Clinical trial NCT02074631: Prevention of Bone Loss After Pediatric Hematopoietic Cell Transplantation
Official title: Prevention of Bone Loss After Pediatric Hematopoietic Cell Transplantation
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Osteopenia
Osteoporosis
Keywords: bone mineral content
bone mineral density
bone formation
bone resorption
pamidronate
children
DXA
bone marrow transplant
Lead sponsor: Masonic Cancer Center, University of Minnesota
Sponsor class: OTHER
First posted: 2014-02-28
Enrollment: 63
Sex: ALL
Minimum age (years): 1
Maximum age (years): 20
Standard ages: CHILD
ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: PREVENTION

Brief summary: This is a Phase 2, open-label, randomized, controlled clinical study of pediatric subjects treated with pamidronate with calcium and vitamin D versus calcium and vitamin D alone following hematopoietic cell transplantation (HCT). The purpose of this study is to test the hypothesis that subjects receiving pamidronate with calcium and vitamin D will have higher lumbar spine bone mineral content (LBMC) measured by dual-energy X-ray tomography (DXA) at 1 year post-HCT than subjects receiving calcium and vitamin D alone (Control Group).


Eligibility criteria: Inclusion Criteria:

* Allogeneic hematopoietic cell transplant for hematologic malignancy (i.e. leukemia, lymphoma including ALL, AML, CML, NHL, HL) in complete remission; myelodysplastic syndrome (active dysplasia and/or blasts are permitted, but must not have active leukemia) or idiopathic severe aplastic anemia (SAA)
* Non-malignant diseases including idiopathic severe aplastic anemia (SAA) and other bone marrow failure disorders, hemoglobinopathies, adrenoleukodystrophy, immune deficiencies/dysregulation disorders who will be receiving myeloablative or reduced toxicity preparative regimens that meet the following criteria:

  * Regimens include those that are TBI based if the TBI dose is \> 500cGy single dose or \> 800cGy fractionated, or doses \<500 cGy if combined with busulfan or treosulfan. These also include chemotherapy only based regimens that contain myeloablative doses of busulfan (\>8mg/kg) or treosulfan without TBI.
  * Patients with severe aplastic anemia are eligible regardless of conditioning regimen
* Myeloablative preparative regimen (for SAA any conditioning therapy allowed)
* Male or female ≥1 but ≤ 20 years of age at time of study enrollment
* Patient or parent(s)/legal guardian(s) is able and willing to provide informed consent. Assent will be obtained per local institutional policy. Subjects who turn 18 during the course of the study will be consented at that time of their next visit by a member of the research staff.

Exclusion Criteria:

* History of a primary bone malignancy involving the lumbar spine
* Prior and/or planned concomitant medical therapy during the study period (through Day 360 post-HCT) with other bisphosphonates, Denosumab, or Teriparatide
* Pregnancy or breastfeeding - menstruating females must have a negative pregnancy test prior to study enrollment and agree to repeat pregnancy testing and contraception use per protocol as pamidronate is Pregnancy Category D - positive evidence of human fetal risk based on adverse reaction data
* Renal insufficiency, defined as creatinine level greater than the upper limit of normal for age
* Hereditary metabolic bone disease or skeletal dysplasia (e.g., osteopetrosis or OI) or primary hyperparathyroidism
* Other indications for HCT, including Fanconi anemia, other form of inherited bone marrow failure diseases, metabolic disorder, hemoglobinopathy, or immune deficiency
