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