Basic Biology of Bisphosphonates

Publisher Summary Bisphosphonates are a class of drugs developed in the past three decades for use in various diseases of bone and calcium metabolism. This chapter deals with the preclinical aspects of these compounds, with emphasis on those related to osteoporosis. Bisphosphonates, formerly called diphosphonates, are compounds characterized by two C–P bonds. If the two bonds are located on the same carbon atom, resulting in a P–C–P structure, the compounds are called geminal bisphosphonates. They are, therefore, analogues of pyrophosphate that contain a carbon instead of an oxygen atom. The main effect of pharmacologically active bisphosphonates is to inhibit bone resorption. Indeed, these compounds proved to be extremely powerful inhibitors of resorption when tested in a variety of conditions, both in vitro and in vivo . The physicochemical effects of many of the bisphosphonates are very similar to those of pyrophosphate. Thus, they inhibit the formation, the aggregation, and also slow down the dissolution of calcium phosphate crystals. All these effects are related to the marked affinity of these compounds for solid-phase calcium phosphate, on the surface of which they bind strongly. This property is of great importance because it is the basis for the use of these compounds as skeletal markers in nuclear medicine and the basis for their selective localization in bone when used as drugs. The inhibition of calcium phosphate formation is closely related to the affinity of the bisphosphonate to the solidphase calcium phosphate. The binding can be bidentate through the two phosphates, as is the case for clodronate, or it can be tridentate through a third moiety, such as a hydroxyl or a nitrogen attached to the carbon atom. This is the case for most bisphosphonates used clinically today. The third binding site increases the affinity and hence the inhibitory effect on calcification.