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Journal of Osteoporosis
Volume 2016 (2016), Article ID 6217286, 22 pages
http://dx.doi.org/10.1155/2016/6217286
Review Article

Sclerostin Antibody Therapy for the Treatment of Osteoporosis: Clinical Prospects and Challenges

Regenerative Medicine Institute, NUI Galway, Biosciences Research Building, Corrib Village, Dangan, Galway, Ireland

Received 23 February 2016; Accepted 21 April 2016

Academic Editor: Merry Jo Oursler

Copyright © 2016 Claire MacNabb et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Linked References

  1. E. M. Lewiecki, “Sclerostin monoclonal antibody therapy with AMG 785: a potential treatment for osteoporosis,” Expert Opinion on Biological Therapy, vol. 11, no. 1, pp. 117–127, 2011. View at Publisher · View at Google Scholar · View at Scopus
  2. B. L. Clarke, “Anti-sclerostin antibodies: utility in treatment of osteoporosis,” Maturitas, vol. 78, no. 3, pp. 199–204, 2014. View at Publisher · View at Google Scholar · View at Scopus
  3. L. Stodieck, AMGEN Countermeasures for Bone and Muscle Loss in Space and on Earth, 2013, http://www.slideshare.net/astrosociety/issrdc-2013-07170800stodieck.
  4. D. Padhi, G. Jang, B. Stouch, L. Fang, and E. Posvar, “Single-dose, placebo-controlled, randomized study of AMG 785, a sclerostin monoclonal antibody,” Journal of Bone and Mineral Research, vol. 26, no. 1, pp. 19–26, 2011. View at Publisher · View at Google Scholar · View at Scopus
  5. Osteoporosis and Osteopenia, 2013, http://decisionresources.com/Products-and-Services/Report?r=dbasmd0213.
  6. B. C. Silva and J. P. Bilezikian, “New approaches to the treatment of osteoporosis,” Annual Review of Medicine, vol. 62, pp. 307–322, 2011. View at Publisher · View at Google Scholar · View at Scopus
  7. T. D. Rachner, S. Khosla, and L. C. Hofbauer, “Osteoporosis: now and the future,” The Lancet, vol. 377, no. 9773, pp. 1276–1287, 2011. View at Publisher · View at Google Scholar · View at Scopus
  8. K. M. P. Akesson, “Capture the fracture: a global campaign to the fragility fracture cycle,” 2012, http://www.iofbonehealth.org/capture-fracture-report-2012.
  9. O. Johnell, “The socioeconomic burden of fractures: today and in the 21st century,” The American Journal of Medicine, vol. 103, no. 2, supplement 1, pp. S20–S26, 1997. View at Publisher · View at Google Scholar
  10. G. Marongiu, M. Mastio, and A. Capone, “Current options to surgical treatment in osteoporotic fractures,” Aging Clinical and Experimental Research, vol. 25, supplement 1, pp. S15–S17, 2013. View at Publisher · View at Google Scholar · View at Scopus
  11. S. C. Mears, “Management of severe osteoporosis in primary total hip arthroplasty,” Current Translational Geriatrics and Experimental Gerontology Reports, vol. 2, no. 2, pp. 99–104, 2013. View at Publisher · View at Google Scholar
  12. E. Hernlund, A. Svedbom, M. Ivergård et al., “Osteoporosis in the European Union: medical management, epidemiology and economic burden: a report prepared in collaboration with the International Osteoporosis Foundation (IOF) and the European Federation of Pharmaceutical Industry Associations (EFPIA),” Archives of Osteoporosis, vol. 8, no. 1-2, article 136, 2013. View at Publisher · View at Google Scholar · View at Scopus
  13. B. L. Riggs and L. J. Melton III, “The worldwide problem of osteoporosis: insights afforded by epidemiology,” Bone, vol. 17, no. 5, supplement 1, pp. S505–S511, 1995. View at Publisher · View at Google Scholar · View at Scopus
  14. H. Hamersma, J. Gardner, and P. Beighton, “The natural history of sclerosteosis,” Clinical Genetics, vol. 63, no. 3, pp. 192–197, 2003. View at Publisher · View at Google Scholar · View at Scopus
  15. A. G. Costa and J. P. Bilezikian, “Sclerostin: therapeutic horizons based upon its actions,” Current Osteoporosis Reports, vol. 10, no. 1, pp. 64–72, 2012. View at Publisher · View at Google Scholar · View at Scopus
  16. W. Balemans, M. Ebeling, N. Patel et al., “Increased bone density in sclerosteosis is due to the deficiency of a novel secreted protein (SOST),” Human Molecular Genetics, vol. 10, no. 5, pp. 537–543, 2001. View at Publisher · View at Google Scholar · View at Scopus
  17. M. E. Brunkow, J. C. Gardner, J. Van Ness et al., “Bone dysplasia sclerosteosis results from loss of the SOST gene product, a novel cystine knot-containing protein,” The American Journal of Human Genetics, vol. 68, no. 3, pp. 577–589, 2001. View at Publisher · View at Google Scholar · View at Scopus
