Parathyroid hormone (PTH) stimulates bone resorption, increasing the serum calcium (Ca) and phosphate (P) levels, and promotes vitamin D production [1-2]. Thus, secondary hyperparathyroidism (SHPT) results in an enhanced risk of renal osteodystrophy, progressive arterial calcification, and cardiovascular morbidity and mortality [3]. The calcium sensing receptor (CaSR) is the fundamental regulator of parathyroid (PT) gland function and PTH secretion, and its activation induced by increased serum Ca levels rapidly reduces the PTH expression and synthesis, and PT gland hyperplasia [4]. On the contrary, reduced serum Ca levels result in decreased CaSR activity, which promotes PTH synthesis and secretion. In addition, CaSR regulates PTH gene expression and upregulates the vitamin D receptor (VDR). VDR activation in the gastrointestinal tract enhances Ca absorption, increasing serum Ca levels and reducing PTH through CaSR activation [5]. In summary, both high serum P and low serum Ca levels, together with low levels of 1,25(OH)2D3 levels, typically in advanced chronic kidney disease (CKD), are key players in the pathogenesis of SHPT [6-7], and the down-regulation of both PT CaSR and VDR play an important role in the development of SHPT [8]. Interestingly, the CaSR and the VDR are biological targets for CKD-mineral bone disorder (MBD) treatment.
In their study, Yang et al. [9] showed the effects of cinacalcet combined with calcitriol on clinical outcomes in 30 hemodialysis patients affected by very severe SHPT (mean baseline PTH = 1,787.3 ± 1,321 pg/mL), with a follow-up of 6 months. Subjects were treated with cinacalcet (25–75 mg) and calcitriol (0.5 μg) daily. Interestingly, at 3 and 6-month follow-up, PTH was reduced by 70%, without any significant change in the total serum Ca levels and 20% reduction in serum P levels [9].
Actual therapy for SHPT consists of 2 main tools: active vitamin D (calcitriol) and calcimimetics (cinacalcet). Usually, parathyroidectomy is a treatment strategy of last resort, when pharmacotherapy has failed. The aim of the treatment is to reduce the serum PTH levels, maintaining serum Ca and P levels within accepted targeted ranges [10]. In HD patients affected by SHPT, calcitriol suppresses PTH, but it elevates Ca and P absorption, promoting the risk of hypercalcemia and hyperphosphatemia [10]. In this study, authors used 0.5 μg/daily of oral calcitriol together with cinacalcet to control extreme SHPT, and patients did not develop either hypercalcemia or hyperphosphatemia. Unlike active vitamin D, cinacalcet does not increase Ca and P. Several clinical studies suggest that cinacalcet, in combination with low-dose of active vitamin D, is effective in controlling PTH [11]. In the ACHIEVE trial, 65% of cinacalcet plus a low dose of active vitamin D patients had a ≥30% reduction in PTH from baseline versus 36% receiving active vitamin D alone [12]. Furthermore, in the -OPTIMA trial in dialysis patients with poorly controlled SHPT, 71% of patients receiving cinacalcet plus low-dose active vitamin D treatment achieved PTH ≤300 pg/mL versus 22% of patients receiving active vitamin D alone [13].
In summary, Yang et al. [9] showed that the combination of cinacalcet with calcitriol in severe SHPT treatment in HD makes sense. In fact, HD patients affected by SHPT with the combination of cinacalcet plus calcitriol also improve the tolerability and further advance the treatment of SHPT. In conclusion, SHPT management has rapidly progressed in the last decade. The introduction of targeted therapies, such as selective VDR and CaSR modulators, offers an increased opportunity to adequately control elevated PTH, especially in patients with CKD receiving dialysis.