{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,22]],"date-time":"2026-09-22T03:51:23Z","timestamp":1790049083807,"version":"4.0.1"},"reference-count":44,"publisher":"Oxford University Press (OUP)","issue":"9","license":[{"start":{"date-parts":[[2011,5,4]],"date-time":"2011-05-04T00:00:00Z","timestamp":1304467200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/journals\/pages\/open_access\/funder_policies\/chorus\/standard_publication_model"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2011,9,1]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:p>Human in vivo models of primary hyperparathyroidism (HPT), humoral hypercalcemia of malignancy (HHM), or lactational bone mobilization for more than 48\u2009hours have not been described previously. We therefore developed 7-day continuous-infusion models using human parathyroid hormone(1\u201334) [hPTH(1\u201334)] and human parathyroid hormone\u2013related protein(1\u201336) [hPTHrP(1\u201336)] in healthy human adult volunteers. Study subjects developed sustained mild increases in serum calcium (10.0\u2009mg\/dL), with marked suppression of endogenous PTH(1\u201384). The maximal tolerated infused doses over a 7-day period (2 and 4\u2009pmol\/kg\/h for PTH and PTHrP, respectively) were far lower than in prior, briefer human studies (8 to 28\u2009pmol\/kg\/h). In contrast to prior reports using higher PTH and PTHrP doses, both 1,25-dihydroxyvitamin D3 [1,25(OH)2D3] and tubular maximum for phosphorus (TmP\/GFR) remained unaltered with these low doses despite achievement of hypercalcemia and hypercalciuria. As expected, bone resorption increased rapidly and reversed promptly with cessation of the infusion. However, in contrast to events in primary HPT, bone formation was suppressed by 30% to 40% for the 7 days of the infusions. With cessation of PTH and PTHrP infusion, bone-formation markers abruptly rebounded upward, confirming that bone formation is suppressed by continuous PTH or PTHrP infusion. These studies demonstrate that continuous exposure of the human skeleton to PTH or PTHrP in vivo recruits and activates the bone-resorption program but causes sustained arrest in the osteoblast maturation program. These events would most closely mimic and model events in HHM. Although not a perfect model for lactation, the increase in resorption and the rebound increase in formation with cessation of the infusions are reminiscent of the maternal skeletal calcium mobilization and reversal that occur following lactation. The findings also highlight similarities and differences between the model and HPT. \u00a9 2011 American Society for Bone and Mineral Research<\/jats:p>","DOI":"10.1002\/jbmr.415","type":"journal-article","created":{"date-parts":[[2011,5,4]],"date-time":"2011-05-04T18:28:43Z","timestamp":1304533723000},"page":"2287-2297","source":"Crossref","is-referenced-by-count":45,"title":["A 7-day continuous infusion of PTH or PTHrP suppresses bone formation and uncouples bone turnover"],"prefix":"10.1093","volume":"26","author":[{"given":"Mara J","family":"Horwitz","sequence":"first","affiliation":[{"name":"Division of Endocrinology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mary Beth","family":"Tedesco","sequence":"additional","affiliation":[{"name":"Division of Endocrinology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Susan M","family":"Sereika","sequence":"additional","affiliation":[{"name":"Center for Research and Evaluation, University of Pittsburgh School of Nursing and Graduate School of Public Health, Pittsburgh, PA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Linda","family":"Prebehala","sequence":"additional","affiliation":[{"name":"Division of Endocrinology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Caren M","family":"Gundberg","sequence":"additional","affiliation":[{"name":"Department