7 Day Continuous Parathyroid Hormone IV Infusion

Osteoporosis Clinical Trial

Official title:

Determining the Maximal Safe Dose of a Continuous Infusion of Parathyroid Hormone(1-34): Effects on Bone Formation

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT00377312
• Other study ID #: 0606127
• Secondary ID: R01DK073039
• Status: Completed
• Phase: Phase 0
• First received: September 14, 2006
• Last updated: July 6, 2012
• Start date: September 2006
• Est. completion date: December 2007

Study information

• Verified date: July 2012
• Source: University of Pittsburgh
• Contact: n/a
• Is FDA regulated: No
• Health authority: United States: Food and Drug Administration
• Study type: Interventional

Clinical Trial 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 PTH in escalating doses on vitamin D metabolism, markers of bone turnover and fractional excretion of urine.

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 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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 19
• Est. completion date: December 2007
• Est. primary completion date: December 2007
• Accepts healthy volunteers: Accepts Healthy Volunteers
• Gender: Both
• Age group: 24 Years to 35 Years

Eligibility

Inclusion Criteria: Healthy Caucasian, Hispanic or Asian subjects of both sexes who are non-smokers and between the ages of 24 - 35 years old will be included in the study. Subjects will be recruited either from the employee pool of the University of Pittsburgh or 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. All women will have a urine pregnancy test performed immediately before starting the study and must not be pregnant.

Exclusion Criteria:Exclusion Criteria: Subjects with cardiac, hypertensive, vascular, renal (serum creatinine of >1.5), pulmonary, endocrine, musculo-skeletal, hepatic, hematologic or malignant or rheumatologic disease will be excluded from the study. Additional exclusion criteria will include: a Body Mass Index (BMI) > 30, anemia (hematocrit less than 36% in women, less than 40% in men), pregnancy, or 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. Also, 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. In addition, 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.

Study Design

Endpoint Classification: Safety/Efficacy Study, Intervention Model: Single Group Assignment, Masking: Single Blind (Subject), Primary Purpose: Treatment

Related Conditions & MeSH terms

• Bone Diseases
• Bone Diseases, Endocrine
• Endocrine System Diseases
• Hyperparathyroidism
• Osteoporosis

Intervention

Drug:
• parathyroid hormone (1-34)
2 pmols/kg/hr and greater

Locations

Country	Name	City	State
United States	University of Pittsburgh Medical Center	Pittsburgh,	Pennsylvania

Sponsors (2)

Lead Sponsor	Collaborator
University of Pittsburgh	National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)

Country where clinical trial is conducted

United States, 

References & Publications (26)

Burtis WJ, Wu T, Bunch C, Wysolmerski JJ, Insogna KL, Weir EC, Broadus AE, Stewart AF. Identification of a novel 17,000-dalton parathyroid hormone-like adenylate cyclase-stimulating protein from a tumor associated with humoral hypercalcemia of malignancy. J Biol Chem. 1987 May 25;262(15):7151-6. — View Citation

Chapotot F, Gronfier C, Spiegel K, Luthringer R, Brandenberger G. Relationships between intact parathyroid hormone 24-hour profiles, sleep-wake cycle, and sleep electroencephalographic activity in man. J Clin Endocrinol Metab. 1996 Oct;81(10):3759-65. — View Citation

Cosman F, Shen V, Xie F, Seibel M, Ratcliffe A, Lindsay R. Estrogen protection against bone resorbing effects of parathyroid hormone infusion. Assessment by use of biochemical markers. Ann Intern Med. 1993 Mar 1;118(5):337-43. Erratum in: Ann Intern Med 1994 Apr 15;120(8):698. — View Citation

el-Hajj Fuleihan G, Klerman EB, Brown EN, Choe Y, Brown EM, Czeisler CA. The parathyroid hormone circadian rhythm is truly endogenous--a general clinical research center study. J Clin Endocrinol Metab. 1997 Jan;82(1):281-6. — View Citation

