Osteoporosis International

, Volume 21, Issue 1, pp 183–187 | Cite as

Bone recovery after zoledronate therapy in thalassemia-induced osteoporosis: a meta-analysis and systematic review

Short Communication



Zoledronate is a promising bisphosphonate that improves the bone mineral density by 0.69 standard deviations in thalassemia-induced osteoporosis, but the entire range of its actions and side effects is currently not fully understood.


Zoledronate is a promising bisphosphonate for the treatment of thalassemia-induced osteoporosis; however, a quantitative summary of its beneficial effect and its effects on the markers of bone turnover are not established.


We conducted a meta-analysis of the published randomized controlled trials using standardized mean difference and a random effects model for improvement in bone mineral density (BMD). We also conducted a systematic review for the influence of zoledronate on markers of bone turnover and bone pain.


We found that zoledronate improves the baseline BMD by 0.69 (95% confidence interval 0.47–0.90) standard deviations—an effect that was more pronounced when BMD was measured at the lumbar spine. However, the mechanistic interpretations of the effects on the markers of bone turnover are not completely clear.


Sufficient evidence exists to demonstrate that 4 mg zoledronate given every 3 months markedly improves the BMD; however, more qualitative and quantitative evidence is required to understand the mechanisms of its action and the potential side effects.


Osteoclasts Thalassemia Zoledronate 


Conflicts of interest



  1. 1.
    Johanson NA (1990) Musculoskeletal problems in hemoglobinopathy. Orthop Clin North Am 21:191–198PubMedGoogle Scholar
  2. 2.
    Michelson J, Cohen A (1988) Incidence and treatment of fractures in thalassemia. J Orthop Trauma 2:29–32CrossRefPubMedGoogle Scholar
  3. 3.
    Pootrakul P, Hungsprenges S, Fucharoen S, Baylink D, Thompson E, English E, Lee M, Burnell J, Finch C (1981) Relation between erythropoiesis and bone metabolism in thalassemia. N Engl J Med 304:1470–1473PubMedCrossRefGoogle Scholar
  4. 4.
    Voskaridou E, Stoupa E, Antoniadou L, Premetis E, Konstantopoulos K, Papassotiriou I, Terpos E (2006) Osteoporosis and osteosclerosis in sickle cell/beta-thalassemia: the role of the RANKL/osteoprotegerin axis. Haematologica 91:813–816PubMedGoogle Scholar
  5. 5.
    Jensen CE, Tuck SM, Agnew JE, Koneru S, Morris RW, Yardumian A, Prescott E, Hoffbrand AV, Wonke B (1998) High incidence of osteoporosis in thalassaemia major. J Pediatr Endocrinol Metab 11(Suppl 3):975–977PubMedGoogle Scholar
  6. 6.
    Jensen CE, Tuck SM, Agnew JE, Koneru S, Morris RW, Yardumian A, Prescott E, Hoffbrand AV, Wonke B (1998) High prevalence of low bone mass in thalassaemia major. Br J Haematol 103:911–915CrossRefPubMedGoogle Scholar
  7. 7.
    Shamshirsaz AA, Bekheirnia MR, Kamgar M, Pourzahedgilani N, Bouzari N, Habibzadeh M, Hashemi R, Shamshirsaz AA, Aghakhani S, Homayoun H, Larijani B (2003) Metabolic and endocrinologic complications in beta-thalassemia major: a multicenter study in Tehran. BMC Endocr Disord 3:4CrossRefPubMedGoogle Scholar
  8. 8.
    Gurevitch O, Slavin S (2006) The hematological etiology of osteoporosis. Med Hypotheses 67:729–735CrossRefPubMedGoogle Scholar
  9. 9.
    Fleisch HA (1997) Bisphosphonates: preclinical aspects and use in osteoporosis. Ann Med 29:55–62CrossRefPubMedGoogle Scholar
