X-linked hypophosphatemia (XLH) is the most common heritable form of rickets/osteomalacia in the US.At all ages and irrespective of treatment there is a high incidence of hyperparathyroidism in XLH. Othermanifestations include calcified entheses and arthritis. The explosion of new knowledge about phosphatemetabolism makes this the right time for revisiting XLH both in terms of its pathogenesis and treatment. Wehypothesize that elevated parathyroid hormone (PTH) levels make a signficiant contribution to the skeletaldisease in XLH and propose to use paricalcitol, a non-hypercalcemic vitamin D analog, to suppresselevated PTH levels in this disease.In the first aim, we will perform a cross-sectional study to identify biomarkers of disease severity. We willdevelop a composite disease score in 70 patients with XLH using clinical parameters, radiographs, bonescintigraphy, and validated symptom questionnaires (WOMAC and SF-36). We will then assess therelationship of this composite score to the area under the curve (AUC) for circulating PTH, phosphate (P),and FGF23 levels, measured over a 24-hrs.In the second aim, we will conduct a 12-month randomized, double blind, placebo-controlled trial ofparicalcitol in subjects with XLH and hyperparathyroidism. The dose will be titrated to achieve at least a 50%reduction in PTH levels. AUC for PTH during diurnal sampling performed at baseline and after 12 monthsof therapy will be the primary outcome measure with the dependent variables being the WOMAC/SF-36scores, and skeletal scintigrams at performed at baseline and post-treatment. We expect correction ofhyperparathyroidism to be accompanied by symptomatic improvement and scintigraphic evidence foramelioration in skeletal disease . If successful, this trial will provide proof of concept for the use ofparicalcitol in the treatment of XLH.This project will establish the clinical relevance of circulating PTH, FGF23 and phosphate asmarkers/mediators of disease in XLH and test the efficacy of non-hypercalcemic vitamin D analog therapyin XLH-associated hyperparathyroidism. The project will also serve as a basis for comparison with later(Phase 1) studies potentially directed at suppression of FGF23 action.
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