Resident Editors: Neil Zhang, MD and Julie Burgess, MD

Faculty Editor: Jeffrey A. Tice, MD

Background

• Vitamin D comes in two forms: D₂ and D₃.  D₂ (ergocalciferol) comes primarily from plant sources. D₃(cholecalciferol) is either synthesized in the skin in response to UVB exposure or comes from dietary sources. Only D₂ is available by prescription in the US, but both D₂ and D₃ are available over the counter. 
• ~ 80% of our Vit D comes from skin synthesis.
• Vit D is then metabolized in the liver to 25(OH) Vit D (calcidiol) which is the major circulating form of Vit D. This is then metabolized in the kidneys to 1-25(OH)₂ Vit D (calcitriol) which is the active form of Vit D. Renal metabolism is triggered by PTH.
• Vit D functions to increase renal calcium reabsorption, increase gut calcium and phosphorus absorption, and decrease PTH synthesis via negative feedback.

Signs and Symptoms

• Often asymptomatic. In mild or moderate deficiency, can have nonspecific MSK pain. In severe deficiency, can have symptoms of diffuse or localized bone pain, bone tenderness, muscle aches, proximal muscle weakness, falls. One study showed that 93% of 150 consecutive patients seen at an inner-city primary care clinic with persistent, non-specific MSK pain were deficient in vitamin D.  

Differential Diagnosis

• Causes of Vit D deficiency include:
  • Decreased skin synthesis
    • Decreased exposure to sunlight
    • Dark skin pigmentation
  • Decreased dietary intake
  • Decreased GI absorption
    • Malabsorption syndromes (eg: Celiac, pancreatic insufficiency, CF, IBD, biliary obstruction, radiation enteritis)
    • s/p bariatric procedures (gastrectomy, intestinal bypass)
  • Decreased hepatic metabolism
    • Liver disease
    • Medications: antiseizure medications (phenytoin, phenobarbital, carbamazepine) and TB medications (rifampin, isoniazid)
  • Decreased renal metabolism
    • CKD
    • Hypoparathyroidism
    • Type 1 Vit D-dependent rickets
  • Increased conversion of 25(OH) Vit to 1-25(OH)₂ Vit D
    • Lymphoma
    • Chronic granulomatous disease (sarcoid, TB, histo, cocci, beryllioisis)
    • Primary hyperparathyroidism
  • Loss of Vit D-binding protein
    • Nephrotic syndrome
    • Peritoneal dialysis
• Other risk factors for Vit D deficiency:
  • Bone disease (osteomalacia, osteoporosis, rickets)
  • Other medications (antifungal medications, cholestyramine)
  • Special populations: African American and Hispanic adults, pregnant and lactating women, older adults with history of falls or non-traumatic fractures, obese adults

Evaluation

• 2015 USPSTF recommendation: There is insufficient evidence for vit D screening in asymptomatic adults.
• Consider testing those at high risk (see Causes and Other Risk Factors above) or with symptoms.
• Check the 25(OH) Vit D level. There is little utility in checking 1-25(OH)₂ Vit D levels as it is not a good indicator of Vit D status (except possibly in disorders in the metabolism of 25(OH) Vit D and phosphate).
  • There is no consensus on the definition of Vit D deficiency, though a 25(OH) Vit D level < 20 ng/mL seems to be the most common threshold used.
  • USPSTF (2015) uses 25(OH) Vit D levels of  < 30 ng/mL to represent Vit D deficiency
  • American Geriatrics Society (2014) recommends targeting a serum 25(OH) Vit D level > 30 ng/mL in older adults, particularly those at higher risk of falls, injuries, and fracture.
  • Endocrine Society (2011) 25(OH) Vit D level reference ranges:
    • <20 ng/ml = deficiency
    • 21-29 ng/ml = insufficiency 
    • 30-100 ng/ml = adequate
  • Institute of Medicine (2010) 25(OH) Vit D level reference ranges:
    • <12 ng/ml = deficiency
    • 12-19 ng/ml = insufficiency (somewhat controversial)
    • >20 ng/ml = adequate (somewhat controversial)
    • >50 ng/ml = potentially harmful 
  • The 2010 IOM report reports that values of at least 20 ng/ml are sufficient and that data do not support health benefits for values >30ng/ml, citing that a value >20 meets the needs of 97.5% of the population. In comparison, the 2011 Endocrine Society Report indicates that levels of 30 ng/ml achieve more appropriate PTH suppression and decreased unmineralized osteoid levels in the blood.

