Bone Mineral Turnover after Allogeneic Hematopoietic Stem Cell Transplantation in Children: A Single Center Cohort Study

Bone mineral metabolism disorders are one of the most frequent late complications after allogeneic hematopoietic stem cell transplantation (HSCT) in children.

The aim of the study was to detect the incidence and risk factors for bone mineral metabolism disorders in children who underwent allogeneic HSCT.

Methods. We analyzed the data of medical charts of 294 children aged 0–17 y.o. who were hospitalized in 1994–2011, received  allogeneic HSCT, and survived for at least a year after intervention.  We determined the cumulative incidence and revealed risk factors for the development of osteopenia/osteoporosis and avascular necrosis.  Osteopenia/ osteoporosis was diagnosed after X-ray examination and annual computer X-ray osteodensitometry of the lumbar spine (during a 5-year period since 2003). The criteria for osteopenia is  bone density z-score 2.0, for osteoporosis — z-score 2.0 and  suffered fractures of the bones of the legs, compression fractures of  the spine and / or 2 fractures of the tubular bones of the hands (for both diagnoses). Avascular necrosis was diagnosed  radiographically and basing on magnetic resonance imaging results  (if there were complaints of pain or limb dysfunctions).

Results. After the allogeneic HSCT during the median follow-up of 7.5 years bone mineral metabolism disorders developed in 48  patient (16%). Osteopenia / osteoporosis development was  associated with the following factors: the age 10 years (frequency  23.2% vs. 12% in children under 10 years, p = 0.014), acute graft- versus-host disease (GVHD) grade II–IV (24.2 vs 8.7% at GVHD  grade 0–I; p = 0.001), chronic GVHD (36.0% in extensive form vs.  14.5% in restricted form and 8.4% in the absence of chronic GVHD; p<0.001), immunosuppressive therapy >12 months (31.9 vs. 6.9% for therapy <3 months; p<0.001), glucocorticosteroid intake >3  months (93.8 vs 8.1% with GCs administration 3 months and 3.2% without GCs administration; p<0.001).

Conclusion. Bone mineral metabolism disorders are revealed in 16% of cases in children who underwent HSCT. Determination of risk factors provides the possibility for timely diagnostics and improvement of therapy results.

1. Dvorak CC, Gracia CR, Sanders JE, et al. NCI, NHLBI/PBMTC first international conference on late effects after pediatric hematopoietic cell transplantation: endocrine challenges- thyroid dysfunction, growth impairment, bone health, and reproductive risks. Biol Blood Marrow Transplant. 2011;17(12):1725–1738. doi: 10.1016/j.bbmt.2011.10.006.

2. Hautmann AH, Elad S, Lawitschka A, et al. Metabolic bone diseases in patients after allogeneic hematopoietic stem cell transplantation: report from the Consensus Conference on Clinical Practice in chronic graft-versus-host disease. Transpl Int. 2011;24(9):867–879. doi: 10.1111/j.1432-2277.2011.01264.x.

3. Tauchmanovà L, Colao A, Lombardi G, et al. Bone loss and its management in long-term survivors from allogeneic stem cell transplantation. J Clin Endocrinol Metab. 2007;92(12):4536–4545. doi: 10.1210/jc.2006–2870.

4. Abou-Mourad YR, Lau BC, Barnett MJ, et al. Long-term outcome after allo-SCT: close follow-up on a large cohort treated with myeloablative regimens. Bone Marrow Transplant. 2010;45(2):295–302. doi: 10.1038/bmt.2009.128.

5. Yao S, McCarthy PL, Dunford LM, et al. High prevalence of earlyonset osteopenia/osteoporosis after allogeneic stem cell transplantation and improvement after bisphosphonate therapy. Bone Marrow Transplant. 2008;41(4):393–398. doi: 10.1038/sj.bmt.1705918.

6. Petropoulou AD, Porcher R, Herr AL, et al. Prospective assessment of bone turnover and clinical bone diseases after allogeneic hematopoietic stem-cell transplantation. Transplantation. 2010;89(11):1354–1361. doi: 10.1097/TP.0b013e3181d84c8e.

7. Czerwiński E, Badurski JE, Marcinowska-Suchowierska E, Osieleniec J. Current understanding of osteoporosis according to the position of the World Health Organization (WHO) and International Osteoporosis Foundation. Ortop Traumatol Rehabil. 2007;9(4):337–356.

8. Petryk A, Bergemann TL, Polga KM, et al. Prospective study of changes in bone mineral density and turnover in children after hematopoietic cell transplantation. J Clin Endocrinol Metab. 2006;91(3):899–905. doi: 10.1210/jc.2005-1927.

