Prevention of Bone Loss After Pediatric Hematopoietic Cell Transplantation

Study Overview
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Brief Summary
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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).

Official Title
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Prevention of Bone Loss After Pediatric Hematopoietic Cell Transplantation

Conditions
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Osteopenia, Osteoporosis

Intervention / Treatment
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* Drug: Pamidronate
* Drug: Calcium and vitamin D


Participation Criteria
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Eligibility Criteria
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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)

Ages Eligible for Study
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Minimum Age: 1 Year
Maximum Age: 20 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Prevention
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Control group<br>Subjects will receive a standard recommended dose of calcium and vitamin D. | Drug: Calcium and vitamin D<br>* All subjects will receive a standard recommended dose of 600 IU/day of vitamin D. Subjects who do not meet the RDA will receive additional calcium supplementation.<br>* Other names: Ergocalciferol;|
| Experimental: Pamidronate Group<br>Subjects randomized to pamidronate treatment will receive infusions approximately 100, 180, and 270 days after HCT along with calcium and vitamin D. | Drug: Pamidronate<br>* Subjects randomized to pamidronate treatment will receive infusions, 1 mg/kg (to a max dose of 60mg) over 4 hours, every 3 months at approximately 100 days, 180 days, and 270 days after HCT.<br>* Other names: Bonapam;Drug: Calcium and vitamin D<br>* All subjects will receive a standard recommended dose of 600 IU/day of vitamin D. Subjects who do not meet the RDA will receive additional calcium supplementation.<br>* Other names: Ergocalciferol;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Lumbar spine bone mineral content |  | 1 year after HCT | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Total body bone mineral content (TBMC; excluding head; adjusted for height, age, sex, Tanner stage, and race) |  | 1 year after HCT | 
| Total bone mineral density (BMD), cortical BMD, trabecular BMD, and estimated bone strength measured by pQCT |  | 1 year after HCT | 
| Cytokine levels (interleukin IL-6, IL-7, and TNF-α) |  | 7 days, 14 days, 21 days, 100 days after HCT | 
| Receptor activator of the nuclear factor-κB ligand [RANKL], osteoprotegerin [OPG], RANKL/OPG ratio |  | 7 days, 14 days, 21 days, and 100 days after HCT | 
| Markers of bone resorption (carboxy-terminal collagen crosslinks [CTX] and deoxypyridinoline [DPD]) |  | 7, 14, 21, 100, 180, 360 days after HCT | 
| Markers of bone formation (procollagen type 1 N-terminal propeptide [P1NP] and osteocalcin [OCN]) |  | 7, 14, 21, 100, 180, 360 days after HCT | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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bone mineral content, bone mineral density, bone formation, bone resorption, pamidronate, children, DXA, bone marrow transplant