7 Day Continuous Parathyroid Hormone IV Infusion
| Status: | Completed |
|---|---|
| Conditions: | Osteoporosis, Endocrine, Endocrine |
| Therapuetic Areas: | Endocrinology, Rheumatology |
| Healthy: | No |
| Age Range: | 24 - 35 |
| Updated: | 4/21/2016 |
| Start Date: | September 2006 |
| End Date: | December 2007 |
Determining the Maximal Safe Dose of a Continuous Infusion of Parathyroid Hormone(1-34): Effects on Bone Formation
Study consists of an eight day inpatient visit on the General Clinical Research Center. The
investigators' specific aims are to:
1. To define the maximum safe dose of a seven day continuous administration of parathyroid
hormone [PTH(1-34)] in healthy human volunteers.
2. To estimate the effect of a seven day continuous administration of parathyroid Hormone
(PTH) in escalating doses on vitamin D metabolism, markers of bone turnover and
fractional excretion of urine.
investigators' specific aims are to:
1. To define the maximum safe dose of a seven day continuous administration of parathyroid
hormone [PTH(1-34)] in healthy human volunteers.
2. To estimate the effect of a seven day continuous administration of parathyroid Hormone
(PTH) in escalating doses on vitamin D metabolism, markers of bone turnover and
fractional excretion of urine.
This study will expand upon earlier infusions studies that demonstrated: 1) There is a
dose-related increase in 1,25 (OH)2 vitamin D in response to PTHrP and PTH over multiple
days. 2) There is a markedly attenuated vitamin D response to PTHrP compared to PTH,
particularly during the second 24 hours. 3) The increase in 1,25 (OH)2 vitamin D is almost
certainly responsible for the greater calcemic effect of PTH compared to PTHrP. 4) PTHrP is
obviously a weaker agonist of 1,25 (OH)2 vitamin D but does not result in its suppression as
is seen in Humoral Hypercalcemia of Malignancy (HHM). Thus, the suppression of 1,25 (OH)2
vitamin D seen in HHM remained unexplained. In addition to assessing the effects of an
infusion of PTHrP and PTH on calcium handling and 1,25(OH)2 vitamin D, we also measured
their effects on markers of bone turnover. Given the clinical observations seen in
Hyperparathyroidism (HPT) and HHM, we anticipated that PTH would stimulate both bone
resorption and formation, while PTHrP would stimulate bone resorption but inhibit formation.
However, we observed that infusions of PTHrP and PTH resulted in an equivalent, rapid
increase in bone resorption as measured by N-telopeptide (NTx) and C-telopeptide (CTx), as
well as a progressive decline in bone formation. There was no difference between PTH and
PTHrP. We assumed that formation would ultimately increase with additional time, as seen in
HPT, and therefore examined an additional group of subjects infused with PTHrP for 96 hours.
However, N-terminal propeptide of type 1 procollagen (P1NP) continued to decline even
further as is seen in HHM in contrast to HPT. We have not yet studied longer infusions of
PTH.
One of the reasons for doing this pilot study is to determine the optimal dosing of PTH over
a week period of time. Intravenous PTH has never been infused into human beings for
prolonged periods of time. The investigators question whether a prolonged continuous
intravenous infusion of PTH will lead to a sustained and progressive suppression of bone
formation as occurs in HHM or an increase in bone formation as occurs in HPT. They also want
to assess the direct influence of long-term continuous PTH infusions on plasma 1,25 (OH)2
vitamin D regulation in healthy human volunteers. We have shown in our previous studies that
doses of 8 picomoles (pmol)/kg/hr PTH given over 48 hours result in sustained mild serum
hypercalcemia, with serum calcium seeming to plateau in the range of 11 - 11.5 mg/dL after
48 hours. A dose of 8 picomoles (pmol)/kg/hr has also been shown to cause desirable effects
on serum 1,25(OH)2 vitamin D and markers of bone turnover, and may therefore be the "ideal"
dose. However, we do not know whether serum calcium will plateau after an infusion of 48
hours with escalating doses or whether it will continue to increase over seven days.
