Prevention of bone loss after pediatric hematopoietic cell transplantation

描述(由申请者提供)：童年和青春期是成年后建立骨量峰值的关键时期。儿童时期的低骨密度(BMD)增加了早期骨质疏松和晚年骨折的风险，由于老年人的行动能力受损，相关的发病率甚至死亡率，这对个人和社会都有严重的影响。我们的长期目标是识别处于骨丢失风险的脆弱儿科人群，以便通过早期干预改善他们的骨健康。这项研究的重点是预防儿童和青少年发生骨丢失的血液系统恶性肿瘤的造血细胞移植(HCT)治疗。这些患者HCT后骨吸收的增加为抗吸收药物的干预提供了机会，然而还没有进行前瞻性研究来检验任何双磷酸盐或其他抗吸收药物在儿童HCT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，将钙和维生素D加帕米磷酸钠与单用钙和维生素D进行对照，以预防儿童HCT后的骨丢失。中心假设是，在HCT后1年，接受帕米磷酸钠、钙和维生素D治疗的受试者(帕米膦酸组)的骨矿含量(BMC)和骨密度(BMD)将分别通过双能X射线吸收测量仪和外周定量CT测量，高于仅接受钙和维生素D治疗的受试者(对照组)。这项研究的基本原理是，在骨吸收高峰期使用帕米磷酸钠可以预防/逆转骨丢失，并对儿童HCT接受者的骨健康有积极的长期影响。我们将追求三个具体目标：1)确定钙和维生素D加帕米磷酸钠与单独使用钙和维生素D对1-18岁接受HCT的60例HCT后BMC和BMD的影响；2)描述与HCT后破骨细胞激活相关的细胞因子水平(IL-6、IL-7、TNF-α)的变化过程及其与BMC和BMD的关系；3)检测HCT后骨转换标志物的变化顺序及其对帕米磷酸钠治疗的反应。目前的研究是创新的，因为它是第一次前瞻性地评估HCT后不久给予的抗吸收药物对儿童BMC和BMD的影响。这项研究有望为儿童HCT后抗吸收药物的有效性提供急需的前瞻性数据，从而对儿童的骨健康和儿童内分泌学领域产生重要的积极影响。该项目试图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。尽管骨转换的生物标记物已被用于成人研究，但关于这些标记物在儿童和青少年中的临床适用性的数据明显不足。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.