  18. D. G. Winkler, M. K. Sutherland, J. C. Geoghegan et al., “Osteocyte control of bone formation via sclerostin, a novel BMP antagonist,” The EMBO Journal, vol. 22, no. 23, pp. 6267–6276, 2003. View at Publisher · View at Google Scholar
  19. C. Krause, O. Korchynskyi, K. de Rooij et al., “Distinct modes of inhibition by sclerostin on bone morphogenetic protein and Wnt signaling pathways,” The Journal of Biological Chemistry, vol. 285, no. 53, pp. 41614–41626, 2010. View at Publisher · View at Google Scholar · View at Scopus
  20. A. R. Wijenayaka, M. Kogawa, H. P. Lim, L. F. Bonewald, D. M. Findlay, and G. J. Atkins, “Sclerostin stimulates osteocyte support of osteoclast activity by a RANKL-dependent pathway,” PLoS ONE, vol. 6, no. 10, Article ID e25900, 2011. View at Publisher · View at Google Scholar · View at Scopus
  21. R. R. Recker, C. T. Benson, T. Matsumoto et al., “A randomized, double-blind phase 2 clinical trial of blosozumab, a sclerostin antibody, in postmenopausal women with low bone mineral density,” Journal of Bone and Mineral Research, vol. 30, no. 2, pp. 216–224, 2015. View at Publisher · View at Google Scholar · View at Scopus
  22. X. Li, Y. Zhang, H. Kang et al., “Sclerostin binds to LRP5/6 and antagonizes canonical Wnt signaling,” The Journal of Biological Chemistry, vol. 280, no. 20, pp. 19883–19887, 2005. View at Publisher · View at Google Scholar · View at Scopus
  23. M. V. Semenov and X. He, “LRP5 mutations linked to high bone mass diseases cause reduced LRP5 binding and inhibition by SOST,” The Journal of Biological Chemistry, vol. 281, no. 50, pp. 38276–38284, 2006. View at Publisher · View at Google Scholar · View at Scopus
  24. R. Sugimura and L. Li, “Noncanonical Wnt signaling in vertebrate development, stem cells, and diseases,” Birth Defects Research Part C: Embryo Today: Reviews, vol. 90, no. 4, pp. 243–256, 2010. View at Publisher · View at Google Scholar · View at Scopus
  25. M. L. Johnson and M. A. Kamel, “The Wnt signaling pathway and bone metabolism,” Current Opinion in Rheumatology, vol. 19, no. 4, pp. 376–382, 2007. View at Publisher · View at Google Scholar · View at Scopus
  26. R. Baron and M. Kneissel, “WNT signaling in bone homeostasis and disease: from human mutations to treatments,” Nature Medicine, vol. 19, no. 2, pp. 179–192, 2013. View at Publisher · View at Google Scholar · View at Scopus
  27. V. Krishnan, H. U. Bryant, and O. A. MacDougald, “Regulation of bone mass by Wnt signaling,” The Journal of Clinical Investigation, vol. 116, no. 5, pp. 1202–1209, 2006. View at Publisher · View at Google Scholar
  28. T. F. Day, X. Guo, L. Garrett-Beal, and Y. Yang, “Wnt/β-catenin signaling in mesenchymal progenitors controls osteoblast and chondrocyte differentiation during vertebrate skeletogenesis,” Developmental Cell, vol. 8, no. 5, pp. 739–750, 2005. View at Publisher · View at Google Scholar · View at Scopus
  29. D. A. Glass II, P. Bialek, J. D. Ahn et al., “Canonical Wnt signaling in differentiated osteoblasts controls osteoclast differentiation,” Developmental Cell, vol. 8, no. 5, pp. 751–764, 2005. View at Publisher · View at Google Scholar · View at Scopus
  30. W. Qiu, L. Chen, and M. Kassem, “Activation of non-canonical Wnt/JNK pathway by Wnt3a is associated with differentiation fate determination of human bone marrow stromal (mesenchymal) stem cells,” Biochemical and Biophysical Research Communications, vol. 413, no. 1, pp. 98–104, 2011. View at Publisher · View at Google Scholar · View at Scopus
  31. K. Maeda, N. Takahashi, and Y. Kobayashi, “Roles of Wnt signals in bone resorption during physiological and pathological states,” Journal of Molecular Medicine, vol. 91, no. 1, pp. 15–23, 2013. View at Publisher · View at Google Scholar
  32. H. Z. Ke, W. G. Richards, X. Li, and M. S. Ominsky, “Sclerostin and Dickkopf-1 as therapeutic targets in bone diseases,” Endocrine Reviews, vol. 33, no. 5, pp. 747–783, 2012. View at Publisher · View at Google Scholar · View at Scopus
  33. Y. Gong, R. B. Slee, N. Fukai et al., “LDL receptor-related protein 5 (LRP5) affects bone accrual and eye development,” Cell, vol. 107, no. 4, pp. 513–523, 2001. View at Publisher · View at Google Scholar
