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Systematic review of the effects of bisphosphonates on bone density and fracture incidence in childhood acute lymphoblastic leukaemia



Skeletal fragility is a common complication of childhood acute lymphoblastic leukaemia (ALL) but the impact of bisphosphonate therapy on bone mass and fracture is unclear. We aim to conduct a systematic review to evaluate the effects of bisphosphonates on bone mineral density (BMD) and fracture incidence in children with ALL.


EMBASE, Medline and the Cochrane Library were thoroughly searched by two researchers. Inclusion criteria was any child under the age of 18 years with a diagnosis of ALL, who had received any bisphosphonate treatment and had serial measurements of bone density performed thereafter. All primary research studies of any study design, excluding case reports, were included.


Ten full text papers were identified with two exclusively meeting the inclusion criteria. Both studies administered bisphosphonates to children receiving maintenance chemotherapy for varying durations. Bone density was assessed at regular intervals by dual x-ray absorptiometry (DXA). The majority of participants had an improvement in bone density at the end of each study. However, no size adjustment of DXA data was performed. Limited information on fracture occurrence was provided by one study but did not include routine screening for vertebral fractures.


This systematic review identified that there is insufficient evidence to support routine use of prophylactic bisphosphonate therapy in childhood ALL for prevention of fracture and improvement of bone mass. Future well-designed clinical trials in those at highest risk of fractures in ALL are now needed.

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Fig. 1


  1. 1.

    Hogler W, Wehl G, van Staa T, Meister B, Klein-Franke A, Kropshofer G (2007) Incidence of skeletal complications during treatment of childhood acute lymphoblastic leukemia: comparison of fracture risk with the general practice research database. Pediatr Blood Cancer 48:21–27

  2. 2.

    te Winkel ML, Pieters R, Hop WC et al (2014) Bone mineral density at diagnosis determines fracture rate in children with acute lymphoblastic leukemia treated according to the DCOG-ALL9 protocol. Bone 59:223–228

  3. 3.

    Strauss AJ, Su JT, Dalton VM, Gelber RD, Sallan SE, Silverman LB (2001) Bony morbidity in children treated for acute lymphoblastic leukemia. J Clin Oncol 19:3066–3072

  4. 4.

    Gordon CM, Leonard MB, Zemel BS, International Society for Clinical D (2014) 2013 pediatric position development conference: executive summary and reflections. J Clin Densitom 17:219–224

  5. 5.

    Halton J, Gaboury I, Grant R, Alos N, Cummings EA, Matzinger M, Shenouda N, Lentle B, Abish S, Atkinson S, Cairney E, Dix D, Israels S, Stephure D, Wilson B, Hay J, Moher D, Rauch F, Siminoski K, Ward LM, and the Canadian STOPP Consortium (2009) Advanced vertebral fracture among newly diagnosed children with acute lymphoblastic leukemia: results of the Canadian Steroid-Associated Osteoporosis in the Pediatric Population (STOPP) research program. J Bone Miner Res 24:1326–1334

  6. 6.

    Alos N, Grant RM, Ramsay T, Halton J, Cummings EA, Miettunen PM, Abish S, Atkinson S, Barr R, Cabral DA, Cairney E, Couch R, Dix DB, Fernandez CV, Hay J, Israels S, Laverdière C, Lentle B, Lewis V, Matzinger MA, Rodd C, Shenouda N, Stein R, Stephure D, Taback S, Wilson B, Williams K, Rauch F, Siminoski K, Ward LM (2012) High incidence of vertebral fractures in children with acute lymphoblastic leukemia 12 months after the initiation of therapy. J Clin Oncol 30:2760–2767

  7. 7.

    Cummings EA, Ma J, Fernandez CV, Halton J, Alos N, Miettunen PM, Jaremko JL, Ho J, Shenouda N, Matzinger MA, Lentle B, Stephure D, Stein R, Sbrocchi AM, Rodd C, Lang B, Israels S, Grant RM, Couch R, Barr R, Hay J, Rauch F, Siminoski K, Ward LM, the Canadian STOPP Consortium (National Pediatric Bone Health Working Group) (2015) Incident vertebral fractures in children with leukemia during the four years following diagnosis. J Clin Endocrinol Metab 100:3408–3417

  8. 8.

