Clinical trial NCT01333267: One Week Comparison Study of PTH and PTHrP Infusions
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 type: INTERVENTIONAL
Overall status: WITHDRAWN
Phase: PHASE1
Conditions: Osteoporosis
Hypercalcemia of Malignancy
Hyperparathyroidism
Bone Diseases, Endocrine
Keywords: Endocrine System Diseases
MusculoSkeletal System Disease
Hormones
Postmenopausal Women
Bone metabolism
Physiologic Properties
African-Americans
Lead sponsor: University of Pittsburgh
Sponsor class: OTHER
First posted: 2011-04-11
Enrollment: 0
Sex: ALL
Minimum age (years): 24
Maximum age (years): 35
Standard ages: ADULT
Accepts healthy volunteers: yes
Allocation: NON_RANDOMIZED
Intervention model: PARALLEL

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.

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.

Eligibility 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.

Primary outcomes:
measure: Safety: The absence of any dose limiting toxicity (DLT) criteria consisting of one major criteria or two minor criteria.
timeFrame: one week
Secondary outcomes:
measure: 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.
timeFrame: one week
Other outcomes:
Locations:
city: Pittsburgh
country: United States
facility: University of Pittsburgh Medical Center
state: Pennsylvania
Study officials:
affiliation: University of Pittsburgh
name: Mara J. Horwitz, MD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Dean T, Vilardaga JP, Potts JT Jr, Gardella TJ. Altered selectivity of parathyroid hormone (PTH) and PTH-related protein (PTHrP) for distinct conformations of the PTH/PTHrP receptor. Mol Endocrinol. 2008 Jan;22(1):156-66. doi: 10.1210/me.2007-0274. Epub 2007 Sep 13.
citation: Horwitz MJ, Tedesco MB, Sereika SM, Syed MA, Garcia-Ocana A, Bisello A, Hollis BW, Rosen CJ, Wysolmerski JJ, Dann P, Gundberg C, Stewart AF. Continuous PTH and PTHrP infusion causes suppression of bone formation and discordant effects on 1,25(OH)2 vitamin D. J Bone Miner Res. 2005 Oct;20(10):1792-803. doi: 10.1359/JBMR.050602. Epub 2005 Jun 6.
citation: Horwitz MJ, Tedesco MB, Sereika SM, Hollis BW, Garcia-Ocana 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. doi: 10.1210/jc.2002-020773.
citation: Nelson DA, Jacobsen G, Barondess DA, Parfitt AM. Ethnic differences in regional bone density, hip axis length, and lifestyle variables among healthy black and white men. J Bone Miner Res. 1995 May;10(5):782-7. doi: 10.1002/jbmr.5650100515.
citation: George A, Tracy JK, Meyer WA, Flores RH, Wilson PD, Hochberg MC. Racial differences in bone mineral density in older men. J Bone Miner Res. 2003 Dec;18(12):2238-44. doi: 10.1359/jbmr.2003.18.12.2238.
citation: Kalkwarf HJ, Zemel BS, Gilsanz V, Lappe JM, Horlick M, Oberfield S, Mahboubi S, Fan B, Frederick MM, Winer K, Shepherd JA. The bone mineral density in childhood study: bone mineral content and density according to age, sex, and race. J Clin Endocrinol Metab. 2007 Jun;92(6):2087-99. doi: 10.1210/jc.2006-2553. Epub 2007 Feb 20.
citation: Hui SL, Dimeglio LA, Longcope C, Peacock M, McClintock R, Perkins AJ, Johnston CC Jr. Difference in bone mass between black and white American children: attributable to body build, sex hormone levels, or bone turnover? J Clin Endocrinol Metab. 2003 Feb;88(2):642-9. doi: 10.1210/jc.2002-020653.
citation: Bachrach LK, Hastie T, Wang MC, Narasimhan B, Marcus R. Bone mineral acquisition in healthy Asian, Hispanic, black, and Caucasian youth: a longitudinal study. J Clin Endocrinol Metab. 1999 Dec;84(12):4702-12. doi: 10.1210/jcem.84.12.6182.
citation: Gilsanz V, Skaggs DL, Kovanlikaya A, Sayre J, Loro ML, Kaufman F, Korenman SG. Differential effect of race on the axial and appendicular skeletons of children. J Clin Endocrinol Metab. 1998 May;83(5):1420-7. doi: 10.1210/jcem.83.5.4765.
