correlates of bone mineral density in the postmenopausal estrogen/progestin interventions trial

JOURNAL OF BONE AND MINERAL RESEARCH Volume 9, Number 9, 1994 Mary Ann Liebert, Inc., Publishers

Correlates of Bone Mineral Density in the Postmenopausal EstrogerdProgestin Interventions Trial

ROBERT MARCUS,' GAIL GREENDALE.* BARBARA A. BLUNT.' TRUDY L. BUSH,4 SHERRY SHERMAN.' ROGER SHERWIN,6 HEINZ WAHNER,' and BRADLEY WELLS'

ABSTRACT

We assessed the cross-sectional relationship of age, menopausal years, body mass, previous estrogen use, and ethnic background to bone mineral status in a sample of 875 healthy postmenopausal women at the time they were recruited from the community to participate in a multicenter clinical trial. The women were 1-10 years postmenopause, 4- years of age, and had not received estrogen replacement therapy within 3 months of enrollment. Of the participants, 89% were white, 69% had a spontaneous menopause, and 53% had a history of previous estrogen replacement therapy. Bone mineral density (BMD) of the lumbar spine ( L M ) and proximal femur was measured by dual-energy x-ray absorptiometry. Results were consistent with a significant negative linear regression of BMD on age or years from menopause. Body mass index (BMI) correlated significantly with BMD at all sites (L 2 4 r = 0.28; femoral neck r = 0.34, p < 0.0oOl). BMD adjusted for age and BMI were higher at both sites in women who had taken estrogen versus those who had not (L2-4 0.976 2 0.009 versus 0.932 k 0.01; femoral neck 0.740 2 0.006 versus 0.708 2 0.008, p < 0.05). Adjusted BMD also increased with duration of ERT. Parity was negatively associated with L24 BMD (p = 0.03) but did not correlate significantly with BMD at the femoral neck. Black women had the highest L 2 4 BMD, and Hispanic women had the highest femoral neck BMD, even when results were adjusted for age and BMI. When data were corrected for differences in bone size, these interethnic differences were no longer significant. We conclude that increased body mass is positively correlated with BMD, and this may confer a degree of skeletal protection to heavier postmenopausal women. Exposure for 5 years to exogenous estrogen is associated with significantly increased age- and BMI-adjusted BMD.

INTRODUCTION BMD with greater precision than was heretofore possible.' To date, relatively few studies have used this technique to describe

ECENT PROSPEcrIVE STUDIES establish the capacity of bone the bone mineral status of normal men and women. One large R mineral density (BMD) measurements to predict fracture cross-sectional analysis of age-related changes in BMD of rates in populations." With the introduction o f dual-energy women has been reported, but the subjects in that study were all x-ray absorptiometry (DXA). it is now possible to estimate at least 65 years of age."

'Department of Medicine, Stanford University, Aging Study Unit, GRECC, Department of Veterans Affairs Medical Center, Palo Alto,

*Departments of Medicine and Obstetrics & Gynecology, University of California, Los Angeles School of Medicine. Los Angeles. California. 'Department of Community & Family Medicine, University of California at San Diego. La Jolla, California, 4Department of Epidemiology, Johns Hopkins University, Baltimore, Maryland. 'National Institute on Aging, Bethesda, Maryland. 'Department of Epidemiology & Preventive Medicine. University of Maryland School of Medicine, Baltimore, Maryland. 'Department of Diagnostic Radiology, Mayo Clinic, Rochester, Minnesota. 'PEP1 Coordinating Center, Department of Public Health Sciences. Bowman-Gray School of Medicine, Winston Salem, North Carolina.

California.

1467

1468 MARCUS ET AL.

The Postmenopausal EstrogedProgestin Interventions trial (PEPI) is a multicenter clinical trial of hormone replacement therapy in healthy postmenopausal women whose age ranges from 45-64 years. Details of the design, protocol, and recruitment strategy of PEPl have been reported.'' 1 2 ) Prim ary end points of the trial are four cardiovascular risk factors: high- density lipoprotein cholesterol, systolic blood pressure, 2 hour post glucose plasma insulin concentration, and plasma fibrino- gen level. As a secondary endpoint, BMD was measured at the lumbar spine and proximal femur at entry and these measurements are being repeated at I2 and 36 months. In this report of cross-sectional baseline results for the 873 normal women who underwent at least one bone density measurement, we describe the relationship of age, menopausal years, body mass index, ethnic background, and prior estrogen use to BMD at the spine and hip.

MATERIALS AND METHODS

Study design

This study is based upon the pretrial cross-sectional baseline data for a sample of 875 postmenopausal women who were recruited, screened, and randomized into one of five treatment groups for a 3 year multicenter, double-blind, placebo-con- trolled trial to test the effects of a placebo and four active treatment regimens on selected cardiovascular risk factors. No trial results are reported here. A complete description of PEP1 eligibility is reported elsewhere.'" but a summary description follows.

