How I Treat Vitamin D Deficiency

Abstract

Importance of Vitamin D

Vitamin D is important in a number of physiologic processes, including calcium absorption, innate and adaptive immunity, and homeostasis of a number of organs. Chronic vitamin D deficiency in adults results in osteoporosis, osteomalacia, muscle weakness, and increased risk of falls.^1–4 Poor vitamin D intake and low blood levels of vitamin D metabolites are associated with increased incidence and severity of several autoimmune diseases involving the T helper type 1 lymphocyte,^5,6 including multiple sclerosis,⁷ rheumatoid arthritis,⁸ type I diabetes,⁹ systemic lupus erythematosis,¹⁰ and psoriasis.^11,12 Lower levels of vitamin D, adjusted for body mass index, are also associated with increased risk of hypertension, myocardial infarction, and death as a result of cardiovascular disease.^13–16

Of particular interest to oncologists is the reduced incidence of some epithelial malignancies, particularly breast and colon, with higher intake or blood levels of vitamin D.^17–23 In some observational studies, higher levels of vitamin D have also been associated with reduced recurrence and mortality from breast, colon, and ovarian cancers.^24–28 Although there is evidence that vitamin D supplementation can improve muscle strength and reduce the number of falls among the elderly and fractures resulting from osteoporosis,^1,29–32 there is little direct evidence that low-dose vitamin D supplementation can significantly reduce cancer incidence or recurrence. Reduction in cancer incidence was observed in a small placebo-controlled trial for calcium and vitamin D (1,100 IU/d), and this reduction seemed greater than that seen with calcium alone, when cancers arising in the first year of the trial were censored.³³ However, no reduction in breast or colon cancer was observed for the calcium and vitamin D arm in the Women's Health Initiative trial, in which the dose of vitamin D for the treatment arm was only 400 IU, and both the placebo and treatment arms were allowed to ingest nonstudy vitamin D up to 1,000 IU/d.^34–36

Regardless of whether vitamin D helps prevent cancer or its recurrence, the high frequency of vitamin D inadequacy in the US population^37,38 and the adverse impact on bone health of both vitamin D depletion and many of today's systemic cancer treatments makes it important for oncologists to understand vitamin D physiology and recognize, treat, and prevent vitamin D deficiency.

Vitamin D Metabolism and Its Role in Breast and Colon Homeostasis

Cholecalciferol (vitamin D3), either ingested or manufactured in the skin in response to sun exposure, must first be converted to the prohormone 25(OH)D in the liver and then to the active hormone 1,25(OH)₂D by tissues containing the 1-α-hydroxylase enzyme. The active form of vitamin D—1,25(OH)₂D—may function in an endocrine fashion, as in the case of 1,25(OH)₂D produced in the kidney, or an autocrine/paracrine manner, as in the case of 1,25(OH)₂D produced in several other organs in which vitamin D plays an important role in homeostasis (Fig 1). The breast and colon are two of these organs, and epithelial cells from both make 1,25(OH)₂D from circulating precursors. In the breast, vitamin D seems to be important in limiting proliferation and neoangiogenesis in response to hormones and growth factors and promoting differentiation.^39–47 In the colon, vitamin D limits proliferation in response to bile acids and other carcinogens and promotes differentiation and expression of adhesion and cell-junction proteins.^48–50

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Figure 1.

Schematic of vitamin D metabolism and actions related to tissue homeostasis. VDR, vitamin D receptor. Data adapted.⁸¹

