Continuous PTH and PTHrP Infusion Causes Suppression of Bone Formation and Discordant Effects on 1,25(OH)2Vitamin D

Abstract

Introduction: 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. Materials and 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.

Maternal Mineral and Bone Metabolism During Pregnancy, Lactation, and Post-Weaning Recovery

“…The increase in PTHrP may imply that it is responsible for stimulating renal 1␣-hydroxylase (Cyp27b1). However, other data suggest that PTHrP may not be as potent as PTH in stimulating Cyp27b1 in vivo (308,413,414,494,988). The extent to which PTHrP stimulates the rise in calcitriol during pregnancy remains to be tested in animal models.…”

“…PTHrP reaches peak levels during lactation and likely stimulates Cyp27b1, but there is some evidence that it may be less potent than PTH in stimulating Cyp27b1 (308,413,414,494,988). C) SUMMARY.…”

Bone Development and Mineral Homeostasis in the Fetus and Neonate: Roles of the Calciotropic and Phosphotropic Hormones

“…As noted below, PTHrP circulates at high levels in fetal blood and through its mimicry of PTH action on the PTH/PTHrP receptor it might stimulate high fetal calcitriol concentrations. However, systematic studies of PTH1R binding and signaling induced by NH 2 -terminal PTH and PTHrP, comparison of their crystal structures, and clinical studies of the effect of NH 2 -terminal PTH and PTHrP infusions, suggest that PTHrP is much less potent than PTH at stimulating the 1␣-hydroxylase (195,269,270,740; reviewed in detail in Ref. 333).…”

Plasma parathyroid hormone-related peptide and bone metabolism in periparturient dairy cows

“…Demineralisation of the skeleton observed in humans during lactation appears to be mediated by PTHrP released from the breast tissue, combined with the effects of low oestrogen levels on the bone turnover (Kovacs, 2005). Although the locally produced PTHrP is a bone anabolic agent (Miao et al, 2005) and given in low doses during a longer period of time, human PTHrP (1-74) is an anabolic for bone (Weir et al, 1992), when administered in continuously high doses, PTHrP stimulates bone resorption and suppresses bone formation, which is equivalent to the effects of PTH in humans (Horwitz et al, 2005). PTHrP binds to, and exerts an effect on the same receptor as PTH -the type 1 PTH receptor (PTHR1) (Juppner, 1999).…”