  34. M. L. Johnson, G. Gong, W. Kimberling, S. M. Recker, D. B. Kimmel, and R. R. Recker, “Linkage of a gene causing high bone mass to human chromosome 11 (11q12-13),” American Journal of Human Genetics, vol. 60, no. 6, pp. 1326–1332, 1997. View at Publisher · View at Google Scholar · View at Scopus
  35. R. D. Little, C. Folz, S. P. Manning et al., “A mutation in the LDL receptor-related protein 5 gene results in the autosomal dominant high-bone-mass trait,” The American Journal of Human Genetics, vol. 70, no. 1, pp. 11–19, 2002. View at Publisher · View at Google Scholar
  36. M. Kato, M. S. Patel, R. Levasseur et al., “Cbfa1-independent decrease in osteoblast proliferation, osteopenia, and persistent embryonic eye vascularization in mice deficient in Lrp5, a Wnt coreceptor,” Journal of Cell Biology, vol. 157, no. 2, pp. 303–314, 2002. View at Publisher · View at Google Scholar · View at Scopus
  37. P. Babij, W. Zhao, C. Small et al., “High bone mass in mice expressing a mutant LRP5 gene,” Journal of Bone and Mineral Research, vol. 18, no. 6, pp. 960–974, 2003. View at Publisher · View at Google Scholar · View at Scopus
  38. W. Wei, D. Zeve, J. M. Suh et al., “Biphasic and dosage-dependent regulation of osteoclastogenesis by β-catenin,” Molecular and Cellular Biology, vol. 31, no. 23, pp. 4706–4719, 2011. View at Publisher · View at Google Scholar
  39. T. P. Hill, D. Später, M. M. Taketo, W. Birchmeier, and C. Hartmann, “Canonical Wnt/β-catenin signaling prevents osteoblasts from differentiating into chondrocytes,” Developmental Cell, vol. 8, no. 5, pp. 727–738, 2005. View at Publisher · View at Google Scholar · View at Scopus
  40. S. L. Holmen, C. R. Zylstra, A. Mukherjee et al., “Essential role of β-catenin in postnatal bone acquisition,” The Journal of Biological Chemistry, vol. 280, no. 22, pp. 21162–21168, 2005. View at Publisher · View at Google Scholar · View at Scopus
  41. I. Kramer, C. Halleux, H. Keller et al., “Osteocyte Wnt/β-catenin signaling is required for normal bone homeostasis,” Molecular and Cellular Biology, vol. 30, no. 12, pp. 3071–3085, 2010. View at Publisher · View at Google Scholar · View at Scopus
  42. J. Albers, J. Keller, A. Baranowsky et al., “Canonical Wnt signaling inhibits osteoclastogenesis independent of osteoprotegerin,” The Journal of Cell Biology, vol. 200, no. 4, pp. 537–549, 2013. View at Publisher · View at Google Scholar · View at Scopus
  43. T. A. Yorgan, S. Peters, A. Jeschke et al., “The anti-osteoanabolic function of sclerostin is blunted in mice carrying a high bone mass mutation of Lrp5,” Journal of Bone and Mineral Research, vol. 30, no. 7, pp. 1175–1183, 2015. View at Publisher · View at Google Scholar · View at Scopus
  44. X. Li, M. S. Ominsky, Q.-T. Niu et al., “Targeted deletion of the sclerostin gene in mice results in increased bone formation and bone strength,” Journal of Bone and Mineral Research, vol. 23, no. 6, pp. 860–869, 2008. View at Publisher · View at Google Scholar · View at Scopus
  45. G. J. Atkins, P. S. Rowe, H. P. Lim et al., “Sclerostin is a locally acting regulator of late-osteoblast/preosteocyte differentiation and regulates mineralization through a MEPE-ASARM-dependent mechanism,” Journal of Bone and Mineral Research, vol. 26, no. 7, pp. 1425–1436, 2011. View at Publisher · View at Google Scholar · View at Scopus
  46. P. Nioi, S. Taylor, R. Hu et al., “Transcriptional profiling of laser capture microdissected subpopulations of the osteoblast lineage provides insight into the early response to sclerostin antibody in rats,” Journal of Bone and Mineral Research, vol. 30, no. 8, pp. 1457–1467, 2015. View at Publisher · View at Google Scholar · View at Scopus
  47. M. K. Robinson, J. Caminis, and M. E. Brunkow, “Sclerostin: how human mutations have helped reveal a new target for the treatment of osteoporosis,” Drug Discovery Today, vol. 18, no. 13-14, pp. 637–643, 2013. View at Publisher · View at Google Scholar · View at Scopus
  48. M. J. C. Moester, S. E. Papapoulos, C. W. G. M. Löwik, and R. L. van Bezooijen, “Sclerostin: current knowledge and future perspectives,” Calcified Tissue International, vol. 87, no. 2, pp. 99–107, 2010. View at Publisher · View at Google Scholar · View at Scopus
  49. E. M. Lewiecki, “Role of sclerostin in bone and cartilage and its potential as a therapeutic target in bone diseases,” Therapeutic Advances in Musculoskeletal Disease, vol. 6, no. 2, pp. 48–57, 2014. View at Publisher · View at Google Scholar · View at Scopus
