Rapid development of renal resistance to low doses of synthetic bovine parathyroid hormone fragment 1-34. Dissociation of urinary cyclic adenosine monophosphate, phosphaturic, and calciuric responses.

Abstract

A B S T R A C T The designing of parathyroid hormone (PTH)-renal dose-response studies in human beings is complicated by the possibility of rapid homologous receptor down-regulation, a phenomenon that is clearly shown to occur in vitro. Large amounts of PTH given to human subjects as serial injections or prolonged infusions cause decreased urinary 3',5'-cyclic adenosine monophosphate (cAMP) responses to subsequent PTH doses, but it is uncertain whether lower doses given over shorter periods similarly cause renal tachyphylaxis to PTH action. Thus, in seven water-loaded adults, we infused in ascending order 10, 30, 75, 150, and 300 U of synthetic bovine PTH fragment (bPTH 1-34) per 70 kg body wt over 15 min on widely separated days ("separate day administration"). On another day, each subject received all five 15-min doses in ascending order at 75-min intervals ("single day administration"). Urine collection intervals were control, 0-30 min (including the PTH infusion), and 30-60 min. Peak nephrogenous cAMP (NcAMP, nmol/100 ml glomerular filtrate) response was linearly related to the dose of PTH (separate day study, r = 0.94, P < 0.001; single day study, r = 0.88, P < 0.001). However, the slope of NcAMP responses plotted against PTH dose for the single day study was only 36% of that derived from separate day administration of the same PTH doses (P < 0.001). After only 40 U (10 + 30) of bPTH 1-34/70 kg, the NcAMP response to 75 U was reduced 44%, and the effect of 300 U/70 kg, when given as the last of the sequential single day infusions, was 64% less than the response to 300 U of bPTH 1-34 given alone (P < 0.001). The phosphaturic response (fractional excretion of phosphorus, FEP [percent]) was also linearly related to bPTH 1-34 dose, but combined administration of the PTH infusions on one day increased FEP at each dose identically with the effects of separate day administration. A transient, dose-related, early hypercalciuric response to bPTH 1-34 also occurred, and was of equal magnitude in both protocols. These studies demonstrate that significant blunting of the NcAMP response to bPTH 1-34 occurs rapidly and follows brief exposure to relatively low doses of hormone. In contrast, there is no effect of recent PTH administration on the phosphaturic and early hypercalciuric actions of bPTH 1-34. This seeming dissociation of PTH effects makes unclear the physiologic importance of PTH-induced cAMP tachyphylaxis in the regulation of final PTH actions. In any case, studies of NcAMP responses in which the occurrence of tachyphylaxis would be undesirable should be designed to avoid prolonged or closely spaced administrations of the hormone. INTRODUCTION The acute administration of exogenous parathyroid hormone (PTH)' causes increased urinary excretion of

Parathyroid Hormone and Glucocorticoid-induced Osteoporosis

“…PTH tonic secretory rate in the GC-treated group was approximately half of the control group, whereas fractional pulsatile PTH secretion was more than doubled (with reduced intervals between peaks) in the GC-treated vs. control groups (P = < 0.01). 42 These abnormalities in PTH secretory dynamics may strengthen the concept that the modality of administration of exogenous PTH is critical for its biological actions and should mimic by the extent that is pharmacologically possible its physiological pattern of secretion [37][38][39][40][41] and give an insight into the efficacy of exogenous intermittent PTH treatment in GIOP. 43 In fact, this redistribution of spontaneous PTH secretion may be interpreted as a compensatory, though inadequate, response to chronic GC excess triggered by low circulating levels of vitamin D or by signals generated from bone such as RANKL-OPG and IGF-I in which GC and PTH have diametrically opposite effects.…”

Episodic Secretion of Parathyroid Hormone in Postmenopausal Women: Assessment by Deconvolution Analysis and Approximate Entropy

“…Continuous PTH administration to animals causes increased bone resorption, variable increases in bone formation, and no net increases in bone volume, while the same PTH doses given as daily injections increase trabecular bone volume (5,6) . Finally, continuous exposure to PTH down‐regulates PTH receptors and decreases PTH‐stimulated adenylate cyclase activity in bone cells or renal cortical membranes (7‐9) . Thus, intermittent exposure of bone remodeling units to PTH may be optimal for the coupling of bone formation and resorption, while loss of PTH pulses and exposure of bone remodeling units to constant PTH levels may contribute to net bone loss and eventual osteoporosis (33) .…”

“…Other human, animal, and in vitro studies suggest that the parathyroidbone axis depends on a pulsatile PTH secretory pattern, and intermittent administration of exogenous PTH enhances bone formation. (2)(3)(4)(5)(6)(7)(8)(9) Finally, reports in small numbers of postmenopausal women suggest that abnormal PTH pulsatility may be associated with osteoporosis. (10,11) However, it is not known whether estrogen deficiency or low bone mass correlate with alterations in basal or pulsatile PTH secretion in postmenopausal women.…”

“…Available studies suggest that PTH is secreted in a dual fashion in healthy young men and women, i.e., in a predominantly tonic mode with superimposed pulses occurring every 15–20 minutes. Other human, animal, and in vitro studies suggest that the parathyroid–bone axis depends on a pulsatile PTH secretory pattern, and intermittent administration of exogenous PTH enhances bone formation (2‐9) . Finally, reports in small numbers of postmenopausal women suggest that abnormal PTH pulsatility may be associated with osteoporosis (10,11) .…”

Synthetic Human Parathyroid Hormone- (1–34) for the Study of Pseudohypoparathyroidism*

“…Other synthetic forms of PTH have been reported to be useful diagnostically, most notably synthetic bovine PTH-(l-34) (14) and synthetic PTH-(1-38) (15), but probably have no particular advantage over the preparation we used.…”