Health Practitioner’s Guide to Prescribing Vitamin D and Calcium

ABSTRACT: Vitamin D and calcium are important for bone health and serve many other important functions in the body; however, some patients may be deficient in these nutrients or at risk of deficiency. This article reviews vitamin D and calcium recommendations and provides strategies healthcare practitioners can use to ensure their patients obtain optimal amounts and prevent both deficiencies and toxicities.

Vitamin D and calcium are essential for normal bone homeostasis and serve a variety of other important functions in the body. Vitamin D enhances the intestinal absorption of calcium, iron, magnesium, phosphate, and zinc, whereas calcium is crucial for proper muscular and nervous system function. Individuals at risk of deficiencies in these nutrients include persons with dairy allergies, those on strict vegetarian or vegan diets, and those who have limited sun exposure. In addition, as our population ages, an increasing number of individuals will be at an increased risk of developing deficiencies in vitamin D and calcium. This may be attributable to a variety of factors, including inadequate dietary intake, decreased ability to absorb nutrients, and use of medications that interact with the absorption and/or metabolism of these essential nutrients.

While the scope of this article does not enable discussion of all of the benefits of vitamin D and calcium, the goal is to provide healthcare practitioners with a better understanding of these nutrients and how to assist their patients in obtaining optimal amounts. It is often a daunting task for patients to understand their daily requirements and how to achieve the goals set for them. This is further complicated by the availability of multiple supplements, each with different dosing regimens, compounds, and lack of product standardization. Healthcare practitioners can help patients understand their vitamin D and calcium needs, but should keep in mind that there are many different ways patients can meet their daily recommended dietary allowance (RDAs) of these nutrients using both dietary and supplementary strategies. _______________________________________________________________________________________________________________________________________________________________________________

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VITAMIN D OVERVIEW

Vitamin D is a fat-soluble prohormone that can be obtained through exposure to the sun or derived from ingested foods or supplements. It is available in two forms: vitamin D₂, also known as ergocalciferol, and vitamin D₃, also known as cholecalciferol. These formulations differ chemically only in their side-chain structure. Vitamin D₂ is most commonly manufactured through the process of ultraviolet (UV) irradiation of ergosterol extracted from yeast, whereas vitamin D₃ is manufactured synthetically by the irradiation of 7-dehydrocholesterol extracted from lanolin. 

Regardless of how vitamin D is manufactured or acquired, these compounds have weak biological activity in their initial form and require enzymatic conversion to produce the more active metabolites that are best used by the body. This occurs through an enzymatic process that starts in the liver, where vitamin D is converted to 25-hydroxyvitamin D [25(OH)D], its major circulating and storage form. This product is then converted to 1,25-dihydroxyvitamin D [1,25(OH)2D], its hormonally active form, by enzymes as it travels through the kidneys. 

Several studies suggest that vitamin D3 is more efficacious in raising serum 25(OH)D concentrations than vitamin D₂.^1,2 In addition, vitamin D₃ has been reported to reduce all-cause mortality in adults compared with other forms of vitamin D.³ Vitamin D₃ is the naturally occurring form of vitamin D in humans and is the form people typically mean when referring to vitamin D.

SOURCES OF VITAMIN D

Synthesis that begins in the skin is the major natural source of vitamin D. Previtamin D₃ is synthesized in the two innermost layers of the epidermis, the stratum basale and the stratum spinosum, from 7-dehydrocholesterol during exposure to UV light (UVB type) at wavelengths between 270 nm and 300 nm. These wavelengths are present in sunlight and in light emitted by UV lamps in tanning beds. Previtamin D₃ undergoes a temperature-dependent spontaneous isomerisation to form vitamin D₃. 

The length of daily exposure required to obtain the sunlight equivalent of oral vitamin D supplementation is difficult to predict on an individual basis and varies based on skin type (ie, lighter skin produces vitamin D more quickly than darker skin), amount of skin exposed, latitude, season, and time of day. Nevertheless, 15 to 30 minutes of unprotected sun exposure two to four times a week is generally recommended to maintain adequate levels of vitamin D. It is important to remember, however, that many individuals may have inadequate exposure to UV light due to lack of outdoor activity and the use of protective sunscreen lotions and clothing. In addition, at northern latitudes, there may not be sufficient UV radiation to synthesize vitamin D, particularly during the winter months. For these reasons, at least in the United States, milk, infant formula, breakfast cereals, and other select foods are fortified with vitamin D. 

