Approach to the management of β thalassemia major associated osteoporosis - A long-standing relationship revisited Osteoporosis in β-thalassemia major

Main Article Content

Maria P. Yavropoulou
Athanasios D. Anastasilakis
Ploutarchos Tzoulis
Symeon Tournis
Efthimia Rigatou
Eva Kassi
Antonis Kattamis
Polyzois Makras

Keywords

Anemia, iron overload, bone cells, bisphosphonates, teriparatide,, denosumab, fractures

Abstract

Adults with β- thalassemia major (β-TM) develop low BMD and fragility fractures at a higher incidence and at a younger age compared to the general population. The disease itself, including direct effects of anemia and iron overload toxicity on bone turnover, genetic susceptibility, thalassemia-related endocrinopathies and acquittance of suboptimal peak bone mass contribute to low bone mass and increased bone fragility frequently encountered among these patients. Current management of osteoporosis requires long-term treatment that can be provided by agents that reduce the risk of all osteoporotic fractures by modulating bone metabolism with different mechanisms of action. These include inhibitors of bone remodeling (e.g., bisphosphonates, denosumab) and stimulators of bone formation (e.g., PTHR1 agonists and sclerostin antibodies). Considering the unique characteristics of osteoporosis associated with β-TM and the clinical importance of balancing the risk/benefit of treatment in the long-term, appropriate use of these therapeutic approaches is essential for patient care. In this review we outline current literature on the use of anti-osteoporotic drugs in β-TM patients with osteoporosis focusing on data on the efficacy, safety, and duration of treatment. In addition, we propose a long-term management plan for β-TM -associated osteoporosis aiming at the optimal patient care for this special population.

