Treatment Effects of Modified-Release Calcifediol on Bone Markers Suggest Higher 25-Hydroxyvitamin D Levels Are Needed for Adequacy in Patients with Stage 3 or 4 CKD

Vitamin D insufficiency (VDI) is defined as serum total 25-hydroxyvitamin D (25D) below 30 ng/mL in clinical practice guidelines applicable to secondary hyperparathyroidism (SHPT) in chronic kidney disease (CKD; Holick et al 2011; K/DOQI 2003; KDIGO 2009).  Current regimens for correcting VDI in CKD successfully raise serum 25D above 30 ng/mL in some patients but are ineffective in controlling SHPT.  A recent study by Ennis et al (1) suggested that 25D levels significantly greater than 30 ng/mL are required to maximally lower elevated intact parathyroid hormone (iPTH) in CKD. 

   The effects of modified-release calcifediol (MRC) on elevated plasma iPTH and serum markers of bone turnover were examined in two identical, randomized, double-blind, placebo-controlled trials conducted in patients with SHPT (>85 pg/mL), stage 3 or 4 CKD and low serum 25D (10-30 ng/mL).  The trials randomized a total of 429 subjects from 77 US sites, stratified by stage, 2:1 to receive oral MRC or placebo for 26 weeks.  MRC dosing started at 30 μg/d at bedtime and increased to 60 μg/d after 12 weeks if plasma iPTH remained above 70 pg/mL.  Of the 429 subjects, 356 (83%) completed treatment and were grouped according to their 25D levels (0-20, >20-40, >40-60, >60-80 or >80 ng/mL) at the end of treatment (EOT).  Mean EOT plasma iPTH, serum total 1,25-dihydroxyvitamin D (1,25D), and serum calcium (Ca), phosphorus (P) and bone formation/resorption markers, as well as urine Ca and P, were compared among the five groups.    

   Baseline demographics were similar for the five groups with mean age of 63.2-68.7 years, mean serum 25D of 16.5-21.5 ng/mL, mean plasma iPTH of 134.8-156.5 pg/mL and mean eGFR of 30.1-32.3 mL/min/1.73m².  More than 95% of subjects treated with MRC achieved serum 25D levels of  greater than 30 ng/mL at EOT.  Mean serum 1,25D progressively rose with increasing serum 25D regardless of CKD stage.  Similarly, and independent of CKD stage, mean plasma iPTH, serum collagen type 1 C-telopeptide and serum procollagen type 1 N-terminal propeptide progressively decreased with increasing 25D.   Serum bone-specific alkaline phosphatase decreased with serum 25D increasing up to >40-60 ng/mL.  No increases in mean serum Ca or P, or urine Ca or P were apparent with increasing serum 25D levels. Treatment-emergent adverse events did not associate with serum 25D levels and appeared to be higher at lower 25D levels.

   In conclusion, MRC increased serum 25D and 1,25D, and reduced plasma iPTH and other serum bone markers in patients with stage 3 or 4 CKD, SHPT and VDI with no effect on serum Ca or P, or urine Ca or P.  Decreases in both plasma iPTH and bone markers were maximal at serum 25D levels above 60 ng/mL.  These findings indicate that serum 25D levels recommended for non-CKD patients are insufficient to control SHPT in stage 3 or 4 CKD and that higher, more effective levels (>60 ng/mL) can be safely achieved with daily MRC.