The Food and Nutrition Board (FNB) at the Institute of Medicine of The National Academies (formerly known as the National Academy of Sciences) establishes the RDA of nutrients. The RDA refers to the average daily level of intake sufficient to meet the nutrient requirements of 97.5% of healthy individuals. The FNB’s recommended RDAs for vitamin D are as follows: men and women aged 19 to 70 years, 600 international units (IU); and men and women older than 70 years, 800 IU.⁴ To achieve adequate levels of vitamin D, all patients should be encouraged to consume foods rich in vitamin D (Table 1)⁴; however, there are few nonfortified foods that have sufficient quantities of vitamin D. In addition, vegetarian diets are usually deficient in vitamin D unless they incorporate fortified foods. 

ASSESSING VITAMIN D LEVELS 

The serum concentration of 25(OH)D is typically used to determine vitamin D status.⁵ It reflects vitamin D produced in the skin and that acquired from supplements and diet. It also has a long plasma half-life due to fat solubility, which generally ranges between 10 and 14 days.⁶ In contrast, serum 1,25(OH)2D is not usually used to determine vitamin D status because it has a shorter half-life and is tightly regulated by parathyroid hormone, calcium, and phosphate. It is not the typical storage form of vitamin D and does not decrease significantly until vitamin D deficiency is already well advanced; however, a serum 1,25(OH)2D assay may be used to monitor vitamin D deficiency in certain patients, such as those with acquired and inherited disorders of vitamin D and phosphate metabolism and in persons with end-stage renal disease.

For maximal benefit to bone, cognition, and neuromuscular health, 25(OH)D levels in the blood should be at least 30 ng/mL (75 mmol/L)⁷; however, the Vitamin D Council recommends levels between 50 ng/mL and 80 ng/mL,⁸ though some research indicates that levels this high may increase all-cause mortality.⁴ When 25(OH)D levels are below 30 ng/mL, the patient has vitamin D insufficiency, and when they are below 20 mg/mL (50 nmol/L), the patient has vitamin D deficiency.^5,9 An individual with vitamin D insufficiency has a lower than normal 25(OH)D level with no signs or symptoms, but still carries an increased risk of a variety of diseases.¹⁰ In contrast, vitamin D deficiency classically manifests as bone disease and is characterized by impaired bone mineralization that leads to bone-softening diseases, including rickets in children and osteomalacia and osteoporosis in adults.¹⁰ In elderly persons, low 25(OH)D levels have been associated with poor physical performance, reduced muscle strength, increased risk of falls and fractures, and increased cognitive impairment.^11-16 

When reviewing patients’ 25(OH)D test results, practitioners should remember that two different units of measure can be used to express vitamin D levels: ng/mL and nmol/L. To interpret the results correctly, it is essential to check which unit the laboratory has used. 

CAUSES OF VITAMIN D INSUFFICIENCY AND DEFICIENCY 

As stated previously, suboptimal levels of vitamin D may result from inadequate nutritional intake, from inadequate exposure to sunlight, and from disorders or medications that limit vitamin D absorption or impair the conversion of vitamin D into more active metabolites. In addition, certain liver, kidney, and hereditary disorders may result in lower levels of vitamin D than are desirable. 

With regard to inadequate nutritional intake, persons with milk allergies, lactose intolerance, or who follow ovo-vegetarianism and veganism tend to have vitamin D-deficient diets. Medications that increase the risk of vitamin D deficiency include anticonvulsants (eg, dilantin, phenobarbital), glucocorticoids, antifungals (eg, ketoconazole), and certain medications for AIDS, as these agents increase metabolization of 25(OH)D in the liver to an inactive form.¹⁷

TREATMENT OF VITAMIN D DEFICIENCY AND INSUFFICIENCY

There are many brands and combination products containing vitamin D and calcium (Table 2). Dosages vary greatly per formulation; therefore, it is essential that patients read labels carefully to make sure they are taking the correct dose of vitamin D and/or calcium. In addition, patients should be advised to keep track of all foods that are a major source of vitamin D to prevent excessive intake and potential toxicity, as many patients do not realize that the RDA reflects a total combination of dietary sources and supplements. 

