Molecular biology of bone remodeling: Implications for new therapeutic targets for osteoporosis

Abstract

Osteoporosis is a major public health problem for adults over age 55 years costing billions of euros/dollars. Over the last 20 years anti-resorptive drugs were the treatment of choice for osteoporosis and most were derived from the bisphosphonate molecule. In the last 7 years remarkable advances in molecular biology and genetics have led to a detailed understanding of the bone remodeling cycle and as a result new therapeutic targets for treatment emerged. These new compounds have different modes of action depending on their role in the bone remodeling cycle. A major discovery was the important role of RANKL (receptor activator of nuclear factor kappa B ligand) secreted by osteoblasts and responsible for stimulating osteoclastic bone resorption. This led to development of a potent monoclonal antibody that blocks its action. This drug should be available soon as a new treatment for osteoporosis. Other molecular targets in resorption have been identified and several specific antagonists are potential treatments. However, a significant limiting factor for a new anti-resorptive drug is the cost of bringing it to the market because of the huge costs of a fracture trial. Although anti-resorptive agents have been the backbone of osteoporosis treatment they do not rebuild bone architecture and development of anabolic agents is needed. These are likely to evolve from an understanding of the LRP/Wnt signaling pathway. Already an antibody against sclerostin has shown promise in animal studies, and not to forget parathyroid hormone which was the first clinically useful anabolic treatment for osteoporosis.