Implications of osteoblast-osteoclast interactions in the management of osteoporosis by antiresorptive agents denosumab and odanacatib

Current Osteoporosis Reports

Volumn 12, Issue 1, 2014, Pages 98-106

  Sims, Natalie A ^a,b   Ng, Kong Wah ^a,b  

^a ST VINCENT'S INSTITUTE OF MEDICAL RESEARCH   (Australia)

^b UNIVERSITY OF MELBOURNE   (Australia)

Author keywords

Cathepsin K; Coupling; Denosumab; Odanacatib; Osteoblast; Osteoclast; RANKL

Indexed keywords

BISPHOSPHONIC ACID DERIVATIVE; CATHEPSIN K; CATHEPSIN K INHIBITOR; DENOSUMAB; ODANACATIB; OSTEOCLAST DIFFERENTIATION FACTOR; PARATHYROID HORMONE; PARATHYROID HORMONE[1-34];

BINDING AFFINITY; BONE DEMINERALIZATION; BONE DENSITY; BONE MASS; BONE REMODELING; BONE STRENGTH; BONE TURNOVER; CELL INTERACTION; DRUG APPROVAL; DRUG BIOAVAILABILITY; DRUG EFFICACY; DRUG HALF LIFE; DRUG MECHANISM; DRUG PROTEIN BINDING; DRUG RESPONSE; DRUG TREATMENT FAILURE; ENZYME INHIBITION; FRACTURE REDUCTION; OSSIFICATION; OSTEOBLAST; OSTEOCLAST; OSTEOCLASTOGENESIS; OSTEOLYSIS; OSTEOPOROSIS; PHASE 2 CLINICAL TRIAL (TOPIC); POSTMENOPAUSE OSTEOPOROSIS; PROTEIN EXPRESSION; PROTEIN PROTEIN INTERACTION; RANDOMIZED CONTROLLED TRIAL (TOPIC); REVIEW; TREATMENT DURATION;

ANTIBODIES, MONOCLONAL, HUMANIZED; BIPHENYL COMPOUNDS; BONE DENSITY CONSERVATION AGENTS; BONE REMODELING; CATHEPSIN K; CELL DIFFERENTIATION; HUMANS; OSTEOBLASTS; OSTEOCLASTS; OSTEOGENESIS; OSTEOPOROSIS; RANK LIGAND;

EID: 84895922008     PISSN: 15441873     EISSN: 15442241     Source Type: Journal    
DOI: 10.1007/s11914-014-0196-1     Document Type: Review

References (91)