The recommended dose of vitamin D depends on whether it is being used for prevention or for treatment of a vitamin D deficiency. The Endocrine Society recommends that adults aged 19 to 69 years take at least 600 IU of vitamin D daily and persons aged 70 years and older take at least 800 IU of vitamin D daily to maximize bone health and neuromuscular function⁵; however, it also acknowledges that this amount may not be sufficient to achieve an adequate blood level in all persons (eg, pregnant women, lactating women). Several reports note that 1500 IU to 2000 IU of vitamin D₃ daily may be needed to consistently achieve 25(OH)D levels above 30 ng/mL.^5,11,18

Adults on anticonvulsant medications, glucocorticoids, antifungals, and certain AIDS medications, as well as persons with malabsorption, may require at least two to three times higher doses of vitamin D for their age group to satisfy their body’s vitamin D requirements.^5,9,17 The most commonly used regimen to treat vitamin D deficiency or insufficiency is 50,000 IU of vitamin D every week for 6 to 8 weeks or until the 25(OH)D levels rise above 30 ng/mL, followed by 1000 IU to 2000 IU daily for maintenance. The maximum dosage available for vitamin D₃ in pill form is currently 5000 IU, but a 50,000 IU pill of vitamin D₂ is available. Many patients prefer to take the 50,000 IU pill monthly for maintenance, as it is more convenient. As long as a patient’s serum 25(OH)D level is satisfactory, there can be some flexibility in the dosing regimen.

VITAMIN D TOXICITY

Excess levels of vitamin D may occur in individuals who consume megadoses of vitamin D supplements or in anyone on high doses for prolonged periods of time, even if taken for malabsorption, renal osteodystrophy, osteoporosis, or psoriasis. The Endocrine Society recommends that doses of vitamin D should not exceed 10,000 IU per day for adults aged 19 years and older.⁵ In contrast, prolonged exposure of the skin to UV radiation cannot produce toxic amounts of vitamin D₃ because of a photoconversion of excess previtamin D₃ to inactive metabolites. 

In general, vitamin D intoxication most commonly occurs in adults taking more than 60,000 IU of vitamin D per day, but can also occur at lower levels.¹⁹ Symptoms of acute intoxication are due to hypercalcemia and may include confusion, polyuria, polydipsia, anorexia, vomiting, and muscle weakness. Chronic toxicity may lead to bone demineralization and pain; however, the greatest risk is the potential for elevated blood calcium levels, which can lead to vascular and tissue calcification and subsequent damage to the heart, blood vessels, and kidneys.⁴ 

In addition, it may cause hypercalciuria with the potential to form kidney stones. Most reports suggest a toxicity threshold for vitamin D of 10,000 IU to 40,000 IU per day and serum 25(OH)D levels of 200 ng/mL to 240 ng/mL (500-600 nmol/L); however, serum 25(OH)D levels above 50 ng/mL to 60 ng/mL (125-150 nmol/L) should be avoided, as they have been associated with increased all-cause mortality.⁴ 

CALCIUM

Calcium is the most abundant mineral in the human body. It is mainly stored in the bones and teeth, making it essential for normal bone homeostasis. Calcium is often coupled with vitamin D to enhance the body’s ability to absorb it, as low concentrations of vitamin D are associated with impaired calcium absorption, a negative calcium balance, and a compensatory rise in parathyroid hormone, leading to excessive bone resorption. In addition, several meta-analyses of trials comparing calcium, vitamin D, or both with placebo or no treatment reported a beneficial reduction in fractures with calcium and calcium plus vitamin D supplementation, but not for those treated with vitamin D alone.^20-24 These findings suggest that supplementation with both calcium and vitamin D are necessary to reduce the risk of fractures. 

