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Forum Discoverwomenseekingmen P Seeking Discover Women Seeking Men 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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Finally, the exponential decay model was also used in the analysis below because it was visually suggested by the results of the Loess analysis. This model is included here also because of precedent: it has been used by several researchers to model the PTHC25(OH)D relation (7). Another, more heuristic technique identifies a threshold by comparing changes in PTH from before treatment to after treatment with 25(OH)D in cohorts determined by baseline 25(OH)D (55). There should not be any significant change in PTH in those patients who began the study with 25(OH)D above the threshold. Conversely, the existence of a threshold implies significant PTH change in patients with 25(OH)D below this point. Paired t tests were used to quantify the significance of PTH change.

The longitudinal design of the current study has several advantages. First, our longitudinal data set allows us to examine the influence of serum 25(OH)D on PTH at various time points and doses and also to study the influence of the change in PTH on the change in PTH at those points. Second, because we are measuring each patient as many as 9 times over 36 mo, we are able to generate a correlation between PTH and 25(OH)D and then to use that information in the modeling process. Having multiple observations per patient also allows us to model changes in bone mineral density over time and at the same time to automatically control for extraneous factors (eg, age or weight differences between participants) that may influence the rate of bone loss measured in the group as a whole. Third, we can merge the observations at each time point into a much larger set (n = 1240) of measurements of PTHC25(OH)D pairs and examine the effect of variation in 25(OH)D on PTH. This study takes particular advantage of this third point. We did not use data collected at baseline (a time when patients were not yet reliably calcium replete) in the mathematical analysis of the Loess, line-line, or exponential decay models. The repeated-measures or longitudinal structure of our data set required that we incorporate the correlation between observations in individual patients into the analyses. This was done by implementing the line-line models by using SAS PROC MIXED. To establish the linear component of the association between PTH and vitamin D, Pearson correlation coefficients were computed for various time points and changes between time points. Independent t tests were used to analyze the group differences in continuous baseline values. Paired t tests were used to analyze differences over time. Nonparametric methods such as Spearman's correlation coefficient were used to confirm parametric results. Fisher's exact test and the chi-square statistic were used for establishing the significance of the relation between categorical variables. Model parameter estimates and their SEs were generated by the use of maximum likelihood functions. The significance threshold for all hypothesis tests was set at = 0.05. Alternative hypotheses were 2-sided.

Systematic review of literature reporting a parathyroid hormoneC25-hydroxyvitamin D threshold

We report below a summary of the PTHC25(OH)D relation literature. Included studies satisfied the following criteria: inclusion in Ovid Medline between 1 January 1995 and 15 December 2005; English language; human-subject studies that had the key words parathyroid hormone, PTH, calcidiol, or hydroxyvitamin D. This search yielded almost 500 abstracts. We then scanned these abstracts to determine whether they specifically discussed a relation between PTH and 25(OH)D, eg, correlation, association, and regression. This scanning identified 44 such publications (5-49), which dealt mainly with normal subjects or subjects seeking care at an osteoporosis center and specifically discussed the bivariate relation between various vitamin D concentrations by examining the relation between PTH and 25(OH)D. Of the 44 publications, 29 provided an estimate of 'optimal' 25(OH)D or of a 25(OH)D threshold by examining the relation between 25(OH)D and PTH. One of these 29 publications found no evidence for a threshold after log transformation of the data (48). Another of the 29 publications (31) provided a separate estimate for each sex and is considered as having 2 separate thresholds. Our own data (5), subjected to the analyses reported below, produced a 31st threshold. Fifteen of the reported thresholds used the DiaSorin RIA for the 25(OH)D assay, and 15 used a more heterogeneous set of assays. These included mainly in-house competitive proteinCbinding (CPB) assays or Nichols Automated Chemiluminescence Assays (Nichols Advantage, San Clemente, CA). We wished to evaluate the reported thresholds as a linear function of other population parameters such as mean serum 25(OH)D and calcium intake. Because of the variability introduced by the inconsistent assay methods, this analysis was done in several ways. We first confined the data set to those DiaSorin RIACbased studies with reported dietary calcium intake. Because only 12 such studies had been identified, we then relaxed the inclusion criteria to allow into the regression analyses the 17 studies that used both DiaSorin and non-DiaSorin assays and that reported dietary calcium intake. A sensitivity analysis incorporating a series of hypothetical CPB-to-RIA conversion factors allowed us to examine the potential effect of including non-DiaSorin assays in the regressions. The results did not differ qualitatively when the different sets of studies were used, and thus the results presented below use the maximal set of those 17 studies that report all necessary data. In all analyses, each data point was weighted proportionally to the sample size of that study. A second weighting scheme using weights proportional to the inverse of the SEM of reported 25(OH)D was also tried. This produced very similar results, and therefore only the weighting by sample size is reported.

