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Vitamin D Deficiency and Related Disorders

Vin Tangpricha, MD, PhD, Associate Professor of Medicine, Division of Endocrinology, Metabolism and Lipids, Emory University School of Medicine
Natasha B Khazai, MD, Instructor of Medicine, Division of Endocrinology, Emory University School of Medicine

Updated: Oct 5, 2009

Introduction

Background

Vitamin D deficiency in children can manifest as rickets (it is the most common cause of nutritional rickets), which presents as bowing of the legs. Vitamin D deficiency in adults results in osteomalacia, which presents as a poorly mineralized skeletal matrix. These adults can experience chronic muscle aches and pains.1 (See images below and Images 1-3.)

Findings in patients with rickets.

Findings in patients with rickets.



Radiograph in a 4-year-old girl with rickets depi...

Radiograph in a 4-year-old girl with rickets depicts bowing of the legs caused by loading.



Anteroposterior and lateral radiographs of the wr...

Anteroposterior and lateral radiographs of the wrist of an 8-year-old boy with rickets demonstrates cupping and fraying of the metaphyseal region.



Vitamin D is important for calcium homeostasis and for optimal skeletal health. The term vitamin D refers to either vitamin D2 or vitamin D3. Vitamin D3, also known as cholecalciferol, is either made in the skin or obtained in the diet from fatty fish. Vitamin D2, also known as ergocalciferol, is obtained from irradiated fungi, such as yeast. Vitamin D2 and vitamin D3 are used to supplement food products or are contained in multivitamins. Past studies suggested that vitamin D3 may be more effective than vitamin D2 in establishing normal vitamin D stores.2,3 However, a study by Holick and colleagues demonstrated that vitamin D2 and vitamin D3 appear to be equipotent in raising 25(OH)D concentrations when given in daily doses of 1000 IU.4

Pathophysiology

Vitamin D deficiency can result from a variety of causes, including inadequate exposure to sunlight, malabsorption problems, lack of vitamin D in breast milk, and the effects of certain medications. (See Causes.)

The production of vitamin D3 in the skin involves a series of reactions initiating with 7-dehydrocholesterol. Upon exposure to ultraviolet B (UVB) radiation between the wavelengths of 290-315 nm, 7-dehydrocholesterol is converted to previtamin D3, which is then converted to vitamin D3 after a thermally induced isomerization reaction in the skin. From the skin, newly formed vitamin D3 enters the circulation by binding to vitamin D binding protein (DBP). In order to become active, vitamin D requires 2 sequential hydroxylations to form 1,25-dihydroxyvitamin D (1,25[OH]2 D).

Vitamin D is initially hydroxylated in the 25 position by the hepatic microsomal and/or mitochondrial enzyme vitamin D 25-hydroxylase. The second hydroxylation occurs in the kidney by the P450 enzyme 25-hydroxyvitamin D-1 alpha-hydroxylase. Upon entering the cell, the 1,25(OH)2 D hormone binds to the vitamin D receptor (VDR). The bound vitamin D receptor then forms a heterodimer with the retinoic acid X receptor (RXR). This heterodimer then goes to the nucleus to bind deoxyribonucleic acid (DNA) and increases transcription of vitamin D–related genes.

The major function of vitamin D is to increase the efficiency of calcium absorption from the small intestine. Heaney and colleagues demonstrated that maximum calcium absorption occurs at levels of 25-hydroxyvitamin D (25[OH]D) greater than 32 ng/mL.5 Vitamin D also enhances the absorption of phosphorus from the distal small bowel. Adequate calcium and phosphorus absorption from the intestine is important for proper mineralization of the bone. The second major function of vitamin D is for the maturation of osteoclasts to resorb calcium from the bones.

Inadequate circulating 25(OH)D is associated with elevated parathyroid hormone (PTH); this condition is called secondary hyperparathyroidism. The rise in PTH may result in increased mobilization of calcium from the bone, which results in decreased mineralization of the bone.

Of note, prolonged exposure to the sun does not cause vitamin D toxicity. This is because after prolonged UVB radiation exposure, the vitamin D made in the skin is further degraded to the inactive vitamin D metabolites tachysterol and lumisterol.  

Frequency

United States

Vitamin D insufficiency is highest among people who are elderly, institutionalized, or hospitalized. In the United States, 60% of nursing home residents6 and 57% of hospitalized patients7 were found to be vitamin D deficient.