Despite such findings, in 2013, the U.S. Preventive Services Task Force (USPSTF) conducted a meta-analysis that included 16 randomized controlled trials that examined the effect of vitamin D supplementation with and without calcium on fracture risk.²⁵ This included five trials comparing vitamin D (400-1370 IU daily) with placebo in more than 14,500 elderly men and women, which found that vitamin D supplementation alone did not reduce fracture risk. It also included 11 trials comparing calcium (500-1200 mg daily) plus vitamin D (300-1100 IU daily) with placebo, which showed that combined supplementation reduced the risk of total fractures; however, the results varied by setting, with the greatest benefit observed in institutionalized older adults.²⁵ 

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Based on its analysis, the USPSTF issued recommendations against vitamin D and calcium supplementation to prevent fractures in adults,^25,26 which generated controversy within the medical community. Based on the USPSTF’s assessment of the available literature, it drew the following conclusions:

• The current evidence is insufficient to assess the balance of the benefits and harms of combined vitamin D and calcium supplementation for the primary prevention of fractures in premenopausal women or in men.

• The current evidence is insufficient to assess the balance of the benefits and harms of daily supplementation with greater than 400 IU of vitamin D₃ and greater than 1000 mg of calcium for the primary prevention of fractures in noninstitutionalized postmenopausal women; thus, the USPSTF recommends against daily supplementation beyond these levels for the primary prevention of fractures in this patient population.

It is important to note, however, that these recommendations were for individuals who were not considered at high risk of developing osteoporosis and who had not already demonstrated signs of reduced bone mineral densities. 

Physicians should also keep in mind that vitamin D and calcium serve purposes beyond protecting bone health and preventing fractures. For example, some have dubbed vitamin D as the “wonder drug of the 21st century.” This is because research is increasingly linking vitamin D deficiency to more chronic illnesses, such as cancer, diabetes, and multiple sclerosis, and not just bone-related diseases, such as rickets and osteomalacia. In addition, cardiovascular mortality and overall mortality and have been found to be inversely related to vitamin D levels.²⁷ It appears that many seemingly disparate conditions are linked to vitamin D deficiency because most cells in the body have vitamin D receptors.²⁸ However, despite increasing research showing vitamin D to be essential for health, it appears that vitamin D is most effective when combined with calcium. For example, another study published in 2013 indicated that supplemental calcium alone or combined with vitamin D₃, but not vitamin D₃ alone, may help reduce serum lipid levels.²⁹ 

Based on the overall literature, we urge healthcare providers to individually assess all the benefits and risks of these supplements for their patients. The determination should not be made solely based on a potential lack of efficacy in just one area, such as fracture prevention. 

DAILY CALCIUM NEEDS AND SOURCES

The FNB has set the RDA of elemental calcium as follows: adult males aged 19 to 70 years, 1000 mg daily; adult males older than 70 years, 1200 mg daily; women aged 19 to 50 years, 1000 mg daily; and women older than 50 years, 1200 mg daily.⁴ Patients with osteoporosis and those who are not able to optimally absorb calcium may require doses as high as 1500 mg per day.⁴

Meeting the RDA of elemental calcium should not be difficult for many patients, as calcium-rich foods are plentiful (Table 3).³⁰ Dairy, including milk, yogurt, and cheese, are rich natural sources of calcium and may serve as the main source of calcium in the diet. Salmon and sardines (with bones) are other good animal-based sources of calcium. However, there are also many plant-based sources, enabling those on vegan diets to obtain enough calcium. These foods include many green vegetables (eg, cabbage, kale, broccoli), lentils, figs, oranges, and almonds. Although most grains do not contain high amounts of calcium unless they are fortified, they still contribute calcium to the diet because they contain some calcium and tend to be consumed more frequently. Other foods that are commonly fortified with calcium include many fruit juices and drinks, tofu, and certain cereals.

CALCIUM SUPPLEMENTATION

Although obtaining calcium from dietary sources is preferrable, calcium supplementation may be warranted in some patients, such as older adults with osteoporosis. Two main forms of calcium supplements are available: calcium carbonate and calcium citrate (Table 2). Calcium carbonate is more commonly available and is inexpensive and convenient; however, it is dependent on stomach acid for maximal absorption and is absorbed most efficiently when taken with food. It also tends to be the most constipating, particularly when taken on an empty stomach. In contrast, calcium citrate is absorbed equally well when taken with or without food, its absorption is not influenced by stomach acidity, and it is nonconstipating. This is a particularly important consideration for older patients, as achlorhydria (ie, absence of hydrochloric acid in gastric secretions) increases with age and many of these individuals are on antacids, H₂ receptor antagonists, or proton pump inhibitors. 

