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Effects of Age and Estrogen Status on Serum Parathyroid Hormone Levels and Biochemical Markers of Bone Turnover in Women: A Population-Based Study¹

Endocrine Research Unit, Division of Endocrinology and Metabolism, Department of Internal Medicine (S.K., B.L.R.), the Sections of Biostatistics (E.J.A.) and Clinical Epidemiology (L.J.M.), Department of Health Sciences Research, Mayo Clinic and Mayo Foundation, Rochester, Minnesota 55905

Address all correspondence and requests for reprints to: Sundeep Khosla, M.D., Mayo Clinic, 200 First Street SW, 5–164 West Joseph, Rochester, Minnesota 55905.

	Abstract

Top Abstract Introduction Subjects and Methods Results Discussion References

 
Although estrogen deficiency is responsible for the increase in bone turnover in early postmenopausal women, age-related factors, such as the progressive increase in serum PTH levels, are believed to be responsible for the increase in bone turnover in elderly women. Whether estrogen deficiency continues to play a role, either directly or indirectly, in the pathogenesis of the increased bone turnover in elderly women remains unclear. Thus, we measured serum PTH, markers of bone turnover, and serum sex steroid levels in a population-based sample of 351 women (age range, 21–94 yr), which included 47 postmenopausal women who were receiving long term estrogen replacement therapy.

Serum PTH increased as a function of age when the premenopausal women and the estrogen-deficient postmenopausal women were analyzed together (r = 0.35; P < 0.001). By contrast, this age-related increase in serum PTH was eliminated in the postmenopausal women receiving long term estrogen therapy, which also resulted in a similar suppression of markers of bone formation and resorption in both the early (20 yr) and late (>20 yr) postmenopausal women. By multivariate analysis, serum 25-hydroxyvitamin D levels were highly predictive of serum PTH levels regardless of menopausal status, whereas serum estrone levels were predictive of markers of bone resorption in the postmenopausal women. We conclude that estrogen deficiency may be responsible not only for the increase in bone turnover in early postmenopausal women, but also indirectly for the secondary hyperparathyroidism and increase in bone turnover found in late postmenopausal women. Residual serum estrogen levels are important determinants of bone resorption in postmenopausal women.

	Introduction

Top Abstract Introduction Subjects and Methods Results Discussion References

 
WITH THE aging of the population, osteoporosis is emerging as a major public health problem (1). In women, the two major causes of bone loss are estrogen deficiency after the menopause and age-related processes (1). Bone turnover increases to high levels in women soon after menopause (2, 3). This is believed to be due principally to a diminution of a direct action of estrogen on bone cells (4). In addition, estrogen deficiency may induce calcium loss by indirect effects on extraskeletal calcium homeostasis. These indirect effects include decreased intestinal calcium absorption (5) and decreased renal calcium conservation (6) after the onset of estrogen deficiency.

Likewise, numerous studies have examined potential mechanisms of age-related bone loss. Levels of serum intact PTH increase progressively with age in women and correlate significantly with increases in bone turnover values (7, 8). Moreover, when PTH secretion is suppressed by 24-h calcium infusion in young adult and elderly women (9), markers for bone turnover decrease to a greater extent in the elderly women, which is consistent with a role for PTH in mediating the age-related increase in bone turnover. PTH secretory dynamics in elderly women show changes consistent with secondary hyperparathyroidism (10), which are reversed either by short term treatment with 1,25-dihydroxyvitamin D (10) or by long term calcium supplementation (11); increases in levels of bone resorption markers in elderly women are also reversed by long term calcium supplementation (11).

To date, the effects of estrogen deficiency and age on bone turnover and serum PTH have principally been studied independently of each other. Possible interactions have not been sought, and these studies have not been population based. Thus, it remains unclear whether estrogen deficiency, which clearly is responsible for the early postmenopausal increase in bone turnover and bone loss, continues to contribute to the increased bone turnover and bone loss in elderly women. To address this issue, we measured serum PTH, markers of bone turnover, and serum sex steroid levels in a population-based sample of 351 women (age range, 21–94 yr), which included 47 postmenopausal women who were receiving long term estrogen replacement therapy. This allowed us to determine how estrogen deficiency and age might interact with regard to their effects on serum PTH and markers of bone turnover and also to identify factors that predict changes in serum PTH and bone turnover in aging women.

