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Vitamin D Status in a Rural Postmenopausal Female Population

Creighton University, Osteoporosis Research Center, Omaha, Nebraska

Address reprint requests to: Joan M. Lappe, Ph.D., Creighton University Medical Center, Osteoporosis Research Center, 601 North 30^th Street—Suite 4820, Omaha, NE 68131. E-mail: jmlappe{at}creighton.edu

	ABSTRACT

TOP FOOTNOTES ABSTRACT INTRODUCTION METHODS RESULTS CONCLUSIONS REFERENCES

 
Background: Inadequate vitamin D nutritional status is increasingly recognized as common in North American and European populations, but the extent of the shortfall and the parameters of the distribution for populations of interest remain uncertain.

Purpose: To report the distribution of values for serum 25-hydroxyvitamin D [25(OH)D] in a population of rural postmenopausal women, together with quantification of factors related to vitamin D status.

Setting: Nine largely agrarian counties in eastern Nebraska (41° N).

Participants: A population-based sample of 1,179 women 55 years of age and older recruited into a four-year trial of calcium and vitamin D supplementation.

Methods: Baseline biochemical, dietary, and anthropometric measurements obtained on entry into trial.

Results: Serum 25(OH)D concentration at baseline varied cyclically with season, with the solar cycle explaining 2.9% of the total variance (P < 0.001). Mean seasonally adjusted 25(OH)D concentration was 71.1 nmol/L. Serum 25(OH)D also exhibited the expected inverse curvilinear relationship with serum parathyroid hormone (PTH), with the inflection point of the curve located at approximately 80 nmol/L. Supplements containing vitamin D were regularly taken by 59% of the cohort (median dose: 200 IU/d). Nevertheless, approximately 4% of all women had values below the laboratory reference range and more than two-thirds fell below 80 nmol/L. Seasonally adjusted serum 25(OH)D concentration was positively correlated with the size of daily vitamin D supplement dose, and negatively with age, weight, and body mass index (P < 0.01 for all). In stepwise multiple linear regression models, weight, age, and supplement dose were independently correlated with seasonally adjusted serum 25(OH)D, and together explained 19% of the total variance of adjusted 25(OH)D concentration. Women taking supplements had only one-sixth the chance of having a 25(OH)D value below the reference limit of the assay, compared to women who did not use supplements.

Conclusions: Approximately two-thirds of this rural population fell below 80 nmol/L, a value considered to be the lower end of the optimal range. Based on the slope of 25(OH)D on supplement dose observed in these women, it would require an additional vitamin D input of nearly 2000 IU/d to reach the goal of an RDA for vitamin D, i.e., to bring 97.5% of the cohort to levels of 80 nmol/L or higher.

Key words: vitamin D, 25-hydroxyvitamin D, parathyroid hormone, calcium intake, supplements, post-menopause

	INTRODUCTION

TOP FOOTNOTES ABSTRACT INTRODUCTION METHODS RESULTS CONCLUSIONS REFERENCES

 
In 1997, the panel on Calcium and Related Nutrients of the Food and Nutrition Board (IOM) proposed the use of serum 25-hydroxyvitamin D concentration [25(OH)D] as the functional indicator of vitamin D nutritional status [1]. Since then several studies have attempted to determine the extent to which various populations may be vitamin D deficient, using varying and often arbitrary cut-off values to define degrees of vitamin D inadequacy. These and other analyses have contributed to a growing recognition that vitamin D status is suboptimal in large segments of the populations of Europe and North America. However, precise values for the distribution parameters (i.e., mean, standard deviation) remain uncertain, partly because of selection bias in many of the reports to date, e.g., a focus on persons with medical disease [2,3], and partly because seasonal, environmental, and ethnic factors that influence serum 25(OH)D vary among the several reports.

In this paper we present data on vitamin D status from the baseline measurements obtained in a large cohort of white women, aged 55 and older, recruited into a trial of calcium and vitamin D supplementation, together with pertinent demographic and physiological information related to vitamin D status. This is one of a very few U.S. population-based studies of vitamin D status to provide 25(OH)D values obtained throughout a full solar cycle and to include parathyroid hormone (PTH) measurements.