Numerous other forms of calcium are found in supplements and fortified foods, including calcium gluconate, calcium lactate, calcium phosphate, and calcium citrate malate. Of these, calcium citrate malate is often found in fortified juices as it is easily absorbed. Another common form of calcium is calcium acetate, which has a lower ability to be absorbed but is frequently prescribed for patients with renal failure to prevent their phosphorous levels from getting too high. Patients receiving this form of calcium may not receive adequate elemental calcium for maximal bone health, even if the metabolic disturbance induced by excess phosphorous is corrected due to only 169 mg of elemental calcium being present in every 667 mg of calcium acetate.³¹ 

Commonly used calcium supplements contain varying amounts of elemental calcium by weight. For example, calcium carbonate is 40% calcium, whereas calcium citrate is 21% calcium.³⁰ However, consumers do not need to calculate the amount of calcium supplied by the various forms of calcium supplements, as the “Supplement Facts” panel lists the actual elemental calcium content of each pill. Nevertheless, the percentage of calcium absorbed depends on the total amount of elemental calcium consumed at one time; as the amount increases, the percentage of absorption decreases. Absorption is highest when doses are 500 mg or less.³⁰ Therefore, it is preferrable for anyone taking more than 500 mg of elemental calcium per day to take smaller, more frequent doses. 

CALCIUM TOXICITY

To prevent excess intake of calcium, patients should be advised to calculate their total daily intake from all food sources as well as from supplements. In general, patients should avoid taking more than 1500 mg of calcium per day, as excess intake may result in hypercalciuria with kidney stone formation.^32,33 In many cases, when patients developed kidney stones upon calcium supplementation, their total calcium intakes were not considered. 

Hypercalcemia is another potential problem, but it is almost never seen in patients taking calcium supplements. Most commonly, it is associated with milk-alkali syndrome, which results when large quantities of milk are ingested along with calcium carbonate supplements over a long period of time. In the past, milk-alkali syndrome was often a side effect of treating peptic ulcer disease with antacids containing calcium carbonate as an acid buffer. It is rarely seen today because better medications that do not contain calcium are available for treating ulcers. 

More recently, several studies have reported an increased risk of myocardial infarction, stroke, and cardiovascular diseases with the use of calcium supplements, but other studies have found no such correlation.^34-38 In addition, some studies that did find a correlation may have been flawed. For example, in a European cohort study that found an increased risk of myocardial infarction with the use of calcium supplements,³⁹ many of the calcium supplement users had an overall lower educational level, were older, and had a longer duration of smoking; the latter two factors are independent risk factors for cardiac disease. While this study also reported a favorable effect on all-cause mortality with high dietary intake of calcium, those with higher dietary intake also had many favorable factors, including younger age and a higher likelihood of having a university degree and of being physically active. In addition, this group was less likely to be overweight/obese, current smokers, or to consume alcohol. 

THE TAKE-AWAYS

Vitamin D and calcium serve many important purposes in the body and are essential for bone health, particularly for preventing osteopenia and osteoporosis as people age. Healthy adults should take between 800 IU and 1000 IU of vitamin D daily and between 1000 and 1200 mg of elemental calcium daily. Maximum daily intake of calcium should not exceed 1500 mg per day to prevent complications. Patients with comorbidities may need to have these doses adjusted. A diet containing three to four servings of dairy products per day can provide adequate dietary intake of vitamin D and calcium. People intolerant to dairy products or who need higher doses should use supplements. All patients should be advised to keep track of their dietary and supplemental intake of calcium and vitamin D to prevent excess intake. In addition, adults with osteoporosis and osteopenia should have their levels of vitamin D monitored to ensure their intake is adequate. ■

Shailendra Singh, MD, is a fellow at the Department of Medicine, Division of Gerontology and Geriatric Medicine, University of Maryland School of Medicine, Baltimore.

Steven R. Gambert, MD, is professor of medicine and associate chair for clinical program development, co-director, Division of Gerontology and Geriatric Medicine, Department of Medicine, University of Maryland School of Medicine; director, Geriatric Medicine, University of Maryland Medical Center and R Adams Cowley Shock Trauma Center; and professor of medicine, Division of Gerontology and Geriatric Medicine, Johns Hopkins University School of Medicine, Baltimore. 

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