Current
therapy for
secondary hyperparathyroidism in
uremia has relatively poor success in achieving the target levels of
parathyroid hormone (PTH),
calcium and
phosphate established by the NKF-K/DOQI guidelines. The discovery and characterization of a new membrane receptor able to sense minimal Ca changes (CaSR) started intensive research in the attempt to characterize better its functions and its finding compounds, which could modulate its activity. CaSR is expressed not only in the cells that secrete
calcium-regulating hormones (parathyroid cells and thyroid C-cells) and in cells involved in
calcium transport mechanisms (ie intestinal cells, bone-forming osteoblasts, and cells of different nephron segments), but also in other tissues with, as yet, a not completely defined role. CaSR stimulation by the agonists is followed by the activation of a great number of
G-proteins mediated intracellular signalling pathways (PLC, PLA,
PLD, PKC, PKA, etc). At the level of parathyroid cells, the main effect is the increase in IP3, followed by a mobilization of intracellular Ca stores, which inhibit PTH secretion in a few seconds or minutes. Long-term CaSR stimulation is also able to induce a reduction in both PTH synthesis and parathyroid cell proliferation. More than 100 mutations of the gene coding for CaSR have been described. Some of these mutations are matched by a gain or reduction/loss of function. Notwithstanding, CaSR is widely represented on different tissue cells, the main clinical manifestations of the above genetic changes mainly involve PTH and
calcium metabolism. A great number of inorganic and organic
cations can interact with the Ca-sensitive N-terminus domain of CaSR, mimicking Ca effects (type I calcimimetics), but these substances have substantial limitations for use in clinical practice. A second class of compounds was produced (NPS R-467, S-467, R-568, S-568,
AMG 073), for use in the clinical setting, type II calcimimetics. These compounds, after having interacted with the membrane-spanning domains of the CaSR, induce conformational changes in the N-terminus domain, increasing its affinity for Ca. The preclinical experiences with calcimimetics demonstrated that they were effective in reducing circulating PTH, preventing the progression of
secondary hyperparathyroidism, suppressing parathyroid cell proliferation, and reversing
osteitis fibrosa at least in animal models. Clinical studies were performed mainly using
AMG 073, due to its greater bioavailability and more consistent pharmacokinetic profile. Clinical studies performed in
primary hyperparathyroidism proved
AMG 073 to be effective in reducing both PTH and Ca serum levels, with a good safety profile. Further studies, mainly focused on the efficacy of
AMG 073 in the control of
secondary hyperparathyroidism in
uremia, confirmed the efficacy of this compound in reducing PTH levels >30% in about 50% of patients. Furthermore, the fall in PTH was matched by a reduction in both
calcium and
phosphate serum levels of about 5-7%, with a significant reduction in
calcium x
phosphate product (about 15%). The latter aspect represents a unique pharmacological profile, as compared to all the other available therapeutic means to control
secondary hyperparathyroidism in
uremia. In addition to their effectiveness, calcimimetics present a relatively safe profile, the only adverse events referred to consist of transient and easily remediable hypocalcemic episodes and some gastrointestinal discomfort symptoms. However, although calcimimetics represent a real advancement in the field of treating
secondary hyperparathyroidism in uremic patients, their use should be matched by the awareness that previously the success of a high number of new drugs proposed have been flawed by negative consequences in the long term. Therefore, strict clinical control is necessary in the next few years when the use of these new compounds will widen.