The 30 publications summarized in Table 1 and analyzed below represent a collective sample of 14 577 patients. The subsample of 16 DiaSorin RIACbased studies represent a collective sample of 8093 patients. The sample of 18 publications with dietary calcium information represents a collective sample of 7176 patients.

TABLE 1 Summary of systematic review of literature reporting a parathyroid hormone (PTH)C25-hydroxyvitamin D threshold1

RESULTS

Baseline characteristics of postmenopausal African American women

The baseline characteristics and demographic profile of the population were reported previously (5). The mean age of the participants was 60 y. Mean body mass index (BMI; in kg/m2) was 29.8 ? 4.6. The dietary intakes of vitamin D and calcium were generally low?184 ? 181 IU/d and 759 ? 582 mg/d, respectively, in the 2 groups. At baseline, 47% of the women were taking supplemental calcium or multivitamins. The baseline demographic profile did not differ significantly between the 2 groups. The baseline serum 25(OH)D ranged from 10.8 to 99.7 nmol/L, and the mean concentration was 45.1 ? 18.8 nmol/L. At enrollment, 67% of the women had serum concentrations of 25(OH)D < 50 nmol/L, and 95% had concentrations below 80 nmol/L. The highest serum PTH was 126.7 pg/mL, and the mean concentration was 41.5 ? 19.5 pg/mL. Eleven percent of the women had serum concentrations of PTH > 65 pg/mL.

Negative correlation between parathyroid hormone and 25-hydroxyvitamin D

Data from the studies that examine the relation between PTH and 25(OH)D almost always find a significant negative correlation in the range of C0.15 to C0.45. We, too, observed this result. In our sample of 208 women who entered the study with baseline measurements, we noted a statistically significant negative linear correlation between PTH and serum 25(OH)D. This relation expresses itself in various ways. For example, the correlation between the 3-mo changes from baseline in PTH and 25(OH)D is negative (r = C0.30, P < 0.0001; n = 163), as is the correlation between the 12-mo changes in PTH and 25(OH)D (r = C0.40, P < 0.0001; n = 164). The correlations between these 2 variables at baseline (r = C0.18, P < 0.01; n = 204), 3 mo (r = C0.23, P < 0.01; n = 163), 12 mo (r = C0.26, P < 0.001; n = 164), and 36 mo (r = C0.22, P < 0.005; n = 152) are also negative. Finally, incorporation of all 1240 available PTHC25(OH)D pairs yields a result of r = C0.23 (P < 0.01). The equivalence between the Pearson correlation and a simple linear model indicates that there is, at least as a first approximation, a significant inverse relation between serum PTH and 25(OH)D.

Loess model results

The Loess model results are depicted in Figure 1. The Hurvich and Simonoff (54) selection method for using the Akaike Information Criteria resulted in a smoothing parameter of 0.6. A heuristic inspection of the smoothed data indicated a 'natural' break point between 40 and 50 nmol/L. Note that the linear fit (thin solid line) is outside the 95% CI boundaries (light dashed lines), which indicates a relative lack of fit for the linear model. This result is confirmed more formally in the mixed-model analysis of variance implementation of the line-line model below.

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.