Everhart-Caye M, Inzucchi SE, Guinness-Henry J, Mitnick MA, Stewart AF. Parathyroid hormone (PTH)-related protein(1-36) is equipotent to PTH(1-34) in humans. J Clin Endocrinol Metab. 1996 Jan;81(1):199-208. — View Citation

Fraher LJ, Hodsman AB, Jonas K, Saunders D, Rose CI, Henderson JE, Hendy GN, Goltzman D. A comparison of the in vivo biochemical responses to exogenous parathyroid hormone-(1-34) [PTH-(1-34)] and PTH-related peptide-(1-34) in man. J Clin Endocrinol Metab. 1992 Aug;75(2):417-23. — View Citation

Harms HM, Schlinke E, Neubauer O, Kayser C, Wüstermann PR, Horn R, Külpmann WR, von zur Mühlen A, Hesch RD. Pulse amplitude and frequency modulation of parathyroid hormone in primary hyperparathyroidism. J Clin Endocrinol Metab. 1994 Jan;78(1):53-7. — View Citation

Henry JG, Mitnick M, Dann PR, Stewart AF. Parathyroid hormone-related protein-(1-36) is biologically active when administered subcutaneously to humans. J Clin Endocrinol Metab. 1997 Mar;82(3):900-6. — View Citation

Hodsman AB, Fraher LJ, Ostbye T, Adachi JD, Steer BM. An evaluation of several biochemical markers for bone formation and resorption in a protocol utilizing cyclical parathyroid hormone and calcitonin therapy for osteoporosis. J Clin Invest. 1993 Mar;91(3):1138-48. — View Citation

Horwitz MJ, Tedesco MB, Gundberg C, Garcia-Ocana A, Stewart AF. Short-term, high-dose parathyroid hormone-related protein as a skeletal anabolic agent for the treatment of postmenopausal osteoporosis. J Clin Endocrinol Metab. 2003 Feb;88(2):569-75. — View Citation

Horwitz MJ, Tedesco MB, Sereika SM, Garcia-Ocaña A, Bisello A, Hollis BW, Gundberg C, Stewart AF. Safety and tolerability of subcutaneous PTHrP(1-36) in healthy human volunteers: a dose escalation study. Osteoporos Int. 2006 Feb;17(2):225-30. Epub 2005 Sep 7. — View Citation

Horwitz MJ, Tedesco MB, Sereika SM, Hollis BW, Garcia-Ocaña A, Stewart AF. Direct comparison of sustained infusion of human parathyroid hormone-related protein-(1-36) [hPTHrP-(1-36)] versus hPTH-(1-34) on serum calcium, plasma 1,25-dihydroxyvitamin D concentrations, and fractional calcium excretion in healthy human volunteers. J Clin Endocrinol Metab. 2003 Apr;88(4):1603-9. — View Citation

Horwitz MJ, Tedesco MB, Sereika SM, Syed MA, Garcia-Ocaña A, Bisello A, Hollis BW, Rosen CJ, Wysolmerski JJ, Dann P, Gundberg C, Stewart AF. Continuous PTH and PTHrP infusion causes suppression of bone formation and discordant effects on 1,25(OH)2 vitamin D. J Bone Miner Res. 2005 Oct;20(10):1792-803. Epub 2005 Jun 6. — View Citation

Jüppner H, Abou-Samra AB, Freeman M, Kong XF, Schipani E, Richards J, Kolakowski LF Jr, Hock J, Potts JT Jr, Kronenberg HM, et al. A G protein-linked receptor for parathyroid hormone and parathyroid hormone-related peptide. Science. 1991 Nov 15;254(5034):1024-6. — View Citation

Ledger GA, Burritt MF, Kao PC, O'Fallon WM, Riggs BL, Khosla S. Role of parathyroid hormone in mediating nocturnal and age-related increases in bone resorption. J Clin Endocrinol Metab. 1995 Nov;80(11):3304-10. — View Citation

