Can calcimimetics inhibit parathyroid hyperplasia? Evidence from preclinical studies.

The cells of the parathyroid gland secrete parathyroid hormone (PTH), which plays a pivotal role in maintaining circulating levels of ionized calcium (Ca2þ) within a narrow physiological range. The main actions of PTH include (i) releasing calcium and phosphorus from bone, (ii) decreasing renal calcium excretion, (iii) increasing urinary phosphorus excretion and (iv) stimulating renal production of calcitriol (1,25dihydroxy vitamin D3), the active form of vitamin D. Vitamin D and its receptors (VDRs) also play key roles in calcium homeostasis: vitamin D acts on VDRs in the intestine to increase calcium absorption, and on VDRs in parathyroid cells to inhibit PTHmRNA synthesis [1]. Secondary hyperparathyroidism (SHPT) represents an adaptive response to the progressively impaired control of calcium, phosphorus and vitamin D in chronic kidney disease (CKD). It is characterized by parathyroid hyperplasia and excessive synthesis and secretion of PTH, resulting in excessive bone resorption, soft-tissue and vascular calcification and significantly increased risk for cardiovascular morbidity and mortality [2,3]. Extracellular calcium is the primary physiological stimulus regulating secretion of PTH and there is an inverse, sigmoidal relationship between the levels of plasma PTH and calcium. A cell surface receptor located on parathyroid cells, the calcium-sensing receptor (CaR), has been recognized as the primary mechanism that mediates the effects of Ca2þ on PTH secretion [4,5]. The CaR also appears to play a key role in the excessive cell proliferation that occurs in parathyroid hyperplasia [5]. Drugs that mimic or potentiate the action of Ca2þ at this receptor, calcimimetics, have become available for treatment of dialysis patients (CKD stage 5) with insufficient control of PTH and calcium and/or phosphate levels on traditional therapies [6]. This article overviews the key pathophysiological mechanisms that drive parathyroid hyperplasia in SHPT and examines the potential of calcimimetics for attenuating this condition, based on emerging data from animal models.