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The Receptor Activator of Nuclear Factor-κB Ligand Inhibitor Osteoprotegerin Is a Bone-Protective Agent in a Rat Model of Chronic Renal Insufficiency and Hyperparathyroidism

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Abstract

Osteoprotegerin (OPG) acts by neutralizing the receptor activator of nuclear factor-κB ligand (RANKL), the primary mediator of osteoclast differentiation, function, and survival. We examined whether OPG could affect the bone loss associated with chronic kidney disease (CKD) in a rodent model of CKD and secondary hyperparathyroidism (SHPT). SHPT was induced in rats by 5/6 nephrectomy (5/6 Nx) and a 1.2% P/0.6% Ca2+ diet. Starting 1 week after 5/6 Nx, rats were treated with vehicle (veh) or OPG-Fc (3 mg/kg, intravenously) every 2 weeks for 9 weeks. At baseline, 3, 6, and 9 weeks, blood was taken and bone mineral density (BMD) and bone mineral content (BMC) were assessed by dual-energy X-ray absorptiometry. Serum parathyroid hormone (sPTH) levels reached 912 pg/ml in 5/6 Nx rats vs. 97 pg/ml in shams at 9 weeks. OPG-Fc had no effect on sPTH or Ca2+ levels throughout the 9-week study, indicating that SHPT was a renal effect independent of bone changes. At 3 weeks, 5/6 Nx-veh rats had osteopenia compared with sham-veh rats and 5/6 Nx-OPG-Fc rats had significantly higher percent changes in whole-body BMC, leg BMD, and lumbar BMD versus 5/6 Nx-veh rats. By 6–9 weeks, elevated sPTH was associated with reversal of bone loss and osteitis fibrosa in the proximal tibial metaphysis. OPG-Fc decreased this sPTH-driven high bone turnover, resulting in augmented thickness of proximal tibial trabeculae in 5/6 Nx rats. Thus, RANKL inhibition with OPG-Fc can block the deleterious effects of continuously elevated sPTH on bone, suggesting that RANKL may be an important therapeutic target for protecting bone in patients with CKD and SHPT.

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Acknowledgments

We thank Holly Zoog for excellent editorial assistance and valuable comments during the preparation of this manuscript.

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Authors and Affiliations

  1. Department of Metabolic Disorders, Amgen Inc, One Amgen Center Drive, Thousand Oaks, 91320, CA

    J. Padagas, M. Colloton, V. Shalhoub, P. Kostenuik, S. Morony, L. Munyakazi, M. Guo, D. Gianneschi, E. Shatzen, Z. Geng, H.-L. Tan, D. Lacey & D. Martin

  2. Anzac Research Institute, Concord Hospital, Hospital Road, Concord, NSW, 2139, Australia

    C. Dunstan

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  1. J. Padagas
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Correspondence to V. Shalhoub.

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Padagas, J., Colloton, M., Shalhoub, V. et al. The Receptor Activator of Nuclear Factor-κB Ligand Inhibitor Osteoprotegerin Is a Bone-Protective Agent in a Rat Model of Chronic Renal Insufficiency and Hyperparathyroidism. Calcif Tissue Int 78, 35–44 (2006). https://doi.org/10.1007/s00223-005-0161-1

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