1. Frost HM. Dynamics of bone remodeling. In: Frost HM, editor. Bone Biodynamics. Boston: Little, Brown & Co; 1964. p. 315-33.
2. Sims NA, Martin TJ. Coupling the activities of bone formation and resorption: a multitude of signals within the basic multicellular unit. BoneKEY Reports. 2014;3: Article 481.
3. Martin TJ, Sims NA. Osteoclast-derived activity in the coupling of bone formation to resorption. Trends Mol Med. 2005;11:76-81. (Pubitemid 40193486)
4. Kong YY, Yoshida H, Sarosi I, Tan HL, Timms E, Capparelli C, et al. OPGL is a key regulator of osteoclastogenesis, lymphocyte development and lymph-node organogenesis. Nature. 1999;397:315-23.
5. Dougall WC, Glaccum M, Charrier K, Rohrbach K, Brasel K, De Smedt T, et al. RANK is essential for osteoclast and lymph node development. Genes Dev. 1999;13:2412-24. (Pubitemid 29453612)
6. Kartsogiannis V, Zhou H, Horwood NJ, Thomas RJ, Hards DK, Quinn JM, et al. Localization of RANKL (receptor activator of NF kappa B ligand) mRNA and protein in skeletal and extraskeletal tissues. Bone. 1999;25:525-34. (Pubitemid 29469458)
7. Horwood NJ, Elliott J, Martin TJ, Gillespie MT. Osteotropic agents regulate the expression of osteoclast differentiation factor and osteoprotegerin in osteoblastic stromal cells. Endocrinology. 1998;139:4743-6. (Pubitemid 28487795)
8. Thomas RJ, Guise TA, Yin JJ, Elliott J, Horwood NJ, Martin TJ, et al. Breast cancer cells interact with osteoblasts to support osteoclast formation. Endocrinology. 1999;140:4451-8. (Pubitemid 30666108)
9. Lacey DL, Timms E, Tan HL, Kelley MJ, Dunstan CR, Burgess T, et al. Osteoprotegerin ligand is a cytokine that regulates osteoclast differentiation and activation. Cell. 1998;93:165-76. (Pubitemid 28180851)
10. Boyle WJ, Simonet WS, Lacey DL. Osteoclast differentiation and activation. Nature. 2003;423:337-42. (Pubitemid 40852708)
11. Russell RG, Croucher PI, Rogers MJ. Bisphosphonates: pharmacology, mechanisms of action and clinical uses. Osteoporos Int. 1999;9 Suppl 2:S66-80. (Pubitemid 29231759)
12. Moen MD, Keam SJ. Spotlight on denosumab in postmenopausal osteoporosis. BioDrugs Clin Immunotherapeutics Biopharm Gene ther. 2011;25:261-4.
13. Howard GA, Bottemiller BL, Turner RT, Rader JI, Baylink DJ. Parathyroid hormone stimulates bone formation and resorption in organ culture: evidence for a coupling mechanism. Proc Natl Acad Sci U S A. 1981;78:3204-8. (Pubitemid 11032017)
14. Tang Y, Wu X, Lei W, Pang L, Wan C, Shi Z, et al. TGF-beta1-induced migration of bone mesenchymal stem cells couples bone resorption with formation. Nature Med. 2009;15:757-65.
15. Walker EC, McGregor NE, Poulton IJ, Pompolo S, Allan EH, Quinn JM, et al. Cardiotrophin-1 is an osteoclast-derived stimulus of bone formation required for normal bone remodeling. J Bone Miner Res. 2008;23:2025-32.
16. Pederson L, Ruan M, Westendorf JJ, Khosla S, Oursler MJ. Regulation of bone formation by osteoclasts involves Wnt/BMP signaling and the chemokine sphingosine-1-phosphate. Proc Natl Acad Sci U S A. 2008;105:20764-9.
17. Vukicevic S, Grgurevic L. BMP-6 and mesenchymal stem cell differentiation. Cytokine Growth Factor Rev. 2009;20:441-8.
18. Takeshita S, Fumoto T, Matsuoka K, Park KA, Aburatani H, Kato S, et al. Osteoclast-secreted CTHRC1 in the coupling of bone resorption to formation. J Clin Invest. 2013;123:3914-24.
19. Negishi-Koga T, Shinohara M, Komatsu N, Bito H, Kodama T, Friedel RH, et al. Suppression of bone formation by osteoclastic expression of semaphorin 4D. Nature Med. 2011;17:1473-80.
20. Dai XM, Zong XH, Akhter MP, Stanley ER. Osteoclast deficiency results in disorganized matrix, reduced mineralization, and abnormal osteoblast behavior in developing bone. J Bone Miner Res. 2004;19:1441-51. (Pubitemid 41094345)
21. Sakagami N, Amizuka N, Li M, Takeuchi K, Hoshino M, Nakamura M, et al. Reduced osteoblastic population and defective mineralization in osteopetrotic (op/op) mice. Micron. 2005;36:688-95. (Pubitemid 41745033)
22. Lian JB, Marks Jr SC. Osteopetrosis in the rat: coexistence of reductions in osteocalcin and bone resorption. Endocrinology. 1990;126:955-62. (Pubitemid 20079508)