  50. X. Li, M. S. Ominsky, K. S. Warmington et al., “Sclerostin antibody treatment increases bone formation, bone mass, and bone strength in a rat model of postmenopausal osteoporosis,” Journal of Bone and Mineral Research, vol. 24, no. 4, pp. 578–588, 2009. View at Publisher · View at Google Scholar · View at Scopus
  51. R. D. Ross, L. H. Edwards, A. S. Acerbo et al., “Bone matrix quality after sclerostin antibody treatment,” Journal of Bone and Mineral Research, vol. 29, no. 7, pp. 1597–1607, 2014. View at Publisher · View at Google Scholar · View at Scopus
  52. M. S. Ominsky, F. Vlasseros, J. Jolette et al., “Two doses of sclerostin antibody in cynomolgus monkeys increases bone formation, bone mineral density, and bone strength,” Journal of Bone and Mineral Research, vol. 25, no. 5, pp. 948–959, 2010. View at Publisher · View at Google Scholar · View at Scopus
  53. D. Padhi, M. Allison, A. J. Kivitz et al., “Multiple doses of sclerostin antibody romosozumab in healthy men and postmenopausal women with low bone mass: a randomized, double-blind, placebo-controlled study,” Journal of Clinical Pharmacology, vol. 54, no. 2, pp. 168–178, 2014. View at Publisher · View at Google Scholar · View at Scopus
  54. M. R. McClung, J. San Martin, P. D. Miller et al., “Opposite bone remodeling effects of teriparatide and alendronate in increasing bone mass,” Archives of Internal Medicine, vol. 165, no. 15, pp. 1762–1768, 2005. View at Publisher · View at Google Scholar · View at Scopus
  55. M. R. McClung, A. Grauer, S. Boonen et al., “Romosozumab in postmenopausal women with low bone mineral density,” The New England Journal of Medicine, vol. 370, no. 5, pp. 412–420, 2014. View at Publisher · View at Google Scholar · View at Scopus
  56. M. R. McClung, A. Chines, J. P. Brown et al., “OP0251effects of 2 years of treatment with romosozumab followed by 1 year of denosumab or placebo in postmenopausal women with low bone mineral density,” Annals of the Rheumatic Diseases, vol. 74, supplement 2, pp. 166–167, 2015. View at Publisher · View at Google Scholar
  57. J. McColm, L. Hu, T. Womack, C. C. Tang, and A. Y. Chiang, “Single- and multiple-dose randomized studies of blosozumab, a monoclonal antibody against sclerostin, in healthy postmenopausal women,” Journal of Bone and Mineral Research, vol. 29, no. 4, pp. 935–943, 2014. View at Publisher · View at Google Scholar · View at Scopus
  58. C. P. Recknor, R. R. Recker, C. T. Benson et al., “The effect of discontinuing treatment with blosozumab: follow-up results of a phase 2 randomized clinical trial in postmenopausal women with low bone mineral density,” Journal of Bone and Mineral Research, vol. 30, no. 9, pp. 1717–1725, 2015. View at Publisher · View at Google Scholar · View at Scopus
  59. Novartis, Novartis Clinical Innovations Pipeline Annual Report, Pharmaceuticals, 2014.
  60. A. Morse, M. M. McDonald, N. H. Kelly et al., “Mechanical load increases in bone formation via a sclerostin-independent pathway,” Journal of Bone and Mineral Research, vol. 29, no. 1, pp. 2456–2467, 2014. View at Publisher · View at Google Scholar · View at Scopus
  61. M.-K. Chang, I. Kramer, H. Keller et al., “Reversing LRP5-dependent osteoporosis and SOST deficiency-induced sclerosing bone disorders by altering WNT signaling activity,” Journal of Bone and Mineral Research, vol. 29, no. 1, pp. 29–42, 2014. View at Publisher · View at Google Scholar · View at Scopus
  62. A. Morse, N. Y. C. Yu, L. Peacock et al., “Endochondral fracture healing with external fixation in the Sost knockout mouse results in earlier fibrocartilage callus removal and increased bone volume fraction and strength,” Bone, vol. 71, pp. 155–163, 2015. View at Publisher · View at Google Scholar · View at Scopus
  63. X. Li, M. S. Ominsky, K. S. Warmington et al., “Increased bone formation and bone mass induced by sclerostin antibody is not affected by pretreatment or cotreatment with alendronate in osteopenic, ovariectomized rats,” Endocrinology, vol. 152, no. 9, pp. 3312–3322, 2011. View at Publisher · View at Google Scholar · View at Scopus
  64. J. S. Finkelstein, A. Hayes, J. L. Hunzelman, J. J. Wyland, H. Lee, and R. M. Neer, “The effects of parathyroid hormone, alendronate, or both in men with osteoporosis,” The New England Journal of Medicine, vol. 349, no. 13, pp. 1216–1226, 2003. View at Publisher · View at Google Scholar · View at Scopus
