Future developments in osteoporosis therapy

Endocrine, Metabolic and Immune Disorders - Drug Targets

Volumn 9, Issue 4, 2009, Pages 371-384

  Ng, K W ^a  

^a UNIVERSITY OF MELBOURNE   (Australia)

Author keywords

Anti resorptives; New therapies; Osteoblast; Osteoclast; Osteoporosis; SARMs; Wnt signaling

Indexed keywords

ADENOSINE TRIPHOSPHATASE INHIBITOR; ANDROGEN RECEPTOR; GLUCOCORTICOID; INTEGRIN; PARATHYROID HORMONE; PROTEIN TYROSINE KINASE INHIBITOR; PROTON TRANSPORTING ADENOSINE TRIPHOSPHATASE; SELECTIVE ANDROGEN RECEPTOR MODULATOR; WNT PROTEIN;

AGING; BONE METABOLISM; DRUG EFFICACY; DRUG SAFETY; FRACTURE; FRAIL ELDERLY; HUMAN; MUSCLE ATROPHY; NONHUMAN; OSTEOBLAST; OSTEOCLAST; OSTEOLYSIS; OSTEOPOROSIS; REVIEW;

ANIMALS; BONE DENSITY CONSERVATION AGENTS; BONE RESORPTION; CATHEPSIN K; CHLORIDE CHANNELS; CLINICAL TRIALS AS TOPIC; FEMALE; HUMANS; INTEGRINS; MALE; MICE; OSTEOBLASTS; OSTEOCLASTS; OSTEOPOROSIS; PARATHYROID HORMONE; RANK LIGAND; RATS; RECEPTORS, ANDROGEN; SIGNAL TRANSDUCTION; SRC-FAMILY KINASES; VACUOLAR PROTON-TRANSLOCATING ATPASES; WNT PROTEINS;

EID: 75749121844     PISSN: 18715303     EISSN: None     Source Type: Journal    
DOI: 10.2174/187153009789839192     Document Type: Review

References (129)

1. Cranney, A.; Guyatt, G.; Griffith, L.; Wells, G.; Tugwell, P. and Rosen, C. (2002) Meta-analyses of therapies for postmenopausal osteoporosis. IX: Summary of meta-analyses of therapies for postmenopausal osteoporosis. Endocr. Rev., 23(4), 570-578.
2. Rosen, C.J. (2005) Clinical practice. Postmenopausal osteoporosis. N. Engl. J. Med., 353(6), 595-603.
3. Raisz, L.G. (2005) Pathogenesis of osteoporosis: concepts, conflicts, and prospects. J. Clin. Invest., 115(12), 3318-3325.
4. Black, D.M.; Delmas, P.D.; Eastell, R.; Reid, I.R.; Boonen, S.; Cauley, J.A.; Cosman, F.; Lakatos, P.; Leung, P.C.; Man, Z.; Mautalen, C.; Mesenbrink, P.; Hu, H.; Caminis, J.; Tong, K.; Rosario-Jansen, T.; Krasnow, J.; Hue, T.F.; Sellmeyer, D.; Eriksen, E.F. and Cummings, S.R. (2007) Once-yearly zoledronic acid for treatment of postmenopausal osteoporosis. N. Engl. J. Med., 356(18), 1809-1822.
5. Delmas, P.D. (2002) Treatment of postmenopausal osteoporosis. Lancet, 359(9322), 2018-2026.
6. Ott, S.M. (2005) Long-term safety of bisphosphonates. J. Clin. Endocrinol. Metab., 90(3), 1897-1899.
7. Seeman, E. and Delmas, P.D. (2006) Bone quality--the material and structural basis of bone strength and fragility. N. Engl. J. Med., 354(21), 2250-2261.
8. Khosla, S.; Burr, D.; Cauley, J.; Dempster, D.W.; Ebeling, P.R.; Felsenberg, D.; Gagel, R.F.; Gilsanz, V.; Guise, T.; Koka, S.; McCauley, L.K.; McGowan, J.; McKee, M.D.; Mohla, S.; Pendrys, D.G.; Raisz, L.G.; Ruggiero, S.L.; Shafer, D.M.; Shum, L.; Silverman, S.L.; Van Poznak, C.H.; Watts, N.; Woo, S.B. and Shane, E. (2007) Bisphosphonate-associated osteonecrosis of the jaw: report of a task force of the American Society for Bone and Mineral Research. J. Bone Miner. Res., 22(10), 1479-1491.
9. Rizzoli, R.; Burlet, N.; Cahall, D.; Delmas, P.D.; Eriksen, E.F.; Felsenberg, D.; Grbic, J.; Jontell, M.; Landesberg, R.; Laslop, A.; Wollenhaupt, M.; Papapoulos, S.; Sezer, O.; Sprafka, M. and Reginster, J.Y. (2008) Osteonecrosis of the jaw and bisphosphonate treatment for osteoporosis. Bone, 42(5), 841-847.
10. Tolar, J.; Teitelbaum, S.L. and Orchard, P.J. (2004) Osteopetrosis. N. Engl. J. Med., 351(27), 2839-2849.
11. Bonewald, L.F. and Johnson, M.L. (2008) Osteocytes, mechanosensing and Wnt signaling. Bone, 42(4), 606-615.
12. Martin, T.J.; Sims, N.A. and Ng, K.W. (2008) Regulatory pathways revealing new approaches to the development of anabolic drugs for osteoporosis. Osteoporos. Int., 19(8), 1125-1138.
13. Bekker, P.J.; Holloway, D.; Nakanishi, A.; Arrighi, M.; Leese, P.T. and Dunstan, C.R. (2001) The effect of a single dose of osteoprotegerin in postmenopausal women. J. Bone Miner Res., 16(2), 348-360.
