Pharmacological diversity among drugs that inhibit bone resorption

• ‘Anti-resorptive’ drugs inhibit osteoclast differentiation or function by diverse mechanisms.
• Bisphosphonates are still the major drugs used for osteoporosis and skeletal complications of cancer.
• The anti-RANK-ligand antibody, denosumab, is also highly effective in osteoporosis and bone oncology.
• Several cathepsin K inhibitors have been studied, but only odanacatib is close to being registered.
• Non-skeletal actions of bisphosphonates may include anti-cancer effects and extension of life span.

Drugs that inhibit bone resorption (‘anti-resorptives’) continue to dominate the therapy of bone diseases characterized by enhanced bone destruction, including Paget's disease, osteoporosis and cancers. The historic use of oestrogens for osteoporosis led on to SERMs (Selective Estrogen Receptor Modulators, e.g. raloxifene and bazedoxifene). Currently the mainstay of treatment worldwide is still with bisphosphonates, as used clinically for over 40 years. The more recently introduced anti-RANK-ligand antibody, denosumab, is also very effective in reducing vertebral, non-vertebral and hip fractures. Odanacatib is the only cathepsin K inhibitor likely to be registered for clinical use. The pharmacological basis for the action of each of these drug classes is different, enabling choices to be made to ensure their optimal use in clinical practice.