High Prevalence of Vitamin D Inadequacy and Implications for Health

Solar UV-B (wavelengths of 290-315 nm) irradiation is the primary source of vitamin D (other than diet supplements) for most people.^{,  ,}  Dietary sources of vitamin D are limited. They include oily fish such as salmon (approximately 400 IU per 3.5 oz), mackerel, and sardines; some fish oils such as cod liver oil (400 IU/tsp); and egg yolks (approximately 20 IU). Some foods are fortified in the United States, including milk (100 IU per 8 oz) and some cereals (100 IU per serving), orange juice (100 IU per 8 oz), some yogurts (100 IU per serving), and margarine.^{,  ,}  Milk is not vitamin D enriched in most European countries; however, margarine and some cereals are. There are 2 forms of vitamin D. Vitamin D₂ (ergocalciferol) comes from irradiation of the yeast and plant sterol ergosterol, and vitamin D₃ (cholecalciferol) is found in oily fish and cod liver oil and is made in the skin. Vitamin D represents vitamin D₂ and vitamin D₃.

Vitamin D from cutaneous synthesis or dietary sources typically occurs only intermittently. Irregular intake of vitamin D, irrespective of the source, can lead to chronic vitamin D inadequacy. This condition has been reported across all age groups, geographic regions, and seasons.^{,  ,  ,  ,  ,  ,  ,  ,  ,}  Enhancing vitamin D levels by taking supplements is usually necessary to achieve the minimum recommended daily intakes; however, compliance is often problematic. In particular, some groups who may be at high risk of vitamin D inadequacy often do not follow regular daily dosing guidelines. Adherence to vitamin D supplementation recommendations is low among elderly patients with osteoporosis. One study showed that, despite receiving counseling on the importance of vitamin D and calcium supplementation, 76% of elderly patients with hip fractures did not comply with recommendations. This is not surprising given thatcompliance declines as the number of medications increases, and elderly patients often take many medications. Similarly, achieving adequate vitamin D intake through milk consumption is unreliable among elderly patients because of the high prevalence of lactose intolerance among this population and the often low levels of vitamin D in the milk supply.

UV-B irradiation of skin triggers photolysis of 7-dehydrocholesterol (provitamin D₃) to previtamin D₃ in the plasma membrane of human skin keratinocytes.^{,  ,}  Once formed in the skin, cell plasma membrane previtamin D₃ is rapidly converted to vitamin D₃ by the skin's temperature. Vitamin D₃ from the skin and vitamin D from the diet undergo 2 sequential hydroxylations, first in the liver to 25(OH)D and then in the kidney to its biologically active form, 1,25-dihydroxyvitamin D (1,25[OH]₂D) (Figure 1). Excessive solar UV-B irradiation will not cause vitamin D intoxication because excess vitamin D₃ and previtamin D₃ are photolyzed to biologically inactive photoproducts.^{,  ,}  Melanin skin pigmentation is an effective natural sunscreen, and increased skin pigment can greatly reduce UV-B-mediated cutaneous synthesis of vitamin D₃ by as much as 99%, similar to applying a sunscreen with a sun protection factor of 15.^,  Keratinocytes are also capable of hydroxylating 25(OH)D to produce 1,25(OH)₂D. The 1,25(OH)₂D (from keratinocyte or renal sources) may regulate keratinocyte differentiation, melanocyte apoptosis, and melanin production,^{,  ,}  and this may be another mechanism for regulating the cutaneous synthesis of vitamin D₃ by negative feedback.

The 1,25(OH)₂D ligand binds with high affinity to the vitamin D receptor (VDR) and triggers an increase in intestinal absorption of both calcium and phosphorus. In addition, vitamin D is involved in bone formation, resorption, and mineralization and in maintaining neuromuscular function^,  (Figure 1). Circulating 1,25(OH)₂D reduces serum parathyroid hormone (PTH) levels directly by decreasing parathyroid gland activity and indirectly by increasing serum calcium. The 1,25(OH)₂D regulates bone metabolism in part by interacting with the VDR in osteoblasts to release biochemical signals, leading to formation of mature osteoclasts. The osteoclasts release collagenases and hydrochloric acid to dissolve the matrix and mineral, releasing calcium into the blood.^{,  ,} 