14. Body, J.J.; Greipp, P.; Coleman, R.E.; Facon, T.; Geurs, F.; Fermand, J.P.; Harousseau, J.L.; Lipton, A.; Mariette, X.; Williams, C.D.; Nakanishi, A.; Holloway, D.; Martin, S.W.; Dunstan, C.R. and Bekker, P.J. (2003) A phase I study of AMGN-0007, a recombinant osteoprotegerin construct, in patients with multiple myeloma or breast carcinoma related bone metastases. Cancer, 97(3 Suppl), 887-892.
15. Kostenuik, P.J. (2005) Osteoprotegerin and RANKL regulate bone resorption, density, geometry and strength. Curr. Opin. Pharmacol., 5(6), 618-625.
16. Romas, E.; Sims, N.A.; Hards, D.K.; Lindsay, M.; Quinn, J.W.; Ryan, P.F.; Dunstan, C.R.; Martin, T.J. and Gillespie, M.T. (2002) Osteoprotegerin reduces osteoclast numbers and prevents bone erosion in collagen-induced arthritis. Am. J. Pathol., 161(4), 1419-1427.
17. Onyia, J.E.; Galvin, R.J.; Ma, Y.L.; Halladay, D.L.; Miles, R.R.; Yang, X.; Fuson, T.; Cain, R.L.; Zeng, Q.Q.; Chandrasekhar, S.; Emkey, R.; Xu, Y.; Thirunavukkarasu, K.; Bryant, H.U. and Martin, T.J. (2004) Novel and selective small molecule stimulators of osteoprotegerin expression inhibit bone resorption. J. Pharmacol. Exp. Ther., 309(1), 369-379.
18. McClung, M.R.; Lewiecki, E.M.; Cohen, S.B.; Bolognese, M.A.; Woodson, G.C.; Moffett, A.H.; Peacock, M.; Miller, P.D.; Lederman, S.N.; Chesnut, C.H.; Lain, D.; Kivitz, A.J.; Holloway, D.L.; Zhang, C.; Peterson, M.C. and Bekker, P.J. (2006) Denosumab in postmenopausal women with low bone mineral density. N. Engl. J. Med., 354(8), 821-831.
19. Sordillo, E.M. and Pearse, R.N. (2003) RANK-Fc: a therapeutic antagonist for RANK-L in myeloma. Cancer, 97(3 Suppl), 802-812.
20. Vega, D.; Maalouf, N.M. and Sakhaee, K. (2007) The role of receptor activator of nuclear factor-{kappa}B (RANK)/RANK ligand/osteoprotegerin: clinical implications. J. Clin. Endocrinol. Metab., 92(12), 4514-4521.
21. Lacey, D.L.; Timms, E.; Tan, H.L.; Kelley, M.J.; Dunstan, C.R.; Burgess, T.; Elliott, R.; Colombero, A.; Elliott, G.; Scully, S.; Hsu, H.; Sullivan, J.; Hawkins, N.; Davy, E.; Capparelli, C.; Eli, A.; Qian, Y.X.; Kaufman, S.; Sarosi, I.; Shalhoub, V.; Senaldi, G.; Guo, J.; Delaney, J. and Boyle, W.J. (1998) Osteoprotegerin ligand is a cytokine that regulates osteoclast differentiation and activation. Cell, 93(2), 165-176.
22. Anderson, D.M.; Maraskovsky, E.; Billingsley, W.L.; Dougall, W.C.; Tometsko, M.E.; Roux, E.R.; Teepe, M.C.; DuBose, R.F.; Cosman, D. and Galibert, L. (1997) A homologue of the TNF receptor and its ligand enhance T-cell growth and dendritic-cell function. Nature, 390(6656), 175-179.
23. Kong, Y.Y.; Yoshida, H.; Sarosi, I.; Tan, H.L.; Timms, E.; Capparelli, C.; Morony, S.; Oliveira-dos-Santos, A.J.; Van, G.; Itie, A.; Khoo, W.; Wakeham, A.; Dunstan, C.R.; Lacey, D.L.; Mak, T.W.; Boyle, W.J. and Penninger, J.M. (1999) OPGL is a key regulator of osteoclastogenesis, lymphocyte development and lymph-node organogenesis. Nature, 397(6717), 315-323.
24. Cross, S.S.; Harrison, R.F.; Balasubramanian, S.P.; Lippitt, J.M.; Evans, C.A.; Reed, M.W. and Holen, I. (2006) Expression of receptor activator of nuclear factor kappabeta ligand (RANKL) and tumour necrosis factor related, apoptosis inducing ligand (TRAIL) in breast cancer, and their relations with osteoprotegerin, oestrogen receptor, and clinicopathological variables. J. Clin. Pathol., 59(7), 716-720.
25. Neville-Webbe, H.L.; Cross, N.A.; Eaton, C.L.; Nyambo, R.; Evans, C.A.; Coleman, R.E. and Holen, I. (2004) Osteoprotegerin (OPG) produced by bone marrow stromal cells protects breast cancer cells from TRAIL-induced apoptosis. Breast Cancer Res. Treat., 86(3), 269-279.
26. Shipman, C.M. and Croucher, P.I. (2003) Osteoprotegerin is a soluble decoy receptor for tumor necrosis factor-related apoptosisinducing ligand/Apo2 ligand and can function as a paracrine survival factor for human myeloma cells. Cancer Res., 63(5), 912-916.
27. Fuller, K.; Lawrence, K.M.; Ross, J.L.; Grabowska, U.B.; Shiroo, M.; Samuelsson, B. and Chambers, T.J. (2008) Cathepsin K inhibitors prevent matrix-derived growth factor degradation by human osteoclasts. Bone, 42(1), 200-211.
28. Hynes, R.O. (1992) Integrins: versatility, modulation, and signaling in cell adhesion. Cell, 69(1), 11-25.
29. Van der Flier, A. and Sonnenberg, A. (2001) Function and interactions of integrins. Cell Tissue Res., 305(3), 285-298.
30. McHugh, K.P.; Hodivala-Dilke, K.; Zheng, M.H.; Namba, N.; Lam, J.; Novack, D.; Feng, X.; Ross, F.P.; Hynes, R.O. and Teitelbaum, S.L. (2000) Mice lacking beta3 integrins are osteosclerotic because of dysfunctional osteoclasts. J. Clin. Invest., 105(4), 433-440.
