One of the primary controls of calcium homeostasis is cal-citriol, the physiologically active form of vitamin D. Humans obtain vitamin D either from subcutaneous photoconversion of 7-dehydrocholesterol in response to sunlight exposure or from dietary sources such as fortified milk, fatty fish, sardines, or eggs. However, 7-dehydrocholesterol (provitamin D3) is an inactive compound that requires two sequential enzymatic hydroxylations to be converted to calcitriol drug.
The first conversion is accomplished by the liver to 25-hy-droxyvitamin D (25-OH-D [calcidiol]) and then by the kidney to 1,25-dihydroxyvitamin D, or 1,25(OH)2D (calcitriol) (Figure 2). The extent of kidney hydroxylation is modulated by PTH, which is affected by the body’s calcium stores. Enzymatic activity is low during periods of calcium repletion; it is increased when enhanced calcium absorption is required.
After calcitriol is formed, it helps reverse low serum calcium levels by binding to the vitamin D receptor (VDR) in its effector cells. This receptor binding induces gene expression, Figure 2 Vitamin D metabolism. AH = exogenous heat; PTH = parathyroid hormone; u.v. B = ultraviolet B radiation. (From Zittermann A. Br J Nutr 2003;89:552-572. Copyright © 2003, Armin Zittermann, PhD. Reproduced with permission.)
which increases the synthesis of calcium transport proteins. Consequently, calcitriol activity increases the efficiency of calcium absorption at each major step in the transcellular intestinal absorption process.
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Prevalence of Vitamin D Deficiency
In light of the high incidence of osteoporosis today and the prominent regulatory role of vitamin D in the absorption of calcium, it should come as no surprise that the prevalence of vitamin D deficiency is substantial. Nutritional vitamin D status is determined by circulating blood levels of 25-OH-D. Although the precise definition of vitamin D “adequacy” or “deficiency” may vary according to any of the currently accepted sources, the prevalence of this malady appears profound.
After assessing the vitamin D status of 212 patients at a South Florida outpatient clinic, Levis et al. found that wintertime 25-OH-D levels averaged 24.9 ± 8.7 ng/mL in men and 22.4 ± 8.2 ng/mL in women. Using levels of 20 ng/mL or less as indicative of vitamin D deficiency, these investigators found a prevalence of 38% in men and 40% in women.
In a study of more than 1,500 women across the U.S. and
Canada by Holick et al., the rate of 25-OH-D levels at 20 ng/mL or below was 18%.
Vieth et al. assessed the seasonal variation in 25-OH-D status of Canadian women. Of all women included in the study, 20% to 30% had levels of 16 ng/mL or less during the winter months. This rate improved substantially, although not completely, in summer months.
The problem of vitamin D deficiency is not confined to North America. In fact, most of the literature characterizing this problem has been published outside the U.S.
Hill et al. characterized the late winter prevalence of 25-OH-D levels at 20 ng/mL or less in postmenopausal Irish women to be 46%, a figure that remained worrisome at 17% in late summer. Chapuy et al. determined the prevalence of “hypovitaminosis D,” defined more conservatively in their study as a serum 25-OH-D level of 12 ng/mL or below, as averaging 14% in a geographically diverse, healthy French population. Perhaps most compellingly, Gallacher et al. noted that 25-OH-D levels in elderly Scottish individuals with prior fractures averaged only 9.9 ng/mL; 91% of these subjects had levels below 20 ng/mL.
Clearly, nutritional vitamin D status is a serious problem around the world—and one that might be even worse when the levels used to determine “sufficiency,” “insufficiency,” and outright “deficiency” are further scrutinized. cheap cialis canadian pharmacy
Optimal Levels of Circulating 25-Hydroxyvitamin D
Levels of circulating 25-OH-D (calcidiol) that are below normal are problematic for bone health because they lead to decreased calcium absorption. What level of circulating 25-OH-D is necessary to optimize calcium absorption?
Heaney et al.54 compared intestinal calcium absorption at different levels of circulating 25-OH-D in 34 postmenopausal women. Patients with 25-OH-D levels of 34.6 ± 9.6 ng/mL absorbed 45% to 65% more calcium than patients whose 25-OH-D levels were 20.1 ± 6.3 ng/mL. This improvement was uniform with both calcium carbonate and citrate.
Impaired calcium absorption secondary to subtherapeutic 25-OH-D levels results in increased PTH secretion. This circulating PTH replenishes serum calcium at the expense of stores in bone by enhancing calcium liberation through bone catab-olism. In the previously mentioned study of Irish women, Hill et al. showed a statistically significant inverse correlation between 25-OH-D and serum PTH, a finding that agrees with other analyses by Pasco and Holick. To ensure bone integrity, it is advisable to keep serum PTH levels low by maintaining sufficient levels of 25-OH-D. Reference 25-OH-D ranges indicative of sufficiency should be established to meet this goal.
Blood levels corresponding to adequacy and inadequacy vary according to the study and the investigators involved. Most studies were conducted under the assumption that the lower limit of normal for 25-OH-D was between 12 and 20 ng/mL
In 1995, Ooms et al. found that 12 ng/mL of 25-OH-D was sufficient to deter PTH elevations in a group of 330 elderly women; in other studies, however, the threshold value was much greater. Thomas63 observed that the statistical significance of the correlation between serum 25-OH-D levels and PTH in 290 hospital inpatients was lost at 25-OH-D levels above 15 ng/mL. That being said, absolute PTH levels were still lower in patients whose vitamin D levels were 20 to 30 ng/mL and above.