Eligibility and recruitment

Healthy postmenopausal women between 45 and 65 years of age were eligible to participate. They were recruited between September 1989 and December 1990 through seven clinical centers throughout the United States (PEPI clinical centers are listed in Acknowledgments). Most of these volunteers re- sponded to newspaper and television announcements and underwent a series of screening visits to determine eligibility for the trial. To be considered eligible, a woman with spontaneous menopause had to have had her last menstrual period at least I but less than 10 years before the first screening visit. Women who had undergone hysterectomy within 2 months of the first screening visit were excluded, but other hysterectomized women who met all other criteria were eligible to participate. Laboratory or clinical exclusion criteria included a circulating follicle-stimulating hormone level <40 IU/ml, suppressed thyroid-stimulating hormone level with a sensitive assay, severe anemia, extreme hyperlipidemia, marked obesity, and moderate hypertension. Women taking estrogen replacement were re- quired to discontinue medication for 3 months before enrolling. Women taking lipid-lowering drugs, anticoagulants, or gluco- corticosteroids or who had adjusted thyroid hormone dosage within 3 months were excluded. The following medical condi- tions or history were exclusionary: thrombembolism associated with estrogen use, history of melanoma, breast, or endometrial cancer, abnormal mammogram or endometrial hyperplasia at baseline, insulin-requiring diabetes mellitus, recent myocardial

infarction, cardiac arrhythmias or congestive heart failure, history of stroke or transient ischemic attack, any cancer except for nonmelanomatous skin cancer diagnosed less than 5 years before entry, history o f nontraumatic hip or spinal fracture, and severe menopausal symptoms. The PEP1 trial will continue through January 1994 and is in progress at the time of this writing.

Measurement of hone mineral

National Institutes of Health funds were provided to the coordinating center to purchase for each clinical center a dualenergy x-ray absorptiometer (QDR IOOO: Hologic, Inc., Waltham. MA). A comprehensive program of centrally coordi- nated instrument calibration, ongoing quality control, and scan review was established at the PEP1 bone density quality control center (BDQCC). In addition to regular Hologic calibration at installation, all instruments were also calibrated before begin- ning the study with a single PEP1 reference standard spine phantom with anatomically correct contour (Hologic, Inc.) to read BMD within 1 % . Calibration strategy for PEPl included annual circulation and rescanning of reference spine and hip phantoms (Hologic, Inc.) at every site. The average coefficient of variation over all clinics for phantom calibration during the period of baseline measurements was 0.46% for the spine and 0.58% for the total hip. Mean 4 standard deviation (SD) of the observed BMD values for the phantoms were I .0259 2 0.0048 g/cm2 at the spine and 0.7912 5 0.0046 g/cm2 for the hip. Additional quality control procedures at each center included scanning a Hologic spine phantom on each day a subject was scanned. For all sites, results from the daily quality control scans were reviewed at the BDQCC and have been uniformly within I % of the standard BMD value.

At the baseline visit, after the first scan was completed, the women stood up from the scanning table and moved freely for a brief period before resuming position for the repeat scan. Spine and hip scans were acquired with the subject supine. Degenera- tive disease, scoliosis. compressions, or other readily identifi- able morphologic abnormalities of the vertebrae were noted. Using the comparison feature of the analysis program, identical regions of interest (ROI) were used on the repeat scans. For the hip, ROI included total hip, femoral neck, Ward's triangle, trochanter, and intertrochanteric areas. Hard copy reports and diskettes including scan data were sent from each densitometry laboratory to the BDQCC. After review and, if necessary, reanalysis following predetermined guidelines at the BDQCC, diskettes and hard copies were sent to the PEP1 coordinating center at the Bowman-Gray School of Medicine, where results were entered into the database. Short-term in vivo estimates of the coefficients of variation for replicate baseline measurements ( I 3 ) were 1 . I % for the lumbar spine and 1.9% for the femoral neck.

Statistical and analytical methods

Replicate scans of both spine and proximal femur were available for 864 women, 2 women had no scans, 872 women had at least one spine scan, and 87 I had at least one femoral neck scan. The mean of replicate scan results at each region of interest or, when replicates were absent, the single-scan results were

CORRELATES OF BONE MINERAL DENSITY 1469

used as the BMD measurement at each ROI for a woman at baseline. When a region of interest was missing, for example. LA (6 women), the total spine result is based upon the two remaining regions, that is, L2-3. Women with nonuniform bone mineral distributions, as in scoliosis, were rarely encountered but were included within the standard ROI.

For this paper, bone mineral data are reported primarily as the conventional bone mineral density (g/cm2) that is. bone mineral content (BMC) within the scan area divided by the projected area A,, within the region of interest. The BMD measurement is more correctly called an areal density. Because bones of larger width and height tend also to be thicker and bone thickness is not factored into estimates of BMD, reliance on this parameter inherently overestimates the bone mineral density of tall people and underestimates the mineral density of short people. Carter et aI.(l4' described another parameter to express bone mineral data in a form that is less sensitive to differences in skeletal size than BMD. This parameter, called the bone mineral apparent density (BMAD). is equal to the BMC divided by estimates of bone volume that are also based upon the densitometry-derived projected area measurements, as follows. For the lumbar spine, BMAD = BMC/A,,'.', and for the femoral neck, BMAD = BMC/A,,2,(7.8' where A,, is equal to the projected area of the

R01."4.'s' To test for ethnic differences, these approximations were examined in addition to the usual BMD values.

Analysis of variance, analysis of covariance, and regression models were fit to the cross-sectional baseline data using SAS software.""' Regression coefficients as well as mean BMD values, unadjusted and/or adjusted, are reported for all women and for selected subgroups. A probability value a of 0.05 was taken arbitrarily as the level of significance to screen for strength of relationships or associations.

