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Bisphosphonates in the management of thalassemia-associated osteoporosis: a systematic review of randomised controlled trials

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Abstract

Bisphosphonates are potent inhibitors of bone resorption, widely used for the management of osteoporosis and fracture prevention. Recent evidence suggests that bisphosphonates may have beneficial effects in the treatment of thalassemia-associated osteoporosis, a complex and multifactorial condition. Here we summarise available data about the efficacy and tolerability of bisphosphonates in beta-thalassemic patients. Randomised controlled trials (RCTs) of bisphosphonates in beta-thalassemia were identified searching PubMed. Studies were reviewed to retrieve relevant clinical information. The following variables were considered to assess the safety and efficacy of bisphosphonates—bone mineral density (BMD), markers of bone turnover, incidence of fragility fracture, bone pain, back pain, and clinical adverse events. Five RCTs were identified, investigating alendronate, clodronate, zoledronic acid and neridronate. All bisphosphonates produced a significant decrease of the markers of bone turnover. Alendronate, neridronate, and zoledronic acid significantly improved BMD at the lumbar spine, femoral neck and total hip. Zoledronic acid and neridronate were also shown to reduce bone and back pain. Probably due to the small sample sizes and to the short duration of the trials, it was not possible to establish the anti-fracture efficacy of bisphosphonates; however, they were well tolerated and adverse events were rare but expected on the basis of previous studies. Sufficient evidence exists to support the use of bisphosphonates in the management of thalassemia-associated osteoporosis (to prevent bone loss and improve the BMD). Further research is warranted to establish their anti-fracture efficacy and long-term safety.

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References

  1. Galanello R, Origa R (2010) Beta-thalassemia. Orphanet J Rare Dis 5:11

    Article  PubMed Central  PubMed  Google Scholar 

  2. Forni GL, Puntoni M, Boeri E, Terenzani L, Balocco M (2009) The influence of treatment in specialized centers on survival of patients with thalassemia major. Am J Hematol 84:317–318

    Article  PubMed  Google Scholar 

  3. Voskaridou E, Terpos E (2004) New insights into the pathophysiology and management of osteoporosis in patients with beta thalassaemia. Br J Haematol 127:127–139

    Article  CAS  PubMed  Google Scholar 

  4. Haidar R, Musallam KM, Taher AT (2011) Bone disease and skeletal complications in patients with β thalassemia major. Bone 48:425–432

    Article  PubMed  Google Scholar 

  5. Vogiatzi MG, Macklin EA, Fung EB et al (2009) Bone disease in thalassemia: a frequent and still unresolved problem. J Bone Miner Res 24:543–557

    Article  PubMed Central  PubMed  Google Scholar 

  6. Fung EB, Harmatz PR, Milet M, Multi-Center Iron Overload Study Group et al (2008) Fracture prevalence and relationship to endocrinopathy in iron overloaded patients with sickle cell disease and thalassemia. Bone 43:162–168

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  7. Vogiatzi MG, Macklin EA, Fung EB et al (2006) Prevalence of fractures among the thalassemia syndromes in North America. Bone 38:571–575

    Article  CAS  PubMed  Google Scholar 

  8. Wonke B, Jensen C, Hanslip JJ et al (1998) Genetic and acquired predisposing factors and treatment of osteoporosis in thalassaemia major. J Pediatr Endocrinol Metab 11:795–801

    PubMed  Google Scholar 

  9. Wonke B (1998) Bone disease in beta-thalassaemia major. Br J Haematol 103:897–901

    Article  CAS  PubMed  Google Scholar 

  10. Morabito N, Gaudio A, Lasco A et al (2004) Osteoprotegerin and RANKL in the pathogenesis of thalassemia-induced osteoporosis: new pieces of the puzzle. J Bone Miner Res 19:722–727

    Article  CAS  PubMed  Google Scholar 

  11. Papapoulos SE (2011) Use of bisphosphonates in the management of postmenopausal osteoporosis. Ann N Y Acad Sci 1218:15–32

    Article  CAS  PubMed  Google Scholar 

  12. Papapoulos SE (2008) Bisphosphonates: how do they work? Best Pract Res Clin Endocrinol Metab 22:831–847

    Article  CAS  PubMed  Google Scholar 

  13. Giusti A, Papapoulos SE (2009) Treatment of male osteoporosis with bisphosphonates. In: Orwoll ES, Bilezikian JP, Vanderschueren D (eds) Osteoporosis in men: the effects of gender on skeletal health, 2nd edn. Academic Press (Elsevier), London, pp 667–679

    Google Scholar 

  14. Rizzoli R, Reginster JY, Boonen S et al (2011) Adverse reactions and drug–drug interactions in the management of women with postmenopausal osteoporosis. Calcif Tissue Int 89:91–104