Treatment

Benefits and harms of treating adults with asymptomatic Vit D deficiency

• Benefits per USPSTF 2015: 
  • No studies regarding benefits of screening for Vit D deficiency.
  • Vit D treatment for Vit D deficient populations is associated with mortality reduction in older, institutionalized adults. Also associated with possible decreased risk of falls in at-risk adults. 
  • Adequate evidence that treating asymptomatic Vit D deficiency has no benefits on cancer, DM2, mortality in community-dwellers, or fracture risk in non-at-risk populations.
  • Inadequate evidence regarding improvement of overall health outcomes, including psychosocial and physical function, in asymptomatic vit D deficiency
• Harms per USPSTF 2015:
  • No studies regarding the harms of screening for Vit D deficiency.
  • Adequate evidence that the harms of treating Vit D deficiency are small to none. 

Dietary and environmental sources

• Sunlight: Per USPSTF 2015: treatment with increased sun exposure (UVB) is generally not recommended for treatment of Vit D deficiency.
• Food:  Fish, dairy, fortified cereals and juices and milk and breads are good sources--salmon (100-1000 IU D₃), canned tuna (230 IU D₃), cod liver oil (400 IU/tsp), egg yolks (20 IU D₃ and D₃), fortified milk and orange juice (100 IU D₃), fortified cereal (100 IU D₃ per serving[TJ1] ), mushrooms (variable amounts).

Supplementation recommendations

• IOM 2010 Recommended Daily Allowance (RDA) for Vitamin D by Age:
  • Adults 18-70 = 600 IU/day
  • Adults >70 = 800 IU/day
• Endocrine Society suggested dietary intake if at risk for Vit D deficiency:
  • Adults 19-64 = 600 IU/day
  • Adults >65 = 800 IU/day
  • Increase dose by 2 or 3 times if obese or on a medication associated with Vit D deficiency (see above)
• The USPSTF has generally found insufficient evidence to assess the benefits and harms of Vit D supplementation as primary prevention to prevent fracture, except recommends Vit D supplementation in community-dwelling adults >65yo who are at increased risk for falls. The USPSTF recommends against daily supplementation with 400 IU or less of Vit D combined with 1000mg or less of calcium for primary prevention of fracture in non-institutionalized postmenopausal women given no fracture reduction and a small increase in incidence of nephrolithiasis.
• AGS (2014) recommends Vit D supplementation of 1000 IU/day with calcium supplementation for all older adults.
• Consider supplementation in patients who do not meet above RDA and with relatively insufficient levels of Vitamin D. Recognize that insufficiency is common, and supplementing patients is considered safe.

Treatment recommendations for Vitamin D deficiency

• The treatment regimens below apply to most patients, but special circumstances may alter dosing requirements.
• Replete with 50,000 IU Vitamin D₂ (by prescription only) by mouth weekly for 8 weeks then recheck levels. Repeat high dose 8 week course as needed until levels >20 ng/ml, followed by 1000-2000 IU supplementation daily.
• Cumulative dose for repletion is more important than schedule (i.e. weekly vs daily).
• Alternative regimens:
  • Vit D 6000 IU/day for 8 weeks.
  • Patients with malabsorptive syndromes, who are obese, or who are taking certain medications (as per above) may require 2-3 times increased dose of Vit D supplementation (Endocrine Society recommends treating deficiency with 6-10,000 IU/day followed by 3-6,000 IU/day once replete).
  • In patients with malabsorption, consider IM Vit D.
  • In patients with impaired hepatic metabolism, consider calcifediol (25(OH) Vit D3).
  • In patients with impaired renal metabolism, consider calcitriol (1-25(OH)₂ Vit D).
• Consider 1500mg/day calcium intake along with Vit D supplementation, though controversial because of association with increased MIs and strokes.
• Monitoring:
  • Consider regular monitoring of Vit D and calcium levels in patients with extrarenal Vit D production (eg granulomatous disorders)
  • Consider assessing for malabsorption syndromes in patients who are persistently resistant to Vit D therapy or with severe deficiency.
  • Once patient is Vit D replete, can consider annual Vit D monitoring.
• The IOM states that 4000 IU should be considered the tolerable upper limit of daily Vitamin D supplementation after repletion.
• The safety of 50,000 units of Vitamin D weekly for 6-8 weeks has not been fully studied during pregnancy, so most providers will replete more slowly (600-800 units of Vit D3 daily). Recommend monitoring urine calcium, especially in women with a history of renal stones.

