چکیده:

مقدمه: پوکی استخوان، بیماری متابولیک استخوان، یکی از مشکلات رو به رشدی است که سلامت و اقتصاد را در سر تا سر جهان تحت تاثیر قرار می دهد. بیس فسفونات ها از جمله داروهای پر مصرفی هستند که به عنوان antiresorptive مورد مصرف گسترده ای قرار دارند و در پیشگیری از شکستگی به عنوان استانداردی طلایی به کار می روند و معمولا در ترکیب با مکمل ویتامین D و کلسیم به کار می روند. چندین داروی جدید نیز برای درمان پوکی استخوان بعد از دوران یائسگی در دسترس است.

موارد پوشش داده شده در این مقاله: محققین در این مقاله برخی از آزمون های جدیدی که در ارتباط با antiresorptive و داروهای آنابولیک انجام شده است را ارائه داده اند. به خصوص، دانش فعلی در مورد داروهایی مطرح شده است که علیه cathepsin K و sclerostin تنظیم می شوند. مسیرهای جدید مورد نظر در مطالعات پیش بالینی نیز مورد بحث قرار گرفته است.

لغات کلیدی: cathepsin K، odanacatib ، پوکی استخوان، دوران پس از یائسگی، romosozumab، آنتی بادی مونوکلونال sclerostin-neutralizing، درمان

مقدمه:

استئوپورز یا پوکی استخوان، بیماری متابولیک استخوان است که به عنوان چالشی رو به رشد، سر تاسر جهان را تحت تاثیر قرار داده است. شیوع این بیماری به دلیل افزایش سن جمعیت، بسیار سریع است و در ایالات متحده آمریکا، سالانه 1.5 میلیون شکستگی ناشی از پوکی استخوان در ناحیه ستون فقرات، لگن، ران و مچ اتفاق می افتد. تخمین زده می شود حدود 50% زنان و حدود 25% مردان در سن 50 سالگی و بالای 50 سال، در طول باقی مانده زندگی خود، یک بار شکستگی ناشی از پوکی استخوان را تجربه می کنند (1).

روش ها:

نتایج:

بحث و گفتگو:

دیدگاه تخصصی

بیس فسفونات های خوراکی (آلندرونیت و ریسدرونیت) و در درجه دوم بیس فسفونات های وریدی(زولدرونیک اسید) از جمله فراوان ترین داروهایی هستند که در درمان پوکی استخوان به کار می روند زیرا هم هزینه پایینی دارند و هم نتایج موثری را در کاهش ریسک شکستگی نشان داده اند.

References:

1. Osteoporosis and Related Bone Diseases National Resource Centre. National Institutes of Health, 2011
2. Russell RG. Bisphosphonates: the first 40 years. Bone 2011;49:2-19
3. Powles TJ, Hickish T, Kanis JA, et al. Effect of tamoxifen on bone mineral density measured by dual-energy x-ray absorptiometry in healthy premenopausal and postmenopausal women. J Clin Oncol 1996;14:78-84
4. Schwarz P. Physical activity and bone strength. Scand J Med Sci Sports 2004;14:1
5. Schwarz P. Dose response dependency in regulation of acute PTH (1-84) release and suppression in normal humans: a citrate and calcium infusion study. Scand J Clin Lab Invest 1993;53:601-5
6. Schwarz P, Sorensen HA, McNair P, Transbol I. Cica-clamp technique: a method for quantifying parathyroid hormone secretion: a sequential citrate and calcium clamp study. Eur J Clin Invest 1993;23:546-53
7. Schwarz P, Sorensen HA, Transbol I. Inter-relations between the calcium set-points of Parfitt and Brown in primary hyperparathyroidism: a sequential citrate and calcium clamp study. Eur J Clin Invest 1994;24:553-8
8. Schwarz P, Hyldstrup L, Transbol I. Cica clamp evaluation of parathyroid responsiveness in chronic hypoparathyroidism: a sequential citrate and calcium clamp study. Miner Electrolyte Metab 1994;20:135-40
9. Verbrugge FH, Gielen E, Milisen K, Boonen S. Who should receive calcium and vitamin D supplementation? Age Ageing 2012;41:576-80
10. Bischoff-Ferrari HA, Willett WC, Orav EJ, et al. A pooled analysis of vitamin D dose requirements for fracture prevention. N Engl J Med 2012;367:40-9
11. Bouillon R, van Schoor NM, Gielen E, et al. Optimal vitamin d status: a critical analysis on the basis of evidence-based medicine. J Clin Endocrinol Metab 2013;98:E1283-304
12. Durup D, Jorgensen HL, Christensen J, et al. A reverse J-shaped association of all-cause mortality with serum 25-hydroxyvitamin D in general practice: the CopD study. J Clin Endocrinol Metab 2012;97:2644-52
13. Sempos CT, Durazo-Arvizu RA, Dawson-Hughes B, et al. Is there a reverse J-shaped association between 25-hydroxyvitamin D and all-cause mortality? Results from the U.S. nationally representative NHANES. J Clin Endocrinol Metab 2013;98:3001-9
14. Dunford JE. Molecular targets of the nitrogen containing bisphosphonates: the molecular pharmacology of prenyl synthase inhibition. Curr Pharm Des 2010;16:2961-9
15. Black DM, Cummings SR, Karpf DB, et al. Randomised trial of effect of alendronate on risk of fracture in women with existing vertebral fractures. Fracture Intervention Trial Research Group.m Lancet 1996;348:1535-41
16. Schwarz P, Jorgensen NR, Mosekilde L, Vestergaard P. The evidence for efficacy of osteoporosis treatment in men with primary osteoporosis: a systematic review and meta-analysis of antiresorptive and anabolic treatment in men. J Osteoporos 2011;2011:259818
17. Boonen S, Reginster JY, Kaufman JM, et al. Fracture risk and zoledronic acid therapy in men with osteoporosis. N Engl J Med 2012;367:1714-23
18. Boyle WJ, Simonet WS, Lacey DL. Osteoclast differentiation and activation. Nature 2003;423:337-42 .. This paper was the first to describe osteoclast diffentiation and activation.
19. Bone HG, Chapurlat R, Brandi ML, et al. The Effect of 3 or 6 years of denosumab exposure in women with postmenopausal osteoporosis: results from the FREEDOM extension. J Clin Endocrinol Metab 2013;98(11):4483-92 . Pivotal study of the efficacy of osteoporosis treatment using Denosumab.
20. Ettinger B, Black DM, Mitlak BH, et al. Reduction of vertebral fracture risk in postmenopausal women with osteoporosis treated with raloxifene: results from a 3-year randomized clinical trial. Multiple Outcomes of Raloxifene Evaluation (MORE) Investigators. JAMA 1999;282:637-45
21. Silverman SL, Christiansen C, Genant HK, et al. Efficacy of bazedoxifene in reducing new vertebral fracture risk in postmenopausal women with osteoporosis: results from a 3-year, randomized, placebo-, and activecontrolled clinical trial. J Bone Miner Res 2008;23:1923-34
22. Cummings SR, Ensrud K, Delmas PD, et al. Lasofoxifene in postmenopausal women with osteoporosis. N Engl J Med 2010;362:686-96
23. Meunier PJ, Roux C, Seeman E, et al. The effects of strontium ranelate on the risk of vertebral fracture in women with postmenopausal osteoporosis. N Engl J Med 2004;350:459-68
