7 Day Continuous Parathyroid Hormone IV Infusion
Condition: Osteoporosis; Bone Diseases, Endocrine; Hyperparathyroidism
MeSH terms: Osteoporosis; Bone Diseases; Bone Diseases, Endocrine; Hyperparathyroidism; Endocrine System Diseases
Study type: Interventional
Phase: Early Phase 1

Summary: 
      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.
    

Detailed description: 
      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.
    

Intervention name(s): Parathyroid Hormone (1-34)
Intervention type(s): Drug
Intervention description(s): PTH(1-34) IV given over a one week period
Other intervention name(s): IND 60,979
Intervention MeSH terms: Hormones; Parathyroid Hormone
Intervention model: Single Group Assignment
Masking: Single (Participant)
Keywords: Endocrine System Diseases; MusculoSkeletal System Disease; Hormone; Physiologic Properties