Abstract
African-American women have a lower risk of fracture than Caucasian women, and this difference is only partially explained by differences in DXA areal bone mineral density (aBMD). Little is known about racial differences in skeletal microarchitecture and the consequences for bone strength. To evaluate potential factors underlying this racial difference in fracture rates, we used high-resolution peripheral quantitative computed tomography (HR-pQCT) to assess cortical and trabecular bone microarchitecture and estimate bone strength using micro-finite element analysis in African-American (n=100) and Caucasian (n=173) women participating in the Study of Women's Health Across the Nation (SWAN). African-American women had larger and denser bones than Caucasians, with greater total area, aBMD, and total volumetric BMD (vBMD) at the radius and tibia metaphysis (p<0.05 for all). African-Americans had greater trabecular vBMD at the radius, but higher cortical vBMD at the tibia. Cortical microarchitecture tended to show the most pronounced racial differences, with higher cortical area, thickness, and volumes in African-Americans at both skeletal sites (p<0.05 for all), and lower cortical porosity in African-Americans at the tibia (p<0.05). African-American women also had greater estimated bone stiffness and failure load at both the radius and tibia. Differences in skeletal microarchitecture and estimated stiffness and failure load persisted even after adjustment for DXA aBMD. The densitometric and microarchitectural predictors of failure load at the radius and tibia were the same in African-American and Caucasian women. In conclusion, differences in bone microarchitecture and density contribute to greater estimated bone strength in African-Americans and probably explain, at least in part, the lower fracture risk of African-American women.
Keywords: HR-pQCT, bone microarchitecture, microfinite element analysis, African-American, Caucasian
Introduction
Cross sectional and longitudinal cohort studies have consistently demonstrated that fracture risk is about 50% lower in African-American than in Caucasian women (1-3). The reasons for these differences are incompletely understood. Although areal bone mineral densities (BMD) of the lumbar spine and proximal femur, as measured by dual-energy X-ray absorptiometry (DXA), are higher in African-American women, differences in BMD account for less than half of the variation in fracture risk (4-9). In theory, differences in bone shape, cortical and trabecular microarchitecture, properties of the bone tissue, and non-skeletal factors such as the risk of falling, could contribute to this ethnic difference in fracture risk. Although bone strength is directly proportional to bone size, lumbar vertebral area and femoral neck area are both lower in African-American than in Caucasian women (5).
Until recently, microarchitectural characteristics of bone could only be assessed by histomorphometric analysis of bone biopsy specimens which, because of its invasive nature, is not suitable for widespread clinical assessment of fracture risk. Recently, however, non-invasive methods, such as high resolution peripheral quantitative computed tomography (HR-pQCT), have become available for assessing cortical and trabecular bone density and microarchitecture and their potential role in skeletal integrity. Because HR-pQCT measures volumetric rather than areal BMD, it avoids projection artifacts due to differences in bone size that are inherent to DXA(10-12). HR-pQCT can also be used to perform micro-finite element analysis (μFEA), a technique that incorporates geometric and material properties of bone into biomechanical measures that reflect whole bone strength (13,14). Cadaveric studies suggest that μFEA predicts femoral and vertebral strength better than areal BMD (15-17) while prospective case-cohort studies suggest that QCT-based FEA predicts fracture even after adjustment for areal BMD (18,19). In this study, we measured areal BMD of the spine, hip, and total body by DXA and assessed bone microarchitecture and estimated strength of the distal radius and tibia using HR-pQCT in 273 African-American or Caucasian women in order to (1) characterize racial differences in bone microarchitecture, volumetric density, and μFEA-derived measures of bone strength; (2) identify the microarchitectural predictors of estimated bone strength; and (3) determine whether these HR-pQCT derived parameters provide information independent of areal BMD and other clinical covariates that may help to explain the lower fracture rates in African-Americans.
Materials and Methods
Subjects and Eligibility Criteria
The Study of Women's Health Across the Nation is a seven-site, longitudinal cohort study in community-based samples of women. Women were initially recruited between 1996 and 1997 and were required to be 42-52 years old, have menstruated within the last 3 months, and belong to one of the site's predesigned race/ethnic groups. The Boston SWAN cohort initially used data from the annual census to provide a random sample of African-American and Caucasian women, the Boston site's pre-designated race/ethnic groups. Ethnicity was determined by subject self-identification. Initial eligibility criteria, cohort recruitment, and determination of menopause stage have been described previously in detail (20). Subjects have been followed prospectively for 15 years, with follow-up visits every 1-2 years. The current study was conducted at the Boston SWAN site during the 11th and 12th follow-up visits, at which time the women were 56-66 years old and 93% were postmenopausal. For the current study, women were excluded if they had a contraindication to DXA and/or HR-pQCT scanning, a history of solid organ transplant, or weight greater than 330 lbs (due to weight limits of the HR-pQCT equipment). The protocol was approved by the Partners Healthcare Institutional Review Board, and all women provided written informed consent.
