One Week Comparison Study of PTH and PTHrP Infusions
One Week Comparison Study of PTH and PTHrP Infusions
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.
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.
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.