citation: Abrams SA, O'brien KO, Liang LK, Stuff JE. Differences in calcium absorption and kinetics between black and white girls aged 5-16 years. J Bone Miner Res. 1995 May;10(5):829-33. doi: 10.1002/jbmr.5650100521.
citation: Gilsanz V, Roe TF, Mora S, Costin G, Goodman WG. Changes in vertebral bone density in black girls and white girls during childhood and puberty. N Engl J Med. 1991 Dec 5;325(23):1597-600. doi: 10.1056/NEJM199112053252302.
citation: Luckey MM, Wallenstein S, Lapinski R, Meier DE. A prospective study of bone loss in African-American and white women--a clinical research center study. J Clin Endocrinol Metab. 1996 Aug;81(8):2948-56. doi: 10.1210/jcem.81.8.8768857.
citation: Thomas PA. Racial and ethnic differences in osteoporosis. J Am Acad Orthop Surg. 2007;15 Suppl 1:S26-30. doi: 10.5435/00124635-200700001-00008.
citation: Han ZH, Palnitkar S, Rao DS, Nelson D, Parfitt AM. Effects of ethnicity and age or menopause on the remodeling and turnover of iliac bone: implications for mechanisms of bone loss. J Bone Miner Res. 1997 Apr;12(4):498-508. doi: 10.1359/jbmr.1997.12.4.498.
citation: Cauley JA, Wampler NS, Barnhart JM, Wu L, Allison M, Chen Z, Hendrix S, Robbins J, Jackson RD; Women's Health Initiative Observational Study. Incidence of fractures compared to cardiovascular disease and breast cancer: the Women's Health Initiative Observational Study. Osteoporos Int. 2008 Dec;19(12):1717-23. doi: 10.1007/s00198-008-0634-y. Epub 2008 Jul 16.
citation: Cauley JA, Palermo L, Vogt M, Ensrud KE, Ewing S, Hochberg M, Nevitt MC, Black DM. Prevalent vertebral fractures in black women and white women. J Bone Miner Res. 2008 Sep;23(9):1458-67. doi: 10.1359/jbmr.080411.
citation: Cauley JA, Lui LY, Ensrud KE, Zmuda JM, Stone KL, Hochberg MC, Cummings SR. Bone mineral density and the risk of incident nonspinal fractures in black and white women. JAMA. 2005 May 4;293(17):2102-8. doi: 10.1001/jama.293.17.2102.
citation: Opotowsky AR, Bilezikian JP. Racial differences in the effect of early milk consumption on peak and postmenopausal bone mineral density. J Bone Miner Res. 2003 Nov;18(11):1978-88. doi: 10.1359/jbmr.2003.18.11.1978.
citation: Cosman F, Nieves J, Dempster D, Lindsay R. Vitamin D economy in blacks. J Bone Miner Res. 2007 Dec;22 Suppl 2:V34-8. doi: 10.1359/jbmr.07s220.
citation: Harris SS, Soteriades E, Dawson-Hughes B; Framingham Heart Study; Boston Low-Income Elderly Osteoporosis Study. Secondary hyperparathyroidism and bone turnover in elderly blacks and whites. J Clin Endocrinol Metab. 2001 Aug;86(8):3801-4. doi: 10.1210/jcem.86.8.7783.
citation: Cosman F, Morgan DC, Nieves JW, Shen V, Luckey MM, Dempster DW, Lindsay R, Parisien M. Resistance to bone resorbing effects of PTH in black women. J Bone Miner Res. 1997 Jun;12(6):958-66. doi: 10.1359/jbmr.1997.12.6.958.
citation: Fuleihan GE, Gundberg CM, Gleason R, Brown EM, Stromski ME, Grant FD, Conlin PR. Racial differences in parathyroid hormone dynamics. J Clin Endocrinol Metab. 1994 Dec;79(6):1642-7. doi: 10.1210/jcem.79.6.7989469.
citation: Aloia JF, Patel M, Dimaano R, Li-Ng M, Talwar SA, Mikhail M, Pollack S, Yeh JK. Vitamin D intake to attain a desired serum 25-hydroxyvitamin D concentration. Am J Clin Nutr. 2008 Jun;87(6):1952-8. doi: 10.1093/ajcn/87.6.1952.
citation: Aloia JF. African Americans, 25-hydroxyvitamin D, and osteoporosis: a paradox. Am J Clin Nutr. 2008 Aug;88(2):545S-550S. doi: 10.1093/ajcn/88.2.545S.