Assessment of Clinical Covariates
Clinical factors, including age (years), cigarette smoking, alcohol intake (drinks per day), medical diagnoses, medication use, reproductive history, menopause stage, and physical activity were assessed at the concurrent visit using standardized interviewer-administered and self-administered questionnaires. History of fractures occurring after age 20 was obtained by self-report at the baseline SWAN visit, and subjects subsequently reported new fractures at each follow-up visit. For the present analysis, fractures of the hand, foot, and face were excluded. At the Boston SWAN site, all reported fractures occurring during the 15 year follow-up period were confirmed by X-ray or physician reports. Subjects also reported any use of osteoporosis medications (including all oral and IV bisphosphonates, selective estrogen receptor modulators, teriparatide, and calcitonin) at the baseline and all follow-up study visits.
Assessment of aBMD
Areal BMD of the lumbar spine in the posterior-anterior (PA) and lateral projections, total hip, femoral neck, and total body were measured by DXA (QDR4500A, Hologic Inc, Bedford, MA). The head was excluded from total body DXA measurements to avoid artifacts from metal jewelry and dental work. For lateral spine scans, C-arm was used to image L2-L4 vertebrae, and L4 was excluded if the pelvis overlaid the vertebral body. A standard quality control program was employed that included daily measurement of a Hologic DXA anthropomorphic spine phantom, visual review of every scan image by a local site investigator experienced in bone densitometry, and central review of a randomly-selected 5% of scans plus all problem scans by Synarc, Inc. (Newark, CA).
Assessment of volumetric BMD, bone microarchitecture, and bone strength
On the same day as their aBMD measurement, volumetric bone density and microarchitecture of the distal radius and tibia were assessed using HR-pQCT (Xtreme CT, Scanco Medical AG, Basserdorf, Switzerland) as previously described (10-12). Quality control was maintained with daily scanning of the manufacturer's phantom. All HR-pQCT scans were reviewed for motion artifact and were repeated if significant motion artifact was noted. Two radius scans and one tibia scan were excluded due to motion artifact on both the initial and the repeat scan. In addition, seven tibia scans could not be obtained due to size limitations or difficulty with limb positioning.
Using Scanco analysis software version V6.0, total bone area (mm2), total and trabecular volumetric bone density (total vBMD, Tb vBMD, mgHA/cm3), and trabecular number (Tb N, mm−1) were measured directly. Trabecular separation (Tb Sp, mm), trabecular thickness (Tb Th, mm), and trabecular distribution (Tb Sp SD, mm) were then calculated.
To characterize cortical microarchitecture, HR-pQCT images were processed by a semi-automated technique implemented in Scanco software (21-23). After image segmentation of cortical bone, the following measures were obtained: cortical bone volume (Ct BV, mm3), cortical volumetric bone mineral density (Ct vBMD, mgHA/cm3), cortical thickness (Ct Th, mm), cortical area (Ct Ar, mm2), trabecular area (Tb Ar, mm2), cortical porosity (Ct Po, %), and endocortical perimeter (mm).
Linear micro-finite element analysis (μFEA) of the entire bone was used to estimate radius and tibia metaphyseal biomechanical properties under uniaxial compression as previously described (24,25). Outcomes included stiffness (kN/m), failure load (kN), load fraction carried by the cortical and trabecular compartments at the proximal and distal regions of interest (%), and apparent modulus (E app, MPa).
Same-day reproducibility (with repositioning) for HR-pQCT measurements at the radius and tibia in our laboratory ranged from 0.2-1.4% for vBMD parameters; 0.3-8.6% for trabecular microarchitecture parameters; 0.6-2.4% for cortical microarchitecture parameters; 7.3-20.2% for cortical porosity measurements; and 2.1-3.0% for μFEA measures. These ranges are similar to previously published reports (10,22).
