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 seven-day continuous infusion models using hPTH(1–34) and 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 seven-day period (2 and 4 pmol/kg/hr, for PTH and PTHrP, respectively) were far lower than in prior, briefer human studies (8–28 pmol/kg/hr). In contrast to prior reports using higher PTH and PTHrP doses, both 1,25(OH)2D and 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 30–40% for the seven 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 is 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.

Mechanisms of vasodilation to PTH 1–84, PTH 1–34, and PTHrP 1–34 in rat bone resistance arteries

“…In conditions such as hyperparathyroidism, PTH 1-84 is continuously produced and released, activates bone resorption, and leads to bone loss [6]. Hypercalcemia, hypercalciuria, augmented bone resorption, and retarded bone formation resulted following 7 days of constant infusion of PTH 1-34 and PTHrP 1-36 in healthy humans [7]. In contrast, intermittent administration (i.e., given as single injections per day) of PTH 1-84, PTH 1-34, and PTHrP 1-36, served to augment bone mass and/or bone mineral density [8][9][10][11][12][13].…”

Mechanical, hormonal and metabolic influences on blood vessels, blood flow and bone

“…The main role of PTH 1–84 is to maintain serum calcium homeostasis and this occurs via bone resorption and calcium retention (Kousteni & Bilezikian 2008). Continual release of PTH 1–84 or administration of PTH 1–34 and PTHrP 1–36 caused declines in bone mineral density and bone formation and increased bone resorption (Hansen et al 2010; Horwitz et al 2011); however, when administered intermittently (e.g., one injection per day), PTH causes bone gain (Stewart et al 2000; Prisby et al 2011; Prisby et al 2013). Further, the anabolic actions of intermittent PTHrP administration have been explored (Amizuka et al 1996; Stewart et al 2000; Horwitz et al 2003; Miao et al 2005; de Castro et al 2012) and are under clinical consideration (Leder et al 2015).…”

Prevention of breast cancer skeletal metastases with parathyroid hormone

“…While the two ligands show very similar response profiles in activating various signaling pathways, the net effects of PTH or PTHrP on bone are dependent on the duration and exposure. For example, while intermittent administration of PTH or a PTHrP analog results in bone formation (28,29), continual infusion of PTH or PTHrP results in increased resorption (30). Activation of the PTH1R receptor leads to regulation of multiple signaling pathways, including the PKA and PKC pathways.…”