Partial attenuated PTH suppression of calcimimetics may be due to the resulting hypocalcemia or a significant decrease in serum calcium levels within the normal reference range without adequate calcium supplementation

Certain dialysis patients with secondary hyperparathyroidism (SHPT) show partial insensitivity to calcimimetics. These agents are allosteric activators of the calcium-sensing receptor (CaSR) and enhance their sensitivity to extracellular calcium, thereby inhibiting parathyroid hormone (PTH) secretion and eliciting a decrease in serum calcium levels. We hypothesize that the partial attenuated PTH suppression of calcimimetics may be due to the resulting hypocalcemia or a significant decrease in serum calcium levels within the normal range without adequate calcium supplementation. Effective suppression of PTH by calcimimetics inevitably lowers serum calcium levels, which may be further aggravated by ongoing bone mineralization following PTH suppression. This hypocalcemic state or decreased extracellular ionized calcium, if not adequately corrected, acts as a strong trigger for excessive PTH secretion through reducing CaSR activation and stimulating parathyroid chief cells and causing hypertrophy and hyperplasia of parathyroid glands, and then establishing a counter-regulatory feedback circuit that diminishes the therapeutic effect of calcimimetics. High incidence of hypocalcemia, observed in clinical trials of calcimimetics, also bolsters the validity of this hypothesis. Such adverse outcomes may be partially alleviated by timely and adequate calcium and vitamin D supplementation.