DESCRIPTION (provided by applicant): The pathophysiology of X-linked hypophosphatemia (XLH) was clarified with the report in 1995 by the HYP Consortium that mutations in the neutral endopeptidase PHEX are the genetic basis for this disorder. By a pathway that remains unclear, loss-of-function mutations in PHEX lead to elevated circulating levels of FGF23. It is now well established that FGF23 is the proximate biological mediator of this syndrome. FGF23 suppresses renal tubular phosphate reabsorption by inhibiting transcription of sodium phosphate co-transporters in the proximal renal tubule. It also suppresses 1-1 hydroxylase activity leading to low or low-normal serum levels of 1,25(OH)2vitamin D, which impairs intestinal phosphate and calcium absorption. These combined biochemical abnormalities result in defective skeletal mineralization manifested as rickets in children and osteomalacia in adults. Conventional therapy for XLH with oral phosphate and calcitriol has several limitations including a low therapeutic/toxicity ratio, and a failure to correct growth retardation in children or the enthesopathy seen in adults. In addition, this treatment regimen causes a further rise in circulating levels of FGF23. Thus, there is a pressing need for better therapy directed at the basic pathophysiology of XLH. As detailed in the Research Strategy, we have identified calcitonin as a novel suppressor of FGF23 production in XLH. A single, subcutaneous injection of calcitonin results in a sustained fall in FGF23 levels in patients with this disease that persists for 16 hrs after drug administration; a change not observed in control subjects. The fall in serum FGF23 is associated with a rise in serum phosphate and circulating levels of 1,25(OH)2vitamin D. These exciting data suggest a novel therapy for XLH. This exploratory clinical trial seeks to establish the efficacy of calcitonin in improving the biochemical abnormalities in untreated adults with XLH. We will test the hypothesis that calcitonin, by lowering circulating levels of FGF23 and raising serum levels of 1,25(OH)2vitamin D, improves phosphate homeostasis in XLH by pursuing the following specific aims: 1. Determine whether 3 months of nasal calcitonin administered at a dose of 400 IU/day significantly lowers integrated 24-hr serum levels of FGF23 in patients with XLH. 2. Evaluate whether nasal calcitonin improves phosphate homeostasis by raising the TmP/GFR and integrated 24 hr serum phosphate concentrations. 3. Assess whether nasal calcitonin improves calcium metabolism in patients with XLH by increasing integrated 24 hr serum levels of 1,25(OH)2vitamin D and enhancing intestinal calcium absorption, as estimated by 24-hr urine calcium. 4. Confirm that nasal calcitonin is well tolerated by quantifying side effects and nasal irritation during the trial. If successful, this study will provide proof-of-principal for the novel use of an FDA-approved drug in treating XLH. This approach, unlike conventional treatment, addresses the underlying pathophysiology in this disorder and would represent the first therapeutic advance for XLH in 30 years. PUBLIC HEALTH RELEVANCE: X-linked hypophosphatemia (XLH) is the most common form of inherited rickets and osteomalacia in the United States. XLH is caused by overproduction of a hormone call FGF23, which makes the body waste phosphate. This study is designed to determine if nasal calcitonin, an already approved drug in the USA, can lower blood levels of FGF23 and reduce phosphate wasting in patients with XLH.

X-linked hypophosphatemia (XLH) is the most common form of inherited rickets and osteomalacia in the United States. XLH is caused by overproduction of a hormone call FGF23, which makes the body waste phosphate. This study is designed to determine if nasal calcitonin, an already approved drug in the USA, can lower blood levels of FGF23 and reduce phosphate wasting in patients with XLH.