Statistical Analysis
Statistical analysis was performed using SAS 9.2 software (SAS Institute Inc., Cary, NC). Clinical characteristics of African-American and Caucasian women were compared using independent samples two-sided t-tests and/or chi-square tests. Primary outcomes were HR-pQCT-derived microarchitectural and volumetric density measures and μFEA results at the radius and tibia. Unadjusted differences in means of aBMD and HR-pQCT parameters between African-American and Caucasian women were examined by using independent samples two-sided t-tests. The group comparisons were then repeated using a multivariate linear regression model (PROC REG) while adjusting for clinical covariates known to affect bone health and those that were significantly different between groups by univariate analysis, including age, weight, current tobacco and alcohol use, current physical activity score, diabetes, and history of systemic use of hormone replacement therapy (HRT), osteoporosis medications (oral or intravenous bisphosphonates or raloxifene), and significant glucocorticoids (as defined by self report of glucocorticoid use >3 months at the baseline visit or report of use at ≥3 subsequent follow up visits). Additional analyses were performed to adjust for aBMD at the total hip in addition to all the aforementioned covariates with the purpose of determining whether HR-pQCT differences between racial groups persisted after adjusting for DXA BMD. Next, to determine microarchitectural predictors associated with failure load at the radius and tibia, we utilized a general linear model with multiple predictors. To account for colinearity in the predictor model, microarchitectural variables were grouped using oblique component variable cluster analysis (26), and, based on biomechanical relevance, one variable was chosen from each cluster to enter into the model. Race was also included to test whether the microarchitectural predictors were sufficient to explain racial differences in failure load. Lastly, sensitivity analysis was performed by repeating all unadjusted and multivariate-adjusted analyses after exclusion of 142 women with a history of one or more of the following conditions known to affect bone: previous systemic HRT use (n=94), previous bisphosphonate or selective estrogen receptor modulator use (n=26), current tamoxifen or aromatase inhibitor use (n=8), prior significant glucocorticoid use (n=31), hypercalcemia (n=2), hyperthyroidism (n=7), and anorexia nervosa (n=4); some subjects had more than one of the above conditions. Data are reported as mean ± standard deviation (SD) unless otherwise noted, and p values ≤0.05 are considered statistically significant.
Results
Cohort Characteristics
One hundred African-American women and 173 Caucasian women underwent HR-pQCT scanning of distal radius and tibia (Table 1). On average, they were 59.9 ± 2.7 years old, and 93% were postmenopausal at this time. Time since the final menstrual period, and history of glucocorticoid, osteoporosis medication, and hormone replacement therapy use were similar between racial groups. Caucasian women weighed less (76.4 ± 16.8 kg vs. 84.6 ± 19.1 kg, p<0.01) and were more likely to drink alcohol than African-American women (p<0.01). African-American women had a lower physical activity score (p<0.01) and were more likely to smoke (p=0.03) than Caucasian women. Medical comorbidities were generally similar between races, although diabetes was more prevalent in the African-American women (25% vs. 5.8%, p<0.01).
Table 1. Clinical characteristics of study cohort.
Values are presented as mean ± SD unless otherwise noted.
| Caucasian (n=173) | African-American (n=100) | p value | |
|---|---|---|---|
|
| |||
| Age (yr) | 60.0 ± 2.8 | 59.6 ± 2.6 | 0.21 |
| Weight (kg) | 76.4 ± 16.8 | 84.6 ± 19.1 | <0.01 |
| Height (cm) | 164.5 ± 5.9 | 163.7 ± 6.7 | 0.31 |
| BMI (kg/m2) | 28.2 ± 5.8 | 31.5 ± 6.5 | <0.01 |
| Physical Activity Score | 8.5 ± 1.8 | 7.7 ± 1.9 | <0.01 |
| Tobacco, n(%) | 16 (9.3) | 18 (18) | 0.03 |
| EtOH, n(%) | 19 (11.0) | 36 (36) | <0.01 |
| None | |||
| <2/day | 140 (75.1) | 63 (63) | |
| ≥2/day | 24 (13.9) | 1 (1) | |
| Current calcium supplement use, n (%) | 67 (39.6) | 28 (28.9) | 0.08 |
| Current vitamin D supplement use, n (%) | 74 (43.8) | 31 (32.0) | 0.06 |
| Current multivitamin use, n (%) | 71 (42.0) | 38 (39.1) | 0.65 |
| Significant glucocorticoid use, n (%) | 18 (10.4) | 13 (13) | 0.51 |
| Osteoporosis medication use, n (%) | 17 (9.8) | 9 (9) | 0.82 |
| Current aromatase inhibitor/tamoxifen use, n (%) | 6 (3.6) | 2 (2.1) | 0.51 |
| Diabetes, n (%) | 10 (5.8) | 25 (25) | <0.01 |
| Osteoporosis, n (%) | 19 (11.0) | 8 (8) | 0.43 |
| Breast cancer, n (%) | 10 (5.8) | 6 (6) | 0.94 |
| Hyperthyroidism, n (%) | 2 (1.2) | 5 (5) | 0.05 |
| Confirmed fracture, n (%) | 22 (12.7) | 9 (9) | 0.35 |
| Age Menarche (yr) | 12.6 ± 1.4 | 12.8 ± 2.1 | 0.30 |
| Menopause duration (month) | 92.0 ± 41.7 | 96.0 ± 43.2 | 0.46 |
| Systemic HRT use, n (%) | 62 (35.8) | 32 (32) | 0.52 |
Areal BMD
Areal BMD of the PA spine, lateral spine, total hip, femoral neck, and total body was significantly higher in African-American women than in Caucasians (p<0.01 for all, Table 2). After adjustment for all clinical covariates (see Methods), African-American women had higher total hip, femoral neck, and total body aBMD, but differences in PA and lateral spine aBMD were no longer statistically significant.
