RANDOMIZED CONTROLLED TRIAL OF CA SUPPLEMENTATION FOR BONE MINERALIZATION IN JRA

背景：儿童时期出现明显的全身性骨量减少 约40%的JRA患者处于青春期。达到一生的巅峰 女性的骨量发生在青春期，而且已经被证明是 在许多JRA患者中降低。既没有公认的治疗方法，也没有 针对JRA患者骨量减少的对照试验。观察性的 对JRA患者的研究记录了次优饮食的高患病率 钙(Ca)和维生素D的摄入量显著低于胃肠道 钙吸收和骨形成率低。 假设：在JRA患者中，每天口服1000毫克的钙 (碳酸钙)和400国际单位的维生素D 24个月将导致 全身骨密度(BMD)增加至少10%以上 用双能X射线骨密度仪(DXA)测量与治疗的比较 使用安慰剂和400IU维生素D，这种增加的骨密度将持续 在试验结束后至少18个月。此外，这个项目 将通过以下方式确定补钙对骨生理的影响 测定血、尿骨相关矿物质(钙、磷)， 激素(甲状旁腺激素和维生素D)、骨形成标志物 (骨钙素、骨骼碱性磷酸酶)和骨吸收标记物 (尿钙/肌酐和吡啶酚交联物)。的影响 维生素D受体等位基因变异对骨生理和骨反应的影响 对钙的补充也将被确定。 方法：192名符合资格标准的JRA患者将被 参加这项前瞻性、随机、双盲、安慰剂对照的研究， 24个月的临床试验(RCT)，然后在6个月和18个月时进行评估 追踪随机对照试验，观察治疗效果的持续性。评估 治疗组随机化和持续平等的有效性， 膳食摄入量的基线和间隔评价(过去和现在)， 合并症，药物，关节疾病严重程度，人体测量学， 青春期状态、体力活动和试验用药依从性 已执行。除了标准的药片计数外，遵从性将是 通过使用微电子技术(定性和定量)进行评估 监测和记录药物容器的打开情况。这一合规性 在试验期间将利用数据来提高患者的依从性 分析作为影响结果的协变量。将从以下地点招募患者 该地区的6个儿科风湿病中心，但所有评估都将 发生在协调中心。统计分析将包括 除了标准的群体平均数推论检验外，分析 利用随机效应模型进行协方差和纵向分析。 意义：此RCT将：1)允许对案例进行批判性评估 补充JRA中的骨矿化；2)增加认识 作为安慰剂组的JRA骨矿化的自然历史 将是第一个关于骨矿化的纵向观察研究 JRA；3)确定JRA患者的临床和实验室特征 对钙和维生素D补充剂反应差的患者 为未来的药理试验确定合适的候选者；4) 确定维生素D基因分型对JRA骨矿化的影响。

BACKGROUND; Significant generalized osteopenia develops during childhood or adolescence in some 40% of JRA patients. Attainment of life long peak bone mass occurs during adolescence for females and ha been shown to be decreased in many JRA patients. There are neither accepted treatments nor controlled trials addressing osteopenia in JRA patients. Observational studies in JRA patients document high prevalence of suboptimal dietary intake of calcium (Ca) and vitamin D, significantly lower gastrointestinal Ca absorption and low bone formation rate. HYPOTHESIS: In JRA patients, daily oral supplementation of 1000 mg of Ca (Ca carbonate) and 400 I.U. of vitamin D for 24 months will result in at least a 10% greater increase in total body bone mineral density (BMD) measured by dual energy x-ray absorptiometry (DXA) compared to treatment with placebo and 400 I.U. vitamin D and this increased BMD will persist for at least 18 months after cessation of the trial. In addition, this project will determine the effect of Ca supplementation on bone physiology by measuring serum and urinary bone related minerals (Ca, phosphorus), hormones (parathyroid and vitamin D's), bone formation markers (osteocalcin, skeletal alkaline phosphatase), and bone resorption markers (urinary Ca/Creatinine and pyridinoline crosslinks). The effects of variants of the vitamin D receptor allele on bone physiology and response to Ca supplementation will also be determined. METHODOLOGY: 192 JRA patients meeting eligibility criteria will be enrolled in this prospective, randomized, double-blind, placebo controlled, 24 month clinical trial (RCT) and then evaluated at 6 and 18 months following the RCT for persistence of treatment effect. To assess effectiveness of randomization and ongoing equality of treatment groups, baseline and interval evaluation of dietary intake (past and current), comorbid illness, medications, articular disease severity, anthropometrics, pubertal status, physical activity and trial medication compliance will be performed. In addition to standard pill counts, compliance will be assessed (qualitative and quantitative) by the use of microelectronic monitoring and recording of medication container opening. This compliance data will be utilized during the trial to improve patient compliance and in analysis as a covariate affecting outcome. Patients will be recruited from 6 pediatric rheumatology centers in the region but all evaluations will occur at the coordinating center. Statistical analyses will include, in addition to standard inferential testing of group means, analysis of covariance and longitudinal analysis utilizing a random effects model. SIGNIFICANCE: This RCT will: 1) allow for a critical assessment of Ca supplementation on bone mineralization in JRA; 2) increase understanding of the natural history of bone mineralization in JRA as the placebo group will be the first longitudinal observational study of bone mineralization in JRA; 3) identify clinical and laboratory characteristics of JRA patients with poor response to Ca and vitamin D supplementation to facilitate identification of suitable candidates for future pharmacologic trials; 4) identify the impact of vitamin D genotypes on bone mineralization in JRA.