	Subjects and Methods

Top Abstract Introduction Subjects and Methods Results Discussion References

 
Study subjects

Subjects were recruited from an age-stratified random sample of women from Rochester, MN, who were selected using the medical records linkage system of the Rochester Epidemiology Project (12). The study population (n = 351) included 138 premenopausal women (age range, 21–54 yr; mean, 35 yr) and 213 postmenopausal women (age range, 34–94 yr; mean, 68 yr) (13). All but 2 of the women were Caucasian, reflecting the ethnic composition of the population (96% white in 1990). The mean years since menopause (ysm) in the postmenopausal group was 22.0 yr (range, 0.3–54.3 yr). Forty-seven of the postmenopausal women (22%) were receiving estrogen replacement therapy. The majority of the women (n = 37) were taking oral conjugated estrogens (Premarin, Wyeth-Ayerst, Philadelphia, PA); 30 women were taking a dose of 0.625 mg/day, 3 were taking 0.3 mg/day, 3 were taking 1.25 mg/day, and 1 was taking 0.9 mg/day. Nine women were taking transdermal estrogen at a dose of 0.05 mg/day. One postmenopausal woman was taking a low dose oral contraceptive containing 30 µg ethinyl estradiol. Twenty-eight of the premenopausal women (20%) were taking oral contraceptives. Eight of the total cohort of 351 women (2%) were taking corticosteroids, and 38 (11%) were taking a diuretic (these individuals were relatively evenly distributed between the untreated and estrogen-treated postmenopausal women). One subject (0.3%) had chronic liver disease, and 1 (0.3%) had sustained a fracture within the past 6 months. None had chronic renal failure.

Study protocol

The protocol was approved by the Mayo institutional review board, and all subjects gave informed consent before participation in the study. Fasting serum samples were obtained between 0800–0900 h, and a 24-h urine collection was also obtained. All samples were stored at -70 C until analyzed. General health was assessed by history and review of the medical record, and the history of estrogen use was confirmed. The duration of current estrogen use was stratified according to the following time intervals: 0–3 months (3 subjects), 3–6 months (1 subject), 6–12 months (1 subject), 1–3 yr (8 subjects), 3–5 yr (16 subjects), 5–10 yr (9 subjects), and more than 10 yr (9 subjects). In addition, a 7-day diet record was used to determine dietary plus supplemental calcium intake.

Laboratory methods

Serum intact PTH was measured by immunochemiluminometric assay (14) [inter- and intraassay coefficients of variations (CV), 14% and 9%, respectively]. Serum osteocalcin was assessed by RIA (interassay CV, <6%) (7). Serum bone alkaline phosphatase (BAP) was measured by enzyme-linked immunosorbent assay (ELISA; interassay CV, <11%) (15). Serum carboxyl-terminal propeptide of type I procollagen (PICP) was also measured by ELISA (Prolagen-C, Metra Biosystems, Mountain View, CA; interassay CV, <7%). Urinary N-telopeptide of type I collagen (NTx) was measured using an ELISA kit (Osteomark, Ostex, Seattle, WA; interassay CV, 10%), as were urinary free pyridinoline and free deoxypyridinoline (Pyrilinks and Pyrilinks-D kits, Metra Biosystems; interassay CVs, <12% and <6%, respectively). RIA kits were used to measure serum estradiol (Diagnostic Products Corp., Los Angeles, CA; interassay CV, <8%), estrone (Diagnostic Biochem Canada, London, Canada; interassay CV, <14%), testosterone (Diagnostic Products Corp.; interassay CV, <12%), dehydroepiandrosterone sulfate (Diagnostic Products Corp.; interassay CV, <7%), sex hormone-binding globulin (SHBG; Wien Laboratories, Succasunna, NJ; interassay CV, <9%), and 25-hydroxyvitamin D (25OHD; Incstar Corp., Stillwater, MN; interassay CV, <16%). The glomerular filtration rate was assessed by measuring 24-h creatinine clearance.

Statistical analysis

The Kruskall-Wallis test was used for an overall comparison among the groups, and the Wilcoxon rank sum test was used for pairwise comparisons. Spearman correlations were used to summarize relationships between pairs of variables. The S-Plus function lowess (16), a robust smoother function (essentially a type of moving average), was used as a means to visually explore the data in Figs. 1 and 2. Regression analysis was used in determining the relationship of serum PTH and the bone turnover markers with age, ysm, and estrogen status. In these models, the independent variables included ysm of 20 yr or less (20 ysm; yes/no), current estrogen therapy (yes/no), and the interaction between the two. Stepwise model selection was used to determine the relationship of calcium intake, creatinine clearance, duration of estrogen therapy, ysm, serum 25OHD, and sex steroids with serum PTH and the bone turnover markers.

View larger version (21K): [in this window] [in a new window]   Figure 1. Serum PTH as a function of age in premenopausal and untreated postmenopausal women combined (dashed line, open circles) and estrogen-treated postmenopausal women (solid line, open triangles). Curve fitting was performed using the S-Plus lowess smoother (16 ) as described in Materials and Methods.