citation: Aloia JF, Talwar SA, Pollack S, Feuerman M, Yeh JK. Optimal vitamin D status and serum parathyroid hormone concentrations in African American women. Am J Clin Nutr. 2006 Sep;84(3):602-9. doi: 10.1093/ajcn/84.3.602.
citation: Aloia JF, Talwar SA, Pollack S, Yeh J. A randomized controlled trial of vitamin D3 supplementation in African American women. Arch Intern Med. 2005 Jul 25;165(14):1618-23. doi: 10.1001/archinte.165.14.1618.
citation: Barrett-Connor E, Siris ES, Wehren LE, Miller PD, Abbott TA, Berger ML, Santora AC, Sherwood LM. Osteoporosis and fracture risk in women of different ethnic groups. J Bone Miner Res. 2005 Feb;20(2):185-94. doi: 10.1359/JBMR.041007. Epub 2004 Oct 18.
citation: Cauley JA, Wu L, Wampler NS, Barnhart JM, Allison M, Chen Z, Jackson R, Robbins J. Clinical risk factors for fractures in multi-ethnic women: the Women's Health Initiative. J Bone Miner Res. 2007 Nov;22(11):1816-26. doi: 10.1359/jbmr.070713.
citation: Faulkner KA, Cauley JA, Zmuda JM, Landsittel DP, Nevitt MC, Newman AB, Studenski SA, Redfern MS. Ethnic differences in the frequency and circumstances of falling in older community-dwelling women. J Am Geriatr Soc. 2005 Oct;53(10):1774-9. doi: 10.1111/j.1532-5415.2005.53514.x.
citation: Finkelstein JS, Lee ML, Sowers M, Ettinger B, Neer RM, Kelsey JL, Cauley JA, Huang MH, Greendale GA. Ethnic variation in bone density in premenopausal and early perimenopausal women: effects of anthropometric and lifestyle factors. J Clin Endocrinol Metab. 2002 Jul;87(7):3057-67. doi: 10.1210/jcem.87.7.8654.
citation: Schnitzler CM, Mesquita JM. Cortical bone histomorphometry of the iliac crest in normal black and white South African adults. Calcif Tissue Int. 2006 Dec;79(6):373-82. doi: 10.1007/s00223-006-0053-z. Epub 2006 Dec 8.
citation: Cummings SR, Cauley JA, Palermo L, Ross PD, Wasnich RD, Black D, Faulkner KG. Racial differences in hip axis lengths might explain racial differences in rates of hip fracture. Study of Osteoporotic Fractures Research Group. Osteoporos Int. 1994 Jul;4(4):226-9. doi: 10.1007/BF01623243.
citation: Perry HM 3rd, Horowitz M, Morley JE, Fleming S, Jensen J, Caccione P, Miller DK, Kaiser FE, Sundarum M. Aging and bone metabolism in African American and Caucasian women. J Clin Endocrinol Metab. 1996 Mar;81(3):1108-17. doi: 10.1210/jcem.81.3.8772584.
citation: Jacobsen SJ, Goldberg J, Miles TP, Brody JA, Stiers W, Rimm AA. Race and sex differences in mortality following fracture of the hip. Am J Public Health. 1992 Aug;82(8):1147-50. doi: 10.2105/ajph.82.8.1147.
citation: Mikuls TR, Saag KG, George V, Mudano AS, Banerjee S. Racial disparities in the receipt of osteoporosis related healthcare among community-dwelling older women with arthritis and previous fracture. J Rheumatol. 2005 May;32(5):870-5.
citation: Alam NM, Archer JA, Lee E. Osteoporotic fragility fractures in African Americans: under-recognized and undertreated. J Natl Med Assoc. 2004 Dec;96(12):1640-5.
citation: Looker AC. The skeleton, race, and ethnicity. J Clin Endocrinol Metab. 2002 Jul;87(7):3047-50. doi: 10.1210/jcem.87.7.8779. No abstract available.
citation: Bell NH, Bilezikian JP, Bone HG 3rd, Kaur A, Maragoto A, Santora AC; MK-063 Study Group. Alendronate increases bone mass and reduces bone markers in postmenopausal African-American women. J Clin Endocrinol Metab. 2002 Jun;87(6):2792-7. doi: 10.1210/jcem.87.6.8575.