* Clinically significant fractures as defined by ISCD (a long bone fracture of the lower extremities, vertebral compression fracture, or two or more long bone fractures of the upper extremities) (88,89) indicated by a cast or a spine x-ray within the last 2 weeks
* Known or suspected allergy to pamidronate or related products
* Planned administration of an investigational study drug or agent that either can interact with pamidronate or have an independent effect on bone mineral density within the 4 weeks prior to randomization (Day 90) or planned use during study participation (Day 90 through Day 360)
* Impending invasive dental procedure that would be expected to occur during study participation (through Day 360)

Primary outcomes:
measure: Lumbar Spine Bone Mineral Content
timeFrame: 1 year after HCT
Secondary outcomes:
measure: Total Body Bone Mineral Content (TBMC; Excluding Head; Adjusted for Height, Age, Sex, Tanner Stage, and Race)
timeFrame: 1 year after HCT
measure: Total Bone Mineral Density (BMD), Cortical BMD, Trabecular BMD, and Estimated Bone Strength Measured by pQCT
timeFrame: 1 year after HCT
measure: Cytokine Levels (Interleukin IL-6, IL-7, and TNF-α)
timeFrame: 7 days, 14 days, 21 days, 90 days after HCT
measure: Receptor Activator of the Nuclear Factor-κB Ligand [RANKL], Osteoprotegerin [OPG]
timeFrame: 7 days, 14 days, 21 days, and 90 days after HCT
measure: Marker of Bone Resorption (Carboxy-terminal Collagen Crosslinks [CTX]
timeFrame: 7, 14, 21, 90, 180, 360 days after HCT
measure: Markers of Bone Formation (Procollagen Type 1 N-terminal Propeptide [P1NP])
timeFrame: 7, 14, 21, 90, 180, 360 days after HCT
measure: Ratio of Receptor Activator of the Nuclear Factor-κB Ligand [RANKL] and Osteoprotegerin [OPG]
timeFrame: 7 days, 14 days, 21 days, and 90 days after HCT
measure: Marker of Bone Resorption Deoxypyridinoline [DPD])
timeFrame: 7, 14, 21, 90, 180, 360 days after HCT
measure: Marker of Bone Formation Osteocalcin [OCN])
timeFrame: 7, 14, 21, 90, 180, 360 days after HCT
Other outcomes:
Locations:
city: Minneapolis
country: United States
facility: University of Minnesota Amplatz Children's Hospital
state: Minnesota
city: Seattle
country: United States
facility: Seattle Children's Hospital
state: Washington
Study officials:
affiliation: University of Minnesota
name: Kyriakie Sarafoglou, MD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Petryk A, Bergemann TL, Polga KM, Ulrich KJ, Raatz SK, Brown DM, Robison LL, Baker KS. Prospective study of changes in bone mineral density and turnover in children after hematopoietic cell transplantation. J Clin Endocrinol Metab. 2006 Mar;91(3):899-905. doi: 10.1210/jc.2005-1927. Epub 2005 Dec 13.
citation: Bhatia S, Ramsay NK, Weisdorf D, Griffiths H, Robison LL. Bone mineral density in patients undergoing bone marrow transplantation for myeloid malignancies. Bone Marrow Transplant. 1998 Jul;22(1):87-90. doi: 10.1038/sj.bmt.1701275.
citation: Nysom K, Holm K, Michaelsen KF, Hertz H, Jacobsen N, Muller J, Molgaard C. Bone mass after allogeneic BMT for childhood leukaemia or lymphoma. Bone Marrow Transplant. 2000 Jan;25(2):191-6. doi: 10.1038/sj.bmt.1702131.
citation: Kaste SC, Shidler TJ, Tong X, Srivastava DK, Rochester R, Hudson MM, Shearer PD, Hale GA. Bone mineral density and osteonecrosis in survivors of childhood allogeneic bone marrow transplantation. Bone Marrow Transplant. 2004 Feb;33(4):435-41. doi: 10.1038/sj.bmt.1704360.
citation: Perkins JL, Kunin-Batson AS, Youngren NM, Ness KK, Ulrich KJ, Hansen MJ, Petryk A, Steinberger J, Anderson FS, Baker KS. Long-term follow-up of children who underwent hematopoeitic cell transplant (HCT) for AML or ALL at less than 3 years of age. Pediatr Blood Cancer. 2007 Dec;49(7):958-63. doi: 10.1002/pbc.21207.
