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Clifford J. Rosen, M.D. (who was a consultant to the IoM)

This Journal feature begins with a case vignette highlighting a common clinical problem. Evidence supporting various strategies is then presented, followed by a review of formal guidelines, when they exist. The article ends with the author’s clinical recommendations.

A healthy 61-year-old white woman is concerned about a low vitamin D level detected during an assessment of her skeletal health. Her menopause began at 54 years of age. She has no history of falls, and there is no family history of hip fracture. She takes no medications or supplements. Her height is 157.5 cm (5 ft 2 in.), and her weight 59.1 kg (130 lb). The results of a physical examination are unremarkable, and the f indings on laboratory studies are normal. The T score for bone mineral density at the hip is −1.5, and the serum level of 25-hydroxyvitamin D is 21 ng per milliliter (53 nmol per liter). What do you advise?

The Clinical Problem

Whereas frank vitamin D deficiency (serum level of 25-hydroxyvitamin D below 10 ng per milliliter 25 nmol per liter) has long been recognized as a medical condition characterized by muscle weakness, bone pain, and fragility fractures, vitamin D “insufficiency,” characterized as a serum level of 25-hydroxyvitamin D of 10 to 30 ng per milliliter (25 to 75 nmol per liter), without overt clinical symptoms, has recently become a concern on the part of physicians and patients.1 Increased attention to this new “syndrome” and its potential complications has led to a substantial increase in testing for the metabolite 25-hydroxyvitamin D, the best clinical measure of vitamin D stores. The number of 25-hydroxyvitamin D assays performed by one major reference laboratory increased by 50% in the fourth quarter of 2009 as compared with the same quarter in 2008, and it is expected that several million tests will be performed this year.2

The implications of vitamin D levels that are below the normal reference range but not markedly reduced and the value of supplementation are incompletely understood. Vitamin D is critical for skeletal mineralization, and numerous observational studies have linked low levels of 25-hydroxyvitamin D to fractures.3-7 Therefore it is not surprising that most observational and randomized, placebo-controlled trials concerning vitamin D insufficiency have focused on skeletal health outcomes. In the past several years, attention has turned to nonskeletal effects of vitamin D insuff iciency, particularly in relation to cardiovascular disease, diabetes mellitus, cancer, and immune dysfunction.8-11 This review summarizes the current understanding and uncertainties regarding vitamin D insuff iciency and the effects of vitamin D supplementation on health outcomes.

S t r a t e g i e s a n d E v i d e n c e

Defining Vitamin D Insufficiency

Interpreting the import of a serum level of 25-hydroxyvitamin D in the “insuff icient” range (i.e., 10 to 30 ng per milliliter) is challenging for several reasons. First, most reference laboratories have raised the lower boundary of the normal range to clinic a l practice

Figure 1. Synthesis and Metabol!!ism of Vitamin D.
Vitamin D is initially generated in the skin from the nonenzymatic conversion of provitamin D3 to previtamin D3. Dietary intake of vitamin D is usually relatively limited, since few foods, with the exception of certain kinds of fish, contain sizable amounts; supplements are commonly used. Vitamin D is either stored in adipose tissue or converted in the liver by the enzyme 25-hydroxylase to 25-hydroxyvitamin D3 (25OHD3), the form that circulates in the highest concentration and reflects solar and dietary exposure. It is converted to the active metabolite, 1,25-dihydroxyvitamin D (1,25OH2D), or calcitriol, in the kidney, although other tissues have 1α-hydroxylase enzymatic activity. The synthesis of calcitriol is enhanced (+) by increasing levels of parathyroid hormone (PTH), which rise in response to lower levels of serum calcium. Reduced levels of serum phosphate can also increase (+) the production of calcitriol. Its synthesis is suppressed (–) by the production of fibroblast growth factor 23 (FGF-23), which is secreted by osteocytes in the bone matrix. Calcitriol inhibits the activity of 1α-hydroxylase (CYP27B1) and stimulates the activity of 24-hydroxylase (CYP24R1), an enzyme that promotes production of 24,25(OH)2D3, a vitamin D product that is not biologically active. In CYP2R1, CYP27B1, and CYP24R1, CYP denotes 30 ng per milliliter. Second, although there are several ways to measure 25-hydroxyvitamin D (radioimmunoassays, enzyme-linked assays, and liquid chromatography with mass spectrometry), the precision and accuracy of the assays, especially in nonreference laboratories, remain problematic.12 Third, 25-hydroxyvitamin D levels change with the seasons, exposure to sunlight, and dietary intake. For example, in northern latitudes, serum levels of 25-hydroxyvitamin D decline by 20% from late summer to midwinter, whereas 30 minutes of full-body exposure to the sun during the summer rapidly generates vitamin D. Regular exposure to sunlight (depending on its strength) can increase the serum level of 25-hydroxyvitamin D.3