To determine what will happen with a prolonged infusion, we plan to start with doses lower
than 8 picomoles (pmol)/kg/hr, and then gradually increase the dose of PTH in successive
groups of subjects. In the event of a significant adverse effect, immediate action will be
taken to reverse it. Protocols will be in place to follow in the event of expected adverse
events such as hypotension, nausea, and muscle cramping. Severe sudden side effects are not
anticipated; however, mild easily reversible side effects are to be expected as an outcome
in order to determine the optimal dose of PTH. This study has been approved by the NIH and
the Data Safety Monitoring Board (DSMB).
Seventy five normal healthy men and women will be screened for an eight day in-patient
admission to the General Clinical Research Center (GCRC). Thirty evaluable research
participants will receive a seven day infusion of a predetermined dose of PTH. Vitals signs,
blood pressure, blood and urine lab results will be monitored frequently as per the study
flow sheet. The starting dose of PTH, 2 picomoles (pmol)/kg, will be given to three normal
healthy subjects. The dose will be escalated in increments with successive groups of three
subjects each, until early adverse effects (mild hypercalcemia, postural hypotension,
tachycardia) are seen. This dose will then be used in future studies. The investigators with
this study are trying to discover if a prolonged continuous intravenous infusion of PTH will
lead to a sustained and progressive suppression of bone formation as occurs in HHM or an
increase in bone formation as occurs in HPT.
Subject Population will consist of healthy young adults, ages 24-35 years, as in our other
safety and physiologic studies. It is anticipated that we will need to screen 75 subjects in
order to obtain 30 evaluable subjects.
dose-related increase in 1,25 (OH)2 vitamin D in response to PTHrP and PTH over multiple
days. 2) There is a markedly attenuated vitamin D response to PTHrP compared to PTH,
particularly during the second 24 hours. 3) The increase in 1,25 (OH)2 vitamin D is almost
certainly responsible for the greater calcemic effect of PTH compared to PTHrP. 4) PTHrP is
obviously a weaker agonist of 1,25 (OH)2 vitamin D but does not result in its suppression as
is seen in Humoral Hypercalcemia of Malignancy (HHM). Thus, the suppression of 1,25 (OH)2
vitamin D seen in HHM remained unexplained. In addition to assessing the effects of an
infusion of PTHrP and PTH on calcium handling and 1,25(OH)2 vitamin D, we also measured
their effects on markers of bone turnover. Given the clinical observations seen in
Hyperparathyroidism (HPT) and HHM, we anticipated that PTH would stimulate both bone
resorption and formation, while PTHrP would stimulate bone resorption but inhibit formation.
However, we observed that infusions of PTHrP and PTH resulted in an equivalent, rapid
increase in bone resorption as measured by N-telopeptide (NTx) and C-telopeptide (CTx), as
well as a progressive decline in bone formation. There was no difference between PTH and
PTHrP. We assumed that formation would ultimately increase with additional time, as seen in
HPT, and therefore examined an additional group of subjects infused with PTHrP for 96 hours.
However, N-terminal propeptide of type 1 procollagen (P1NP) continued to decline even
further as is seen in HHM in contrast to HPT. We have not yet studied longer infusions of
PTH.
One of the reasons for doing this pilot study is to determine the optimal dosing of PTH over
a week period of time. Intravenous PTH has never been infused into human beings for
prolonged periods of time. The investigators question whether a prolonged continuous
intravenous infusion of PTH will lead to a sustained and progressive suppression of bone
formation as occurs in HHM or an increase in bone formation as occurs in HPT. They also want
to assess the direct influence of long-term continuous PTH infusions on plasma 1,25 (OH)2
vitamin D regulation in healthy human volunteers. We have shown in our previous studies that
doses of 8 picomoles (pmol)/kg/hr PTH given over 48 hours result in sustained mild serum
hypercalcemia, with serum calcium seeming to plateau in the range of 11 - 11.5 mg/dL after
48 hours. A dose of 8 picomoles (pmol)/kg/hr has also been shown to cause desirable effects
on serum 1,25(OH)2 vitamin D and markers of bone turnover, and may therefore be the "ideal"
dose. However, we do not know whether serum calcium will plateau after an infusion of 48
hours with escalating doses or whether it will continue to increase over seven days.