	METHODS

TOP FOOTNOTES ABSTRACT INTRODUCTION METHODS RESULTS CONCLUSIONS REFERENCES

 
Study Subjects
The subjects were 1,179 community-dwelling white women randomly selected from the population of healthy postmenopausal women over 55 years of age in a nine-county farming area of eastern Nebraska, U.S.A., centered at latitude 41° N.

A full-service market research firm randomly selected telephone numbers from all households with listed numbers in the nine-county rural sample area. The firm continued calling until they had identified 1,180 women who met the inclusion and exclusion criteria and were willing to participate in a four year prospective study of calcium and vitamin D supplementation. The participants were enrolled into study between May 2000 and July 2001. The study was approved by the Creighton University Institutional Review Board, and signed informed consent was obtained from each participant.

To be included in the prospective study, women needed to be at least four years past last menses, in generally good health, living independently in the community, and weighing less than 300 pounds. Exclusion criteria included: 1) a medical diagnosis of any chronic kidney disease, 2) Paget’s or other metabolic bone disease, and 3) history of cancer except for a) superficial basal or squamous cell carcinoma of the skin and b) other malignancies treated curatively more than 10 years prior to entry into study.

Data for the analyses reported in this paper were collected at the baseline visits that took place over the 14 month enrollment period. One woman was excluded after entry, when she disclosed a history of hypoparathyroidism following thyroidectomy and reported having taken 50,000 IU of vitamin D daily for the past 25 years.

Medical History and Anthropometric Variables
At baseline, medical and social history and height and weight were obtained. Participants were weighed without outer wear or shoes on a Detecto balance beam scale (Cardinal Scale Manufacturing Company, Webb City, MO). A wall-mounted Harpenden stadiometer was used to measure height. Participants were asked about current use of medications and supplements.

Laboratory
Serum samples for 25(OH)D, parathyroid hormone (PTH) and calcium were collected after a 3-hour fast. Participants were asked not to take vitamin or mineral supplements that morning. Serum 25(OH)D was measured by radioimmunoassay (Nichols/Quest Diagnostics, San Clemente, CA). The coefficient of variation (CV) for intra-assay was 5.1% and inter-assay was 7.9%. All analyses were completed in a single laboratory that participates in the Quality Assurance Program for Vitamin D (DEQAS) [4].

PTH was measured with the Intact PTH immunoassay, a two-site immunoradiometric assay (IRMA) for the measurement of the intact 84 amino acid chain of PTH. Intra-assay variation (CV) at 40 pg/ml is 3.4% and at 266 pg/ml, 1.8%. Inter-assay variation at 38 pg/ml is 5.6% and at 277 pg/ml, 6.1%. Serum calcium was determined with the ion specific electrode (ISE) method using a Beckman Coulter LS-20 Analyzer (Beckman Coulter, Fullerton, CA).

Dietary Calcium Intake
The dietary calcium history was taken according to the method described by Block [5] and modified to include liquid diet supplements that are frequently used by women in this population.

Statistical Analysis
Data were analyzed with SPSS for Windows, Release 12.0 (Chicago, IL). Standard descriptive statistics were used for normally distributed variables; medians and suitable quantiles were used for those not normally distributed. The Chi-square test was used to evaluate differences in numbers of individuals with serum 25(OH)D values below the reference range by supplement use. Univariate and stepwise multiple regression were used to determine the association of variables previously reported to be linked to serum 25(OH)D. Seasonal adjustment of 25(OH)D was made by fitting the data to a sine curve, using the curve fitter of SigmaPlot (Systat Software, Inc., Point Richmond, CA).

The relationships between 25(OH)D and serum calcium, PTH, and dietary calcium were evaluated with non-linear weighted least squares regression analysis.

