Cinacalcet for Fibroblast Growth Factor 23 (FGF23)-Mediated Hypophosphatemia (Hypophosphatemic Rickets)

Background: * Hypophosphatemia is a condition where a person has low levels of phosphorus in the blood. Low blood phosphorus can cause muscle and bone weakness (such as rickets) and teeth problems. One cause of the condition is having too much fibroblast growth factor 23 (FGF23). FGF23 is a hormone that causes the kidney to get rid of phosphorus in the urine. It can also prevent the body from making vitamin D, which helps the body absorb phosphorus in food. * Many people with low blood phosphorus take high doses of phosphorus and calcium medications. However, one side effect of these drugs is increased blood levels of parathyroid hormone (PTH). The drug cinacalcet can help lower PTH levels, which may decrease the amount of phosphorus lost in the urine and increase the phosphorus levels in the blood. Researchers want to see if cinacalcet can help blood phosphorus and decrease the amount of phosphorus supplements that people need to take. Objectives: \- To see if cinacalcet can be a safe and effective treatment for people with low phosphorus conditions due to high FGF23. Eligibility: \- Individuals between 18 and 70 years of age who have different forms of hypophosphatemic rickets and tumor-induced hypophosphatemia Design: * Participants will have up to 25 study visits over about 28 weeks. * Participants will be screened with a physical exam and medical history. Blood and urine samples will be collected. * Up to three more lab visits for blood and urine tests will be required before treatment. Imaging studies of the bones, spine, and kidneys will be performed. * Participants will have a 3-night hospital stay to start treatment. They will take cinacalcet once a day. Treatment will be monitored with frequent blood tests and imaging studies. * Participants will continue to take cinacalcet once a day for 3 weeks. They will have regular study visits to monitor the treatment. * There will be up to two other overnight hospital stays (1 to 3 nights) to adjust cinacalcet doses. The dose will increase until the maximum dose is reached, or side effects develop. * After the end of the cinacalcet study, participants will have several more followup visits to monitor the effects of treatment.

Sex

All

Minimum age

18 Years

Maximum age

70 Years

* INCLUSION CRITERIA:

  1. \<TAB\>Chronological age: 18-70 years
  2. \<TAB\>Diagnosis of a genetic form of FGF23-mediated hypophosphatemia:

     1. \<TAB\>X-linked hypophosphatemic rickets (XLH)
     2. \<TAB\>Autosomal dominant hypophosphatemic rickets (ADHR)
     3. \<TAB\>Autosomal recessive hypophosphatemic rickets (ARHR)

     Or, diagnosis of a non-genetic form of FGF23-mediated hypophosphatemia, i.e. tumor-induced osteomalacia (TIO)
  3. \<TAB\>Ability to understand and provide informed consent
  4. \<TAB\>Ability to complete the protocol scheduled assessments and medication regimen
  5. \<TAB\>Women of child-bearing potential (not surgically sterile via tubal ligation, bilateral oophorectomy or hysterectomy, or who are not postmenopausal for greater than or equal to 1 year) must agree to practice adequate contraception that may include, but is not limited to, abstinence, monogamous relationship with vasectomized partner, barrier methods such as condoms, diaphragms, spermicides, intrauterine devices, and licensed hormonal methods for the duration of the treatment portion of the study.

EXCLUSION CRITERIA:

1. \<TAB\>Chronic or recurrent hypocalcemia defined by a serum calcium \< 8.4 mg/dL (2.1 mmol/L)
2. \<TAB\>Tertiary hyperparathyroidism as evidenced by concurrent PTH and calcium levels above the upper limit of normal
3. \<TAB\>History of parathyroid surgery and/or hypoparathyroidism
4. \<TAB\>Hypercalciuria as defined as \> 4 mg/kg/day (0.1 mmol/kg/day) on optimized conventional therapy (as determined during SOC optimization phase)
5. \<TAB\>Moderate to severe hepatic insufficiency as defined by total bilirubin \> 2 mg/dL and serum albumin \< 3 g/dL and International Normalized Ratio (INR) \>2 OR presence of ascites or hepatic encephalopathy.
6. \<TAB\>A calculated eGFR \< 50 mL/min/1.73 m(2), using the CKD-EPI equation
7. \<TAB\>History of a non-febrile seizure disorder
8. \<TAB\>History of a clinically significant cardiac arrhythmia
9. \<TAB\>History of chronic gastrointestinal disease
10. \<TAB\>Current therapy (at the time of informed consent) bisphosphonates, calcitonin, diuretics or medications that may have a significant drug interaction with cinacalcet
11. \<TAB\>Known hypersensitivity to cinacalcet or any of its constituents
12. \<TAB\>Positive pregnancy test or lactation
13. \<TAB\>Use of another investigational agent (i.e., in the context of a clinical trial, use of an investigational product that may have impact on the study) within the last 3 months

• BACKGROUNDChen L, Liu H, Sun W, Bai X, Karaplis AC, Goltzman D, Miao D. Fibroblast growth factor 23 overexpression impacts negatively on dentin mineralization and dentinogenesis in mice. Clin Exp Pharmacol Physiol. 2011 Jun;38(6):395-402. doi: 10.1111/j.1440-1681.2011.05526.x. PMID 21488937
• BACKGROUNDMakitie O, Doria A, Kooh SW, Cole WG, Daneman A, Sochett E. Early treatment improves growth and biochemical and radiographic outcome in X-linked hypophosphatemic rickets. J Clin Endocrinol Metab. 2003 Aug;88(8):3591-7. doi: 10.1210/jc.2003-030036. PMID 12915641
• BACKGROUNDBastepe M, Juppner H. Inherited hypophosphatemic disorders in children and the evolving mechanisms of phosphate regulation. Rev Endocr Metab Disord. 2008 Jun;9(2):171-80. doi: 10.1007/s11154-008-9075-3. Epub 2008 Mar 26. PMID 18365315