RESULTS

Some general characteristics of the study population are shown in Table I : 70% of the women were between SO and 60 years of age, the mean age is 56.1 years, and 89% of the subjects were white (of mainly European ancestry). Among the women who had undergone a spontaneous menopause (69% of the study population), 49% had experienced their final menstrual period less than 5 years before the baseline visit. Of the 274 women who had undergone hysterectomy, 155 (57%) had a simple hysterectomy and I 19 (43%) had removal of one or both ovaries. For women with spontaneous menopause, 16% were between 1 and 2 years of their last menstrual period, with approximately 10-12% of the group at each additional year until 8 years; only 2% were 10 years or longer from last menses. Of the entire sample 53% had taken estrogen at some time in the past. A more detailed description of the baseline characteristics of PEP1 participants has been reported.(12'

Bone mineral density by region of interest

Unadjusted BMD at the spine and proximal femur are given for all women in Table 2. All values were distributed in bell-shaped curves. The means differed significantly among clinical centers only for total hip (p = 0.0403) and intertrochanter (p = 0.01 14). Therefore, we did not adjust L2-4 or

TABLE I. MEAN 5 SD O R FREQUENCIFS (8) FOR SELECTED CHARACTERISTICS OF STUDY SAMPLE (875)

AT RANDOMIZATION

Age, years Age distribution, years

45-49 50-54 55-59 60-64

White Hispanic Black Asian Native American

Menopause status Spontaneous Surgical (and others)

Ethnic background

Hysterectomy alone One ovary removed Two ovaries removed

Time from last menses (spontaneous only)," years

1-1.9 2-2.9 3-3.9 4-4.9 5-5.9 6 4 . 9 7-7.9 8-8.9 9-9.9

10-10.7 Previous estrogen use

Yes. with progestin Yes, no progestin No

Weight, kg BMI, kg/m2

56.1 2 4.3

71 (8) 291 (33) 326 (37) 187 (21)

601 (69) 274 (31) 155 (18) 56 (6) 63 (7)

95 (15.9) 71 (11.9) 65 (10.9) 62 (10.4) 65 (10.9) 60 (10.0) 63 (10.5) 53 (8.8) 53 (8.8) 12 (2.0)

293 (33) 171 (20) 411 (47) 69.2 ? 12.7 26.0 5 4.5

T w o women with all bone density measurements missing are excluded.

femoral neck values for center in any analyses. Spine BMD was progressively higher from L2 to LA. Hip BMD was highest for the intertrochanteric region and lowest for Ward's triangle. The

TABLE 2. BMD (C/CM2) FOR LUMBAR SPINE AND PROXIMAL FEMUR BY REION OF INTEREST

~~ _______~ ~ ~ ____

Region of interest n Mean 2 SD

Lumbar spine L2 L3 LA L2-4

Proximal femur Total hip Femoral neck Trochanter Intertrcxhanter Ward's triangle

872 872 866 872

87 I 87 I 87 I 87 I 87 1

0.915 f 0. I53 0.966 f 0.158 1.013 2 0.174 0.%8 f 0.155

0.858 2 0.124 0.732 2 0. I I I 0.638 f 0.103 1.017 f 0.151 0.548 2 0. I I7

1470 MARCUS ET AL.

1.50

1.25

1-00

Ep

T 0*75 0.50

0.25

0.00 . 1

45 50 55 60 65

AGE FIG. 1. X age (p < 0.05). U,, and &, indicate upper and lower 95% confidence limits.

L2-4 BMD (g/cm2) by age for all women, n = 872. The regression equation for mean L2-4 BMD is I .38 - 0.0074

term "total hip" includes the femoral neck, intertrochanter, and trochanter as outlined on the computer screen. Individual regions of the hip correlated positively with each other ( r = 0.7% 0.90, p < O.OOO1). Lumbar spine BMD also correlated positively with hip BMD (r = 0.644.71 , p < O.OOO1). Because of their usual clinical application, we restrict the remainder of data presentation to the lumbar spine (L2-4) and the femoral neck unless otherwise noted.

Relationship of age and years since menopause to BMD

Age-associated declines in BMD were observed for each bone site. For L2-4, r = -0.21 and at the femoral neck, r = -0.18. Slopes were similar for women who underwent natural menopause and those reporting surgical menopause or hysterectomy, so BMD regressions on age at baseline for the femoral neck and spine are shown for all women (Figs. I and 2).

BMD also declined with years since menopause, and the slopes per menopausal year were steeper than observed per year of age. Although R2 values for menopausal years were generally higher than for chronologic age, determination of menopausal years could be made only for the women with natural menopause. Consequently, in most subsequent analyses BMD is corrected for the linear effect of age rather than menopausal years so that all women can be included.

To examine whether bone loss may be curvilinear with age or menopausal years, squared terms were added to the regressions

of BMD on age or on menopausal years. In each case these cross-sectional data were most consistent with a linear relationship.

Relationship c$ weight, height, and body mass index to BMD

Weight alone and height alone were both significantly (p = O.OOO1) correlated with BMDat both sites. For weight, the correlation with spine and femoral neck BMD was 0.32 and 0.41, respectively. For height, these correlations were 0.21 and 0.19, respectively. Body mass index [BMI = weight (kg)/ height (m')] alone was positively and more highly correlated than age alone with BMD at both sites (L2-4 r = 0.28; femoral neck r = 0.34, p < O.OOO1).

For all women, the linear regressions of spine and femoral neck BMD on BMI were highly significant, with positive slopes of 0.0096 and 0.0087 BMD units per unit increase in BMI, respectively. Overall, the quadratic effect of BMI was not significant. The linear interaction effect of age and BMI was significant for spine (p = 0.0337) but not for femoral neck. However, the contribution of the age-BMI interaction explained only 3.8% of the R2 value. Therefore, covariance adjustments for the simultaneous linear effects of age and BMI without the interaction were used in tests of differences among subgroups.

Relationship of history of estrogen exposure to BMD

Stratification of women by BMI quintile illustrates progressive rises in mean BMD at both the spine and hip with each


1.50

1.25

; 1.00 0 W

2 0.75 & 8 0.50 W Lr,

0.25

0.00 45 50 55 60 65

AGE FIG. 2. 1.07 - 0.0061 X age @ < 0.05). U,, and b5 indicate upper and lower 95% confidence limits.

