Bisphosphonates: From the laboratory to the clinic and back again
Bisphosphonates: From the laboratory to the clinic and back again
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DOI：
10.1016/s8756-3282(99)00116-7
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发表时间：
1999-07-01
期刊：
影响因子：
4.1
通讯作者：
Rogers, MJ
中科院分区：
文献类型：
--
作者：
Russell, RGG;Rogers, MJ
用作骨吸收抑制剂的双膦酸盐（BP）均含有两个连接到单个碳原子上的膦酸盐基团，形成“P-C-P”结构。因此，二膦酸盐是天然存在的含焦磷酸盐化合物的稳定类似物，这有助于解释它们的细胞内和细胞外作用模式。双膦酸盐吸附骨矿物质并抑制骨吸收。双膦酸盐的作用方式最初归因于对羟基磷灰石晶体的物理化学作用，但人们逐渐清楚，细胞作用也必须参与其中。在更复杂的化合物中观察到的显着结构-活性关系表明，最大活性所需的药效团不仅取决于双膦酸盐部分，还取决于关键特征，例如烷基或杂环侧链中的氮取代。几种双膦酸盐（例如依替膦酸盐、氯膦酸盐、帕米膦酸盐、阿仑膦酸盐、替鲁膦酸盐、 利塞膦酸盐和伊班膦酸盐）被认为是治疗佩吉特骨病、骨髓瘤和骨转移等临床疾病的有效方法。双膦酸盐现在也被认为是预防和治疗骨质疏松症的成功抗骨吸收剂。特别是，依替膦酸钠和阿仑膦酸钠在许多国家被批准作为治疗药物，两者都可以增加骨量，并将绝经后妇女脊柱、髋部和其他部位的骨折率降低至控制率的大约一半。除了抑制破骨细胞外，双膦酸盐能够降低近骨重塑单位的激活频率和出生率，并可能增强骨矿化，也可能有助于减少骨折。双膦酸盐的临床药理学特点是肠道吸收低，但在骨中高度选择性定位和保留。显着的副作用很小。目前双膦酸盐的问题包括新化合物的引入、治疗方案的选择（例如，使用间歇给药而不是连续给药）、静脉注射与口服治疗、最佳治疗持续时间、与其他药物的组合以及将其使用扩展到其他病症，包括类固醇相关的骨质疏松症、男性骨质疏松症、关节炎和骨质减少 双磷酸盐通过选择性地吸收和吸附到骨骼的矿物质表面来抑制骨吸收，从而干扰破骨细胞的作用。双膦酸盐很可能被破骨细胞内化并干扰特定的生化过程并诱导细胞凋亡。产生这些效应的分子机制正变得越来越清晰。最近的研究表明，双膦酸盐至少可以分为两组，具有不同的作用方式。与焦磷酸盐非常相似的双膦酸盐（例如氯膦酸盐和依替膦酸盐）可以通过代谢方式掺入 ATP 的不可水解类似物中，从而抑制 ATP 依赖性细胞内酶。更有效的含氮双膦酸盐（例如帕米膦酸盐、阿仑膦酸盐、利塞膦酸盐和伊班膦酸盐）不会以这种方式代谢，但可以抑制甲羟戊酸途径的酶，从而阻止类异戊二烯化合物的生物合成，而类异戊二烯化合物对于小 GTP 酶的翻译后修饰至关重要。蛋白质异戊二烯化的抑制和这些关键调节蛋白功能的破坏解释了破骨细胞活性的丧失和细胞凋亡的诱导。这些不同的作用方式可能解释了化合物之间在临床效果方面的细微差异。 总之，双膦酸盐现已被确立为治疗骨疾病的一类重要药物，并且其作用方式正在被阐明。因此，它们的全部治疗潜力正在逐渐被实现。 (C) 1999 年，Elsevier Science Inc. 保留所有权利。
Bisphosphonates (BPs) used as inhibitors of bone resorption all contain two phosphonate groups attached to a single carbon atom, forming a "P-C-P" structure. The bisphosphonates are therefore stable analogues of naturally occurring pyrophosphate-containing compounds, which now helps to explain their intracellular as well as their extracellular modes of action. Bisphosphonates adsorb to bone mineral and inhibit bone resorption. The mode of action of bisphosphonates was originally ascribed to physico-chemical effects on hydroxyapatite crystals, but it has gradually become clear that cellular effects must also be involved. The marked structure-activity relationships observed among more complex compounds indicate that the pharmacophore required for maximal activity not only depends upon the bisphosphonate moiety but also on key features, e.g., nitrogen substitution in alkyl or heterocyclic side chains.Several bisphosphonates (e.g., etidronate, clodronate, pamidronate, alendronate, tiludronate, risedronate, and ibandronate) are established as effective treatments in clinical disorders such as Paget's disease of bone, myeloma, and bone metastases. Bisphosphonates are also now well established as successful antiresorptive agents for the prevention and treatment of osteoporosis. In particular, etidronate and alendronate are approved as therapies in many countries, and both can increase bone mass and produce a reduction in fracture rates to approximately half of control rates at the spine, hip, and other sites in postmenopausal women. Is addition to inhibition of osteoclasts, the ability of bisphosphonates to reduce the activation frequency and birth rates of nea bone remodeling units, and possibly to enhance osteon mineralisation, may also contribute to the reduction in fractures.The clinical pharmacology of bisphosphonates is characterized by low intestinal absorption, but highly selective localization and retention in bone. Significant side effects are minimal. Current issues with bisphosphonates include the introduction of new compounds, the choice of therapeutic regimen (e.g., the use of intermittent dosing rather than continuous), intravenous vs, oral therapy, the optimal duration of therapy, the combination with other drugs, and extension of their use to other conditions, including steroid associated osteoporosis, male osteoporosis, arthritis, and osteopenic disorders in childhood.Bisphosphonates inhibit bone resorption by being selectively taken up and adsorbed to mineral surfaces in bone, where they interfere with the action of osteoclasts. It is likely that bisphosphonates are internalized by osteoclasts and interfere with specific biochemical processes and induce apoptosis. The molecular mechanisms by which these effects are brought about are becoming clearer. Recent studies show that bisphosphonates can be classified into at least two groups with different modes of action. Bisphosphonates that closely resemble pyrophosphate (such as clodronate and etidronate) can be metabolically incorporated into nonhydrolysable analogues of ATP that may inhibit ATP-dependent intracellular enzymes. The more potent, nitrogen-containing bisphosphonates (such as pamidronate, alendronate, risedronate, and ibandronate) are not metabolized in this way but can inhibit enzymes of the mevalonate pathway, thereby preventing the biosynthesis of isoprenoid compounds that are essential for the posttranslational modification of small GTPases. The inhibition of protein prenylation and the disruption of the function of these key regulatory proteins explains the loss of osteoclast activity and induction of apoptosis. These different modes of action might account for subtle differences between compounds in terms of their clinical effects.In conclusion, bisphosphonates are now established as an important class of drugs for the treatment of bone diseases, and their mode of action is being unravelled. As a result, their full therapeutic potential is gradually being realized. (C) 1999 by Elsevier Science Inc. All rights reserved.