RANDOMIZED CONTROLLED TRIAL OF CA SUPPLEMENTATION FOR BONE MINERALIZATION IN JRA

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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.