A randomized multicenter trial of paricalcitol versus calcitriol for secondary hyperparathyroidism in stages 3-4 CKD

Abstract

Background and objectives: Calcitriol is used to treat secondary hyperparathyroidism in patients with CKD. Paricalcitol is less calcemic and phosphatemic in preclinical studies and in some trials in dialysis patients, but head-to-head comparisons in nondialysis patients are lacking. A large meta-analysis of trials concluded that these agents did not consistently reduce parathyroid hormone (PTH) and increased the risk of hypercalcemia and hyperphosphatemia. Therefore, the objective of this multicenter trial was to compare the rate of hypercalcemia between calcitriol and paricalcitol, while suppressing PTH 40%-60%.

Design, setting, participants, & measurements: Patients with stages 3-4 CKD (n=110) with a PTH level >120 pg/ml were recruited and randomized to 0.25 μg/d of calcitriol or 1 μg/d of paricalcitol between April 2009 and July 2011. Subsequent dose adjustments were by protocol to achieve 40%-60% PTH suppression below baseline. The primary endpoint was the rate of confirmed hypercalcemia of >10.5 mg/dl between groups.

Results: Forty-five patients in each group completed the 24 weeks of treatment. Both agents suppressed PTH effectively (-52% with paricalcitol and -46% with calcitriol; P=0.17), although the paricalcitol group reached a 40% reduction in PTH sooner at a median 8 weeks (interquartile range [IQR], 4, 12) versus 12 weeks (IQR, 8, 18; P=0.02) and had a lower pill burden of 240 (IQR, 180, 298) versus 292 (IQR, 231, 405; P=0.01). Confirmed hypercalcemia was very low in both groups (three with paricalcitol and one with calcitriol) and was not significantly different (P=0.36). Both groups had small increases in calcium and phosphorus levels (0.3-0.4 mg/dl in each electrolyte) and significant decreases in alkaline phosphatase, a marker of high bone turnover, with no significant differences between groups.

Conclusions: These results show that both calcitriol and paricalcitol achieved sustained PTH and alkaline phosphatase suppression in stages 3-4 CKD, with small effects on serum calcium and phosphorus and a low incidence of hypercalcemia.

Keywords: calcium; chronic renal disease; hyperparathyroidism; vitamin D.

Figure 1.

Patient disposition. Enrollment, randomization, and follow-up of study participants. PTH, parathyroid hormone.

Figure 2.

Percentage change in mean PTH suppression over time. The target PTH suppression was 40%–60% below each patient’s baseline PTH measurement. Solid symbols are the paricalcitol group, and open symbols are the calcitriol group. All on-treatment results were significantly below baseline PTH in both groups (P<0.05). *P<0.01 (PTH suppression was significantly greater at these times in the paricalcitol group compared with the calcitriol group).

Figure 3.

Proportion of patients achieving ≥40% suppression in PTH at any time during the trial by study week. The median time to at least a 40% reduction in PTH was earlier in the paricalcitol group (8 weeks; IQR, 4, 12) compared with the calcitriol group (12 weeks; IQR, 8, 18; P=0.02). IQR, interquartile range.

Figure 4.

Mean change in calcium and phosphorus during and after withdrawal of treatment. Data are shown as the mean values±SD from baseline in serum calcium (A) and phosphorus (B) during treatment and 1 week after treatment withdrawal at week 24. Solid symbols are the paricalcitol group, and open symbols are the calcitriol group. *P<0.05 versus baseline for paricalcitol; **P<0.05 versus baseline for calcitriol. Week 25 calcium and phosphorus values are also significantly lower than week 24 values (P<0.05), but are not different from baseline.