Continuous PTH and PTHrP infusion causes suppression of bone formation and discordant effects on 1,25(OH)2 vitamin D.
Osteoblast activity and plasma 1,25(OH)2 vitamin D are increased in HPT but suppressed in HHM. To model HPT and HHM, we directly compared multiday continuous infusions of PTH versus PTHrP in humans. Continuous infusion of both PTH and PTHrP results in marked and prolonged suppression of bone formation; renal 1,25(OH)2D synthesis was stimulated effectively by PTH but poorly by PTHrP.


BACKGROUND
PTH and PTH-related protein (PTHrP) cause primary hyperparathyroidism (HPT) and humoral hypercalcemia of malignancy (HHM), respectively. Whereas HHM and HPT resemble one another in many respects, osteoblastic bone formation and plasma 1,25(OH)2 vitamin D are increased in HPT but reduced in HHM.


METHODS
We performed 2- to 4-day continuous infusions of escalating doses of PTH and PTHrP in 61 healthy young adults, comparing the effects on serum calcium and phosphorus, renal calcium and phosphorus handling, 1,25(OH)2 vitamin D, endogenous PTH(1-84) concentrations, and plasma IGF-1 and markers of bone turnover.


RESULTS
PTH and PTHrP induced comparable effects on renal calcium and phosphorus handling, and both stimulated IGF-1 and bone resorption similarly. Surprisingly, PTH was consistently more calcemic, reflecting a selectively greater increase in renal 1,25(OH)2 vitamin D production by PTH. Equally surprisingly, continuous infusion of both peptides markedly, continuously, and equivalently suppressed bone formation.


CONCLUSIONS
PTHrP and PTH produce markedly different effects on 1,25(OH)2 vitamin D homeostasis in humans, leading to different calcemic responses. Moreover, both peptides produce profound suppression of bone formation over multiple days, contrasting with events in HPT, but mimicking HHM. These findings underscore the facts that the mechanisms underlying the anabolic skeletal response to PTH and PTHrP in humans is poorly understood, as are the signal transduction mechanisms that link the renal PTH receptor to 1,25(OH)2 vitamin D synthesis. These studies emphasize that much remains to be learned regarding the normal regulation of vitamin D metabolism and bone formation in response to PTH and PTHrP in humans.
Horwitz
Mara J
MJ
Division of Endocrinology, The University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 15213, USA.
Tedesco
Mary Beth
MB
Sereika
Susan M
SM
Syed
Mushtaq A
MA
Garcia-Ocaña
Adolfo
A
Bisello
Alessandro
A
Hollis
Bruce W
BW
Rosen
Clifford J
CJ
Wysolmerski
John J
JJ
Dann
Pamela
P
Gundberg
Caren
C
Stewart
Andrew F
AF
D000328:Adult; D050071:Bone Density Conservation Agents / Q000008:administration & dosage*; D002117:Calcitriol / Q000097:blood*; D002118:Calcium / Q000097:blood; D005260:Female; D006801:Humans; D006934:Hypercalcemia / Q000097:blood* / Q000139:chemically induced; D008297:Male; D010006:Osteoblasts / Q000378:metabolism; D010012:Osteogenesis / Q000187:drug effects*; D044162:Parathyroid Hormone-Related Protein / Q000008:administration & dosage*; D019379:Teriparatide / Q000008:administration & dosage*
D050071:Bone Density Conservation Agents; D044162:Parathyroid Hormone-Related Protein; D019379:Teriparatide; D002117:Calcitriol; D002118:Calcium