    Dal Osto LC, Konji VN, Halton J, Matzinger MA, Bassal M, Rauch F, Ward LM (2016) The spectrum of recovery from fracture-induced vertebral deformity in pediatric leukemia. Pediatr Blood Cancer 63:1107–1110

  9. 9.

    Ward LM, Ma J, Lang B, Ho J, Alos N, Matzinger MA, Shenouda N, Lentle B, Jaremko JL, Wilson B, Stephure D, Stein R, Sbrocchi AM, Rodd C, Lewis V, Israels S, Grant RM, Fernandez CV, Dix DB, Cummings EA, Couch R, Cairney E, Barr R, Abish S, Atkinson SA, Hay J, Rauch F, Moher D, Siminoski K, Halton J, the Steroid-Associated Osteoporosis in the Pediatric Population (STOPP) Consortium (2018) Bone morbidity and recovery in children with acute lymphoblastic leukemia: results of a six-year prospective cohort study. J Bone Miner Res 33:1435–1443

  10. 10.

    Warner JT, Evans WD, Webb DK, Bell W, Gregory JW (1999) Relative osteopenia after treatment for acute lymphoblastic leukemia. Pediatr Res 45:544–551

  11. 11.

    Arikoski P, Komulainen J, Voutilainen R, Riikonen P, Parviainen M, Tapanainen P, Knip M, Kroger H (1998) Reduced bone mineral density in long-term survivors of childhood acute lymphoblastic leukemia. J Pediatr Hematol Oncol 20:234–240

  12. 12.

    Tillmann V, Darlington AS, Eiser C, Bishop NJ, Davies HA (2002) Male sex and low physical activity are associated with reduced spine bone mineral density in survivors of childhood acute lymphoblastic leukemia. J Bone Miner Res 17:1073–1080

  13. 13.

    Kadan-Lottick N, Marshall JA, Baron AE, Krebs NF, Hambidge KM, Albano E (2001) Normal bone mineral density after treatment for childhood acute lymphoblastic leukemia diagnosed between 1991 and 1998. J Pediatr 138:898–904

  14. 14.

    van der Sluis IM, van den Heuvel-Eibrink MM, Hahlen K, Krenning EP, de Muinck Keizer-Schrama SM (2000) Bone mineral density, body composition, and height in long-term survivors of acute lymphoblastic leukemia in childhood. Med Pediatr Oncol 35:415–420

  15. 15.

    Rodan GA, Reszka AA (2002) Bisphosphonate mechanism of action. Curr Mol Med 2:571–577

  16. 16.

    Ward LM, Konji VN, Ma J (2016) The management of osteoporosis in children. Osteoporos Int 27:2147–2179

  17. 17.

    Simm PJ, Biggin A, Zacharin MR, Rodda CP, Tham E, Siafarikas A, Jefferies C, Hofman PL, Jensen DE, Woodhead H, Brown J, Wheeler BJ, Brookes D, Lafferty A, Munns CF, on behalf of the APEG Bone Mineral Working Group (2018) Consensus guidelines on the use of bisphosphonate therapy in children and adolescents. J Paediatr Child Health 54:223–233

  18. 18.

    Joseph S, McCarrison S, Wong SC (2016) Skeletal fragility in children with chronic disease. Horm Res Paediatr 86:71–82

  19. 19.

    Goldbloom EB, Cummings EA, Yhap M (2005) Osteoporosis at presentation of childhood ALL: management with pamidronate. Pediatr Hematol Oncol 22:543–550

  20. 20.

    Padhye B, Dalla-Pozza L, Little DG, Munns CF (2013) Use of zoledronic acid for treatment of chemotherapy related osteonecrosis in children and adolescents: a retrospective analysis. Pediatr Blood Cancer 60:1539–1545

  21. 21.