Table 2. BMD by DXA for Caucasian and African-American women.
Clinical covariate adjusted model included the following covariates: age, weight, any HRT use, history of osteoporosis medication use, prior significant glucocorticoid use, current tobacco and EtOH use, current physical activity score, and diabetes. Values are presented as mean ± SE unless otherwise noted. Bolded values indicate significantly better areal BMD than the other racial group.
| Unadjusted | Clinical Covariate Adjusted | |||||
|---|---|---|---|---|---|---|
|
| ||||||
| DXA aBMD | Caucasian | African-American | p value | Caucasian | African-American | p value |
|
| ||||||
| Total Body (g/cm2) | 1.077 ± 0.008 | 1.158 ± 0.013 | <.0001 | 1.088 ± 0.009 | 1.138 ± 0.012 | 0.002 |
| Total Hip (g/cm2) | 0.911 ± 0.010 | 1.006 ± 0.015 | <.0001 | 0.928 ± 0.010 | 0.976 ± 0.013 | 0.005 |
| Femoral Neck (g/cm2) | 0.761 ± 0.009 | 0.879 ± 0.014 | <.0001 | 0.775 ± 0.009 | 0.854 ± 0.012 | <.0001 |
| PA Spine (g/cm2) | 0.986 ± 0.013 | 1.065 ± 0.017 | 0.0002 | 1.004 ± 0.012 | 1.033 ± 0.016 | 0.184 |
| Lateral Spine (g/cm2) | 0.705 ± 0.009 | 0.747 ± 0.015 | 0.014 | 0.714 ± 0.010 | 0.728 ± 0.015 | 0.447 |
Volumetric BMD and microarchitecture
HR-pQCT images of the radius and tibia of a representative African-American subject and Caucasian subject are presented in Figure 1. In unadjusted analyses, all differences between African-American and Caucasian women favored improved skeletal characteristics in African-Americans (Table 3). Total vBMD and total cross-sectional area of the radius and tibia were significantly higher in African-Americans than Caucasians. Trabecular vBMD at the radius and cortical vBMD of the tibia were also significantly higher in African-Americans. Trabecular thickness, cortical area, cortical bone volume and cortical thickness were significantly greater in African-Americans at both the radius and the tibia, and cortical porosity was significantly lower at the tibia in African-American women.
Figure 1. HR-pQCT scans of the radius (left) and tibia (right) in a representative Caucasian subject (top) and African-American subject (bottom).
The thicker cortical and trabecular bone of the American-American subject is apparent at both the radius and the tibia.
Table 3. HR-pQCT measurements at the radius and tibia for Caucasian and African-American women.
Clinical covariate adjusted model included the following covariates: age, weight, any HRT use, history of osteoporosis medication use, prior significant glucocorticoid use, current tobacco and EtOH use, current physical activity score, and diabetes. An additional multivariate model including areal BMD of the total hip as a covariate is also shown. Values are presented as mean ± SE unless otherwise noted. Bolded values indicate significantly better skeletal characteristics than the other racial group.
| Unadjusted | Clinical Covariate Adjusted | aBMD and Clinical Covariate Adjusted | |||||||
|---|---|---|---|---|---|---|---|---|---|
|
| |||||||||
| RADIUS | Caucasian | African-American | p value | Caucasian | African-American | p value | Caucasian | African-American | p value |
|
| |||||||||
| Total Area (mm2) | 260.6 ± 3.6 | 272.7 ± 5.1 | 0.049 | 262.1 ± 3.8 | 270.1 ± 5.2 | 0.246 | 260.9 ± 3.8 | 272.3 ± 5.2 | 0.097 |
| Total vBMD (mgHA/cm3) | 300.1 ± 5.3 | 321.8 ± 7.1 | 0.014 | 303.2 ± 5.6 | 316.4 ± 7.6 | 0.185 | 308.5 ± 4.7 | 306.7 ± 6.4 | 0.830 |
| Tb vBMD mgHA/cm3) | 148.5 ± 2.9 | 159.5 ± 3.8 | 0.023 | 150.6 ± 3.0 | 155.9 ± 4.1 | 0.324 | 154.0 ± 2.4 | 149.9 ± 3.3 | 0.345 |
