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Original Studies |
Creighton University (R.P.H.), John A. Creighton University Professorship, School of Medicine (M.J.B.-L.), Osteoporosis Research Center, and School of Nursing (M.S.D.), Omaha, Nebraska 68131; Boston University Medical Center, Vitamin D Research Laboratory (T.C.C., M.F.H.), Boston, Massachusetts 00000
Address all correspondence and requests for reprints to: Robert P. Heaney, M. D., Creighton University, 601 North 30th St., Suite 4841, Omaha, Nebraska 68131.
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Abstract |
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 Top Abstract IntroductionSubjects and MethodsResultsDiscussionReferences |
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Introduction |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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Those findings suggested that 25(OH)D may itself promote calcium absorption at physiological concentrations. That conclusion was directly supported by a pair of studies, in which Brickman et al. (8) and Colodro et al. (9) measured 47Ca absorption in response to graded doses of 25(OH)D and of 1,25(OH)2D. They found, in normal subjects, a molar potency for 25(OH)D only two orders of magnitude lower than for of 1,25(OH)2D. In view of the fact that physiological concentrations of 25(OH)D are typically three orders of magnitude greater than those of 1,25(OH)2D, this relative potency suggested that 25(OH)D might account for a larger fraction of the vitamin D-like activity in the circulating plasma than was generally considered likely and could therefore explain the results of clinical studies.
For these reasons, we judged that the relative roles of vitamin D and its metabolites in the normal calcium economy needed to be re-evaluated. Accordingly, the purposes of the present study were 1) to determine the dose-response relationships of vitamin D and its principal metabolites, using calcium absorption efficiency in healthy young adults as the response variable; 2) to compare the findings with the earlier, provocative results of Colodro et al. (9); and 3) to estimate the relative contributions of 25(OH)D and 1,25(OH)2D to calcium absorption under physiological conditions.
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Subjects and Methods |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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The subjects were men who were free of health problems and who
took no medications known to affect calcium metabolism or skeletal
physiology, as determined by interview. To limit the effects of
nonstudy sources of vitamin D, we performed the tests in midwinter and
excluded candidates who either reported usual milk consumption of more
than 0.47 L/day (16 fl oz/day) or who would be exposed to sunlight (via
travel to a sunny climate) during the study or in the preceding month.
We accepted several candidates who regularly used daily multivitamins
(typically containing 10 µg of vitamin D, equivalent to 400 IU), but
who agreed to abstain from them during their participation in the study
and for at least one week before entering it. The Creighton University
Institutional Review Board approved the protocol, and each subject gave
informed consent. After entering, two subjects withdrew for personal
reasons. The 116 who finished the study included two Hispanics, three
blacks, five subjects of Asian origin, and 106 whites. Table 1
presents data characterizing them.
There were no significant differences in anthropometric variables or
serum chemistries in the men assigned to the three agents. However,
baseline absorption fraction for those assigned to 25(OH)D was
slightly, but significantly, lower than for those receiving
1,25(OH)2D (0.250 vs. 0.289).
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The study was planned to measure within-individual changes in calcium absorption efficiency in response to three doses each of vitamin D3, 25(OH)D, and 1,25(OH)2D. Dosage levels and duration of treatment for the nine groups were as follows: • Vitamin D3 at 25, 250, and 1250 µg/d1 for eight weeks • 25(OH)D at 10, 20, and 50 µg/d2 for four weeks • 1,25(OH)2D at 0.5, 1.0, and 2.0 µg/d3 for two weeks
Subjects were assigned to one of the three vitamin D compounds on the basis of personal scheduling considerations, but were allocated to dosage level within compound by use of a random number scheme. Vitamin D3 capsules in each dosage were custom-manufactured by Tishcon Corp. (Westbury, NY) and their potency confirmed by analysis of their vitamin D3 content. 25(OH)D was given in the form of Calderol (provided without charge by Organon, Inc., West Orange, NJ), and 1,25(OH)2D was given as Rocaltrol (provided without charge by Roche Laboratories, Nutley, NJ). Materials were repackaged by qualified pharmacy personnel in fully-labeled, child-resistant vials. The subjects were instructed to take their capsules by mouth at bedtime.
Subjects returned their medication vials at the time of the second absorption test, and the remaining pills were tallied. Compliance was very high (mean: 98.9%; median: 100%). Actual daily dosage, used in certain of the analyses, was calculated from the number of pills consumed, divided by the number of days on treatment.
Each subject was tested twice–immediately before and after his prescribed treatment period. At both visits, the following measurements were made: total calcium, vitamin D3, 25(OH)D, and 1,25(OH)2D in fasting serum; height by stadiometer; weight, in light clothing without shoes, by use of an electronic digital strain gauge scale (Healthometer, Bridgeview, IL); and calcium absorption efficiency. Thus, the serum samples obtained for vitamin D metabolite determinations were collected just a few minutes before performing each calcium absorption test. All visits took place between January 3 and April 3, to coincide with the annual nadir of circulating 25(OH)D levels related to sunlight intensity in the temperate northern hemisphere, and thus to minimize the effect of variations in solar vitamin D.
