The purpose of the present study was to investigate the effectiveness of cinacalcet-based vs. vitamin D based regimen in treating SHPT, achieving the K/DOQI targets for PD patients, and the cinacalcet effect on FGF23 suppression. The present study did not show a difference in the reduction of iPTH since it did not achieve the target enrollment number. However, the present study exhibited that serum FGF23 was significantly reduced during cinacalcet treatment. Moreover, cinacalcet effect on the FGF23 suppression was independent of its effect on serum iPTH, Ca, P, and the exposure to oral vitamin D.
Recent studies have shown that high levels of FGF23 are associated with poor outcomes such as left ventricular hypertrophy [15, 16], progression of CKD  and increased overall mortality . FGF23 could be a better prognosis predictor of cardiovascular disease than any other biomarkers. Therefore, reduction of FGF23 may become a novel target of treating SHPT for lowering cardiovascular risk and improving prognosis of CKD patients.
It is well documented in a few recent randomized clinical trials that cinacalcet is more efficient than conventional vitamin D based therapy in treating SHPT in hemodialysis patients [14, 18, 19]. Furthermore, post hoc analysis of these studies reported that cinacalcet modulated FGF23 reduction. However, the specific mechanism of cinacalcet effect on FGF23 suppression has not been elucidated. Therefore, it remains to be investigated whether cinacalcet lowers FGF23 per se or indirectly via modulating other mineral metabolic parameters. Several studies showed that the cinacalcet group received lower dose of vitamin D and exhibited lower level of PTH, compared with those receiving conventional vitamin D based therapy [14, 18]. It is well known that PTH and vitamin D stimulate FGF23 production [20–22]. Therefore, one could postulate that the suppression of FGF23 in the cinacalcet group may be associated with lower exposure to vitamin D and lower level of PTH. Koizumi et al.  allowed relatively constant dosage of vitamin D during the study period. Since the dosage of vitamin D was allowed to be titrated according to the biochemical parameters in the present study, the cinacalcet group was prescribed with lower dose of vitamin D than the control group. However, in our univariate analysis, neither vitamin D dose nor other mineral metabolic parameters such as iPTH, Ca and P were associated with FGF23 change. Cinacalcet treatment was independently associated with FGF23 reduction, after adjustment to the age and sex. One could postulate that cinacalcet per se might have a modulatory effect on the FGF23 level.
The mechanism underlying the more direct association of FGF23 reduction with cinacalcet is yet unclear. FGF23 is synthesized and released by bone cells, mainly osteocytes [1, 2]. Osteocyte and osteoblast were shown to express calcium sensing receptor (CaSR). Cinacalcet acts mainly by allosteric binding to the CaSR on the parathyroid cell membrane for regulating calcium homeostasis. Whether cinacalcet directly acts on the CaSR at the bone cells to regulate FGF23 secretion needs to be investigated.
The strengths of this study include prospective, randomized study and a design to follow change of FGF23 levels in PD patients with cinacalcet treatment, compared with conventional vitamin D treatment. Moreover, unlike other study reporting an effect of cinacalcet on the FGF23 reduction , the present study showed an independent association between cinacalcet treatment and FGF23 reduction. Unlike the EVOLVE trial, there was no possibility of cross-over of medication between the two arms, since cinacalcet was not commercially available in Korea during the study period .
However, the present study has a limitation of a small sample size and an open-labeled study. The investigators of the CUPID Study finished the recruitment prematurely before target number of enrollment was reached. This was because enrollment was delayed due to lack of subjects who fulfilled the strict inclusion criteria. This resulted in lack of statistical power to prove a difference in the iPTH reduction between two groups, which was the primary endpoint of the present study. Besides, the prescribed dose of cinacalcet was 30.2 ± 18.0 mg/day during assessment phase, which means our subjects received lower dose of cinacalcet than that reported in other studies [14, 18]. This might be another explanation for the negative result as regards to the primary end point. Cinacalcet group exhibited more drop-outs that the control group. The analysis of FGF23 change was performed on a per-protocol basis. This may have resulted in a selection bias because only subjects who were more tolerable to the medication were included in the analysis. Dietary phosphorus intake, which is another determinant of serum FGF23 in CKD [24, 25] could not be assessed in the present study. However, there were no significant differences the prescribed dose of oral phosphate binders and serum P levels between the two groups (data not shown). Therefore, we could postulate that the dietary P intake was similar between the two groups, although the present study did not analyze dietary phosphorus intake.