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  15. Khosla S, Burr D, Cauley J et al (2007) Bisphosphonate-associated osteonecrosis of the jaw: report of a task force of the American Society for Bone and Mineral Research. J Bone Miner Res 22:1479–1491

    Article  PubMed  Google Scholar 

  16. Giusti A, Hamdy NA, Papapoulos SE (2010) Atypical fractures of the femur and bisphosphonate therapy: a systematic review of case/case series studies. Bone 47:169–180

    Article  CAS  PubMed  Google Scholar 

  17. Morabito N, Lasco A, Gaudio A et al (2002) Bisphosphonates in the treatment of thalassemia-induced osteoporosis. Osteoporos Int 13:644–649

    Article  CAS  PubMed  Google Scholar 

  18. Pennisi P, Pizzarelli G, Spina M, Riccobene S, Fiore CE (2003) Quantitative ultrasound of bone and clodronate effects in thalassemia-induced osteoporosis. J Bone Miner Metab 21:402–408

    Article  PubMed  Google Scholar 

  19. Voskaridou E, Anagnostopoulos A, Konstantopoulos K et al (2006) Zoledronic acid for the treatment of osteoporosis in patients with beta-thalassemia: results from a single-center, randomized, placebo-controlled trial. Haematologica 91:1193–1202

    CAS  PubMed  Google Scholar 

  20. Gilfillan CP, Strauss BJ, Rodda CP et al (2006) A randomized, double-blind, placebo-controlled trial of intravenous zoledronic acid in the treatment of thalassemia-associated osteopenia. Calcif Tissue Int 79:138–144

    Article  CAS  PubMed  Google Scholar 

  21. Forni GL, Perrotta S, Giusti A et al (2012) 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 158:274–282

    Article  CAS  PubMed  Google Scholar 

  22. Voskaridou E, Christoulas D, Konstantinidou M, Tsiftsakis E, Alexakos P, Terpos E (2008) 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 93:1588–1590

    Article  CAS  PubMed  Google Scholar 

  23. Voskaridou E, Christoulas D, Antoniadou L, Terpos E (2008) Continuous increase in erythropoietic activity despite the improvement in bone mineral density by zoledronic acid in patients with thalassemia intermedia-induced osteoporosis. Acta Haematol 119:40–44

    Article  PubMed  Google Scholar 

  24. Voskaridou E, Christoulas D, Plata E et al (2012) High circulating sclerostin is present in patients with thalassemia-associated osteoporosis and correlates with bone mineral density. Horm Metab Res [Epub ahead of print]

  25. Voskaridou E, Christoulas D, Xirakia C et al (2009) Serum Dickkopf-1 is increased and correlates with reduced bone mineral density in patients with thalassemia-induced osteoporosis. Reduction post-zoledronic acid administration. Haematologica 94:725–728

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  26. Mamtani M, Kulkarni H (2010) Bone recovery after zoledronate therapy in thalassemia-induced osteoporosis: a meta-analysis and systematic review. Osteoporos Int 21:183–187

    Article  CAS  PubMed  Google Scholar 

  27. Black DM, Cummings SR, Karpf DB et al (1996) Randomised trial of effect of alendronate on risk of fracture in women with existing vertebral fractures. Fracture Intervention Trial Research Group. Lancet 348:1535–1541

    Article  CAS  PubMed  Google Scholar 

  28. Cummings SR, Black DM, Thompson DE et al (1998) Effect of alendronate on risk of fracture in women with low bone density but without vertebral fractures: results from the Fracture Intervention Trial. JAMA 280:2077–2082

    Article  CAS  PubMed  Google Scholar 

  29. Liberman UA, Weiss SR, Broll J et al (1995) Effect of oral alendronate on bone mineral density and the incidence of fractures in postmenopausal osteoporosis. The Alendronate Phase III Osteoporosis Treatment Study Group. N Engl J Med 333:1437–1443

    Article  CAS  PubMed  Google Scholar 

  30. Pols HA, Felsenberg D, Hanley DA et al (1999) Multinational, placebo-controlled, randomized trial of the effects of alendronate on bone density and fracture risk in postmenopausal women with low bone mass: results of the FOSIT study. Fosamax International Trial Study Group. Osteoporos Int 9:461–468

    Article  CAS  PubMed  Google Scholar 

  31. Harris ST, Watts NB, Genant HK et al (1999) Effects of risedronate treatment on vertebral and nonvertebral fractures in women with postmenopausal osteoporosis: a randomized controlled trial. Vertebral Efficacy with Risedronate Therapy (VERT) Study Group. JAMA 282:1344–1352

    Article  CAS  PubMed  Google Scholar 

  32. McClung MR, Geusens P, Miller PD et al (2001) Effect of risedronate on the risk of hip fracture in elderly women. Hip Intervention Program Study Group. N Engl J Med 344:333–340