  65. J. S. Finkelstein, B. Z. Leder, S.-A. M. Burnett et al., “Effects of teriparatide, alendronate, or both on bone turnover in osteoporotic men,” The Journal of Clinical Endocrinology & Metabolism, vol. 91, no. 8, pp. 2882–2887, 2006. View at Publisher · View at Google Scholar · View at Scopus
  66. L. Cui, H. Cheng, C. Song et al., “Time-dependent effects of sclerostin antibody on a mouse fracture healing model,” Journal of Musculoskeletal & Neuronal Interactions, vol. 13, no. 2, pp. 178–184, 2013. View at Google Scholar · View at Scopus
  67. P. K. Suen, Y.-X. He, D. H. K. Chow et al., “Sclerostin monoclonal antibody enhanced bone fracture healing in an open osteotomy model in rats,” Journal of Orthopaedic Research, vol. 32, no. 8, pp. 997–1005, 2014. View at Publisher · View at Google Scholar · View at Scopus
  68. M. S. Ominsky, C. Li, X. Li et al., “Inhibition of sclerostin by monoclonal antibody enhances bone healing and improves bone density and strength of nonfractured bones,” Journal of Bone and Mineral Research, vol. 26, no. 5, pp. 1012–1021, 2011. View at Publisher · View at Google Scholar · View at Scopus
  69. M. M. McDonald, A. Morse, K. Mikulec et al., “Inhibition of sclerostin by systemic treatment with sclerostin antibody enhances healing of proximal tibial defects in ovariectomized rats,” Journal of Orthopaedic Research, vol. 30, no. 10, pp. 1541–1548, 2012. View at Publisher · View at Google Scholar · View at Scopus
  70. M. U. Jawad, K. E. Fritton, T. Ma et al., “Effects of sclerostin antibody on healing of a non-critical size femoral bone defect,” Journal of Orthopaedic Research, vol. 31, no. 1, pp. 155–163, 2013. View at Publisher · View at Google Scholar · View at Scopus
  71. C. S. Yee, L. Xie, S. Hatsell et al., “Sclerostin antibody treatment improves fracture outcomes in a type i diabetic mouse model,” Bone, vol. 82, pp. 122–134, 2016. View at Publisher · View at Google Scholar
  72. M. S. Virk, F. Alaee, H. Tang, M. S. Ominsky, H. Z. Ke, and J. R. Lieberman, “Systemic administration of sclerostin antibody enhances bone repair in a critical-sized femoral defect in a rat model,” The Journal of Bone & Joint Surgery—American Volume, vol. 95, no. 8, pp. 694–701, 2013. View at Publisher · View at Google Scholar · View at Scopus
  73. F. Alaee, M. S. Virk, H. Tang et al., “Evaluation of the effects of systemic treatment with a sclerostin neutralizing antibody on bone repair in a rat femoral defect model,” Journal of Orthopaedic Research, vol. 32, no. 2, pp. 197–203, 2014. View at Publisher · View at Google Scholar · View at Scopus
  74. J. Levin, Acceleration of Fracture Healing with CDP7851/AMG785 Will Not Move into Phase 3, FierceBiotech, 2013, http://www.fiercebiotech.com/press-releases/acceleration-fracture-healing-cdp7851amg785-will-not-move-phase-3.
  75. K. Sarahrudi, A. Thomas, C. Albrecht, and S. Aharinejad, “Strongly enhanced levels of sclerostin during human fracture healing,” Journal of Orthopaedic Research, vol. 30, no. 10, pp. 1549–1555, 2012. View at Publisher · View at Google Scholar · View at Scopus
  76. F. Agholme, X. Li, H. Isaksson, H. Z. Ke, and P. Aspenberg, “Sclerostin antibody treatment enhances metaphyseal bone healing in rats,” Journal of Bone and Mineral Research, vol. 25, no. 11, pp. 2412–2418, 2010. View at Publisher · View at Google Scholar · View at Scopus
  77. A. S. Virdi, M. Liu, K. Sena et al., “Sclerostin antibody increases bone volume and enhances implant fixation in a rat model,” The Journal of Bone & Joint Surgery—American Volume, vol. 94, no. 18, pp. 1670–1680, 2012. View at Publisher · View at Google Scholar · View at Scopus
  78. S. Liu, A. S. Virdi, K. Sena, and D. R. Sumner, “Sclerostin antibody prevents particle-induced implant loosening by stimulating bone formation and inhibiting bone resorption in a rat model,” Arthritis and Rheumatism, vol. 64, no. 12, pp. 4012–4020, 2012. View at Publisher · View at Google Scholar · View at Scopus
  79. A. S. Virdi, J. Irish, K. Sena et al., “Sclerostin antibody treatment improves implant fixation in a model of severe osteoporosis,” The Journal of Bone & Joint Surgery—AmericanVolume, vol. 97, no. 2, pp. 133–140, 2015. View at Publisher · View at Google Scholar · View at Scopus
  80. A. Eddleston, M. Marenzana, A. R. Moore et al., “A short treatment with an antibody to sclerostin can inhibit bone loss in an ongoing model of colitis,” Journal of Bone and Mineral Research, vol. 24, no. 10, pp. 1662–1671, 2009. View at Publisher · View at Google Scholar · View at Scopus