| Ct vBMD (mgHA/cm3) | 945.2 ± 4.6 | 952.3 ± 4.9 | 0.317 | 945.8 ± 4.5 | 951.1 ± 6.1 | 0.505 | 948.2 ± 4.3 | 946.5 ± 5.7 | 0.825 |
|
| |||||||||
| Tb Number (mm-1) | 1.85 ± 0.02 | 1.87 ± 0.03 | 0.624 | 1.88 ± 0.02 | 1.83 ± 0.03 | 0.311 | 1.90 ± 0.02 | 1.80 ± 0.03 | 0.012 |
| Tb Thickness (mm) | 0.066 ± 0.001 | 0.071 ± 0.001 | 0.002 | 0.066 ± 0.001 | 0.071 ± 0.001 | 0.009 | 0.067 ± 0.001 | 0.070 ± 0.001 | 0.146 |
| Tb Separation (mm) | 0.489 ± 0.008 | 0.485 ± 0.014 | 0.811 | 0.482 ± 0.009 | 0.497 ± 0.013 | 0.368 | 0.475 ± 0.008 | 0.511 ± 0.011 | 0.017 |
| Tb Distribution (μm) | 0.226 ± 0.007 | 0.216 ± 0.010 | 0.428 | 0.221 ± 0.007 | 0.224 ± 0.010 | 0.828 | 0.215 ± 0.007 | 0.234 ± 0.009 | 0.112 |
| Tb Area (mm2) | 209.5 ± 3.7 | 216.2 ± 5.2 | 0.291 | 210.4 ± 4.0 | 214.8 ± 5.4 | 0.539 | 208.7 ± 3.9 | 217.8 ± 5.3 | 0.201 |
|
| |||||||||
| Ct Area (mm2) | 53.79 ± 0.67 | 59.45 ± 1.01 | <.0001 | 54.53 ± 0.69 | 58.18 ± 0.94 | 0.003 | 54.93 ± 0.65 | 57.39 ± 0.89 | 0.037 |
| Ct Bone Volume (mm3) | 447.5 ± 6.2 | 498.6 ± 9.0 | <.0001 | 453.8 ± 6.3 | 487.7 ± 8.6 | 0.003 | 457.8 ± 5.9 | 479.9 ± 8.1 | 0.039 |
| Ct Thickness (mm) | 0.851 ± 0.014 | 0.9261 ± 0.019 | 0.001 | 0.858 ± 0.014 | 0.914 ± 0.020 | 0.032 | 0.867 ± 0.014 | 0.898 ± 0.019 | 0.208 |
| Ct Porosity (%) | 2.69 ± 0.13 | 2.42 ± 0.12 | 0.159 | 2.65 ± 0.12 | 2.49 ± 0.16 | 0.456 | 2.61 ± 0.12 | 2.57 ± 0.16 | 0.854 |
| Endocortical Perimeter (mm) | 66.47 ± 0.62 | 67.13 ± 0.87 | 0.525 | 66.61 ± 0.66 | 66.88 ± 0.89 | 0.815 | 66.33 ± 0.64 | 67.40 ± 0.88 | 0.354 |
|
| |||||||||
| TIBIA | |||||||||
|
| |||||||||
| Total Area (mm2) | 677.1 ± 8.5 | 713.6 ± 11.9 | 0.011 | 679.7 ± 8.7 | 709.0 ± 11.7 | 0.059 | 676.6 ± 8.6 | 713.8 ± 11.7 | 0.017 |
| Total vBMD (mgHA/cm3) | 274.0 ± 4.2 | 288.9 ± 5.8 | 0.036 | 278.6 ± 4.4 | 280.8 ± 6.0 | 0.778 | 282.4 ± 3.6 | 273.7 ± 4.9 | 0.181 |
| Tb vBMD mgHA/cm3) | 160.7 ± 2.8 | 165.4 ± 3.6 | 0.297 | 163.5 ± 2.8 | 160.5 ± 3.8 | 0.537 | 165.9 ± 2.4 | 156.2 ± 3.3 | 0.027 |
| Ct vBMD (mgHA/cm3) | 857.9 ± 5.4 | 891.2 ± 6.6 | 0.0002 | 863.4 ± 5.2 | 881.8 ± 7.1 | 0.049 | 866.5 ± 4.6 | 875.1 ± 6.3 | 0.306 |
|
| |||||||||
| Tb Number (mm-1) | 1.87 ± 0.03 | 1.85 ± 0.04 | 0.751 | 1.90 ± 0.03 | 1.80 ± 0.04 | 0.035 | 1.91 ± 0.02 | 1.78 ± 0.03 | 0.002 |
| Tb Thickness (mm) | 0.072 ± 0.001 | 0.075 ± 0.001 | 0.047 | 0.072 ± 0.001 | 0.075 ± 0.001 | 0.100 | 0.073 ± 0.001 | 0.074 ± 0.001 | 0.376 |
| Tb Separation (mm) | 0.481 ± 0.008 | 0.486 ± 0.011 | 0.787 | 0.474 ± 0.008 | 0.500 ± 0.011 | 0.075 | 0.469 ± 0.008 | 0.510 ± 0.010 | 0.004 |
| Tb Distribution (μm) | 0.237 ± 0.009 | 0.229 ± 0.009 | 0.557 | 0.233 ± 0.009 | 0.235 ± 0.012 | 0.894 | 0.228 ± 0.008 | 0.245 ± 0.011 | 0.250 |
| Tb Area (mm2) | 570.1 ± 8.7 | 597.7 ± 12.3 | 0.063 | 570.7 ± 9.1 | 596.7 ± 12.4 | 0.112 | 566.8 ± 8.9 | 602.9 ± 12.2 | 0.026 |
|
| |||||||||
| Ct Area (mm2) | 112.1 ± 1.2 | 121.0 ± 2.3 | 0.0002 | 114.3 ± 1.3 | 117.3 ± 1.8 | 0.210 | 115.0 ± 1.3 | 115.8 ± 1.7 | 0.702 |
| Ct Bone Volume (mm3) | 890.6 ± 11.2 | 978.4 ± 20.5 | <.0001 | 909.6 ± 12.0 | 945.4 ± 16.4 | 0.097 | 916.5 ± 11.1 | 931.1 ± 15.1 | 0.466 |
| Ct Thickness (mm) | 1.152 ± 0.016 | 1.234 ± 0.027 | 0.005 | 1.170 ± 0.018 | 1.203 ± 0.024 | 0.303 | 1.180 ± 0.017 | 1.183 ± 0.023 | 0.923 |
| Ct Porosity (%) | 7.58 ± 0.23 | 6.47 ± 0.27 | 0.003 | 7.42 ± 0.22 | 6.74 ± 0.31 | 0.094 | 7.33 ± 0.21 | 6.95 ± 0.29 | 0.319 |
| Endocortical Perimeter (mm) | 98.8 ± 0.8 | 100.6 ± 1.0 | 0.156 | 98.9 ± 0.8 | 100.4 ± 1.1 | 0.292 | 98.6 ± 0.8 | 101.0 ± 1.1 | 0.112 |
