Novel targets for the prevention of osteoporosis - Lessons learned from studies of metabolic bone disorders

Expert Opinion on Therapeutic Targets

Volumn 19, Issue 11, 2015, Pages 1575-1584

  Henriksen, Kim ^a   Thudium, Christian Schneider ^a   Christiansen, Claus ^a   Karsdal, Morten Asser ^a  

^a NORDIC BIOSCIENCE A S   (Denmark)

Author keywords

anabolic; anti resorptive; osteoporosis; treatment

Indexed keywords

ABALOPARATIDE; CATHEPSIN K INHIBITOR; ODANACATIB; ONO 5334; PARATHYROID HORMONE; SCLEROSTIN; STRONTIUM RANELATE; UNCLASSIFIED DRUG; BONE DENSITY CONSERVATION AGENT;

BONE TURNOVER; DRUG TARGETING; FEMALE; HUMAN; METABOLIC BONE DISEASE; NONHUMAN; OSTEOPOROSIS; PHASE 2 CLINICAL TRIAL (TOPIC); PHASE 3 CLINICAL TRIAL (TOPIC); POSTMENOPAUSE OSTEOPOROSIS; RANDOMIZED CONTROLLED TRIAL (TOPIC); REVIEW; ANIMAL; BONE DISEASES, METABOLIC; BONE REMODELING; COMPLICATION; DRUG DESIGN; DRUG EFFECTS; MOLECULARLY TARGETED THERAPY; OSTEOPOROTIC FRACTURES; PATHOPHYSIOLOGY;

ANIMALS; BONE DENSITY CONSERVATION AGENTS; BONE DISEASES, METABOLIC; BONE REMODELING; DRUG DESIGN; HUMANS; MOLECULAR TARGETED THERAPY; OSTEOPOROSIS; OSTEOPOROTIC FRACTURES;

EID: 84946721609     PISSN: 14728222     EISSN: 17447631     Source Type: Journal    
DOI: 10.1517/14728222.2015.1045415     Document Type: Review

References (98)