24. Farlay D, Boivin G, Panczer G, et al. Long-term strontium ranelate administration in monkeys preserves characteristics of bone mineral crystals and degree of mineralization of bone. J Bone Miner Res 2005;20:1569-78
25. Reginster JY, Felsenberg D, Boonen S, et al. Effects of long-term strontium ranelate treatment on the risk of nonvertebral and vertebral fractures in postmenopausal osteoporosis: results of a five-year, randomized, placebo-controlled trial. Arthritis Rheum 2008;58:1687-95
26. Abrahamsen B, Grove EL, Vestergaard P. Nationwide registry-based analysis of cardiovascular risk factors and adverse outcomes in patients treated with strontium ranelate. Osteoporos Int 2013; published online, doi:10.1007/ s00198-013-2469-4
27. Cooper C, Fox KM, Borer JS. Ischaemic cardiac events and use of strontium ranelate in postmenopausal osteoporosis: a nested case-control study in the CPRD. Osteoporos Int 2013; published online, doi:10.1007/s00198-013-2582-4
28. 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 . Pivotal study of the efficacy of osteoporosis treatment using PTH.
29. 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
30. Schilling AF, Mulhausen C, Lehmann W, et al. High bone mineral density in pycnodysostotic patients with a novel mutation in the propeptide of cathepsin K. Osteoporos Int 2007;18:659-69
31. Janssens K, Van HW. Molecular genetics of too much bone. Hum Mol Genet 2002;11:2385-93
32. Gardner JC, van Bezooijen RL, Mervis B, et al. Bone mineral density in sclerosteosis; affected individuals and gene carriers. J Clin Endocrinol Metab 2005;90:6392-5
33. Gauthier JY, Chauret N, Cromlish W, et al. The discovery of odanacatib (MK- 0822), a selective inhibitor of cathepsin K. Bioorg Med Chem Lett 2008;18:923-8
34. 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;25:937-47
35. McClung MR, Boonen S, Torring O, et al. Effect of denosumab treatment on the risk of fractures in subgroups of women with postmenopausal osteoporosis. J Bone Miner Res 2012;27:211-18
36. Cusick T, Chen CM, Pennypacker BL, 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
37. 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 .. First clincal data on the use of odanacatib for the treatment of osteoporosis.
38. Li X, Warmington KS, Niu QT, et al. Inhibition of sclerostin by monoclonal antibody increases bone formation, bone mass, and bone strength in aged male rats. J Bone Miner Res 2010;25:2647-56
39. Li X, Ominsky MS, Warmington KS, 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 2011;152:3312-22
40. 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 .. First promising study on the anabolic effect of Sclerostin antibody in treatment of osteoporosis in a rat model.
41. Secreto FJ, Hoeppner LH, Westendorf JJ. Wnt signaling during fracture repair. Curr Osteoporos Rep 2009;7:64-9
42. Hoeppner LH, Secreto FJ, Westendorf JJ. Wnt signaling as a therapeutic target for bone diseases. Expert Opin Ther Targets 2009;13:485-96
43. Padhi D, Jang G, Stouch B, et al. Singledose, placebo-controlled, randomized study of AMG 785, a sclerostin monoclonal antibody. J Bone Miner Res 2011;26:19-26
44. McColm J, Hu L, Womack T, et al. Single- and multiple-dose randomized studies of blosozumab, a monoclonal antibody against sclerostin, in healthy postmenopausal women. J Bone Miner Res 2013; published online, doi:10.1002/jbmr.2092
45. 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
46. Cabal A, Mehta K, Ross DS, et al. A semimechanistic model of the timecourse of release of PTH into plasma following administration of the calcilytic JTT-305/MK-5442 in humans. J Bone Miner Res 2013;28:1830-6
47. Schwarz P, Sorensen HA, Transbol I, McNair P. Regulation of acute parathyroid hormone release in normal humans: combined calcium and citrate clamp study. Am J Physiol 1992;263:E195-8
48. Schwarz P, Sorensen HA, Transbol I. Inter-relations between the calcium set- points of Parfitt and Brown in primary hyperparathyroidism: a sequential citrate and calcium clamp study. Eur J Clin Invest 1994;24:553-8
49. Schwarz P, Madsen JC, Rasmussen AQ, et al. Evidence for a role of intracellular stored parathyroid hormone in producing hysteresis of the PTH-calcium relationship in normal humans. Clin Endocrinol (Oxf) 1998;48:725-32
