Structural organization and biological relevance of oscillatory parathyroid hormone secretion

Abstract

Parathyroid gland secretory activity exhibits seasonal and circadian fluctuations, which are in synchrony with changes in serum calcium, phosphate, and bone turnover. In addition, an ultradian rhythm exists, which comprises seven pulses per hour, accounts for 30% of basal parathyroid hormone (PTH) release, and is highly sensitive to changes in ionized calcium. Acute hypocalcemia induces a selective, severalfold increase in pulse frequency and amplitude, whereas hypercalcemia suppresses the pulsatile secretion component, as does prolonged calcitriol therapy. Chronic renal failure is associated with a GFR dependent decrease in metabolic PTH clearance accounting for a two- to threefold increase in plasma PTH concentrations, a consistent increase of PTH burst mass and frequency, and a markedly reduced capacity to counteract changes in ionized calcium by modulation of pulsatile PTH release. Continuous PTH excess destroys bone, whereas intermittent administration of pharmacological doses of PTH improves bone morphology and strength in experimental and clinical settings. The molecular mechanisms of the exposure pattern dependent, contrasting biological effects of PTH may involve differential regulation of osteoblastic G protein signaling feedback circuits. In this context, calcimimetic and calcilytic agents are promising new therapeutic tools allowing for tight control of plasma PTH and restoration of circadian PTH rhythmicity.