When vitamin D levels are inadequate, calcium and phosphorus homeostasis becomes impaired. Vitamin D is primarily responsible for regulating the efficiency of intestinal calcium absorption. In a low vitamin D state, the small intestine can absorb approximately 10% to 15% of dietary calcium. When vitamin D levels are adequate, intestinal absorption of dietary calcium more than doubles, rising to approximately 30% to 40%.^{,  ,  ,}  Thus, when vitamin D levels (25[OH]D) are low, calcium absorption is insufficient to satisfy the calcium requirements not only for bone health but also for most metabolic functions and neuromuscular activity. The body responds by increasing the production and release of PTH into the circulation (Figure 1). The increase in PTH restores calcium homeostasis by increasing tubular reabsorption of calcium in the kidney, increasing bone calcium mobilization from the bone, and enhancing the production of 1,25(OH)₂ D.^, 

Serum 25(OH)D is the major circulating metabolite of vitamin D and reflects vitamin D inputs from cutaneous synthesis and dietary intake. The serum 25(OH)D level is the standard clinical measure of vitamin D status.^,  Although 1,25(OH)₂D is the active form of vitamin D, it should not be measured to determine vitamin D status. It usually is normal or even elevated in patients with vitamin D deficiency.^{,  ,}  Testing of serum 25(OH)D is most useful in patients who are at risk of vitamin D deficiency, including elderly patients, infirm patients, children and adults with increased skin pigmentation, patients with fat malabsorption syndromes, and patients with osteoporosis. This measurement is also useful for purposes of planning or monitoring vitamin D therapy. Clinical assays of 25(OH)D include the Nichols Advantage Assay (chemiluminescence protein-binding assay, the DiaSorin radioimmunoassay, and the benchmark high-performance liquid chromatography assays and liquid chromatography mass spectroscopy assays. The chemiluminescence protein-binding assay and the radioimmunoassay are most commonly used to determine patient vitamin D status. Recent reports have raised concerns about the degree of variability between assays and between laboratories, even when using the same assay.^{,  ,  ,  ,}  Although reliable and consistent evaluation of serum 25(OH)D levels remains an issue, reliable laboratories currently exist, and efforts are in progress to improve and standardize assays to enhance accuracy and reproducibility at other laboratories.^{,  ,} 

As noted previously, vitamin D plays a central role in calcium and phosphorus homeostasis and skeletal health. Since impaired calcium metabolism due to low serum 25(OH)D levels triggers secondary hyperparathyroidism, increased bone turnover, and progressive bone loss,^{,  ,  ,  ,  ,}  the optimal range of circulating 25(OH)D for skeletal health has been proposed as the range that reduces PTH levels to a minimum^{,  ,}  and calcium absorption is maximal. Several studies have shown that PTH levels plateau to a minimum steady-state level as serum 25(OH)D levels approach and rise above approximately 30 ng/mL (75 nmol/L)^{,  ,  ,  ,  ,}  (Figure 2, left).

Vitamin D inadequacy constitutes a largely unrecognized epidemic in many populations worldwide.^{,  ,  ,  ,  ,  ,  ,  ,}  It has been reported in healthy children,^{,  ,  ,  ,}  young adults,^{,  ,}  especially African Americans,^{,  ,  ,  ,}  and middle-aged and elderly adults.^{,  ,  ,  ,  ,  ,  ,  ,  ,  ,  ,  ,  ,  ,  ,  ,  ,  ,  ,  ,}  Typically, the prevalence of low 25(OH)D levels (<20 ng/mL [50 nmol/L]) is approximately 36% in otherwise healthy young adults aged 18 to 29 years, 42% in black women aged 15 to 49 years, 41% in outpatients aged 49 to 83 years, up to 57% in general medicine inpatients in the United States, and even higher in Europe (28%-100% of healthy and 70%-100% of hospitalized adults).^{,  ,} 