	RESULTS

TOP FOOTNOTES ABSTRACT INTRODUCTION METHODS RESULTS CONCLUSIONS REFERENCES

 
Pertinent demographic and descriptive information is set forth in Table 1. The age and BMI distributions of the sample were typical for over-55 women in our state. Most of the women were overweight (mean BMI = 29.0 kg/m²; 37.5% were obese). Median total calcium intake was over 1000 mg/d (25 mmol/d), with an average of nearly 400 mg (10 mmol) coming from supplements. Ten women had baseline serum PTH and calcium levels above the upper limit of the reference range [65 pg/ml and 10.0 mg/dl (2.5 mmol/L), respectively] and therefore had a presumptive diagnosis of asymptomatic primary hyperparathyroidism. Data from these individuals were included in the descriptive statistics, but were excluded from certain of the ancillary analyses described below.

The distribution of the seasonally adjusted serum 25(OH)D values is shown in Fig. 1. As is visually evident, the distribution is approximately normal. Of greater interest is the proportion of individuals in this rural population with values below specified cutoff points. Slightly more than 4% were below the lower end of the laboratory reference range (37.5 nmol/L), 14.4% were below 50 nmol/L, and 68.5% were below 80 nmol/L.

View larger version (22K): [in this window] [in a new window]   Fig. 1. Frequency distribution of seasonally adjusted 25(OH)D values in a rural cohort of women aged 55 and older. N = 1179. The smooth curve is the best fit Gaussian curve for the distribution. (Copyright, Robert P. Heaney, 2005. Used with permission.)

View larger version (20K): [in this window] [in a new window]   Fig. 2. Plot of serum 25(OH)D concentrations as a function of supplemental vitamin D intake. N = 1179. The diagonal line is the least squares best fit regression line through the data, together with its confidence interval. (To convert IU to µg, divide the horizontal axis values by 40.) (Copyright, Robert P. Heaney, 2005. Used with permission.)

View larger version (21K): [in this window] [in a new window]   Fig. 3. Plot of serum PTH as a function of serum 25(OH)D. The solid line is the best fit regression line through the data using an exponentially decreasing model. (Copyright, Robert P. Heaney, 2005. Used with permission.)

View larger version (21K): [in this window] [in a new window]   Fig. 4. Plot of the least-squares regression lines for a three-parameter exponential fit describing the relationship of serum PTH to serum 25(OH)D for normal weight, overweight, and obese women in our study cohort. The equations are identical in form to that employed in Fig. 3. The general similarity of the three curves is evident. (Copyright, Robert P. Heaney, 2005. Used with permission.)

Finally, we examined the association of total calcium intake and serum PTH concentration and found, for the cohort as a whole, a weakly negative relationship (slope: –0.0048; P = < 0.001). We further examined this issue, as above, by dividing the cohort on the basis of vitamin D status, using a cut-point of 80 nmol/L. Above an adjusted 25(OH)D value of 80, the relationship between PTH and calcium intake was not statistically significant (P = 0.17), while below, the slope was –0.0057 (P < 0.001).

	DISCUSSION

 
The data presented here represent one of only three population-based studies of serum 25(OH)D concentration for North America [6,7]. Having reliable population-level data on the distribution of 25(OH)D is important both for the accurate estimation of the size of problem of vitamin D inadequacy and, from the measured dispersion of values in the population, for estimating the effect of population-wide efforts at vitamin D supplementation and/or food fortification, particularly as these may affect the extremes of the distribution.

We have assembled with this study the two other N. American population-based studies [6,7], one French population-based study [8], one Australian population-based study [9], and six others consisting of convenience or disease-based samples [3,10–14] in the form of Table 4. The Table shows specifically the proportion of each study population with values below 37.5 nmol/L (the lower end of the reference range for several assays) and below 80 nmol/L (the lower end of the likely physiological optimal range; see also below). These estimates were based upon the parameters either reported for or calculated from each study, assuming Gaussian distributions of the values. In the three North American population-based studies, from 62 to 75% of all female participants had values below the optimal range. Our own data constitute a value squarely in the middle of that range. Similar percentages were reported for most of the studies involving convenience samples or disease populations. It seems clear that, no matter how sampled, substantially more than half of all older women have suboptimal vitamin D status.

