One Week Comparison Study of PTH and PTHrP Infusions

• ClinicalTrials.gov Identifier: NCT01333267
• Recruitment Status: Withdrawn
• First Posted: April 11, 2011
• Last Update Posted: December 5, 2014
• Sponsor: University of Pittsburgh
• Information provided by (Responsible Party): Mara Horwitz, University of Pittsburgh

Study Description

Brief Summary:

This is a dose escalation study to determine the maximum tolerable dose of Parathyroid Hormone-related Protein, PTHrP, or Parathyroid Hormone, PTH, that can be given safely over one week in healthy African-American volunteers. The investigators plan to infuse low doses of intravenous PTHrP or PTH to determine if it leads to a sustained and progressive suppression of bone formation as occurs in humoral hypercalcemia of malignancy (HHM) or an increase in bone formation as occurs in hyperparathyroidism (HPT). Additionally, the investigators will assess the direct influence of PTHrP and PTH on vitamin D metabolism, markers of bone turnover, and fractional excretion of calcium. These results will be compared to previous studies of Caucasian volunteers.

Condition or disease	Intervention/treatment	Phase
Osteoporosis; Hypercalcemia of Malignancy; Hyperparathyroidism; Bone Diseases, Endocrine	Drug: Parathyroid Hormone-related Protein (1-36); Drug: parathyroid hormone (1-34); Drug: PTH (1-34) and PTHrP (1-36)	Phase 1

Detailed Description:

This study will expand upon earlier infusion studies in healthy Caucasian and Asian volunteers in which continuous infusions of PTH and PTHrP were given for six-, 12-, and 48 hours. These studies 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 remains 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 primary 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. Because of these findings, it was surmised that infusions of a longer duration would lead to an increase in bone formation and 1,25 (OH)2D production with both peptides, as is seen in HPT. Very recently, we have completed a seven-day infusion model in healthy Caucasian and Asian volunteers to test this hypothesis (J. Bone Min. Res., 2011). A total of 22 individuals were given either seven-day infusions of PTH or PTHrP, and maximal safe doses were found to be 2 and 4 picomoles (pmol)/kg/hour, respectively, lower than the doses used in previous, briefer infusion studies. All patients developed sustained but very mild hypercalcemia (mean = 10.3 mg/dL) and hypercalciuria with rapid increase in bone resorption. Surprisingly, bone formation again was suppressed for the entire seven days with a robust rebound in bone formation on cessation of the respective peptide. This is consistent with what may occur during lactation and HHM, but again contrary to what occurs in HPT.

The previous infusion studies were done only in Caucasian and Asian volunteers as there are extensively documented physiologic differences in bone metabolism between African-Americans and Caucasians. Much of the racial differences noted in bone metabolism come from the osteoporosis literature. African-Americans are known to have higher bone mineral densities (BMD) and to be at lower risk of developing fragility fractures. There are many factors which may explain these racial differences in bone metabolism, including altered calcium economy, vitamin D differences, peak attained bone mass, muscle mass and obesity, mechanism of falls, remodeling rates, bone micro-architecture, hip axis geometry, and other unknown hereditary differences. It is also well established that African-Americans on average, have lower 25-OH vitamin D concentrations and thus higher PTH levels. Despite elevations in PTH, there is paradoxically no increase in bone loss indicating that a relative skeletal resistance to PTH may exist. We hope that by performing this seven-day infusion protocol in healthy African-American volunteers we can learn more about racial differences in bone turnover, renal calcium, PTH concentrations, vitamin D metabolism, and skeletal responses to lactation in this under-studied population.

Ninety healthy African-American men and women will be screened for an eight-day inpatient admission to the Clinical & Translational Research Center (CTRC). Sixty evaluable research participants will receive a seven day infusion of a predetermined dose of either PTHrP or PTH. Vital signs and blood and urine tests will be monitored frequently as per the study flow sheet. The starting dose of either peptide, 2 picomoles (pmols)/kg, will be given to three normal healthy subjects. Via a dose escalation protocol, 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 determined safe dose will then be given to 10 subjects. This dose escalation study design has been used in several prior studies at this institution in order to achieve a sustained mild serum hypercalcemia in the 10.5-11 mg/dL range in research studies. The investigators with this study are trying to determine a safe dose of PTHrP and PTH in African-American volunteers and determining if this population has the same physiologic response as Caucasians.

Subject population will consist of healthy young African-American adults, ages 24-35. It is anticipated that we will need to screen 90 patients in order to obtain 60 evaluable subjects.

Study Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 0 participants
• Allocation: Non-Randomized
• Intervention Model: Parallel Assignment
• Masking: Single (Participant)
• Official Title: Comparison of Skeletal and Mineral Metabolism Responses in Healthy African-Americans and Caucasians Using a Continuous Seven-Day Parathyroid Hormone (PTH) or Parathyroid Hormone-related Protein (PTHrP) Infusion
• Study Start Date: January 2015
• Estimated Primary Completion Date: July 2017
• Estimated Study Completion Date: July 2017