1. Seeman E, Delmas PD. Bone quality-The material and structural basis of bone strength and fragility. N Engl J Med 2006;354:2250-61
2. Henriksen K, Bollerslev J, Everts V, Karsdal MA. Osteoclast activity and subtypes as a function of physiology and pathology-implications for future treatments of osteoporosis. Endocr Rev 2011;32:31-63
3. Karsdal MA, Martin TJ, Bollerslev J, et al. Are nonresorbing osteoclasts sources of bone anabolic activity? J Bone Miner Res 2007;22:487-94
4. Harvey N, Earl S, Cooper C. Epidemiology of osteoporotic fractures. In: Primer on the metabolic bone diseases and disorders of mineral metabolism. 6th Edition. 2006. 244-8
5. Appelman-Dijkstra NM, Papapoulos SE. Novel approaches to the treatment of osteoporosis. Best Pract Res Clin Endocrinol Metab 2014;28:843-57
6. Martin TJ, Seeman E. New mechanisms and targets in the treatment of bone fragility. Clin Sci (Lond) 2007;112:77-91
7. Rachner TD, Khosla S, Hofbauer LC. Osteoporosis: now and the future. Lancet 2011;377:1276-87
8. Chavassieux P, Meunier PJ, Roux JP, et al. Bone histomorphometry of transiliac paired bone biopsies after 6 or 12 months of treatment with oral strontium ranelate in 387 osteoporotic women: randomized comparison to alendronate. J Bone Miner Res 2014;29:618-28
9. Bolland MJ, Grey A. A comparison of adverse event and fracture efficacy data for strontium ranelate in regulatory documents and the publication record. BMJ Open 2014;4:e005787
10. Crandall CJ, Newberry SJ, Diamant A, et al. Comparative effectiveness of pharmacologic treatments to prevent fractures: an updated systematic review. Ann Intern Med 2014;161:711-23
11. Delmas PD, Ensrud KE, Adachi JD, et al. Efficacy of raloxifene on vertebral fracture risk reduction in postmenopausal women with osteoporosis: four-year results from a randomized clinical trial. J Clin Endocrinol Metab 2002;87:3609-17
12. Cummings SR, San MJ, McClung MR, et al. Denosumab for prevention of fractures in postmenopausal women with osteoporosis. N Engl J Med 2009;361:756-65
13. Eastell R, Christiansen C, Grauer A, et al. Effects of denosumab on bone turnover markers in postmenopausal osteoporosis. J Bone Miner Res 2011;26(3):530-7
14. Khan AA, Morrison A, Hanley DA, et al. Diagnosis and management of osteonecrosis of the jaw: A systematic review and international consensus. J Bone Miner Res 2015;30:3-23
15. Reid IR. Efficacy, effectiveness and side effects of medications used to prevent fractures. J Intern Med 2014. [Epub ahead of print]
16. Neer RM, Arnaud CD, Zanchetta JR, et al. Effect of parathyroid hormone (1-34) on fractures and bone mineral density in postmenopausal women with osteoporosis. N Engl J Med 2001;344:1434-41
17. Subbiah V, Madsen VS, Raymond AK, et al. Of mice and men: divergent risks of teriparatide-induced osteosarcoma. Osteoporos Int 2010;21:1041-5
18. Winkler DG, Sutherland MK, Geoghegan JC, et al. Osteocyte control of bone formation via sclerostin, a novel BMP antagonist. EMBO J 2003;22:6267-76
19. van Bezooijen RL, Roelen BA, Visser A, et al. Sclerostin is an osteocyte-expressed negative regulator of bone formation, but not a classical BMP antagonist. J Exp Med 2004;199:805-14
20. Poole KE, van Bezooijen RL, Loveridge N, et al. Sclerostin is a delayed secreted product of osteocytes that inhibits bone formation. FASEB J 2005;19:1842-4
21. Balemans W, Van Hul W. The genetics of LRP5 in bone-A story of extremes. Endocrinology 2007;148(6):2622-9
22. Brunkow ME, Gardner JC, Van NJ, et al. Bone dysplasia sclerosteosis results from loss of the SOST gene product, a novel cystine knot-containing protein. Am J Hum Genet 2001;68:577-89
23. Lewiecki EM. Role of sclerostin in bone and cartilage and its potential as a therapeutic target in bone diseases. Ther Adv Musculoskelet Dis 2014;6:48-57
24. van Lierop AH, Hamdy NA, van Egmond ME, et al. Van Buchem disease: clinical, biochemical, and densitometric features of patients and disease carriers. J Bone Miner Res 2013;28:848-54
25. Moester MJ, Papapoulos SE, Lowik CW, van Bezooijen RL. Sclerostin: current knowledge and future perspectives. Calcif Tissue Int 2010;87:99-107
26. Li X, Ominsky MS, Warmington KS, et al. Sclerostin antibody treatment increases bone formation, bone mass, and bone strength in a rat model of postmenopausal osteoporosis. J Bone Miner Res 2009;24:578-88
