Integrin antagonists as inhibitors of bone resorption: implications for treatment.

Abstract

Currently 'accepted' treatments for bone disease utilise drugs that inhibit osteoclastic bone resorption; these lead to a reduction in subsequent bone loss and thence, indirectly, to an increase in bone mass and fewer fractures. Three classes of compounds currently form the mainstay of therapy for osteoporosis: oestrogens (hormone-replacement therapy), 'selective oestrogen receptor modulators' and the bisphosphonates. Problems of patient compliance, real or theoretical long-term toxicological risks and the lack of bone anabolic agents of clinical utility suggest that there is a need for the development of further novel osteoclast resorption inhibitors. Recent biological and genetic findings in the area of bone cell function have led to the identification of new drug targets. These drugs include agents that (directly or indirectly): inhibit osteoclast adhesion to bone matrix; modify osteoclast differentiation; act on the proton pump and hence affect extracellullar acidification; antagonise extracellular enzymes that are involved in bone matrix protein degradation. Particular emphasis is placed in the present review on the evaluation of antagonists of alphavbeta3 integrin-mediated cell adhesion for use in bone disease. The wealth of new agents being developed suggests that resorption inhibition will be the best treatment for osteoporosis in the short to medium term, with the long-term aim still being toward developing anabolic drugs or cell therapeutics.