SYMPOSIUM ON OSTEOPOROSIS

Vitamin D deficiency is very common in the United States and often goes unrecognized by primary care physicians. This oversight is unfortunate, because vitamin D plays an important role in bone development and muscle function. It also facilitates absorption of calcium and phosphate from the gut and kidney, suppresses parathyroid hormone (PTH), and acts on osteoblasts to stimulate bone formation.

Vitamin D deficiency is a risk factor for osteoporosis, osteomalacia, falls, and fractures. Other, less studied functions include roles in muscle strength and in prevention of autoimmune diseases (eg, type 1 diabetes, rheumatoid arthritis, multiple sclerosis) and cancer (eg, prostate, colon).1

Sources of vitamin D

There are two sources of vitamin D: (1) synthesis in the skin from UV-B sunlight xposure and (2) food. UV-B radiation converts 7-dehydrocholesterol, a lipid in the epidermis, to previtamin D3. This rearranges to vitamin D3 within hours, binds with vitamin D-binding protein, and enters the circulation. Just 10 to 15 minutes of exposure to sunlight on face, hands, and arms each day, 2 to 3 days a week, is required to synthesize sufficient amounts of vitamin D. Only a few natural foods, such as fatty fish, cod liver oil, and egg yolks, contain vitamin D. Fortified foods are the major dietary source of vitamin D and include milk, breakfast cereal, margarine, butter, and certain brands of orange juice and yogurt. Ice cream and cheese are not fortified.

See symposium articles on pages 8 and 17.

Recommendations for daily intake

The Food and Nutrition Board of the Institute of Medicine currently recommends the following daily vitamin D intake levels: 200 international units (IU) from birth to age 50 years, 400 IU from age 51 to 70 years, 600 IU for ages over 70 years, and 800 IU for patients who are homebound or institutionalized.2 However, clinical studies3,4 indicate that these recommendations may be too low and that the minimum intake of vitamin D for adults should be 800 to 1,000 IU per day.

Risk factors for vitamin D deficiency

There are many risk factors for vitamin D deficiency (table 1). The two most commonly seen by primary care physicians are decreased skin synthesis and inadequate dietary or supplemental intake.

Skin synthesis of vitamin D declines with age because of epidermal thinning, loss of total lipid content, and decreased blood flow in the skin. It has been shown that people aged 62 to 80 years have 25-hydroxyvitamin D3 (25[OH]D3) levels three times lower than people aged 22 to 30 years after the same sunlight exposure.5 Although only short exposures to adequate sunlight are sufficient to maintain a normal level of vitamin D, latitude and time of year significantly influence skin synthesis.

In latitudes more than 35 degrees north of the equator (eg, Boston, Seattle), vitamin D production does not take place from November through February, regardless of the length of sun exposure.6 In lower latitudes (eg, Los Angeles, Atlanta), vitamin D synthesis is adequate throughout the year. Lack of sun exposure can also result from excessive use of sunscreen, complete clothing coverage, skin pigmentation dark enough to block UV-B transmission, and being homebound or institutionalized, all of which are common causes of vitamin D deficiency.

Inadequate dietary intake of vitamin D is another common cause of vitamin D deficiency. Fortified foods are the major source of dietary vitamin D, but they are often unreliable, because they do not always contain the amount of vitamin D listed on the label. Studies have found that up to 70% of milk samples in North America do not contain the 400 IU per quart of vitamin D that they advertise.7 Also, patients' dietary intake can vary enormously. One study of 333 women showed that the intake of vitamin D varied from 20 IU to 1,600 IU each day.8

Decreased gastrointestinal absorption is another common cause of vitamin D deficiency. Vitamin D absorption occurs in the proximal small bowel and is facilitated by chylomicrons. Abnormalities of the hepatobiliary tree, proximal small bowel, and pancreas can interfere with the absorption and enterohepatic circulation of vitamin D. These abnormalities include malabsorption syndromes, inflammatory bowel disease, celiac sprue, chronic steatorrhea, cystic fibrosis, and pancreatic insufficiency. Bariatric surgery, which is being performed more often because of the increasing prevalence of obesity, is now becoming a more common cause of vitamin D deficiency.