citation: Neer RM, Arnaud CD, Zanchetta JR, Prince R, Gaich GA, Reginster JY, Hodsman AB, Eriksen EF, Ish-Shalom S, Genant HK, Wang O, Mitlak BH. Effect of parathyroid hormone (1-34) on fractures and bone mineral density in postmenopausal women with osteoporosis. N Engl J Med. 2001 May 10;344(19):1434-41. doi: 10.1056/NEJM200105103441904.
citation: Lau EM, Suriwongpaisal P, Lee JK, Das De S, Festin MR, Saw SM, Khir A, Torralba T, Sham A, Sambrook P. Risk factors for hip fracture in Asian men and women: the Asian osteoporosis study. J Bone Miner Res. 2001 Mar;16(3):572-80. doi: 10.1359/jbmr.2001.16.3.572.
citation: Awumey EM, Mitra DA, Hollis BW, Kumar R, Bell NH. Vitamin D metabolism is altered in Asian Indians in the southern United States: a clinical research center study. J Clin Endocrinol Metab. 1998 Jan;83(1):169-73. doi: 10.1210/jcem.83.1.4514.
citation: Looker AC, Orwoll ES, Johnston CC Jr, Lindsay RL, Wahner HW, Dunn WL, Calvo MS, Harris TB, Heyse SP. Prevalence of low femoral bone density in older U.S. adults from NHANES III. J Bone Miner Res. 1997 Nov;12(11):1761-8. doi: 10.1359/jbmr.1997.12.11.1761.
citation: Wright NM, Papadea N, Willi S, Veldhuis JD, Pandey JP, Key LL, Bell NH. Demonstration of a lack of racial difference in secretion of growth hormone despite a racial difference in bone mineral density in premenopausal women--a Clinical Research Center study. J Clin Endocrinol Metab. 1996 Mar;81(3):1023-6. doi: 10.1210/jcem.81.3.8772569.
citation: Heaney RP. Bone mass, the mechanostat, and ethnic differences. J Clin Endocrinol Metab. 1995 Aug;80(8):2289-90. doi: 10.1210/jcem.80.8.7629221. No abstract available.
citation: Cundy T, Cornish J, Evans MC, Gamble G, Stapleton J, Reid IR. Sources of interracial variation in bone mineral density. J Bone Miner Res. 1995 Mar;10(3):368-73. doi: 10.1002/jbmr.5650100306.
citation: Wright NM, Renault J, Willi S, Veldhuis JD, Pandey JP, Gordon L, Key LL, Bell NH. Greater secretion of growth hormone in black than in white men: possible factor in greater bone mineral density--a clinical research center study. J Clin Endocrinol Metab. 1995 Aug;80(8):2291-7. doi: 10.1210/jcem.80.8.7543111.
citation: Looker AC, Johnston CC Jr, Wahner HW, Dunn WL, Calvo MS, Harris TB, Heyse SP, Lindsay RL. Prevalence of low femoral bone density in older U.S. women from NHANES III. J Bone Miner Res. 1995 May;10(5):796-802. doi: 10.1002/jbmr.5650100517.
citation: Looker AC, Wahner HW, Dunn WL, Calvo MS, Harris TB, Heyse SP, Johnston CC Jr, Lindsay RL. Proximal femur bone mineral levels of US adults. Osteoporos Int. 1995;5(5):389-409. doi: 10.1007/BF01622262.
citation: Villa ML. Cultural determinants of skeletal health: the need to consider both race and ethnicity in bone research. J Bone Miner Res. 1994 Sep;9(9):1329-32. doi: 10.1002/jbmr.5650090902. No abstract available.
citation: Baron JA, Barrett J, Malenka D, Fisher E, Kniffin W, Bubolz T, Tosteson T. Racial differences in fracture risk. Epidemiology. 1994 Jan;5(1):42-7. doi: 10.1097/00001648-199401000-00008.
citation: Silverman SL, Madison RE. Decreased incidence of hip fracture in Hispanics, Asians, and blacks: California Hospital Discharge Data. Am J Public Health. 1988 Nov;78(11):1482-3. doi: 10.2105/ajph.78.11.1482.
citation: Looker AC, Flegal KM, Melton LJ 3rd. Impact of increased overweight on the projected prevalence of osteoporosis in older women. Osteoporos Int. 2007 Mar;18(3):307-13. doi: 10.1007/s00198-006-0241-8. Epub 2006 Oct 20.