Calcitonin for Treating X-linked Hypophosphatemia

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
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.