View larger version (20K): [in this window] [in a new window]   Figure 2. Serum PTH as a function of ysm in the untreated postmenopausal women (dashed line, open circles) and the estrogen-treated postmenopausal women (solid line, open triangles). Curve fitting was as noted in Fig. 1.

	Results

Top Abstract Introduction Subjects and Methods Results Discussion References

Serum PTH increased as a function of age when the premenopausal women and the untreated postmenopausal women were analyzed as a group (r = 0.35; P < 0.001; Fig. 1). By contrast, the relationship with age was best described as a biphasic curve in the estrogen-treated postmenopausal women; compared to the untreated women, serum PTH levels were higher in the estrogen-treated women up to approximately age 70 yr, but then decreased in the estrogen-treated women to levels below those in untreated women (Fig. 1). Consequently, the age-related increase in serum PTH found in the untreated postmenopausal women was absent in the estrogen-treated women. A similar relationship was evident when serum PTH was plotted as a function of ysm (Fig. 2), with the curve for the estrogen-treated postmenopausal women crossing the curve for the untreated women at 18–20 yr postmenopause. Therefore, the relationship between the effects of estrogen therapy on serum PTH levels as a function of ysm was analyzed in a multivariate model with serum PTH as the dependent variable and 20 ysm or >20 ysm, current estrogen therapy, and an interaction between the two as the independent variables. As shown in Table 1, there was a significant interaction between 20 ysm or >20 ysm and current estrogen therapy (P = 0.029), indicating that the effects of estrogen therapy on serum PTH levels were indeed related to ysm.

View this table: [in this window] [in a new window]   Table 1. Multivariate model of the relationship between serum PTH and ysm (20 or >20 yr), current estrogen replacement therapy (ERT), and an interaction between ysm (20 or >20 yr) and current ERT among an age-stratified sample of women from Rochester, MN

Although the effects of estrogen therapy on serum PTH levels differed based on ysm, its effects on bone turnover were similar in both the 20 and >20 ysm postmenopausal women (Table 2). Both serum osteocalcin and BAP were higher in the early and late postmenopausal women than in the premenopausal women and were lower in the estrogen-treated postmenopausal women than in the untreated women regardless of ysm. All three resorption markers showed similar changes in the untreated and estrogen-treated postmenopausal women. Serum PICP, however, behaved somewhat differently (see below). In addition, the data in Table 2 also clearly show that although the untreated women who were more than 20 yr postmenopausal had higher levels of serum osteocalcin, BAP, and all of the resorption markers compared to the premenopausal women, the corresponding women taking estrogen had values for these markers that were either similar to or below the levels found in the premenopausal women. Thus, as for serum PTH, these data suggest that estrogen therapy prevented the age-related increase in bone turnover.

View larger version (22K): [in this window] [in a new window]   Figure 3. Serum PICP vs. serum osteocalcin levels in the premenopausal women (dashed lines, open squares; r = 0.51; P < 0.001), untreated postmenopausal women (solid lines, open circles; r = 0.41; P < 0.001), and estrogen-treated postmenopausal women (dotted lines, open triangles; r = 0.37; P = 0.01). The slope of this relationship was significantly lower (P < 0.01) in both groups of postmenopausal women than that in the premenopausal women.

In addition to the effects of estrogen therapy, we examined other variables that could be related to serum PTH or the bone turnover markers (Table 3). To reduce the number of multivariate models and also ensure adequate numbers of subjects in each model, the groups were divided into premenopausal, untreated postmenopausal, and estrogen-treated postmenopausal women, with ysm 20 or >20 used as an independent variable in the multivariate analysis. Table 4 shows the results of the simple regression analysis between serum PTH, serum osteocalcin, and urinary NTx vs. these variables. The results for one formation and one resorption marker are presented to simplify the analysis. However, similar relationships were noted for the other formation and resorption markers. Serum 25OHD levels were inversely correlated with serum PTH levels in all three groups. In the untreated postmenopausal women, the free sex steroid indexes (estradiol, estrone, and testosterone divided by SHBG) were inversely correlated with both serum osteocalcin and urinary NTx. In the estrogen-treated postmenopausal women, the serum free estradiol and estrone indexes were negatively correlated with urinary NTx, but not serum osteocalcin.

