Physiologic Regulation of FGF-23
Physiologic Regulation of FGF-23
This study will explore the regulation of fibroblast growth factor-23 (FGF-23). It is a
 hormone recently identified as a regulator of the blood levels of phosphorus and vitamin D,
 both of which are essential for overall health and especially important for bone health. The
 parathyroid hormone (PTH) regulates phosphorus and calcium, but people with
 hypoparathyroidism or pseudohypoparathyroidism do not have sufficient PTH action. There are
 genetic diseases that influence FGF-23, causing abnormal metabolism of phosphorus and vitamin
 D, thus affecting the bones. Also, there are rare tumors that may cause overproduction of
 FGF-23 causing debilitating bone disease.

 Patients ages 18 and older who have low PTH levels, or are resistant to PTH action, and take
 calcitriol and calcium supplements, who are not pregnant, and who do not have kidney
 disorders may be eligible for this study. During the 4-day study, patients will be provided
 with a controlled diet that has a lower than usual phosphorus content. On day 1, patients
 will be admitted to the NIH Clinic Center and undergo blood and urine tests to measure
 calcium, phosphorus, vitamin D, and FGF-23. They will continue with their regular medicine
 for hypoparathyroidism. On that day and throughout the study, patients will fast from 10:00
 p.m. to 8:00 a.m. the following day. On day 2, patients will continue fasting until 4:00 p.m.
 A tube will be placed in the vein of each arm: one for drawing blood and the other for
 infusing calcium. Just one intravenous (IV) line will be used on the other days. Patients
 will receive calcium chloride for 8 hours, at a dose carefully monitored by a machine. The
 purpose is to bring the blood calcium level to the high normal range or just above. Blood and
 urine samples will be collected periodically, to check for effects of calcium chloride on
 FGF-23 and PTH. On days 3 and 4, patients will not take calcitriol and calcium but will
 receive injections of PTH, under the skin, two times each day. On day 3, blood and urine
 samples will be again be collected for analysis. On day 4, patients will receive one dose of
 calcitriol by IV. The total amount of blood drawn during this study will be about 5 ounces.

 ...
Vitamin D and phosphate are central to normal mineral homeostasis and important in many
 physiologic functions including skeletal integrity. For several decades parathyroid hormone
 (PTH) has been recognized as a central regulator of serum vitamin D and phosphate levels.
 Recently, FGF-23 has been identified as central in the regulation of the metabolism of
 vitamin D and serum phosphorus. The organ primarily responsible for the physiologic
 production of FGF-23 appears to be the skeleton. The study of FGF-23 metabolism and its
 direct effect on mineral metabolism is confounded by the classic endocrine feedback loops
 that exist among serum calcium, phosphorus, 1,25-(OH)2-vitamin D (1,25-D), and PTH. It is
 possible that any of these (phosphorus, calcium, 1,25-D, and/or PTH) are important in the
 regulation of serum FGF-23. The goal of this study is to identify what factors regulate serum
 FGF-23.

 To overcome the confounding effect of PTH, we will study patients deficient in PTH
 (hypoparathyroidism) or resistant to PTH at the kidney (pseudohypoparathyroidism type 1B,
 PHP1B). The kidney is one of the primary organs responsible for regulating serum phosphorus
 and generating 1,25-D. It is the target of PTH and FGF-23. While patients with PHP1B are
 resistant to the action of PTH at the kidney, they are sensitive to the action of PTH at the
 bone, the tissue that produces FGF-23. Physiologic manipulation of the serum phosphorus,
 1,25-D, calcium, and PTH in subjects with hypoparathyroidism or PHP1B will allow for a nearly
 complete dissection of the factors that are potential regulators of serum FGF-23.
-  INCLUSION CRITERIA

 Adult hypoparathyroid patients, as defined by low or inappropriately normal PTH levels
 despite hypocalcemia, who are on a stable treatment regimen of calcitriol and calcium
 supplementation, and who are willing to participate in the study will be eligible.

 Adult PHP1B patients as defined by the clinical syndrome of elevated PTH and phosphorus and
 confirmed by methylation analysis of the GNAS gene.

 EXCLUSION CRITERIA

 Renal insufficiency as evidenced by a creatinine clearance of less than 50 ml/min

 Medically unstable patients

 Uncontrolled comorbid conditions, e.g., diabetes, coronary artery disease, congestive heart
 failure, or cerebrovascular disease.

 Digitalis therapy

 Patients on diuretic therapy, especially thiazides

 Pregnant and lactating women

 Patients whose hypoparathyroidism is caused by severe calcium-sensing receptor defects.
 These patients begin to have marked symptoms of "hypercalcemia" when the serum calcium is
 in the mid-normal range.

 Patients under 18 years of age

 Patients with history of any bone cancer, skeletal metastases or previous radiotherapy to
 the skeleton, unexplained elevations of serum alkaline phosphatase