27. Ominsky MS, Vlasseros F, Jolette J, et al. Two doses of sclerostin antibody in cynomolgus monkeys increases bone formation, bone mineral density, and bone strength. J Bone Miner Res 2010;25:948-59
28. Ominsky MS, Niu QT, Li C, et al. Tissue-level mechanisms responsible for the increase in bone formation and bone volume by sclerostin antibody. J Bone Miner Res 2014;29:1424-30
29. Recker RR, Benson CT, Matsumoto T, et al. A randomized, double-blind phase 2 clinical trial of blosozumab, a sclerostin antibody, in postmenopausal women with low bone mineral density. J Bone Miner Res 2015;30:216-24
30. McClung MR, Grauer A, Boonen S, et al. Romosozumab in postmenopausal women with low bone mineral density. N Engl J Med 2014;370:412-20
31. Boyden LM, Mao J, Belsky J, et al. High bone density due to a mutation in LDL-receptor-related protein 5. N Engl J Med 2002;346:1513-21
32. Bollerslev J, Grontved A, Andersen PE Jr. Autosomal dominant osteopetrosis: an otoneurological investigation of the two radiological types. Laryngoscope 1988;98:411-13
33. Bollerslev J. Autosomal dominant osteopetrosis: bone metabolism and epidemiological, clinical, and hormonal aspects. Endocr Rev 1989;10:45-67
34. Lories RJ, Corr M, Lane NE. To Wnt or not to Wnt: The bone and joint health dilemma. Nat Rev Rheumatol 2013;9:328-39
35. Bouaziz W, Funck-Brentano T, Lin H, et al. Loss of sclerostin promotes osteoarthritis in mice via ss-catenin-dependent and-independent Wnt pathways. Arthritis Res Ther 2015;17:24
36. Chan BY, Fuller ES, Russell AK, et al. Increased chondrocyte sclerostin may protect against cartilage degradation in osteoarthritis. Osteoarthritis Cartilage 2011;19:874-85
37. Roudier M, Li X, Niu QT, et al. Sclerostin is expressed in articular cartilage but loss or inhibition does not affect cartilage remodeling during aging or following mechanical injury. Arthritis Rheum 2013;65:721-31
38. Kumarasinghe DD, Hopwood B, Kuliwaba JS, et al. An update on primary hip osteoarthritis including altered Wnt and TGF-beta associated gene expression from the bony component of the disease. Rheumatology (Oxford) 2011;50:2166-75
39. Evenepoel P, D'Haese P, Brandenburg V. Romosozumab in postmenopausal women with osteopenia. N Engl J Med 2014;370:1664
40. McClung MR, Grauer A. Romosozumab in postmenopausal women with osteopenia. N Engl J Med 2014;370:1664-5
41. Black DM, Greenspan SL, Ensrud KE, et al. The effects of parathyroid hormone and alendronate alone or in combination in postmenopausal osteoporosis. N Engl J Med 2003;349:1207-15
42. Wysolmerski JJ. Parathyroid hormonerelated protein: an update. J Clin Endocrinol Metab 2012;97:2947-56
43. Ferrandon S, Feinstein TN, Castro M, et al. Sustained cyclic AMP production by parathyroid hormone receptor endocytosis. Nat Chem Biol 2009;5:734-42
44. Miao D, He B, Jiang Y, et al. Osteoblast-derived PTHrP is a potent endogenous bone anabolic agent that modifies the therapeutic efficacy of administered PTH 1-34. J Clin Invest 2005;115:2402-11
45. Horwitz MJ, Tedesco MB, Sereika SM, et al. Safety and tolerability of subcutaneous PTHrP(1-36) in healthy human volunteers: A dose escalation study. Osteoporos Int 2006;17:225-30
46. Horwitz MJ, Tedesco MB, Sereika SM, et al. Continuous PTH and PTHrP infusion causes suppression of bone formation and discordant effects on 1,25 (OH)2 vitamin D. J Bone Miner Res 2005;20:1792-803
47. Leder BZ, O'Dea LS, Zanchetta JR, et al. Effects of abaloparatide, a human parathyroid hormone-related Peptide analog, on bone mineral density in postmenopausal women with osteoporosis. J Clin Endocrinol Metab 2015;100:697-706
48. Horwitz MJ, Tedesco MB, Garcia-Ocana A, et al. Parathyroid hormone-related protein for the treatment of postmenopausal osteoporosis: defining the maximal tolerable dose. J Clin Endocrinol Metab 2010;95:1279-87
49. Horwitz MJ, Tedesco MB, Gundberg C, et al. Short-term, high-dose parathyroid hormone-related protein as a skeletal anabolic agent for the treatment of postmenopausal osteoporosis. J Clin Endocrinol Metab 2003;88:569-75
50. Available from: http://investors.radiuspharm.com/releasedetail.cfm?releaseid=888584 2015
51. Nemeth EF, Shoback D. Calcimimetic and calcilytic drugs for treating bone and mineral-related disorders. Best Pract Res Clin Endocrinol Metab 2013;27:373-84
