Skip to main content

Advertisement

Log in

Osteoprotegerin as a potential therapy for osteoporosis

  • Published:
Current Osteoporosis Reports Aims and scope Submit manuscript

Abstract

The discovery and characterization of the RANKL/RANK/ OPG signaling pathway and the identification of its role in the pathogenesis of bone loss have provided the rationale for the development of drugs with the ability to modulate RANK-induced osteoclastogenesis. In vivo studies have identified interfering with the RANKL/RANK interaction as a potential therapeutic target in the management of osteoporosis. Two agents capable of blocking the binding of RANKL to RANK have been so far tested in clinical studies—osteoprotegerin (Fc-OPG fusion molecule) and the RANKL-antibody (AMG 162). Both have been found to have profound inhibitory effects on bone resorption, with AMG 162 appearing to be overall superior to OPG. Data are still very scarce, however, and much remains to be uncovered before novel strategies capable of modulating the RANKL/OPG signaling pathway could be safely and effectively used in the management of osteoporosis.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Similar content being viewed by others

References and Recommended Reading

  1. Suda T, Takahashi N, Udagawa N, et al.: Modulation of osteoclast differentiation and function by the new members of the tumor necrosis factor receptor and ligand families. Endocr Rev 1999, 20:345–357.

    Article  PubMed  CAS  Google Scholar 

  2. Manolagas SC: Birth and death of bone cells: basic regulatory mechanisms and implications for the pathogenesis and treatment of osteoporosis. Endocr Rev 2000, 21:115–137.

    Article  PubMed  CAS  Google Scholar 

  3. Duong LT, Rodan GA: Regulation of osteoclast formation and function. Rev Endocr Metab Disord 2001, 2:95–104.

    Article  PubMed  CAS  Google Scholar 

  4. Teitelbaum SL: Bone resorption by osteoclasts. Science 2000, 289:1504–1508.

    Article  PubMed  CAS  Google Scholar 

  5. Khosla S: Minireview: the OPG/RANKL/RANK system. Endocrinology 2001, 142:5050–5055.

    Article  PubMed  CAS  Google Scholar 

  6. Boyle WJ, Simonet WS, Lacey DL: Osteoclast differentiation and activation. Nature 2003, 423337–4233342. Very clear review article providing insight into the mechanisms of osteoclastogenesis and activation of bone resorption with particular reference to the role of the RANK signaling pathway.

  7. Baron R: Arming the osteoclasts. Nat Med 2004, 10:458–460.

    Article  PubMed  CAS  Google Scholar 

  8. Tanaka S, Takahashi N, Udagawa N, et al.: Macrophage colony-stimulating factor is indispensable for both proliferation and differentiation of osteoclast progenitors. J Clin Invest 1993, 91:257–263.

    Article  PubMed  CAS  Google Scholar 

  9. Lacey DL, Timms E, Tan H-L, et al.: Osteoprotegerin (OPG) ligand is a cytokine that regulates osteoclast differentiation and activation. Cell 1998, 93:165–176.

    Article  PubMed  CAS  Google Scholar 

  10. Hsu H, Lacey DL, Dunstan CR, et al.: Tumor necrosis factor receptor family member RANK mediates osteoclast differentiation and activation induced by osteoprotegerin ligand. Proc Natl Acad Sci U S A 1999, 96:3540–3545.

    Article  PubMed  CAS  Google Scholar 

  11. Kong YY, Yoshida H, Sarosi I, et al.: OPGL is a key regulator of osteoclastogenesis, lymphocyte development and lymphnode organogenesis. Nature 1999, 397:315–323.

    Article  PubMed  CAS  Google Scholar 

  12. Sheperd R, Gao Y, Qien W, et al.: IL-7 induces bone loss in estrogen deficient mice by a mechanism involving activation and expansion of TNF producing T lymphocytes. J Bone Miner Res 2003, 18(Suppl_2):S16.

    Google Scholar 

  13. Toraldo G, Roggia C, Qian WP, et al.: IL-7 induces bone loss in vivo by induction of receptor activator of nuclear factor kappa B ligand and tumor necrosis factor alpha from T cells. Proc Natl Acad Sci U S A 2003, 100:125–130.

    Article  PubMed  CAS  Google Scholar 

  14. Weitzmann MN, Roggia C, Toraldo G, et al.: Increased production of IL-7 uncouples bone formation from bone resorption during estrogen deficiency. J Clin Invest 2002, 110:1643–1650.

    PubMed  CAS  Google Scholar 

  15. Simonet WS, Lacey DL, Dunstan CR, et al.: Osteoprotegerin: a novel secreted protein involved in the regulation of bone density. Cell 1997, 89:309–319.

    Article  PubMed  CAS  Google Scholar 

  16. 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 U S A 1998, 95:3597–3602.

    Article  PubMed  CAS  Google Scholar 

  17. Emery JG, McDonnell P, Burke MB, et al.: Osteoprotegerin is a receptor for the cytotoxic ligand TRAIL. J Biol Chem 1998, 273:14363–14367.