Sources of Vitamin D and Standard Doses of Vitamin D Supplements

Vitamin D sufficiency is defined in terms of the serum level of the prohormone 25(OH)D required for bone health, which is 30 to 32 ng/mL. Maintenance of a 30 to 32 ng/mL serum level requires approximately 2,200 to 3,000 IU/d of vitamin D from all sources, including ultraviolet light exposure, food, and supplements.^20,51,52 Recommendations from the Institute of Medicine for vitamin D supplementation suggest 200 IU of vitamin D daily from birth through age 50 years, 400 IU/d for individuals age 51 to 70 years, and 600 IU/d for those age 70 years or older.⁵³ These recommendations presume some sun exposure and vitamin D intake from food and are not adequate to treat vitamin D deficiency.^54,55 Historically, the source of most vitamin D has been ultraviolet light–induced skin manufacture of cholecalciferol. A single whole-body dose of ultraviolet radiation associated with minimal erythema produces 10,000 IU of vitamin D.⁵⁵ Thus, 15 to 20 minutes of daily sun exposure without sunscreen in lower midwestern and southern latitudes between 10:00 am and 3:00 pm is usually sufficient to ensure adequate synthesis of vitamin D metabolites. Large excesses of vitamin D3 from prolonged sun exposure are destroyed in the skin, making vitamin D toxicity from sun exposure improbable.^54,55 In contrast, with the exception of coldwater ocean fish, food is a poor source of vitamin D.⁵⁴ Three ounces of herring, which few individuals eat, provides 1,300 IU of vitamin D, 3.5 oz of the more commonly ingested salmon provides 350 IU, and 1 teaspoon of cod liver oil provides approximately 400 IU. However, the amount of vitamin D in 1 cup of fortified milk or orange juice is only 100 IU, with 50-100 IU per cup of breakfast cereal or tablespoon of margarine.^54,56,57 Today, with more time spent indoors and increased use of sunscreen, higher basal intakes of 1,000 to 2,000 IU/d from supplements are recommended to avoid vitamin D deficiency.^23,58–60 Multiple vitamins generally contain 400 IU of vitamin D, and calcium supplements provide 200 to 400 IU of vitamin D. Vitamin D3 supplements without other additives are readily available over the counter in 400, 1,000, and 2,000 IU strengths at pharmacies and most grocery stores. These supplements are much smaller in size than pills containing calcium and vitamin D and generally cost $10 or less for a 3-month supply. At similar doses, vitamin D3 may be more potent than vitamin D2 (ergocalciferol), which is obtained from plants.⁶¹ The Institute of Medicine lists 2,000 IU/d as the upper tolerable limit, but in fact, there is little evidence of toxicity unless doses of 10,000 IU of vitamin D3/d are exceeded.^53,62

Definition of Vitamin D Deficiency and Incidence in US Population

Vitamin D adequacy is currently defined as a function of calcium homeostasis, with lower vitamin D levels resulting in reduced absorption of calcium from the gut and/or elevations of parathyroid hormone (PTH) considered inadequate. Blood levels of the prohormone 25(OH)D, with a half-life of 2 to 3 weeks, are used to describe vitamin D sufficiency rather than levels of 1,25(OH)₂D, which has a half-life of only 3 to 4 hours.^54,58 Furthermore, in early vitamin D depletion, blood levels of 1,25(OH)₂D can be misleading because they may rise initially in response to elevations in PTH, which is sensitive to reductions in 25(OH)D, before they begin to fall with prolonged precursor depletion.^51,63

Who Should Have Serum 25(OH)D Levels Assessed?

How to Treat Vitamin D Deficiency

The first step in treating vitamin D deficiency is to obtain a baseline 25(OH)D blood level and then decide on the target replacement level and how quickly that target must be reached (Table 1). Each 1,000 IU of vitamin D3 daily in addition to what the patient is currently ingesting will raise the level of 25(OH)D by 10 ng/mL after a few weeks. Note that more may be required for individuals who are obese, because vitamin D is sequestered in adipose tissue.⁷⁹

A common example encountered by an oncologist would be that of an asymptomatic postmenopausal woman about to begin aromatase-inhibitor therapy who is found to have mild osteopenia. Her 25(OH)D level is 20 ng/mL. In addition to ensuring adequate calcium intake, if the target 25(OH)D serum level is 40 ng/mL, the simplest treatment is to ask her to take an extra 2,000 IU of over-the-counter vitamin D3, checking the 25(OH)D level again at 3 months. It should be cautioned that 1% of the population may have occult primary hyperparathyroidism, which may be unmasked by vitamin D and calcium supplementation, resulting in hypercalcemia.⁸⁰ For individuals of average weight with insufficiency only during the winter months who get appreciable sun exposure during the summer, we usually suggest vitamin D3 supplementation only during the late fall, winter, and early spring.

A different scenario might involve a woman with a body mass index of 35 kg/m² ready to begin antihormonal therapy who already complains of fatigue, weakness, and diffuse arthralgias. A 25(OH)D level of 9 ng/mL shows evidence of severe vitamin D deficiency and is likely responsible for some or all of her symptoms. In this case, the 25(OH)D level should be increased as quickly as possible with either 4,000 IU vitamin D3 daily or 30,000 IU weekly, checking the level again at 6 and 12 weeks. When the desired level is achieved, maintenance of 40 ng/mL is usually possible with 2,000 IU per day, but in the case of obese women, higher doses may be needed.⁷⁹

The importance of educating patients, checking compliance, and monitoring 25(OH)D levels every 3 months during treatment of deficiency and early maintenance phases cannot be overstressed. Patients easily get confused. We have observed situations in which weekly high-dose vitamin D was taken daily by mistake. In summary, vitamin D plays an important role in the homeostasis of a variety of organ systems. The precise roles that vitamin D plays in prevention of cancer and recurrence—along with the blood levels necessary to carry out those roles—have yet to be defined. In the meantime, oncologists are encouraged to check vitamin D levels in individuals about to undergo treatment that could impact bone and muscle health, replace deficiencies, and maintain 25(OH)D at levels optimum for musculoskeletal health.

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