Vitamin D inadequacy is particularly common among patients with osteoporosis (Table 1). A recent systematic review by Gaugris et al concluded that the prevalence of inadequate 25(OH)D levels appears to be high in postmenopausal women and especially those with osteoporosis and a history of fracture. This review, which included 30 studies published between January 1994 and April 2004, examined the prevalence of vitamin D inadequacy reported as serum 25(OH)D levels below various values. The results of a recent cross-sectional, observational study conducted at 61 sites across North America showed that 52% of postmenopausal women receiving therapy for osteoporosis had 25(OH)D levels of less than 30 ng/mL (75 nmol/L).The high prevalence of vitamin D inadequacy in that study was consistent across all age groups and North American geographic regions studied. The prevalence of very low serum 25(OH)D levels (<12 ng/mL [30 nmol/L]) was 76% among patients with osteoporosis in another study. A global study of vitamin D status in postmenopausal women with osteoporosis showed that 24% had 25(OH)D levels less than 10 ng/mL (25 nmol/L), with the highest prevalence reported in central and southern Europe. Vitamin D inadequacy is common even among patients with osteoporosis living at lower latitudes in highly sunny climates. For instance, 53% of community-dwelling women with osteoporosis living in Southern California had 25(OH)D levels less than 30 ng/mL (75 nmol/L). In a study of patients 50 years and older hospitalized for nontraumatic fractures, 97% had 25(OH)D levels less than 30 ng/mL (75 nmol/L). Studies in the United Kingdom and South Africa reported that 13% to 33% of patients with hip fractures had histological evidence of osteomalacia that may have been caused by chronic vitamin D deficiency.^{,  ,  ,} 

Vitamin D inadequacy is also common among nonwhite populations and populations with low dietary or supplementary vitamin D intake or minimal exposure to sunlight. A study of Asian adults in the United Kingdom showed that 82% had 25(OH)D levels less than 12 ng/mL (30 nmol/L) during the summer season, with the proportion increasing to 94% during the winter months. A study of 1546 African American women in the United States, ranging in age from 15 to 49 years, showed that more than 40% had serum 25(OH)D levels less than 15 ng/mL (37 nmol/L). A much higher proportion (84%) of elderly black adults in Boston, Mass, had serum 25(OH)D levels less than 20 ng/mL (50 nmol/L). Even children are at risk. A cross-sectional clinic-based study of 307 children (11-18 years old) in Boston reported that 52% of African American and Hispanic children had 25(OH)D levels of 20 ng/mL (50 nmol/L) or less. Sullivan et al observed that at the end of winter and summer 48% and 17%, respectively, of white girls (9-11 years of age) in Maine also had 25(OH)D levels less than 20 ng/mL (50 nmol/L). Even in sunny countries such as Lebanon, vitamin D inadequacy is common in schoolchildren.

Physical factors that attenuate UV-B exposure, including clothing, sunscreens, and glass shielding, markedly reduce or completely eliminate the production of vitamin D₃ in the skin. At latitudes above 37°N and below 37°S, sunlight is insufficient to induce cutaneous vitamin D₃ synthesis during the winter months.^{,  ,}  Nevertheless, latitude is not the only determinant of 25(OH)D levels.^{,  ,  ,  ,  ,}  The high prevalence of osteomalacia in Saudi Arabian women, rickets in Saudi children, and vitamin D deficiencies in both may be attributable to their cultural practice of wearing clothing that covers the entire body and avoiding direct sunlight.^, 

Biological factors that inhibit cutaneous vitamin D synthesis and bioavailability include skin pigmentation,^{,  ,}  medication use, body fat content, fat malabsorption, and age.^,  Increased skin pigmentation can reduce cutaneous vitamin D₃ production as much as 99.9%.^{,  ,}  Certain drugs (eg, anticonvulsants, corticosteroids, rifampin, and cholestyramine) may adversely affect metabolism or bioavailability of vitamin D.^{,  ,}  Recent studies have shown that body mass index and body fat content are inversely related to serum 25(OH)D levels and directly related to PTH levels,^{,  ,  ,}  which is likely due to vitamin D sequestration in body fat compartments. Dietary sources of vitamin D are limited, and obtaining a sufficient amount from regular diet is often problematic for many people whose diet does not normally include the few foods that are naturally rich in vitamin D. Patients with fat malabsorption syndromes, including sprue, cystic fibrosis, and Crohn disease, are at especially high risk of vitamin D deficiency.^,  Among elderly patients, multiple factors contribute to vitamin D inadequacy, including dietary deficiencies and decreased cutaneous synthesis due to reduced ability of the skin to synthesize vitamin D₃. A 70-year-old produces approximately 4 times less vitamin D via cutaneous synthesis compared with a 20-year-old.^,  Increasing age has been associated with lower 25(OH)D levels regardless of season. Age does not alter dietary vitamin D absorption, but if an individual is taking cholestyramine, vitamin D will not be absorbed efficiently.

