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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

Phase 1
24 Years
35 Years
Not Enrolling
Osteoporosis, Hypercalcemia of Malignancy, Hyperparathyroidism, Bone Diseases, Endocrine

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Trial Information

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

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 NTx and 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 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's) 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 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 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

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 at UPMC

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 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.

Type of Study:


Study Design:

Allocation: Non-Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Parallel Assignment, Masking: Single Blind (Subject)

Outcome Measure:

Safety: The absence of any dose limiting toxicity (DLT) criteria consisting of one major criteria or two minor criteria.

Outcome Time Frame:

one week

Safety Issue:


Principal Investigator

Mara J. Horwitz, MD

Investigator Role:

Principal Investigator

Investigator Affiliation:

University of Pittsburgh


United States: Food and Drug Administration

Study ID:




Start Date:

January 2013

Completion Date:

July 2014

Related Keywords:

  • Osteoporosis
  • Hypercalcemia of Malignancy
  • Hyperparathyroidism
  • Bone Diseases, Endocrine
  • Endocrine System Diseases
  • MusculoSkeletal System Disease
  • Hormones
  • Postmenopausal Women
  • Bone metabolism
  • Physiologic Properties
  • African-Americans
  • Bone Diseases
  • Bone Diseases, Endocrine
  • Neoplasms
  • Endocrine System Diseases
  • Hypercalcemia
  • Hyperparathyroidism
  • Osteoporosis



University of Pittsburgh Medical CenterPittsburgh, Pennsylvania  15213