Calcium absorption testing
Calcium absorption efficiency was measured as absorption fraction by use of a 5-hr single isotope method described previously (10, 11). This method measures total absorption, both active and passive, and has been shown to yield the same results as produced by classical balance methods adjusted for endogenous fecal calcium losses (12). The standard deviation of the difference between replicate measurements in the same individual with this method is 0.042. As each dosage group contained 12–14 individuals, that level of precision meant that we had a power of 0.90 to find a difference of 0.043 or greater, within each treatment group.
The calcium load was 7.5 mmol, given as milk and labeled with approximately 185 kBq (equivalent to 5.0 µCi) 45Ca contained in a submicrogram quantity of high specific activity 45CaCl2 (Amersham, Arlington Heights, IL). The tracer was added to the milk 16 hr before dosing, and individual servings were sealed and refrigerated until use. The test load was given in the morning as a part of a standard breakfast, after an overnight fast, and with abstinence from alcohol for at least 3 days. Three subjects who identified themselves as milk-intolerant took two caplets of Lactaid Extra Strength dietary supplement (McNeil Consumer Products Co., Ft. Washington, PA) with the test load (at both tests). The breakfast consisted of three slices of unenriched white bread toast, buttered, with a serving of water, coffee, or tea (no sugar was allowed). The meal was consumed under supervision. Halfway through the breakfast, the labeled milk was consumed. To assure full ingestion of the tracer, the milk container was rinsed repeatedly with distilled water and the rinsings consumed. Fluid intakes were standardized to provide a similar degree of gastric distention for all participants. At the second visit (post-treatment), correction was made for residual serum calcium radioactivity from the earlier test.
The absorption method has been calibrated in female subjects against the double-isotope reference method (13), by adjusting for body size (and, thus, volume of distribution) using empirical power functions of weight and height (10, 11). To estimate absorption fraction in the male subjects in the present study, we adjusted the results from the use of this algorithm upwards by a factor of 1.15, to reflect the relative difference in body water for males and females of the same body mass index (14). However, for the principal purposes of the present study, we collected data on within-subject change. Therefore, none of the statistical analyses are dependent upon the method of calculation of absorption, nor upon adjustment for male-female body compositional differences. We use adjusted fractional absorption in what follows solely to facilitate discussion of the results in terms of a familiar physiological phenomenon.
Analytical methods
Serum Ca was measured by atomic absorption spectrophotometry (model 2380, Perkin-Elmer Corp., Norwalk, CT). Serum samples for vitamin D metabolites were protected from light during processing, frozen promptly at -20 C, and shipped on dry ice to the Vitamin D Skin and Bone Research Laboratory of the Boston University Medical Center for analysis. The Vitamin D3 assay involved lipid extraction of the serum specimens, fractionation by use of rapid reverse-phase cartridge chromatography and high-performance liquid chromatography, and quantitation by use of ultraviolet absorptiometry, with a detection limit of 2.6 nmol/L (15). Vitamin D levels were measured in all subjects assigned to receive vitamin D itself but in only a 40% random sample of the others. The assay for 25(OH)D [25(OH)D2 and 25(OH)D3] involved ethanol extraction of the serum, followed by a protein-binding assay, with a detection limit of 12.5 nmol/L (16). The assay for 1,25(OH)2D [1,25(OH)2D2 and 1,25(OH)2D3] involved solvent extraction of the serum, followed by a radio-receptor assay, with a detection limit of 12 pmol/L (17). Pre-and post-treatment samples for a given subject were tested in the same run.
Statistical methods
The CRUNCH software package, version 4.04 (CRUNCH Software Corp., Oakland, CA) was used for all statistical analyses. Measured changes for each treatment group were tested against a null hypothesis of no difference both by use of the Student’s t test for matched pairs, and by standard regression models (in which both dose and log of dose were used as the X-variable). Baseline values for the various variables in the three treatment groups prior to dose randomization were tested by ANOVA. Dose-response relationships were tested by standard bivariate and multivariate linear regression.
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Results |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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Relationships between vitamin D metabolite levels and absorption fraction at baseline were tested by both simple univariate regression and by multiple regression models, combining serum 1,25(OH)2D and 25(OH)D levels as independent variables. Even with the pooled sample (n = 116), no statistically significant relationships with baseline absorptive performance were found for serum levels of either metabolite.