23. Kostenuik PJ, Capparelli C, Morony S, Adamu S, Shimamoto G, Shen V, et al. OPG and PTH-(1-34) have additive effects on bone density and mechanical strength in osteopenic ovariectomized rats. Endocrinology. 2001;142:4295-304. (Pubitemid 32907057)
24. Bateman TA, Dunstan CR, Ferguson VL, Lacey DL, Ayers RA, Simske SJ. Osteoprotegerin mitigates tail suspension-induced osteopenia. Bone. 2000;26:443-9. (Pubitemid 30204464)
25. Childs LM, Paschalis EP, Xing L, Dougall WC, Anderson D, Boskey AL, et al. In vivo RANK signaling blockade using the receptor activator of NF-kappaB:Fc effectively prevents and ameliorates wear debris-induced osteolysis via osteoclast depletion without inhibiting osteogenesis. J Bone Miner Res. 2002;17:192-9. (Pubitemid 34087651)
26. Kostenuik PJ, Nguyen HQ, McCabe J, Warmington KS, Kurahara C, Sun N, et al. Denosumab, a fully human monoclonal antibody to RANKL, inhibits bone resorption and increases BMD in knock-in mice that express chimeric (murine/human) RANKL. J Bone Miner Res. 2009;24:182-95.
27. Pierroz DD, Bonnet N, Baldock PA, Ominsky MS, Stolina M, Kostenuik PJ, et al. Are osteoclasts needed for the bone anabolic response to parathyroid hormone? A study of intermittent parathyroid hormone with denosumab or alendronate in knock-in mice expressing humanized RANKL. J Biol Chem. 2010;285:28164-73.
28. Ominsky MS, Kostenuik PJ, Cranmer P, Smith SY, Atkinson JE. The RANKL inhibitor OPG-Fc increases cortical and trabecular bone mass in young gonad-intact cynomolgus monkeys. Osteoporos Int. 2007;18:1073-82. (Pubitemid 47020009)
29. • Ominsky MS, Stouch B, Schroeder J, Pyrah I, Stolina M, Smith SY, et al. Denosumab, a fully human RANKL antibody, reduced bone turnover markers and increased trabecular and cortical bone mass, density, and strength in ovariectomized cynomolgus monkeys. Bone. 2011;49:162-73. Evidence that anti-RANKL reduces bone formation in a preclinical model.
30. Kostenuik PJ, Smith SY, Jolette J, Schroeder J, Pyrah I, Ominsky MS. Decreased bone remodeling and porosity are associated with improved bone strength in ovariectomized cynomolgus monkeys treated with denosumab, a fully human RANKL antibody. Bone. 2011;49:151-61.
31. Furuya Y, Inagaki A, Khan M, Mori K, Penninger JM, Nakamura M, et al. Stimulation of bone formation in cortical bone of mice treated with a receptor activator of nuclear factor-kappaB ligand (RANKL)-binding peptide that possesses osteoclastogenesis inhibitory activity. J Biol Chem. 2013;288:5562-71.
32. Cummings SR, San Martin J, McClung MR, Siris ES, Eastell R, Reid IR, et al. Denosumab for prevention of fractures in postmenopausal women with osteoporosis. N Engl J Med. 2009;361:756-65.
33. McClung MR, Lewiecki EM, Cohen SB, Bolognese MA, Woodson GC, Moffett AH, et al. Denosumab in postmenopausal women with low bone mineral density. N Engl J Med. 2006;354:821-31. (Pubitemid 43290920)
34. •• Reid IR, Miller PD, Brown JP, Kendler DL, Fahrleitner-Pammer A, Valter I, et al. Effects of denosumab on bone histomorphometry: the FREEDOM and STAND studies. J Bone Miner Res. 2010;25:2256-65. Histomorphometric evidence showing that denosumab profoundly reduces osteoblasts numbers and bone formation in both cortical and trabecular bone.
35. Black DM, Delmas PD, Eastell R, Reid IR, Boonen S, Cauley JA, et al. Once-yearly zoledronic acid for treatment of postmenopausal osteoporosis. N Engl J Med. 2007;356:1809-22. (Pubitemid 46698462)
36. Brown JP, Prince RL, Deal C, Recker RR, Kiel DP, de Gregorio LH, et al. Comparison of the effect of denosumab and alendronate on BMD and biochemical markers of bone turnover in postmenopausal women with low bone mass: a randomized, blinded, phase 3 trial. J Bone Miner Res. 2009;24:153-61.
37. Miller PD, Bolognese MA, Lewiecki EM, McClung MR, Ding B, Austin M, et al. Effect of denosumab on bone density and turnover in postmenopausal women with low bone mass after long-term continued, discontinued, and restarting of therapy: a randomized blinded phase 2 clinical trial. Bone. 2008;43:222-9.