50. 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
51. Stewart AF, Cain RL, Burr DB, et al. Six-month daily administration of parathyroid hormone and parathyroid hormone-related protein peptides to adult ovariectomized rats markedly enhances bone mass and biomechanical properties: a comparison of human parathyroid hormone 1-34, parathyroid hormone-related protein 1-36, and SDZparathyroid hormone 893. J Bone Miner Res 2000;15:1517-25
52. Brenner L, Hansen K, Clarkin M, et al. Safety and tolerability of BA058 transdermal, a novel analog of hPTHrP delivered via a microneedle patch:results of a phase 2 clinical trial [abstract]. JBMR 2013; (Suppl 1):S481
53. Horwitz MJ, Augustine M, Kahn L, et al. A comparison of parathyroid hormone-related protein (1-36) and parathyroid hormone (1-34) on markers of bone turnover and bone density in postmenopausal women: the PrOP study. J Bone Miner Res 2013;28:2266-76
54. Spinella-Jaegle S, Roman-Roman S, Faucheu C, et al. Opposite effects of bone morphogenetic protein-2 and transforming growth factor-beta1 on osteoblast differentiation. Bone 2001;29:323-30
55. Blum B, Moseley J, Miller L, et al. Measurement of bone morphogenetic proteins and other growth factors in demineralized bone matrix. Orthopedics 2004;27:s161-5
56. Baud’huin M, Solban N, Cornwall-Brady M, et al. A soluble bone morphogenetic protein type IA receptor increases bone mass and bone strength. Proc Natl Acad Sci USA 2012;109:12207-12
57. Ke HZ, Richards WG, Li X, Ominsky MS. Sclerostin and Dickkopf-1 as therapeutic targets in bone diseases. Endocr Rev 2012;33:747-83
58. Alves RD, Eijken M, Bezstarosti K, et al. Activin A suppresses osteoblast mineralization capacity by altering extracellular matrix composition and impairing matrix vesicle production. Mol Cell Proteomics 2013;12(10):2890-900
59. Anastasilakis AD, Polyzos SA, Makras P, et al. Circulating activin-A is elevated in postmenopausal women with low bone mass: the three-month effect of zoledronic acid treatment. Osteoporos Int 2013;24:2127-32
60. Inose H, Zhou B, Yadav VK, et al. Efficacy of serotonin inhibition in mouse models of bone loss. J Bone Miner Res 2011;26:2002-11
61. Shimada T, Hasegawa H, Yamazaki Y, et al. FGF-23 is a potent regulator of vitamin D metabolism and phosphate homeostasis. J Bone Miner Res 2004;19:429-35
62. Prie D, Urena TP, Friedlander G. Latest findings in phosphate homeostasis. Kidney Int 2009;75:882-9
63. Giustina A, Mazziotti G, Canalis E. Growth hormone, insulin-like growth factors, and the skeleton. Endocr Rev 2008;29:535-59
64. Shane E, Burr D, Ebeling PR, 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
65. Shane E, Burr D, Abrahamsen B, et al. Atypical subtrochanteric and diaphyseal femoral fractures: second report of a task force of the american society for bone and mineral research. J Bone Miner Res 2014;29:1-23 .. First report on atypical fractures after long time treatment by bisphosphonates.
66. Boonen S, Ferrari S, Miller PD, et al. Postmenopausal osteoporosis treatment with antiresorptives: effects of discontinuation or long-term continuation on bone turnover and fracture risk -- a perspective. J Bone Miner Res 2012;27:963-74
67. Hermann AP, Abrahamsen B. The bisphosphonates: risks and benefits of long term use. Curr Opin Pharmacol 2013;13:435-9
68. Eastell R, Walsh JS, Watts NB, Siris E. Bisphosphonates for postmenopausal osteoporosis. Bone 2011;49:82-8
69. Abrahamsen B, Grove EL, Vestergaard P. Nationwide registry-based analysis of cardiovascular risk factors and adverse outcomes in patients treated with strontium ranelate. Osteoporosis Int 2013; In press
70. Suresh E, Pazianas M, Abrahamsen B. Safety issues with bisphosphonate therapy for osteoporosis. Rheumatology (Oxford) 2014;53(1):19-31
71. Li X, Ominsky MS, Niu QT, et al. Targeted deletion of the sclerostin gene in mice results in increased bone formation and bone strength. J Bone Miner Res 2008;23:860-9
72. Richards JB, Zheng HF, Spector TD. Genetics of osteoporosis from genomewide association studies: advances and challenges. Nat Rev Genet 2012;13:576-88
73. Seeman E. Age- and menopause-related bone loss compromise cortical and trabecular microstructure. J Gerontol A Biol Sci Med Sci 2013;68:1218-25