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Discoverwomenseekingmen N Discover Women Seeking Men 0 Szh 1 Discover Women Seeking Men Optimal vitamin D status and serum parathyroid hormone concentrations in African American women--《美国临床营养学杂志》--医学期刊频道--首席医学网

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FIGURE 1. Loess plot (solid line) and 95% CI of the Loess plot (dotted lines) of parathyroid hormone as a function of 25-hydroxyvitamin D. n = 124. The linear regression line (- - -) is outside the 95% CI for 25-hydroxyvitamin D concentrations <30 or >110 nmol/L.

Line-line results

The Loess model results suggest that a 2-slope spline model will fit the data. The mixed model discussed above estimates the threshold to be 44 nmol/L. The slope regressing PTH on 25(OH)D of the first segment is different from zero (slope = C0.44, P = 0.0001). The slope of the second segment (C0.05) does not differ significantly from zero (P > 0 0.05), and the difference between the slopes of the first and second segments is highly significant (P = 0.0001), which indicates a change in the rate at which PTH increases as 25(OH)D drops below 44 nmol/L. Most important, the nonlinear threshold model is significantly better than the simple straight line (P < 0.0001).

Figure 1 indicates that our study data are consistent with a model with a threshold of 40C50 nmol/L. A series of statistical models gives converging evidence that a threshold value of 44 nmol/L fits the data. At this value, R2 was increased to 6.9%; this was higher than the R2 of any other threshold model and was a significantly better fit than the linear model (F1,184 = 24.3, P < 0.0001).

These results were obtained after adjustment for the correlation structure between the multiple measurements obtained from each subject. A mixed-model analysis of variance was used to compare the incremental contribution of using a knot and a simple linear model. A model with a knot of 44 nmol/L and an 'unstructured' correlation structure were found to fit the data by using the minimum Akaike Information Criteria in conjunction with the criterion, imposed for model simplification, that the slope after the threshold not differ significantly from zero. (When this restriction is relaxed, the threshold with the best fit is 40 nmol/L. But the slope of the regression line after 40 nmol/L does not differ clinically or significantly from the slopes after 44 nmol/L.)

Several authors have used an exponential decay model to model the PTHC25(OH)D relation. Figure 1 also indicates that this curve should fit the data. Indeed, it is difficult to visually distinguish the 2 curves (not shown). In a graph of the exponential decay model, a plateau appears between 40 and 50 nmol/L. The actual fitted equation is

(1)

These parameters are almost identical to those reported by Chapuy et al (7) in a publication commonly cited by others who are using an exponential decay model. Although the fit of the line-line and the exponential models is almost identical from a statistical perspective, we suggest that the line-line model has several advantages over the exponential model. First, the shape of the Loess model result is most similar to that of the line-line model. Second, the line-line model allows for further decline in PTH beyond the threshold; it is expected that 'mega-doses' of vitamin D will further suppress PTH. Finally, the line-line model allows for a clear-cut determination of the threshold point, whereas the exponential model does not.

The threshold estimate of 40C50 nmol 25(OH)D/L is confirmed by noting that the maximal ratio of PTH change in patients below the threshold to the change in patients above the threshold occurred?ie, the difference between the change in PTH (baseline to 1 y = C13.4) in patients with < 42 nmol 25(OH)D/L at baseline and the change in PTH (baseline to 1 y = C2.8) in patients with > 42 nmol 25(OH)D/L at baseline was greatest?when 42 nmol 25(OHD)/L was used as the threshold. Patients with 25(OH)D concentrations below this point did not show clinically and statistically significant changes as a result of their treatment with vitamin D3. Finally, there were highly significant differences via paired t tests in the change in PTH from baseline to 1 y in those active patients who began the study with a 25(OH)D value < 42 nmol/L. Conversely, the group with 25(OH)D concentrations > 42 nmol/L did not experience any significant change in PTH. Threshold values close to 42 nmol 25(OH)D/L had similar statistical characteristics.

Systematic review of the literature on optimal 25-hydroxyvitamin D concentrations

Data from the systematic literature review are summarized in Table 1. The reported studies included subjects with age ranges from 10 y old to the elderly; some studies include both men and women. When the earlier studies were performed, the CPB assay was still in use. Most recent studies used RIAs, in particular the DiaSorin assay. BMI was generally not reported, although it is a determinant of serum PTH (56). Dietary intakes of calcium and vitamin D were generally below those recommended by the Food and Nutrition Board. Surprisingly, the calcium or vitamin D intake was not even reported in some studies. In no study did estimated vitamin D intake approach the currently recommended intake. The estimated optimal serum concentration of 25(OH)D varied from 25 to 122 nmol/L. The highest estimates were reported for either CPB (57) or Nichols Advantage (58) assays, both of which give inappropriately high values for serum 25(OH)D. Indeed, the 4 highest thresholds were all from studies that used the CPB assay. Half of the studies provided estimates of 50 nmol/L for optimal 25(OH)D and a third (10 studies) provided estimates between 40 and 50 nmol 25(OH)D/L.

Although the variability in threshold estimates is multifactorial, varied calcium intake and vitamin D status appear to be 2 of the more significant factors. A cross-tabulation of dichotomous dietary calcium intakes (above and below 1000 mg/d) with dichotomous thresholds (above and below 50 nmol/L) indicates that a lower calcium intake is associated with a higher reported threshold (chi-square test: 7.6; P < 0.02). The Pearson correlation between these 2 variables of C0.62 (P = 0.01; n = 18) confirms this inverse relation. A univariate analysis of all 30 studies (31 reported thresholds) documents the effect that mean 25(OH)D has on the reported threshold. A highly significant (P = 0.001) Pearson correlation of 0.55 indicates the linear association between these 2 variables. The following linear equation implies that there is an almost one-to-one increase in the computed threshold for each 1-nmol/L increase in the mean 25(OH)D concentration.

