title: A 7-day continuous infusion of PTH or PTHrP suppresses bone formation and uncouples bone turnover.
abstract: Human in vivo models of primary hyperparathyroidism (HPT), humoral hypercalcemia of malignancy (HHM), or lactational bone mobilization for more than 48 hours have not been described previously. We therefore developed 7-day continuous-infusion models using human parathyroid hormone(1-34) [hPTH(1-34)] and human parathyroid hormone-related protein(1-36) [hPTHrP(1-36)] in healthy human adult volunteers. Study subjects developed sustained mild increases in serum calcium (10.0 mg/dL), with marked suppression of endogenous PTH(1-84). The maximal tolerated infused doses over a 7-day period (2 and 4 pmol/kg/h for PTH and PTHrP, respectively) were far lower than in prior, briefer human studies (8 to 28 pmol/kg/h). In contrast to prior reports using higher PTH and PTHrP doses, both 1,25-dihydroxyvitamin D(3) [1,25(OH)(2) D(3) ] 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.
authors.affiliation: Division of Endocrinology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA. horwitz@pitt.edu
authors.forename: Mara J
authors.initials: MJ
authors.lastname: Horwitz
authors.forename: Mary Beth
authors.initials: MB
authors.lastname: Tedesco
authors.forename: Susan M
authors.initials: SM
authors.lastname: Sereika
authors.forename: Linda
authors.initials: L
authors.lastname: Prebehala
authors.forename: Caren M
authors.initials: CM
authors.lastname: Gundberg
authors.forename: Bruce W
authors.initials: BW
authors.lastname: Hollis
authors.forename: Alessandro
authors.initials: A
authors.lastname: Bisello
authors.forename: Adolfo
authors.initials: A
authors.lastname: Garcia-Ocaña
authors.forename: Raquel M
authors.initials: RM
authors.lastname: Carneiro
authors.forename: Andrew F
authors.initials: AF
authors.lastname: Stewart
mesh_terms: D000328:Adult; D015415:Biomarkers / Q000097:blood; D016723:Bone Remodeling / Q000187:drug effects*; D001862:Bone Resorption / Q000097:blood; D002117:Calcitriol / Q000097:blood; D002118:Calcium / Q000097:blood; D003710:Demography; D005260:Female; D006801:Humans; D007262:Infusions, Intravenous; D007477:Ions; D007668:Kidney / Q000378:metabolism; D008297:Male; D008903:Minerals / Q000378:metabolism; D010012:Osteogenesis / Q000187:drug effects*; D010281:Parathyroid Hormone / Q000008:administration & dosage* / Q000097:blood / Q000494:pharmacology*; D044162:Parathyroid Hormone-Related Protein / Q000008:administration & dosage* / Q000494:pharmacology*; D010758:Phosphorus / Q000097:blood; D013997:Time Factors; D055815:Young Adult
chemical_list: D015415:Biomarkers; D007477:Ions; D008903:Minerals; D010281:Parathyroid Hormone; D044162:Parathyroid Hormone-Related Protein; D010758:Phosphorus; D002117:Calcitriol; D002118:Calcium