Abstract 708 | PDF Downloads 412

References

1. De Sanctis V, Soliman AT, Elsedfy H, et al , I CET. Osteoporosis in thalassemia major: an update and the I-CET 2013 recommendations for surveillance and treatment. Pediatr Endocrinol Rev. 2013;11(2):167-180.
2. Michelson J, Cohen A. Incidence and treatment of fractures in thalassemia. J Orthop Trauma. 1988;2(1):29-32.
3. Dede AD, Trovas G, Chronopoulos E, et al. Thalassemia-associated osteoporosis: a systematic review on treatment and brief overview of the disease. Osteoporos Int. 2016;27(12):3409-3425.
4. Baldini M, Forti S, Marcon A, et al. Endocrine and bone disease in appropriately treated adult patients with beta-thalassemia major. Ann Hematol. 2010;89(12):1207-1213.
5. Canatan D. The Thalassemia center of Antalya State Hospital: 15 years of experience (1994 to 2008). J Pediatr Hematol Oncol. 2013;35(1):24-27.
6. Leung TF, Chu Y, Lee V, et al. Long-term effects of pamidronate in thalassemic patients with severe bone mineral density deficits. Hemoglobin. 2009;33(5):361-369.
7. Voskaridou E, Terpos E. New insights into the pathophysiology and management of osteoporosis in patients with beta thalassaemia. Br J Haematol. 2004;127(2):127-139.
8. Vogiatzi MG, Macklin EA, Fung EB, et al , Thalassemia Clinical Research N. Bone disease in thalassemia: a frequent and still unresolved problem. J Bone Miner Res. 2009;24(3):543-557.
9. Mylona M, Leotsinides M, Alexandrides T, Zoumbos N, Dimopoulos PA. Comparison of DXA, QCT and trabecular structure in beta-thalassaemia. Eur J Haematol. 2005;74(5):430-437.
10. Ekbote V, Padidela R, Khadilkar V, et al. Increased prevalence of fractures in inadequately transfused and chelated Indian children and young adults with beta thalassemia major. Bone. 2021;143:115649.
11. Centis F, Tabellini L, Lucarelli G, et al. The importance of erythroid expansion in determining the extent of apoptosis in erythroid precursors in patients with beta-thalassemia major. Blood. 2000;96(10):3624-3629.
12. Gaudio A, Morabito N, Catalano A, Rapisarda R, Xourafa A, Lasco A. Pathogenesis of Thalassemia Major-associated Osteoporosis: A Review with Insights from Clinical Experience. J Clin Res Pediatr Endocrinol. 2019;11(2):110-117.
13. Cazzola M, De Stefano P, Ponchio L, et al. Relationship between transfusion regimen and suppression of erythropoiesis in beta-thalassaemia major. Br J Haematol. 1995;89(3):473-478.
14. Arnett TR. Acidosis, hypoxia and bone. Arch Biochem Biophys. 2010;503(1):103-109.
15. Lu H, Lian L, Shi D, Zhao H, Dai Y. Hepcidin promotes osteogenic differentiation through the bone morphogenetic protein 2/small mothers against decapentaplegic and mitogen-activated protein kinase/P38 signaling pathways in mesenchymal stem cells. Mol Med Rep. 2015;11(1):143-150.
16. Hiram-Bab S, Liron T, Deshet-Unger N, et al . Erythropoietin directly stimulates osteoclast precursors and induces bone loss. FASEB J. 2015;29(5):1890-1900.
17. Shen GS, Yang Q, Jian JL, et al. Hepcidin1 knockout mice display defects in bone microarchitecture and changes of bone formation markers. Calcif Tissue Int. 2014;94(6):632-639.
18. Tian Q, Wu S, Dai Z, et al. Iron overload induced death of osteoblasts in vitro: involvement of the mitochondrial apoptotic pathway. PeerJ. 2016;4:e2611.
19. Jiang Z, Wang H, Qi G, Jiang C, Chen K, Yan Z. Iron overload-induced ferroptosis of osteoblasts inhibits osteogenesis and promotes osteoporosis: An in vitro and in vivo study. IUBMB Life. 2022.
20. Balogh E, Tolnai E, Nagy B, Jr., et al. Iron overload inhibits osteogenic commitment and differentiation of mesenchymal stem cells via the induction of ferritin. Biochim Biophys Acta. 2016;1862(9):1640-1649.
21. Tsay J, Yang Z, Ross FP, et al. Bone loss caused by iron overload in a murine model: importance of oxidative stress. Blood. 2010;116(14):2582-2589.