Arms and Interventions

Arm	Intervention/treatment
Experimental: PTHrP group; Subjects receive PTHrP(1-36) starting with doses of 2 picomoles (pmols)/kg/hr for one week. Subsequent dosing groups are determined by the response to PTHrP doses.	Drug: Parathyroid Hormone-related Protein (1-36); PTHrP (1-36) intravenously at 2 picomoles (pmols)/kg/hr for one week; doses will be increased by 2 picomoles (pmols)/kg/hr in subsequent subjects.; Other Names: PTHrP(1-36); Bone anabolic agents; Drug: PTH (1-34) and PTHrP (1-36); This is a dose escalation study to determine the maximum tolerable dose of Parathyroid Hormone-related Protein, PTHrP, or Parathyroid Hormone, PTH, that can be given safely over one week in healthy African-American volunteers. The investigators plan to infuse low doses of intravenous PTHrP or PTH to determine if it leads to a sustained and progressive suppression of bone formation as occurs in humoral hypercalcemia of malignancy (HHM) or an increase in bone formation as occurs in hyperparathyroidism (HPT). Additionally, the investigators will assess the direct influence of PTHrP and PTH on vitamin D metabolism, markers of bone turnover, and fractional excretion of calcium.; Other Names: Parathyroid Hormone-related Protein (1-36); PTHrP(1-36); IND 49,175; Parathyroid Hormone (1-34); PTH (1-34); IND 60,979
Experimental: PTH dosing group; Subjects receive PTH(1-34) starting with doses of 2 picomoles (pmols)/kg/hr for one week. Subsequent dosing groups are determined by the response to PTH doses.	Drug: parathyroid hormone (1-34); PTH (1-34) intravenously at 2 picomoles (pmols)/kg/hr for one week; doses will be increased by 2 picomoles (pmols)/kg/hr in subsequent subjects.; Other Names: PTH(1-34); Bone anabolic agent; Drug: PTH (1-34) and PTHrP (1-36); This is a dose escalation study to determine the maximum tolerable dose of Parathyroid Hormone-related Protein, PTHrP, or Parathyroid Hormone, PTH, that can be given safely over one week in healthy African-American volunteers. The investigators plan to infuse low doses of intravenous PTHrP or PTH to determine if it leads to a sustained and progressive suppression of bone formation as occurs in humoral hypercalcemia of malignancy (HHM) or an increase in bone formation as occurs in hyperparathyroidism (HPT). Additionally, the investigators will assess the direct influence of PTHrP and PTH on vitamin D metabolism, markers of bone turnover, and fractional excretion of calcium.; Other Names: Parathyroid Hormone-related Protein (1-36); PTHrP(1-36); IND 49,175; Parathyroid Hormone (1-34); PTH (1-34); IND 60,979

Outcome Measures

Primary Outcome Measures :

1. Safety: The absence of any dose limiting toxicity (DLT) criteria consisting of one major criteria or two minor criteria. [ Time Frame: one week ]

Secondary Outcome Measures :

1. Blood collections analyzed for measurements of PTH(1-34), PTH(1-84), 25-OH vitamin D, 1,25(OH)2 vitamin D, markers of bone metabolism, and fractional excretion of calcium measurements. [ Time Frame: one week ]

Eligibility Criteria

• Ages Eligible for Study: 24 Years to 35 Years (Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: Yes

Criteria

Inclusion Criteria:

• Healthy African-American subjects of both sexes between the ages of 24-35 years, who are able to spend one week on the Clinical & Translational Research Center (CTRC) at the University of Pittsburgh Medical Center (UPMC) Montefiore.

Exclusion Criteria:

• Subjects with cardiac, vascular, renal (serum creatinine > 1.5), pulmonary, endocrine, musculoskeletal, hepatic, hematologic, malignant, or rheumatologic disease will be excluded.
• Those found to have vitamin D deficiency, defined as a 25-OH vitamin D level < 10 ng/mL will also be excluded.
• Additionally, those with BMI > 30, anemia (hematocrit < 36% in women, <40% in men), significant alcohol use, illicit drug use, hypertension (BP>160/90), or baseline hypotension (systolic blood pressure < 90mmHg) will be excluded.
• Those taking chronic medications (except oral contraceptive pills (OCP's) or stable doses of thyroid replacement) or those who have received an investigational drug in the past 90 days will also be excluded.
• Prior participants in PTH or PTHrP studies will not be eligible to participate.
• Additionally pregnant women and lactating women will be excluded; all women will have a urine pregnancy test performed immediately before starting the study.

Contacts and Locations

Locations

United States, Pennsylvania

University of Pittsburgh Medical Center

Pittsburgh, Pennsylvania, United States, 15213

Sponsors and Collaborators

University of Pittsburgh

Investigators

• Principal Investigator: Mara J. Horwitz, MD; University of Pittsburgh

More Information

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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.

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• Responsible Party: Mara Horwitz, Associate Professor, University of Pittsburgh School of Medicine, University of Pittsburgh
• ClinicalTrials.gov Identifier: NCT01333267
• Other Study ID Numbers: PRO10060214
• First Posted: April 11, 2011
• Last Update Posted: December 5, 2014
• Last Verified: December 2014

Keywords provided by Mara Horwitz, University of Pittsburgh:

Endocrine System Diseases; MusculoSkeletal System Disease; Hormones; Postmenopausal Women; Bone metabolism; Physiologic Properties; African-Americans

Additional relevant MeSH terms:

Osteoporosis; Bone Diseases; Bone Diseases, Endocrine; Hypercalcemia; Hyperparathyroidism; Endocrine System Diseases; Bone Diseases, Metabolic; Musculoskeletal Diseases; Metabolic Diseases; Parathyroid Diseases; Calcium Metabolism Disorders; Water-Electrolyte Imbalance; Hormones; Testosterone Congeners; Parathyroid Hormone; Parathyroid Hormone-Related Protein; Anabolic Agents; Hormones, Hormone Substitutes, and Hormone Antagonists; Physiological Effects of Drugs; Calcium-Regulating Hormones and Agents