of Orthopedics and Rehabilitation, Yale University School of Medicine, New Haven, CT, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bruce W","family":"Hollis","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, Medical University of South Carolina, Charleston, SC, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alessandro","family":"Bisello","sequence":"additional","affiliation":[{"name":"Division of Endocrinology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Adolfo","family":"Garcia-Oca\u00f1a","sequence":"additional","affiliation":[{"name":"Division of Endocrinology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Raquel M","family":"Carneiro","sequence":"additional","affiliation":[{"name":"Division of Endocrinology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andrew F","family":"Stewart","sequence":"additional","affiliation":[{"name":"Division of Endocrinology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2011,5,4]]},"reference":[{"key":"2024020317585244200_bib1","doi-asserted-by":"crossref","first-page":"123","DOI":"10.1002\/9780470623992.ch25","volume-title":"Primer on the Metabolic Bone Diseases and Disorders of Mineral Metabolism","author":"Nissenson","year":"2008","edition":"7th ed"},{"key":"2024020317585244200_bib2","doi-asserted-by":"crossref","first-page":"24371","DOI":"10.1074\/jbc.271.40.24371","article-title":"Structural and physiologic characterization of the mid-region secretory form of PTHrP","volume":"271","author":"Wu","year":"1996","journal-title":"J Biol Chem."},{"key":"2024020317585244200_bib3","first-page":"1377","volume-title":"Endocrinology","author":"Juppner","year":"2006","edition":"5th ed"},{"key":"2024020317585244200_bib4","doi-asserted-by":"crossref","first-page":"156","DOI":"10.1210\/me.2007-0274","article-title":"Altered selectivity of parathyroid hormone (PTH) and PTH-related protein (PTHrP) for distinct conformations of the PTH\/PTHrP receptor","volume":"22","author":"Dean","year":"2008","journal-title":"Mol Endocrinol."},{"key":"2024020317585244200_bib5","doi-asserted-by":"crossref","first-page":"127","DOI":"10.1002\/9780470623992.ch26","volume-title":"Primer on the Metabolic Bone Diseases and Disorders of Mineral Metabolism","author":"Wysolmerski","year":"2008","edition":"7th ed"},{"key":"2024020317585244200_bib6","first-page":"832","article-title":"Maternal-fetal calcium and bone metabolism during pregnancy, puerperium, and lactation","volume":"18","author":"Kovacs","year":"1997","journal-title":"Endocr Rev."},{"key":"2024020317585244200_bib7","first-page":"1555","volume-title":"Endocrinology","author":"Stewart","year":"2006","edition":"5th ed"},{"key":"2024020317585244200_bib8","doi-asserted-by":"crossref","first-page":"1377","DOI":"10.1056\/NEJM198012113032401","article-title":"Biochemical evaluation of patients with cancer-associated hypercalcemia: evidence for humoral and non-humoral groups","volume":"303","author":"Stewart","year":"1980","journal-title":"N Engl J Med."},{"key":"2024020317585244200_bib9","doi-asserted-by":"crossref","first-page":"219","DOI":"10.1210\/jcem-55-2-219","article-title":"Quantitative bone histomorphometry in humoral hypercalcemia of malignancy: uncoupling of bone cell activity","volume":"55","author":"Stewart","year":"1982","journal-title":"J Clin Endo Metab."},{"key":"2024020317585244200_bib10","first-page":"607","article-title":"Differences in bone and vitamin D metabolism between primary hyperparathyroidism and malignancy-associated hypercalcemia","volume":"81","author":"Nakayama","year":"1996","journal-title":"J Clin Endocrinol Metab."},{"key":"2024020317585244200_bib11","doi-asserted-by":"crossref","first-page":"523","DOI":"10.1056\/NEJM199708213370803","article-title":"The effect of calcium supplementation on bone density during lactation and after weaning","volume":"337","author":"Kalkwarf","year":"1997","journal-title":"N Engl J Med."