22. Yang J, Dong D, Luo X, Zhou J, Shang P, Zhang H. Iron Overload-Induced Osteocyte Apoptosis Stimulates Osteoclast Differentiation Through Increasing Osteocytic RANKL Production In Vitro. Calcif Tissue Int. 2020;107(5):499-509.
23. Jia P, Xu YJ, Zhang ZL, et al. Ferric ion could facilitate osteoclast differentiation and bone resorption through the production of reactive oxygen species. J Orthop Res. 2012;30(11):1843-1852.
24. Ma J, Wang A, Zhang H, et al. Iron overload induced osteocytes apoptosis and led to bone loss in Hepcidin(-/-) mice through increasing sclerostin and RANKL/OPG. Bone. 2022:116511.
25. Wong P, Fuller PJ, Gillespie MT, Milat F. Bone Disease in Thalassemia: A Molecular and Clinical Overview. Endocr Rev. 2016;37(4):320-346.
26. Ralston SH, Uitterlinden AG. Genetics of osteoporosis. Endocr Rev. 2010;31(5):629-662.
27. Wonke B, Jensen C, Hanslip JJ, et al. Genetic and acquired predisposing factors and treatment of osteoporosis in thalassaemia major. J Pediatr Endocrinol Metab. 1998;11 Suppl 3:795-801.
28. Perrotta S, Cappellini MD, Bertoldo F, et al. Osteoporosis in beta-thalassaemia major patients: analysis of the genetic background. Br J Haematol. 2000;111(2):461-466.
29. Gaudio A, Morabito N, Xourafa A, et al. Role of genetic pattern on bone mineral density in thalassemic patients. Clin Biochem. 2010;43(10-11):805-807.
30. Dresner Pollack R, Rachmilewitz E, Blumenfeld A, Idelson M, Goldfarb AW. Bone mineral metabolism in adults with beta-thalassaemia major and intermedia. Br J Haematol. 2000;111(3):902-907.
31. Bielinski BK, Darbyshire PJ, Mathers L, et al. Impact of disordered puberty on bone density in beta-thalassaemia major. Br J Haematol. 2003;120(2):353-358.
32. Ang AL, Tzoulis P, Prescott E, Davis BA, Barnard M, Shah FT. History of myocardial iron loading is a strong risk factor for diabetes mellitus and hypogonadism in adults with beta thalassemia major. Eur J Haematol. 2014;92(3):229-236.
33. Tzoulis P, Ang AL, Shah FT, et al. Prevalence of low bone mass and vitamin D deficiency in beta-thalassemia major. Hemoglobin. 2014;38(3):173-178.
34. Anapliotou ML, Kastanias IT, Psara P, Evangelou EA, Liparaki M, Dimitriou P. The contribution of hypogonadism to the development of osteoporosis in thalassaemia major: new therapeutic approaches. Clin Endocrinol (Oxf). 1995;42(3):279-287.
35. Soliman AT, De Sanctis V, Elalaily R, Yassin M. Insulin-like growth factor- I and factors affecting it in thalassemia major. Indian J Endocrinol Metab. 2015;19(2):245-251.
36. Toumba M, Skordis N. Osteoporosis syndrome in thalassaemia major: an overview. J Osteoporos. 2010;2010:537673.
37. Soliman A, De Sanctis V, Yassin M, Abdelrahman MO. Growth hormone - insulin-like growth factor-I axis and bone mineral density in adults with thalassemia major. Indian J Endocrinol Metab. 2014;18(1):32-38.
38. Seif El Dien HM, Esmail RI, Magdy RE, Lotfy HM. Deferoxamine-induced dysplasia-like skeletal abnormalities at radiography and MRI. Pediatr Radiol. 2013;43(9):1159-1165.
39. Wong P, Polkinghorne K, Kerr PG, et al. Deferasirox at therapeutic doses is associated with dose-dependent hypercalciuria. Bone. 2016;85:55-58.
40. Wong P, Fuller PJ, Gillespie MT, et al. Thalassemia bone disease: the association between nephrolithiasis, bone mineral density and fractures. Osteoporos Int. 2013;24(7):1965-1971.
41. Morabito N, Russo GT, Gaudio A, et al. The "lively" cytokines network in beta-Thalassemia Major-related osteoporosis. Bone. 2007;40(6):1588-1594.
42. Nancollas GH, Tang R, Phipps RJ, et al. Novel insights into actions of bisphosphonates on bone: differences in interactions with hydroxyapatite. Bone. 2006;38(5):617-627.
