Vitamin D Analogues

Vitamin D analogues include native vitamin D (cholecalciferol, ergocalciferol), the 25-hydroxylated form (calcifediol) and active forms (calcitriol, alfacalcidol, paricalcitol, doxercalciferol). They treat deficiency, rickets and osteomalacia, hypoparathyroidism and secondary hyperparathyroidism, and topical analogues treat psoriasis.

Mechanism. They bind the vitamin D receptor, raising intestinal absorption of calcium and phosphate, renal calcium reabsorption and bone mineralisation, and suppressing PTH. Cholecalciferol needs 25-hydroxylation in the liver and 1-alpha hydroxylation in the kidney. Calcitriol is active directly. Alfacalcidol needs only hepatic 25-hydroxylation.

Pharmacokinetics. Cholecalciferol has a half-life of weeks; calcitriol half-life is hours, giving fast effect and fast offset. Conversion: 1 microgram equals 40 IU.

Deficiency treatment. Cholecalciferol 50,000 IU (1250 micrograms) weekly for 6 to 8 weeks or 6000 IU daily for 8 weeks, then maintenance 800 to 2000 IU daily.

Calcitriol. Hypoparathyroidism 0.25 to 2 micrograms daily in divided doses; chronic kidney disease secondary hyperparathyroidism 0.25 micrograms daily.

Alfacalcidol. 0.25 to 1 microgram daily; children 0.05 micrograms/kg daily.

Paricalcitol. 0.04 to 0.1 micrograms/kg intravenously at dialysis, or orally 1 to 2 micrograms daily. Less hypercalcaemia than calcitriol.

Topical calcipotriol. For plaque psoriasis, limited to under 100 g weekly to avoid hypercalcaemia.

• Nutritional deficiency, osteomalacia: cholecalciferol (50,000 IU weekly for 6 to 8 weeks, then 800 to 2000 IU daily) with calcium 500 to 1000 mg daily; treat until 25-hydroxyvitamin D is over 75 nmol/L (30 ng/mL).
• Nutritional rickets in children: vitamin D 2000 IU daily for 12 weeks (or a single high dose of 300,000 IU where adherence is doubtful), with calcium 500 mg daily. In many African settings the cause is low dietary calcium, so calcium is essential.
• Prevention: infants 400 IU daily; adults at risk 800 to 1000 IU daily; pregnancy 600 to 800 IU daily.
• Hypoparathyroidism: calcitriol or alfacalcidol with calcium, aiming for serum calcium at the lower end of normal.
• Chronic kidney disease: correct native vitamin D first; active analogues only for severe progressive hyperparathyroidism.

Special groups. Pregnancy: native vitamin D is safe, active analogues only for hypoparathyroidism. Breastfeeding: infants need 400 IU daily regardless. Children: dose by age and weight. Older adults: 800 IU daily with calcium. Kidney impairment: native vitamin D is not activated, so active forms are used. Liver impairment: use calcifediol or active forms. Regional: tuberculosis and sarcoid-type granulomatous disease raise the risk of hypercalcaemia with vitamin D; rifampicin, isoniazid, efavirenz and anticonvulsants lower levels.

Adverse effects. Hypercalcaemia, hypercalciuria, nephrocalcinosis and stones, hyperphosphataemia with active analogues, and vitamin D toxicity at 25-hydroxyvitamin D over 375 nmol/L (150 ng/mL).

Contraindications. Hypercalcaemia, hypervitaminosis D, and hyperphosphataemia for active analogues.

Interactions. Thiazides raise calcium. Digoxin toxicity with hypercalcaemia. Phenytoin, carbamazepine and rifampicin lower vitamin D, so use higher doses. Magnesium is needed for activation.

Monitoring. 25-hydroxyvitamin D at 8 to 12 weeks after loading, calcium, phosphate and PTH. For active analogues, calcium weekly after a change, then monthly.

Referral and escalation. Hypercalcaemia, rickets not responding after 3 months, hypoparathyroidism, and kidney disease.