},{"key":"2024020317585244200_bib12","first-page":"302","volume-title":"Primer on the Metabolic Bone Diseases and Disorders of Mineral Metabolism","author":"Silverberg","year":"2008","edition":"7th ed"},{"key":"2024020317585244200_bib13","first-page":"1533","volume-title":"Endocrinology","author":"Silverberg","year":"2006","edition":"5th ed"},{"key":"2024020317585244200_bib14","doi-asserted-by":"crossref","first-page":"1249","DOI":"10.1056\/NEJM199910213411701","article-title":"A 10-year prospective study of primary hyperparathyroidism with or without parathyroid surgery","volume":"341","author":"Silverberg","year":"2000","journal-title":"N Engl J Med."},{"key":"2024020317585244200_bib15","first-page":"199","article-title":"Parathyroid hormone-related protein(1-36) is equipotent with parathyroid hormone(1-34) in humans","volume":"81","author":"Everhart-Caye","year":"1996","journal-title":"J Clin Endocrinol Metab."},{"key":"2024020317585244200_bib16","first-page":"1525","article-title":"Parathyroid hormone-related protein (1-36) stimulates renal tubular calcium reabsorption in normal human volunteers: implications for the pathogenesis of humoral hypercalcemia of malignancy","volume":"86","author":"Syed","year":"2001","journal-title":"J Clin Endocrinol Metab."},{"key":"2024020317585244200_bib17","doi-asserted-by":"crossref","first-page":"1603","DOI":"10.1210\/jc.2002-020773","article-title":"Direct comparison of sustained infusion of hPTHrP(1-36) versus hPTH(1-34) on serum calcium, plasma 1,25(OH)2 vitamin D concentrations and fractional calcium excretion in healthy human volunteers","volume":"88","author":"Horwitz","year":"2003","journal-title":"J Clin Endocrinol Metab."},{"key":"2024020317585244200_bib18","doi-asserted-by":"crossref","first-page":"1792","DOI":"10.1359\/JBMR.050602","article-title":"Continuous infusion of parathyroid hormone versus parathyroid hormone-related protein in humans: discordant effects on 1,25(OH)2 vitamin D and prolonged suppression of bone formation","volume":"20","author":"Horwitz","year":"2005","journal-title":"J Bone Min Res."},{"key":"2024020317585244200_bib19","doi-asserted-by":"crossref","first-page":"241","DOI":"10.1002\/jbmr.5650030218","article-title":"Changes in serum levels of type I and III procollagen extension peptides during infusion of human parathyroid hormone fragment (1-34)","volume":"3","author":"Simon","year":"1988","journal-title":"J Bone Miner Res."},{"key":"2024020317585244200_bib20","first-page":"511","article-title":"Effects of gonadal steroid suppression on skeletal sensitivity to parathyroid hormone in men","volume":"86","author":"Leder","year":"2001","journal-title":"J Clin Endocrinol Metab."},{"key":"2024020317585244200_bib21","doi-asserted-by":"crossref","first-page":"337","DOI":"10.7326\/0003-4819-118-5-199303010-00003","article-title":"Estrogen protection against bone-resorbing effects of parathyroid hormone infusion: assessment by use of biochemical markers","volume":"118","author":"Cosman","year":"1993","journal-title":"Ann Int Med."},{"key":"2024020317585244200_bib22","doi-asserted-by":"crossref","first-page":"372","DOI":"10.1056\/NEJM198108133050704","article-title":"Deficient production of 1,25-Dihydroxyvitamin D in elderly osteoporotic patients","volume":"305","author":"Slovik","year":"1981","journal-title":"N Engl J Med."},{"key":"2024020317585244200_bib23","doi-asserted-by":"crossref","first-page":"596","DOI":"10.1172\/JCI113358","article-title":"A synthetic human parathyroid hormone-like protein stimulates bone resorption and causes hypercalcemia in rats","volume":"81","author":"Stewart","year":"1988","journal-title":"J Clin Invest."