Vitamin D3 (Cholecalciferol) is Strongly Preferred Over D2 (Ergocalciferol) for Treating Vitamin D Deficiency
Vitamin D3 (cholecalciferol) should be your first-line choice for treating vitamin D deficiency, as it is approximately 87% more potent than D2, maintains serum levels significantly longer, and produces 2-3 fold greater vitamin D storage in the body. 1
Why D3 is Superior to D2
Pharmacokinetic Advantages
D3 is 3.2-fold more potent than D2 at raising serum 25(OH)D levels - each microgram of D3 increases serum levels by 4.8 nmol/L compared to only 1.5 nmol/L for D2. 2
D3 maintains serum 25(OH)D concentrations for longer periods, particularly advantageous when using intermittent dosing regimens (weekly or monthly). 3, 4
In head-to-head trials using 50,000 IU weekly for 12 weeks, D3 produced a mean 25(OH)D increase of 45 ng/mL versus only 24 ng/mL for D2 (P <0.001). 1
Real-world evidence from 15,716 patients showed D3 injections increased serum vitamin D by 6.1 ng/mL compared to only 3.2 ng/mL for D2 injections, despite D2 containing double the molar units. 5
Clinical Guideline Consensus
The National Comprehensive Cancer Network, Clinical Infectious Diseases guidelines, and multiple other major societies recommend D3 over D2 due to higher bioefficacy and longer duration of action. 3, 4
D3 is the form of vitamin D specified in the most accepted and internationally recognized clinical guidelines on osteoporosis management. 6
Standard Treatment Protocol Using D3
Loading Phase for Deficiency (<20 ng/mL)
Administer cholecalciferol (D3) 50,000 IU once weekly for 8-12 weeks. 3, 4
Use 12 weeks for severe deficiency (<10 ng/mL) and 8 weeks for moderate deficiency (10-20 ng/mL). 3
Target serum 25(OH)D level of at least 30 ng/mL for optimal anti-fracture efficacy. 3, 4
Maintenance Phase
After achieving target levels, transition to 800-2,000 IU daily of D3. 3, 4
Alternative: 50,000 IU monthly (equivalent to approximately 1,600 IU daily). 3
For elderly patients (≥65 years), minimum 800 IU daily is recommended. 3
Monitoring Protocol
Recheck 25(OH)D levels 3 months after initiating treatment to allow levels to plateau. 3, 4
Continue monitoring annually once stable and in target range. 3
Ensure adequate calcium intake of 1,000-1,500 mg daily from diet plus supplements. 3, 4
Why D2 Was Historically Used (But Shouldn't Be Now)
Historical Context
Older guidelines from 2003 (K/DOQI) suggested ergocalciferol might be safer than cholecalciferol, but this was based on limited evidence and has been superseded. 4
In the United States, prescription high-dose formulations (50,000 IU capsules) were historically only available as D2, while D3 was primarily over-the-counter in lower doses. 4
This created a prescribing pattern where physicians defaulted to the available D2 formulation, not because it was superior. 4
Current Reality
D3 is now widely available in prescription-strength 50,000 IU formulations (FDA-approved cholecalciferol softgel capsules). 7
The historical availability argument no longer applies - prescribe D3 instead. 4
Special Populations
Chronic Kidney Disease (CKD Stages 3-4)
Use standard nutritional vitamin D replacement with cholecalciferol for CKD patients with GFR 20-60 mL/min/1.73m². 3, 8
Never use active vitamin D analogs (calcitriol, alfacalcidol, doxercalciferol, paricalcitol) to treat nutritional vitamin D deficiency - they bypass normal regulatory mechanisms and carry higher hypercalcemia risk. 3, 8
Reserve active vitamin D analogs only for advanced CKD (GFR <30 mL/min/1.73m²) with persistent PTH >300 pg/mL despite adequate 25(OH)D repletion. 8
Malabsorption Syndromes
For post-bariatric surgery, inflammatory bowel disease, or pancreatic insufficiency, intramuscular D3 50,000 IU is preferred when available. 3
When IM unavailable, use substantially higher oral D3 doses: 4,000-5,000 IU daily for 2 months. 3
Critical Pitfalls to Avoid
Do not use D2 simply because it's available as a prescription formulation - D3 is now available in equivalent prescription doses and is pharmacologically superior. 4, 1
Avoid single ultra-high loading doses (>300,000 IU) as they may be inefficient or potentially harmful. 3
Do not confuse nutritional vitamin D (cholecalciferol/ergocalciferol) with active vitamin D analogs - they are not interchangeable. 3, 8
Ensure the 25(OH)D assay measures both D2 and D3 if the patient has received D2 supplementation. 3
Safety Profile
Daily doses up to 4,000 IU of D3 are completely safe for adults, with some evidence supporting up to 10,000 IU daily for several months. 3, 4
Toxicity typically only occurs with prolonged daily doses exceeding 10,000 IU or serum 25(OH)D levels above 100 ng/mL. 3
Upper safety limit for 25(OH)D is 100 ng/mL. 3