Calcitonin for Treating X-linked Hypophosphatemia
Condition: Hypophosphatemic Rickets, X Linked Dominant
MeSH terms: Rickets; Familial Hypophosphatemic Rickets; Rickets, Hypophosphatemic; Hypophosphatemia
Study type: Interventional

Summary: 
      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.
    

Detailed description: 
      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.
    

Intervention name(s): nasal salmon calcitonin; Saline Nasal Spray Placebo
Intervention type(s): Drug; Drug
Intervention description(s): 400 IU daily in two sprays (one to each nares)
Other intervention name(s): Miacalcin; Fortical
Intervention MeSH terms: Calcitonin; Salmon calcitonin; Calcitonin Gene-Related Peptide; Katacalcin
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Double (Participant, Investigator)
Primary purpose: Treatment
Keywords: X linked hypophosphatemia; calcitonin; FGF twenty three