9. Weilbaecher KN. Mechanisms of osteoporosis after hematopoietic cell transplantation. Biol Blood Marrow Transplant. 2000;6(2A):165–174. doi: 10.1016/s1083-8791(00)70039-5. 10. Tauchmanovà L, De Rosa G, Serio B, et al. Avascular necrosis in long-term survivors after allogeneic or autologous stem cell transplantation: a single center experience and a review. Cancer. 2003;97(10):2453–2461. doi: 10.1002/cncr.11373.

10. Socié G, Cahn JY, Carmelo J, Vernant JP, Jouet JP, Ifrah N, et al. Avascular necrosis of bone after allogeneic bone marrow transplantation: analysis of risk factors for 4388 patients by the Société Française de Greffe de Moëlle (SFGM). Br J Haematol. 1997;97(4):865–870. doi: 10.1046/j.1365-2141.1997.1262940.x.

11. Schulte CM, Beelen DW. Low pretransplant bone-mineral density and rapid bone loss do not increase risk for avascular osteonecrosis after allogeneic hematopoietic stem cell transplantation. Transplantation. 2005;79(12):1748–1755. doi: 10.1097/01.tp.0000164353.86447.db.

12. Faraci M, Békássy AN, De Fazio V, et al. Non-endocrine late complications in children after allogeneic haematopoietic SCT. EBMT Paediatric and Late Effects Working Parties. Bone Marrow Transplant. 2008;41 Suppl 2:S49–57. doi: 10.1038/bmt.2008.55.

13. Torii Y, Hasegawa Y, Kubo T, et al. Osteonecrosis of the femoral head after allogeneic bone marrow transplantation. Clin Orthop Relat Res. 2001;(382):124–132. doi: 10.1097/00003086-200101000-00019.

14. Karimova EJ, Rai SN, Howard SC, et al. Femoral head osteonecrosis in pediatric and young adult patients with leukemia or lymphoma. J Clin Oncol. 2007;25(12):1525–1531. doi: 10.1200/JCO.2006.07.9947.

15. McClune BL, Polgreen LE, Burmeister LA, et al. Screening, prevention and management of osteoporosis and bone loss in adult and pediatric hematopoietic cell transplant recipients. Bone Marrow Transplant. 2011;46(1):1–9. doi: 10.1038/bmt.2010.198.

16. Baim S, Leonard MB, Bianchi ML, et al. Official Positions of the International Society for Clinical Densitometry and executive summary of the 2007 ISCD Pediatric Position Development Conference. J Clin Densitom. 2008;11(1):6–21. doi: 10.1016/j.jocd.2007.12.002.

17. Rizzo JD, Wingard JR, Tichelli A, et al. Recommended screening and preventive practices for long-term survivors after hematopoietic cell transplantation: joint recommendations of the European Group for Blood and Marrow Transplantation, the Center for International Blood and Marrow Transplant Research, and the American Society of Blood and Marrow Transplantation. Biol Blood Marrow Transplant. 2006;12(2):138–151. doi: 10.1016/j.bbmt.2005.09.012.

18. Li Х, Brazauskas R, Wang Z, et al. Avascular necrosis of bone following allogeneic hematopoietic cell transplantation in children and adolescents. Biol Blood Marrow Transplant. 2014;20(4):587–592. doi: 10.1016/j.bbmt.2013.12.567.

19. Schulte C, Beelen DW, Schaefer UW, Mann K. Bone loss in longterm survivors after transplantation of hematopoietic stem cells: a prospective study. Osteoporos Int. 2000;11(4):344–353. doi: 10.1007/s001980070124.

20. Schimmer AD, Minden MD, Keating A. Osteoporosis after blood and marrow transplantation: clinical aspects. Biol Blood Marrow Transplant. 2000;6(2A):175–181. doi: 10.1016/s1083-8791(00)70040-1.

21. Savani BN, Donohue T, Kozanas E, et al. Increased risk of bone loss without fracture risk in long-term survivors after allogeneic stem cell transplantation. Biol Blood Marrow Transplant. 2007;13(5):517–520. doi: 10.1016/j.bbmt.2007.01.085.

22. Wasilewski-Masker K, Kaste SC, Hudson MM, et al. Bone mineral density deficits in survivors of childhood cancer: longterm follow-up guidelines and review of the literature. Pediatrics. 2008;121(3):e705–713. doi: 10.1542/peds.2007-1396.

23. Grover M, Bachrach LK. Osteoporosis in children with chronic illnesses: diagnosis, monitoring, and treatment. Curr Osteoporos Rep. 2017;15(4):271–282. doi: 10.1007/s11914-017-0371-2.

