Optimal dosing and delivery of parathyroid hormone and its analogues for osteoporosis and hypoparathyroidism - translating the pharmacology

Abstract

In primary hyperparathyroidism (PHPT), bone loss results from the resorptive effects of excess parathyroid hormone (PTH). Under physiological conditions, PTH has actions that are more targeted to homeostasis and to bone accrual. The predominant action of PTH, either catabolic, anabolic or homeostatic, can be understood in molecular and pharmacokinetic terms. When administered intermittently, PTH increases bone mass, but when present continuously and in excess (e.g. PHPT), bone loss ensues. This dual effect of PTH depends not only on the dosing regimen, continuous or intermittent, but also on how the PTH molecule interacts with various states of its receptor (PTH/PTHrP receptor) influencing downstream signalling pathways differentially. Altering the amino-terminal end of PTH or PTHrP could emphasize the state of the receptor that is linked to an osteoanabolic outcome. This concept led to the development of a PTHrP analogue that interacts preferentially with the transiently linked state of the receptor, emphasizing an osteoanabolic effect. However, designing PTH or PTHrP analogues with prolonged state of binding to the receptor would be expected to be linked to a homeostatic action associated with the tonic secretory state of the parathyroid glands that is advantageous in treating hypoparathyroidism. Ideally, further development of a drug delivery system that mimics the physiological tonic, circadian, and pulsatile profile of PTH would be optimal. This review discusses basic, translational and clinical studies that may well lead to newer approaches to the treatment of osteoporosis as well as to different PTH molecules that could become more advantageous in treating hypoparathyroidism.

Keywords: PTH; PTHrP; abaloparatide; clinical pharmacology; hypoparathyroidism; osteoporosis; parathyroid hormone; primary hyperparathyroidism.

Figure 1

Binding selectivity for the different conformational states of the parathyroid hormone/PTHrP receptor leads to differential effects on downstream signalling. The preferential binding of abaloparatide for the R^G state elicits a transient cyclic AMP signalling response favouring a more anabolic effect whereas teriparatide has a preferential binding for the R⁰ state and portends towards a more prolonged cyclic AMP signalling response and a more pronounced catabolic effect

Figure 2

The two panels show the relative binding affinities of abaloparatide and teriparatide to two distinct parathyroid hormone (PTH)/PTHrP conformations (R^G and R⁰). ¹²⁵I–M‐PTH (1–15) is the competitive tracer radioligand that binds selectively to the R^G conformation while ¹²⁵I–PTH (1–34) is the competitive tracer radioligand that binds selectively to the R⁰ conformation (adapted from 104)

Figure 3

Representative using high‐resolution peripheral quantitative computed tomography images of the distal radius of a patient with primary hyperparayhyroidism (A) and a healthy subject (B) 44

Figure 4

Median change from baseline in the serum bone formation (s‐PINP) and resorption (s‐CTX) marker over time during placebo, teriparatide and abaloparatide treatment of postmenopausal women with osteoporosis (n = 184 placebo, n = 189 abaloparatide, and n = 227 teriparatide participants) 107

Figure 5

Schematic of physiological system model to describe calcium homeostasis and bone remodelling 97

Figure 6

Daily steady‐state changes in plasma calcium (dashed line, left axis) and parathyroid hormone (PTH; solid line, right axis) predicted by the model after 1 month of once‐daily PTH 1–34 administration (20 μg teriparatide) 97

Figure 7

Percent of baseline (%) following once‐daily PTH 1–34 (20 μg teriparatide) administration for (A) plasma calcium (solid line) and phosphate (dot dash line), (B) plasma PTH (solid grey line) and calcitriol (solid line), and (C) bone‐related osteoclast (dashed line) and osteoblast (solid line). The solid bands in panels (A) and (B) represent the peak‐to‐trough fluctuations in plasma calcium (A) and PTH (B), respectively. Circles (O) and triangles (Δ) represent observed urine N‐telopeptide and bone‐specific alkaline phosphatase (C), respectively 97

Figure 8

Primary hyperparathyroidism instituted in the model as a progressive increase in endogenous parathyroid gland production of parathyroid hormone (PTH) to affect an approximate 3‐fold increase in plasma PTH leading to percent of baseline (%) values for (A) plasma calcium (dashed line) and phosphate (solid line), (B) plasma PTH (dashed line) and calcitriol (solid line), and (C) bone‐related osteoclast (dashed line) and osteoblast (solid line) function. A horizontal reference (dotted line) is included on each figure at the baseline value of 100% 97

Figure 9

Primary hypoparathyroidism instituted in the model as an immediate 50% lowering of endogenous parathyroid gland production of parathyroid hormone (PTH) leading to changes in percent of baseline (%) for (A) plasma calcium (dashed line) and phosphate (solid line), (B) plasma PTH (dashed line) and calcitriol (solid line), and (C) bone‐related osteoclast (dashed line) and osteoblast (solid line) function. A horizontal reference (dotted line) is included on each figure at the baseline value of 100% 97