  81. X.-X. Chen, W. Baum, D. Dwyer et al., “Sclerostin inhibition reverses systemic, periarticular and local bone loss in arthritis,” Annals of the Rheumatic Diseases, vol. 72, no. 10, pp. 1732–1736, 2013. View at Publisher · View at Google Scholar · View at Scopus
  82. C. Hamann, M. Rauner, Y. Höhna et al., “Sclerostin antibody treatment improves bone mass, bone strength, and bone defect regeneration in rats with type 2 diabetes mellitus,” Journal of Bone and Mineral Research, vol. 28, no. 3, pp. 627–638, 2013. View at Publisher · View at Google Scholar · View at Scopus
  83. B. P. Sinder, M. M. Eddy, M. S. Ominsky, M. S. Caird, J. C. Marini, and K. M. Kozloff, “Sclerostin antibody improves skeletal parameters in a Brtl/+ mouse model of osteogenesis imperfecta,” Journal of Bone and Mineral Research, vol. 28, no. 1, pp. 73–80, 2013. View at Publisher · View at Google Scholar · View at Scopus
  84. A. G. Costa, J. P. Bilezikian, and E. M. Lewiecki, “The potential use of antisclerostin therapy in chronic kidney disease—mineral and bone disorder,” Current Opinion in Nephrology and Hypertension, vol. 24, no. 4, pp. 324–329, 2015. View at Publisher · View at Google Scholar · View at Scopus
  85. Y. Ren, X. Han, S. P. Ho et al., “Removal of SOST or blocking its product sclerostin rescues defects in the periodontitis mouse model,” FASEB Journal, vol. 29, no. 7, pp. 2702–2711, 2015. View at Publisher · View at Google Scholar
  86. A. Roschger, P. Roschger, P. Keplingter et al., “Effect of sclerostin antibody treatment in a mouse model of severe osteogenesis imperfecta,” Bone, vol. 66, pp. 182–188, 2014. View at Publisher · View at Google Scholar · View at Scopus
  87. D. Gatti, F. Antoniazzi, R. Prizzi et al., “Intravenous neridronate in children with osteogenesis imperfecta: a randomized controlled study,” Journal of Bone and Mineral Research, vol. 20, no. 5, pp. 758–763, 2005. View at Publisher · View at Google Scholar · View at Scopus
  88. R. Sakkers, D. Kok, R. Engelbert et al., “Skeletal effects and functional outcome with olpadronate in children with osteogenesis imperfecta: a 2-year randomised placebo-controlled study,” The Lancet, vol. 363, no. 9419, pp. 1427–1431, 2004. View at Publisher · View at Google Scholar · View at Scopus
  89. M. P. Whyte, W. H. McAlister, D. V. Novack, K. L. Clements, P. L. Schoenecker, and D. Wenkert, “Bisphosphonate-induced osteopetrosis: novel bone modeling defects, metaphyseal osteopenia, and osteosclerosis fractures after drug exposure ceases,” Journal of Bone and Mineral Research, vol. 23, no. 10, pp. 1698–1707, 2008. View at Publisher · View at Google Scholar · View at Scopus
  90. L. M. Ward, F. Rauch, M. P. Whyte et al., “Alendronate for the treatment of pediatric osteogenesis imperfecta: a randomized placebo-controlled study,” Journal of Clinical Endocrinology and Metabolism, vol. 96, no. 2, pp. 355–364, 2011. View at Publisher · View at Google Scholar · View at Scopus
  91. F. Rauch, C. F. Munns, C. Land, M. Cheung, and F. H. Glorieux, “Risedronate in the treatment of mild pediatric osteogenesis imperfecta: a randomized placebo-controlled study,” Journal of Bone and Mineral Research, vol. 24, no. 7, pp. 1282–1289, 2009. View at Publisher · View at Google Scholar · View at Scopus
  92. A. D. Letocha, H. L. Cintas, J. F. Troendle et al., “Controlled trial of pamidronate in children with types III and IV osteogenesis imperfecta confirms vertebral gains but not short-term functional improvement,” Journal of Bone and Mineral Research, vol. 20, no. 6, pp. 977–986, 2005. View at Publisher · View at Google Scholar · View at Scopus
  93. J. L. Vahle, M. Sato, G. G. Long et al., “Skeletal changes in rats given daily subcutaneous injections of recombinant human parathyroid hormone (1–34) for 2 years and relevance to human safety,” Toxicologic Pathology, vol. 30, no. 3, pp. 312–321, 2002. View at Publisher · View at Google Scholar · View at Scopus
  94. J. C. Marini, E. Hopkins, F. H. Glorieux et al., “Positive linear growth and bone responses to growth hormone treatment in children with types III and IV osteogenesis imperfecta: high predictive value of the carboxyterminal propeptide of type I procollagen,” Journal of Bone and Mineral Research, vol. 18, no. 2, pp. 237–243, 2003. View at Publisher · View at Google Scholar · View at Scopus
