Osteoporosis Clinical Trial
Official title:
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 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 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
NTx and 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, 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 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 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 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 DSMB.
Seventy five normal healthy men and women will be screened for an eight day in-patient
admission to the 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 picomols/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.
;
Endpoint Classification: Safety/Efficacy Study, Intervention Model: Single Group Assignment, Masking: Single Blind (Subject), Primary Purpose: Treatment
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