In a patient with vitamin D deficiency, which is preferred—ergocalciferol (vitamin D₂) or cholecalciferol (vitamin D₃)—and what are the recommended repletion and maintenance dosing regimens?

Cholecalciferol (Vitamin D₃) is Preferred Over Ergocalciferol (Vitamin D₂) for Vitamin D Deficiency

Cholecalciferol (vitamin D₃) should be used as first-line therapy for vitamin D deficiency because it raises serum 25(OH)D levels approximately 2.5 times more effectively than ergocalciferol (vitamin D₂) and maintains these levels for longer periods. 1, 2

Evidence Supporting Cholecalciferol Superiority

Comparative Efficacy Data

• Meta-analysis of 1,277 participants across 24 studies demonstrates that cholecalciferol increases total 25(OH)D levels by an average of 15.69 nmol/L (approximately 6.3 ng/mL) more than ergocalciferol at equivalent doses. 1

• In CKD patients specifically, cholecalciferol produces 2.7 ng/mL increase per 100,000 IU administered versus only 1.1 ng/mL with ergocalciferol—a 2.5-fold difference in potency. 2

• A head-to-head trial comparing 500,000 IU cholecalciferol (given as 50,000 IU daily × 10 days) versus 600,000 IU ergocalciferol (single dose) showed cholecalciferol increased 25(OH)D by 47 ng/mL versus only 10 ng/mL with ergocalciferol over similar time periods. 3

Mechanism of Superior Efficacy

• Cholecalciferol has higher bioavailability and maintains serum concentrations longer than ergocalciferol, particularly important when using intermittent (weekly or monthly) dosing regimens. 4, 5

• Ergocalciferol may actually decrease endogenous 25(OH)D₃ levels—in one study, a 600,000 IU ergocalciferol dose reduced 25(OH)D₃ by an average of 4 ng/mL in 37 subjects, potentially counteracting its own benefit. 3

Recommended Repletion Regimens

For Severe Deficiency (<10 ng/mL)

• Cholecalciferol 50,000 IU once weekly for 12 weeks, then transition to maintenance dosing. 4, 6

• Alternative intensive regimen: Cholecalciferol 8,000 IU daily for 4 weeks, then 4,000 IU daily for 2 months. 4

For Moderate Deficiency (10-20 ng/mL)

• Cholecalciferol 50,000 IU once weekly for 8 weeks, then maintenance. 4, 7

For Insufficiency (20-30 ng/mL)

• Add 1,000-2,000 IU cholecalciferol daily to current intake and recheck in 3 months. 7

• Alternative: Cholecalciferol 50,000 IU once monthly (equivalent to approximately 1,600 IU daily). 4

Maintenance Dosing After Repletion

• Standard maintenance: 800-2,000 IU cholecalciferol daily to maintain 25(OH)D ≥30 ng/mL. 4, 7, 6

• For patients ≥60 years: Minimum 800 IU daily, with 1,000 IU daily preferred for optimal fracture and fall prevention. 4, 6

• Convenient monthly alternative: 50,000 IU cholecalciferol once monthly provides equivalent maintenance. 4

Monitoring Protocol

• Check serum calcium and phosphorus at 1 month after initiating or changing vitamin D dose, then every 3 months during treatment. 4, 6

• Recheck 25(OH)D levels 3 months after completing loading phase to confirm repletion (target ≥30 ng/mL). 7, 6

• Once stable at target, monitor 25(OH)D annually. 4, 6

Special Populations

Chronic Kidney Disease (Stages 3-4)

• Use standard nutritional cholecalciferol replacement with the same dosing regimens as above—do NOT use active vitamin D analogs (calcitriol, alfacalcidol, doxercalciferol, paricalcitol) for nutritional deficiency. 4, 6

• CKD patients show particularly robust response to cholecalciferol, with younger females and those with lower baseline 25(OH)D benefiting most. 2

Malabsorption Syndromes

• For documented malabsorption (post-bariatric surgery, inflammatory bowel disease, celiac disease), consider intramuscular cholecalciferol 50,000 IU if oral supplementation fails, or use substantially higher oral doses (4,000-5,000 IU daily for 2 months). 7

Critical Safety Considerations

• Discontinue all vitamin D immediately if serum corrected calcium exceeds 10.2 mg/dL (2.54 mmol/L). 4, 6

• Daily doses up to 4,000 IU cholecalciferol are completely safe for long-term use; doses up to 10,000 IU daily have been used safely in CKD patients for over 1 year. 4, 6

• The upper safety limit for serum 25(OH)D is 100 ng/mL—toxicity is rare below this threshold. 7

When Ergocalciferol May Be Acceptable

• If cholecalciferol is unavailable or cost-prohibitive, ergocalciferol can be used but requires higher cumulative doses to achieve the same effect. 4

• Some evidence suggests ergocalciferol may be safer than cholecalciferol in advanced CKD, though both are acceptable. 6

• When using ergocalciferol, ensure laboratory measures total 25(OH)D (both D₂ and D₃ metabolites) to accurately assess response. 7

Common Pitfalls to Avoid

• Do not use 400-600 IU daily doses for deficiency treatment—these are insufficient for repletion and only appropriate for maintenance in replete individuals. 7

• Avoid single mega-doses >300,000 IU as they may paradoxically increase fall and fracture risk. 7

• Never substitute active vitamin D analogs for nutritional vitamin D deficiency—they bypass normal regulation and dramatically increase hypercalcemia risk. 4, 6

• Do not measure 25(OH)D earlier than 3 months after starting or changing therapy—levels require this time to plateau. 7