Measuring vitamin D

The serum 25(OH)D3 level best reflects the body's supply. Although 1,25-dihydroxyvitamin D3 (1,25[OH]2D3) is the biologically active form of vitamin D, it is not a good measure of the body's storage supply and should not be used. The laboratory definition of vitamin D deficiency is extremely controversial. Reference ranges, based on population studies, vary considerably among laboratories. The lack of standardization, in addition to different measuring methods, has made it difficult to define the level of deficiency.

Many experts think that vitamin D deficiency is the 25(OH)D3 level at which the PTH concentration rises to maintain the serum calcium level at the expense of the bone (secondary hyperpara-thyroidism).9 Population studies have found this level to be about 31 ng/mL (77 nmol/L).10 However, the more conventional level currently used in laboratories is in the range of 15 to 20 ng/mL (37 to 50 nmol/L).

Prevalence of vitamin D deficiency

The prevalence of vitamin D deficiency varies according to the population studied. Age, latitude, season, race, and lifestyle all play important roles in vitamin D status. Clearly, homebound or institutionalized persons have a high prevalence of vitamin D deficiency. In one study, the prevalence ranged from 38% in nursing home residents to 54% in housebound community dwellers.11

Less recognized is the frequency of vitamin D deficiency in healthy African Americans, regardless of age, and in healthy adolescents and young adults. The third National Health and Nutrition Examination Survey (NHANES III) included more than 18,000 adolescents and adults living at latitudes of 32 or more degrees north and found that vitamin D insufficiency was very common, although a severe deficiency was not.12 The lowest vitamin D levels were in African Americans, most likely because of decreased skin synthesis due to dark pigmentation. A study of 1,546 healthy African American and 1,426 white women between ages 15 and 49 years (participants in NHANES III) showed that 42% and 4%, respectively, had a mild to moderate vitamin D de-ficiency (<15 ng/mL [37 nmol/L]).13 Twelve percent of the African American women and less than 1% of the white women had a severe deficiency (<8 ng/mL [20 nmol/L]).

Reinforcing the observation that latitude and season play a role in vitamin D deficiency, vitamin D levels were measured in healthy men and women living in Boston at the end of summer and winter.14 Low vitamin D levels (<20 ng/mL [50 nmol/L]) were found in 30% at the end of winter and in 11% at the end of summer. Surprisingly, 32% of the youngest age-group (18 to 29 years) had vitamin D insufficiency at the end of winter as compared with 16% in the oldest age-group (>50 years). This discrepancy may be because older persons take a multivitamin that provides vitamin D.

Clinical presentation

The clinical presentation of vitamin D deficiency depends on the severity. People with a mild to moderate deficiency are asymptomatic or may have nonspecific, diffuse musculoskeletal pain.15 Those with severe deficiency may have deep bone pain, diffuse muscle pain, hip pain, proximal weakness, or fractures. They may report difficulty with gait, walking up stairs, and getting out of a chair, in addition to falls.16

Treatment

Patients with vitamin D deficiency require high doses of the vitamin until their total body stores have been replenished. Subsequently, they should be switched to a maintenance dose to prevent future deficiency. The amount and form of vitamin D are dependent on the severity and mechanism of the deficiency. Various forms of vitamin D are available for treatment (table 2). Oral ergocalciferol (Calciferol, Drisdol) or cholecalciferol is the treatment of choice in patients with normal renal and hepatic function. Calcium supplements should be recommended to bring the total elemental calcium intake (diet and supplement) to 1,500 mg per day.

A patient with a mild to moderate vitamin D deficiency due to limited sun exposure or poor oral intake should be replenished with 50,000 IU of ergocalciferol a week for 6 to 8 weeks. For a severe deficiency (<8 ng/mL [20 nmol/L]), it is reasonable to take 50,000 IU orally twice a week for 6 to 8 weeks. A patient with severe malabsorption may require even higher weekly doses. Even patients with significant malabsorption will absorb more than 60% of vitamin D in this form.

