Prevention of bone loss after pediatric hematopoietic cell transplantation

描述（由申请人提供）：童年和青春期是在成年后建立骨量峰值的关键时期。儿童期低骨密度（BMD）增加了生命后期早期骨质疏松症和骨折的风险，这对老年人的活动能力受损、相关发病率甚至死亡率具有严重的个人和社会影响。我们的长期目标是确定易受骨质流失风险的儿科人群，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骨质流失，发生在儿童和青少年接受造血细胞移植（HCT）治疗血液恶性肿瘤。这些患者在HCT后发生的骨吸收增加为抗骨吸收剂的干预提供了机会，但尚未进行前瞻性研究，以检查任何双膦酸盐或其他抗骨吸收剂对儿童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加帕米膦酸盐与钙和维生素D单独预防儿童HCT后骨质流失的效果。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）的骨矿物质含量（BMC）和骨密度（BMD）分别由双能x线吸收仪和外周定量CT测量，高于单独接受钙和维生素D治疗的受试者（对照组）。本研究的基本原理是，在骨吸收高峰期使用帕米膦酸盐治疗可以预防/逆转骨丢失，并对儿童HCT受者的骨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加帕米膦酸盐与单独钙和维生素D对60例1-18岁HCT患者的BMC和BMD的影响；2)表征HCT后与破骨细胞活化相关的细胞因子（IL-6、IL-7、TNF-a）水平变化的时间过程及其与BMC和BMD的关系；3)观察HCT后骨转换标志物的变化顺序及其对帕米膦酸盐治疗的反应。目前的研究是创新的，因为它是第一个前瞻性评估HCT后不久使用抗吸收剂对儿童BMC和BMD的影响。本研究为儿童HCT后抗骨吸收药物的有效性提供了急需的前瞻性数据，有望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。该项目旨在研究的预防性干预可能对当前的临床实践产生影响。虽然骨转换的生物标志物已被用于成人研究，但这些标志物在儿童和青少年中的临床适用性数据却非常缺乏。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。

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.