31. Teitelbaum, S.L. (2000) Bone resorption by osteoclasts. Science, 289(1), 1504-1508.
32. Rodan, S.B. and Rodan, G.A. (1997) Integrin function in osteoclasts. J. Endocrinol., 154 (Suppl), S47-56.
33. Duong, L.T. and Rodan, G.A. (1999) The role of integrins in osteoclast function. J. Bone Miner. Metab., 17(1), 1-6.
34. Murphy, M.G.; Cerchio, K.; Stoch, S.A.; Gottesdiener, K.; Wu, M. and Recker, R. (2005) Effect of L-000845704, an alphaVbeta3 integrin antagonist, on markers of bone turnover and bone mineral density in postmenopausal osteoporotic women. J. Clin. Endocrinol. Metab., 90(4), 2022-2028.
35. Gelb, B.D.; Moissoglu, K.; Zhang, J.; Martignetti, J.A.; Bromme, D. and Desnick, R.J. (1996) Cathepsin K: isolation and characterization of the murine cDNA and genomic sequence, the homologue of the human pycnodysostosis gene. Biochem. Mol. Med., 59(2), 200-206.
36. Everts, V.; Hou, W.S.; Rialland, X.; Tigchelaar, W.; Saftig, P.; Bromme, D.; Gelb, B.D. and Beertsen, W. (2003) Cathepsin K deficiency in pycnodysostosis results in accumulation of non-digested phagocytosed collagen in fibroblasts. Calcif. Tissue Int., 73(4), 380-386.
37. Kiviranta, R.; Morko, J.; Uusitalo, H.; Aro, H.T.; Vuorio, E. and Rantakokko, J. (2001) Accelerated turnover of metaphyseal trabecular bone in mice overexpressing cathepsin K. J. Bone Miner. Res., 16(8), 1444-1452.
38. Saftig, P.; Hunziker, E.; Wehmeyer, O.; Jones, S.; Boyde, A.; Rommerskirch, W.; Moritz, J.D.; Schu, P. and von Figura, K. (1998) Impaired osteoclastic bone resorption leads to osteopetrosis in cathepsin-K-deficient mice. Proc. Natl. Acad. Sci. USA, 95(23), 13453-13458.
39. Yamashita, D.S. and Dodds, R.A. (2000) Cathepsin K and the design of inhibitors of cathepsin K. Curr. Pharm. Des., 6(1), 1-24.
40. Tavares, F.X.; Boncek, V.; Deaton, D.N.; Hassell, A.M.; Long, S.T.; Miller, A.B.; Payne, A.A.; Miller, L.R.; Shewchuk, L.M.; Wells-Knecht, K.; Willard, D.H., Jr.; Wright, L.L. and Zhou, H.Q. (2004) Design of potent, selective, and orally bioavailable inhibitors of cysteine protease cathepsin k. J. Med. Chem., 47(3), 588-599.
41. Peroni, A.; Zini, A.; Braga, V.; Colato, C.; Adami, S. and Girolomoni, G. (2008) Drug-induced morphea: Report of a case induced by balicatib and review of the literature. J. Am. Acad. Dermatol., 59(1), 125-129.
42. Rodan, S.B. and Duong le, T. (2008) Cathepsin K - a new molecular target for osteoporosis. IBMS BoneKEy, 5(1), 16-24.
43. Gauthier, J.Y.; Chauret, N.; Cromlish, W.; Desmarais, S.; Duong le, T.; Falgueyret, J.P.; Kimmel, D.B.; Lamontagne, S.; Leger, S.; LeRiche, T.; Li, C.S.; Masse, F.; McKay, D.J.; Nicoll-Griffith, D.A.; Oballa, R.M.; Palmer, J.T.; Percival, M.D.; Riendeau, D.; Robichaud, J.; Rodan, G.A.; Rodan, S.B.; Seto, C.; Therien, M.; Truong, V.L.; Venuti, M.C.; Wesolowski, G.; Young, R.N.; Zamboni, R. and Black, W.C. (2008) The discovery of odanacatib (MK-0822), a selective inhibitor of cathepsin K. Bioorg. Med. Chem. Lett., 18(3), 923-928.
44. Kumar, S.; Dare, L.; Vasko-Moser, J.A.; James, I.E.; Blake, S.M.; Rickard, D.J.; Hwang, S.M.; Tomaszek, T.; Yamashita, D.S.; Marquis, R.W.; Oh, H.; Jeong, J.U.; Veber, D.F.; Gowen, M.; Lark, M.W. and Stroup, G. (2007) A highly potent inhibitor of cathepsin K (relacatib) reduces biomarkers of bone resorption both in vitro and in an acute model of elevated bone turnover in vivo in monkeys. Bone, 40(1), 122-131.
45. Soriano, P.; Montgomery, C.; Geske, R. and Bradley, A. (1991) Targeted disruption of the c-src proto-oncogene leads to osteopetrosis in mice. Cell, 64(4), 693-702.
46. Insogna, K.L.; Sahni, M.; Grey, A.B.; Tanaka, S.; Horne, W.C.; Neff, L.; Mitnick, M.; Levy, J.B. and Baron, R. (1997) Colonystimulating factor-1 induces cytoskeletal reorganization and c-srcdependent tyrosine phosphorylation of selected cellular proteins in rodent osteoclasts. J. Clin. Invest., 100(10), 2476-2485.
47. Boyce, B.F.; Yoneda, T.; Lowe, C.; Soriano, P. and Mundy, G.R. (1992) Requirement of pp60c-src expression for osteoclasts to form ruffled borders and resorb bone in mice. J. Clin. Invest., 90(4), 1622-1627.
48. Marzia, M.; Sims, N.A.; Voit, S.; Migliaccio, S.; Taranta, A.; Bernardini, S.; Faraggiana, T.; Yoneda, T.; Mundy, G.R.; Boyce, B.F.; Baron, R. and Teti, A. (2000) Decreased c-Src expression enhances osteoblast differentiation and bone formation. J. Cell Biol., 151(2), 311-320.
