Rogers Michael J
Bone Research Group, Department of Medicine & Therapeutics, Institute of Medical Sciences, Foresterhill, Aberdeen AB25 2ZD, Scotland, UK.
Curr Pharm Des. 2003;9(32):2643-58. doi: 10.2174/1381612033453640.
Bisphosphonates are currently the most important and effective class of anti-resorptive drugs available, but the exact molecular mechanisms by which they inhibit osteoclast-mediated bone resorption have only recently been identified. Due to the targeting of bisphosphonates to bone mineral and the ability of osteoclasts to release bone-bound bisphosphonate, a direct effect on mature osteoclasts appears to be the most important route of action. As a result of recent discoveries concerning their molecular mechanism of action, bisphosphonates can be grouped into two classes. The simple bisphosphonates that closely resemble PPi (such as clodronate, etidronate and tiludronate) can be metabolically incorporated into non-hydrolysable analogues of ATP that accumulate intracellularly in osteoclasts, resulting in induction of osteoclast apoptosis. By contrast, the more potent, nitrogen-containing bisphosphonates (such as pamidronate, alendronate, risedronate, ibandronate and zoledronate) appear to act as analogues of isoprenoid diphosphate lipids, thereby inhibiting FPP synthase, an enzyme in the mevalonate pathway. Inhibition of this enzyme in osteoclasts prevents the biosynthesis of isoprenoid lipids (FPP and GGPP) that are essential for the post-translational farnesylation and geranylgeranylation of small GTPase signalling proteins. Loss of bone-resorptive activity and osteoclast apoptosis is due primarily to loss of geranylgeranylated small GTPases. Identification of FPP synthase as the target of nitrogen-containing bisphosphonates has also helped explain the molecular basis for the adverse effects of these agents in the GI tract and on the immune system.
双膦酸盐类药物是目前可用的最重要且最有效的抗骨吸收药物，但它们抑制破骨细胞介导的骨吸收的确切分子机制直到最近才被确定。由于双膦酸盐靶向骨矿物质以及破骨细胞释放骨结合双膦酸盐的能力，对成熟破骨细胞的直接作用似乎是最重要的作用途径。基于其分子作用机制的最新发现，双膦酸盐可分为两类。与焦磷酸（PPi）非常相似的简单双膦酸盐（如氯膦酸盐、依替膦酸盐和替鲁膦酸盐）可通过代谢整合到ATP的不可水解类似物中，这些类似物在破骨细胞内积累，从而诱导破骨细胞凋亡。相比之下，更有效的含氮双膦酸盐（如帕米膦酸盐、阿仑膦酸盐、利塞膦酸盐、伊班膦酸盐和唑来膦酸盐）似乎作为类异戊二烯二磷酸脂质的类似物起作用，从而抑制甲羟戊酸途径中的一种酶——法尼基焦磷酸合酶（FPP合酶）。在破骨细胞中抑制这种酶可防止类异戊二烯脂质（FPP和GGPP）的生物合成，而这些脂质对于小GTPase信号蛋白的翻译后法尼基化和香叶基香叶基化至关重要。骨吸收活性丧失和破骨细胞凋亡主要是由于香叶基香叶基化的小GTPase缺失所致。将FPP合酶鉴定为含氮双膦酸盐的靶点也有助于解释这些药物在胃肠道和免疫系统中产生不良反应的分子基础。