},{"key":"2024020317585244200_bib24","first-page":"900","article-title":"Parathyroid hormone-related protein(1-36) is biologically active when administered subcutaneously to humans","volume":"82","author":"Henry","year":"1997","journal-title":"J Clin Endocrinol Metab."},{"key":"2024020317585244200_bib25","first-page":"2786","article-title":"Dissociation of bone formation from resorption during two-week treatment with hPTHrP(1-36) in humans: potential as an anabolic therapy for osteoporosis","volume":"83","author":"Plotkin","year":"1998","journal-title":"J Clin Endocrinol Metab."},{"key":"2024020317585244200_bib26","doi-asserted-by":"crossref","first-page":"586","DOI":"10.1093\/clinchem\/42.4.586","article-title":"Quantification of circulating 1,25(OH)2D by RIA with an 125-I-labled tracer","volume":"42","author":"Hollis","year":"1996","journal-title":"Clin Chem."},{"key":"2024020317585244200_bib27","doi-asserted-by":"crossref","first-page":"1345","DOI":"10.1210\/jcem-73-6-1345","article-title":"Response of the parathyroid gland to infusion of human parathyroid hormone (1-34): demonstration of suppression of endogenous secretion using immunoradiometric intact PTH-(1-84) assay","volume":"73","author":"Cosman","year":"1991","journal-title":"J Clin Endocrinol Metab."},{"key":"2024020317585244200_bib28","doi-asserted-by":"crossref","first-page":"244","DOI":"10.1002\/9780470623992.ch51","volume-title":"Primer on the Metabolic Bone Diseases and Disorders of Mineral Metabolism","author":"Cosman","year":"2008","edition":"7th ed"},{"key":"2024020317585244200_bib29","doi-asserted-by":"crossref","first-page":"1138","DOI":"10.1172\/JCI116273","article-title":"An evaluation of several biochemical markers for bone formation and resorption in a protocol utilizing cyclical parathyroid hormone and calcitonin therapy for osteoporosis","volume":"91","author":"Hodsman","year":"1993","journal-title":"J Clin Inves."},{"key":"2024020317585244200_bib30","doi-asserted-by":"crossref","first-page":"4607","DOI":"10.1210\/endo.138.11.5505","article-title":"Effects of programmed administration of human parathyroid hormone fragment (1-34) on bone histomorphometry and serum chemistry in rats","volume":"138","author":"Dobnig","year":"1997","journal-title":"Endocrinology."},{"key":"2024020317585244200_bib31","doi-asserted-by":"crossref","first-page":"2233","DOI":"10.1359\/JBMR.050821","article-title":"Multiple mechanisms are involved in inhibition of osteoblast differentiation by PTHrP and PTH in KS483 Cells","volume":"20","author":"van der Horst","year":"2005","journal-title":"J Bone Miner Res."},{"key":"2024020317585244200_bib32","doi-asserted-by":"crossref","first-page":"2961","DOI":"10.1172\/JCI119491","article-title":"Parathyroid hormone exerts disparate effects on osteoblast differentiation depending on exposure time in rat osteoblastic cells","volume":"99","author":"Ishizuya","year":"1997","journal-title":"J Clin Invest."},{"key":"2024020317585244200_bib33","doi-asserted-by":"crossref","first-page":"5","DOI":"10.1359\/JBMR.041016","article-title":"Comparison of the action of transient and continuous PTH on primary osteoblast cultures expressing differentiation stage-specific GFP","volume":"20","author":"Wang","year":"2005","journal-title":"J Bone Miner Res."},{"key":"2024020317585244200_bib34","doi-asserted-by":"crossref","first-page":"4074","DOI":"10.1210\/en.2005-0480","article-title":"Evidence that the cells responsible for marrow fibrosis in a rat model of hyperparathyroidism are pre-osteoblasts","volume":"146","author":"Lotinun","year":"2005","journal-title":"Endocrinology."},{"key":"2024020317585244200_bib35","first-page":"2210","article-title":"Biochemical markers of bone turnover in lactating and nonlactating postpartum women","volume":"80","author":"Sowers","year":"1995","journal-title":"J Clin Endocrinol Metab."