Regulation of bone remodeling and emerging breakthrough drugs for osteoporosis and osteolytic bone metastases

Major advances have been made in the past 10 years in our understanding of the molecular basis of bone cell formation and bone remodeling. For example, the discovery of osteoprotegerin, the decoy receptor and inhibitor of receptor activator of NF-kappaB ligand (RANKL), and the RANKL/receptor activator of NF-kappaB (RANK) signaling pathway that is essential for osteoclastogenesis, has helped clarify the mechanisms regulating osteoclast formation, activation, and survival. PTH, like most other osteoclast stimulating factors, promotes RANKL production by osteoblast/stromal cells when they are exposed to it continuously, but when given intermittently it stimulates bone formation and reduces fracture risk in postmenopausal women. This anabolic effect is associated with increased expression of insulin-like and fibroblast growth factors and decreased osteoblast apoptosis. Src tyrosine kinase is essential for osteoclast activation and also negatively regulates osteoblast activity. Thus, it is a well-validated therapeutic target for the prevention of postmenopausal and other forms of bone loss. Preliminary in vitro and in vivo studies of specifically designed, bone targeted, nonpeptide Src inhibitors have shown that these compounds inhibit bone resorption and stimulate new bone formation. The design of drugs using structure/function approaches such as this should lead to the development of novel therapeutics that could be used to counteract the negative effects of chronic renal failure on the skeleton.