    Article  CAS  PubMed  Google Scholar 

  33. Reginster JY, Minne HW, Sorensen OH et al (2000) Randomized trial of the effects of risedronate on vertebral fractures in women with established postmenopausal osteoporosis. Vertebral Efficacy with Risedronate Therapy (VERT) Study Group. Osteoporos Int 11:83–91

    Article  CAS  PubMed  Google Scholar 

  34. Chesnut CH III, Skag A, Christiansen C et al (2004) Effects of oral ibandronate administered daily or intermittently on fracture risk in postmenopausal osteoporosis. J Bone Miner Res 19:1241–1249

    Article  CAS  Google Scholar 

  35. Black DM, Delmas PD, Eastell R et al (2007) Once-yearly zoledronic acid for treatment of postmenopausal osteoporosis. N Engl J Med 356:1809–1822

    Article  CAS  PubMed  Google Scholar 

  36. Lyles KW, Colón-Emeric CS, Magaziner JS et al (2007) Zoledronic acid and clinical fractures and mortality after hip fracture. N Engl J Med 357:1799–1809

    Article  CAS  PubMed  Google Scholar 

  37. Brumsen C, Papapoulos SE, Lips P et al (2002) Daily oral pamidronate in women and men with osteoporosis: a 3-year randomized placebo-controlled clinical trial with a 2-year open extension. J Bone Miner Res 17:1057–1064

    Article  CAS  PubMed  Google Scholar 

  38. McCloskey E, Selby P, Davies M et al (2004) Clodronate reduces vertebral fracture risk in women with postmenopausal or secondary osteoporosis: results of a double-blind, placebo-controlled 3-year study. J Bone Miner Res 19:728–736

    Article  CAS  PubMed  Google Scholar 

  39. McCloskey EV, Beneton M, Charlesworth D et al (2007) Clodronate reduces the incidence of fractures in community-dwelling elderly women unselected for osteoporosis: results of a double-blind, placebo controlled randomized study. J Bone Miner Res 22:135–141

    Article  CAS  PubMed  Google Scholar 

  40. Coleman R, de Boer R, Eidtmann H et al (2012) Zoledronic acid (zoledronate) for postmenopausal women with early breast cancer receiving adjuvant letrozole (ZO-FAST study): final 60-month results. Ann Oncol [Epub ahead of print]

  41. Llombart A, Frassoldati A, Paija O et al (2012) Immediate administration of zoledronic acid reduces aromatase inhibitor-associated bone loss in postmenopausal women with early breast cancer: 12-month analysis of the E-ZO-FAST trial. Clin Breast Cancer 12:40–48

    Article  CAS  PubMed  Google Scholar 

  42. Brufsky AM, Harker WG, Beck JT et al (2012) Final 5-year results of Z-FAST trial: adjuvant zoledronic acid maintains bone mass in postmenopausal breast cancer patients receiving letrozole. Cancer 118:1192–1201

    Article  CAS  PubMed  Google Scholar 

  43. Varenna M, Bertoldo F, Di Monaco M, Giusti A, Martini G, Rossini M (2013) Safety profile of drugs used in the treatment of osteoporosis: a systematical review of the literature. Reumatismo 65:143–166

    Article  CAS  PubMed  Google Scholar 

  44. Grey A, Bolland MJ, Horne A et al (2012) Five years of anti-resorptive activity after a single dose of zoledronate: results from a randomized double-blind placebo-controlled trial. Bone 50:1389–1393

    Article  CAS  PubMed  Google Scholar 

  45. Black DM, Reid IR, Boonen S et al (2012) The effect of 3 versus 6 years of zoledronic acid treatment of osteoporosis: a randomized extension to the HORIZON-Pivotal Fracture Trial (PFT). J Bone Miner Res 27:243–254

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  46. Black DM, Schwartz AV, Ensrud KE et al (2006) Effects of continuing or stopping alendronate after 5 years of treatment: the Fracture Intervention Trial Long-term Extension (FLEX): a randomized trial. JAMA 296:2927–2938

    Article  CAS  PubMed  Google Scholar 

  47. Chatterjee R, Shah FT, Davis BA et al (2012) Prospective study of histomorphometry, biochemical bone markers and bone densitometric response to pamidronate in β-thalassaemia presenting with osteopenia-osteoporosis syndrome. Br J Haematol 159:462–471

    Article  CAS  PubMed  Google Scholar 

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Conflict of interest

Dr Giusti serves as consultant for Dynamicom (CME provider, Milano, Italy), Merck & Co. and Eli Lilly.

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Correspondence to Andrea Giusti.

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Giusti, A. Bisphosphonates in the management of thalassemia-associated osteoporosis: a systematic review of randomised controlled trials. J Bone Miner Metab 32, 606–615 (2014). https://doi.org/10.1007/s00774-014-0584-8

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  • DOI: https://doi.org/10.1007/s00774-014-0584-8

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