After adjustment for clinical covariates, differences in vBMD were largely eliminated, except for higher cortical vBMD at the tibia in African-American women. Cortical area, cortical bone volume, and cortical thickness also remained statistically higher in African-Americans after covariate adjustment at the radius, although these latter cortical differences did not persist at the tibia. After adjustment for clinical covariates, the African-Americans' trabecular thickness remained significantly greater than Caucasians' at the radius, but at the tibia their trabecular number unexpectedly was significantly lower than Caucasians'.
Further adjustment for femoral aBMD in addition to clinical covariates led to greater total cross-sectional area for African-Americans at the tibia. Cortical area and cortical bone volume remained significantly higher at the radius for African-Americans. However, adjustment for aBMD led to surprising improvements in trabecular parameters among Caucasian women, including statistically higher trabecular number and decreased trabecular spacing at the radius and tibia along with higher trabecular vBMD at the tibia as compared with African-American women.
Finite Element Analysis
Estimated bone stiffness and failure load, derived from μFEA, were significantly greater in African-Americans than in Caucasians at both the radius and the tibia, and these differences remained significant after adjustment for clinical covariates and for areal BMD (Figure 2). E App, an index of resistance to compressive forces independent of bone geometry, was also greater in African-Americans in unadjusted analyses, although this difference did not persist after adjustment for clinical covariates and areal BMD (data not shown). The percentage of load carried by cortical and trabecular bone at proximal and distal sites did not differ between races at either the radius or the tibia (data not shown).
Figure 2. Mean ± SE of unadjusted and multiple covariate adjusted stiffness and failure load at the radius and tibia for Caucasian and African-American women.
Multiple covariate adjusted model included the following covariates: age, weight, any HRT use, history of osteoporosis medication use, prior significant glucocorticoid use, current tobacco and EtOH use, current physical activity score, diabetes, and DXA total hip aBMD. * indicates p<0.05 versus Caucasians.
Predictors of Failure Load
HR-pQCT-derived microarchitectural and BMD variables were grouped using cluster analysis into the following six categories: total cross-sectional area and perimeter; trabecular microarchitecture; cortical area and volume; cortical pore characteristics; trabecular volumetric density; and cortical volumetric density. Based on a priori assumed biomechanical relevance, one variable from each cluster was chosen to be incorporated into the multivariate model for predictors of the μFEA-estimated failure load at the radius and tibia. All women were pooled into this single analysis. The strongest predictors of estimated failure load at the radius and tibia were total cross-sectional area, trabecular vBMD, cortical thickness, and to a lesser extent trabecular number (Table 4). Cortical porosity was a modest predictor of failure load at the tibia but not at the radius. Cortical vBMD was not a predictor of failure load at either site. Altogether, these predictors explained 88% and 90% of the variation in μFEA-estimated failure load at the radius and tibia, respectively. Race was not a predictor of failure load independent of these variables (p=0.21 and 0.12 at the radius and tibia, respectively).
