**4. Calcimimetics**

Calcimimetics are allosteric modulators of the calcium sensing receptor that sensitize the receptor to extracellular calcium. This results in reduced PTH secretion and inhibited parathyroid cell proliferation (Nemeth et al., 1998; Chin et al., 2000). This decrease in serum PTH is accompanied by control of serum calcium and phosphorus levels in patients with sHPT as well as a halt or regression of parathyroid gland hyperplasia (Meola et al., 2009). Initial phase III trials and various observational studies have shown that cinacalcet enables more patients to reach the recommended biochemical targets (Block et al., 2004; Lindberg et al., 2005; Urena et al., 2009) and allows sustained biochemical control for long term up to 3 years (Sprague et al., 2009). At present cinacalcet hydrochloride is the only calcimimetic available for clinical use. In contrast to VDRA, cinacalcet decreases all three important biochemical parameters of CKD-MBD (PTH, phosphorus, calcium) (Urena et al., 2009). In addition to excellent results on laboratory parameters, cinacalcet has also shown favourable effects on cardiovascular hospitalization, bone fracture rate, parathyroidectomy rate and quality of life (Cunningham et al., 2005). In a prospectively designed observational study use of cinacalcet on top of standard sHPT therapy with VDRA and phosphate binders resulted in a 26% lower all-cause mortality and a 24% lower cardiovascular mortality than in patients without cinacalcet, with the largest survival benefit for patients with most severe sHPT (PTH >600 pg/mL) (Block et al., 2010). The ongoing double-blind, randomised placebo-controlled EVOLVE trial (Evaluation of cinacalcet HCl therapy to lower cardiovascular events) currently determines whether cinacalcet reduces all-cause mortality or non-fatal cardiovascular events (Chertow et al., 2007).

Generally, initial therapy starts with a daily dose of 30 mg followed by dose-titration every 2 to 4 weeks if necessary. Serum calcium levels must be monitored regularly because of its known hypocalcemic effect.

Whereas VDRA reduce PTH gene transcription and hormone synthesis over a period of several hours or even days, cinacalcet inhibits PTH secretion within minutes, with a maximal decrease occurring within 2 to 4 hours after administration. Besides gastrointestinal side effects, hypocalcemia is one of the most common adverse events seen with cinacalcet. It is thought to occur after decreased mobilization of calcium from bone caused by lowered PTH levels. In most patients, this hypocalcemia can be successfully managed with dose adjustments or a combination with low doses of VDRA in patients with moderate to severe sHPT. Clinical trials have demonstrated the superior suppression of PTH production and control of calcium and phosphorus in hemodialysis patients who use cinacalcet, both as adjunctive therapy to VDRA and as primary therapy with reduced doses of VDRA , compared with sHPT therapy with VDRA and phosphate binders only (Chertow et al., 2006; Block et al., 2008; Fishbane et al., 2008; Messa et al., 2008).