However, vitamin D insufficiency is not restricted to the elderly and hospitalized population; several studies have found a high prevalence of vitamin D deficiency among healthy, young adults. A study from Boston determined that nearly two thirds of healthy, young adults in Boston were vitamin D insufficient at the end of winter.8

International

Similar rates of vitamin D deficiency have been reported in Europe9 and Canada. A greater prevalence of vitamin D deficiency exists in Middle Eastern countries. A study of 316 young adults aged 30-50 from the Middle East showed that 72.8% had 25(OH)D values of less than 15 ng/dL (that is, severely deficient). This was significantly more common in women than in men (83.9% vs 48.5%). The difference between sexes probably reflects the cultural and religious practices leading to less skin exposure in women than in men.10,11,12,13

Mortality/Morbidity

  • The treatment of vitamin D insufficiency can decrease the risk of hip and nonvertebral fractures.14,15 A meta-analysis by Boonen et al of postmenopausal women and of men aged 50 years or older reporting a risk of hip fracture found that oral vitamin D supplementation reduced the risk of hip fractures by 18% when vitamin D and calcium were taken together.16 Most of the trials that demonstrated the antifracture efficacy of vitamin D used approximately 800 IU of vitamin D3. The minimum 25(OH)D level at which antifracture efficacy was observed was 30 ng/ml (74 nmol/L), suggesting a threshold for optimal levels of 25(OH)D for fracture protection.
  • Bischoff-Ferrari et al, in another meta-analysis, evaluated the efficacy of oral vitamin D supplementation in the prevention of hip and other nonvertebral bone fractures.17 The analysis, of individuals aged 65 years or older, took into account 12 double-blind, randomized, controlled trials (RCTs) for nonvertebral fractures (n = 42,279) and 8 RCTs for hip fractures (n = 40,886), comparing the results obtained from the use of oral vitamin D (with or without calcium) with those derived from the administration of calcium alone and from placebo use.

    The results indicated that vitamin D offers dose-dependent protection against fractures. In this study, doses of more than 400 IU per day were found to reduce fractures by at least 20% in individuals aged 65 years or older. In contrast to the Boonen study, the investigators maintained that these effects were independent of calcium supplementation.
  • Vitamin D insufficiency contributes to osteoporosis by decreasing intestinal calcium absorption.5,18 Treatment of vitamin D deficiency has been shown to improve bone mineral density.19,20 An analysis of the Third National Health and Nutrition Examination Survey (NHANES III) demonstrated a positive correlation between circulating 25(OH)D levels and bone mineral density.21
  • Vitamin D supplementation has been associated with a reduction in falls involving the older population. A meta-analysis demonstrated that vitamin D supplementation resulted in a reduction in falls of about 22% in ambulatory and institutionalized elderly subjects, as compared with controls.22,23
  • Epidemiologic data suggest that vitamin D deficiency places adults at risk for developing cancer24,25,26,27,28 ; these apparently include breast, colon, and prostate cancer.29,30 Several studies using cultured cancer cells in mice models have also supported the notion that vitamin D prevents the growth of cancers.31 Larger, randomized clinical trials are underway in humans to establish the role of vitamin D in the prevention of cancers.
  • Vitamin D insufficiency may increase the risk for type I and type II diabetes mellitus.32,33 In NHANES III, lower vitamin D status was associated with higher fasting glucose and 2-hour glucose after an oral glucose tolerance test.34 Furthermore, vitamin D supplementation in adults has been associated with improved insulin sensitivity in several small, case-control studies.32
  • A meta-analysis evaluated the effect of vitamin D supplementation (using a mean supplementation dosage of about 500 IU daily) on all-cause mortality in 18 randomized controlled trials and found a 7% relative risk reduction for death.35

Race

Darker skin interferes with the cutaneous synthesis of vitamin D. A study from by Holick and coauthors demonstrated that non-Hispanic black subjects require 6 times the amount of UV radiation necessary to produce the similar serum vitamin D concentration seen in non-Hispanic white subjects.36 The explanation for the increased radiation necessary to increase vitamin D levels is that melanin absorbs ultraviolet radiation. 

A higher prevalence of vitamin D insufficiency exists among non-Hispanic black persons. Dawson-Hughes and colleagues demonstrated that in Boston, 73% of elderly black subjects were vitamin D insufficient, compared with 35% of elderly non-Hispanic whites.37 In a large survey of 1500 healthy black women younger than 50 years, 40% were vitamin D deficient (25[OH]D <16 ng/mL), as compared with 4% of 1400 white women in that study.38 The decreased efficacy of vitamin D production by darker-pigmented skin explains the higher prevalence of vitamin D insufficiency among darker-skinned adults. 

