Parathyroid hormone-related protein for the treatment of postmenopausal osteoporosis: defining the maximal tolerable dose

Abstract

Context: PTH is the only approved skeletal anabolic agent for the treatment of human osteoporosis. Unlike PTH, which is a mixed anabolic and catabolic agent, PTHrP displays features suggesting that it may be a pure anabolic agent when intermittently administered. The full dose range of PTHrP is unknown.

Objectives: The primary objective of the study was to define the complete therapeutic window and dose-limiting toxicities of PTHrP. The secondary objective was to determine whether PTHrP retains a pure anabolic profile at the highest usable doses.

Design: This was a single-blinded, two-part, dose-escalating clinical trial.

Setting: The study was conducted in a university academic setting.

Patients or other participants: Participants included 41 healthy postmenopausal women between the ages of 45 and 75 yr.

Intervention: INTERVENTIONs included PTHrP(1-36) or placebo in a dose-escalating design for 3 wk.

Main outcome measures: Safety measures (hypercalcemia, nausea, vomiting, hemodynamics, flushing, miscellaneous) and bone turnover markers were measured.

Results: Intermittent PTHrP was administered safely and without serious adverse events in subjects receiving 500 and 625 microg/d for 3 wk. Subjects receiving 750 microg/d developed mild hypercalcemia. Bone turnover markers suggested that even at the highest doses, daily sc PTHrP may not activate bone resorption, i.e. may be purely anabolic. Interestingly, when hypercalcemia occurred, it may have resulted not from bone resorption but from activation of intestinal calcium absorption by 1,25 dihydroxyvitamin D.

Conclusions: In doses as high as 750 microg/d, in contrast to PTH, intermittently administered PTHrP appears to act as a pure skeletal anabolic agent. Surprisingly, PTHrP in the high doses studied activates 1,25 dihydroxyvitamin D production. Dosing information obtained herein can be used to design a longer term head-to-head comparative efficacy trial of PTHrP vs. PTH.

Figure 1

Bone turnover markers In subjects treated with PTHrP for 3 wk: selective activation of bone formation. Error bars indicate se of individual data points. In this and subsequent figures, when error bars are not visible, they are small and hidden within the corresponding symbol. The color code is shown in A. A, Serum osteocalcin measurements in the four groups. The changes at 500, 625, and 750 μg/d were statistically significant (P < 0.05 vs. placebo). B, Serum P1NP measurements. The changes at 500 and 625 μg/d were statistically significant (P < 0.01 vs. placebo and over time). C, Serum NTX measurements. There were no statistically significant differences over time. D, Serum CTX measurements. There were no statistically significant differences. Note that PTHrP treatment activated both of the two markers of bone formation but had no effects on resorption.

Figure 2

Total and ionized serum calcium on d 1–21 and at multiple times throughout d 21. Error bars and group symbols/colors are as in Fig. 1. A, Total serum calcium over the 21 d of the study. PTHrP treatment had no statistically significant effect on total serum calcium in the 500 μg/d group but transient and mild effects on the 625 μg/d group (P < 0.04 vs. placebo d 5 and 10, P < 0.005 over time). Three of six subjects in the 750 group became mildly hypercalcemic (P < 0.004 vs. placebo on d 10) and were discontinued on d 5–10 according to protocol. Accordingly, values for the 750 μg/d shown on d 15–21 in this and subsequent figures do not include these three subjects. See text for details. B, Ionized serum calcium over the 21 d of the study. Again, there was no statistically significant change in the 500 μg/d group, but both the 625 and 750 μg groups did develop statistically significant hypercalcemia (P < 0.03). C, Total serum calcium over the final 24 h of the study. There was a statistically significant increase in the 750 μg/d group at 6 and 12 h after dose (P < 0.05 vs. placebo) but no statistically significant changes over time in the other groups. D, Ionized serum calcium over the final 24 h of the study. There were no statistically significant changes over time in any of the groups. Multiply total and ionized calcium values by 0.25 to convert milligrams per deciliter to millimoles per liter.

Figure 3

Serum PTH, 1,25(OH)₂D, and urinary calcium excretion in the four groups. Error bars and group symbols are as in Fig. 1. A, Endogenous PTH (1-84) declined in all three PTHrP groups (P < 0.01 vs. placebo). To convert picograms per milliliter to picomoles, divide by 10. B, 1,25(OH)₂D increased in each PTHrP group during the study (P < 0.03 over time). To convert to picomoles per liter, multiply by 2.6. C, Fasting fractional calcium excretion. Whereas the four groups began the study with different values, reflecting the small numbers of subjects, there was no significant change over time in any of the four groups during the study. D, Twenty-four-hour calcium excretion on d 0 and d 21 of the study. Note that whereas fasting fractional calcium excretion did not increase with treatment (C), 24-h urine calcium excretion did tend to increase during the study, although these changes achieved statistical significance only in the 625 μg/d group (P < 0.0001 over time, P < 0.05 vs. placebo). Also note that only 10 of 15 placebo subjects and five of 10 subjects in the 500 μg/d and placebo groups had these measurements because they were added to the protocol after the initial 10 subjects were enrolled.

Figure 4

Individual changes in 24-h urine calcium in the four groups. Symbols and colors are as in Fig. 1. Samples were collected at baseline on d 21 or termination of the study in subjects reaching DLT. Horizontal bars represent the mean for each time point. A, Individual placebo subjects (n = 10). B, Individual subjects receiving PTHrP 500 μg/d (n = 5). C, Individual subjects receiving PTHrP 625 μg/d (n = 10). D, Individual subjects receiving PTHrP 750 μg/d (n = 6).