38. McClung MR, Lewiecki EM, Ho PR, Bolognese MA, Ding B, Geller ML, et al. Management trends after 8 years of denosumab: follow-up after a 1-year observational phase of the phase 2 extension study. Endocr Rev. 2013;34:OR10-6.
39. Tam CS, Heersche JN, Murray TM, Parsons JA. Parathyroid hormone stimulates the bone apposition rate independently of its resorptive action: differential effects of intermittent and continuous administration. Endocrinology. 1982;110:506-12. (Pubitemid 12162946)
40. Frolik CA, Black EC, Cain RL, Satterwhite JH, Brown-Augsburger PL, Sato M, et al. Anabolic and catabolic bone effects of human parathyroid hormone (1-34) are predicted by duration of hormone exposure. Bone. 2003;33:372-9. (Pubitemid 37103254)
41. Jiang Y, Zhao JJ, Mitlak BH, Wang O, Genant HK, Eriksen EF. Recombinant human parathyroid hormone (1-34) [teriparatide] improves both cortical and cancellous bone structure. J Bone Miner Res. 2003;18:1932-41. (Pubitemid 37377441)
42. Neer RM, Arnaud CD, Zanchetta JR, Prince R, Gaich GA, Reginster JY, 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. (Pubitemid 32402100)
43. Finkelstein JS, Hayes A, Hunzelman JL, Wyland JJ, Lee H, Neer RM. The effects of parathyroid hormone, alendronate, or both in men with osteoporosis. N Engl J Med. 2003;349:1216-26. (Pubitemid 37152031)
44. Black DM, Greenspan SL, Ensrud KE, Palermo L, McGowan JA, Lang TF, et al. The effects of parathyroid hormone and alendronate alone or in combination in postmenopausal osteoporosis. N Engl J Med. 2003;349:1207-15. (Pubitemid 37152030)
45. • Tsai JN, Uihlein AV, Lee H, Kumbhani R, Siwila-Sackman E, McKay EA, et al. Teriparatide and denosumab, alone or combined, in women with postmenopausal osteoporosis: the DATA study randomized trial. Lancet. 2013;382:50-6. Although limited to biochemical and BMD data, this is the first clinical study suggesting that combination therapy of PTH and RANKL inhibitionmay be of more benefit than using either agent alone.
46. Karsdal MA, Martin TJ, Bollerslev J, Christiansen C, Henriksen K. Are nonresorbing osteoclasts sources of bone anabolic activity? J Bone Miner Res. 2007;22:487-94. (Pubitemid 47457424)
47. Karsdal MA, Neutzsky-Wulff AV, Dziegiel MH, Christiansen C, Henriksen K. Osteoclasts secrete non-bone derived signals that induce bone formation. Biochem Biophys Res Commun. 2008;366:483-8. (Pubitemid 50010416)
48. Reiser J, Adair B, Reinheckel T. Specialized roles for cysteine cathepsins in health and disease. J Clin Invest. 2010;120:3421-31.
49. Leung P, Pickarski M, Zhuo Y, Masarachia PJ, Duong LT. The effects of the cathepsin K inhibitor odanacatib on osteoclastic bone resorption and vesicular trafficking. Bone. 2011;49:623-35.
50. Yamaza T, Goto T, Kamiya T, Kobayashi Y, Sakai H, Tanaka T. Study of immunoelectron microscopic localization of cathepsin K in osteoclasts and other bone cells in the mouse femur. Bone. 1998;23:499-509. (Pubitemid 28529454)
51. Vaaraniemi J, Halleen JM, Kaarlonen K, Ylipahkala H, Alatalo SL, Andersson G, et al. Intracellular machinery for matrix degradation in bone-resorbing osteoclasts. J Bone Miner Res. 2004;19:1432-40. (Pubitemid 41094344)
52. Xia L, Kilb J, Wex H, Li Z, Lipyansky A, Breuil V, et al. Localization of rat cathepsin K in osteoclasts and resorption pits: inhibition of bone resorption and cathepsin K-activity by peptidyl vinyl sulfones. Biol Chem. 1999;380:679-87. (Pubitemid 29322358)
53. Garnero P, Borel O, Byrjalsen I, Ferreras M, Drake FH, McQueney MS, et al. The collagenolytic activity of cathepsin K is unique among mammalian proteinases. J Biol Chem. 1998;273:32347-52. (Pubitemid 29177183)
54. Gelb BD, Shi GP, Chapman HA, Desnick RJ. Pycnodysostosis, a lysosomal disease caused by cathepsin K deficiency. Science. 1996;273:1236-8.
55. Nishi Y, Atley L, Eyre DE, Edelson JG, Superti-Furga A, Yasuda T, 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. (Pubitemid 29521785)