    Article  PubMed  CAS  Google Scholar 

  18. Wiley SR, Schooley K, Smolak PJ, et al.: Identification and characterization of a new member of the TNF family that induces apoptosis. Immunity 1995, 3:673–682.

    Article  PubMed  CAS  Google Scholar 

  19. Bucay N, Sarosi I, Dunstan CR, et al.: Osteoprotegerindeficient mice develop early onset osteoporosis and arterial calcification. Genes Dev 1998, 12:1260–1268.

    Article  PubMed  CAS  Google Scholar 

  20. Li J, Sarosi I, Yan XQ, Morony S, et al.: RANK is the intrinsic hematopoietic cell surface receptor that controls osteoclastogenesis and regulation of bone mass and calcium metabolism. Proc Natl Acad Sci U S A 2000, 97:1566–1571.

    Article  PubMed  CAS  Google Scholar 

  21. Mundy GR: The bone microenvironment and metastasis. Cancer Treat Rev 2005, 31(Suppl 1):S11.

    Google Scholar 

  22. Dougau W, Tometsko M, Armstrong A, et al.: RANK ligand directly induces osteoclastogenic, angiogenic, chemoattractive and invasive factors on RANK-expressing human cancer cells MDA-MB-231 and PC3. Cancer Treat Rev 2005, 31(Suppl 1):S24.

    Google Scholar 

  23. Croucher P, Holen I, Eaton C: Nonosseous effects of osteoprotegerin. Cancer Treat Rev 2005, 31(Suppl 1):S14.

    Google Scholar 

  24. Hofbauer LC, Schoppet M: Clinical implications of the osteoprotegerin/ RANKL/ RANK system for bone and vascular diseases. JAMA 2004, 292:490–495. Comprehensive review of role of alterations in the RANKL/OPG system in the pathogenesis of a number of diseases affecting the skeleton with an interesting discussion on potential therapeutic implications of these findings.

    Article  PubMed  CAS  Google Scholar 

  25. Hofbauer LC, Gori F, Riggs BL, et al.: Stimulation of osteoprotegerin ligand and inhibition of osteoprotegerin production by glucocorticoids in human osteoblastic lineage cells: potential paracrine mechanisms of glucocorticoid-induced osteoporosis. Endocrinology 1999, 140:4382–4389.

    Article  PubMed  CAS  Google Scholar 

  26. Sasaki N, Kusano E, Ando Y, et al.: Glucocorticoid decreases circulating osteoprotegerin (OPG). Nephrol Dial Transplant 2001, 16:479–482.

    Article  PubMed  CAS  Google Scholar 

  27. Sivagurunathan S, Muir MM, Brennan TC, et al.: Influence of glucocorticoids on human osteoclast generation and activity. J Bone Miner Res 2005, 20:390–398.

    Article  PubMed  CAS  Google Scholar 

  28. Hofbauer LC, Khosla S, Dunstan CR, et al.: Estrogen stimulates gene expression and protein production of osteoprotegerin in human osteoblastic cells. Endocrinology 1999, 140:4367–4370.

    Article  PubMed  CAS  Google Scholar 

  29. Shevde NK, Bendixen A, Dienger KM, Pike JW: Estrogens suppress RANK ligand-induced osteoclast differentiation via a stromal cell independent mechanism involving c-Jun repression. Proc Natl Acad Sci U S A 2000, 977:829–834.

    Google Scholar 

  30. Eghbali-Fatourechi G, Khosla S, Sanyal A, et al.: Role of RANK ligand in mediating increased bone resorption in early postmenopausal women. J Clin Invest 2003, 111:1221–1230.

    PubMed  CAS  Google Scholar 

  31. Pacifici R: Estrogen, cytokines, and pathogenesis of postmenopausal osteoporosis. J Bone Miner Res 1996, 11:1043–1051.

    Article  PubMed  CAS  Google Scholar 

  32. Riggs BL, Sundeep K, Meltn LJ III: Sex steroids and the construction and conservation of the adult skeleton. Endocr Rev 2002, 23:279–302.

    Article  PubMed  CAS  Google Scholar 

  33. Bord S, Ireland DC, Beavan SR, Compston JE: The effects of estrogen on osteoprotegerin, RANKL and estrogen receptor expression in human osteoblasts. Bone 2003, 32:136–141.

    Article  PubMed  CAS  Google Scholar 

  34. Viereck V, Grundker C, Blaschke S, et al.: Raloxifene concurrently stimulates osteoprotegerin and inhibits interleukin-6 production by human trabecular osteoblasts. J Clin Endocrinol Metab 2003, 88:4206–4213.

    Article  PubMed  CAS  Google Scholar 

  35. Schett G, Stefan K, Redlich K, et al.: Soluble RANKL and risk of nontraumatic fracture. JAMA 2004, 291:1108–1113.

    Article  PubMed  CAS  Google Scholar 

  36. Mezquita-Raya P, de la Higuera M, Fernandez Garcia F, et al.: The contribution of serum osteoprotegerin to bone mass and vertebral fractures in postmenopausal women. Osteoporos Int 2005, Online.

