Petkovich Martin, Melnick Joel, White Jay, Tabash Samir, Strugnell Stephen, Bishop Charles W
Cancer Research Institute, 355 Botterell Hall, Queen's University, Kingston, ON K7L 3N6, Canada.
OPKO Health, Renal Division, Miami, FL 33137, USA.
J Steroid Biochem Mol Biol. 2015 Apr;148:283-9. doi: 10.1016/j.jsbmb.2014.11.022. Epub 2014 Nov 22.
Vitamin D insufficiency is prevalent in chronic kidney disease (CKD) and associated with secondary hyperparathyroidism (SHPT) and increased risk of bone and vascular disease. Unfortunately, supplementation of stage 3 or 4 CKD patients with currently recommended vitamin D2 or D3 regimens does not reliably restore serum total 25-hydroxyvitamin D to adequacy (≥30ng/mL) or effectively control SHPT. Preclinical and clinical studies were conducted to evaluate whether the effectiveness of vitamin D repletion depends, at least in part, on the rate of repletion. A modified-release (MR) oral formulation of calcifediol (25-hydroxyvitamin D3) was developed which raised serum 25-hydroxyvitamin D3 and calcitriol levels gradually. Single doses of either bolus intravenous (IV) or oral MR calcifediol were administered to vitamin D deficient rats. Bolus IV calcifediol produced rapid increases in serum 25-hydroxyvitamin D3, calcitriol and FGF23, along with significant induction of CYP24A1 in both kidney and parathyroid gland. In contrast, oral MR calcifediol produced gradual increases in serum 25-hydroxyvitamin D3 and calcitriol and achieved similar hormonal exposure, yet neither CYP24A1 nor FGF23 were induced. A 10-fold greater exposure to bolus IV than oral MR calcifediol was required to similarly lower intact parathyroid hormone (iPTH). Single doses of oral MR (450 or 900μg) or bolus IV (450μg) calcifediol were administered to patients with stage 3 or 4 CKD, SHPT and vitamin D insufficiency. Changes in serum 25-hydroxyvitamin D3 and calcitriol and in plasma iPTH were determined at multiple time-points over the following 42 days. IV calcifediol produced abrupt and pronounced increases in serum 25-hydroxyvitamin D3 and calcitriol, but little change in plasma iPTH. As in animals, these surges triggered increased vitamin D catabolism, as evidenced by elevated production of 24,25-dihydroxyvitamin D3. In contrast, MR calcifediol raised serum 25-hydroxyvitamin D3 and calcitriol gradually, and meaningfully lowered plasma iPTH levels. Taken together, these studies indicate that rapid increases in 25-hydroxyvitamin D3 trigger CYP24A1 and FGF23 induction, limiting effective exposure to calcitriol and iPTH reduction in SHPT. They also support further investigation of gradual vitamin D repletion for improved clinical effectiveness. This article is part of a Special Issue entitled "17th Vitamin D Workshop".
维生素D缺乏在慢性肾脏病（CKD）中普遍存在，与继发性甲状旁腺功能亢进（SHPT）以及骨骼和血管疾病风险增加相关。遗憾的是，按照目前推荐的维生素D2或D3方案对3期或4期CKD患者进行补充，并不能可靠地将血清总25-羟基维生素D恢复至充足水平（≥30ng/mL），也无法有效控制SHPT。开展了临床前和临床研究，以评估维生素D补充的有效性是否至少部分取决于补充速度。研发了一种缓释（MR）口服制剂的骨化二醇（25-羟基维生素D3），它能使血清25-羟基维生素D3和骨化三醇水平逐渐升高。对维生素D缺乏的大鼠单次给予大剂量静脉注射（IV）或口服MR骨化二醇。大剂量静脉注射骨化二醇使血清25-羟基维生素D3、骨化三醇和FGF23迅速升高，同时在肾脏和甲状旁腺中显著诱导CYP24A1。相比之下，口服MR骨化二醇使血清25-羟基维生素D3和骨化三醇逐渐升高，并达到相似的激素暴露水平，但未诱导CYP24A1和FGF23。要使完整甲状旁腺激素（iPTH）同样降低，大剂量静脉注射所需的暴露量是口服MR骨化二醇的10倍。对3期或4期CKD、SHPT且维生素D缺乏的患者单次给予口服MR（450或900μg）或大剂量静脉注射（450μg）骨化二醇。在接下来的42天内的多个时间点测定血清25-羟基维生素D3、骨化三醇和血浆iPTH的变化。静脉注射骨化二醇使血清25-羟基维生素D3和骨化三醇急剧且显著升高，但血浆iPTH变化不大。与动物实验一样，这些激增引发了维生素D分解代谢增加，24,25-二羟基维生素D3生成增加证明了这一点。相比之下，MR骨化二醇使血清25-羟基维生素D3和骨化三醇逐渐升高，并显著降低了血浆iPTH水平。综上所述，这些研究表明25-羟基维生素D3的快速升高会触发CYP24A1和FGF23的诱导，限制骨化三醇的有效暴露以及SHPT中iPTH的降低。它们还支持进一步研究逐渐补充维生素D以提高临床疗效。本文是名为“第17届维生素D研讨会”的特刊的一部分。