Age

Vitamin D production in the skin declines with advancing age, making elderly populations more dependent on dietary vitamin D. For the average older person, higher dietary intake of vitamin D may be required to achieve optimal serum levels of 25(OH)D.33

Clinical

History

Vitamin D deficiency is often a silent disease. As previously mentioned, vitamin D deficiency in children can present as bowing of the legs from rickets. In adults, vitamin D deficiency results in osteomalacia, which presents as a poorly mineralized skeletal matrix. Adults in these cases can experience chronic muscle aches and pains.1

Vitamin D deficiency is the most common cause of nutritional rickets. Rare genetic forms of rickets occur because of defects in vitamin D metabolism. Vitamin D – dependent rickets type I occurs because of a defect in the renal 25-hydroxyvitamin D-1 alpha-hydroxylase that results in decreased 1,25(OH) 2 D production. Vitamin D – dependent rickets type II occurs when a mutation exists in the VDR.

Physical

  • In children with a severe vitamin D deficiency, the examination may reveal bowing in the legs.
  • In adults with a severe vitamin D deficiency, the examination can reveal periosteal bone pain. This is best detected using firm pressure on the sternal bone or tibia.

Causes

  • Inadequate exposure to sunlight - This causes a deficiency in cutaneously synthesized vitamin D. Adults in nursing homes or health care institutions are at a particularly high risk.39
  • Vitamin D malabsorption problems - People who have undergone resection of the small intestine are at risk for this condition. Diseases associated with vitamin D malabsorption include celiac sprue, short bowel syndrome,40 and cystic fibrosis.41
  • Minimal amounts of vitamin D in human breast milk - The American Academy of Pediatrics recommends vitamin D supplementation starting at age 2 months for infants fed exclusively with breast milk.42
  • Medications - Some medications are associated with vitamin D deficiency. Drugs such as Dilantin, phenobarbital, and rifampin can induce hepatic p450 enzymes to accelerate the catabolism of vitamin D.

Differential Diagnoses

Other Problems to Be Considered

Lack of dietary intake
Inadequate sunlight exposure
Malabsorptive diseases (celiac sprue, short bowel syndrome, cystic fibrosis)
Antiepileptic medications that accelerate vitamin D metabolism (phenytoin, phenobarbital)
End-stage liver disease

Workup

Laboratory Studies

  • Serum 25(OH)D - The circulating half-life of 25(OH)D is 2 weeks. This is the best test to determine vitamin D status. A 25(OH)D level of less than 32 ng/mL is considered vitamin D insufficient.43  A 25(OH)D level of less than 15 or 20 ng/mL have been used to define vitamin D deficiency.  Intestinal calcium absorption is optimized at levels above 32 ng/mL5,18 . Parathyroid hormone levels start to rise at 25(OH)D levels below 31 ng/mL,44 which is another marker of vitamin D insufficiency.
  • Parathyroid hormone (PTH) - Although not always required for the diagnosis of vitamin D insufficiency, a serum PTH may be used to help establish the diagnosis of vitamin D insufficiency. Often, patients with vitamin D insufficiency have a corresponding elevated PTH, indicating secondary hyperparathyroidism. An inverse relationship exists between PTH and 25(OH)D levels.44 Usually, PTH levels decrease after the correction of a vitamin D insufficiency.

Treatment

Medical Care

Vitamin D deficiency can be corrected using various methods, although no standard treatment regimen exists. The following are expert recommendations for the prevention and treatment of vitamin D deficiency.45

Prevention of Vitamin D Deficiency

  • Children
    • Breastfeeding (up to age 1 y) - 400 IU vitamin D3 per day + sensible sun exposure
    • Inadequate sun exposure or dark skin (ages 1-18 y) - 400-1000 IU vitamin D3 per day + sensible sun exposure
  • Adults
    • Inadequate sun exposure or if aging (age >50 y), pregnant, or lactating
      • 800-1000 IU vitamin D3 per day + sensible sun exposure, or
      • 50,000 IU vitamin D3 per month + sensible sun exposure
    • Malabsorption syndromes - 50,000 IU of vitamin D2 every week
    • Drugs that increase the metabolism of activated vitamin D - 50,000 IU vitamin D2 every 1, 2, or 4 weeks