  10. 10.
    Gaudio A, Morabito N, Xourafa A, Macri I, Meo A, Morgante S, Trifiletti A, Lasco A, Frisina N (2008) Bisphosphonates in the treatment of thalassemia-associated osteoporosis. J Endocrinol Invest 31:181–184PubMedGoogle Scholar
  11. 11.
    Mahachoklertwattana P (2006) Zoledronic acid for the treatment of thalassemia-induced osteonecrosis. Haematologica 91:1155APubMedGoogle Scholar
  12. 12.
    Gilfillan CP, Strauss BJ, Rodda CP, Bowden DK, Kean AM, Obaid M, Crawford BA (2006) A randomized, double-blind, placebo-controlled trial of intravenous zoledronic acid in the treatment of thalassemia-associated osteopenia. Calcif Tissue Int 79:138–144CrossRefPubMedGoogle Scholar
  13. 13.
    Morabito N, Lasco A, Gaudio A, Crisafulli A, Di Pietro C, Meo A, Frisina N (2002) Bisphosphonates in the treatment of thalassemia-induced osteoporosis. Osteoporos Int 13:644–649CrossRefPubMedGoogle Scholar
  14. 14.
    Otrock ZK, Azar ST, Shamseddeen WA, Habr D, Inati A, Koussa S, Mahfouz RA, Taher AT (2006) Intravenous zoledronic acid treatment in thalassemia-induced osteoporosis: results of a phase II clinical trial. Ann Hematol 85:605–609CrossRefPubMedGoogle Scholar
  15. 15.
    Otrock ZK, Mahfouz RA, Charafeddine KM, Rayes RF, Zahed LF, Taher AT (2008) Vitamin D receptor genotypes and response to zoledronic acid therapy in thalassemia-induced osteoporosis. Ann Hematol 87:947–948CrossRefPubMedGoogle Scholar
  16. 16.
    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 21:402–408CrossRefPubMedGoogle Scholar
  17. 17.
    Perifanis V, Vyzantiadis T, Tziomalos K, Vakalopoulou S, Garipidou V, Athanassiou-Metaxa M, Harsoulis F (2007) Effect of zoledronic acid on markers of bone turnover and mineral density in osteoporotic patients with beta-thalassaemia. Ann Hematol 86:23–30CrossRefPubMedGoogle Scholar
  18. 18.
    Perifanis V, Vyzantiadis T, Vakalopoulou S, Tziomalos K, Garypidou V, Athanassiou-Metaxa M, Harsoulis F (2004) Treatment of beta-thalassaemia-associated osteoporosis with zoledronic acid. Br J Haematol 125:91–92 author reply 93-4CrossRefPubMedGoogle Scholar
  19. 19.
    Voskaridou E, Anagnostopoulos A, Konstantopoulos K, Stoupa E, Spyropoulou E, Kiamouris C, Terpos E (2006) Zoledronic acid for the treatment of osteoporosis in patients with beta-thalassemia: results from a single-center, randomized, placebo-controlled trial. Haematologica 91:1193–1202PubMedGoogle Scholar
  20. 20.
    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 119:40–44CrossRefPubMedGoogle Scholar
  21. 21.
    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 93:1588–1590CrossRefPubMedGoogle Scholar
  22. 22.
    Voskaridou E, Terpos E, Spina G, Palermos J, Rahemtulla A, Loutradi A, Loukopoulos D (2003) Pamidronate is an effective treatment for osteoporosis in patients with beta-thalassaemia. Br J Haematol 123:730–737CrossRefPubMedGoogle Scholar
  23. 23.
    Wonke B, Jensen C, Hanslip JJ, Prescott E, Lalloz M, Layton M, Erten S, Tuck S, Agnew JE, Raja K, Davies K, Hoffbrand AV (1998) Genetic and acquired predisposing factors and treatment of osteoporosis in thalassaemia major. J Pediatr Endocrinol Metab 11(Suppl 3):795–801PubMedGoogle Scholar
  24. 24.
    USFDA (2008) Information for Healthcare Professionals. http://www.fda.gov/cder/drug/InfoSheets/HCP/bisphosphonatesHCP.htm
  25. 25.
