Tiludronate. A new treatment for an old ailment: Paget's disease of bone

Tiludronate ([[(4-chlorophenyl)thio]-methylene]-bis-phosphonate, ClPsMBP, Skelid, Sanofi) is a powerful inhibitor of bone resorption which has been shown to be a highly effective and safe agent for the treatment of Paget's disease of bone. Preclinical studies in vitro and in vivo have demonstrated a dose-dependent inhibitory effect on bone resorption. Unlike other bisphosphonates, tiludronate does not seem to interfere with the differentiation of osteoclasts or with their access to bone mineral. Bone tolerance studies indicate that tiludronate has an excellent therapeutic window. Thus, at the doses which induce a substantial inhibition of bone resorption it neither causes an appreciable effect on mineralisation, nor impairs biomechanical bone resistance. New formulations of tiludronate (tablets) have a bioavailability of 6% (2-11%) when ingested under optimal conditions. The pharmacokinetic profile of tiludronate is linear. Approximately 50% of the absorbed dose is bound to bone and the rate of release from this site is limited by bone turnover. Several open uncontrolled, open randomised, and double-blind, placebo-controlled studies carried out in patients with active Paget's disease have demonstrated that tiludronate reduces bone pain and produces an intense and sustained biochemical response. 3-6 months after starting tiludronate therapy, serum alkaline phosphatase levels fall far more than 50% from baseline values, reaching normal values in a percentage of the cases ranging from 35-70%. At present, tiludronate, together with pamidronate and alendronate, appear to be the drugs of choice for first-line use in the management of relatively young patients at risk of having long-term complications, when long-lasting control of disease activity is required.