Femoral neck BMD (g/cm2) by age for all women, n = 87 I . The regression equation for mean femoral neck BMD is

quintile. This increase is similar for those who reported use of estrogen replacement therapy (ERT) at menopause as well as for those who did not (Table 3). No significant difference in mean age or mean menopausal years was observed across BMI quintiles. Regression coefficients for age within BMI quintiles are shown in Table 4. These suggest an influence of BMI on the age-associated decrease in lumbar spine, but not femoral neck BMD. although the 10 regression coefficients did not differ significantly from the common coefficients for age (-0.007 for spine and -0.006 for femoral neck) in Figs. I and 2.

When the common slopes were used, the interaction between BMI quintile and ERT was also not significant. However, the main effects of ERT adjusted for the common linear effects of BMI and age were significant for both the spine and femoral neck in the age model (Table 5 ) for all women. For women with spontaneous menopause, estrogen use, adjusted for years beyond menopause and BMI, was not significant at the spine, but it was for the femoral neck (Table 5 ) .

BMD means at both the spine and femoral neck adjusted for age and BMI were higher in women who reported receiving

TABLE 3. BMD LEVELS (MEAN -t SD) FOR SPINE AND FEMORAL NECK BY BMI QUINTILE AND HISTORY OF ESTROGEN REPLACEMENT THERAPY

n Spine Femoral neck

No ERT (n = 409) 1 (16.9-22.3) 2 (22.4-24.0) 3 (24.1-26.2) 4 (26.3-29.7) 5 (29.8-39.7)

ERT ( n = 464) 1 (16.9-22.3) 2 (22.4-24.0) 3 (24.1-26.2) 4 (26.3-29.7) 5 (29.8-39.7)

70 77 81 87 94

104 98 94 88 80

0.917 2 0.152 0.918 f 0.141 0.924 f 0.147 0.984 f 0.147 1.044 f 0.146

0.928 ? 0.151 0.958 f 0.135 0.983 f 0.151 0.977 2 0.143 1.035 2 0.181

0.673 f 0.096 0.694 2 0.091 0.707 f 0. I I I 0.744 2 0.101 0.798 2 0.102

0.694 2 0.116 0.719 f 0.102 0.740 2 0.100 0.756 f 0. I I5 0.787 f 0.109

1472 MARCUS ET AL.

TABLE 4. COEFFICIENTS FOR THE REGRESSION OF UNADJUSTED BMD ON AGE FOR SPINE AND FEMORAL NECK

BY BMI QUINI-ILE A N D HISTORY OF ESTROGEN REPLACEMENT THERAPY

Spine" Femoral neck" BMI

quintile No ERT ERT N o ERT ERT

I -0.0091' -0.0083h -0.0082h -0.0056' 2 -0.0095' -0.0087" -0,0057' -0.0070' 3 -0.0106' -0.0057 -0.0106' -0.0052h 4 -0.0102' -0.0017 -0.0089' -0.0020 5 -0.0019 -0.0079h -0.0055h -0.0032

"As a group of 10, these were not significantly different from the respective overall regression coefficients for BMD on age for all quintiles and ERT groups combined, spine (p = 0.66) and femoral neck (p = 0.43).

hFor test of hypothesis that the coefficient = 0, 0.01 < p < 0.05.

'For test of hypothesis that the coefficient = 0, p < 0.01.

exogenous estrogen than in women who reported no estrogen (Table 6). Women who previously took either oral contraceptive (OC) medication or ERT alone, as well as those who took a combination of ERT and OC, had higher BMD levels. The adjusted means for ERT alone and for ERT + OC are very similar (Table 6).

To estimate the effect of duration of estrogen exposure, with or without OC, on BMD, two analyses were done; the first used estrogen replacement therapy as a continuous variable; the second divided exposure into five categories: never, < I year, 1-1.9 years, 2-4.9 years, and 2 5 years exposure. Results were similar, and we report data for the grouped exposures in Table 7. Significant overall effects of estrogen replacement duration were observed at both the spine and the femoral neck after adjustment for age and BMI. Adjusted duration group means are lowest for those with no exposure and, except for those reporting less than I year, increase steadily with each exposure group to a maximum at 5+ years (Table 7). Although these results suggest an exposure effect that increases in slope with duration, the quadratic effect of exposure in the continuous model (not shown) was not significant.

Ethnic differences in B M D

Although 89% of PEP1 participants were white, sufficient numbers of black, Hispanic, and Asian-American women provided baseline information to make some comparisons of ethnic differences in bone mass. Unadjusted mean BMD was highest at both the spine and hip in black women and was lowest for Asians (Table 8). Although BMD values for black women remained highest after adjustment for age and BMI, the relative position of spine values increased for Asian women. When BMD values were corrected for bone size (BMAD), black women maintained the highest values at the spine, but adjusted femoral neck BMAD was greatest for Asians (Table 8). Adjusting ethnic group mean BMD and BMAD values for years of estrogen use in addition to age and BMI gave essentially the same means.

B M D and other variables

A total of 599 women had experienced a spontaneous menopause, and 273 had undergone a hysterectomy before menopause. Overall, noconsistent interaction in rate of BMD decline was observed according to type of menopause, irrespective of menopausal use of estrogen.

Only 293 of the 464 women who t o o k estrogen also took a progestin. There was no significant effect of progestin after adjusting for age. BMI. and menopausal status, nor was there a significant interaction o f progestin by type of menopause (natural versus other). The mean BMD values at the spine adjusted for age and BMI for women with and without a history of progestin use were 0.984 and 0.968 glcm2 (p = 0.37); at the femoral neck the corresponding values were 0.743 and 0.730 glcm' (p = 0.24).