49. Schwartzberg, P.L. (1998) The many faces of Src: multiple functions of a prototypical tyrosine kinase. Oncogene, 17(11 Reviews), 1463-1468.
50. Boyce, B.F.; Xing, L.; Yao, Z.; Yamashita, T.; Shakespeare, W.C.; Wang, Y.; Metcalf, C.A., III; Sundaramoorthi, R.; Dalgarno, D.C.; Iuliucci, J.D. and Sawyer, T.K. (2006) Src Inhibitors in Metastatic Bone Disease. Clin. Cancer Res., 12(20), 6291s-6295.
51. Laitala, T. and Vaananen, H.K. (1994) Inhibition of bone resorption in vitro by antisense RNA and DNA molecules targeted against carbonic anhydrase II or two subunits of vacuolar H(+)-ATPase. J. Clin. Invest., 93(6), 2311-2318.
52. Lee, S.H.; Rho, J.; Jeong, D.; Sul, J.Y.; Kim, T.; Kim, N.; Kang, J.S.; Miyamoto, T.; Suda, T.; Lee, S.K.; Pignolo, R.J.; Koczon-Jaremko, B.; Lorenzo, J. and Choi, Y. (2006) v-ATPase V0 subunit d2-deficient mice exhibit impaired osteoclast fusion and increased bone formation. Nat. Med., 12(12), 1403-1409.
53. Sundquist, K.; Lakkakorpi, P.; Wallmark, B. and Vaananen, K. (1990) Inhibition of osteoclast proton transport by bafilomycin A1 abolishes bone resorption. Biochem. Biophys. Res. Commun., 168(1), 309-313.
54. Keeling, D.J.; Herslof, M.; Mattsson, J.P. and Ryberg, B. (1998) Tissue-selective inhibition of vacuolar acid pumps. Acta Physiol. Scand Suppl., 643, 195-201.
55. Visentin, L.; Dodds, R.A.; Valente, M.; Misiano, P.; Bradbeer, J.N.; Oneta, S.; Liang, X.; Gowen, M. and Farina, C. (2000) A selective inhibitor of the osteoclastic V-H(+)-ATPase prevents bone loss in both thyroparathyroidectomized and ovariectomized rats. J. Clin. Invest., 106(2), 309-318.
56. Del Fattore, A.; Peruzzi, B.; Rucci, N.; Recchia, I.; Cappariello, A.; Longo, M.; Fortunati, D.; Ballanti, P.; Iacobini, M.; Luciani, M.; Devito, R.; Pinto, R.; Caniglia, M.; Lanino, E.; Messina, C.; Cesaro, S.; Letizia, C.; Bianchini, G.; Fryssira, H.; Grabowski, P.; Shaw, N.; Bishop, N.; Hughes, D.; Kapur, R.P.; Datta, H.K.; Taranta, A.; Fornari, R.; Migliaccio, S. and Teti, A. (2006) Clinical, genetic, and cellular analysis of 49 osteopetrotic patients: implications for diagnosis and treatment. J. Med. Genet., 43(4), 315-325.
57. Schaller, S.; Henriksen, K.; Sorensen, M.G. and Karsdal, M.A. (2005) The role of chloride channels in osteoclasts: ClC-7 as a target for osteoporosis treatment. Drug News Perspect., 18(8), 489-495.
58. Martin, T.J. and Sims, N.A. (2005) Osteoclast-derived activity in the coupling of bone formation to resorption. Trends Mol. Med., 11(2), 76-81.
59. Karsdal, M.A.; Martin, T.J.; Bollerslev, J.; Christiansen, C. and Henriksen, K. (2007) Are nonresorbing osteoclasts sources of bone anabolic activity? J. Bone Miner. Res., 22(4), 487-494.
60. Schaller, S.; Henriksen, K.; Sveigaard, C.; Heegaard, A.M.; Helix, N.; Stahlhut, M.; Ovejero, M.C.; Johansen, J.V.; Solberg, H.; Andersen, T.L.; Hougaard, D.; Berryman, M.; Shiodt, C.B.; Sorensen, B.H.; Lichtenberg, J.; Christophersen, P.; Foged, N.T.; Delaisse, J.M.; Engsig, M.T. and Karsdal, M.A. (2004) The chloride channel inhibitor NS3736 [corrected] prevents bone resorption in ovariectomized rats without changing bone formation. J. Bone Miner. Res., 19(7), 1144-1153.
61. Black, D.M.; Greenspan, S.L.; Ensrud, K.E.; Palermo, L.; McGowan, J.A.; Lang, T.F.; Garnero, P.; Bouxsein, M.L.; Bilezikian, J.P. and Rosen, C.J. (2003) The effects of parathyroid hormone and alendronate alone or in combination in postmenopausal osteoporosis. N. Engl. J. Med., 349(13), 1207-1215.
62. Neer, R.M.; Arnaud, C.D.; Zanchetta, J.R.; Prince, R.; Gaich, G.A.; Reginster, J.Y.; Hodsman, A.B.; Eriksen, E.F.; Ish-Shalom, S.; Genant, H.K. and Wang, O. (2001) Effect of parathyroid hormone (1-34) on fractures and bone mineral density in postmenopausal women with osteoporosis. N. Engl. J. Med., 344(19), 1434-1441.
63. Frolik, C.A.; Black, E.C.; Cain, R.L.; Satterwhite, J.H.; Brown-Augsburger, P.L.; Sato, M. and Hock, J.M. (2003) Anabolic and catabolic bone effects of human parathyroid hormone (1-34) are predicted by duration of hormone exposure. Bone, 33(3), 372-379.
64. Shoback, D.M.; Bilezikian, J.P.; Turner, S.A.; McCary, L.C.; Guo, M.D. and Peacock, M. (2003) The calcimimetic cinacalcet normalizes serum calcium in subjects with primary hyperparathyroidism. J. Clin. Endocrinol. Metab., 88(12), 5644-5649.
