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.

Figure 1

Bone Remodeling - showing the various stages and the factors involved. Also shown is the development of osteoblasts and osteoclasts from precursors. The factors in bold red are currently being used and/or under active investigation in clinical studies, others in green are potential targets based on animal and in vitro studies. RANK (Receptor Activator of Nuclear Factor-Kappa B), RANKL (Receptor Activator of Nuclear Factor-Kappa B Ligand), OPG (Osteoprotegerin), TNF α (Tumor Necrosis Factor alpha), IL (Interleukin), PGE 2 (Prostaglandin E 2), PTHrP (Parathyroid Hormone related peptide), PTH (Parathyroid Hormone), 1,25(OH)₂ D3 (1,25 – dihydroxyvitamin D 3), CBF A1 (Core Binding factor alpha 1) BMP (Bone Morphogenic protein), TGF β (Transforming Growth Factor beta), IGF (Insulin like growth factor), m-CSF (Monocyte colony stimulating factor), NF-kB (Nuclear factor kappaB), NFAT (Nuclear Factor of Activated T-cells) *The function of Vitamin D3 in bone is complex and is dependent on serum calcium. If serum calcium is low, vitamin D increases bone resorption and if its high/normal, vitamin D promotes bone formation.

Figure 2

Osteoclasts, osteoblasts and osteocytes: various molecules involved in bone remodeling. Those shown in bold red are currently being used and/or under active investigation in clinical studies, others in green are potential targets based on animal and in vitro studies. CA □□ (Carbonic anhydrase iso enzyme 2), Cl channel (Chloride channel), TRAP (Tartarate resistant acid phosphatase), Trph1 (Tryptophan hydroxylase 1), CREB (cAMP (cyclic adenosine mono phosphate) response element binding protein), Wnt (Wingless type and integrase 1), Dkk (Dickkopf-1), WIF (Wnt inhibitory factor), sFRP (Secreted frizzled related protein), Lrp5/6 (Low density lipoprotein receptor related protein 5/6)