Prevention of bone loss after pediatric hematopoietic cell transplantation

描述（由申请方提供）：儿童期和青春期是在成年后建立峰值骨量的关键时期。儿童期骨矿物质密度（BMD）低会增加老年人早期骨质疏松症和骨折的风险，由于老年人的活动能力受损，相关的发病率甚至死亡率，这具有严重的个人和社会影响。我们的长期目标是识别易受骨质流失风险的儿童人群，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儿童和青少年接受造血细胞移植（HCT）治疗血液系统恶性肿瘤时发生的骨丢失。在这些患者中，HCT后发生的骨吸收增加为抗吸收剂的干预提供了机会，但尚未进行前瞻性研究来检查任何双膦酸盐或其他抗吸收剂在儿科HCT接受者中的有效性。因此，我们建议进行一项前瞻性、随机对照临床试验，比较钙和维生素D加帕米膦酸盐与单独钙和维生素D预防儿童HCT后骨丢失。中心假设是，与仅接受钙和维生素D治疗的受试者（对照组）相比，接受帕米膦酸盐和钙和维生素D治疗的受试者（帕米膦酸盐组）在HCT后1年分别通过双能X线吸收测定法和外周定量CT测量的骨矿物质含量（BMC）和BMD更高。本研究的基本原理是，在骨吸收峰值时使用帕米膦酸盐治疗可以预防/逆转骨丢失，并对儿童HCT接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名年龄1-18岁的受者在HCT后BMC和BMD的影响; 2）表征细胞因子水平变化的时间过程（IL-6、IL-7、TNF-α）与HCT后破骨细胞的活化有关，并与BMC、BMD相关; 3）检测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地评估HCT后不久给予的抗吸收剂对儿童BMC和BMD的影响。这项研究预计将对儿童的骨骼健康和儿科内分泌学领域产生重要的积极影响，因为它提供了儿科HCT后抗吸收剂有效性方面急需的前瞻性数据。该项目旨在研究的预防性干预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，但这些标志物在儿童和青少年中的临床适用性数据非常缺乏。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丢失的潜在机制。

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.