Receptor activator of nuclear factor kappa B ligand (RANKL) plays a key role in bone destruction across a range of conditions including osteoporosis, treatment-induced bone loss, rheumatoid arthritis, and fuels a vicious cycle of bone destruction and tumor growth in metastatic disease and multiple myeloma. ^1-7 RANKL is the final common mediator that regulates bone remodeling.

• RANKL is the primary mediator of osteoclast formation, function, and survival^8-12 in both cortical and trabecular bone throughout the body.¹³
• RANKL, produced by osteoblasts and other cells, causes osteoclast precursors to form and differentiate into active (mature) osteroclasts. ^9,10
• RANKL is the final common mediator that regulates bone remodeling.^11,14
• RANKL has direct catabolic effects on cortical and trabecular bone, including reductions in bone density, volume, and strength.¹³

Excess RANK Ligand activity drives bone destruction across a broad range of conditions. The body naturally produces a protein called osteoprotegerin (OPG) that neutralizes the effects of RANK Ligand, keeping the bone loss process in check. ¹¹

• OPG acts as a decoy receptor, preventing RANKL from binding to its receptor, RANK, on the surface of osteoclasts and their precursors, thus helping to maintain a balance in bone remodeling.^8,12,15,16
• In many bone-loss conditions, bone resorption rates overwhelm bone formation rates, causing an imbalance in bone remodeling.¹⁶
• In preclinical models, increases in RANKL or decreases in OPG caused significant reductions in bone density, volume, and strength. ^12,13,16-18

In preclinical models, RANKL inhibition has been shown to increase cortical and trabecular bone density, volume, and strength. ^17,19,20

• Observations across a wide range of animal disease models have confirmed that RANKL inhibition reduced osteoclast activity and that this effect was reversible. ^2,19,21
• RANKL inhibition had no direct adverse effect on osteoblast numbers. ²²
• These actions led to increased density, volume, and thickness of cortical and trabecular bone, resulting in significant increases in bone-strength measures in these animals.^17,19,20

Scientists are currently investigating RANK Ligand inhibition as a novel therapeutic approach.

References

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2. Kong Y-Y, Feige U, Sarosi I, et al. Activated T cells regulate bone loss and joint destruction in adjuvant arthritis through osteoprotegerin ligand. Nature. 1999;402:304-309.
3. Kitazawa S, Kitazawa R. RANKL is a prerequisite for cancer-associated osteolytic lesions. J Pathol. 2002;198:228-236.
4. Farrugia AN, Atkins GJ, To LB, et al. Receptor activator of nuclear factor- kB ligand expression by human myeloma cells mediates osteoclast formation in vitro and correlates with bone destruction in vivo.Cancer Res. 2003;63:5438-5445.
5. Sezer O, Heider U, Jakob C, Eucker J, Possinger K. Human bone marrow myeloma cells express RANKL. J Clin Oncol. 2002;20:353-354.
6. Hofbauer LC, Gori F, Riggs L, et al. Stimulation of osteoprotegerin ligand and inhibition of osteoprotegerin production by glucocorticoids in human osteoblastic lineage cells. Endocrinology. 1999;140:4382-4389.
7. Hofbauer LC, Shui C, Riggs BL, et al. Effects of immunosuppressants on receptor activator of NF- kB ligand and osteoprotegerin production by human osteoblastic and coronary artery smooth muscle cells. Biochem Biophys Res Commun. 2001;280:334-339.
8. Lacey DL, Timms E, Tan HL, et al. Osteoprotegerin ligand is a cytokine that regulates osteoclast differentiation and activation. Cell. 1998;93:165-176.
9. Yasuda H, Shima N, Nakagawa N, et al. Osteoclast differentiation factor is a ligand for osteoprotegerin osteoclastogenesis-inhibitory factor and is identical to TRANCE/ RANKL.Proc Natl Acad Sci USA. 1998;95:3597-3602.
10. Fuller K, Wong B, Fox S, Choi Y, Chambers TJ. TRANCE is necessary and sufficient for osteoblast-mediated activation of bone resorption in osteoclasts. J Exp Med. 1998;188:997-1001.
11. Lacey DL, Tan HL, Lu J, et al. Osteoprotegerin ligand modulates murine osteoclast survival in vitro and in vivo. Am J Pathol. 2000;157:435-448.
12. Boyle WJ, Simonet WS, Lacey DL. Osteoclast differentiation and activation. Nature. 2003;423:337-342.
13. Yuan YY, Lau AG, Kostenuik PJ, et al. RANKL has detrimental effects on cortical and trabecular bone volume, mineralization and bone strength in mice. Presented at the 27th Annual Meeting of the American Society for Bone and Mineral Research; September 23-37, 2005; Nashville, Tenn.
14. O’Brien EA, Williams JHH, Marshall MJ. Osteoprotegerin ligand regulates osteoclast adherence to the bone surface in mouse calvaria. Biochem Biophys Res Commun. 2000;274:281-290.
15. Simonet WS, Lacey DL, Dunstan CR, et al. Osteoclast differentiation and activation. Cell. 1997;89:309-319.
16. Hofbauer LC, Schoppet M. Clinical implications of the osteoprotegerin/RANKL/RANK system for bone and vascular diseases. JAMA. 2004;292:490-495.
17. Ross AB, Bateman TA, Kostenuik PJ, et al. The effects of osteoprotegerin on the mechanical properties of rat bone. J Mater Sci Mater Med. 2001;12:583-588.
18. Mizuno A, Kanno T, Hoshi M, et al. Transgenic mice overexpressing soluble osteoclast differentiation factor (sODF) exhibit severe osteoporosis. J Bone Miner Metab. 2002;20:337-334.
19. Kostenuik PJ, Ominsky MS, Cranmer P, Atkinson J. The RANKL antagonist OPG-Fc causes significant increases in cortical bone thickness, density, and bone strength index in adult female cynomolgus monkeys. Abstract/poster presented at: 5th European Congress on Clinical & Economic Aspects of Osteoporosis & Osteoarthritis, March 16-19, 2005; Rome, Italy.
20. Kostenuik PJ, Capparelli C, Morony S, et al. OPG and PTH-(1-34) have additive effects on bone density and mechanical strength in osteopenic ovariectomized rats. Endocrinology. 2001;142:4295-4304.
21. Schett G, Redlich K, Hayer S, et al. Osteoprotegerin protects against generalized bone loss in tumor necrosis factor-transgenic mice. Arthritis Rheum. 2003;48:2042-2051.
22. Kostenuik PJ, et al. Coupling of bone resorption and bone formation: a comparison of a RANKL antagonist (OPG) and bisphosphonates in mice. J Bone Miner Res. 2004;19(suppl 1):S415. Abstract M300.