It was noteworthy that fully two-thirds of our sample were below 80 nmol/L, despite the fact that more than half of our cohort used supplements containing vitamin D. Indeed, the principal effect of supplement taking in this population would appear to have been ensuring that relatively few individuals had serum 25(OH)D values that fell below the reference level for the assay. This is seen, for example, in the more than 6-fold higher risk of falling below the reference range for women not taking supplements, compared to supplement-users [Table 2].

Although there is an emerging consensus that the optimal range for 25(OH)D values lies above 75–80 nmol/L for most populations [15], there still remains some uncertainty as to whether such a threshold value is applicable to all populations; a few investigators, using a variety of indices, have reported effective cutoff points as low as 30–50 nmol/L [16–20]. As noted above, some of the differences between studies may reflect assay differences, while others, possible biological differences between populations (e.g., Iceland [20]). Our data, which appear to be very similar to those published by Chapuy et al. [21] several years ago, show very clearly that, if one uses PTH as the indicator variable, the cutoff must be close to 80 nmol/L, at least for our assay and for this population. Other data converge on the same estimate. For example, the LOWESS plots from NHANES-III relating bone mineral density [22] to 25(OH)D in the U.S. population show that, while the largest difference gradient is found in the low range of serum 25(OH)D values, nevertheless, there is a continuing positive association above 30–50 nmol/L, up to well above 80 nmol/L. The same pattern is seen for lower extremity neuromuscular function [23]. Because the positive slopes of these relationships become smaller at higher 25(OH)D values, an effect would be more difficult to detect in small samples or in more mildly deficient populations.

Interpretation of the observed biphasic relationship for calcium intake and PTH hinges on an understanding of the threshold character of calcium as a nutrient, i.e., that a relationship between intake and various biological endpoints exists below a threshold intake level, but not above that value, where additional calcium intake produces no additional effect [24]. It would appear that a 25(OH)D concentration 80 nmol/L effectively allows the calcium intake of most of the participants to be located at or above their individual calcium intake thresholds, i.e., it permits sufficiently efficient calcium absorption to meet the body’s calcium requirements without requiring augmented PTH production and secretion. Thus, variation in absorbed calcium intake above that level would have little evident effect on PTH values obtained at random times during the day. This same dichotomous relationship between PTH and calcium intake was recently reported by Steinsgrimsdottir et al. for an Icelandic population, but with a cut-point closer to 50 nmol/L [20].

A similar conclusion is reached when one examines the biphasic relationship of serum 25(OH)D and serum calcium. Because it promotes calcium absorption, one would predict that vitamin D adequacy would support a slightly higher serum calcium, other things being equal. As we noted, precisely that relationship was found for the cohort taken as a whole, but when split, was statistically significant only for those with serum 25(OH)D below 80 nmol/L.

The high degree of consistency for the cut-point for these three indirect indices of vitamin D adequacy [i.e., PTH on 25(OH)D, PTH response to total calcium intake, and serum calcium on 25(OH)D] strongly supports the conclusion that 25(OH)D values below 80 nmol/L are suboptimal.

The proportion of the variation of serum 25(OH)D in our sample that could be explained by the variables already known to affect 25(OH)D (age, body weight, vitamin D ingestion, and season) still accounted for less than 25% of the total variance. It is likely that much of the remainder is a reflection of varying sun exposure across this population, together with analytical error. We have shown elsewhere that, at the latitude at which this study was conducted (41° N), outdoor workers have a seasonal difference between end of summer and end of winter amounting to approximately 50 nmol/L [25]. Hence it seems likely that individual variations in habitual sun exposure could be a major contributor to the dispersion of the values around the seasonally adjusted mean.

Given the abnormalities of vitamin D metabolism often reported in obese subjects, it was interesting to see that the curvilinear relationship between serum PTH and 25(OH)D was basically similar across all three weight classes (Fig. 4). However, the significantly higher value for the Y-axis intercept in the obese women was statistically significantly different from the other two weight classes, and indicates a larger PTH response in obese women to low vitamin D nutritional status. The mechanism for this difference is not clear.