Changes in calcium absorption efficiency
Table 2 provides summary data for
within-subject changes in calcium absorption fraction, both in absolute
values and as a percent of baseline, for each of the nine treatment
groups. Significant increases in calcium absorption efficiency occurred
in seven of the nine groups. The highest dose of 1,25(OH)2D
elevated absorption efficiency by 73% and the highest dose of vitamin
D by 44 percent. Out of the nine treatment groups, the only ones
failing to show a significant absorptive increase were those who
received the two lower doses of vitamin D3. While
1,25(OH)2D treatment elevated serum 1,25(OH)2D
levels as expected, neither 25(OH)D nor vitamin D3 produced
changes in serum 1,25(OH)2D levels (Table 3). Thus the increases in absorption
efficiency for 25(OH)D and for vitamin D3 were not due to
conversion to circulating total 1,25(OH)2D.
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Figure 1 compares the relationships
of doses of 1,25(OH)2D and 25(OH)D and percent change in
calcium absorption fraction, and Table 4
presents the parameters of the relationships using absolute absorptive
change (rather than percent change). (In Table 4, "adjusted dose"
refers to the assigned dose, adjusted both for compliance and for body
weight.)
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, a mean increase of 25% in absorption efficiency
was produced by both 50 µg/day of 25(OH)D and 0.5 µg/day
1,25(OH)2D, for a relative molar potency of the two
compounds in vivo of 1:100. The zero effect doses for the
two lines (i.e. the X-axis intercepts) differ by a ratio of
only 1:16. 25(OH)D and calcium absorption efficiency
In multiple regression models of the absorptive change in the
vitamin D3-treated subjects, testing serum levels of all
three compounds as independent variables, only post-treatment serum
25(OH)D proved to be significantly associated with absorption fraction.
Accordingly, to explore further the relationship between 25(OH)D and
calcium absorption, the data from the vitamin D3 and
25(OH)D-treated subjects were pooled. Figure 2 shows the relationship of change in
circulating 25(OH)D produced by treatment and change in calcium
absorption efficiency. (The open circles represent the
subjects who took 25(OH)D, and the closed circles, those who
took vitamin D3.) As can be seen, the largest increases in
circulating 25(OH)D were produced by vitamin D3 (high
dose). As the figure also suggests, the two groups can be represented
by the same regression line. (This approach was validated by performing
the regression calculations separately for the two treatment groups.
The slopes and intercepts were numerically very close and did not
differ significantly from one another.) The effect of change in 25(OH)D
was apparent even when the analysis was restricted to the lower end of
the distribution (e.g. an increase in 25(OH)D of <200
nmol/L). For this subgroup, the mean change in absorption efficiency
was +0.030 ± 0.006, SEM; P < 0.01).
The slope of the composite regression, shown in Fig. 2, means that
absorption fraction changed by +0.000146 for every nmol/L increase in
serum 25(OH)D.
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presents the results. The slope of
absorption on 25(OH)D level was +0.0000849, substantially the same as
found via analysis of treatment-induced changes. When multiple
regression models were constructed, serum 1,25(OH)2D level
did not contribute significantly; nevertheless, when values were
adjusted in the model for 1,25(OH)2D, the slope was
+0.0000934.
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Discussion |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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, our
dose-response data for 25(OH)D are remarkably similar to those reported
earlier by Colodro et al (9). Further, as reported above and
shown in Fig. 1, the dose-response data indicate that the
absorption-promoting activity of an increment in circulating 25(OH)D is
1/100th as great as that of 1,25(OH)2D. This is very close
to the value of 1/125 reported by Colodro et al. (9).
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The absence of a detectable relationship between D-metabolite level and absorption fraction under baseline (untreated) conditions complicates any attempt to address these issues. A partial explanation lies in the fact that the absorption method used measures total absorption, passive as well as active. At calcium loads of the size used in this study, about half of total absorption is probably passive (18, 19), i.e. not vitamin D-mediated; variations around that partition, coupled with analytical variability, might well obscure an underlying relationship, given values for both variables only within the normal range. However, the clear effects of induced increments in D-metabolite levels (which serve to expand both ranges) may permit an approach to partition of absorptive activity between the D metabolites at baseline.
The slope of absorption fraction on serum 25(OH)D, adjusted for 1,25(OH)2D, ranged from +0.0000849 in the univariate model to +0.0000934 in the multivariate model. The corresponding slope from our earlier study, in which we had also augmented 25(OH)D levels (6), was +0.00070. Because the confidence limits of neither slope excluded the other, we pooled the two estimates, weighting for differences in sample size, to yield a composite value of +0.000299 (i.e. absorption fraction rises by an increment of 0.000299 for every rise in serum 25(OH)D of 1 nmol/L). Because the mean 25(OH)D level at baseline was 68 nmol/L, this approach suggests that, of the total absorption value (0.298), about 0.020 was related to circulating 25(OH)D.