citation: Daniels MW, Wilson DM, Paguntalan HG, Hoffman AR, Bachrach LK. Bone mineral density in pediatric transplant recipients. Transplantation. 2003 Aug 27;76(4):673-8. doi: 10.1097/01.TP.0000076627.70050.53.
citation: Mostoufi-Moab S, Ginsberg JP, Bunin N, Zemel B, Shults J, Leonard MB. Bone density and structure in long-term survivors of pediatric allogeneic hematopoietic stem cell transplantation. J Bone Miner Res. 2012 Apr;27(4):760-9. doi: 10.1002/jbmr.1499.
citation: Jackowski SA, Kontulainen SA, Cooper DM, Lanovaz JL, Baxter-Jones AD. The timing of BMD and geometric adaptation at the proximal femur from childhood to early adulthood in males and females: a longitudinal study. J Bone Miner Res. 2011 Nov;26(11):2753-61. doi: 10.1002/jbmr.468.
citation: Kaste SC, Rai SN, Fleming K, McCammon EA, Tylavsky FA, Danish RK, Rose SR, Sitter CD, Pui CH, Hudson MM. Changes in bone mineral density in survivors of childhood acute lymphoblastic leukemia. Pediatr Blood Cancer. 2006 Jan;46(1):77-87. doi: 10.1002/pbc.20553.
citation: Ross PD, Davis JW, Epstein RS, Wasnich RD. Pre-existing fractures and bone mass predict vertebral fracture incidence in women. Ann Intern Med. 1991 Jun 1;114(11):919-23. doi: 10.7326/0003-4819-114-11-919.
citation: Baxter-Jones AD, Faulkner RA, Forwood MR, Mirwald RL, Bailey DA. Bone mineral accrual from 8 to 30 years of age: an estimation of peak bone mass. J Bone Miner Res. 2011 Aug;26(8):1729-39. doi: 10.1002/jbmr.412.
citation: Polgreen LE, Rudser K, Deyo M, Smith A, Baker KS, Petryk A. Changes in biomarkers of bone resorption over the first six months after pediatric hematopoietic cell transplantation. Pediatr Transplant. 2012 Dec;16(8):852-7. doi: 10.1111/j.1399-3046.2012.01780.x. Epub 2012 Aug 20.
citation: Grigg AP, Shuttleworth P, Reynolds J, Schwarer AP, Szer J, Bradstock K, Hui C, Herrmann R, Ebeling PR. Pamidronate reduces bone loss after allogeneic stem cell transplantation. J Clin Endocrinol Metab. 2006 Oct;91(10):3835-43. doi: 10.1210/jc.2006-0684. Epub 2006 Jul 11.
citation: Kananen K, Volin L, Laitinen K, Alfthan H, Ruutu T, Valimaki MJ. Prevention of bone loss after allogeneic stem cell transplantation by calcium, vitamin D, and sex hormone replacement with or without pamidronate. J Clin Endocrinol Metab. 2005 Jul;90(7):3877-85. doi: 10.1210/jc.2004-2161. Epub 2005 Mar 29.
citation: Glorieux FH. Treatment of osteogenesis imperfecta: who, why, what? Horm Res. 2007;68 Suppl 5:8-11. doi: 10.1159/000110463. Epub 2007 Dec 10.
citation: Land C, Rauch F, Travers R, Glorieux FH. Osteogenesis imperfecta type VI in childhood and adolescence: effects of cyclical intravenous pamidronate treatment. Bone. 2007 Mar;40(3):638-44. doi: 10.1016/j.bone.2006.10.010. Epub 2006 Nov 28.
citation: Devogelaer JP, Malghem J, Maldague B, Nagant de Deuxchaisnes C. Radiological manifestations of bisphosphonate treatment with APD in a child suffering from osteogenesis imperfecta. Skeletal Radiol. 1987;16(5):360-3. doi: 10.1007/BF00350961.
citation: Rauch F, Glorieux FH. Osteogenesis imperfecta. Lancet. 2004 Apr 24;363(9418):1377-85. doi: 10.1016/S0140-6736(04)16051-0.
