摘要：

Bisphosphonates (once called diphosphonates) are analogues of pyrophosphates. Pyrophosphates are ubiquitous compounds that are rapidly degraded in vivo by pyrophosphatases. Whereas pyrophosphates consist of two phosphonic acids joined to an oxygen (phosphorous-oxygen-phosphorous [P-O-P] structure), geminal bisphosphonates have a phosphorous-carbon-phosphorous (P-C-P) structure (Fig. 1) that is essentially impervious to chemical and enzymatic hydrolysis.46 The two phosphonic acids cause bisphosphonates to be avidly adsorbed onto the surface of hydroxyapatite crystals in bone, primarily at sites of active bone remodeling. The first bisphosphonates were synthesized in the nineteenth century by Menschutkin99 and Von Baeyer and Hofmann.53 The initial uses for bisphosphonates in industry were as antiscaling and anticorrosive agents in washing powders and water and oil brines to prevent the deposition of calcium carbonate scale. The clinical utility of these agents was advanced in the 1960s by Fleisch, Russell, and Francis.48,50,54 The bone-seeking property of bisphosphonates has made them useful for a variety of diagnostic and therapeutic purposes, including nuclear bone scans. Along with drugs such as estrogen and calcitonin, bisphosphonates alter bone remodeling by reducing bone resorption and are considered “antiresorptive” agents. The general chemical structure of bisphosphonates is shown in Figure 1. Substitution of different side chains for hydrogen at locations R1 and R2 changes the potency and side-effect profile of the compounds (Table 1).47,136 Short alkyl side chains characterize the first-generation bisphosphonates (etidronate and clodronate). Second-generation compounds, such as alendronate and pamidronate, have amino-terminal groups and are known as aminobisphosphonates. (Tiludronate does not have an amino-terminal group but is generally classified as a second-generation compound based on its time of development and potency). Risedronate, a third-generation bisphosphonate, has a cyclic side chain. The antiresorptive properties increase approximately ten-fold between generations. Newer bisphosphonates, such as ibandronate,105 zoledronate,7,34 olpadronate,33 and incandronate,150 are even more potent.51

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