A similar analysis of the absorption activity related to 1,25(OH)2D yielded an estimate of 0.128. The total for 1,25(OH)2D and 25(OH)D is thus 0.128 + 0.020, or 0.148, i.e. just about half of actual total absorption. This total is consistent with previous estimates of passive absorption in the range of 10–20% of intake (18, 19, 20). Thus, taking this approach, about one eighth of total circulating vitamin D absorptive activity in these subjects can be attributed to 25(OH)D, and seven eighths to 1,25(OH)2D.
The relatively small slopes of absorption fraction on serum
25(OH)D levels discussed in the foregoing would seem to be somewhat at
variance with the dose-response effect seen in Fig. 1. There, a 50 µg
dose of 25(OH)D evoked a 25% increase in absorption efficiency. Yet
the rise in serum 25(OH)D required to produce a 25% increase in
absorption (i.e. +0.0745), from the equation in Fig. 2
(i.e. a change of +395 nmol/L), is substantially higher than
the mean change actually produced in serum 25(OH)D at the 50 µg dose
level. In other words, the absorptive response appears greater than
would be expected for the evoked rise in serum 25(OH)D. This
discrepancy opens up the possibility that some of the absorptive effect
of these agents was mediated by a first-pass effect on the intestinal
mucosa during the compound’s own absorption. Mortensen and Charles
(21) have reported what may be a similar first pass effect of vitamin D
itself. (The concentration of the D-metabolite within the mucosa
could, of course, be many orders of magnitude higher at the time of its
absorption than its subsequent serum level.)
Alternatively, there may have been some conversion of vitamin
D3 to 5,6-trans-vitamin D3, as has been
reported in both rats and humans (22, 23, 24). This metabolite is a pseudo
1
(OH) analog of 1,25(OH)2D3 and has been
reported to increase intestinal calcium transport in anephric rats
(22). Yet another explanation, suggested by Veith (25) as the basis for
the enhanced calcium absorption of vitamin D toxicity, is based on the
fact that 25(OH)D binds more tightly than 1,25(OH)2D to
circulating D-binding protein (DBP). Elevated 25(OH)D3
levels, therefore, could displace 1,25(OH)2D from DBP and
thereby increase its free concentration. Thus 1,25(OH)2D
would be more active, and absorption would rise, without a change in
the total measured 1,25(OH)2D concentration.
As noted earlier, we performed these studies in late winter to
minimize variations in vitamin D status in our subjects. Nevertheless,
there is no reason to suspect actual vitamin D insufficiency in any of
them. All subjects were healthy and well-nourished. Moreover, at no
dose did vitamin D produce an increase in total serum
1,25(OH)2D level. This is in contrast with the study of
Francis et al. (4) who found that giving less than 1000 IU
of extra vitamin D to older women in the north of England produced
changes in both 1,25(OH)2D and absorption fraction. We
found no such changes at the 1000 IU treatment level, and we interpret
this difference to mean, therefore, that the changes in absorption
produced by both 25(OH)D and vitamin D in this study do not represent
simple repair of a nutritional deficit. Rather than enhancing 1-
hydroxylation by expanding the precursor pool for
1,25(OH)2D, these compounds, at the dosages used, produce
an absorptive effect in their own right. Clinicians and investigators
using these compounds at high doses will want to be aware of this
effect.
In conclusion, both 25(OH)D and vitamin D3 itself, in large doses, can raise calcium absorption efficiency. Neither compound produces an increase in circulating total 1,25(OH)2D. The absorptive effect of vitamin D3 seems mainly to be mediated by its conversion to 25(OH)D. Whether this effect occurs directly by binding to the vitamin D receptor, by a topical (first pass) effect in the intestine, by formation of the 5,6-trans metabolite, or by increasing free 1,25(OH)2D is still to be resolved. Calculations from the data produced in this study suggest that up to one eighth of total vitamin D absorptive activity under conditions of health may be the result of circulating 25(OH)D. This activity of 25(OH)D, plus its relatively long half time in plasma, may be the reason 25(OH)D activity is often reported to be better correlated with absorption than the more labile serum 1,25(OH)2D (4, 5, 6, 7).
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Acknowledgments |
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Footnotes |
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Received December 9, 1996.
Revised March 20, 1997.
Revised August 22, 1997.
Accepted August 26, 1997.
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References |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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-hydroxy-vitamin D3 and 1,25-dihydroxy-vitamin
D3 in man. J Clin Invest. 57:1540–1547.
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 P. J. Malloy, J. W. Pike, and D. Feldman The Vitamin D Receptor and the Syndrome of Hereditary 1,25-Dihydroxyvitamin D-Resistant Rickets Endocr. Rev., April 1, 1999; 20(2): 156 - 188. [Abstract] [Full Text]
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R. P. Heaney Excess Dietary Protein May Not Adversely Affect Bone J. Nutr., June 1, 1998; 128(6): 1054 - 1057. [Abstract] [Full Text]
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