Physiologic Regulation of FGF-23
| Status: | Completed |
|---|---|
| Conditions: | Endocrine |
| Therapuetic Areas: | Endocrinology |
| Healthy: | No |
| Age Range: | 18 - Any |
| Updated: | 4/21/2016 |
| Start Date: | July 2006 |
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.
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.
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
We found this trial at
1
site
9000 Rockville Pike
Bethesda, Maryland 20892
Bethesda, Maryland 20892
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