Bisphosphonates are potent inhibitors of osteoclast mediated bone resorption. These compounds are stable analogues of the inorganic pyrophosphate (PPi), which is an endogenous regulator of bone mineralization. Characteristics Bisphosphonates were developed in the nineteenth century for industrial use, in particular as “water softeners.” The first clinical use of bisphosphonates in humans was in the 1960s for the treatment of Paget disease, a focal disorder of bone remodeling due to abnormally increased osteoclast-mediated bone resorption. So far, bisphosphonates have been successfully studied in several clinical disorders characterized by an alteration in bone resorption, such as metastatic and osteolytic bone diseases, hypercalcemia of malignancy and osteoporosis. All bisphosphonates share a common structure which consists of two phosphate groups attached to a single carbon atom (P-C-P). The P-C-P group is responsible for the affinity of these drugs for the bone, since it is essential for binding to hydroxyapatite or hydroxylapatite. The substitution in the R1 and R2 side chains give rise to a variety of compounds with different potency and biological effects. For instance, the presence of a hydroxyl group in the R1 side chain confers a higher affinity for the bone mineral. The R2 side chains directly influence the potency of bisphosphonates for inhibiting osteoclast-mediated bone resorption. In particular, the bisphosphonates containing a basic primary nitrogen atom in an alkyl chain (such as pamidronate and alendronate) are 10–100 times more potent than non nitrogen bisphosphonates. Indeed, the higher antiresorptive potency is obtained when the R2 side chain contains a nitrogen atom within a heterocyclic ring (as in risendronate and zoledronate).