One limitation of this study is that our cohort included only white women, although they were representative of the population from which they were sampled. The strengths of our study include the fact that it was population-based, that it included detailed information about, and/or measurements of, many of the correlates of vitamin D and calcium status, and that the serum PTH values were drawn randomly throughout any given day, thus giving a more representative, if individually incomplete, picture of PTH response to prevailing calcium intakes. (Morning fasting values, by contrast, are all, by definition, obtained in a calcium-deprived state.) A further strength was the fact that all of the serum 25(OH)D values were determined by a single assay, in a single laboratory, participating in the DEQAS Quality Assurance Program for Vitamin D [4], on samples obtained over only a 14-month period. In addition, having quantitative values for supplemental vitamin D intake in the members of the cohort enabled us to explore the relationship between supplementation and serum values of 25(OH)D, and hence to estimate the effect of further supplementation.

The slope of serum 25(OH)D on daily vitamin D supplement dose in our cohort was 0.0249 nmol/L/IU/d (or 0.996 nmol/L/µg/d). Prior work from our center using controlled vitamin D dosing had produced a similar value for slope, i.e., 0.70 nmol/L/µg/d [26]. Various other reports from which slope calculations can be derived yield values most of which fall in the range of 0.6 to 1.2 nmol/L/µg/d [27]. Hence, the response to vitamin D supplementation in the women of this cohort is very congruent with the large and still growing body of data on serum 25(OH)D change in response to various steady state oral doses of cholecalciferol. Having such information allows prediction of response to plausible steady state vitamin D₃ dosing. For example, our observed slope (0.996 nmol/L/µg/d) predicts an elevation of 25 nmol/L for an additional daily oral input of 1000 IU (i.e., 25 µg).

The importance of having distributional data such as we present here is that it allows better estimation of the effect of various population-wide, public health stratagems to improve vitamin D status. One of us (RPH) has estimated elsewhere, based on calculations derived from NHANES-III [7] and using a slightly smaller value for the slope of 25(OH)D on dose, that it would take 2600 IU vitamin D per day to ensure that 97.5% of all women in the U.S. over age 60 had 25(OH)D values above 80 nmol/L [27]. A similar calculation for the distribution of values in this population, and using its observed slope of 25(OH)D on supplement dose, produces a required dose of 1968 IU/d. (Note: This is in addition to all other prevailing inputs.) As discussed in detail elsewhere [28,29], such doses, although much higher than the currently recommended oral intakes [1], are not likely to produce intoxication, as the resulting serum 25(OH)D levels, even for individuals already two standard deviations above the population mean (i.e., 112 nmol/L in this cohort), are not predicted even to approach possibly toxic levels (i.e., above 250 nmol/L).

	CONCLUSIONS

TOP FOOTNOTES ABSTRACT INTRODUCTION METHODS RESULTS CONCLUSIONS REFERENCES

 
In this population-based sample of generally healthy postmenopausal women who reside in a rural area of the Midwestern U.S.A., prevalence of inadequate vitamin D status is very high, even though more than half of the women reported taking vitamin D supplements in doses approximating the current recommendations for total intake. Indirect indices of vitamin D inadequacy generated in this population strongly indicate that serum 25(OH)D values below 80 nmol/L are suboptimal. Calculations based on the slope of the serum 25(OH)D response to vitamin D supplement dose show that an additional intake of nearly 2000 IU/d would be needed to ensure that 97.5% of all women in this population had 25(OH)D values above 80 nmol/L. Our findings emphasize the importance of increasing vitamin D intake in postmenopausal women.

	FOOTNOTES

TOP FOOTNOTES ABSTRACT INTRODUCTION METHODS RESULTS CONCLUSIONS REFERENCES

 
Work reported in this paper was supported by DHHS Grant AG14683.

Received September 15, 2005. Accepted December 15, 2005.

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TOP FOOTNOTES ABSTRACT INTRODUCTION METHODS RESULTS CONCLUSIONS REFERENCES

 

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