Evaluation of Therapies for Secondary Hyperparathyroidism Associated with Vitamin D Insufficiency in Chronic Kidney Disease

Introduction: Parathyroid hormone-lowering responses after administration of three different therapies capable of raising serum total 25-hydroxyvitamin D (25OHD) were evaluated in patients with secondary hyperparathyroidism (SHPT), vitamin D insufficiency (VDI) and stage 3 or 4 chronic kidney disease (CKD). Methods: Sixty-nine adult subjects with intact parathyroid hormone (iPTH) >= 85 and <500 pg/mL and VDI (25OHD <30 ng/mL) were randomized after >= 4 weeks washout to two months of open-label treatment with: 1) extended-release calcifediol (ERC) 60 mcg/day; 2) immediate-release calcifediol (IRC) 266 mcg/month; 3) high-dose cholecalciferol (HDC) 300,000 IU/month; or 4) paricalcitol plus low-dose cholecalciferol (PLDC) 1 or 2 mcg and 800 IU/day, used as reference hormone replacement therapy. Serum 25OHD, calcium (Ca) and phosphorus (P) and plasma iPTH and adverse events were monitored weekly. No clinically significant differences were observed at baseline between treatment groups. Results: Sixty-two subjects completed the study per-protocol (PP; 14-17 per group). Mean (SD) 25OHD and iPTH at baseline were 20.6 (6.6) ng/mL and 148 (90) pg/mL, respectively. Mean 25OHD increased at end of treatment (EOT) to 82.9 (17.0) ng/mL with ERC (P<0.001) and 30.8 (11.6) ng/mL with HDC (P<0.05), but remained unchanged with IRC and PLDC. EOT 25OHD levels reached >= 30 ng/mL in all subjects treated with ERC and in 44% with HDC. All subjects attained EOT 25OHD levels >= 50 ng/mL with ERC versus none with other therapies. iPTH response rates at EOT (>= 10, 20 or 30% below baseline) were similar for ERC and PLDC; rates for IRC and HDC were much lower. No significant changes from baseline were observed in ionized or corrected total Ca or P in any group. One episode of hypercalcemia (>10.3 mg/dL) occurred with PLDC. Hyperphosphatemia (>5.5 mg/dL) occurred once with ERC, eight times with HDC, three times with IRC and twice with PLDC. Conclusion: ERC was highly effective in both raising serum 25OHD and decreasing iPTH in patients with SHPT, VDI and stage 3 or 4 CKD. iPTH-lowering response rates with ERC were similar to daily PLDC, the reference therapy; rates with IRC or HDC were significantly lower. ERC is an attractive alternative to vitamin D hormone therapy in CKD patients.