Age at first or last pregnancy was not significantly related to BMD at any site. Parity adjusted forage and BMI was negatively associated with BMD at the spine (JI = 0.03) but did not correlate significantly with BMD at the hip (p = 0.49). Specific relationships of BMD to diet. medication use. and lifestyle factors will be separately reported. However, to determine whether these variables might have confounded the results presented here, we estimated the combined effects of estrogen replacement history, age. and BMI o n BMD with no other variables in the model (reduced model) and then with the following variables included:.calcium intake, both dietary and

TABLE 5. ADJUSTED RE~~KESSION COEFFICIENTS A N D SIGNIFICANCE LEVE1.S FOR REGRESSION OF BMD ON THREE VARIABLES BY SITE

Spine Femoral neck

Model and variable Coeficient p Value Coefficient p Value

All women ( n = 872) Estrogen use (no or yes) -0.02 I3 0.0323 -0.0180 0.009 Age, years -0.0073 o.Oo01 -0.OO60 o.Oo01 BMI, kglm' 0.0096 O.OOO1 0.0087 o.Oo01

Women with spontaneous menopause (n = 598)

Estrogen use (no or ues) -0.0136 0.2467 -0.0179 0.0325 Years since menopause -0.0150 o.Oo01 -0.0109 o.Oo01 BMI. kg/m2 0.0102 O.Oo01 0.0093 O.~Xx)I

CORRELATES OF BONE MINERAL DENSITY I473

TABLE 6. BONE MINERAL DENSITY (G/CM2, MEAN ? SEM) ACCORDING TO PREVIOUS ESTRWEN EXPOSURE, ADJUSTED FOR AGE A N D BMI"

Previous estrogen n Spine ( L 2 4 ) Femoral neck

None I62 0.932 f 0.012 0.708 * 0.008 0.732 2 0.006 BCP only 247 0.973 ? 0.009

ERT only I83 0.980 ? 0.01 1 0.742 2 0.008 BCP + ERT 280 0.976 ? 0.009 0.740 2 0.006

"BCP, birth control pills; ERT. estrogen replacement therapy only; SEM. standard error of the mean. Significance levels for F test of hypothesis that BMD means are equal for all four estrogen use groups are as follows: spine, p = 0.007; femoral neck, p = 0.005.

supplemental, percentage of calories from ethanol, leisure time exercise, smoking status, and number of live births (adjusted model). Both the order of magnitude and the p values for the significance of the ERT, age, and BMI regression coefficients were essentially the same whether adjusted for these several additional variables or not. Generally, the R' for the adjusted regressions was increased by about 10% over the reduced model.

DISCUSSION

We report here the bone mineral status of a sample of about 873 healthy, primarily white, postmenopausal American women. These cross-sectional results permit an examination of the associations of age and body mass with BMD and confirm a positive association of exogenous estrogen use on bone mineral status. In addition, they provide BMD values at the lumbar spine and femoral neck for White. Hispanic, Black. and Asian ethnic groups, although the number of women is relatively small for each minority group.

The bone mineral data reported here are for a large sample of women aged 45-65 years who are 1-10 years postmenopause. They are the first sample from this age group described to date for whom the interactions of menopausal age, body habitus, prior estrogen exposure, and ethnicity have been systematically explored using dual-energy x-ray absorptiometry . The observed mean and standard deviations for BMD at the lumbar spine and proximal femur are similar to age-based normative data provided by the Hologic-Corp. and to reported series."'.'''

It is commonly accepted that the first several years after menopause are associated with accelerated bone loss that later diminishes to a stable annual loss of about I % . " y ~ 2 0 ' This understanding derives primarily from cross-sectional studies, although a few longitudinal reports ~ u p p o r t ' ~ ~ . ~ ~ ' or refute'23' this model. In this cross-sectional study, regressions of BMD versus age or years from last menses are best described as negative linear functions. Although we found no statistically significant curvilinear component in the regression model of menopausal bone loss from either the spine or hip, the sign of the coefficient in the menopausal years model was in the direction showing a diminution of the rate of loss with increasing years since menopause. Note that women who experienced natural menopause more than 10 years earlier were not eligible for PEPI; hence it is not possible to estimate BMD levels beyond 10 years. The regression coefficient for changes in femoral neck BMD with age, -0.006. is very similar to that reported for older women. -0.0056.'"' At the lumbar spine, however, the regression coefficient in the present study, -0.0074, is more than twice that in a large study of older women, -0.0027.'"' It is possible that bone loss from the lumbar spine is considerably greater during the years 45-64 than after 65 years. However, it is also likely that the BMD measurements in older women are confounded by such artifacts as degenerative joint disease or aortic calcifications that would tend to increase apparent BMD, thus minimizing the estimation of decreases in BMD with age. We recognize the limitations in making inferences regarding longitudinal changes from cross-sectional data. Moreover, the exclusion from this study of women still within the first year from last menses may have limited our ability to detect an early

TABLE 7. EFFECT OF ESTROGEN E X P ~ S ~ J R E DURATION ON BMD ADJUSTED FOR AGE AND BMI"

1-24 spine Femoral neck

Mean f SEM Mean f SEM Exposure years n BMD (glcm') n BMD (glcm')

0 409 0.957 ? 0.007 408 0.723 2 0.005 < I I I3 0.971 2 0.014 1 I4 0.738 2 0.009 1-1.9 96 0.963 f 0.015 96 0.726 ? 0.010 2-4.9 140 0.%9 2 0.012 140 0.742 f 0.009 5.0+ I I3 1.009 f 0.014 I12 0.755 ? 0.010

"Significance levels for F tests that the adjusted exposure year group means are equal are: spine, p = 0.0244; femoral neck, p = 0.031 I .