To determine what will happen with a prolonged infusion, we plan to start with doses lower
than 8 picomoles (pmol)/kg/hr, and then gradually increase the dose of PTH in successive
groups of subjects. In the event of a significant adverse effect, immediate action will be
taken to reverse it. Protocols will be in place to follow in the event of expected adverse
events such as hypotension, nausea, and muscle cramping. Severe sudden side effects are not
anticipated; however, mild easily reversible side effects are to be expected as an outcome
in order to determine the optimal dose of PTH. This study has been approved by the NIH and
the Data Safety Monitoring Board (DSMB).
Seventy five normal healthy men and women will be screened for an eight day in-patient
admission to the General Clinical Research Center (GCRC). Thirty evaluable research
participants will receive a seven day infusion of a predetermined dose of PTH. Vitals signs,
blood pressure, blood and urine lab results will be monitored frequently as per the study
flow sheet. The starting dose of PTH, 2 picomoles (pmol)/kg, will be given to three normal
healthy subjects. The dose will be escalated in increments with successive groups of three
subjects each, until early adverse effects (mild hypercalcemia, postural hypotension,
tachycardia) are seen. This dose will then be used in future studies. The investigators with
this study are trying to discover if a prolonged continuous intravenous infusion of PTH will
lead to a sustained and progressive suppression of bone formation as occurs in HHM or an
increase in bone formation as occurs in HPT.
Subject Population will consist of healthy young adults, ages 24-35 years, as in our other
safety and physiologic studies. It is anticipated that we will need to screen 75 subjects in
order to obtain 30 evaluable subjects.
Inclusion Criteria:
- Healthy Caucasian, Hispanic or Asian subjects
- Males and Females
- Non-smoker
- Ages 24 - 35 years old
- Subjects will be recruited either from the employee pool of the University of
Pittsburgh or the University of Pittsburgh Medical Center (UPMC), or the general
population living in the vicinity.
- Participation in this study by an employee or a potential employee at the University
of Pittsburgh or UPMC has no effect on their employment or potential employment.
- Participants in the study will be required to discontinue all vitamins and health
food supplements two weeks prior to the study.
Exclusion Criteria:
- Cardiac, hypertensive, vascular, renal (serum creatinine of >1.5), pulmonary,
endocrine, musculoskeletal, hepatic, hematologic or malignant or rheumatologic
disease
- Body Mass Index (BMI) > 30,
- Anemia (hematocrit less than 36% in women, less than 40% in men),
- Pregnancy (all women will have a urine pregnancy test performed immediately before
starting the study and must not be pregnant)
- Significant alcohol or drug abuse or
- Baseline hypotension (systolic blood pressure less than 90 mm/Hg).
- Subjects will be excluded for abnormal levels of any of the screening labs including:
ionized and total serum calcium, phosphorus, creatinine, albumin, 25-hydroxyvitamin
D, and PTH. Pregnancy
- Subjects taking any chronic medications except oral contraceptives and stable doses
of thyroid hormone, or those who have received any investigational drug in past 90
days will be excluded from the study.
- Subjects may not participate in this study more than once.
- Any subject who has previously received PTH or PTHrP, a related peptide, may not
participate in this study.
Minority Inclusion/Exclusion Statement: We will not include African-Americans because this
group has been demonstrated by a number of investigators to display resistance to PTH, and
may create wider statistical variation and a need for larger numbers of study subjects per
group.
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