Table 4. Multiple covariate adjusted standardized effects of the predictors of mean failure load at the radius and tibia.
Standardized effects provide the relative importance of the predictor to the mean failure load.
| Predictor | Radius | Tibia | ||
|---|---|---|---|---|
|
| ||||
| Standardized Effect | p value | Standardized Effect | p value | |
|
| ||||
| Total cross-sectional area | 0.647 | <.0001 | 0.671 | <.0001 |
| Tb vBMD | 0.829 | <.0001 | 0.778 | <.0001 |
| Tb Number | -0.262 | <.0001 | -0.213 | <.0001 |
| Ct Thickness | 0.504 | <.0001 | 0.535 | <.0001 |
| Ct Porosity | -0.044 | 0.269 | -0.119 | 0.017 |
| Ct vBMD | 0.096 | 0.057 | 0.074 | 0.211 |
| Race | 0.029 | 0.212 | 0.034 | 0.115 |
Sensitivity analysis
All analyses were repeated after excluding subjects with a history of glucocorticoid use, osteoporosis medication use, systemic hormone replacement therapy use, current aromatase inhibitor or tamoxifen use, hypercalcemia, hyperthyroidism, and/or anorexia nervosa. Results of unadjusted and multiple covariate-adjusted comparisons of African-Americans and Caucasians were similar in this subset (n=131) to results obtained from the entire cohort (data not shown).
Discussion
In this study, we found that African-American women had more favorable values for a variety of cortical and trabecular bone densitometric and microarchitectural indices, resulting in higher estimated bone strength that persisted even after adjustment for clinical covariates and aBMD. Total volumetric BMD was higher in African-Americans than in Caucasians at both the radius and the tibia in unadjusted analyses. In the radius, this difference was largely due to higher trabecular vBMD, while in the tibia the difference was largely due to higher cortical vBMD in the African-American women. In general, the differences in bone microarchitecture between African-Americans and Caucasians tended to be more pronounced in measures of cortical than trabecular bone. Adjustment for weight and other covariates attenuated racial differences to a greater extent in the tibia than in the radius, suggesting that the etiology of the racial differences in bone microarchitecture is different in weight-bearing versus non-weight bearing bone. Predictors of failure load were the same in Caucasians and African-Americans, suggesting that advantages in these parameters in African-Americans lead to their greater estimated bone strength.
To our knowledge, this is the first study to report differences between postmenopausal Caucasian and African-American women in bone microarchitecture and predicted strength using HR-pQCT. In unadjusted analyses, African-American women had larger and denser bones, greater trabecular and cortical thickness, and greater cortical bone volume at both the radius and the tibia. Cortical porosity was also lower in the tibia of African-Americans. These results are similar to several small studies that used bone histomorphometry in predominantly younger women to show that African-Americans have higher cortical and trabecular thickness than Caucasians (27-29), although not all histomorphometric studies have been consistent (30). Although DXA-measured lumbar vertebral area and femoral neck area are lower in African-American women than in Caucasian women (5), studies using QCT have reported densitometric and geometric advantages in African-Americans compared to Caucasians, primarily within cortical bone at the femur (31-33). These skeletal advantages are also apparent in studies of African-American children utilizing pQCT (34,35). However, all these QCT and pQCT studies were limited by larger voxel size, which made them unable to distinguish microarchitectural features of bone.
HR-pQCT can detect variation in bone microarchitecture that may account for well-known racial/ethnic differences in fracture rates. For example, in comparison to Caucasians, Chinese-American women have smaller bones but higher cortical vBMD and better trabecular bone microarchitecture (36,37), findings that are consistent with their lower fracture rate. In contrast, our findings in African-American and Caucasian women suggest that differences in bone size, as well as cortical density and cortical microarchitecture, likely explain the lower fracture risk of African-American women. Longitudinal observations are needed to substantiate this hypothesis.
The factors that account for differences in bone microarchitecture between African-Americans and Caucasians are not well-characterized. In our cohort, physical activity levels were lower and tobacco use and rates of diabetes and hyperthyroidism were higher in African-Americans. However, these characteristics are generally associated with greater skeletal fragility, and therefore cannot explain the improved microarchitectural and densitometric characteristics observed in African-Americans. We performed multivariate adjustment to explore clinical factors (including weight) that might explain the skeletal differences observed between African-Americans and Caucasians. This eliminated many of the racial differences in bone microarchitecture at the weight-bearing tibia, but not at the non-weight-bearing radius, consistent with the hypothesis that the higher average body mass of African-Americans may contribute to their improved skeletal characteristics at skeletal sites exposed to mechanical loading.