65. Nemeth, E.F.; Delmar, E.G.; Heaton, W.L.; Miller, M.A.; Lambert, L.D.; Conklin, R.L.; Gowen, M.; Gleason, J.G.; Bhatnagar, P.K. and Fox, J. (2001) Calcilytic compounds: potent and selective Ca2+ receptor antagonists that stimulate secretion of parathyroid hormone. J. Pharmacol. Exp. Ther., 299(1), 323-331.
66. Gowen, M.; Stroup, G.B.; Dodds, R.A.; James, I.E.; Votta, B.J.; Smith, B.R.; Bhatnagar, P.K.; Lago, A.M.; Callahan, J.F.; DelMar, E.G.; Miller, M.A.; Nemeth, E.F. and Fox, J. (2000) Antagonizing the parathyroid calcium receptor stimulates parathyroid hormone secretion and bone formation in osteopenic rats. J. Clin. Invest., 105(11), 1595-1604.
67. Wodarz, A. and Nusse, R. (1998) Mechanisms of Wnt signaling in development. Annu. Rev. Cell Dev. Biol., 14, 59-88.
68. Uusitalo, M.; Heikkila, M. and Vainio, S. (1999) Molecular genetic studies of Wnt signaling in the mouse. Exp. Cell Res., 253(2), 336-348.
69. Westendorf, J.J.; Kahler, R.A. and Schroeder, T.M. (2004) Wnt signaling in osteoblasts and bone diseases. Gene, 341, 19-39.
70. Gong, Y.; Slee, R.B.; Fukai, N.; Rawadi, G.; Roman-Roman, S.; Reginato, A.M.; Wang, H.; Cundy, T.; Glorieux, F.H.; Lev, D.; Zacharin, M.; Oexle, K.; Marcelino, J.; Suwairi, W.; Heeger, S.; Sabatakos, G.; Apte, S.; Adkins, W.N.; Allgrove, J.; Arslan-Kirchner, M.; Batch, J.A.; Beighton, P.; Black, G.C.; Boles, R.G.; Boon, L.M.; Borrone, C.; Brunner, H.G.; Carle, G.F.; Dallapiccola, B.; De Paepe, A.; Floege, B.; Halfhide, M.L.; Hall, B.; Hennekam, R.C.; Hirose, T.; Jans, A.; Juppner, H.; Kim, C.A.; Keppler-Noreuil, K.; Kohlschuetter, A.; LaCombe, D.; Lambert, M.; Lemyre, E.; Letteboer, T.; Peltonen, L.; Ramesar, R.S.; Romanengo, M.; Somer, H.; Steichen-Gersdorf, E.; Steinmann, B.; Sullivan, B.; Superti-Furga, A.; Swoboda, W.; van den Boogaard, M.J.; Van Hul, W.; Vikkula, M.; Votruba, M.; Zabel, B.; Garcia, T.; Baron, R.; Olsen, B.R. and Warman, M.L. (2001) LDL receptor-related protein 5 (LRP5) affects bone accrual and eye development. Cell, 107(4), 513-523.
71. Boyden, L.M.; Mao, J.; Belsky, J.; Mitzner, L.; Farhi, A.; Mitnick, M.A.; Wu, D.; Insogna, K. and Lifton, R.P. (2002) High bone density due to a mutation in LDL-receptor-related protein 5. N. Engl. J. Med., 346(20), 1513-1521.
72. Kato, M.; Patel, M.S.; Levasseur, R.; Lobov, I.; Chang, B.H.; Glass, D.A., 2nd; Hartmann, C.; Li, L.; Hwang, T.H.; Brayton, C.F.; Lang, R.A.; Karsenty, G. and Chan, L. (2002) Cbfa1-independent decrease in osteoblast proliferation, osteopenia, and persistent embryonic eye vascularization in mice deficient in Lrp5, a Wnt coreceptor. J. Cell Biol., 157(2), 303-314.
73. Babij, P.; Zhao, W.; Small, C.; Kharode, Y.; Yaworsky, P.J.; Bouxsein, M.L.; Reddy, P.S.; Bodine, P.V.; Robinson, J.A.; Bhat, B.; Marzolf, J.; Moran, R.A. and Bex, F. (2003) High bone mass in mice expressing a mutant LRP5 gene. J. Bone Miner. Res., 18(6), 960-974.
74. Rawadi, G.; Vayssiere, B.; Dunn, F.; Baron, R. and Roman-Roman, S. (2003) BMP-2 controls alkaline phosphatase expression and osteoblast mineralization by a Wnt autocrine loop. J. Bone Miner. Res., 18(10), 1842-1853.
75. Johnson, M.L.; Harnish, K.; Nusse, R. and Van Hul, W. (2004) LRP5 and Wnt signaling: a union made for bone. J. Bone Miner. Res., 19(11), 1749-1757.
76. Mbalaviele, G.; Sheikh, S.; Stains, J.P.; Salazar, V.S.; Cheng, S.L.; Chen, D. and Civitelli, R. (2005) Beta-catenin and BMP-2 synergize to promote osteoblast differentiation and new bone formation. J. Cell Biochem., 94(2), 403-418.
77. van Meurs, J.B.; Trikalinos, T.A.; Ralston, S.H.; Balcells, S.; Brandi, M.L.; Brixen, K.; Kiel, D.P.; Langdahl, B.L.; Lips, P.; Ljunggren, O.; Lorenc, R.; Obermayer-Pietsch, B.; Ohlsson, C.; Pettersson, U.; Reid, D.M.; Rousseau, F.; Scollen, S.; Van Hul, W.; Agueda, L.; Akesson, K.; Benevolenskaya, L.I.; Ferrari, S.L.; Hallmans, G.; Hofman, A.; Husted, L.B.; Kruk, M.; Kaptoge, S.; Karasik, D.; Karlsson, M.K.; Lorentzon, M.; Masi, L.; McGuigan, F.E.; Mellstrom, D.; Mosekilde, L.; Nogues, X.; Pols, H.A.; Reeve, J.; Renner, W.; Rivadeneira, F.; van Schoor, N.M.; Weber, K.; Ioannidis, J.P. and Uitterlinden, A.G. (2008) Large-scale analysis of association between LRP5 and LRP6 variants and osteoporosis. JAMA, 299(11), 1277-1290.