What does a serum 25-hydroxyvitamin D level represent? Vitamin D is produced by the nonenzymatic conversion of provitamin D to previtamin D in the skin during exposure to sunlight emitting ultraviolet radiation in the narrow band of 290 to 315 nm (Fig. 1). Some vitamin D also comes from food sources (between 100 and 200 IU per day). Vitamin D is converted in the liver to 25-hydroxyvitamin D, a partially water-soluble form with a shorter half-life than vitamin D that circulates bound to vitamin D–binding protein. About 40 to 50% of circulating 25-hydroxyvitamin D is derived from skin conversion.1,3 The active form of vitamin D is 1,25-dihydroxyvitamin D, which is generated primarily in the kidney. It circulates in lower concentrations than 25-hydroxyvitamin D but has much greater affinity for the vitamin D receptor and is biologically more potent. Low levels of 1,25-dihydroxyvitamin D do not ref lect low levels of 25-hydroxyvitamin D but result from other causes, most commonly renal insuff iciency and less frequently oncogenic osteomalacia.

The serum 25-hydroxyvitamin D level is the best indicator of overall vitamin D status because this measurement ref lects total vitamin D from dietary intake and sunlight exposure, as well as the conversion of vitamin D from adipose stores in the liver.13,14 According to the National Health and Nutrition Evaluation Survey (NHANES), in the United States, the average dietary intake of vitamin D (including supplements) may be as low as 200 IU per day (with differences according to age).15 Skin-derived synthesis of vitamin D is quite variable, depending on pigmentation, latitude, season, clothing, age, sunscreen use, and local weather conditions. Levels of 25-hydroxyvitamin D are considerably lower among blacks than among whites because of greater pigmentation in blacks. In healthy whites, serum levels of 25-hydroxyvitamin D may vary according to environmental, hormonal, genetic, and nutritional factors.3,14 The body-mass index (BMI), for example, is inversely related to the serum 25-hydroxyvitamin D level, and obese patients typically have levels in the range of 10 to 20 ng per milliliter (25 to 50 nmol per liter); these differences may be due in part to lower levels of exercise and sunlight exposure in obese persons than lean persons. Several conditions cause very low serum levels of 25-hydroxyvitamin D (i.e., below 10 ng per milliliter), including poor dietary intake of vitamin D coupled with negligible sun exposure; malabsorption due to inf lammatory bowel disease, gluten enteropathy, gastric surgery, biliary disease, or intestinal overgrowth; use of antiseizure medications (e.g., phenobarbital or phenytoin); and long-term use of glucocorticoids.1,3

Defining a level of serum 25-hydroxyvitamin D as low or insufficient depends on the level that is defined as normal. Previously, according to the World Health Organization, levels below 10 ng per milliliter were considered def icient and levels below 20 ng per milliliter were classified as insuff icient.16 However, with the recent changes in laboratory reference ranges, a normal level is now typically def ined as a serum level of 30 to 76 ng per milliliter (75 to 190 nmol per liter). When that range is used, the estimated prevalence of vitamin D insufficiency is as high as 50 to 80% in the general population.17,18 According to the NHANES for 2005 and 2006, the mean 25-hydroxyvitamin D level among several age groups was 24 ng per milliliter (60 nmol per liter), a level considered to be insuff icient according to some standards.15