Orloff JJ, Ribaudo AE, McKee RL, Rosenblatt M, Stewart AF. A pharmacological comparison of parathyroid hormone receptors in human bone and kidney. Endocrinology. 1992 Oct;131(4):1603-11. — View Citation

Orloff JJ, Wu TL, Heath HW, Brady TG, Brines ML, Stewart AF. Characterization of canine renal receptors for the parathyroid hormone-like protein associated with humoral hypercalcemia of malignancy. J Biol Chem. 1989 Apr 15;264(11):6097-103. — View Citation

Plawner LL, Philbrick WM, Burtis WJ, Broadus AE, Stewart AF. Cell type-specific secretion of parathyroid hormone-related protein via the regulated versus the constitutive secretory pathway. J Biol Chem. 1995 Jun 9;270(23):14078-84. — View Citation

Plotkin H, Gundberg C, Mitnick M, Stewart AF. Dissociation of bone formation from resorption during 2-week treatment with human parathyroid hormone-related peptide-(1-36) in humans: potential as an anabolic therapy for osteoporosis. J Clin Endocrinol Metab. 1998 Aug;83(8):2786-91. — View Citation

Prank K, Nowlan SJ, Harms HM, Kloppstech M, Brabant G, Hesch RD, Sejnowski TJ. Time series prediction of plasma hormone concentration. Evidence for differences in predictability of parathyroid hormone secretion between osteoporotic patients and normal controls. J Clin Invest. 1995 Jun;95(6):2910-9. — View Citation

Samuels MH, Veldhuis J, Cawley C, Urban RJ, Luther M, Bauer R, Mundy G. Pulsatile secretion of parathyroid hormone in normal young subjects: assessment by deconvolution analysis. J Clin Endocrinol Metab. 1993 Aug;77(2):399-403. — View Citation

Schmitt CP, Obry J, Feneberg R, Veldhuis JD, Mehls O, Ritz E, Schaefer F. Beta1-adrenergic blockade augments pulsatile PTH secretion in humans. J Am Soc Nephrol. 2003 Dec;14(12):3245-50. — View Citation

Stewart AF, Cain RL, Burr DB, Jacob D, Turner CH, Hock JM. Six-month daily administration of parathyroid hormone and parathyroid hormone-related protein peptides to adult ovariectomized rats markedly enhances bone mass and biomechanical properties: a comparison of human parathyroid hormone 1-34, parathyroid hormone-related protein 1-36, and SDZ-parathyroid hormone 893. J Bone Miner Res. 2000 Aug;15(8):1517-25. — View Citation

Stewart AF, Wu T, Goumas D, Burtis WJ, Broadus AE. N-terminal amino acid sequence of two novel tumor-derived adenylate cyclase-stimulating proteins: identification of parathyroid hormone-like and parathyroid hormone-unlike domains. Biochem Biophys Res Commun. 1987 Jul 31;146(2):672-8. — View Citation

Syed MA, Horwitz MJ, Tedesco MB, Garcia-Ocaña A, Wisniewski SR, Stewart AF. Parathyroid hormone-related protein-(1--36) stimulates renal tubular calcium reabsorption in normal human volunteers: implications for the pathogenesis of humoral hypercalcemia of malignancy. J Clin Endocrinol Metab. 2001 Apr;86(4):1525-31. — View Citation

Wu TL, Vasavada RC, Yang K, Massfelder T, Ganz M, Abbas SK, Care AD, Stewart AF. Structural and physiologic characterization of the mid-region secretory species of parathyroid hormone-related protein. J Biol Chem. 1996 Oct 4;271(40):24371-81. — View Citation

* Note: There are 26 references in all — Click here to view all references

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Blood collections for safety measurements including serum ionized and total calcium, phosphorus and creatinine		one week	Yes
Secondary	Blood collections analyzed for measurements of PTH(1-34), PTH(1-84), 25-hydroxy Vitamin D, 1,25 (OH)2 vitamin D and markers of bone turnover.		one week	No

External Links

•   University of Pittsburgh's clinical research study website.