78. Yang-Snyder, J.; Miller, J.R.; Brown, J.D.; Lai, C.J. and Moon, R.T. (1996) A frizzled homolog functions in a vertebrate Wnt signaling pathway. Curr. Biol., 6(10), 1302-1306.
79. Slusarski, D.C.; Corces, V.G. and Moon, R.T. (1997) Interaction of Wnt and a Frizzled homologue triggers G-protein-linked phosphatidylinositol signalling. Nature, 390(6658), 410-413.
80. Hsieh, J.C.; Rattner, A.; Smallwood, P.M. and Nathans, J. (1999) Biochemical characterization of Wnt-frizzled interactions using a soluble, biologically active vertebrate Wnt protein. Proc. Natl. Acad. Sci. USA, 96(7), 3546-3551.
81. He, X.; Saint-Jeannet, J.P.; Wang, Y.; Nathans, J.; Dawid, I. and Varmus, H. (1997) A member of the Frizzled protein family mediating axis induction by Wnt-5A. Science, 275(5306), 1652-1654.
82. Pinson, K.I.; Brennan, J.; Monkley, S.; Avery, B.J. and Skarnes, W.C. (2000) An LDL-receptor-related protein mediates Wnt signalling in mice. Nature, 407(6803), 535-538.
83. Mao, B.; Wu, W.; Li, Y.; Hoppe, D.; Stannek, P.; Glinka, A. and Niehrs, C. (2001) LDL-receptor-related protein 6 is a receptor for Dickkopf proteins. Nature, 411(6835), 321-325.
84. Mao, J.; Wang, J.; Liu, B.; Pan, W.; Farr, G.H., 3rd; Flynn, C.; Yuan, H.; Takada, S.; Kimelman, D.; Li, L. and Wu, D. (2001) Low-density lipoprotein receptor-related protein-5 binds to Axin and regulates the canonical Wnt signaling pathway. Mol. Cell, 7(4), 801-809.
85. Hay, E.; Faucheu, C.; Suc-Royer, I.; Touitou, R.; Stiot, V.; Vayssiere, B.; Baron, R.; Roman-Roman, S. and Rawadi, G. (2005) Interaction between LRP5 and Frat1 mediates the activation of the Wnt canonical pathway. J. Biol. Chem., 280(14), 13616-13623.
86. Balemans, W. and Van Hul, W. (2007) The genetics of low-density lipoprotein receptor-related protein 5 in bone: a story of extremes. Endocrinology, 148(6), 2622-2629.
87. Li, X.; Zhang, Y.; Kang, H.; Liu, W.; Liu, P.; Zhang, J.; Harris, S.E. and Wu, D. (2005) Sclerostin binds to LRP5/6 and antagonizes canonical Wnt signaling. J. Biol. Chem., 280(20), 19883-19887.
88. Bodine, P.V.; Zhao, W.; Kharode, Y.P.; Bex, F.J.; Lambert, A.J.; Goad, M.B.; Gaur, T.; Stein, G.S.; Lian, J.B. and Komm, B.S. (2004) The Wnt antagonist secreted frizzled-related protein-1 is a negative regulator of trabecular bone formation in adult mice. Mol. Endocrinol., 18(5), 1222-1237.
89. Morvan, F.; Boulukos, K.; Clement-Lacroix, P.; Roman Roman, S.; Suc-Royer, I.; Vayssiere, B.; Ammann, P.; Martin, P.; Pinho, S.; Pognonec, P.; Mollat, P.; Niehrs, C.; Baron, R. and Rawadi, G. (2006) Deletion of a single allele of the Dkk1 gene leads to an increase in bone formation and bone mass. J. Bone Miner. Res., 21(6), 934-945.
90. Li, J.; Sarosi, I.; Cattley, R.C.; Pretorius, J.; Asuncion, F.; Grisanti, M.; Morony, S.; Adamu, S.; Geng, Z.; Qiu, W.; Kostenuik, P.; Lacey, D.L.; Simonet, W.S.; Bolon, B.; Qian, X.; Shalhoub, V.; Ominsky, M.S.; Zhu Ke, H.; Li, X. and Richards, W.G. (2006) Dkk1-mediated inhibition of Wnt signaling in bone results in osteopenia. Bone, 39(4), 754-766.
91. Tian, E.; Zhan, F.; Walker, R.; Rasmussen, E.; Ma, Y.; Barlogie, B. and Shaughnessy, J.D., Jr. (2003) The role of the Wnt-signaling antagonist DKK1 in the development of osteolytic lesions in multiple myeloma. N. Engl. J. Med., 349(26), 2483-2494.
92. Yaccoby, S.; Ling, W.; Zhan, F.; Walker, R.; Barlogie, B. and Shaughnessy, J.D., Jr. (2007) Antibody-based inhibition of DKK1 suppresses tumor-induced bone resorption and multiple myeloma growth in vivo. Blood, 109(5), 2106-2111.
93. Clement-Lacroix, P.; Ai, M.; Morvan, F.; Roman-Roman, S.; Vayssiere, B.; Belleville, C.; Estrera, K.; Warman, M.L.; Baron, R. and Rawadi, G. (2005) Lrp5-independent activation of Wnt signaling by lithium chloride increases bone formation and bone mass in mice. Proc. Natl. Acad. Sci. USA, 102(48), 17406-17411.