Treatment of Vitamin D deficiency

  • Children
    • Breastfeeding without vitamin D supplementation (up to age 1 y) - Vitamin D2 or vitamin D3, 1000-2000 IU per day with calcium supplementation
    • Inadequate sun exposure or dark skin (ages 1-18 y) - 50,000 IU vitamin D2 every week for 8 weeks
  • Adults
    • Inadequate sun exposure, or if aging (age >50 y), pregnant, or lactating - 50,000 IU vitamin D2 per week for 8 weeks (Repeat for another 8 weeks if 25(OH)D remains less than 30 ng/mL.
    •  Malabsorption syndromes
      • UVB irradiation (tanning bed or portable UVB device)
      • 50,000 IU of vitamin D2 every day or every other day
    • Drugs that increase the metabolism of activated vitamin D - 50,000 IU vitamin D2 every 2 weeks for 8-10 weeks or every week if 25(OH)D is less than 30 ng/dL

Diet

Individuals who do not have exposure to sunlight are at risk for vitamin D deficiency if they do not ingest adequate amounts of foods that contain vitamin D.

However, most dietary sources of vitamin D do not contain sufficient amounts of vitamin D to satisfy daily requirements. Foods thought to contain high amounts of vitamin D3 are oily fish, such as salmon, mackerel, and blue fish, as well as fortified milk and other dairy products. A single serving (3.5 oz) of wild-caught salmon has 988 ± 524 IU vitamin D3, an amount that remains unchanged after baking but that decreases by 50% if the salmon is fried in vegetable oil.46 In comparison, farm-raised salmon has only 25% the content of vitamin D3 found in the flesh of wild salmon, whereas blue fish and mackerel have even lower vitamin D3 levels, at 280 ± 68 and 24 IU, respectively.46 Fortified milk may contain less than the stated amount of vitamin D3 on the product (in some cases less than 80% of the amount).47 Vegetables are not a good source for vitamin D.

The following foods contain the indicated amounts of vitamin D, as reported by the US Department of Agriculture's (USDA's) Nutrient Data Laboratory:

  • Fortified milk (8 oz) - 100 IU
  • Fortified orange juice (8 oz)48 - 100 IU
  • Fortified cereal (1 serving) - 40-80 IU
  • Pickled herring (100 g) - 680 IU
  • Canned salmon with bones (100 g) - 624 IU
  • Mackerel (100 g) - 360 IU
  • Canned sardines (100 g) - 272 IU
  • Codfish (100 g) - 44 IU
  • Swiss cheese (100 g) - 44 IU
  • Raw shiitake mushrooms (100 g) - 76 IU
  • Most multivitamins (1 tab) - 400 IU

Medication

The goals of pharmacotherapy are to correct the vitamin D deficiency, reduce morbidity, and prevent complications.

Fat-soluble vitamins

Vitamin D promotes absorption of calcium and phosphorus in the small intestine. It also promotes renal tubule resorption of phosphate.


Ergocalciferol (Calciferol, Drisdol)

Most widely available form of vitamin D. Ergocalciferol stimulates calcium and phosphate absorption from the small intestine and promotes calcium release from bone into the blood.

Dosing

Adult

625 mcg/d to 5 mg/d (25,000-200,000 U) PO

Pediatric

1.25-5 mg/d (50,000-200,000 U) PO

Interactions

Colestipol, mineral oil, and cholestyramine may decrease absorption of ergocalciferol from small intestine; thiazide diuretics may increase effects of vitamin D

Contraindications

Documented hypersensitivity; hypercalcemia, malabsorption syndrome

Precautions

Pregnancy

A - Fetal risk not revealed in controlled studies in humans

C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus

Precautions

Pregnancy category C if dose exceeds the RDA; caution with impaired renal function, renal stones, heart disease, or arteriosclerosis

Follow-up

Further Outpatient Care

  • After correction of their vitamin D status with oral vitamin D, patients should have a repeat test of their 25(OH)D level to confirm that they are in the normal range. If a patient remains persistently low despite several attempts at correction with oral vitamin D, a trial of UVB light therapy (ie, by tanning lamps) may be considered to improve vitamin D status.

Deterrence/Prevention

  • See Diet.

Complications

  • See Mortality/Morbidity.

Miscellaneous

Medicolegal Pitfalls

  • Vitamin D status should be assessed in all patients with osteoporosis. If they have vitamin D deficiency, these patients should have their 25(OH)D levels corrected.
  • Infants fed exclusively with breast milk should have vitamin D supplementation as recommended by the American Academy of Pediatrics.
  • Physicians should exercise caution when recommending over-the-counter vitamin D supplementation. Some brands may not contain the amount of vitamin D stated on the bottle.

Multimedia

Findings in patients with rickets.

Media file 1: Findings in patients with rickets.

Radiograph in a 4-year-old girl with rickets depi...

Media file 2: Radiograph in a 4-year-old girl with rickets depicts bowing of the legs caused by loading.