citation: Speiser PW, Clarson CL, Eugster EA, Kemp SF, Radovick S, Rogol AD, Wilson TA; LWPES Pharmacy and Therapeutic Committee. Bisphosphonate treatment of pediatric bone disease. Pediatr Endocrinol Rev. 2005 Dec;3(2):87-96.
citation: Castillo H, Samson-Fang L; American Academy for Cerebral Palsy and Developmental Medicine Treatment Outcomes Committee Review Panel. Effects of bisphosphonates in children with osteogenesis imperfecta: an AACPDM systematic review. Dev Med Child Neurol. 2009 Jan;51(1):17-29. doi: 10.1111/j.1469-8749.2008.03222.x.
citation: DiMeglio LA, Ford L, McClintock C, Peacock M. Intravenous pamidronate treatment of children under 36 months of age with osteogenesis imperfecta. Bone. 2004 Nov;35(5):1038-45. doi: 10.1016/j.bone.2004.07.003.
citation: Glorieux FH, Bishop NJ, Plotkin H, Chabot G, Lanoue G, Travers R. Cyclic administration of pamidronate in children with severe osteogenesis imperfecta. N Engl J Med. 1998 Oct 1;339(14):947-52. doi: 10.1056/NEJM199810013391402.
citation: Henderson RC, Lark RK, Kecskemethy HH, Miller F, Harcke HT, Bachrach SJ. Bisphosphonates to treat osteopenia in children with quadriplegic cerebral palsy: a randomized, placebo-controlled clinical trial. J Pediatr. 2002 Nov;141(5):644-51. doi: 10.1067/mpd.2002.128207.
citation: Plotkin H, Coughlin S, Kreikemeier R, Heldt K, Bruzoni M, Lerner G. Low doses of pamidronate to treat osteopenia in children with severe cerebral palsy: a pilot study. Dev Med Child Neurol. 2006 Sep;48(9):709-12. doi: 10.1017/S0012162206001526.
citation: Grissom LE, Kecskemethy HH, Bachrach SJ, McKay C, Harcke HT. Bone densitometry in pediatric patients treated with pamidronate. Pediatr Radiol. 2005 May;35(5):511-7. doi: 10.1007/s00247-004-1393-3. Epub 2005 Jan 18.
citation: Gandrud LM, Cheung JC, Daniels MW, Bachrach LK. Low-dose intravenous pamidronate reduces fractures in childhood osteoporosis. J Pediatr Endocrinol Metab. 2003 Jul-Aug;16(6):887-92. doi: 10.1515/jpem.2003.16.6.887.
citation: Brumsen C, Hamdy NA, Papapoulos SE. Long-term effects of bisphosphonates on the growing skeleton. Studies of young patients with severe osteoporosis. Medicine (Baltimore). 1997 Jul;76(4):266-83. doi: 10.1097/00005792-199707000-00005.
citation: Przkora R, Herndon DN, Sherrard DJ, Chinkes DL, Klein GL. Pamidronate preserves bone mass for at least 2 years following acute administration for pediatric burn injury. Bone. 2007 Aug;41(2):297-302. doi: 10.1016/j.bone.2007.04.195. Epub 2007 May 8.
citation: Carpenter PA, Hoffmeister P, Chesnut CH 3rd, Storer B, Charuhas PM, Woolfrey AE, Sanders JE. Bisphosphonate therapy for reduced bone mineral density in children with chronic graft-versus-host disease. Biol Blood Marrow Transplant. 2007 Jun;13(6):683-90. doi: 10.1016/j.bbmt.2007.02.001. Epub 2007 Apr 6.
citation: Whyte MP, Wenkert D, Clements KL, McAlister WH, Mumm S. Bisphosphonate-induced osteopetrosis. N Engl J Med. 2003 Jul 31;349(5):457-63. doi: 10.1056/NEJMoa023110. No abstract available.