There are two rationales for setting the low end of the normal range for 25-hydroxyvitamin D at 30 ng per milliliter: one, put forward in studies published in the past several years, suggests that levels of parathyroid hormone (PTH) rise when levels of 25-hydroxyvitamin D fall below 30 ng per milliliter3,13,19; the other, proposed in earlier studies, suggests that active calcium absorption is optimal when the level of 25-hydroxyvitamin D is 30 ng per milliliter.20 However, both tenets are now being questioned.14 Data indicate that the relationship of PTH and 25-hydroxyvitamin D is not curvilinear, and there is substantial variation in PTH levels when 25-hydroxyvitamin D levels are between 20 and 30 ng per milliliter. There is no absolute threshold level of serum 25-hydroxyvitamin D at which PTH levels rise.13,19 Furthermore, although the information derived from dual isotope analysis is the most accurate measure of calcium absorption, there are too few studies to establish an absolute cutoff for levels of 25-hydroxyvitamin D above which calcium absorption is not enhanced. Generally, peak absorption of calcium occurs at levels between 20 and 30 ng per milliliter.

Vitamin D and Bone Health

Although recent attention has focused on the nonskeletal effects of vitamin D, it is well established that vitamin D is critical for bone mineralization.1,8-11 Therefore, it is not surprising that most studies of vitamin D have assessed outcomes for skeletal health. Several observational studies of the associations between serum levels of 25-hydroxyvitamin D and skeletal health have had conf licting results. A report from Ottawa on 15 studies (3 prospective cohort studies and 12 case–control studies) concluded that associations between serum 25-hydroxyvitamin D concentrations and fractures, falls, and performance measures (tests of gait, stability, and activity) among postmenopausal women or elderly men were inconsistent.21 A more recent report from the Agency for Healthcare Research and Quality (AHRQ) and Tufts Medical Center, analyzing the same observational studies, concluded that there was fair, or reasonable, evidence of an association between lower serum concentrations of 25-hydroxyvitamin D and an increased risk of falls among institutionalized elderly persons.22

Randomized, controlled trials of vitamin D supplementation have addressed its effects on skeletal outcomes, but most of these trials involved supplementation with both vitamin D and calcium, making it impossible to separate out the effects attributable specif ically to vitamin D. The results of a 2007 meta-analysis of 29 trials of supplementation with both calcium and vitamin D or with calcium alone suggested that daily supplementation with 1200 mg of calcium and at least 800 IU of vitamin D resulted in reduced rates of fracture and a modest increase in bone mineral density, but the relationship between serum 25-hydroxyvitamin D levels and skeletal outcomes was not assessed.23 A 2009 Cochrane meta-analysis of 10 trials testing the effects of vitamin D supplementation alone and 8 trials testing the effects of vitamin D plus calcium showed no signif icant relationship between vitamin D supplementation alone and a reduction in the risk of fracture.24 However, the study conf irmed the conclusion of the 2007 meta-analysis that calcium plus vitamin D was marginally effective in reducing the risk of fracture in older persons as compared with no supplementation (odds ratio, 0.89; 95% conf idence interval, 0.80 to 0.99).

Despite the observational data suggesting an inverse association between serum levels of 25-hydroxyvitamin D and the risk of falls among institutionalized elderly persons, the evidence is inconsistent, with some studies showing a benef it and others showing no effect of vitamin D supplementation on the risk of fractures or falls in various populations.22,25 Similarly, a randomized study conducted by the Women’s Health Initiative showed a nonsignif icant reduction in hip fractures among women receiving a total of 700 IU of vitamin D and more than 2000 mg of calcium per day.26 However, the high baseline intake of calcium (an average of 1100 to 1200 mg per day) and vitamin D (approximately 300 IU per day) in the placebo group may have limited the ability of the investigators to detect effects of supplementation. Subgroup analyses of women over 60 years of age and of those who adhered to their supplementation regimen showed a significant reduction in hip fractures with supplementation, but these results must be interpreted with caution. Randomized trials of supplementation with vitamin D2 or D3 (with daily doses ranging from 400 to 822 IU) published after the AHRQ–Tufts analysis also failed to show signif icant effects of vitamin D supplementation on the risk of fracture or falls in older populations.27,28 However, in one of those trials, vitamin D supplementation at a dose of 400 IU daily improved gait speed and reduced body sway.27

