Integrin antagonists as inhibitors of bone resorption: implications for treatment

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 fractur es. Three classes of compounds currently form the mainstay of therapy for o steoporosis: oestrogens (hormone-replacement therapy), 'selective oestrogen receptor modulators' and the bisphosphonates. Problems of patient complian ce, 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 de velopment of further novel osteoclast resorption inhibitors. Recent biologi cal and genetic findings in the area of bone cell function have led to the identification of new drug targets. These drugs include agents that (direct ly or indirectly): inhibit osteoclast adhesion to bone matrix; modify osteo clast differentiation; act on the proton pump and hence affect extracellull ar acidification; antagonise extracellular enzymes that are involved in bon e matrix protein degradation. Particular emphasis is placed in the present review on the evaluation of antagonists of alphav beta3 integrin-mediated c ell adhesion for use in bone disease. The wealth of new agents being develo ped suggests that resorption inhibition will be the best treatment for oste oporosis in the short to medium term, with the long-term aim still being to ward developing anabolic drugs or cell therapeutics.