43. Tsartsalis AN, Lambrou GI, Tsartsalis D, et al. The role of biphosphonates in the management of thalassemia-induced osteoporosis: a systematic review and meta-analysis. Hormones (Athens). 2018;17(2):153-166.
44. Stefanopoulos D, Papaioannou NA, Papavassiliou AG, et al. A contemporary therapeutic approach to bone disease in beta-thalassemia - a review. J Frailty Sarcopenia Falls. 2018;3(1):13-25.
45. Morabito N, Lasco A, Gaudio A, et al. Bisphosphonates in the treatment of thalassemia-induced osteoporosis. Osteoporos Int. 2002;13(8):644-649.
46. Skordis N, Ioannou YS, Kyriakou A, et al. Effect of bisphosphonate treatment on bone mineral density in patients with thalassaemia major. Pediatr Endocrinol Rev. 2008;6 Suppl 1:144-148.
47. Forni GL, Perrotta S, Giusti A, et al. Neridronate improves bone mineral density and reduces back pain in beta-thalassaemia patients with osteoporosis: results from a phase 2, randomized, parallel-arm, open-label study. Br J Haematol. 2012;158(2):274-282.
48. Pennisi P, Pizzarelli G, Spina M, Riccobene S, Fiore CE. Quantitative ultrasound of bone and clodronate effects in thalassemia-induced osteoporosis. J Bone Miner Metab. 2003;21(6):402-408.
49. Voskaridou E, Terpos E, Spina G, et al. Pamidronate is an effective treatment for osteoporosis in patients with beta-thalassaemia. Br J Haematol. 2003;123(4):730-737.
50. Chatterjee R, Shah FT, Davis BA, et al. Prospective study of histomorphometry, biochemical bone markers and bone densitometric response to pamidronate in beta-thalassaemia presenting with osteopenia-osteoporosis syndrome. Br J Haematol. 2012;159(4):462-471.
51. Gilfillan CP, Strauss BJ, Rodda CP, et al. A randomized, double-blind, placebo-controlled trial of intravenous zoledronic acid in the treatment of thalassemia-associated osteopenia. Calcif Tissue Int. 2006;79(3):138-144.
52. Voskaridou E, Anagnostopoulos A, Konstantopoulos K, et al. Zoledronic acid for the treatment of osteoporosis in patients with beta-thalassemia: results from a single-center, randomized, placebo-controlled trial. Haematologica. 2006;91(9):1193-1202.
53. Voskaridou E, Christoulas D, Konstantinidou M, Tsiftsakis E, Alexakos P, Terpos E. Continuous improvement of bone mineral density two years post zoledronic acid discontinuation in patients with thalassemia-induced osteoporosis: long-term follow-up of a randomized, placebo-controlled trial. Haematologica. 2008;93(10):1588-1590.
54. Perifanis V, Vyzantiadis T, Tziomalos K, et al. Effect of zoledronic acid on markers of bone turnover and mineral density in osteoporotic patients with beta-thalassaemia. Ann Hematol. 2007;86(1):23-30.
55. Giusti A. Bisphosphonates in the management of thalassemia-associated osteoporosis: a systematic review of randomised controlled trials. J Bone Miner Metab. 2014;32(6):606-615.
56. Stathopoulos IP, Liakou CG, Katsalira A, et al. The use of bisphosphonates in women prior to or during pregnancy and lactation. Hormones (Athens). 2011;10(4):280-291.
57. Leung TY, Lao TT. Thalassaemia in pregnancy. Best Pract Res Clin Obstet Gynaecol. 2012;26(1):37-51.
58. Chatterjee R, Bajoria R, Shah FT, Porter JB, Fedele S. High index of suspicion for early diagnosis of alendronate-induced stage zero osteonecrosis of jaw in thalassaemia major. Br J Haematol. 2014;166(2):292-294.
59. Anastasilakis AD, Pepe J, Napoli N, et al. Osteonecrosis of the Jaw and Antiresorptive Agents in Benign and Malignant Diseases: A Critical Review Organized by the ECTS. J Clin Endocrinol Metab. 2022;107(5):1441-1460.
60. Lampropoulou-Adamidou K, Tournis S, Triantafyllopoulos IK. Atypical femoral fracture in a beta-thalassemia major patient with previous bisphosphonate use: case report and a review of the literature. J Musculoskelet Neuronal Interact. 2016;16(1):75-78.