Several large observational studies have addressed the question of whether there is a threshold level of 25-hydroxyvitamin D below which adverse skeletal outcomes are more likely to occur. In one study of elderly men, levels below 16 ng per milliliter (40 nmol per liter) were associated with a greater risk of fracture, whereas in another study, men with levels below 20 ng per milliliter had greater rates of femoral bone loss than men with higher levels.29,30 In a longitudinal study, Osteoporotic Fractures in Men (MrOs), older men with serum levels of 25-hydroxyvitamin D that were less than 20 ng per milliliter had a higher risk of hip fracture than men with higher levels.31 In a prospective study of older women, 25-hydroxyvitamin D levels between 24 and 26 ng per milliliter (60 to 65 nmol per liter) were associated with the lowest risk of hip fracture; no additional risk reduction was noted above that level.32 However, in a study of older New Zealand women, levels of 25-hydroxyvitamin D below 20 ng per milliliter were not associated with an increased risk of fracture during 5 years of follow-up.33

Vitamin D and Other Health Effects Observational studies in large cohorts have shown signif icant associations between low levels of 25-hydroxyvitamin D (i.e., below 20 ng per milli-liter) and an increased risk of metabolic, neoplastic, and immune disorders such as type 1 diabetes mellitus and multiple sclerosis.7-11 The two conditions most often connected with low levels of vitamin D are atherosclerosis and diabetes mellitus.34-36 For example, a signif icantly increased risk of type 2 diabetes has been reported among persons with levels of vitamin D that are insufficient (below 30 ng per milliliter), even after adjustment for BMI and percentage of body fat.8,35

Similarly, another prospective study showed that levels of serum 25-hydroxyvitamin D below 20 ng per milliliter were associated with an increased risk of cardiovascular disease.10 However, there are not enough data from large, randomized, controlled trials to assess whether vitamin D supplementation reduces the risk of chronic diseases other than osteoporosis.

Areas of Uncertainty

The dynamics of vitamin D storage and reentry into the circulation remain poorly understood, particularly in obese persons.37 Optimal dosage regimens for vitamin D remain uncertain. In general, for every 100 IU of vitamin D taken in, there is an increase of roughly 1 ng per milliliter (3 nmol per liter) in the serum level of 25-hydroxyvitamin D; the lower the baseline level of 25hydroxyvitamin D, the greater the rise with vitamin D supplementation. Most trials assessing the association between 25-hydroxyvitamin D levels and the risk of fractures and falls have used daily doses of vitamin D between 400 and 1000 IU. Data are scarce on the effects of long-term supplementation with doses greater than 1000 IU per day. In a recently published randomized, placebocontrolled trial involving elderly persons not living in institutions, those who received an oral dose of 500,000 IU of vitamin D once a year for 3 years had a signif icantly increased rate of falls and fractures, as compared with those who received placebo, particularly in the f irst 3 months after dosing.38 These results suggest that high intermittent doses of vitamin D, as compared with daily doses, may be metabolized and used differently. Finally, data are lacking from large randomized, controlled trials designed to determine whether vitamin D supplementation reduces the risk of other major diseases, such as colon cancer, for which there are observational data suggesting a reduction in risk with supplementation. The ongoing Vitamin D and Omega-3 Trial (VITAL; ClinicalTrials.gov number, NCT01169259), a 5-year, randomized, placebo-controlled trial involving 20,000 U.S. men and women is examining vitamin D supplementation (2000 IU per day), with or without supplementation of n–3 fatty acids, for the primary prevention of cancer and cardiovascular disease.

Toxicity from vitamin D supplementation is rare and consists principally of acute hypercalcemia, which usually results from doses that exceed 10,000 IU per day; associated serum levels of 25-hydroxyvitamin D are well above 150 ng per milliliter (375 nmol per liter).39 The tolerable upper level of daily vitamin D intake recently set by the Institute of Medicine (IOM) is 4000 IU.14

The long-term effects of supplementation at doses above 4000 IU per day are not known, and risks cannot be ruled out. Recent observational studies have suggested associations between serum levels of 25-hydroxyvitamin D above 60 ng per milliliter (150 nmol per liter) and increased risks of pancreatic cancer, vascular calcif ication, and death from any cause,34,40,41 but the observational nature of these studies precludes an assessment of cause and effect. More longitudinal studies and controlled trials are needed.