1474 MARCUS ET AL.

TABLE 8. ETHNIC DIFFERENCES IN BONE MINERAL DENSITY AND APPARENT DENSITY

Unadjusted a Adjusted for age and BMf'

Spine ( L 2 4 ) . Femoral neck, Spine (L2-#), Femoral neck, mean 2 SD mean f SD mean f SEM mean f SEM

BMD, g/cm2 White (n = 774) 0.968 f 0.155 0.727 2 0.109 0.971 2 0.005 0.730 f 0.004 Hispanic ( n = 47) 0.926 2 0. I30 0.753 2 0.106 0.911 2 0.021 0.741 2 0.015 Black ( n = 31) 1.053 2 0.173 0.828 2 0.123 1.004 f 0.027 0.788 2 0.019 Asian ( n = 16) 0.920 f 0.166 0.699 f 0.101 0.942 f 0.037 0.715 2 0.024

White (774) 0.145 f 0.023 0.147 IC_ 0.030 0.145 ? 0.001 0.148 f 0.001 Hispanic (47) 0.141 2 0.019 0.155 2 0.029 0.139 2 0.003 0.152 2 0.004 Black (31) 0.157 2 0.026 0.162 2 0.025 0. I50 f 0.004 0.156 f 0.005 Asian (16) 0.138 2 0.023 0.158 f 0.036 0.141 2 0.005 0.161 f 0.007

Wnadjusted BMD values: p = 0.0024 for spine and p = O.OOO1 for femoral neck (ANOVA). Unadjusted BMAD values:

bAdjusted BMD values: p = 0.0185 for spine and p = 0.0288 for femoral neck. Adjusted BMAD values: p = 0.1354 for spine

BMAD, g/cm3

p = 0.008 for spine andp = 0.01 19 for femoral neck.

and p = 0. I249 for femoral neck.

accelerated rate of bone loss. Subsequent follow-up examina- tions in PEP1 will permit a 3 year longitudinal analysis to be made.

These results confirm previous observations that body mass is positively associated with BMD in ~ o m e n . " . ~ ~ - ~ " Overall stratification of subjects by BMI shows a progressive rise in BMD at the spine and hip for each BMI quintile. In contrast to Dawson-Hughes et al. , '27) we observed very similar negative regression slopes for femoral neck BMD versus age in the no-ERT women in the highest and lowest BM1 quintiles. In a 2 year follow-up of their subjects, the Dawson-Hughes group found that higher body mass protects against loss of mineral from the spine, but not from the femoral neck."" Thus the femoral neck results of this cross-sectional study are consistent with the longitudinal data of Dawson-Hughes and colleagues. Although the emphasis of this cross-sectional analysis has been on age-related changes in BMD, it is certainly possible that higher BMD in heavier women to some degree reflects greater acquisition of bone mass at skeletal maturity. It is not certain whether the protective effects of body mass on BMD are caused by increased mechanical loading or increased circulating levels of endogenous estrogen,"2' or whether they differ for spine and hip.

The results support the conclusion that use of exogenous estrogen conserves BMD. Women who had taken estrogen replacement therapy had significantly higher mean BMD than those who had not, and this increase persisted after adjustments for age (or menopausal years) and BMI were made. Moreover, the degree of skeletal benefit appears to increase with duration of estrogen use. We found the highest adjusted BMD values in women who had taken estrogen for 5 years or more. In this regard, Weiss et al.'33' reported that 5 years of estrogen exposure was necessary to confer protection against hip and forearm fracture.

An apparent skeletal benefit was observed for women who had used oral contraceptives as well as for those who had taken estrogen after menopause. Because of their age, these women were likely to have been exposed to contraceptive estrogen doses

that were relatively higher than those used today. We therefore speculate that estrogen dose was an important contributor to this skeletal protection. As stated, we found no additional effect of progestins taken with replacement estrogen. However, the progestin most likely to have been taken, medroxyprogesterone acetate, is not androgenic and exerts only modest effects on bone turnover. The influence of contraceptive androgenic progestins on these results remains unknown, and without more specific knowledge about preparations or doses taken we cannot make any statement concerning them.

The possibility that differences in BMD may underlie observed variation in fracture experience among ethnic groups continues to be of great interest. For example, cross-sectional studies from North America and Africa report an increased bone mass of black compared with white women that persists even

contrast, although fracture rates are reported to be lower among Hispanic ~ o m e n , ' ~ ~ . ~ ~ ) BMD does not appear to differ substan- tially from that of non-Hispanic whites. Bauer et at.'" reported greater values at the hip of premenopausal Mexican-American women, but Benson et al.'4') and McCormick et al.(42) found no differences in cortical bone mass of adults or children, respectively. Most healthy older women in Japan have BMD values below the arbitrary "fracture threshold" proposed for white women, despite a 30-50% lower incidence of hip fra~ture.'~''

Although the numbers of minority women in PEP1 are small and statistical power to detect ethnic differences is therefore low, we found black women to have the highest BMD at the spine and femoral neck and Hispanic women to have higher BMD at the femoral neck than white or Asian women, even when results were adjusted for age and BMI. However, when the data were corrected for approximate differences in bone size by calculating BMAD, most interethnic differences in bone mineral no longer achieved statistical significance. This suggests that ethnic variation in BMD status may reflect bone size rather than volumetric mineral density. One suggestive result to emerge from this analysis was the observation that whereas femoral neck BMD was significantly lower in Asian women than in all other

when BMI, age, and other factors are ~ o n t r o l l e d . " ~ - ~ ~ ) B Y


groups, femoral neck BMAD was actually highest in Asians. The reported hip fracture incidence is relatively low in Asian women despite an apparent deficit in femoral bone mass.(44' The BMAD results for this small group of 17 Asian women suggest that this apparent deficit may be an artifact related to having smaller bones.