56. Fratzl-Zelman N, Valenta A, Roschger P, Nader A, Gelb BD, Fratzl P, et al. Decreased bone turnover and deterioration of bone structure in two cases of pycnodysostosis. J Clin EndocrinolMetab. 2004;89:1538-47. (Pubitemid 38507900)
57. de Vernejoul MC, Kornak U. Heritable sclerosing bone disorders: presentation and new molecular mechanisms. Ann N Y Acad Sci. 2010;1192:269-77.
58. Saftig P, Hunziker E, Wehmeyer O, Jones S, Boyde A, Rommerskirch W, et al. Impaired osteoclastic bone resorption leads to osteopetrosis in cathepsin-K-deficient mice. Proc Natl Acad Sci U S A. 1998;95:13453-8. (Pubitemid 28522993)
59. Gowen M, Lazner F, Dodds R, Kapadia R, Feild J, Tavaria M, 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. (Pubitemid 29455813)
60. Pennypacker B, Shea M, Liu Q, Masarachia P, Saftig P, Rodan S, et al. Bone density, strength, and formation in adult cathepsinK (-/-) mice. Bone. 2009;44:199-207.
61. le Duong T. Therapeutic inhibition of cathepsin K - reducing bone resorption while maintaining bone formation. BoneKEY Rep. 2012;21:167.
62. Ng KW. Potential role of odanacatib in the treatment of osteoporosis. Clin Intervent Aging. 2012;7:235-47.
63. Zerbini CA, McClung MR. Odanacatib in postmenopausal women with low bone mineral density: a review of current clinical evidence. Therapeut Advan Musculoskel Dis. 2013;5:199-209.
64. Gauthier JY, Chauret N, Cromlish W, Desmarais S, le Duong T, Falgueyret JP, et al. The discovery of odanacatib (MK-0822), a selective inhibitor of cathepsin K. Bioorg Medic Chem Lett. 2008;18:923-8. (Pubitemid 351179363)
65. Pennypacker BL, le Duong T, Cusick TE, Masarachia PJ, Gentile MA, Gauthier JY, et al. Cathepsin K inhibitors prevent bone loss in estrogen-deficient rabbits. J Bone Miner Res. 2011;26:252-62.
66. Lark MW, Stroup GB, James IE, Dodds RA, Hwang SM, Blake SM, et al. A potent small molecule, nonpeptide inhibitor of cathepsin K (SB 331750) prevents bone matrix resorption in the ovariectomized rat. Bone. 2002;30:746-53. (Pubitemid 34467997)
67. Stroup GB, Lark MW, Veber DF, Bhattacharyya A, Blake S, Dare LC, et al. Potent and selective inhibition of human cathepsin K leads to inhibition of bone resorption in vivo in a nonhuman primate. J Bone Miner Res. 2001;16:1739-46. (Pubitemid 32911477)
68. • Cusick T, Chen CM, Pennypacker BL, Pickarski M, Kimmel DB, Scott BB, et al. Odanacatib treatment increases hip bone mass and cortical thickness by preserving endocortical bone formation and stimulating periosteal bone formation in the ovariectomized adult rhesus monkey. J Bone Miner Res. 2012;27:524-37. Preclinical histomorphometric data indicating increased periosteal bone formation, and preserved bone formation at other sites, in monkeys treated with Odanacatib.
69. Masarachia PJ, Pennypacker BL, Pickarski M, Scott KR, Wesolowski GA, Smith SY, 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;27:509-23.
70. Stroup GB, Kumar S, Jerome CP. Treatment with a potent cathepsin K inhibitor preserves cortical and trabecular bone mass in ovariectomized monkeys. Calcif Tissue Int. 2009;85:344-55.
71. Jerome C, Missbach M, Gamse R. Balicatib, a cathepsin K inhibitor, stimulates periosteal bone formation in monkeys. Osteoporos Int. 2012;23:339-49.
72. Williams DS, McCracken PJ, Purcell M, Pickarski M, Mathers PD, Savitz AT, et al. Effect of odanacatib on bone turnover markers, bone density and geometry of the spine and hip of ovariectomized monkeys: a head-to-head comparison with alendronate. Bone. 2013;56:489-96.
73. Fratzl-Zelman N, Roschger P, Fisher JE, le Duong T, Klaushofer K. Effects of Odanacatib on bone mineralization density distribution in thoracic spine and femora of ovariectomized adult rhesus monkeys: a quantitative backscattered electron imaging study. Calcif Tissue Int. 2013;92:261-9.
74. Yamane H, Sakai A, Mori T, Tanaka S, Moridera K, Nakamura T. The anabolic action of intermittent PTH in combination with cathepsin K inhibitor or alendronate differs depending on the remodeling status in bone in ovariectomized mice. Bone. 2009;44:1055-62.