(2)

Part of the variability in these estimates can also be explained by the fact that different models and methods were used to estimate the threshold. These varied from the sophisticated mixed-model approach to a nave, intuitive, visual approach (5, 20, 25, 26).

Multiple regression analysis suggests that serum 25(OH)D and dietary calcium influence the reported threshold independently; together they account for 67% of the variance in reported thresholds among the 18 available studies. The overall model P value was 0.0003 (F2,15 = 15.1), and the contribution of dietary calcium to the prediction of the threshold remained significant even after control for serum 25(OH)D. Partial P values were both < 0.01. Because calcium intake was not reported in 13 studies, conclusions based on dietary calcium are only suggestive.

A nonsignificant negative correlation of C0.27 was found between PTH and dietary calcium in the 18 studies with reported dietary calcium intakes. Recently, Steingrimsdottir et al (46) reported a calcium intake x optimal 25(OH)D interaction for an effect on PTH, which we are able to confirm through our literature review. We found that, in those studies with 25(OH)D of > 50 nmol/L, calcium intake did not affect PTH. But in those studies with a mean 25(OH)D of < 50 nmol/L, dietary calcium was inversely related to PTH: within this subset, PTH was 6 pg/mL lower in the set of studies with dietary calcium > 800 mg/d than in the studies with dietary calcium < 800 mg/d (interaction F1,14 = 3.5, P = 0.08).

DISCUSSION

Our data suggest that a serum concentration of 40C50 nmol 25(OH)D/L is needed to prevent a rise in PTH concentrations in calcium-sufficient African American women in midlife. We reviewed the English-language literature that reported a threshold estimate and found that most estimates clustered between 40 and 50 nmol/L or 70 and 80 nmol/L. Indeed, almost half of the studies in our literature review reported a threshold 50 nmol/L and one-third reported thresholds between 40 and 50 nmol/L, findings that are consistent with the value we observed. Thus, we take exception to the statement of Dawson-Hughes et al (59), 'These estimates of the threshold serum 25(OH)D vary widely but there is a cluster in the 75C80 nmol range.' A equally evident cluster is found between 40 and 50 nmol/L.

The variability in the estimates for the 25(OH)D threshold may be explained by ethnic differences in calcium economy, the extent of vitamin D insufficiency, different calcium intakes, inaccuracy of 25(OH)D assays, the age and health of the populations studied, and the mathematical analyses used. We studied only African American women. Our findings may not be generalizable to other ethnic groups. It should be noted that osteoporotic fractures are less common and bone density is higher in African American women than in women of other races/ethnicities, despite the lower serum 25(OH)D of African Americans (60). Heaney (61) estimated that African American women require 300 mg/d less calcium intake than do white women.

Most of the studies examining optimal vitamin D status do not control for calcium intake. Consideration of optimal vitamin D intake without knowing calcium intake is problematic. In each study in which the calcium intake exceeded 1000 mg/d, the estimated optimal serum 25(OH)D was 50 nmol/L. It is of interest that the most recent Cochrane Database of Systematic Reviews concluded that, whereas vitamin D with calcium marginally reduced hip and other nonvertebral fractures, no effect was seen when vitamin D was given alone (62). Again, the interaction between vitamin D status and calcium intake should be considered in making nutritional recommendations.

Our population had a mean age of 60 y, whereas several of the studies from the literature were done in the elderly. Renal function declines with aging, and higher concentrations of 25(OH)D are needed to prevent a rise in serum PTH in the elderly (48). Indeed, a number of studies have documented secondary hyperparathyroidism in the elderly, and calcium with vitamin D supplementation has prevented fragility fractures in some (but not all) studies. Moreover, the effect of vitamin D effects on muscle may help prevent falls in the elderly, thereby reducing fracture risk (63).

Another cogent argument against recommending a vitamin D intake based mainly on a threshold derived from the scattergram of PTH versus 25(OH)D comes from our study (5). Using various models and techniques, we were able to consistently show a threshold value in our data. Despite our finding a threshold of 40C50 nmol 25(OH)D/L, those participants above and below the putative threshold did not differ significantly in loss of bone mineral density. Another analysis attempted to associate the rate of change in bone mineral density with 25(OH)D; no correlation was found between serum 25(OH)D and rates of bone loss (5).

The whole concept of a specific threshold is suspect because such a threshold may be partly an artifact of the reported serum 25(OH)D. In a global survey, Lips et al (57) found a wide range of mean serum concentrations of 25(OH)D across and within continents. Because the threshold is directly related to the observed serum 25(OH)D, it is not surprising that there is similar wide variability in reported thresholds across the 30 studies that we reviewed. Identifying a single optimal 25(OH)D value among this variability is problematic. Furthermore, the average reported correlation across the 25 studies that reported a correlation between PTH and vitamin D was C0.30. Thus, serum 25(OH)D 'explains' 9% of the variance in PTH. A wide range in reported thresholds is found, because these thresholds are calculated from a wide range of populations, assays, and statistical techniques all applied to a weak biological phenomenon (ie, a linear r2 of 9%). The wide variability in threshold estimates is another reason for caution in using that concept in making dietary recommendations for heterogeneous populations.