Calcitonin for Treating X-linked Hypophosphatemia

• Area under the curve for FGF23 [ Time Frame: Time 0 ] [ Designated as safety issue: No ]
  FGF23 will be measured serially during a 24 hour admission and AUC calculated.
  
  
• Area under the curve for FGF23 [ Time Frame: 3 months ] [ Designated as safety issue: No ]
  FGF23 will be measured serially during a 24 hour admission at 3 months and AUC calculated and compared to baseline.
  
  

• Area under the curve for serum phosphate and fasting TmP/GFR [ Time Frame: Time 0 ] [ Designated as safety issue: No ]
  Serum phosphate will be measured serially during a 24 hr admission, AUC calculated, and fasting Tmp/GFR calculated.
  
  
• Area under the curve for 1,25(OH)2vitamin D [ Time Frame: Time 0 ] [ Designated as safety issue: No ]
  Serum 1,25(OH)2vitamin D will be measured serially during a 24 hr admission and AUC calculated.
  
  
• Nasal congestion [ Time Frame: Time 0 ] [ Designated as safety issue: Yes ]
  This symptom will be assessed at baseline
  
  
• Area under the curve for serum phosphate and fasting TmP/GFR [ Time Frame: Time 3 months ] [ Designated as safety issue: No ]
  Serum phosphate will be measured serially during a 24 hr admission at 3 months and AUC calculated and compared to baseline. Fasting Tmp/GFR will be measured at 3 months and compared to baseline.
  
  
• Area under the curve for 1,25(OH)2vitamin D [ Time Frame: Time 3 months ] [ Designated as safety issue: No ]
  Serum 1,25(OH)2vitamin D will be measured serially during a 24 hr admission and AUC calculated and results will be compared to baseline values.
  
  
• Nasal congestion [ Time Frame: Time 1 month ] [ Designated as safety issue: Yes ]
  This symptom will be assessed.
  
  
• Nasal congestion [ Time Frame: Time 2 months ] [ Designated as safety issue: Yes ]
  This symptom will be assessed.
  
  
• Nasal congestion [ Time Frame: Time 3 months ] [ Designated as safety issue: Yes ]
  This symptom will be assessed.
  
  
• Nasal ulceration [ Time Frame: Time 0 ] [ Designated as safety issue: Yes ]
  This symptom will be assessed at baseline
  
  
• Allergic reactions [ Time Frame: Time 0 ] [ Designated as safety issue: Yes ]
  This symptom will be assessed at baseline
  
  
• Nasal ulceration [ Time Frame: Time 1 month ] [ Designated as safety issue: Yes ]
  This symptom will be assessed.
  
  
• Allergic reactions [ Time Frame: Time 1 month ] [ Designated as safety issue: Yes ]
  This symptom will be assessed.
  
  
• Nasal ulceration [ Time Frame: Time 2 months ] [ Designated as safety issue: Yes ]
  This symptom will be assessed.
  
  
• Allergic reactions [ Time Frame: Time 2 months ] [ Designated as safety issue: Yes ]
  This symptom will be assessed.
  
  
• Nasal ulceration [ Time Frame: Time 3 months ] [ Designated as safety issue: Yes ]
  This symptom will be assessed.
  
  
• Allergic reactions [ Time Frame: Time 3 months ] [ Designated as safety issue: Yes ]
  This symptom will be assessed.
  
  

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.