Several studies have suggested that vitamin D supplementation may be most effective in reducing fractures and falls in institutionalized elderly persons, in whom serum levels of 25-hydroxyvitamin D are often below 20 ng per milliliter.42-44

Yet the optimal replacement dose in this population is still not known. A large, long-term, randomized trial is warranted to examine the effects of several different doses of vitamin D on physical performance measures and the incidence of falls and fractures in the institutionalized elderly population.

Guidelines from professional societies

At an international workshop on vitamin D held in 2007, there was agreement that most of the world’s population is not getting an amount of vitamin D suff icient to maintain healthy bone mass and minimize the risk of fracture. The workshop members also agreed that vitamin D insuff iciency decreases muscle strength and increases the risk of falls.45 The recommendation from that group, made on the basis of available observational data, was that the minimum desirable serum level of 25-hydroxyvitamin D is 20 ng per milliliter. Three years later, Osteoporosis Canada issued a report stating that the 25-hydroxyvitamin D level should be at least 30 ng per milliliter and that vitamin D insuff iciency should be def ined as a level of 10 to 29 ng per milliliter.46 In 2010, the International Osteoporosis Foundation issued a position statement on vitamin D status, also based on observational data, recommending a target serum level of 25-hydroxyvitamin D of 30 ng per milliliter in all elderly persons and stating that vitamin D intakes as high as 2000 IU per day may be necessary to attain the recommended level in some persons.47 In contrast, the IOM report, based on evidence from observational studies and recent randomized trials, suggests that a serum level of 20 ng per milliliter of 25-hydroxyvitamin D would protect 97.5% of the population against adverse skeletal outcomes such as fractures and falls.14

Conclusions and Recommendations

The woman described in the vignette is a healthy postmenopausal woman with slightly low bone mineral density and a 25-hydroxyvitamin D level of 21 ng per milliliter. Although the laboratory that performed the measurement, and many other laboratories, would label that level as insuff icient, she is certainly not def icient in vitamin D. According to the Fracture Risk Assessment Tool (FRAX) developed by the World Health Organization, the probability that she will sustain a hip fracture over the next 10 years is less than 1%. Moreover, she is not at high risk for falls and is unlikely to have osteomalacia.48

Hence, for patients such as this one, I would recommend an exercise program and a total calcium intake of 1200 mg per day. There remains uncertainty about whether vitamin D supplementation is appropriate for her, and if so, what the dose should be, although the recent IOM guidelines recommend 600 IU daily for a postmenopausal woman who is not at high risk for fractures or falls and 800 IU daily for persons who have a very high risk of osteoporosis or who are older than 70 years of age.14 I would explain that despite the recent focus in the media on the potential role of vitamin D in reducing the risk of various chronic diseases, this hypothesis requires testing in large, randomized, controlled trials, and vitamin D cannot currently be recommended for the purpose of reducing the risk of heart disease or cancer.
– – – –
Dr. Rosen reports serving as an unpaid consultant for Lexicon Genetics and serving on the Vitamin D Subcommittee for the IOM, for which he received reimbursement for travel expenses. No other potential conf lict of interest relevant to this article was reported.

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41. Melamed ML, Michos ED, Post W, Astor B. 25-Hydroxyvitamin D levels and the risk of mortality in the general population. Arch Intern Med 2008;168:1629-37.
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44. LeBoff MS, Kohlmeier L, Hurwitz S, Franklin J, Wright J, Glowacki J. Occult vitamin D def iciency in postmenopausal US women with acute hip fracture. JAMA 1999;281:1505-11.
45. Norman AW, Bouillon R, Whiting SJ, Veith R, Lips P. 13th Workshop consensus for vitamin D nutritional guidelines. J Steroid Biochem Mol Biol 2007;103:204-5.
46. Hanley DA, Cranney A, Jones G, et al. Vitamin D in adult health and disease: a review and guideline statement from Osteoporosis Canada. CMAJ 2010;182(12): E610-E618.
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48. Priemel M, von Domarus C, Klatte TO, et al. Bone mineralization defects and vitamin D def iciency: histomorphometric analysis of iliac crest bone biopsies and circulating 25-hydroxyvitamin D in 675 patients. J Bone Miner Res 2010;25: 305-12.

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See also VitaminDWiki

• Vitamin D Recommendations from around the world
• IoM again fails to look at interactions - Nov 2010
• Wonder about conflict of interest of IoM panel members
  • Includes Rosen conflict of Interest