INTRODUCTION TO BISPHOSPHONATES AND THE CLINICAL-PHARMACOLOGY OF ALENDRONATE

Bisphosphonates, characterized by P-C-P bonds, are stable analogues of naturally occurring inorganic pyrophosphate (PPi), which contains cle avable P-O-P bonds. The mode of action of these compounds was original ly ascribed to their ability to adsorb strongly to hydroxyapatite crys tals, and to inhibit their growth and dissolution. It has gradually be come clear that this concept is insufficient to account for all their effects, and that cellular actions are involved, particularly with the more potent compounds. The bisphosphonates represent a novel class of drug, and have opened up new approaches in the therapy of bone diseas es. Several bisphosphonates, notably etidronate, clodranate, tiludrona te, pamidronate and alendronate (ALN), have been registered for variou s clinical applications. Depending on the compound, these include use as agents for bone scanning and as drugs for the treatment of Paget's disease, hypercalcaemia of malignancy, bone metastases and osteoporosi s. As a class, the bisphosphonates are characterized by poor intestina l absorption but marked inhibitory effects on bone resorption. They ta rget to bone and the main route of elimination is in the urine. The id eal bisphosphonate would display consistent intestinal absorption, con sistent and reversible effects on bone turnover, low toxicity, e.g. on bone mineralization and on the gut, and perhaps shortened residence t ime in bone. Present-day compounds, such as ALN, fulfil these ideals t o a substantial degree. Alendronate is one of the more potent bisphosp honates currently undergoing clinical investigation for the treatment of osteoporosis The pharmacokinetics of ALN are similar to those of ot her bisphosphonates. Clinical trials show that ALN has substantial eff ects on preventing bone loss and increasing bone mass, and can reduce fractures at several skeletal sites Bisphosphonates such as ALN clearl y have much to offer in adding to the treatment options available for osteoporosis. Several other potential applications for bisphosphonates exist, and, in this sense, the current interest in bisphosphonates is only an early step in realizing their full potential.