94. Kulkarni, N.H.; Onyia, J.E.; Zeng, Q.; Tian, X.; Liu, M.; Halladay, D.L.; Frolik, C.A.; Engler, T.; Wei, T.; Kriauciunas, A.; Martin, T.J.; Sato, M.; Bryant, H.U. and Ma, Y.L. (2006) Orally bioavailable GSK-3alpha/beta dual inhibitor increases markers of cellular differentiation in vitro and bone mass in vivo. J. Bone Miner. Res., 21(6), 910-920.
95. Kulkarni, N.H.; Wei, T.; Kumar, A.; Dow, E.R.; Stewart, T.R.; Shou, J.; N'Cho, M.; Sterchi, D.L.; Gitter, B.D.; Higgs, R.E.; Halladay, D.L.; Engler, T.A.; Martin, T.J.; Bryant, H.U.; Ma, Y.L. and Onyia, J.E. (2007) Changes in osteoblast, chondrocyte, and adipocyte lineages mediate the bone anabolic actions of PTH and small molecule GSK-3 inhibitor. J. Cell Biochem., 102(6), 1504-1518.
96. Balemans, W.; Ebeling, M.; Patel, N.; Van Hul, E.; Olson, P.; Dioszegi, M.; Lacza, C.; Wuyts, W.; Van Den Ende, J.; Willems, P.; Paes-Alves, A.F.; Hill, S.; Bueno, M.; Ramos, F.J.; Tacconi, P.; Dikkers, F.G.; Stratakis, C.; Lindpaintner, K.; Vickery, B.; Foernzler, D. and Van Hul, W. (2001) Increased bone density in sclerosteosis is due to the deficiency of a novel secreted protein (SOST). Hum. Mol. Genet., 10(5), 537-543.
97. Balemans, W.; Patel, N.; Ebeling, M.; Van Hul, E.; Wuyts, W.; Lacza, C.; Dioszegi, M.; Dikkers, F.G.; Hildering, P.; Willems, P.J.; Verheij, J.B.; Lindpaintner, K.; Vickery, B.; Foernzler, D. and Van Hul, W. (2002) Identification of a 52 kb deletion downstream of the SOST gene in patients with van Buchem disease. J. Med. Genet., 39(2), 91-97.
98. Keller, H. and Kneissel, M. (2005) SOST is a target gene for PTH in bone. Bone, 37(2), 148-158.
99. Silvestrini, G.; Ballanti, P.; Leopizzi, M.; Sebastiani, M.; Berni, S.; Di Vito, M. and Bonucci, E. (2007) Effects of intermittent parathyroid hormone (PTH) administration on SOST mRNA and protein in rat bone. J. Mol. Histol., 38(4), 261-269.
100. van Bezooijen, R.L.; ten Dijke, P.; Papapoulos, S.E. and Lowik, C.W. (2005) SOST/sclerostin, an osteocyte-derived negative regulator of bone formation. Cytokine Growth Factor Rev., 16(3), 319-327.
101. Sutherland, M.K.; Geoghegan, J.C.; Yu, C.; Winkler, D.G. and Latham, J.A. (2004) Unique regulation of SOST, the sclerosteosis gene, by BMPs and steroid hormones in human osteoblasts. Bone, 35(2), 448-454.
102. Leupin, O.; Kramer, I.; Collette, N.M.; Loots, G.G.; Natt, F.; Kneissel, M. and Keller, H. (2007) Control of the SOST bone enhancer by PTH using MEF2 transcription factors. J. Bone Miner. Res., 22(12), 1957-1967.
103. Tu, X.; Joeng, K.S.; Nakayama, K.I.; Nakayama, K.; Rajagopal, J.; Carroll, T.J.; McMahon, A.P. and Long, F. (2007) Noncanonical Wnt signaling through G protein-linked PKCdelta activation promotes bone formation. Dev. Cell, 12(1), 113-127.
104. Takada, I.; Mihara, M.; Suzawa, M.; Ohtake, F.; Kobayashi, S.; Igarashi, M.; Youn, M.Y.; Takeyama, K.; Nakamura, T.; Mezaki, Y.; Takezawa, S.; Yogiashi, Y.; Kitagawa, H.; Yamada, G.; Takada, S.; Minami, Y.; Shibuya, H.; Matsumoto, K. and Kato, S. (2007) A histone lysine methyltransferase activated by noncanonical Wnt signalling suppresses PPAR-gamma transactivation. Nat. Cell Biol., 9(11), 1273-1285.
105. Krishnan, V.; Bryant, H.U. and Macdougald, O.A. (2006) Regulation of bone mass by Wnt signaling. J. Clin. Invest., 116(5), 1202-1209.
106. Dong, J.; Peng, J.; Zhang, H.; Mondesire, W.H.; Jian, W.; Mills, G.B.; Hung, M.C. and Meric-Bernstam, F. (2005) Role of glycogen synthase kinase 3beta in rapamycin-mediated cell cycle regulation and chemosensitivity. Cancer Res., 65(5), 1961-1972.
107. Clevers, H. (2006) Wnt/beta-catenin signaling in development and disease. Cell, 127(3), 469-480.
108. Vanderschueren, D.; Vandenput, L.; Boonen, S.; Lindberg, M.K.; Bouillon, R. and Ohlsson, C. (2004) Androgens and bone. Endocr. Rev., 25(3), 389-425.
109. Vanderschueren, D.; Van Herck, E.; Suiker, A.M.; Visser, W.J.; Schot, L.P.; Chung, K.; Lucas, R.S.; Einhorn, T.A. and Bouillon, R. (1993) Bone and mineral metabolism in the androgen-resistant (testicular feminized) male rat. J. Bone Miner. Res., 8(7), 801-809.
110. Vanderschueren, D.; Venken, K.; Ophoff, J.; Bouillon, R. and Boonen, S. (2006) Clinical Review: Sex steroids and the periosteum--reconsidering the roles of androgens and estrogens in periosteal expansion. J. Clin. Endocrinol. Metab., 91(2), 378-382.
111. Leder, B.Z.; LeBlanc, K.M.; Schoenfeld, D.A.; Eastell, R. and Finkelstein, J.S. (2003) Differential effects of androgens and estrogens on bone turnover in normal men. J. Clin. Endocrinol. Metab., 88(1), 204-210.
