Background/Aims: Vitamin D insufficiency and secondary hyperparathyroidism (SHPT) are associated with increased morbidity and mortality in chronic kidney disease (CKD) and are poorly addressed by current treatments. The present clinical studies evaluated extended-release (ER) calcifediol, a novel vitamin D prohormone repletion therapy designed to gradually correct low serum total 25-hydroxyvitamin D, improve SHPT control and minimize the induction of CYP24A1 and FGF23. Methods: Two identical multicenter, randomized, double-blind, placebo-controlled studies enrolled subjects from 89 US sites. A total of 429 subjects, balanced between studies, with stage 3 or 4 CKD, SHPT and vitamin D insufficiency were randomized 2:1 to receive oral ER calcifediol (30 or 60 µg) or placebo once daily at bedtime for 26 weeks. Most subjects (354 or 83%) completed dosing, and 298 (69%) entered a subsequent open-label extension study wherein ER calcifediol was administered without interruption for another 26 weeks. Results: ER calcifediol normalized serum total 25-hydroxyvitamin D concentrations (>30 ng/ml) in >95% of per-protocol subjects and reduced plasma intact parathyroid hormone (iPTH) by at least 10% in 72%. The proportion of subjects receiving ER calcifediol who achieved iPTH reductions of ≥30% increased progressively with treatment duration, reaching 22, 40 and 50% at 12, 26 and 52 weeks, respectively. iPTH lowering with ER calcifediol was independent of CKD stage and significantly greater than with placebo. ER calcifediol had inconsequential impact on serum calcium, phosphorus, FGF23 and adverse events. Conclusion: Oral ER calcifediol is safe and effective in treating SHPT and vitamin D insufficiency in CKD.

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Based on the finding that retinoic acid (RA) increases 1,25-dihydroxyvitamin D3 [1,25-(OH)2D3] receptor number in ROS 17/2 cells, we investigated the effects of RA on the ability of 1,25-(OH)2D3 to regulate alkaline phosphatase activity and PTH-responsive adenylate cyclase in these cells. A maximally effective dose of 1,25-(OH)2D3 (10(-8) M) caused a 75-80% increase in alkaline phosphatase activity and an approximately 70-75% attenuation of the cAMP response to PTH, while RA (10(-6) M) decreased alkaline phosphatase activity by 30-45% and decreased PTH-stimulated cAMP levels by approximately 20%. Preincubation with RA did not enhance the 1,25-(OH)2D3-induced increases in alkaline phosphatase activity. The ED50 values for control and RA-treated cultures were approximately 8 X 10(-10) M and 6 X 10(-10) M, respectively. With regard to PTH responsiveness, the effects of RA preincubation on the 1,25-(OH)2D3 attenuation of cAMP response varied with the concentration of 1,25-(OH)2D3. At low doses (less than 10(-9) M), the effects of 1,25-(OH)2D3 and RA were additive. At higher doses of 1,25-(OH)2D3, the effects of RA and 1,25-(OH)2D3 were not additive, and there were no differences between control- and RA-treated cultures. The ED50 values for control- and RA-treated cultures were 10(-10) M and 3 X 10(-11) M, respectively. None of the above effects were observed using equimolar doses of the vitamin D3 metabolites 24,25-dihydroxyvitamin D3 and 25-hydroxyvitamin D3. The data show that pretreating ROS 17/2A cells with RA to increase 1,25-(OH)2D3 receptors does not correspond with a concomitant increase in the cellular responsiveness to 1,25-(OH)2D3, as measured by increases in alkaline phosphatase activity and decreases in PTH-responsive adenylate cyclase.

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While it is well established that active vitamin D treatment increases dietary phytate phosphate utilization, the mechanism by which intestinal alkaline phosphatase (IAP) participates in phytate phosphate use is less clear. The ability of human IAP (hIAP) oral antibodies to prevent dietary phytate phosphate utilization in the presence of 1α-hydroxycholecalciferol (1α-(OH) D3) in a chick model was investigated. hIAP specific chicken immunoglobulin Y (IgY) antibodies were generated by inoculating laying hens with 17 synthetic peptides derived from the human IAP amino acid sequence and harvesting egg yolk. Western blot analysis showed all antibodies recognized hIAP and 6 of the 8 antibodies selected showed modest inhibition of hIAP activity in vitro (6 to 33% inhibition). In chicks where dietary phosphate was primarily in the form of phytate, 4 selected hIAP antibodies inhibited 1α-(OH) D3-induced increases in blood phosphate, one of which, generated against selected peptide (MFPMGTPD), was as effective as sevelamer hydrochloride in preventing the 1α-(OH) D3-induced increase in blood phosphate, but ineffective in preventing an increase in body weight gain and bone ash induced by 1α-(OH) D3. These studies demonstrated that orally-delivered antibodies to IAP limit dietary phytate-phosphate utilization in chicks treated with 1α-(OH) D3, and implicate IAP as an important host enzyme in increasing phytate phosphate bioavailability in 1α-(OH) D3 fed chicks.