View this table: [in this window] [in a new window]   Table 5. Multivariate models for serum PTH, serum osteocalcin, and urinary NTx vs. the parameters in Table 4 and ysm (20 or >20 yr) in different subgroups of women from Rochester, MN

View larger version (26K): [in this window] [in a new window]   Figure 4. Serum PTH vs. serum 25OHD levels in the premenopausal women (dashed lines, open squares; r = -0.37; P < 0.001), untreated postmenopausal women (solid lines, open circles; r = -0.25; P < 0.01), and estrogen-treated postmenopausal women (dotted lines, open triangles; r = -0.43; P < 0.01). The slopes were not significantly different in the three groups of women.

	Discussion

Top Abstract Introduction Subjects and Methods Results Discussion References

These data also indicate that the number of ysm may be an important determinant of the effects of estrogen therapy on serum PTH levels. Previous studies have found that estrogen therapy may result in increases (20, 21, 22, 23), decreases (24), or no change (25, 26, 27) in serum PTH levels. Moreover, in previous studies from our own group, we noted similar differences in the response of serum PTH to estrogen. In the study of elderly (mean age, 74 yr) women noted above (19), the women taking estrogen had significantly lower serum PTH levels than the untreated women, whereas in an earlier study of much younger postmenopausal women (mean age, 51 yr) (6), estrogen therapy was associated with an increase in serum PTH levels. Combining the results of these previous studies with our present findings, these observations are consistent with the hypothesis that within the first 20 yr after the menopause, the direct skeletal effects of estrogen deficiency are primarily responsible for the increase in bone resorption. In these women, estrogen therapy reduces bone resorption directly, and this is associated with a compensatory increase in serum PTH levels. In the late (>20 yr) postmenopausal women, on the other hand, estrogen therapy is associated with lower serum PTH levels; in fact, estrogen therapy appears to reverse the age-related increase in serum PTH. This is consistent with the hypothesis that the extraskeletal effects of estrogen on intestinal calcium absorption (5) and renal calcium handling (6) and perhaps direct effects on PTH secretion (28) are primarily responsible for the lower serum PTH levels in these women. Thus, in these late postmenopausal women, the extraskeletal effects of estrogen deficiency may be permissive for the development of secondary hyperparathyroidism and increased bone resorption; treatment with estrogen, in turn, would then reverse both of these abnormalities, as was observed. Although these hypotheses of different early and late consequences of estrogen deficiency are consistent with our findings, we recognize the potential limitations of a cross-sectional study such as ours, and more studies are clearly needed to further address this concept. Moreover, the relationship between serum estradiol and PTH may be even more complex, because although estrogen therapy appeared to prevent the age-related increase in serum PTH levels, serum estradiol was weakly predictive of PTH in the untreated postmenopausal women. Indeed, our data suggest a possible dose-related effect of estrogen on serum PTH that requires additional study.

Our data also indicate that vitamin D status, as reflected by serum 25OHD levels, is a strong predictor of serum PTH regardless of menopausal status or estrogen therapy. Several previous studies have reported similar findings (8, 29), and these data reinforce suggestions (29) that adequate vitamin D intake is important in preventing secondary hyperparathyroidism.

Our findings with respect to the differences between serum PICP levels and the other two bone formation markers (serum osteocalcin and BAP) also suggest that postmenopausal women may have a defect in type I collagen synthesis. Similar findings have been reported by Ebeling et al. (30), who also noted that although serum osteocalcin and BAP levels were higher in postmenopausal compared to premenopausal women, PICP levels were not different between the two groups.

Finally, we found that residual estrogen levels, particularly serum estrone, were significant predictors of markers of bone resorption in postmenopausal women. This is consistent with previous observations by Slemenda et al., who reported that serum estrone levels correlate significantly with longitudinal changes in bone mineral density in postmenopausal women (31, 32). Cross-sectional studies (33) have also noted a significant association between bone mineral density and serum estrone levels in postmenopausal women, and our data suggest that these effects may be mediated in part by decreases in bone resorption.

In conclusion, our data suggest that estrogen deficiency is responsible not only for the increase in bone turnover in early postmenopausal women, but also indirectly for the secondary hyperparathyroidism and increase in bone turnover in late postmenopausal women. Thus, estrogen deficiency may play a permissive role in the pathogenesis of the age-related increases in serum PTH and bone turnover. Regardless of menopausal status, however, serum 25OHD levels are important predictors of serum PTH levels. Finally, these data also indicate that residual estrogen levels are important determinants of bone turnover in postmenopausal women.

	Acknowledgments

 
We thank Mrs. Carol McAlister for the biochemical analyses, and Mrs. Cindy Crowson for assistance with the data analyses.

	Footnotes

 
¹ This work was supported by Research Grant AR-27065 from the NIAMSD, USPHS.

Received October 1, 1996.

Revised December 27, 1996.

Accepted January 22, 1997.

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