Many studies, including ours, have demonstrated that African-American women have higher DXA-measured aBMD than other ethnic groups (4-9). However, higher aBMD does not entirely account for the reduction in fracture risk seen in African-American women. For example, Cauley et al found that the relative risk of fracture was lower in African-Americans even after adjustment for aBMD and other risk factors (4). Therefore, to explore racial differences in bone microarchitecture and volumetric density independent of aBMD, we performed additional analyses while including aBMD in the multivariate adjustment model. We found that cortical area and cortical bone volume at the radius, as well as total cross-sectional area and trabecular area at the tibia remained significantly higher in African-Americans even after adjustment for aBMD. In contrast to findings on the unadjusted analyses, adjustment for aBMD led to Caucasians having more favorable trabecular microarchitecture, including increased trabecular number and decreased trabecular separation at the radius and tibia and higher trabecular vBMD at the tibia, as compared with African-Americans. Despite this improved trabecular micoarchitecture in Caucasian women, estimated bone stiffness and failure load remained significantly greater in African-Americans after multivariate adjustments that included aBMD. The finding that estimated bone strength remains higher in African-American women despite inferior features of trabecular micro-architecture suggests that the favorable cortical bone characteristics of African-American women have a greater impact on whole bone strength than the potential advantages of trabecular bone microarchitecture observed in Caucasian women.
Finally, to determine the contribution of individual bone microarchitectural characteristics to whole bone strength, we assessed the microarchitectural predictors of failure load, as estimated by μFEA, at the radius and tibia. We found that total cross-sectional area, trabecular vBMD, and cortical thickness were the strongest HR-pQCT-derived predictors of failure load at both the radius and tibia, with cortical porosity also associated with failure load at the tibia. These HR-pQCT-derived predictors of bone strength are similar to those identified in other populations including healthy postmenopausal women, young female athletes, and non-athletes (38,39). Importantly, the predictors of failure load at the radius and tibia were the same in African-American and Caucasian women. Because African-Americans tended to have superior values for each of these predictors compared to Caucasians in unadjusted analyses, advantages in these bone microarchitectural and densitometric characteristics explain their greater predicted bone strength and likely contribute to their reduced fracture risk.
Our study has several important strengths, including the relatively large sample size, the detailed clinical information regarding factors affecting skeletal health, and the use of a high-resolution non-invasive imaging technique to assess bone microarchitecture and estimate bone strength via finite element analysis. In addition, inter-observer variability was minimized by utilizing a single operator for all HR-pQCT analyses. Our study also has several limitations. Although SWAN was designed to study women across the menopausal transition, nearly all women were already postmenopausal by the time we obtained measurements using HR-pQCT. Thus, our cross-sectional design cannot capture the dynamic changes that occur in the skeleton during the menopause transition, nor can we make inferences about skeletal status in premenopausal Caucasian and African-American women. Because women in our primary analysis were not excluded on the basis of medical conditions and medications known to affect bone, it is possible that these factors may affect the results despite our multivariate adjustments for them. However, results were similar in sensitivity analyses where all women with bone-modifying disorders or taking bone-active medications were excluded. Finally, the HR-pQCT measurements were obtained at the peripheral skeleton only, and further studies are needed to determine whether the racial differences observed here are representative of other skeletal sites.
In summary, African-American women have structurally advantageous differences in bone density and microarchitecture compared with Caucasian women, some of which remained significant after multivariate adjustment including aBMD. Differences in bone microarchitecture and density explain most of the variation in μFEA-predicted failure load and likely account for the lower fracture risk observed in African-American women.
Acknowledgments
The Study of Women's Health Across the Nation (SWAN) has grant support from the National Institutes of Health (NIH), DHHS, through the National Institute on Aging (NIA), the National Institute of Nursing Research (NINR) and the NIH Office of Research on Women's Health (ORWH) (Grants NR004061; AG012505, AG012535, AG012531, AG012539, AG012546, AG012553, AG012554, AG012495). The HR-pQCT measurements were made possible by an NCRR Shared Equipment Grant (1S10RR023405-01). The content of this manuscript is solely the responsibility of the authors and does not necessarily represent the official views of the NIA, NINR, ORWH or the NIH.
Footnotes
Disclosures: All authors state that they have no conflicts of interest.
Authors Roles: Study conduct and data collection: APT, ES, ECT, JSF, RN. Data analysis: EWY, HL, MSP. Data interpretation: MSP, EWY, JSF, MLB, RN. Drafting manuscript: MSP, EWY, JSF. Revising manuscript content: JSF, MLB, RN. Approving final manuscript: all authors. MSP and EWY take responsibility for the integrity of the data analysis.
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