What is the preferred treatment for vitamin D deficiency, vitamin D2 or vitamin D3, in adults?

Vitamin D3 (Cholecalciferol) is Strongly Preferred Over Vitamin D2 (Ergocalciferol) for Treating Vitamin D Deficiency in Adults

Vitamin D3 (cholecalciferol) should be your first-line choice for vitamin D supplementation because it maintains serum 25(OH)D levels significantly longer and demonstrates superior bioavailability compared to vitamin D2 (ergocalciferol). 1

Why Vitamin D3 is Superior

Vitamin D3 is particularly advantageous when using intermittent dosing regimens (weekly or monthly) because it maintains serum 25(OH)D concentrations for longer periods than vitamin D2. 1 This pharmacokinetic advantage translates to more consistent vitamin D levels and better clinical outcomes. 1

In a real-world comparative effectiveness study, vitamin D3 injections increased serum vitamin D by 6.1 ng/mL, while vitamin D2 injections (despite containing double the molar units at 600,000 IU versus 300,000 IU) only increased levels by 3.2 ng/mL—less than half the effect. 2 This demonstrates that even when vitamin D2 is given at higher doses, it remains inferior to vitamin D3. 2

When Vitamin D2 May Be Acceptable

While vitamin D3 is preferred, vitamin D2 can be used as an alternative when vitamin D3 is unavailable, particularly for the standard loading regimen of 50,000 IU weekly for 8-12 weeks. 1 However, you should be aware that patients may require closer monitoring and potentially higher maintenance doses when using vitamin D2. 1

One study showed that daily doses of 1,000 IU of vitamin D2 versus D3 produced equivalent increases in total 25(OH)D levels over 11 weeks. 3 However, this equivalence only applies to daily dosing at lower doses—not to the intermittent high-dose regimens commonly used in clinical practice. 3

Practical Treatment Protocol

Loading Phase for Deficiency (<20 ng/mL)

• Administer 50,000 IU of vitamin D3 (cholecalciferol) once weekly for 8-12 weeks. 1
• For severe deficiency (<10 ng/mL), use the full 12-week course. 1
• If vitamin D3 is unavailable, 50,000 IU of vitamin D2 (ergocalciferol) weekly can be substituted, but expect a less robust response. 4

Maintenance Phase

• After completing the loading phase, transition to 800-2,000 IU of vitamin D3 daily. 1
• Alternative: 50,000 IU of vitamin D3 monthly (equivalent to approximately 1,600 IU daily). 1
• Target serum 25(OH)D level: ≥30 ng/mL for optimal anti-fracture efficacy. 1

Essential Co-Interventions

• Ensure adequate calcium intake of 1,000-1,500 mg daily from diet plus supplements if needed. 1
• Calcium supplements should be taken in divided doses of no more than 600 mg at once for optimal absorption. 1

Monitoring Protocol

• Recheck 25(OH)D levels 3 months after initiating treatment to allow levels to plateau and accurately reflect response. 1
• If using intermittent dosing (weekly or monthly), measure levels just prior to the next scheduled dose. 1
• Continue monitoring annually once stable levels are achieved. 1

Critical Pitfalls to Avoid

• Never use active vitamin D analogs (calcitriol, alfacalcidol, doxercalciferol, paricalcitol) to treat nutritional vitamin D deficiency—these bypass normal regulatory mechanisms and carry higher risk of hypercalcemia. 1
• Avoid single ultra-high loading doses (>300,000 IU) as they may be inefficient or potentially harmful. 1
• Do not assume vitamin D2 and D3 are interchangeable at the same doses for intermittent regimens—vitamin D3 is superior. 1

Safety Considerations

• Daily doses up to 4,000 IU of vitamin D3 are generally safe for adults. 1
• The upper safety limit for 25(OH)D is 100 ng/mL. 1
• Vitamin D toxicity is rare and typically only occurs with prolonged daily doses exceeding 10,000 IU or serum levels above 100 ng/mL. 1

Special Populations

Chronic Kidney Disease (Stages 3-4)

• Use standard nutritional vitamin D replacement with cholecalciferol (preferred) or ergocalciferol—do not use active vitamin D analogs for nutritional deficiency. 1
• CKD patients are at particularly high risk due to reduced sun exposure, dietary restrictions, and urinary losses. 1

Malabsorption Syndromes

• For patients with documented malabsorption (post-bariatric surgery, inflammatory bowel disease, celiac disease), intramuscular vitamin D3 50,000 IU is the preferred route as it results in significantly higher 25(OH)D levels compared to oral supplementation. 1
• When IM is unavailable, substantially higher oral doses (4,000-5,000 IU daily) are required. 1