  95. M. Roudier, X. Li, Q.-T. Niu et al., “Sclerostin is expressed in articular cartilage but loss or inhibition does not affect cartilage remodeling during aging or following mechanical injury,” Arthritis and Rheumatism, vol. 65, no. 3, pp. 721–731, 2013. View at Publisher · View at Google Scholar · View at Scopus
  96. M. H. Napimoga, C. Nametala, F. L. Da Silva et al., “Involvement of the Wnt-β-catenin signalling antagonists, sclerostin and dickkopf-related protein 1, in chronic periodontitis,” Journal of Clinical Periodontology, vol. 41, no. 6, pp. 550–557, 2014. View at Publisher · View at Google Scholar · View at Scopus
  97. U. Kuchler, U. Y. Schwarze, T. Dobsak et al., “Dental and periodontal phenotype in sclerostin knockout mice,” International Journal of Oral Science, vol. 6, no. 2, pp. 70–76, 2014. View at Publisher · View at Google Scholar · View at Scopus
  98. P. Han, S. Ivanovski, R. Crawford, and Y. Xiao, “Activation of the canonical Wnt signaling pathway induces cementum regeneration,” Journal of Bone and Mineral Research, vol. 30, no. 7, pp. 1160–1174, 2015. View at Publisher · View at Google Scholar · View at Scopus
  99. A. D. Taut, Q. Jin, J.-H. Chung et al., “Sclerostin antibody stimulates bone regeneration after experimental periodontitis,” Journal of Bone and Mineral Research, vol. 28, no. 11, pp. 2347–2356, 2013. View at Publisher · View at Google Scholar · View at Scopus
  100. H. Chen, X. Xu, M. Liu et al., “Sclerostin antibody treatment causes greater alveolar crest height and bone mass in an ovariectomized rat model of localized periodontitis,” Bone, vol. 76, pp. 141–148, 2015. View at Publisher · View at Google Scholar · View at Scopus
  101. K. G. Murphy and J. C. Gunsolley, “Guided tissue regeneration for the treatment of periodontal intrabony and furcation defects. A systematic review,” Annals of Periodontology, vol. 8, no. 1, pp. 266–302, 2003. View at Publisher · View at Google Scholar · View at Scopus
  102. S. Ivanovski, C. Vaquette, S. Gronthos, D. W. Hutmacher, and P. M. Bartold, “Multiphasic scaffolds for periodontal tissue engineering,” Journal of Dental Research, vol. 93, no. 12, pp. 1212–1221, 2014. View at Publisher · View at Google Scholar · View at Scopus
  103. S. Pelletier, L. Dubourg, M.-C. Carlier, A. Hadj-Aissa, and D. Fouque, “The relation between renal function and serum sclerostin in adult patients with CKD,” Clinical Journal of the American Society of Nephrology, vol. 8, no. 5, pp. 819–823, 2013. View at Publisher · View at Google Scholar · View at Scopus
  104. M. Kanbay, D. Siriopol, M. Saglam et al., “Serum sclerostin and adverse outcomes in nondialyzed chronic kidney disease patients,” Journal of Clinical Endocrinology and Metabolism, vol. 99, no. 10, pp. E1854–E1861, 2014. View at Publisher · View at Google Scholar · View at Scopus
  105. V. M. Brandenburg, R. Kramann, R. Koos et al., “Relationship between sclerostin and cardiovascular calcification in hemodialysis patients: a cross-sectional study,” BMC Nephrology, vol. 14, article 219, 2013. View at Publisher · View at Google Scholar · View at Scopus
  106. R. Kramann, V. M. Brandenburg, L. J. Schurgers et al., “Novel insights into osteogenesis and matrix remodelling associated with calcific uraemic arteriolopathy,” Nephrology Dialysis Transplantation, vol. 28, no. 4, pp. 856–868, 2013. View at Publisher · View at Google Scholar · View at Scopus
  107. L. J. Schurgers, E. C. M. Cranenburg, and C. Vermeer, “Matrix Gla-protein: the calcification inhibitor in need of vitamin K,” Thrombosis and Haemostasis, vol. 100, no. 4, pp. 593–603, 2008. View at Publisher · View at Google Scholar · View at Scopus
  108. M. Hayashi, I. Takamatsu, Y. Kanno, T. Yoshida, T. Abe, and Y. Sato, “A case-control study of calciphylaxis in Japanese end-stage renal disease patients,” Nephrology Dialysis Transplantation, vol. 27, no. 4, pp. 1580–1584, 2012. View at Publisher · View at Google Scholar · View at Scopus
  109. R. L. van Bezooijen, S. E. Papapoulos, and C. W. Löwik, “Bone morphogenetic proteins and their antagonists: the sclerostin paradigm,” Journal of Endocrinological Investigation, vol. 28, no. 8, supplement, pp. 15–17, 2005. View at Publisher · View at Google Scholar · View at Scopus
  110. L. Desjardins, S. Liabeuf, R. B. Oliveira et al., “Uremic toxicity and sclerostin in chronic kidney disease patients,” Nephrologie & therapeutique, vol. 10, no. 6, pp. 463–470, 2014. View at Google Scholar