52. Kimura S, Nakagawa T, Matsuo Y, et al. JTT-305, an orally active calcium-sensing receptor antagonist, stimulates transient parathyroid hormone release and bone formation in ovariectomized rats. Eur J Pharmacol 2011;668:331-6
53. John MR, Harfst E, Loeffler J, et al. AXT914 a novel, orally-active parathyroid hormone-releasing drug in two early studies of healthy volunteers and postmenopausal women. Bone 2014;64:204-10
54. Fitzpatrick LA, Dabrowski CE, Cicconetti G, et al. Ronacaleret, a calcium-sensing receptor antagonist, increases trabecular but not cortical bone in postmenopausal women. J Bone Miner Res 2012;27:255-62
55. Drake FH, Dodds RA, James IE, et al. Cathepsin K, but not cathepsins B, L, or S, is abundantly expressed in human osteoclasts. J Biol Chem 1996;271:12511-16
56. Garnero P, Borel O, Byrjalsen I, et al. The collagenolytic activity of cathepsin K is unique among mammalian proteinases. J Biol Chem 1998;273:32347-52
57. Gelb BD, Shi GP, Chapman HA, Desnick RJ. Pycnodysostosis, a lysosomal disease caused by cathepsin K deficiency. Science 1996;273:1236-8
58. Nishi Y, Atley L, Eyre DE, et al. Determination of bone markers in pycnodysostosis: effects of cathepsin K deficiency on bone matrix degradation. J Bone Miner Res 1999;14:1902-8
59. Saftig P, Hunziker E, Wehmeyer O, et al. Impaired osteoclastic bone resorption leads to osteopetrosis in cathepsin-K-deficient mice. Proc Natl Acad Sci USA 1998;95:13453-8
60. Gowen M, Lazner F, Dodds R, et al. Cathepsin K knockout mice develop osteopetrosis due to a deficit in matrix degradation but not demineralization. J Bone Miner Res 1999;14:1654-63
61. Kiviranta R, Morko J, Alatalo SL, et al. Impaired bone resorption in cathepsin K-deficient mice is partially compensated for by enhanced osteoclastogenesis and increased expression of other proteases via an increased RANKL/OPG ratio. Bone 2005;36:159-72
62. Pennypacker B, Shea M, Liu Q, et al. Bone density, strength, and formation in adult cathepsin K (-/-) mice. Bone 2009;44:199-207
63. Lotinun S, Kiviranta R, Matsubara T, et al. Osteoclast-specific cathepsin K deletion stimulates S1P-dependent bone formation. J Clin Invest 2013;123(2):666-81
64. Xie H, Cui Z, Wang L, et al. PDGF-BB secreted by preosteoclasts induces angiogenesis during coupling with osteogenesis. Nat Med 2014;20:1270-8
65. Boonen S, Rosenberg E, Claessens F, et al. Inhibition of cathepsin K for treatment of osteoporosis. Curr Osteoporos Rep 2012;10:73-9
66. Zhuo Y, Gauthier JY, Black WC, et al. Inhibition of bone resorption by the cathepsin K inhibitor odanacatib is fully reversible. Bone 2014;67:269-80
67. Pennypacker BL, Chen CM, Zheng H, et al. Inhibition of cathepsin K increases modeling-based bone formation, and improves cortical dimension and strength in adult ovariectomized monkeys. J Bone Miner Res 2014;29:1847-58
68. Cusick T, Pennypacker B, Scott K, et al. Effects of odanacatib on bone mass, turnover and strength in the femoral neck of estrogen deficient adult rhesus monkeys. J Bone Miner Res 2009;24(Suppl):abstract FR0416. Ref Type: Generic
69. Masarachia PJ, Pennypacker BL, Pickarski M, et al. Odanacatib reduces bone turnover and increases bone mass in the lumbar spine of skeletally mature ovariectomized rhesus monkeys. J Bone Miner Res 2012;27(3):509-23
70. Pennypacker B, Wesolowski G, Heo J, Duong LT. Effects of odanacatib on central femur cortical bone in estrogendeficient adult rhesus monkeys. J Bone Miner Res 2009;24(Suppl 1):abstract 1171
71. Ochi Y, Yamada H, Mori H, et al. Effects of eight-month treatment with ONO-5334, a cathepsin K inhibitor, on bone metabolism, strength and microstructure in ovariectomized cynomolgus monkeys. Bone 2014;65:1-8
72. Bone HG, Dempster DW, Eisman JA, et al. Odanacatib for the treatment of postmenopausal osteoporosis: development history and design and participant characteristics of LOFT, the Long-Term Odanacatib Fracture Trial. Osteoporos Int 2015;26:699-712
73. Bone HG, McClung MR, Roux C, et al. Odanacatib, a cathepsin-k inhibitor for osteoporosis: A two-year study in postmenopausal women with low bone density. J Bone Miner Res 2010;25(5):937-47
74. Eisman JA, Bone HG, Hosking DJ, et al. Odanacatib in the treatment of postmenopausal women with low bone mineral density: Three-year continued therapy and resolution of effect. J Bone Miner Res 2011;26(2):242-51
