What are the adverse events associated with Vitamin D3 (Cholecalciferol)?

From the Guidelines

Vitamin D3 (Cholecalciferol) is associated with adverse events such as kidney stones, transient hypercalcemia, and hypercalciuria, particularly when combined with calcium supplementation.

Adverse Events

• The most common adverse events associated with Vitamin D3 supplementation include:
  • Kidney stones: The Women's Health Initiative trial reported a small increase in the risk for renal stones (hazard ratio, 1.17 [CI, 1.02 to 1.34]) with daily supplementation of 400 IU of vitamin D3 combined with 1000 mg of calcium 1.
  • Transient hypercalcemia: This is a rare adverse event associated with vitamin D supplementation, particularly with high doses 1.
  • Hypercalciuria: This is another rare adverse event associated with vitamin D supplementation, particularly with high doses 1.

Dose and Supplementation

• The recommended daily dose of vitamin D3 is 800-1000 IU, with a caveat that many patients may need more than the recommended amount and should be repleted based on serum 25(OH)D level 1.
• Vitamin D3 supplementation should be used with caution, particularly when combined with calcium supplementation, due to the increased risk of adverse events such as kidney stones 1.

Patient Population

• The adverse events associated with vitamin D3 supplementation are more likely to occur in older adults, particularly those with a history of kidney stones or hypercalcemia 1.
• Patients with serum 25(OH)D levels below 30 ng/mL may require higher doses of vitamin D3 supplementation, which increases the risk of adverse events 1.

From the FDA Drug Label

ADVERSE REACTIONS Hypervitaminosis D is characterized by effects on the following organ system: Renal: Impairment of renal function with polyuria, nocturia, polydipsia, hypercalciuria, reversible azotemia, hypertension, nephrocalcinosis, generalized vascular calcification, or irreversible renal insufficiency which may result in death. CNS: Mental retardation Soft Tissues: Widespread calcification of the soft tissues, including the heart, blood vessels, renal tubules, and lungs. Skeletal: Bone demineralization (osteoporosis) in adults occurs concomitantly. Decline in the average rate of linear growth and increased mineralization of bones in infants and children (dwarfism), vague aches, stiffness, and weakness. Gastrointestinal: Nausea, anorexia, constipation. Metabolic: Mild acidosis, anemia, weight loss.

The adverse events associated with Vitamin D3 (Cholecalciferol) include:

• Renal impairment: polyuria, nocturia, polydipsia, hypercalciuria, reversible azotemia, hypertension, nephrocalcinosis, generalized vascular calcification, or irreversible renal insufficiency
• CNS effects: mental retardation
• Soft tissue calcification: widespread calcification of the heart, blood vessels, renal tubules, and lungs
• Skeletal effects: bone demineralization (osteoporosis), decline in the average rate of linear growth, increased mineralization of bones (dwarfism), vague aches, stiffness, and weakness
• Gastrointestinal effects: nausea, anorexia, constipation
• Metabolic effects: mild acidosis, anemia, weight loss 2

From the Research

Adverse Events Associated with Vitamin D3 (Cholecalciferol)

The following adverse events have been associated with Vitamin D3 (Cholecalciferol) supplementation:

• Hypercalcemia: an increased risk of hypercalcemia has been reported in several studies, including 3 and 4
• Falls: an increased risk of falls has been reported in study 3
• Hospitalization: an increased risk of hospitalization has been reported in study 3
• Hypercalciuria: some studies have reported a trend towards increased hypercalciuria, although the results are inconclusive 4
• Kidney stones: no significant increase in kidney stones has been reported in studies 3 and 4

Safety of High-Dose Vitamin D3 Supplementation

Several studies have investigated the safety of high-dose Vitamin D3 supplementation:

• A study of monthly high-dose vitamin D3 supplementation for up to 4 years found no significant increase in adverse events 5
• A study of daily 7000-IU vitamin D3 supplementation for 12 months in HIV-infected children and young adults found no serious adverse safety events 6
• A pilot study of a single oral ultra-high dose of cholecalciferol found no adverse effects like hypercalcemia or hypercalciuria 7

Dose-Response Relationship

The relationship between Vitamin D3 dose and adverse events is not fully understood:

• Study 3 found that supplemental vitamin D doses of 3200-4000 IU/d appear to increase the risk of hypercalcemia and some other adverse events
• Study 4 found a trend towards increased hypercalcemia with high-dose vitamin D supplementation, although the results were not significant
• Study 6 found no safety events with daily 7000-IU vitamin D3 supplementation for 12 months