Both Chapuy59 and Holick56 found a negative correlation between PTH and 25-OH-D levels; PTH continued to decline until 25-OH-D levels reached 31 ng/mL and 29.8 ng/mL, respectively. Malabanan et al.66 determined that the level of maximal 25-OH-D effect was present at 20 ng/mL, but the low number of patients in that study (35) pale in comparison to the 3,000 enrolled by Chapuy and Holick. online pharmacy uk
In a study of more than 400 elderly patients by Dawson-Hughes et al., the maximal suppressive effect of vitamin D on PTH continued up to a level of 44 ng/mL. Most profound were the results of Vieth and associates, who used mathematical modeling and data from more than 1,700 patients to determine that the inverse relationship between 25-OH-D levels and PTH could continue up to 25-OH-D concentrations as high as 67 ng/mL.
Although the exact point at which PTH levels are lowest in a given individual is probably subject to a number of factors, the studies reviewed here suggest that a desirable goal would be a level of 30 ng/mL of 25-OH-D or greater for the general population. The important question then becomes: at what amount of oral vitamin D supplementation do most people achieve this goal?
Effect of Supplemental Oral Vitamin D on Circulating 25-Hydroxyvitamin D Levels
Considerable research has been conducted on the dose dependence of oral vitamin D supplementation on serum 25-OH-D (calcidiol) levels. In light of the aforementioned serum 25-OH-D levels needed to maximally suppress PTH secretion, these findings cast doubt upon the ability of the Adequate Intake (AI) for vitamin D to reliably achieve this goal: 400 IU in people 51 to 70 years of age and younger and 600 IU in those older than 70 years of age.
Much research concerning the effects of 400 IU of vitamin D daily has been conducted in older people. Ooms et al. found that this amount increased serum 25-OH-D levels from 10.8 to 24.8 ng/mL in a population with a mean age of 80.1 years. These results were remarkably similar to those obtained by Chel et al.
In a study of patients with a mean age of 75 years, Larsen et al. showed that 25-OH-D levels increased from 14.8 to 18.8 ng/mL after supplementation with 400 IU of vitamin D daily. It is unclear whether an additional 200 IU of vitamin D (to achieve 600 IU daily, according to current guidelines for this age group) would be sufficient to consistently increase serum 25-OH-D above a level of 30 ng/mL in these patients. However, because intestinal vitamin D absorption efficiency does not appear to decrease with age, a comparable patient younger than 50 years of age with baseline vitamin D levels such as those seen in these patient populations would be in danger of not achieving optimal 25-OH-D status with a daily supplement of oral vitamin D 400 IU. Apcalis Oral Jelly
Peacock et al. assessed the impact of 600 IU of oral vitamin D daily on subsequent 25-OH-D levels. This dose was remarkably potent, boosting baseline 25-OH-D levels from 24.2 to 47 ng/mL in 75-year-old patients.
Studies conducted with 800 IU of vitamin D daily also produced generally higher 25-OH-D levels than those seen in studies of 400 IU, although patients’ baseline levels also tended to be higher. Patel, Tfelt-Hansen, and Hunter showed increases from 27.2 to 37.4 ng/mL, from 26.4 to 45 ng/mL, and from 28 to 42 ng/mL, respectively, in middle-aged women. Harris et al. found a uniform increase from 24 to 33 ng/mL in younger men (18 to 35 years of age) and in older men (62 to 79 years of age).
Barger-Lux et al., in a mathematical calculation performed with data from 28-year-old men, predicted a remarkable increase from 26.8 to 64.4 ng/mL with 800 IU of oral vitamin D daily. Equally convincing were the results of earlier work done by Chapuy et al., who documented increases of from 16 to 42 ng/mL when their population of 84-year-old women received 800 IU of vitamin D daily.
In summary, dosing of at least 800 IU of vitamin D would be far more likely than the current recommendations to consistently produce a desirable serum level of 25-OH-D and optimal PTH suppression in patients at various ages. Even at this level of dosing, it is conceivable that a subgroup of patients with very low 25-OH-D levels, such as the ones described ear-lier,57,59 would still not achieve vitamin D sufficiency by the newer threshold goals. In a study by Grados et al, 800 IU of vitamin D improved a markedly deficient mean baseline value of 7 ng/mL to only 29 ng/mL.
Oral Supplementation with Vitamins D2 and Vitamin D3
Vitamin D2 (ergocalciferol) and vitamin D3 (cholecalciferol) are similar in structure but behave differently in humans in terms of their metabolic disposition and bioavailability.
When Trang et al.77 gave 72 patients 4,000 IU of either vitamin D2 or vitamin D3 daily for 14 days, the increase in serum levels of 25-OH-D was 70% greater in the vitamin D3 cohort. Similarly, Armas et al. found that a single oral dose of 50,000 IU of vitamin D2 given to 20 male volunteers produced serum 25-OH-D increases that peaked after only three days, whereas the equivalent dose of vitamin D3 produced a continual increase in 25-OH-D that peaked at two weeks. These two studies confirmed earlier work by Tjelleson et al., who found that 4,000 IU of vitamin D2 did not produce the increase in total 25-OH-D seen with an equivalent dose of vitamin D3. generic cialis in uk
Aside from concerns over metabolic activity, Harris et al.80 showed that the bioavailability of equal doses of vitamin D2 was much greater in nine younger men (22 to 28 years of age) than in nine older men (65 to 73 years of age). This effect proved to be unique to vitamin D2 when the same authors conducted a similar study with vitamin D3 and saw no difference among the two age groups. For these reasons, oral vitamin D supplementation should consist of vitamin D3 (cholecalciferol) to ensure optimal absorption and a maximal serum 25-OH-D response. (Most references that publish vitamin D requirements state their recommendations in terms of vitamin D3 units.)