  37. Osteoporosis Methodology Group and The Osteoporosis Research Advisory Group. Meta-analyses of therapies for postmenopausal osteoporosis. Endocr Rev 2002, 4:496–551.

    Google Scholar 

  38. Cheng X, Kinosaki M, Takami M, et al.: Disabling of receptor activator of nuclear factor-kB (RANK) receptor complex by novel osteoprotegerin-like peptidomimetics restores bone loss in vivo. J Biol Chem 2004, 279:8269–8277.

    Article  PubMed  CAS  Google Scholar 

  39. Honore P, Luger NM, Sabino MA, et al.: Osteoprotegerin blocks bone cancer-induced skeletal destruction, skeletal pain and pain-related neurochemical reorganisation of the spinal cord. Nat Med 2000, 6:521–528.

    Article  PubMed  CAS  Google Scholar 

  40. Min H, Morony S, Sarosi I, et al.: Osteoprotegerin reverses osteoporosis by inhibiting endosteal osteoclasts and prevents vascular calcification by blocking a process resembling osteoclastogenesis. J Exp Med 2000, 192:463–474.

    Article  PubMed  CAS  Google Scholar 

  41. Bekker PJ, Holloway D, Nakanishi A, et al.: The effect of a single dose of osteoprotegerin in postmenopausal women. J Bone Miner Res 2001, 16:348–360. Only study published so far on the clinical use of OPG in postmenopausal women.

    Article  PubMed  CAS  Google Scholar 

  42. Body JJ, Greipp P, Coleman RE, et al.: A phase I study of AMGN-0007, a recombinant osteoprotegerin construct, in patients with multiple myeloma or breast carcinoma related bone metastases. Cancer 2003, 97(Suppl 3):887–892. Demonstrates that OPG is at least as potent as pamidronate in inhibiting cancer-induced bone resorption.

    Article  PubMed  Google Scholar 

  43. Oyajobi BO, Anderson DM, Traianedes K, et al.: Therapeutic efficacy of a soluble receptor activator of nuclear factor kB-IgG Fc fusion protein in suppressing bone resorption and hypercalcemia in a model of humoral hypercalcemia of malignancy. Cancer Res 2001, 61:2572–2578.

    PubMed  CAS  Google Scholar 

  44. Bekker PJ, Holloway D, Rasmussen AS, et al.: A single-dose placebo-controlled study of AMG 162, a fully human monoclonal antibody to RANKL, in postmenopausal women. J Bone Miner Res 2004, 19:1059–1066. This paper outlines the anti-resorptive efficacy and safety of a single subcutaneous dose of AMG 162 in 49 postmenopausal women in a randomized, double-blind, placebo-controlled, dose escalation study with a follow-up period of 6 to 9 months.

    Article  PubMed  CAS  Google Scholar 

  45. Pan B, Farrugia AN, To LB, et al.: The nitrogen-containing bisphosphonate, zoledronic acid, influences RANKL expression in human osteoblast-like cells by activating TNF-alpha converting enzyme (TACE). J Bone Miner Res 2004, 19:147–54.

    Article  PubMed  CAS  Google Scholar 

  46. Kobayashi Y, Hashimoto F, Miyamoto H, et al.: Force-induced osteoclast apoptosis in vivo is accompanied by elevation in transforming growth factor b and osteoprotegerin expression. J Bone Miner Res 2000, 15:1924–1934.

    Article  PubMed  CAS  Google Scholar 

  47. Onyia JE, Galvin RJ, Ma YL, et al.: Novel and selective small molecule stimulators of osteoprotegerin expression inhibit bone resorption. J Pharmacol Exp Ther 2004, 309:369–379.

    Article  PubMed  CAS  Google Scholar 

  48. Kostenuik PJ, Paul C, Smith S, et al.: The RANKL antagonist OPG-Fc causes significant increases in cortical bone mineral area, content and density in adult cynomolgus monkeys. J Bone Miner Res 2004, 19(Suppl 1):S19.

    Google Scholar 

  49. Smith BB, Cosenza ME, Mancini A, et al.: A toxicity profile of osteoprotegerin in the cynomolgus monkey. Int J Toxicol 2003, 22:403–412.

    PubMed  CAS  Google Scholar 

  50. McClung MR, Lewiecki EM, Bolognese MA, et al.: AMG 162 increases bone mineral density (BMD) within 1 month in postmenopausal women with low BMD. J Bone Miner Res 2004, 19(Suppl 1):S20.

    Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Rights and permissions

Reprints and permissions

About this article

Cite this article

Hamdy, N.A.T. Osteoprotegerin as a potential therapy for osteoporosis. Curr Osteoporos Rep 3, 121–125 (2005). https://doi.org/10.1007/s11914-996-0014-5

Download citation

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11914-996-0014-5

Keywords

Navigation