    Lee JM, Kim JE, Bae SH, Hah JO (2013) Efficacy of pamidronate in children with low bone mineral density during and after chemotherapy for acute lymphoblastic leukemia and non-Hodgkin lymphoma. Blood Res 48:99–106

  22. 22.

    Wiernikowski JT, Barr RD, Webber C, Guo CY, Wright M, Atkinson SA (2005) Alendronate for steroid-induced osteopenia in children with acute lymphoblastic leukaemia or non-Hodgkin's lymphoma: results of a pilot study. J Oncol Pharm Pract 11:51–56

  23. 23.

    Wasilewski-Masker K, Kaste SC, Hudson MM, Esiashvili N, Mattano LA, Meacham LR (2008) Bone mineral density deficits in survivors of childhood cancer: long-term follow-up guidelines and review of the literature. Pediatrics 121:e705–e713

  24. 24.

    Sala A, Barr RD (2007) Osteopenia and cancer in children and adolescents: the fragility of success. Cancer 109:1420–1431

  25. 25.

    Sala A, Mattano LA Jr, Barr RD (2007) Osteonecrosis in children and adolescents with cancer - an adverse effect of systemic therapy. Eur J Cancer 43:683–689

  26. 26.

    Barr RD, Guo CY, Wiernikowski J, Webber C, Wright M, Atkinson S (2002) Osteopenia in children with acute lymphoblastic leukemia: a pilot study of amelioration with Pamidronate. Med Pediatr Oncol 39:44–46

  27. 27.

    Lethaby C, Wiernikowski J, Sala A, Naronha M, Webber C, Barr RD (2007) Bisphosphonate therapy for reduced bone mineral density during treatment of acute lymphoblastic leukemia in childhood and adolescence: a report of preliminary experience. J Pediatr Hematol Oncol 29:613–616

  28. 28.

    Brown JJ, Zacharin MR (2005) Attempted randomized controlled trial of pamidronate versus calcium and calcitriol supplements for management of steroid-induced osteoporosis in children and adolescents. J Paediatr Child Health 41:580–582

  29. 29.

    Nasomyont N, Hornung LN, Gordon CM, Wasserman H (2019) Outcomes following intravenous bisphosphonate infusion in pediatric patients: a 7-year retrospective chart review. Bone 121:60–67

  30. 30.

    Crabtree NJ, Arabi A, Bachrach LK, Fewtrell M, El-Hajj Fuleihan G, Kecskemethy HH, Jaworski M, Gordon CM, International Society for Clinical D (2014) Dual-energy X-ray absorptiometry interpretation and reporting in children and adolescents: the revised 2013 ISCD pediatric official positions. J Clin Densitom 17:225–242

  31. 31.

    Crofton PM, Ahmed SF, Wade JC, Stephen R, Elmlinger MW, Ranke MB, Kelnar CJ, Wallace WH (1998) Effects of intensive chemotherapy on bone and collagen turnover and the growth hormone axis in children with acute lymphoblastic leukemia. J Clin Endocrinol Metab 83:3121–3129

  32. 32.

    Arikoski P, Komulainen J, Riikonen P, Voutilainen R, Knip M, Kroger H (1999) Alterations in bone turnover and impaired development of bone mineral density in newly diagnosed children with cancer: a 1-year prospective study. J Clin Endocrinol Metab 84:3174–3181

  33. 33.

    Ward LM, Rauch F (2018) Anabolic therapy for the treatment of osteoporosis in childhood. Curr Osteoporos Rep 16:269–276

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Correspondence to S. C. Wong.

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SCW has received consultancy fees from Novartis.

The rest of the authors have no conflict of interest to declare.

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Harris, A.M., Lee, A.R. & Wong, S.C. Systematic review of the effects of bisphosphonates on bone density and fracture incidence in childhood acute lymphoblastic leukaemia. Osteoporos Int 31, 59–66 (2020). https://doi.org/10.1007/s00198-019-05082-8

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  • Bone health
  • Dual-energy absorptiometry
  • Leukaemia
  • Pamidronate
  • Vertebral fracture
  • Zoledronate