Once the appropriate 25(OH)D3 level has been reached, the patient should be switched to maintenance therapy. This dose can be quite variable, depending on the patient's needs. A patient with a vitamin D deficiency from inadequate sunlight or dietary intake needs 1,000 IU daily, whereas a patient with significant malabsorption from Crohn's disease may need 50,000 IU daily. If a patient with severe malabsorption is unresponsive to a high dose of ergocalciferol (or it is intolerable), the patient should be switched to the oral form of calcitriol (1,25[OH]2D3) (Rocaltrol). If this is poorly absorbed, then the injectable form of calcitriol (Calcijex) is indicated.

Vitamin D replacement in the form of calcitriol (oral or intravenous) is often needed in patients with chronic renal disease. Vitamin D dosing in this situation depends on the patient's calcium, phosphate, and PTH levels and is beyond the scope of this article. Calcifediol (Calderol) is useful in patients with severe liver disease and those taking medications that impair metabolism of 25(OH)D3, such as phenytoin (Dilantin) and phenobarbital (Bellatal, Luminal, Solfoton).

Laboratory monitoring

Once vitamin D deficiency has been confirmed, serum calcium and PTH levels should be checked. If these levels are normal, the treatment goal is to bring the vitamin D level into the higher end of the normal range. If serum calcium and PTH levels are abnormal?\as seen with moderate to severe deficiencies?\PTH, calcium, and 25(OH)D3 levels should be monitored carefully, starting 6 to 8 weeks after initiating therapy. The goal is to reach a 25(OH)D3 level at which both PTH and calcium normalize. The patient's dose may need to be increased an additional 6 to 8 weeks to achieve this goal. It is important to avoid vitamin D toxicity, which can cause hypercalcemia, hypercalciuria (nephrolithiasis), and accelerated bone resorption. Toxic effects are uncommon and have been reported only in patients taking high daily doses of ergocalciferol (?†40,000 IU) for weeks to months.4,17 However, experts recommend avoiding daily doses greater than 10,000 IU (in patients without malabsorption). Toxicity is more likely to occur with calcitriol than with ergocalciferol. The costs of tests vary among laboratories, but at our institution, a serum PTH test is $87.00 and a 25(OH)D3 test is $76.50.

Treatment benefits

Two randomized controlled trials18,19 have shown that vitamin D and calcium supplements increase bone mineral density and reduce fracture rates in elderly patients with marginal vitamin D status. A study of 1,400 ambulatory women with a mean age of 84 years18 showed that those treated with 800 IU of vitamin D and 1.2 g of calcium each day had 23% fewer hip fractures than those receiving placebo after 36 months. The PTH and vitamin D levels had normalized in the treated group but remained abnormal in the placebo group. There is also evidence that vitamin D supplements can prevent falls in the elderly. A meta-analysis of 1,237 persons20 showed that elderly patients taking vitamin D supplements had a 22% decrease in falls compared with patients receiving pla-cebo, presumably because of the influence of vitamin D on muscle strength.

Prevention

Vitamin D deficiency can be prevented by recommending that all patients maintain appropriate sunlight exposure or dietary intake. However, in northern latitudes, where skin synthesis does not occur in the winter, vitamin D requirements must be met through dietary intake or supplementation. Experts recommend that adults get at least 800 IU of dietary vitamin D each day.

Conclusion

Vitamin D deficiency is a common clinical problem in the United States. Because most patients with mild deficiency are asymptomatic, physicians should have a high index of suspicion in populations at highest risk for deficiency. Identification and treatment of patients with vitamin D deficiency is important for optimal bone development and muscle strength.

Dr Powell is assistant professor, department of medicine, University of Washington School of Medicine and General Internal Medicine Center, Seattle. Dr Greenberg is associate professor, department of medicine, University of Washington School of Medicine and General Internal Medicine Center, Seattle.
Correspondence: Heidi S. Powell, MD, University of Washington General Internal Medicine Center, 4245 Roosevelt Way NE, Seattle, WA 98105. E-mail: powell@u.washington.edu.

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