One Week Comparison Study of PTH and PTHrP Infusions

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.