羟戊酸途径中的关键分支点酶法尼基焦磷酸合酶（FPPS）。FPPS产生类异戊二烯脂质，用于破骨细胞功能所必需的小GTP结合蛋白的翻译后修饰。对其他细胞途径的影响，如防止骨细胞凋亡，正在成为其他潜在的重要作用机制。作为一个类别，BP具有几个共同的属性。然而，与其他类别的药物一样，各种不同的BP之间存在明显的化学，生物化学和药理学差异。每种BP都有独特的特征，这可能有助于解释BP之间在骨折复位开始速度、不同骨骼部位的抗骨折疗效以及骨转换抑制程度和持续时间方面的潜在重要临床差异。随着我们接近发现其生物效应的40周年，仍有更多的机会将其特性用于医学目的。
The bisphosphonates (BPs) are well established as the treatments of choice for disorders of excessive bone resorption, including Paget's disease of bone, myeloma and bone metastases, and osteoporosis. There is considerable new knowledge about how BPs work. Their classical pharmacological effects appear to result from two key properties: their affinity for bone mineral and their inhibitory effects on osteoclasts. Mineral binding affinities differ among the clinically used BPs and may influence their differential distribution within bone, their biological potency, and their duration of action. The inhibitory effects of the nitrogen-containing BPs (including alendronate, risedronate, ibandronate, and zoledronate) on osteoclasts appear to result from their inhibition of farnesyl pyrophosphate synthase (FPPS), a key branch-point enzyme in the mevalonate pathway. FPPS generates isoprenoid lipids used for the post-translational modification of small GTP-binding proteins essential for osteoclast function. Effects on other cellular pathways, such as preventing apoptosis in osteocytes, are emerging as other potentially important mechanisms of action. As a class, BPs share several common properties. However, as with other classes of drugs, there are obvious chemical, biochemical, and pharmacological differences among the various individual BPs. Each BP has a unique profile that may help to explain potential important clinical differences among the BPs, in terms of speed of onset of fracture reduction, antifracture efficacy at different skeletal sites, and the degree and duration of suppression of bone turnover. As we approach the 40th anniversary of the discovery of their biological effects, there remain further opportunities for using their properties for medical purposes.