Chronic severe vitamin D deficiency in infants and children causes bone deformation due to poor mineralization, commonly known as rickets.^,  In adults, proximal muscle weakness, bone pain, and osteomalacia may develop.^{,  ,  ,  ,}  Less severe vitamin D inadequacy prevents children and adolescents from attaining their optimal genetically programmed peak bone mass and in adults leads to secondary hyperparathyroidism, increased bone turnover, and progressive loss of bone, increasing the risk of osteoporosis.

Vitamin D deficiency during skeletal maturation disrupts chondrocyte maturation and inhibits the normal mineralization of the growth plates. This causes a widening of the epiphyseal plates at the end of the long bones in rachitic children and bulging of costochondral junctions (rachitic rosary).^,  Secondary hyperparathyroidism causes phosphaturia and hypophosphatemia. The resulting inadequate calcium-phosphorus product results in poor mineralization, making the skeleton less rigid. When the rachitic child begins to stand, gravity causes bowing of the long bones in the lower extremities, resulting in bowed legs or knocked knees.^, 

In adults, the epiphyseal plates are fused, and secondary hyperparathyroidism and resulting phosphaturia have moresubtle, but equally devastating, skeletal consequences. Chronic vitamin D inadequacy in adults can result in secondary hyperparathyroidism, increased bone turnover, enhanced bone loss, increased risk of fragility fracture, and (rarely) hypocalcemic tetany.^{,  ,  ,  ,  ,  ,}  The increase in PTH-mediated osteoclastogenesis results in increased numbers and activity of osteoclasts. The osteoclasts resorb bone via enzymatic degradation of the collagen matrix and secretion of hydrochloric acid, releasing calcium and phosphorus into the extracellular space. The result is increased skeletal porosity, defective bone mineralization, decreased bone mineral density (BMD), osteoporosis, and increased fragility-fracture risk.^{,  ,  ,  ,}  When 25(OH)D levels are less than approximately 10 ng/mL (25 nmol/L), osteomalacia is usually present.^{,  ,  ,  ,  ,}  Some studies suggest that serum 25(OH)D levels greater than 30 ng/mL (75 nmol/L) may be required to maximize intestinal calcium absorption and prevent secondary hyperparathyroidism-induced skeletal conditions^{,  ,  ,  ,  ,}  (Figure 2).

Unlike patients with osteoporosis, patients with osteomalacia often complain of skeletal pain.^{,  ,}  This pain can be elicited on physical examination by applying minimal pressure with the thumb or forefinger on the sternum or anterior tibia. Although the exact cause of the aching sensation that patients often complain of is unknown, it is possible that the collagen-rich osteoid that is laid down on the periosteal surface of the skeleton may become swollen similar to the hydration of gelatin-based food products (eg, Jell-O). This swelling could put outward pressure on the periosteal covering that is innervated with nocioceptors. Patients with osteomalacia are often misdiagnosed as having fibromyalgia, chronic fatigue syndrome, or myocytis and treated inappropriately with nonsteroidal anti-inflammatory agents.^, 