citation: Rauch F, Plotkin H, Travers R, Zeitlin L, Glorieux FH. Osteogenesis imperfecta types I, III, and IV: effect of pamidronate therapy on bone and mineral metabolism. J Clin Endocrinol Metab. 2003 Mar;88(3):986-92. doi: 10.1210/jc.2002-021371.
citation: Astrom E, Soderhall S. Beneficial effect of long term intravenous bisphosphonate treatment of osteogenesis imperfecta. Arch Dis Child. 2002 May;86(5):356-64. doi: 10.1136/adc.86.5.356.
citation: Steelman J, Zeitler P. Treatment of symptomatic pediatric osteoporosis with cyclic single-day intravenous pamidronate infusions. J Pediatr. 2003 Apr;142(4):417-23. doi: 10.1067/mpd.2003.137.
citation: Ward LM, Denker AE, Porras A, Shugarts S, Kline W, Travers R, Mao C, Rauch F, Maes A, Larson P, Deutsch P, Glorieux FH. Single-dose pharmacokinetics and tolerability of alendronate 35- and 70-milligram tablets in children and adolescents with osteogenesis imperfecta type I. J Clin Endocrinol Metab. 2005 Jul;90(7):4051-6. doi: 10.1210/jc.2004-2054. Epub 2005 Apr 12.
citation: Zacharin M, Bateman J. Pamidronate treatment of osteogenesis imperfecta--lack of correlation between clinical severity, age at onset of treatment, predicted collagen mutation and treatment response. J Pediatr Endocrinol Metab. 2002 Feb;15(2):163-74. doi: 10.1515/jpem.2002.15.2.163.
citation: Janssen van Doorn K, Neyns B, Van der Niepen P, Verbeelen D. Pamidronate-related nephrotoxicity (tubulointerstitial nephritis) in a patient with osteolytic bone metastases. Nephron. 2001 Dec;89(4):467-8. doi: 10.1159/000046123. No abstract available.
citation: Machado CE, Flombaum CD. Safety of pamidronate in patients with renal failure and hypercalcemia. Clin Nephrol. 1996 Mar;45(3):175-9.
citation: Lin JH. Bisphosphonates: a review of their pharmacokinetic properties. Bone. 1996 Feb;18(2):75-85. doi: 10.1016/8756-3282(95)00445-9.
citation: Papapoulos SE, Cremers SC. Prolonged bisphosphonate release after treatment in children. N Engl J Med. 2007 Mar 8;356(10):1075-6. doi: 10.1056/NEJMc062792. No abstract available.
citation: Ward KA, Adams JE, Freemont TJ, Mughal MZ. Can bisphosphonate treatment be stopped in a growing child with skeletal fragility? Osteoporos Int. 2007 Aug;18(8):1137-40. doi: 10.1007/s00198-007-0330-3. Epub 2007 Feb 6.
citation: Rauch F, Cornibert S, Cheung M, Glorieux FH. Long-bone changes after pamidronate discontinuation in children and adolescents with osteogenesis imperfecta. Bone. 2007 Apr;40(4):821-7. doi: 10.1016/j.bone.2006.11.020. Epub 2007 Jan 12.
citation: Whyte MP, McAlister WH, Novack DV, Clements KL, Schoenecker PL, Wenkert D. Bisphosphonate-induced osteopetrosis: novel bone modeling defects, metaphyseal osteopenia, and osteosclerosis fractures after drug exposure ceases. J Bone Miner Res. 2008 Oct;23(10):1698-707. doi: 10.1359/jbmr.080511.
citation: Janz KF, Letuchy EM, Eichenberger Gilmore JM, Burns TL, Torner JC, Willing MC, Levy SM. Early physical activity provides sustained bone health benefits later in childhood. Med Sci Sports Exerc. 2010 Jun;42(6):1072-8. doi: 10.1249/MSS.0b013e3181c619b2.