75. Langdahl B, Binkley N, Bone H, et al. Odanacatib in the treatment of postmenopausal women with low bone mineral density: five years of continued therapy in a phase 2 study. J Bone Miner Res 2012;27:2251-8
76. Eastell R, Nagase S, Ohyama M, et al. Safety and efficacy of the cathepsin K inhibitor ONO-5334 in postmenopausal osteoporosis: The OCEAN study. J Bone Miner Res 2011;26:1303-12
77. Eastell R, Nagase S, Small M, et al. Effect of ONO-5334 on bone mineral density and biochemical markers of bone turnover in postmenopausal osteoporosis: 2-year results from the OCEAN study. J Bone Miner Res 2014;29:458-66
78. Available from: http://www. mercknewsroom.com/news-release/research-and-development-news/merckannounces-data-pivotal-phase-3-fractureoutcomes-st 2015
79. Hou WS, Li Z, Gordon RE, et al. Cathepsin K is a critical protease in synovial fibroblast-mediated collagen degradation. Am J Pathol 2001;159:2167-77
80. Quintanilla-Dieck MJ, Codriansky K, Keady M, et al. Expression and regulation of cathepsin K in skin fibroblasts. Exp Dermatol 2009;18:596-602
81. Quintanilla-Dieck MJ, Codriansky K, Keady M, et al. Cathepsin K in melanoma invasion. J Invest Dermatol 2008;128:2281-8
82. Ng KW, Martin TJ. New therapeutics for osteoporosis. Curr Opin Pharmacol 2014;16:58-63
83. Kornak U, Kasper D, Bosl MR, et al. Loss of the ClC-7 chloride channel leads to osteopetrosis in mice and man. Cell 2001;104:205-15
84. Bollerslev J, Henriksen K, Nielsen MF, et al. Autosomal dominant osteopetrosis revisited: lessons from recent studies. Eur J Endocrinol 2013;169:R39-57
85. Henriksen K, Gram J, Schaller S, et al. Characterization of osteoclasts from patients harboring a G215R mutation in ClC-7 causing autosomal dominant osteopetrosis type II. Am J Pathol 2004;164:1537-45
86. Josephsen K, Praetorius J, Frische S, et al. Targeted disruption of the Cl-/. Proc Natl Acad Sci USA 2009;106:1638-41
87. Bollerslev J, Steiniche T, Melsen F, Mosekilde L. Structural and histomorphometric studies of iliac crest trabecular and cortical bone in autosomal dominant osteopetrosis: A study of two radiological types. Bone 1989;10:19-24
88. Bollerslev J, Marks SC Jr, Pockwinse S, et al. Ultrastructural investigations of bone resorptive cells in two types of autosomal dominant osteopetrosis. Bone 1993;14:865-9
89. Schaller S, Henriksen K, Sveigaard C, et al. The chloride channel inhibitor n53736 prevents bone resorption in ovariectomized rats without changing bone formation. J Bone Miner Res 2004;19:1144-53
90. Karsdal MA, Henriksen K, Sorensen MG, et al. Acidification of the osteoclastic resorption compartment provides insight into the coupling of bone formation to bone resorption. Am J Pathol 2005;166:467-76
91. Henriksen K, Karsdal MA, Martin TJ. Osteoclast-derived coupling factors in bone remodeling. Calcif Tissue Int 2014;94:88-97
92. Henriksen K, Andreassen KV, Thudium CS, et al. A specific subtype of osteoclasts secretes factors inducing nodule formation by osteoblasts. Bone 2012;51:353-61
93. Thudium CS, Moscatelli I, Flores C, et al. A comparison of osteoclast-rich and osteoclast-poor osteopetrosis in adult mice sheds light on the role of the osteoclast in coupling bone resorption and bone formation. Calcif Tissue Int 2014;95:83-93
94. Pederson L, Ruan M, Westendorf JJ, et al. Regulation of bone formation by osteoclasts involves Wnt/BMP signaling and the chemokine sphingosine-1-phosphate. Proc Natl Acad Sci USA 2008;105:20764-9
95. Quint P, Ruan M, Pederson L, et al. Sphingosine 1 phosphate (S1P) receptors 1 and 2 coordinately induce osteoblast migration through S1P activation of complementary kinase pathways. J Biol Chem 2013;288(8):5398-406
96. Kasper D, Planells-Cases R, Fuhrmann JC, et al. Loss of the chloride channel ClC-7 leads to lysosomal storage disease and neurodegeneration. EMBO J 2005;24:1079-91
97. Waguespack SG, Hui SL, Dimeglio LA, Econs MJ. Autosomal dominant osteopetrosis: clinical severity and natural history of 94 subjects with a chloride channel 7 gene mutation. J Clin Endocrinol Metab 2007;92:771-8
98. Neutzsky-Wulff AV, Sims NA, Supanchart C, et al. Severe developmental bone phenotype in ClC-7 deficient mice. Dev Biol 2010;344:1001-10