Important caveats

• Hypersensitivity to Vitamin D supplementation can be seen in patients with chronic granulomatous diseases, some lymphomas, bone metastases, and those with primary hyperparathyroidism.  

Toxicity

• Rare harms are from Vit D toxicity (hypercalcemia, hyperphosphatemia, hypercalciuria, and PTH suppression), Vit D plus calcium treatment (nephrolithiasis), or sun exposure (increased risk for skin cancer).
• Doses up to 10,000 IU of Vitamin D₃ have been tolerated for up to 5 months without causing toxicity.  Usually not seen until 25(OH) vit D >150, however, can occur as low as 88.  Be aware that patients may be taking other Vitamin D supplements and may not be aware (often added to other supplements and vitamins).
• Need to be careful in supplementing patients with granulomatous disease or lymphomas. 

References

Bordelon, P, Ghetu MV, Langan RC. Recognition and Management of Vitamin D Deficiency. Am Fam Physician 2009; 80(8):841-6.

Holick, MF. Vitamin D deficiency. N Engl J Med 2007;357:266-81. 

Holick MF, Binkley NC, Bischoff-Ferrari HA, Gordon CM, Hanley DA, Heaney RP, Murad MH, Weaver CM, “Endocrine Society Evaluation, treatment, and prevention of vitamin D deficiency: an Endocrine Society clinical practice guideline.” J Clin Endocrinol Metab. 2011 Jul;96(7):1911-30. Epub 2011 Jun 6.

Institute of Medicine 2011 Dietary reference intakes for calcium and vitamin D. Washington, DC: The National Academies Press.

LeBlanc ES, Zakher B, Daeges M, Pappas M, Chou R. Screening for Vitamin D Deficiency: A Systematic Review for the U.S. Preventive Services Task Force. Annals of Internal Medicine. 2014.

American Geriatrics Society Workgroup on Vitamin D Supplementation for Older Adults. “Recommendations Abstracted from the American Geriatrics Society Consensus Statement on Vitamin D for Prevention of Falls and Their Consequences.” Journal of the American Geriatrics Society 62, no. 1 (January 2014): 147–52. https://doi.org/10.1111/jgs.12631.

LeBlanc, Erin S., Bernadette Zakher, Monica Daeges, Miranda Pappas, and Roger Chou. “Screening for Vitamin D Deficiency: A Systematic Review for the U.S. Preventive Services Task Force.” Annals of Internal Medicine 162, no. 2 (January 20, 2015): 109–22. https://doi.org/10.7326/M14-1659.

LeFevre, Michael L., and U.S. Preventive Services Task Force. “Screening for Vitamin D Deficiency in Adults: U.S. Preventive Services Task Force Recommendation Statement.” Annals of Internal Medicine 162, no. 2 (January 20, 2015): 133–40. https://doi.org/10.7326/M14-2450.

Weaver, C., D. Alexander, C. Boushey, B. Dawson-Hughes, J. Lappe, M. LeBoff, S. Liu, A. Looker, T. Wallace, and D. Wang. “Calcium plus Vitamin D Supplementation and Risk of Fractures: An Updated Meta-Analysis from the National Osteoporosis Foundation.” Osteoporosis International 27, no. 1 (January 2016): 367–76. https://doi.org/10.1007/s00198-015-3386-5.