In summary, this analysis suggests that increased body mass and sustained exposure to replacement estrogen at menopause both confer skeletal protection to postmenopausal women. Although the results are most consistent with a linear model of menopausal bone loss, their cross-sectional nature does not permit firm conclusions in this regard. Finally, the results suggest that differences in bone mass among ethnic groups may reflect bone size rather than differences in volumetric mineral density.

ACKNOWLEDGMENTS

The Postmenopausal EstrogedProgestin Interventions trial is supported by cooperative agreement research grants (UOI -

UOI-HL40207, UOI-HL40231, U01-HL40232, and UOI- HL40273) from the National Heart. Lung, and Blood Institute; the National Institute of Child Health and Human Development; the National Institute of Arthritis and Musculoskeletal and Skin Diseases; the National Institute of Diabetes and Digestive and Kidney Diseases, and the National Institute on Aging. Packaged medications and placebos for PEP1 were provided by Wyeth- Ayerst Laboratories, Schering-Plough Research Institute, and the Upjohn Company. PEPI clinical centers are located at George Washington University, Washington, DC. Johns Hop- kins University, Baltimore, MD, Stanford University, Palo Alto, CA, University of California, Los Angeles, CA, Univer- sity of California, San Diego, CA. University of Iowa, Iowa City, IA, and University of Texas, San Antonio, TX. The PEPI coordinating center is located at the Bowman-Gray School of Medicine, Winston-Salem, NC. The bone density quality control center is located at the Department of Diagnostic Radiology, Mayo Clinic, Rochester, MN.

HL40154, UOI - H M I 85, UOI-HLA0195. UOI-HL40205,

REFERENCES

I .

2.

3.

4 .

5 .

Wasnich RD, Ross PD, Heilbrun LK, Vogel JM 1985 Prediction of postmenopausal fracture risk with use of bone mineral measurements. Am J Obstet Gynecol 153745-751. Hui SL. Slemenda CW, Johnston CC Jr. 1988 Age and bone mass as predictors of fracture in a prospective study. J Clin Invest 81 : 1804- 1809. Hui SL, Slemenda CW, Johnston CC Jr. 1989 Baseline measurement of bone mass predicts fracture in white women. Ann Intern Med I I I t355-36 I . Cummings SR. Black DM, Nevitt MC, Browner WS, Cauley JA, Genant HK, Mascioli SR. Scott JC. Seeley DG. Steiger P. Vogt TM. Study of Osteoporotic Fractures Research Group 1990 Appen- dicular bone density and age predict hip fracture in women. JAMA 263665468. Black DM, Cummings SR, Genant HK, Nevitt MC. Palermo L. Browner WS 1992 Axial and appendicular bone density predict fractures in older women. J Bone Miner Res 7:633-638.

6 . Melton U 111, Atkinson El, O'Fallon WM. Wahner HW. Riggs BL 1993 Long-tern fracture prediction by bone mineral assessed at different skeletal sites. J Bone Miner Res 8:1227-34.

7. Wahner HW. Dunn WL, Bronw ML, Morin RL, Riggs BL 1988 Comparison of dualenergy x-ray absorptiometry for bone mineral measurements of the lumbar spine. Mayo Clin Roc 63: 1075-1084.

8 . Steiger P, Cummings SR, Black DM. Spencer NE, Genant HK 1992 Age-related decrements in bone mineral density in women over65. J Bone Miner Res 7Zi25-632.

9 . Postmenopausal Estrogedhgestins lnterentions Trial Investiga- tors I993 The Postmenopausal Estrogedhgestins Interventions trial: The PEP1 recruitment experience. Cont Clin Trials (in

10. Postmenopausal Estrogenlhgestins lnterentions Trial Investiga- tors I993 The Postmenopausal Estrogedhgestins Interventions trial: Rationale. design and conduct. Cont Clin Trials (in press).

1 I . Postmenopausal Estrogedhgestins lnterentions Trial Investiga- tors 1993 The Postmenopausal EstrogenlProgestins Interventions trial: Laboratory methods. Cont Clin Trials (in press).

12. Postmenopausal Estrogenlhgestins lnterentions Trial Investiga- tors I993 The Postmenopausal EstrogedProgestins Interventions trial: Baseline results. Cont Clin Trials (in press).

13. Canner PL. Krol WF. Forman SA 1983 Internal quality control programs. Cont Clin Trials 4:441-466.

14. Carter DR. Bouxsein ML. Marcus R 1992 New approaches for interpreting projected bone densitometry data. J Bone Miner Res 7: 137-145.

15. Katzman DK, Bachrach LK, Carter DR, Marcus R 1991 Clinical and anthropometric correlates of bone mineral acquisitions in healthy adolescent girls. J Clin Endocrinol Metab 73: 1332-1339.

16. SAS Institute 1985 SAS User's Guide: Statistics, Version 5 . SAS Institute, Inc.. Cary, NC.

17. Strause L, Bracker M , Saltman P, Sartoris D, Kerr E 1989 A comparison of quantitative dualenergy radiographic absorptiometry and dual photon absorptiometry of the lumbar spine in postmenopausal women. Calcif Tiss Int 45:288-291.

18. Holbrook TL. Barren-Connor E. Klauber M, Sartoris D 1991 A population-based comparison of quantitative dualenergy x-ray absorptiometry and dual-photon absorptiometry of the spine and hip. Calcif Tissue Int 49:305-307.

19. Smith DM. Khairi MRA. Norton J, Johnston CC Jr. 1976 Age and activity effects on rate of bone mineral loss. J Clin Invest 58:74f- 721.

press).