75. Perry MJ, McDougall KE, Hou SC, Tobias JH. Impaired growth plate function in bmp-6 null mice. Bone. 2008;42:216-25. (Pubitemid 350297190)
76. Zmuda JM, Yerges LM, Kammerer CM, Cauley JA, Wang X, Nestlerode CS, et al. Association analysis of WNT10B with bone mass and structure among individuals of African ancestry. J Bone Miner Res. 2009;24:437-47.
77. Henriksen K, Flores C, Thomsen JS, Bruel AM, Thudium CS, Neutzsky-Wulff AV, et al. Dissociation of bone resorption and bone formation in adult mice with a nonfunctional V-ATPase in osteoclasts leads to increased bone strength. PLoS One. 2011;6:e27482.
78. Fuller K, Lawrence KM, Ross JL, Grabowska UB, Shiroo M, Samuelsson B, et al. Cathepsin K inhibitors prevent matrix-derived growth factor degradation by human osteoclasts. Bone. 2008;42:200-11. (Pubitemid 350302017)
79. Lotinun S, Kiviranta R, Matsubara T, Alzate JA, Neff L, Luth A, et al. Osteoclast-specific cathepsin K deletion stimulates S1P-dependent bone formation. J Clin Invest. 2013;123:666-81.
80. Jensen PR, Andersen TL, Pennypacker BL, Duong LT, Delaisse JM. The bone resorption inhibitors odanacatib and alendronate affect post-osteoclastic events differently in ovariectomized rabbits. Calcif Tissue Int. 2013;94:212-22.
81. Stoch SA, Zajic S, Stone J, Miller DL, Van Dyck K, Gutierrez MJ, et al. Effect of the cathepsin K inhibitor odanacatib on bone resorption biomarkers in healthy postmenopausal women: two double-blind, randomized, placebo-controlled phase I studies. Clin Pharmacol Therapeut. 2009;86:175-82.
82. Bone HG, McClung MR, Roux C, Recker RR, Eisman JA, Verbruggen N, et al. Odanacatib, a cathepsin-K inhibitor for osteoporosis: a two2-year study in postmenopausal women with low bone density. J Bone Miner Res. 2010;25:937-47.
83. • Brixen K, Chapurlat R, Cheung AM, Keaveny TM, Fuerst T, Engelke K, et al. Bone density, turnover, and estimated strength in postmenopausal women treated with odanacatib: a randomized trial. J Clin Endocrinol Metab. 2013;98:571-80. Clinical trial data indicating the benefit of Odanacatib treatment on BMD and biochemical markers of bone turnover. Additional studies showing whether fracture risk is reduced are required.
84. Eisman JA, Bone HG, Hosking DJ, McClung MR, Reid IR, Rizzoli R, et al. Odanacatib in the treatment of postmenopausal women with low bone mineral density: 3-year continued therapy and resolution of effect. J Bone Miner Res. 2011;26:242-51.
85. Neele SJ, Evertz R, De Valk-De RG, Roos JC, Netelenbos JC. Effect of 1 year of discontinuation of raloxifene or estrogen therapy on bone mineral density after 5 years of treatment in healthy postmenopausal women. Bone. 2002;30:599-603. (Pubitemid 34270498)
86. Grey A, Bolland MJ, Wattie D, Horne A, Gamble G, Reid IR. The antiresorptive effects of a single dose of zoledronate persist for 2 years: a randomized, placebo-controlled trial in osteopenic postmenopausal women. J Clin Endocrinol Metab. 2009;94:538-44.
87. Bone HG, Bolognese MA, Yuen CK, Kendler DL, Miller PD, Yang YC, et al. Effects of denosumab treatment and discontinuation on bone mineral density and bone turnover markers in postmenopausal women with low bone mass. J Clin Endocrinol Metab. 2011;96:972-80.
88. Langdahl B, Binkley N, Bone H, Gilchrist N, Resch H, Rodriguez Portales J, et al. Odanacatib in the treatment of postmenopausal women with low bone mineral density: 5 years of continued therapy in a phase 2 study. J Bone Miner Res. 2012;27:2251-8.
89. Khosla S, Burr D, Cauley J, Dempster DW, Ebeling PR, Felsenberg D, et al. Bisphosphonate-associated osteonecrosis of the jaw: report of a task force of the American Society for Bone and Mineral Research. J Bone Miner Res. 2007;22:1479-91. (Pubitemid 351229318)
90. Shane E, Burr D, Ebeling PR, Abrahamsen B, Adler RA, Brown TD, et al. Atypical subtrochanteric and diaphyseal femoral fractures: report of a task force of the American Society for Bone and Mineral Research. J Bone Miner Res. 2010;25:2267-94.
91. Bauer DC. Discontinuation of odanacatib and other osteoporosis treatments: here today and gone tomorrow? J Bone Miner Res. 2011;26:239-41.