Some, but not all, observational studies have linked vitamin D inadequacy (or lower vitamin D intake) to an increased risk of hip and other nonvertebral fractures.^,  Moreover some, but not all, clinical trials and observational studies have reported that dietary vitamin D supplementation (often given together with calcium) lowers fracture risk^{,  ,  ,  ,  ,}  (Figure 3). Bischoff-Ferrari et al recently conducted a systematic review and meta-analysis of double-blind randomized controlled trials (RCTs), the highest level of evidence, to assess the efficacy of vitamin D (vitamin D₃ [cholecalciferol] or vitamin D₂ [ergocalciferol]) supplementation with or without calcium supplementation vs calcium supplementation alone or placebo for preventing hip and nonvertebral fractures in elderly patients (≥60 years of age). Statistical justification was provided for pooling trials with higher vitamin D doses separately from those with lower doses. On the basis of the analysis of 3 RCTs for hip fracture risk involving 5572 subjects and 5 RCTs for nonvertebreal fracture risk involving 6098 subjects, the authors concluded that daily vitamin D supplementation between 700 and 800 IU with or without calcium appears to reduce hip fracture risk by 26% and nonvertebral fracture risk by 23% vs calcium alone or placebo in ambulatory or institutionalized elderly persons. No effect on fracture risk was observed in 2 trials that used a lower dose of 400 IU/d. A population-based, 3-year cluster randomized intervention study involving 9605 community-dwelling elderly adults (≥66 years of age) found that 400 IU/d of vitamin D with 1000 mg of calcium produced a 16% fracture risk reduction, although this lower-quality trial did not meet the inclusion criteria for the meta-analysis described herein. A separate systematic review and meta-analysis conducted several years earlier that included RCTs involving either vitamin D or its analogues reported a 37% reduction in the relative risk of vertebral fracture.^, 

Two trials that failed to detect an effect on fracture risk were published soon after the meta-analysis was conducted. Porthouse et al conducted an open-label RCT to assess whether 1000 mg of calcium daily with 800 IU of vitamin D₃ supplementation reduced fracture risk among 3314 women 70 years and older with one or more risk factors for hip fracture. The incidence of hip and other clinical fractures did not differ significantly between groups after a median follow-up of 25 months. Another randomized, double-blinded, controlled trial with a factorial design examined the effect on fracture risk. A total of 5292 patients were randomized to receive vitamin D with or without calcium, calcium alone, or placebo. After a 24-month follow-up, the authors found no significant differences in fracture rates among the 4 groups. However, compliance with the medication had declined to 63% after 24 months and may have been as low as 45% if nonresponders to the evaluation questionnaire were included. Data from a randomized, double-blind, placebo-controlled trial of 9440 community-dwelling adults (75-100 years old) randomized to receive either an annual injection of 300,000 IU of cholecalciferol (comparable to a 822-IU daily dose) or matching placebo disclosed no effect on fracture occurrence between groups. However, since 25(OH)D levels were not evaluated, it is unknown whether the intramuscular vitamin D₃ was completely bioavailable. Most intramuscular preparations are not very bioavailable, which is why they are no longer available in the United States.

Decreased BMD is a major risk factor for fractures, and some studies have linked vitamin D inadequacy or low intake of vitamin D to low BMD.^{,  ,}  Some randomized trials have also shown a benefit.^{,  ,  ,  ,}  For example, a double-blinded RCT randomized 249 healthy ambulatory postmenopausal women with usual daily intakes of 100 IU of vitamin D to receive 400 IU of vitamin D supplements or placebo daily. All participants also received 377 mg/d of calcium. At the end of 1 year, the vitamin D group had significantly reduced wintertime bone loss and improved net BMD of the spine. By contrast, however, another RCT reported no effect of vitamin D supplementation on bone loss or bone turnover markers in calcium-replete postmenopausal African American women. The earlier meta-analysis that pooled data from RCTs that included vitamin D analogues found a small nonsignificant BMD increase of 0.4% relative to the control groups.^, 

Many of the vitamin D supplementation studies reported herein included concurrent calcium supplementation; therefore, the observed benefits of vitamin D supplementation may be confounded or obscured by the effects of concurrent calcium supplements and cannot be ascribed to vitamin D alone. Although the meta-analysis by Bischoff-Ferrari et al reported that vitamin D supplementation with or without calcium supplementation reduced fracture risks, the factorial design of the Record Evaluation of Calcium or Vitamin D (RECORD) trial concluded that vitamin D supplementation with or without calcium supplementation had no significant effect on fracture risk reduction. It is also possible that the benefits of vitamin D on fracture risk reduction (and BMD) may be greater in those with vitamin D deficiency or low calcium intake at baseline. In the RECORD trial, only 60 participants (1.1%) had their serum baseline 25(OH)D levels measured. Thus, we cannot know if the lack of effect on fracture risk in the RECORD trial might be related to pretreatment levels of vitamin D and/or calcium. The hierarchy of evidence for the role of vitamin D in BMD^{,  ,  ,  ,  ,  ,  ,  ,  ,  ,  ,  ,  ,  ,  ,}  changes and fracture reduction is given in Table 2.