What is Activated Vitamin D?
Activated vitamin D (1,25-dihydroxyvitamin D, also called calcitriol) is a hormone—not a nutritional supplement—that directly suppresses parathyroid hormone (PTH) by binding to vitamin D receptors in the parathyroid glands, intestine, kidney, and bone. 1
Key Distinction: Nutritional vs. Activated Vitamin D
Activated vitamin D must be clearly distinguished from its precursor, nutritional vitamin D (cholecalciferol/D3 or ergocalciferol/D2). 1 This distinction is critical because:
Nutritional vitamin D (cholecalciferol or ergocalciferol) requires two sequential hydroxylations—first in the liver to 25-hydroxyvitamin D, then in the kidney to the active form 1,25-dihydroxyvitamin D. 2
Activated vitamin D (calcitriol, alfacalcidol, paricalcitol, or doxercalciferol) bypasses the need for kidney conversion and directly activates vitamin D receptors throughout the body. 2, 3
Role in Chronic Kidney Disease and Secondary Hyperparathyroidism
Why CKD Patients Need Activated Vitamin D
In diseased kidneys, the activation of vitamin D is diminished, resulting in a rise of PTH and subsequent secondary hyperparathyroidism. 2 Decreased levels of 1,25(OH)₂D have been observed in early stages of chronic kidney disease, and these decreased levels—along with resultant elevated PTH—often precede abnormalities in serum calcium and phosphorus. 2
When to Use Activated Vitamin D
In CKD stages 3-4, therapy with active vitamin D sterols (calcitriol, alfacalcidol, or doxercalciferol) is indicated when:
- Serum 25(OH)-vitamin D levels are >30 ng/mL (nutritional deficiency has been corrected), AND 1
- Plasma intact PTH levels are above the target range for the CKD stage, AND 1
- Serum corrected total calcium is <9.5 mg/dL, AND 1
- Serum phosphorus is <4.6 mg/dL 1
In dialysis patients with secondary hyperparathyroidism (PTH >300 pg/mL), active vitamin D sterols should be used rather than nutritional vitamin D supplementation, with intermittent intravenous administration preferred over oral dosing for superior PTH suppression. 4
Critical Pitfall to Avoid
Never use activated vitamin D analogs (calcitriol, alfacalcidol, doxercalciferol, paricalcitol) to treat nutritional vitamin D deficiency. 5, 6, 4 These agents bypass normal regulatory mechanisms, do not correct 25(OH)D levels, and carry higher risk of hypercalcemia. 5, 6 For nutritional deficiency, use ergocalciferol or cholecalciferol instead. 5, 6
Mechanism of Action
Activated vitamin D's biological actions are mediated through binding of the vitamin D receptor (VDR), which results in selective activation of vitamin D responsive pathways. 2 Vitamin D and paricalcitol reduce parathyroid hormone levels by inhibiting PTH synthesis and secretion. 2
The endogenous VDR activator binds to VDRs present in the parathyroid gland, intestine, kidney, and bone to maintain parathyroid function and calcium and phosphorus homeostasis. 2 VDR activation is essential for proper formation and maintenance of normal bone. 2
Monitoring Requirements During Active Vitamin D Therapy
During therapy with vitamin D sterols, the following monitoring schedule is required: 1
- Serum calcium and phosphorus: At least monthly for the first 3 months after initiation, then every 3 months thereafter 1
- Plasma PTH levels: At least every 3 months for 6 months, then every 3 months thereafter 1
Dose Adjustments
If PTH falls below target range: Hold active vitamin D sterol therapy until PTH rises above target range, then resume at half the previous dose. 1
If serum calcium exceeds 9.5 mg/dL: Hold therapy until calcium returns to <9.5 mg/dL, then resume at half the previous dose. 1
If serum phosphorus rises to >4.6 mg/dL: Hold active vitamin D therapy, initiate or increase phosphate binder dose until phosphorus falls to <4.6 mg/dL, then resume prior dose. 1
Systemic Effects Beyond PTH Suppression
Circulating calcitriol derives at least in part from renal 1α-hydroxylation, but it is also hydroxylated locally in other tissues where it produces autocrine and paracrine effects. 1 These effects have been implicated in immune function, prevention of malignancy, and reduced cardiovascular disease occurrence in people with and without CKD. 1
Recent data showing that pulsatile, intravenous vitamin D treatment (calcitriol or paricalcitol) confers a survival advantage in the dialysis population has generated new interest in understanding the systemic effects of VDR activation. 3
Available Formulations
Active vitamin D sterols available for clinical use include: 1, 4
- Calcitriol (1,25-dihydroxyvitamin D₃)
- Alfacalcidol (1α-hydroxyvitamin D₃)
- Doxercalciferol (1α-hydroxyvitamin D₂)
- Paricalcitol (synthetic vitamin D₂ analog)
Newer vitamin D analogs (19-nor-paricalcitol and doxercalciferol) have been developed with selective VDR activity and lower hypercalcemic response compared to calcitriol. 7 These agents adequately control secondary hyperparathyroidism with minimal changes in serum calcium and phosphorus levels during treatment. 7