    USFDA (2008) Early Communication of an Ongoing Safety Review. http://www.fda.gov/cder/drug/early_comm/bisphosphonates.htm
  26. 26.
    Black DM, Delmas PD, Eastell R, Reid IR, Boonen S et al (2007) Once-yearly zoledronic acid for treatment of postmenopausal osteoporosis. N Engl J Med 356:1809–1822CrossRefPubMedGoogle Scholar
  27. 27.
    Lyles KW, Colon-Emeric CS, Magaziner JS, Adachi JD, Pieper CF, Mautalen C, Hyldstrup L, Recknor C, Nordsletten L, Moore KA, Lavecchia C, Zhang J, Mesenbrink P, Hodgson PK, Abrams K, Orloff JJ, Horowitz Z, Eriksen EF, Boonen S (2007) Zoledronic acid in reducing clinical fracture and mortality after hip fracture. N Engl J Med 357:1799–1809 nihpa40967CrossRefPubMedGoogle Scholar
  28. 28.
    Borgna-Pignatti C, Cappellini MD, De Stefano P, Del Vecchio GC, Forni GL, Gamberini MR, Ghilardi R, Origa R, Piga A, Romeo MA, Zhao H, Cnaan A (2005) Survival and complications in thalassemia. Ann N Y Acad Sci 1054:40–47CrossRefPubMedGoogle Scholar
  29. 29.
    Toumba M, Sergis A, Kanaris C, Skordis N (2007) Endocrine complications in patients with Thalassaemia Major. Pediatr Endocrinol Rev 5:642–648PubMedGoogle Scholar
  30. 30.
    Derchi G, Bellone P, Forni GL, Lupi G, Jappelli S, Randazzo M, Zino V, Vecchio C (1992) Cardiac involvement in thalassaemia major: altered atrial natriuretic peptide levels in asymptomatic patients. Eur Heart J 13:1368–1372PubMedGoogle Scholar
  31. 31.
    Mamtani M, Kulkarni H (2008) Influence of iron chelators on myocardial iron and cardiac function in transfusion-dependent thalassaemia: a systematic review and meta-analysis. Br J Haematol 141:882–890CrossRefPubMedGoogle Scholar
  32. 32.
    Patane S, Marte F (2008) Abnormal troponin I levels in a thalassemia major patient with high ferritin concentration, permanent atrial fibrillation and without acute coronary syndrome. Int J Cardiol doi: 10.1016/j.ijcard.2008.06.039
  33. 33.
    Angelopoulos NG, Goula A, Katounda E, Rombopoulos G, Kaltzidou V, Kaltsas D, Konstandelou E, Tolis G (2007) Markers of bone metabolism in eugonadal female patients with beta-thalassemia major. Pediatr Hematol Oncol 24:481–491CrossRefPubMedGoogle Scholar
  34. 34.
    Angelopoulos NG, Goula A, Katounda E, Rombopoulos G, Kaltzidou V, Kaltsas D, Malaktari S, Athanasiou V, Tolis G (2007) Circulating osteoprotegerin and receptor activator of NF-kappaB ligand system in patients with beta-thalassemia major. J Bone Miner Metab 25:60–67CrossRefPubMedGoogle Scholar
  35. 35.
    Voskaridou E, Terpos E (2004) New insights into the pathophysiology and management of osteoporosis in patients with beta thalassaemia. Br J Haematol 127:127–139CrossRefPubMedGoogle Scholar
  36. 36.
    Brown JE, Ellis SP, Lester JE, Gutcher S, Khanna T, Purohit OP, McCloskey E, Coleman RE (2007) Prolonged efficacy of a single dose of the bisphosphonate zoledronic acid. Clin Cancer Res 13:5406–5410CrossRefPubMedGoogle Scholar
  37. 37.
    Reginster JY, Malaise O, Neuprez A, Jouret VE, Close P (2007) Intermittent bisphosphonate therapy in postmenopausal osteoporosis: progress to date. Drugs Aging 24:351–359CrossRefPubMedGoogle Scholar

Copyright information

© International Osteoporosis Foundation and National Osteoporosis Foundation 2009

Authors and Affiliations

  1. 1.Lata Medical Research FoundationNagpurIndia
  2. 2.San AntonioUSA

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