Anteroposterior and lateral radiographs of the wr...

Media file 3: Anteroposterior and lateral radiographs of the wrist of an 8-year-old boy with rickets demonstrates cupping and fraying of the metaphyseal region.

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Keywords

vitamin D deficiency, D vitamin, vitamin D, vitamin D calcium, vitamin D3, low vitamin D, rickets, osteomalacia, vitamin D2, deficiency of vitamin D, cholecalciferol, ergocalciferol, nutritional rickets, fat soluble vitamins, elevated parathyroid hormone, PTH, secondary hyperparathyroidism, vitamin B2, calcium absorption, phosphorus absorption, bone mineralization, 25-hydroxyvitamin D, 1,25-dihydroxyvitamin D, 1,25(OH)2D, circulating 25(OH)D, osteoporosis, bone mineral density, cutaneous synthesis of vitamin D, cutaneous vitamin D production, vitamin D synthesis, melanin, vitamin D malabsorption, calcium absorption from the small intestine, vitamin D insufficiency

Contributor Information and Disclosures

Author

Vin Tangpricha, MD, PhD, Associate Professor of Medicine, Division of Endocrinology, Metabolism and Lipids, Emory University School of Medicine
Vin Tangpricha, MD, PhD is a member of the following medical societies: American College of Clinical Endocrinologists, American College of Endocrinology, Endocrine Society, and Massachusetts Medical Society
Disclosure: NIH Grant/research funds Other

Coauthor(s)

Natasha B Khazai, MD, Instructor of Medicine, Division of Endocrinology, Emory University School of Medicine
Natasha B Khazai, MD is a member of the following medical societies: American Association of Clinical Endocrinologists and Endocrine Society
Disclosure: Nothing to disclose.

Medical Editor

Udaya M Kabadi, MD, Professor, Department of Medicine, University of Iowa College of Medicine
Disclosure: Nothing to disclose.

Pharmacy Editor

Francisco Talavera, PharmD, PhD, Senior Pharmacy Editor, eMedicine
Disclosure: eMedicine Salary Employment

Managing Editor

Romesh Khardori, MD, Chief, Division of Endocrinology, Metabolism and Molecular Medicine, Professor, Department of Internal Medicine, Southern Illinois University School of Medicine
Romesh Khardori, MD is a member of the following medical societies: American Association of Clinical Endocrinologists, American College of Physicians, American Diabetes Association, American Federation for Medical Research, American Medical Association, American Society of Andrology, Endocrine Society, and Illinois State Medical Society
Disclosure: Nothing to disclose.

CME Editor

Mark Cooper, MBBS, PhD, FRACP, Head, Diabetes & Metabolism Division, Baker Heart Research Institute, Professor of Medicine, Monash University
Disclosure: Nothing to disclose.

Chief Editor

George T Griffing, MD, Professor of Medicine, St Louis University School of Medicine
George T Griffing, MD is a member of the following medical societies: American Association for the Advancement of Science, American College of Medical Practice Executives, American College of Physician Executives, American College of Physicians, American Diabetes Association, American Federation for Medical Research, American Heart Association, Central Society for Clinical Research, Endocrine Society, International Society for Clinical Densitometry, and Southern Society for Clinical Investigation
Disclosure: Nothing to disclose.

Further Reading

Related eMedicine topics:
 Disorders of Bone Mineralization
Hyperparathyroidism
Hypocalcemia [Emergency Medicine]
Hypocalcemia [Nephrology]
Hypocalcemia [Pediatrics: General Medicine]
Osteoporosis
Rickets [Pediatrics: General Medicine]
Rickets [Radiology]

Clinical guidelines:
Optimizing bone health and calcium intakes of infants, children, and adolescents. American Academy of Pediatrics - Medical Specialty Society. 1999 (revised 2006 Feb). 8 pages. NGC:004848

Prevention of rickets and vitamin D deficiency in infants, children, and adolescents. American Academy of Pediatrics - Medical Specialty Society. 2003 Apr (revised 2008 Nov). 11 pages. NGC:006924

Clinical trials:
Controlled Trial of Prenatal Vitamin D3 Supplementation to Prevent Vitamin D Deficiency in Mothers and Their Infants

Defining Vitamin D Insufficiency in School Age Children: A Randomized Placebo Controlled Trial of Vitamin D3 (Vitamin D RCT)

Safety of Vitamin D in the Elderly

Vitamin D Deficiency in Patients With Hypertension

Vitamin D Dose-Response Study to Establish Dietary Requirements in Infants

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