  111. L. Viaene, G. J. Behets, K. Claes et al., “Sclerostin: another bone-related protein related to all-cause mortality in haemodialysis?” Nephrology Dialysis Transplantation, vol. 28, no. 12, pp. 3024–3030, 2013. View at Publisher · View at Google Scholar · View at Scopus
  112. C. Drechsler, P. Evenepoel, M. G. Vervloet et al., “High levels of circulating sclerostin are associated with better cardiovascular survival in incident dialysis patients: results from the NECOSAD study,” Nephrology Dialysis Transplantation, vol. 30, no. 2, pp. 288–293, 2015. View at Publisher · View at Google Scholar · View at Scopus
  113. S. M. Moe, N. X. Chen, C. L. Newman et al., “Anti-sclerostin antibody treatment in a rat model of progressive renal osteodystrophy,” Journal of Bone and Mineral Research, vol. 30, no. 3, pp. 499–509, 2015. View at Publisher · View at Google Scholar
  114. C. L. Newman, N. X. Chen, E. Smith et al., “Compromised vertebral structural and mechanical properties associated with progressive kidney disease and the effects of traditional pharmacological interventions,” Bone, vol. 77, pp. 50–56, 2015. View at Publisher · View at Google Scholar · View at Scopus
  115. V. Boschert, E.-M. Muth, A. Knappik, C. Frisch, and T. D. Mueller, “Crystallization and preliminary X-ray crystallographic analysis of the sclerostin-neutralizing Fab AbD09097,” Acta Crystallographica Section F: Structural Biology Communications, vol. 71, part 4, pp. 388–392, 2015. View at Publisher · View at Google Scholar · View at Scopus
  116. Q. Yao, J. Ni, Y. Hou, L. Ding, L. Zhang, and H. Jiang, “Expression of sclerostin scFv and the effect of sclerostin scFv on healing of osteoporotic femur fracture in rats,” Cell Biochemistry and Biophysics, vol. 69, no. 2, pp. 229–235, 2014. View at Publisher · View at Google Scholar · View at Scopus
  117. L. A. Johnson, Amgen, UCB Halt Testing of Drug for Fracture Healing, But Continue Testing for Osteoporosis, Associated Press, 2013, http://news.yahoo.com/amgen-ucb-halt-testing-fracture-203100125.html.
  118. J. C. Gardner, R. L. van Bezooijen, B. Mervis et al., “Bone mineral density in sclerosteosis; affected individuals and gene carriers,” The Journal of Clinical Endocrinology and Metabolism, vol. 90, no. 12, pp. 6392–6395, 2005. View at Publisher · View at Google Scholar · View at Scopus
  119. R. T. Moon, A. D. Kohn, G. V. De Ferrari, and A. Kaykas, “WNT and β-catenin signalling: diseases and therapies,” Nature Reviews Genetics, vol. 5, no. 9, pp. 691–701, 2004. View at Publisher · View at Google Scholar · View at Scopus
  120. H. Clevers and R. Nusse, “Wnt/β-catenin signaling and disease,” Cell, vol. 149, no. 6, pp. 1192–1205, 2012. View at Publisher · View at Google Scholar · View at Scopus
  121. M. Kahn, “Can we safely target the WNT pathway?” Nature Reviews Drug Discovery, vol. 13, no. 7, pp. 513–532, 2014. View at Publisher · View at Google Scholar · View at Scopus
  122. M. Jia, S. Chen, B. Zhang et al., “Effects of constitutive β-catenin activation on vertebral bone growth and remodeling at different postnatal stages in mice,” PLoS ONE, vol. 8, no. 9, Article ID e74093, 2013. View at Publisher · View at Google Scholar
  123. S. Chen, J. Feng, Q. Bao et al., “Adverse effects of osteocytic constitutive activation of ß-catenin on bone strength and bone growth,” Journal of Bone and Mineral Research, vol. 30, no. 7, pp. 1184–1194, 2015. View at Publisher · View at Google Scholar · View at Scopus
  124. R. Baron and E. Hesse, “Update on bone anabolics in osteoporosis treatment: rationale, current status, and perspectives,” The Journal of Clinical Endocrinology and Metabolism, vol. 97, no. 2, pp. 311–325, 2012. View at Publisher · View at Google Scholar · View at Scopus
  125. M. Stolina, D. Dwyer, Q.-T. Niu et al., “Temporal changes in systemic and local expression of bone turnover markers during six months of sclerostin antibody administration to ovariectomized rats,” Bone, vol. 67, pp. 305–313, 2014. View at Publisher · View at Google Scholar · View at Scopus
  126. M. Co, Merck Announces Data from Pivotal Phase 3 Fracture Outcomes Study for Odanacatib, an Investigational Oral, Once-Weekly Treatment for Osteoporosis, 2014, http://www.mercknewsroom.com/news-release/research-and-development-news/merck-announces-data-pivotal-phase-3-fracture-outcomes-st.