Comparative effectiveness of therapeutic modalities in X-linked hypophosphatemia

Brigham And Women'S Hospital, Boston MA

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Abstract

DESCRIPTION (provided by applicant): X-linked hypophosphatemia (XLH) is characterized by elevated FGF23 levels, which leads to hypophosphatemia and decreased 1,25-dihydroxyvitamin D production. The current treatment includes daily supplementation with phosphate and 1,25-dihydroxyvitamin D, which are not well tolerated and do not uniformly prevent rickets. We aim to compare the ability of chronic low dose or intermittent high dose 1,25-dihydroxyvitamin D or FGF23 blocking antibodies to normalize mineral ions, modulate mineral regulatory hormones, and prevent rickets in hyp mice (murine model of XLH). We have previously shown that hypophosphatemia impairs hypertrophic chondrocyte apoptosis and leads to rickets. Unlike hyp mice, hypophosphatemic Npt2a null mice with elevated 1,25-dihydroxyvitamin D levels have normal growth plates. Our preliminary results demonstrate that treatment of hypertrophic chondrocytes with 1,25-dihydroxyvitamin D induces basal and phosphate-induced ERK1/2 phosphorylation, which is required for phosphate-mediated hypertrophic chondrocyte apoptosis. These studies suggest a role for 1,25-dihydroxyvitamin D in preventing impaired hypertrophic chondrocyte apoptosis in hypophosphatemic states. We hypothesize that treatment with 1,25-dihydroxyvitamin D will attenuate hypophosphatemia and promote hypertrophic chondrocyte apoptosis. Administration of anti-FGF23 antibodies will improve 1,25- dihydroxyvitamin D production and decrease urinary phosphate excretion, thereby increasing serum phosphate and promoting growth plate maturation. Studies with PTHrP null mice have shown PTH/PTHrP to be an inhibitor of growth plate maturation. Moreover, the growth plates in hyp mice have elevated PTHrP expression. We have demonstrated that treatment of hypertrophic chondrocytes with PTH inhibits ERK1/2 phosphorylation in response to phosphate. All three treatment strategies that we propose should decrease PTH/PTHrP levels by increasing 1,25-dihydroxyvitamin D. In particular, intermittent high dosing of 1,25-dihydroxyvitamin D has been shown to effectively suppress PTH levels. We hypothesize that this decrease in PTH/PTHrP may directly and indirectly improve hypertrophic chondrocyte apoptosis by increasing p-ERK1/2 and phosphate. In specific aim 1, we will compare the ability of chronic low dose or intermittent high dose 1,25-dihydroxyvitamin D or anti-FGF23 antibodies to attenuate mineral ion abnormalities and promote growth in hyp mice. Bone mineral density will be evaluated to examine the effects of these three treatments on mineralization. We also propose to compare the efficacy of the three treatments and identify the molecular basis for the improvement of the growth plate phenotype through histological, in situ hybridization, and immunohistochemical analyses.