24. Лисицын А.О., Алексеева Е.И., Пинелис В.Г., и др. Опыт применения ибандроновой кислоты у больных с тяжелым течением ревматических болезней и системным остеопорозом // Вопросы современной педиатрии. — 2010. — Т.9. — №1 — С. 116–121. [Lisitsin AO, Alexeeva EI, Pinelis VG, et al. Experience of treatment with ibandronic acid in patients with severe rheumatological diseases and systemic osteoporosis. Current pediatrics. 2010;9(1):116–121. (In Russ).]

25. Почкайло А.С. Современные подходы к лечению остеопороза у детей // Медицинские новости. — 2013 — №7. — С. 42–48. [Pochkailo AS. Modern approaches to the treatment of osteoporosis in children. Meditsinskie novosti. 2013;(7):42–48. (In Russ).]

26. Bachrach LK, Ward LM. Clinical review 1: bisphosphonate use in childhood osteoporosis. J Clin Endocrinol Metab. 2009;94(2):400–409. doi: 10.1210/jc.2008-1531.

27. Aricò M, Boccalatte MF, Silvestri D, et al. Osteonecrosis: an emerging complication of intensive chemotherapy for childhood acute lymphoblastic leukemia. Haematologica. 2003;88(7):747–753.

28. Bürger B, Beier R, Zimmermann M, et al. Osteonecrosis: a treatment related toxicity in childhood acute lymphoblastic leukemia (ALL) — experiences from trial ALL-BFM 95. Pediatr Blood Cancer. 2005;44(3):220–225. doi: 10.1002/pbc.20244.

29. Faraci M, Calevo MG, Lanino E, et al. Osteonecrosis after allogeneic stem cell transplantation in childhood. A case-control study in Italy. AIEOP-SCT Group. Haematologica. 2006;91(8):1096–1099.

30. French D, Hamilton LH, Mattano LA Jr, et al. A PAI-1 (SERPINE1) polymorphism predicts osteonecrosis in children with acute lymphoblastic leukemia: a report from the Children’s Oncology Group. Children’s Oncology Group. Blood. 2008;111(9):4496–4499. doi: 10.1182/blood-2007-11-123885.

31. Ferrari P, Schroeder V, Anderson S, et al. Association of plasminogen activator inhibitor-1 genotype with avascular osteonecrosis in steroid-treated renal allograft recipients. Transplantation. 2002;74(8):1147–1152. doi: 10.1097/01.TP.0000035848.73883.1B.

32. Sharma S, Leung WH, Deqing P, et al. Osteonecrosis in children after allogeneic hematopoietic cell transplantation: study of prevalence, risk factors and longitudinal changes using MR imaging. Bone Marrow Transplant. 2012;47(8):1067–1074. doi: 10.1038/bmt.2011.234.

33. Pengde K, Fuxing P, Bin S, et al. Lovastatin inhibits adipogenesis and prevents osteonecrosis in steroid-treated rabbits. Joint Bone Spine. 2008;75(6):696–701. doi: 10.1016/j.jbspin.2007.12.008.

34. Yang J, Wang L, Xu Y, et al. [An experimental osteonecrosis of femoral head induced by a combination of a single low-dose lipopolysaccharide and methylprednisone. (In Chinese).] Zhongguo Xiu Fu Chong Jian Wai Ke Za Zhi. 2008;22(3):271–275.

35. Carpenter PA, Kitko CL, Elad S, et al. National Institutes of Health Consensus Development Project on Criteria for Clinical Trials in Chronic Graft-versus-Host Disease: V. The 2014 Ancillary Therapy and Supportive Care Working Group Report. Biol Blood Marrow Transplant. 2015;21(7):1167–1187. doi: 10.1016/j.bbmt.2015.03.024.

36. Ji WF, Ding WH, Ma ZC, et al. [Three-tunnels core decompression with implantation of bone marrow stromal cells (bMSCs) and decalcified bone matrix (DBM) for the treatment of early femoral head necrosis. (In Chinese).] Zhongguo Gu Shang. 2008;21(10):776–778.

37. Jones KB, Seshadri T, Krantz R, et al. Cell-based therapies for osteonecrosis of the femoral head. Biol Blood Marrow Transplant. 2008;14(10):1081–1087. doi: 10.1016/j.bbmt.2008.06.017.

38. Tzaribachev N, Vaegler M, Schaefer J, et al. Mesenchymal stromal cells: a novel treatment option for steroid-induced avascular osteonecrosis. Isr Med Assoc J. 2008;10(3):232–234.