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) osteoclasts.^9,10
• RANK Ligand has been implicated in altering the adherence of osteoclasts to the bone surface and suppresses apoptosis of mature osteoclasts.^11,14
• RANK Ligand has direct catabolic effects on cortical and trabecular bone including reductions in bone density, volume, and strength.¹³

The body naturally produces a protein called osteoprotegerein (OPG) that neutralizes the effects of RANKL, keeping the bone loss process in check. OPG binding to RANKL immediately blocks osteoclast differentiation and induces apoptosis of mature osteoclasts to halt further bone resorption. ^{8,10,11,15,16}

Excess RANK Ligand activity drives bone destruction across a broad range of conditions. RANK Ligand has direct catabolic effects on cortical and trabecular bone including reductions in bone density, volume, and strength.¹³ In preclinical models, RANKL inhibition has been shown to increase cortical and trabecular bone density, volume and strength. ^17,18,19

• Observations across a wide range of animal disease models have confirmed that RANKL inhibition reduced osteoclast activity and that this effect was reversible.^2,18,20
• RANKL inhibition had no direct adverse effect on osteoblasts numbers.²¹
• 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. ^17,18,19

  References

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19. 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.
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