20. Mazess RB 1982 On aging bone loss. Clin Orthop 165:239-252. 21. Hui SL. Wiske PS, Norton JA. Johnston CC Jr. 1982 A prospective

study of change in bone mass with age in postmenopausal women. J Chron Dis 3 5 7 I 5-725.

22. Harris S. Dallal GE, Dawson-Hughes B 1992 Influence of body weight on rates of change in bone density of the spine, hip, and radius in postmenopausal women. Calcif Tissue Int 50: 19-23.

23. Riggs BL, Wahner HW, Melton U 111, Richelson LS, Judd H, Offord KP 1986 Rates of bone loss in the appendicular and axial skeletons of women. Evidence of substantial vertebral bone loss before menopause. J Clin Invest 77:1487-1491.

24. Riggs BL, Wahner HW, Dunn WL, Mazess RB. Offord KP, Melton U 111 1981 Differential changes in bone mineral density of the appendicular and axial skeleton with aging. J Clin Invest 67:328-335.

25. Yano K , Wasnich RD, Vogel JM, Heilbrun LK 1984 Bone mineral measurements among middle-aged and elderly Japanese residents in Hawaii. Am J Epidemiol 119:751-764.

26. Nilas L, Gotfredsen A. Christiansen C 1986 Total and local bone mass before and after normalization for indices of bone and body size. Scand J Lab Invest 4653-57.

27. Dawson-Hughes B, Shipp C, Sadowski L, Dallal G 1987 Bone density of the radius, spine. and hip in relation to percent of ideal

1476 MARCUS ET AL.

body weight in postmenopausal women. Calcif Tiss Int 40:310- 314.

28. Bevier WC, Wiswell RA. Pyka G. Kozak KC, Newhall KM. Marcus R 1989 Relationship of body composition, muscle strength. and aerobic capacity to bone mineral density in older men and women. J Bone Miner Res 4:421-432.

29. Pocock N. Eisman J. Gwinn T. Sambrook P. Kelly P, Freund 1, Yeates M 1989 Muscle strength. physical fitness and weight but not age predict femoral neck bone mass. J Bone Miner Res 4:441-448.

30. Harris S, Dawson-Hughes B 1992 Rates of change in bone mineral density of the spine, heel, femoral neck and radius in healthy postmenopausal women. Bone Miner 17:87-95.

31. Nordin BEC, Need AG. Bridges A. Horowitz M 1992 Relative contributions of years since menopause, age. and weight to vertebral density in postmenopausal women. J Clin Endocrinol Metab

32. Longcope C. Pratt JH. Schneider SH. Fineberg S E 1987 Aromati- zation of androgens by muscle and adipose tissue in vivo. J Clin Endocrinol Metab 46:146-152.

33. Weiss NS, Ure CL. Ballard JH. Williams AR. Daling JR 1980 Decreased risk of fractures of the hip and lower forearm with postmenopausal use of estrogen. N Engl J Med 303:1195-1198.

34. Solomon L 1979 Bone density in ageing Caucasian and African populations. Lancet 2: 1326- 1330.

35. DeSimone DP. Stevens J , Edwards J. Shary J , Gordon L, Bell NH 1989 Influence of body habitus and race on bone mineral density of the midradius. hip. and spine in aging women. J Bone Miner Res 4827-830.

36. Meier DE, Luckey MM, Wallenstein S, Lapinski RH. Catherwood B I992 Racial differences in pre- and postmenopausal bone homeo- stasis: Association with bone density. J Bone Miner Res 7: I I8 I - 1189.

37. Ortiz 0. Russell M. Dalety TL, Baumgartner RN. Waki M. Lichtman S, Wang J , Pierson RJ. Heymsfield SJ 1992 Differences in skeletal muscle and bone mineral mass between black and white

74:20-23.

females and their relevance to estimates of body composition. Am J Clin Nutr 55:&13.

38. BauerRL. Diehl AK. BartonSA, BrenderJ, DeyoRA 1986Riskof postmenopausal hip fracture in Mexican American women. Am J Public Health 76: 1020-1021.

39. Silverman SL, Madison RE 1988 Decreased incidence of hip fracture in Hispanics, Asians, and blacks: California Hospital Discharge Data. Am J Public Health 78:1482-1483.

40. Bauer RL. Haffner SM 1992 Axial skeletal bone density in Mexican-American and nonhispanic white women. J Bone Miner Res (Suppl)’l:S 195.

4 I . Renson BW, Prihoda TJ, Glass BJ I99 I Variations in adult cortical bone mass as measured by a panoramic mandibular index. Oral Surg Oral Med Oral Pathol 71:349-356.

42. McCormick DP, Ponder SW. Fawcett HD. Palmer JL 1991 Spinal bone mineral density in 335 normal and obese children and adolescents: Evidence for ethnic and sex differences. J Bone Miner Res 6507-5 13.

43. Norimatsu H. Mori S. Uesato T. Yoshikawa T, Katsuyama N 1989 Bone mineral density of the spine and proximal femur in normal and osteoporotic subjects in Japan. Bone Miner 9 2 1 3-222.

44. Maggi S. Kelsey J , Litvak J , Heyse S P 1991 Incidence of hip fractures in the elderly: A cross-national analysis. Osteoporosis Int 1:232-241.

Address reprint requests to: Robert Marcus, M.D.

VA Medical Center 3801 Miranda Avenue

Palo Alto. CA 94304

GRECC 182-B

Received in original form October 18. 1993; in revised form January 25, 1994; accepted February 23, 1994.

correlates of bone mineral density in the postmenopausal estrogen/progestin interventions trial

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