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.

Trial registration: ClinicalTrials.gov NCT00377312 NCT00580788.

Copyright © 2011 American Society for Bone and Mineral Research.

Figures

Figure 1. Changes in Serum Calcium, Phosphorus

Total Serum Calcium (Upper Left). The legend describes the line colors and symbols for the five patient groups. The light grey bar in the middle of the panel indicates the baseline calcium concentration (9.65 ± 0.07 mg/dl) (mean ± SD). The dark grey bar in the top of the panel indicates the duration of the PTH and PTHrP infusions. Vertical bars indicate SEM. There was no statistical difference among the groups at baseline (p = 0.3) but there was a statistically significant increase over time in the 2 pmol/kg/hr PTH and 4 pmol/kg/hr PTHrP groups (p <0.0001). There was no statistically significant difference in calcemic response between these two groups. Ionized Serum Calcium. (Upper Right). There was no difference among the groups at baseline, but there was a statistically significant increase in time for both the 2 pmol/kg/hr PTH and 4 pmol/kg/hr PTHrP groups (p <0.0001). Serum Phosphorus (Lower Panel). There were no significant differences in serum phosphorus at baseline, nor important changes during the infusions.

Figure 2. Changes in Endogenous PTH(1–84) and Plasma 1,25(OH)2D

See Figure 1 for explanation of bar, line and symbol colors. Endogenous serum PTH declined rapidly and robustly during the PTH and PTHrP infusions, even in the PTHrP 2 pmol/kg/hr group in which serum calcium did not appreciably change. Plasma 1,25(OH)2D did not increase in response to the infusions, and actually decreased by Day 8 for the PTHrP 4 pmol/kg/hr group (p = 0.01).

Figure 3. Changes in Renal Calcium and Phosphorus Excretion

See Figure 1 for explanation of bar, line and symbol colors. Fractional Calcium Excretion (Upper Left). The upper light bar represents the fractional calcium excretion (mean ±SD = 6.5) in response to a calcium infusion in which the serum calcium was “clamped” at 10.3 mg/dl, and endogenous PTH suppressed by infusion of calcium chloride (16). Fractional calcium excretion increased significantly (p = 0.002) during the infusion, reflecting the increase in filtered calcium load, but was far below the 6.5% range observed with similar degrees of hypercalcemia and filtered load observed with the calcium clamp, revealing comparable anti-calciuric effects of PTH and PTHrP even at these low doses. 24 Hour Calcium Excretion (Upper Right). 24 hour calcium excretion, expressed as calcium per gm of creatinine, obtained at the conclusion of the study approached the hypercalciuric range. The mean 24-hour urine creatinine in the two MTD groups were 1.06 ± 0.3 and 1.49 ± 0.1 for the PTH and PTHrP groups, respectively. TmP/GFR (Bottom Panel). There were no changes in TmP/GFR, indicating that these low doses of PTH and PTHrP did not induce phosphaturia.

Figure 4

A. Changes in Bone Resorption Markers. See Figure 1 for explanation of bar, line and symbol colors. Both serum NTX and CTX increased rapidly, and significantly in response to low-dose PTH and PTHrP infusion (p < 0.008 and p < 0.0001, respectively), and declined abruptly with cessation of the infusions. B. Changes in Bone Formation Markers. Serum P1NP was suppressed and remained so throughout the 7-day infusions(p< 0.0001), and promptly rebounded with cessation of the infusions (p=0.01). BSAP also declined significantly during the course of the study (p = 0.0001), but less robustly than for P1NP. The significant decline is mostly attributable to the PTHrP 4 pmol/kg/hr group (P=0.001).

Figure 4

A. Changes in Bone Resorption Markers. See Figure 1 for explanation of bar, line and symbol colors. Both serum NTX and CTX increased rapidly, and significantly in response to low-dose PTH and PTHrP infusion (p < 0.008 and p < 0.0001, respectively), and declined abruptly with cessation of the infusions. B. Changes in Bone Formation Markers. Serum P1NP was suppressed and remained so throughout the 7-day infusions(p< 0.0001), and promptly rebounded with cessation of the infusions (p=0.01). BSAP also declined significantly during the course of the study (p = 0.0001), but less robustly than for P1NP. The significant decline is mostly attributable to the PTHrP 4 pmol/kg/hr group (P=0.001).