},{"key":"2024020317585244200_bib36","doi-asserted-by":"crossref","first-page":"209","DOI":"10.1016\/S0301-2115(02)00237-3","article-title":"The effects of pregnancy and lactation on hormonal status and biochemical markers of bone turnover","volume":"106","author":"Csaba","year":"2003","journal-title":"Eur J Obstet Gynecol Reprod Biol."},{"key":"2024020317585244200_bib37","first-page":"464","article-title":"Effects of calcium supplementation on calcium homeostasis and bone turnover in lactating women","volume":"84","author":"Kalkwarf","year":"1999","journal-title":"J Clin Endocrinol and Metab."},{"key":"2024020317585244200_bib38","doi-asserted-by":"crossref","first-page":"1312","DOI":"10.1002\/jbmr.5650100907","article-title":"Changes in bone mineral density and markers of bone remodeling during lactation and postweaning in women consuming high amounts of calcium","volume":"10","author":"Cross","year":"1995","journal-title":"J Bone Miner Res."},{"key":"2024020317585244200_bib39","first-page":"1562","article-title":"On the mechanism of cancellous bone preservation in postmenopausal women with mild primary hyperparathyroidism","volume":"84","author":"Dempster","year":"1999","journal-title":"J Clin Endocrinol Metab."},{"key":"2024020317585244200_bib40","doi-asserted-by":"crossref","first-page":"2910","DOI":"10.1172\/JCI117998","article-title":"Hesch R-D. Time series prediction of parathyroid hormone concentration","volume":"95","author":"Prank","year":"1995","journal-title":"J Clin Invest."},{"key":"2024020317585244200_bib41","doi-asserted-by":"crossref","first-page":"3245","DOI":"10.1097\/01.ASN.0000101240.47747.7F","article-title":"Beta adrenergic blockade augments pulsatile PTH secretion in humans","volume":"14","author":"Schmitt","year":"2003","journal-title":"JASN."},{"key":"2024020317585244200_bib42","first-page":"3759","article-title":"Relationships between intact PTH and 24-hour profiles, sleep-wake cycle, and sleep electroencephalographic activity in man","volume":"81","author":"Chapotot","year":"1996","journal-title":"J Clin Endocrinol Metab."},{"key":"2024020317585244200_bib43","doi-asserted-by":"crossref","first-page":"1458","DOI":"10.1359\/jbmr.080411","article-title":"Prevalent verbral fractures in black women and white women","volume":"23","author":"Cauley","year":"2008","journal-title":"J Bone Miner Res."},{"issue":"(Suppl 2)","key":"2024020317585244200_bib44","doi-asserted-by":"crossref","first-page":"v34","DOI":"10.1359\/jbmr.07s220","article-title":"Vitamin D economy in blacks","volume":"22","author":"Cosman","year":"2007","journal-title":"J Bone Miner Res."}],"container-title":["Journal of Bone and Mineral Research"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/api.wiley.com\/onlinelibrary\/tdm\/v1\/articles\/10.1002%2Fjbmr.415","content-type":"unspecified","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/academic.oup.com\/jbmr\/article-pdf\/26\/9\/2287\/56558307\/415_ftp.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/jbmr\/article-pdf\/26\/9\/2287\/56558307\/415_ftp.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2024,4,6]],"date-time":"2024-04-06T14:23:00Z","timestamp":1712413380000},"score":1,"resource":{"primary":{"URL":"https:\/\/academic.oup.com\/jbmr\/article\/26\/9\/2287-2297\/7598007"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2011,5,4]]},"references-count":44,"journal-issue":{"issue":"9","published-online":{"date-parts":[[2011,5,4]]},"published-print":{"date-parts":[[2011,9,1]]}},"URL":"https:\/\/doi.org\/10.1002\/jbmr.415","relation":{},"ISSN":["0884-0431","1523-4681"],"issn-type":[{"value":"0884-0431","type":"print"},{"value":"1523-4681","type":"electronic"}],"subject":[],"published-other":{"date-parts":[[2011,9,1]]},"published":{"date-parts":[[2011,5,4]]}}}