citation: Meyer U, Romann M, Zahner L, Schindler C, Puder JJ, Kraenzlin M, Rizzoli R, Kriemler S. Effect of a general school-based physical activity intervention on bone mineral content and density: a cluster-randomized controlled trial. Bone. 2011 Apr 1;48(4):792-7. doi: 10.1016/j.bone.2010.11.018. Epub 2010 Dec 15.
citation: Buison AM, Kawchak DA, Schall JI, Ohene-Frempong K, Stallings VA, Leonard MB, Zemel BS. Bone area and bone mineral content deficits in children with sickle cell disease. Pediatrics. 2005 Oct;116(4):943-9. doi: 10.1542/peds.2004-2582.
citation: Burnham JM, Shults J, Semeao E, Foster B, Zemel BS, Stallings VA, Leonard MB. Whole body BMC in pediatric Crohn disease: independent effects of altered growth, maturation, and body composition. J Bone Miner Res. 2004 Dec;19(12):1961-8. doi: 10.1359/JBMR.040908. Epub 2004 Sep 20.
citation: Horlick M, Wang J, Pierson RN Jr, Thornton JC. Prediction models for evaluation of total-body bone mass with dual-energy X-ray absorptiometry among children and adolescents. Pediatrics. 2004 Sep;114(3):e337-45. doi: 10.1542/peds.2004-0301.
citation: Petryk A, Polgreen LE, Zhang L, Hodges JS, Dengel DR, Hoffmeister PA, Steinberger J, Baker KS. Bone mineral deficits in recipients of hematopoietic cell transplantation: the impact of young age at transplant. Bone Marrow Transplant. 2014 Feb;49(2):258-63. doi: 10.1038/bmt.2013.156. Epub 2013 Oct 14.
citation: Marshall WA, Tanner JM. Variations in pattern of pubertal changes in girls. Arch Dis Child. 1969 Jun;44(235):291-303. doi: 10.1136/adc.44.235.291. No abstract available.
citation: Marshall WA, Tanner JM. Variations in the pattern of pubertal changes in boys. Arch Dis Child. 1970 Feb;45(239):13-23. doi: 10.1136/adc.45.239.13.
citation: Holick MF, Binkley NC, Bischoff-Ferrari HA, Gordon CM, Hanley DA, Heaney RP, Murad MH, Weaver CM; Endocrine Society. Evaluation, treatment, and prevention of vitamin D deficiency: an Endocrine Society clinical practice guideline. J Clin Endocrinol Metab. 2011 Jul;96(7):1911-30. doi: 10.1210/jc.2011-0385. Epub 2011 Jun 6.
citation: Ross AC, Manson JE, Abrams SA, Aloia JF, Brannon PM, Clinton SK, Durazo-Arvizu RA, Gallagher JC, Gallo RL, Jones G, Kovacs CS, Mayne ST, Rosen CJ, Shapses SA. The 2011 report on dietary reference intakes for calcium and vitamin D from the Institute of Medicine: what clinicians need to know. J Clin Endocrinol Metab. 2011 Jan;96(1):53-8. doi: 10.1210/jc.2010-2704. Epub 2010 Nov 29.
citation: Misra M, Pacaud D, Petryk A, Collett-Solberg PF, Kappy M; Drug and Therapeutics Committee of the Lawson Wilkins Pediatric Endocrine Society. Vitamin D deficiency in children and its management: review of current knowledge and recommendations. Pediatrics. 2008 Aug;122(2):398-417. doi: 10.1542/peds.2007-1894.
citation: Gordon CM, Williams AL, Feldman HA, May J, Sinclair L, Vasquez A, Cox JE. Treatment of hypovitaminosis D in infants and toddlers. J Clin Endocrinol Metab. 2008 Jul;93(7):2716-21. doi: 10.1210/jc.2007-2790. Epub 2008 Apr 15.
citation: Tauchmanova L, Colao A, Lombardi G, Rotoli B, Selleri C. Bone loss and its management in long-term survivors from allogeneic stem cell transplantation. J Clin Endocrinol Metab. 2007 Dec;92(12):4536-45. doi: 10.1210/jc.2006-2870. Epub 2007 Oct 2.