112. Meier, C.; Nguyen, T.V.; Handelsman, D.J.; Schindler, C.; Kushnir, M.M.; Rockwood, A.L.; Meikle, A.W.; Center, J.R.; Eisman, J.A. and Seibel, M.J. (2008) Endogenous sex hormones and incident fracture risk in older men: the Dubbo Osteoporosis Epidemiology Study. Arch. Intern. Med., 168(1), 47-54.
113. Liu, P.Y.; Swerdloff, R.S. and Veldhuis, J.D. (2004) Clinical review 171: The rationale, efficacy and safety of androgen therapy in older men: future research and current practice recommendations. J. Clin. Endocrinol. Metab., 89(10), 4789-4796.
114. Negro-Vilar, A. (1999) Selective androgen receptor modulators (SARMs): a novel approach to androgen therapy for the new millennium. J. Clin. Endocrinol. Metab., 84(10), 3459-3462.
115. Johnson, K.A. (2006) Editorial: The SERM of my dreams. J. Clin. Endocrinol. Metab., 91(10), 3754-3756.
116. McDonnell, D.P. (1999) The Molecular Pharmacology of SERMs. Trends Endocrinol. Metab., 10(8), 301-311.
117. Smith, C.L. and O'Malley, B.W. (2004) Coregulator function: a key to understanding tissue specificity of selective receptor modulators. Endocr. Rev., 25(1), 45-71.
118. Kastelan, D.; Giljevic, Z.; Kraljevic, I. and Korsic, M. (2006) Selective estrogen receptor modulators: A possible new treatment of osteoporosis in males. Med. Hypotheses, 67(5), 1052-1053.
119. Ettinger, B.; Black, D.M.; Mitlak, B.H.; Knickerbocker, R.K.; Nickelsen, T.; Genant, H.K.; Christiansen, C.; Delmas, P.D.; Zanchetta, J.R.; Stakkestad, J.; Gluer, C.C.; Krueger, K.; Cohen, F.J.; Eckert, S.; Ensrud, K.E.; Avioli, L.V.; Lips, P.; Cummings, S.R. and for the Multiple Outcomes of Raloxifene Evaluation, I. (1999) Reduction of vertebral fracture risk in postmenopausal women with osteoporosis treated with raloxifene: results from a 3-year randomized clinical trial. JAMA, 282(7), 637-645.
120. Cauley, J.A.; Norton, L.; Lippman, M.E.; Eckert, S.; Krueger, K.A.; Purdie, D.W.; Farrerons, J.; Karasik, A.; Mellstrom, D.; Ng, K.W.; Stepan, J.J.; Powles, T.J.; Morrow, M.; Costa, A.; Silfen, S.L.; Walls, E.L.; Schmitt, H.; Muchmore, D.B.; Jordan, V.C. and Ste-Marie, L.G. (2001) Continued breast cancer risk reduction in postmenopausal women treated with raloxifene: 4-year results from the MORE trial. Multiple outcomes of raloxifene evaluation. Breast Cancer Res. Treat., 65(2), 125-134.
121. Heemers, H.V. and Tindall, D.J. (2007) Androgen receptor (AR) coregulators: a diversity of functions converging on and regulating the AR transcriptional complex. Endocr. Rev., 28(7), 778-808.
122. Rosen, J. and Negro-Vilar, A. (2002) Novel, non-steroidal, selective androgen receptor modulators (SARMs) with anabolic activity in bone and muscle and improved safety profile. J. Musculoskelet. Neuronal. Interact., 2(3), 222-224.
123. Neumann, F. and Topert, M. (1986) Pharmacology of antiandrogens. J. Steroid Biochem., 25(5B), 885-895.
124. Gao, W.; Kim, J. and Dalton, J.T. (2006) Pharmacokinetics and pharmacodynamics of nonsteroidal androgen receptor ligands. Pharm. Res., 23(8), 1641-1658.
125. Gao, W. and Dalton, J.T. (2007) Expanding the therapeutic use of androgens via selective androgen receptor modulators (SARMs). Drug Discov. Today, 12(5-6), 241-248.
126. Gao, W.; Kearbey, J.D.; Nair, V.A.; Chung, K.; Parlow, A.F.; Miller, D.D. and Dalton, J.T. (2004) Comparison of the pharmacological effects of a novel selective androgen receptor modulator, the 5alpha-reductase inhibitor finasteride, and the antiandrogen hydroxyflutamide in intact rats: new approach for benign prostate hyperplasia. Endocrinology, 145(12), 5420-5428.
127. Ostrowski, J.; Kuhns, J.E.; Lupisella, J.A.; Manfredi, M.C.; Beehler, B.C.; Krystek, S.R., Jr.; Bi, Y.; Sun, C.; Seethala, R.; Golla, R.; Sleph, P.G.; Fura, A.; An, Y.; Kish, K.F.; Sack, J.S.; Mookhtiar, K.A.; Grover, G.J. and Hamann, L.G. (2007) Pharmacological and x-ray structural characterization of a novel selective androgen receptor modulator: potent hyperanabolic stimulation of skeletal muscle with hypostimulation of prostate in rats. Endocrinology, 148(1), 4-12.
128. Higuchi, R.I.; Thompson, A.W.; Chen, J.H.; Caferro, T.R.; Cummings, M.L.; Deckhut, C.P.; Adams, M.E.; Tegley, C.M.; Edwards, J.P.; Lopez, F.J.; Kallel, E.A.; Karanewsky, D.S.; Schrader, W.T.; Marschke, K.B. and Zhi, L. (2007) Potent, nonsteroidal selective androgen receptor modulators (SARMs) based on 8H-[1,4]oxazino[2,3-f]quinolin-8-ones. Bioorg. Med. Chem. Lett., 17(19), 5442-5446.
129. Thevis, M.; Kohler, M. and Schanzer, W. (2008) New drugs and methods of doping and manipulation. Drug Discov. Today, 13(1-2), 59-66.