61. Kearns AE, Khosla S, Kostenuik PJ. Receptor activator of nuclear factor kappaB ligand and osteoprotegerin regulation of bone remodeling in health and disease. Endocr Rev. 2008;29(2):155-192.
62. Voskaridou E, Stoupa E, Antoniadou L, et al. Osteoporosis and osteosclerosis in sickle cell/beta-thalassemia: the role of the RANKL/osteoprotegerin axis. Haematologica. 2006;91(6):813-816.
63. Morabito N, Gaudio A, Lasco A, et al. Osteoprotegerin and RANKL in the pathogenesis of thalassemia-induced osteoporosis: new pieces of the puzzle. J Bone Miner Res. 2004;19(5):722-727.
64. Yassin MA, Soliman AT, De Sanctis V, Abdelrahman MO, Aziz Bedair EM, AbdelGawad M. Effects of the anti-receptor activator of nuclear factor kappa B ligand denusomab on beta thalassemia major-induced osteoporosis. Indian J Endocrinol Metab. 2014;18(4):546-551.
65. Yassin MA, Abdel Rahman MO, Hamad AA, et al. Denosumab versus zoledronic acid for patients with beta-thalassemia major-induced osteoporosis. Medicine (Baltimore). 2020;99(51):e23637.
66. Voskaridou E, Ntanasis-Stathopoulos I, Papaefstathiou A, et al. Denosumab in transfusion-dependent thalassemia osteoporosis: a randomized, placebo-controlled, double-blind phase 2b clinical trial. Blood Adv. 2018;2(21):2837-2847.
67. Voskaridou E, Ntanasis-Stathopoulos I, Christoulas D, et al. Denosumab effects on serum levels of the bone morphogenetic proteins antagonist noggin in patients with transfusion-dependent thalassemia and osteoporosis. Hematology. 2019;24(1):318-324.
68. Diker-Cohen T, Rosenberg D, Avni T, Shepshelovich D, Tsvetov G, Gafter-Gvili A. Risk for Infections During Treatment With Denosumab for Osteoporosis: A Systematic Review and Meta-analysis. J Clin Endocrinol Metab. 2020;105(5) (5):dgz322.
69. Anastasilakis AD, Makras P, Yavropoulou MP, Tabacco G, Naciu AM, Palermo A. Denosumab Discontinuation and the Rebound Phenomenon: A Narrative Review. J Clin Med. 2021;10(1) :152.
70. Makras P, Appelman-Dijkstra NM, Papapoulos SE, et al. The Duration of Denosumab Treatment and the Efficacy of Zoledronate to Preserve Bone Mineral Density After Its Discontinuation. J Clin Endocrinol Metab. 2021;106(10):e4155-e4162.
71. Tsourdi E, Zillikens MC, Meier C, et al. Fracture risk and management of discontinuation of denosumab therapy: a systematic review and position statement by ECTS. J Clin Endocrinol Metab. 2020; 26:dgaa756.
72. Cohen A, Stein EM, Recker RR, et al. Teriparatide for idiopathic osteoporosis in premenopausal women: a pilot study. J Clin Endocrinol Metab. 2013;98(5):1971-1981.
73. Orwoll ES, Shapiro J, Veith S, et al. Evaluation of teriparatide treatment in adults with osteogenesis imperfecta. J Clin Invest. 2014;124(2):491-498.
74. Lampropoulou-Adamidou K, Trovas G, Triantafyllopoulos IK, et al. Teriparatide Treatment in Patients with Pregnancy- and Lactation-Associated Osteoporosis. Calcif Tissue Int. 2021;109(5):554-562.
75. Cosman F, Dempster DW. Anabolic Agents for Postmenopausal Osteoporosis: How Do You Choose? Curr Osteoporos Rep. 2021;19(2):189-205.
76. Estell EG, Rosen CJ. Emerging insights into the comparative effectiveness of anabolic therapies for osteoporosis. Nat Rev Endocrinol. 2021;17(1):31-46.
77. Gagliardi I, Celico M, Gamberini MR, et al. Efficacy and Safety of Teriparatide in Beta-Thalassemia Major Associated Osteoporosis: A Real-Life Experience. Calcif Tissue Int. 2022;111(1):56-65.
78. Trotta A, Corrado A, Cantatore FP. [Anabolic therapy of induced osteoporosis in beta-thalassaemia major: case report and literature review]. Reumatismo. 2010;62(2):119-126.
79. Tournis S, Dede AD, Savvidis C, Triantafyllopoulos IK, Kattamis A, Papaioannou N. Effects of teriparatide retreatment in a patient with beta-thalassemia major. Transfusion. 2015;55(12):2905-2910.
80. Eastell R, Nickelsen T, Marin F, et al. Sequential treatment of severe postmenopausal osteoporosis after teriparatide: final results of the randomized, controlled European Study of Forsteo (EUROFORS). J Bone Miner Res. 2009;24(4):726-736.
81. Leder BZ, Tsai JN, Uihlein AV, et al. Denosumab and teriparatide transitions in postmenopausal osteoporosis (the DATA-Switch study): extension of a randomised controlled trial. Lancet. 2015;386(9999):1147-1155.
82. Shane E, Shiau S, Recker RR, et al. Denosumab After Teriparatide in Premenopausal Women With Idiopathic Osteoporosis. J Clin Endocrinol Metab. 2022;107(4):e1528-e1540.
83. Miller PD, Lewiecki EM, Krohn K, Schwartz E. Teriparatide: Label changes and identifying patients for long-term use. Cleve Clin J Med. 2021;88(9):489-493.
84. Cosman F, Eriksen EF, Recknor C, et al. Effects of intravenous zoledronic acid plus subcutaneous teriparatide [rhPTH(1-34)] in postmenopausal osteoporosis. J Bone Miner Res. 2011;26(3):503-511.
85. 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(19):1434-1441.
86. Farmakis D, Porter J, Taher A, Domenica Cappellini M, Angastiniotis M, Eleftheriou A. 2021 Thalassaemia International Federation Guidelines for the Management of Transfusion-dependent Thalassemia. Hemasphere. 2022;6(8):e732.
87. Anastasilakis AD, Yavropoulou MP, Makras P, et al. Increased osteoclastogenesis in patients with vertebral fractures following discontinuation of denosumab treatment. Eur J Endocrinol. 2017;176(6):677-683.
88. Anastasilakis AD, Makras P. Multiple clinical vertebral fractures following denosumab discontinuation. Osteoporos Int. 2016;27(5):1929-1930.
89. Tsourdi E, Langdahl B, Cohen-Solal M, et al. Discontinuation of Denosumab therapy for osteoporosis: A systematic review and position statement by ECTS. Bone. 2017;105:11-17.
90. Anastasilakis AD, Polyzos SA, Yavropoulou MP, Makras P. Combination and sequential treatment in women with postmenopausal osteoporosis. Expert Opin Pharmacother. 2020;21(4):477-490.
91. Diez-Perez A, Adachi JD, Agnusdei D, et al, Group ICIRW. Treatment failure in osteoporosis. Osteoporos Int. 2012;23(12):2769-2774.
92. Lewiecki EM. Osteoporosis: Treat-to-Target. Curr Osteoporos Rep. 2017;15(2):103-109.