Prevention of bone loss after pediatric hematopoietic cell transplantation

预防小儿造血细胞移植后骨质流失

• 批准号: 8754512
• 负责人: KEVIN S BAKER
• 金额: $ 44.37万
• 依托单位: UNIVERSITY OF MINNESOTA
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-09-01 至 2019-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8754512
• 关键词: Adolescence; Adolescent; Adult; Age; Biological Markers; Body Composition; Bone Density; Bone Marrow Transplantation; Bone Mineral Contents; Bone Resorption; Calcium; Child; Childhood; Complement Factor B; Control Groups; Data; Diet; Disease; Early Intervention; Effectiveness; Elderly; Employee Strikes; Endocrinology; Equilibrium; Face; Fracture; Glucocorticoids; Goals; Head; Height; Hematologic Neoplasms; Individual; Infusion procedures; Interleukin-6; Interleukin-7; Intervention; Left; Life; Malignant - descriptor; Measures; Morbidity - disease rate; Non-Malignant; Nuclear; Osteocalcin; Osteoclasts; Osteogenesis; Osteoporosis; Patients; Peripheral; Physical activity; Populations at Risk; Prevention; Preventive Intervention; Procedures; Prospective Studies; Quality of life; Race; Radial; Randomized; Randomized Controlled Clinical Trials; Recommended Dietary Allowance; Regimen; Rest; Risk; Risk Factors; Source; Staging; Stem cells; Supplementation; Survivors; TNF gene; TRANCE protein; Time; Transplantation; Vertebral column; Vitamin D; Weight Gain; Work; aged; bisphosphonate; bone health; bone loss; bone mass; bone strength; bone turnover; clinical application; clinical practice; cytokine; functional outcomes; hematopoietic cell transplantation; improved; innovation; insight; meetings; modifiable risk; mortality; pamidronate; prevent; prospective; public health relevance; receptor; response; sex; skeletal; substantia spongiosa; success; tibia; young adult

DESCRIPTION (provided by applicant): Childhood and adolescence are critical time periods for establishing peak bone mass for the rest of the adult life. Low bone mineral density (BMD) in childhood increases the risk of early osteoporosis and bone fracture later in life, which has serious individual and societal implications due to the impaired mobility, the associated morbidity and even mortality in older adults. Our long-term goal is to identify vulnerable pediatri populations at risk for bone loss in order to improve their bone health through an early intervention. This study focuses on the prevention of bone loss that occurs in children and adolescents treated with hematopoietic cell transplantation (HCT) for hematologic malignancies. An increase in bone resorption that occurs after HCT in these patients offers an opportunity for intervention with an anti-resorptive agent, yet no prospective studies have been performed that examine the effectiveness of any bisphosphonate or other anti-resorptive agent in pediatric HCT recipients. Therefore, we propose to conduct a prospective, randomized controlled clinical trial of calcium and vitamin D plus pamidronate versus calcium and vitamin D alone to prevent bone loss after pediatric HCT. The central hypothesis is that subjects treated with pamidronate and calcium and vitamin D (Pamidronate Group) will have higher bone mineral content (BMC) and BMD measured by dual-energy x-ray absorptiometry and by peripheral quantitative CT, respectively, at 1 year post-HCT than subjects receiving calcium and vitamin D alone (Control Group). The rationale for this study is that treatment with pamidronate at the time of peak bone resorption can prevent/reverse bone loss and have a positive long-term impact on bone health in pediatric HCT recipients. We will pursue three specific aims: 1) To determine the impact of calcium and vitamin D plus pamidronate versus calcium and vitamin D alone on BMC and BMD following HCT in 60 recipients aged 1-18 years at HCT; 2) To characterize the time course of changes in cytokine levels (IL-6, IL-7, TNF-a) associated with the activation of osteoclasts after HCT and their association with BMC and BMD; 3) To examine the sequence of changes in markers of bone turnover after HCT and their response to pamidronate treatment. The current study is innovative in that it is the first to prospectively evaluate the effects of an anti- resortive agent administered shortly after HCT on BMC and BMD in children. This study is expected to have an important positive impact on bone health in children and the field of pediatric endocrinology by providing much needed prospective data on the effectiveness of an anti-resorptive agent after pediatric HCT. The preventive intervention that this project seeks to examine is likely to have an impact on current clinical practice. While biomarkers of bone turnover have been used in adult studies, there is a striking paucity of data on the clinical applicability of these markers in children and adolescents. Evaluating changes in these markers and cytokines after HCT will provide insight into the underlying mechanisms of bone loss.

描述（由申请人提供）：儿童期和青春期是在成年后的余生中建立峰值骨量的关键时期。儿童期骨矿物质密度 (BMD) 较低会增加晚年早期骨质疏松症和骨折的风险，由于老年人活动能力受损、相关发病率甚至死亡率，这会产生严重的个人和社会影响。我们的长期目标是识别面临骨质流失风险的弱势儿科人群，以便通过早期干预改善他们的骨骼健康。本研究的重点是预防因血液恶性肿瘤接受造血细胞移植（HCT）治疗的儿童和青少年发生的骨质流失。这些患者 HCT 后发生的骨吸收增加为使用抗骨吸收剂进行干预提供了机会，但尚未进行前瞻性研究来检验任何双膦酸盐或其他抗骨吸收剂对儿科 HCT 接受者的有效性。因此，我们建议开展一项前瞻性、随机对照临床试验，比较钙和维生素 D 加帕米膦酸与单独使用钙和维生素 D 的比较，以预防儿科 HCT 后的骨质流失。中心假设是，在 HCT 后 1 年，接受帕米膦酸盐、钙和维生素 D 治疗的受试者（帕米膦酸盐组）将比单独接受钙和维生素 D 的受试者（对照组）具有更高的骨矿物质含量 (BMC) 和 BMD，分别通过双能 X 射线骨密度测定法和外周定量 CT 测量。这项研究的基本原理是，在骨吸收高峰时使用帕米膦酸钠治疗可以预防/逆转骨质流失，并对儿科 HCT 接受者的骨骼健康产生积极的长期影响。我们将追求三个具体目标： 1) 确定钙和维生素 D 加帕米磷酸与单独钙和维生素 D 对 60 名 1-18 岁 HCT 接受者 HCT 后 BMC 和 BMD 的影响； 2) 表征HCT后与破骨细胞激活相关的细胞因子水平（IL-6、IL-7、TNF-a）变化的时间过程及其与BMC和BMD的关系； 3) 检查HCT后骨转换标志物的变化顺序及其对帕米膦酸钠治疗的反应。目前的研究具有创新性，因为它是第一个前瞻性评估 HCT 后不久施用的抗诉药物对儿童 BMC 和 BMD 的影响。这项研究预计将对儿童骨骼健康和儿科内分泌学领域产生重要的积极影响，为儿科 HCT 后抗骨吸收剂的有效性提供急需的前瞻性数据。该项目寻求研究的预防性干预措施可能会对当前的临床实践产生影响。虽然骨转换的生物标志物已用于成人研究，但有关这些标志物在儿童和青少年中的临床适用性的数据却非常缺乏。评估 HCT 后这些标志物和细胞因子的变化将有助于深入了解骨质流失的潜在机制。