Potential new drug targets for osteoporosis

Abstract

Osteoporosis is a worldwide health problem with a high prevalence. Agents for the treatment of osteoporosis are classified as either antiresorptive or anabolic. Antiresorptive agents work by inhibiting the activity of osteoclasts and, therefore, reducing bone resorption. Currently available antiresorptive agents include bisphosphonates, selective estrogen-receptor modulators, calcitonin and estrogen. Various novel antiresorptive agents are in development. Receptor activator of nuclear factor kappa B ligand is an important cytokine involved in osteoclast activation; denosumab, a fully human monoclonal antibody to this molecule, has finished a major fracture trial. Assessment is underway of odanacatib--an inhibitor of cathepsin K, which is an osteoclast enzyme required for resorption of bone matrix. Glucagon-like peptide 2 is being evaluated for the prevention of the nocturnal rise in bone resorption without affecting bone formation. Anabolic agents act by stimulating formation of new bone. The only anabolic agent currently available in the US is teriparatide--recombinant human parathyroid hormone (PTH)(1-34)--and recombinant human PTH(1-84) is available in Europe. PTH stimulates osteoblast function and bone formation. Novel anabolic agents in development include: antibodies such as sclerostin and dickkopf-1 that target molecules involved in Wnt signaling, a pathway that regulates gene transcription of proteins that are important for osteoblast function; an antagonist to the calcium-sensing receptor; and an activin receptor fusion protein, which functions as an activin antagonist and has shown promise as an anabolic agent in early human trials.