Calcitonin for Treating X-linked Hypophosphatemia
Calcitonin for Treating X-linked Hypophosphatemia
X-linked hypophosphatemia (XLH) is the most common form of inherited rickets in the United
 States. It also causes bone disease in adults. 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 US, can lower blood levels of FGF23 and
 reduce phosphate wasting in patients with XLH. In this study the investigators will:

 1. Determine whether nasal calcitonin significantly lowers integrated 24-hour blood levels
 of FGF23 in patients with XLH.

 2. Evaluate whether nasal calcitonin improves serum phosphate levels in XLH.

 3. Assess whether nasal calcitonin improves blood levels of the active form of vitamin D
 and calcium absorption from the intestine.

 4. Make sure that nasal calcitonin is safe and well tolerated.
The pathophysiology of X-linked hypophosphatemia (XLH) was clarified with the report in 1995
 by the HYP Consortium led by Dr. Michael Econs, that mutations in the neutral endopeptidase
 PHEX, are the genetic basis for this disorder (Nature Genetics 11:130). 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 the major sodium phosphate co-transporters in the proximal renal tubule. In addition, it
 suppresses 1-α hydroxylase activity leading low to low-normal serum levels of
 1,25(OH)2vitamin D. This in turn impairs intestinal phosphate and calcium absorption. These
 combined biochemical abnormalities lead to persistent defects in skeletal mineralization
 manifested as rickets in children and osteomalacia in adults. Conventional therapy for XLH
 consists of oral therapy with phosphate supplements and calcitriol and requires ingestion of
 medications 4-6 times daily. There are several limitations to conventional therapy including
 its inability to correct growth retardation in children or the enthesopathy so frequently
 seen in adults. Furthermore, it is now clear that this therapeutic approach causes a further
 rise in circulating levels of FGF23 in XLH. Thus, there is an urgent need for more
 appropriate therapy directed at the basic pathophysiology of this disorder. 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 that persists for 16 hours 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 data are very exciting as they 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, will improve phosphate homeostasis in patients with XLH.
 To test this hypothesis we will pursue the following specific aims: 1. Determine whether 3
 months of nasal calcitonin administered at a dose of 400 IU/day significantly lowers
 integrated 24-hour 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-hour 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.
Inclusion Criteria:

 -  age ≥18 or greater

 -  an established diagnosis of XLH

 -  fasting serum calcium ≤10.5 mg/dl

 -  fasting PTH at time of screen </= 1.7 times the upper limit of normal

 Exclusion Criteria:

 -  estimated creatinine clearance < 60 cc/min and/or serum creatinine > 1.5 mg/dl;

 -  serum 25(OH)vitamin D < 30 ng/ml. Potential study subjects who have a serum
 25(OH)vitamin D < 30 ng/ml will be supplemented with 25(OH)vitamin D to achieve a
 serum value > 30 ng/ml and then re- screened

 -  inability to comply with instructions and appropriate follow up visits

 -  treatment with agents that may skeletal metabolism such as glucocorticoids,
 bisphosphonates, denosumab, teriparatide, estrogen and anticonvulsants.