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Keywords:

  • HIP FRACTURE;
  • BONE MINERAL DENSITY;
  • OSTEOPOROSIS;
  • QUANTITATIVE COMPUTED TOMOGRAPHY

Abstract

  1. Top of page
  2. Abstract
  3. Introduction
  4. Subjects and Methods
  5. Results
  6. Discussion
  7. Disclosures
  8. Acknowledgements
  9. References
  10. Supporting Information

This prospective case-cohort study aimed to map the distribution of bone density in the proximal femur and examine its association with hip fracture. We analyzed baseline quantitative computed tomography (QCT) scans in 250 men aged 65 years or older, which comprised a randomly-selected subcohort of 210 men and 40 cases of first hip fracture during a mean follow-up period of 5.5 years. We quantified cortical, trabecular, and integral volumetric bone mineral density (vBMD), and cortical thickness (CtTh) in four quadrants of cross-sections along the length of the femoral neck (FN), intertrochanter (IT), and trochanter (TR). In most quadrants, vBMDs and CtTh were significantly (p < 0.05) lower in cases compared to the subcohort and these deficits were present across the entire proximal femur. To examine the association of QCT measurements with hip fracture, we merged the two quadrants in the medial and lateral aspects of the FN, IT, and TR. At most sites, QCT measurements were associated significantly (p < 0.001) with hip fracture, the hazard ratio (HR) adjusted for age, body mass index (BMI), and clinical site for a 1-SD decrease ranged between 2.28 (95% confidence interval [CI], 1.44–3.63) to 6.91 (95% CI, 3.11–15.53). After additional adjustment for total hip (TH) areal BMD (aBMD), trabecular vBMDs at the FN, TR, and TH were still associated with hip fracture significantly (p < 0.001), the HRs ranged from 3.21 (95% CI, 1.65–6.24) for the superolateral FN to 6.20 (95% CI, 2.71–14.18) for medial TR. QCT measurements alone or in combination did not predict fracture significantly (p > 0.05) better than TH aBMD. With an area under the receiver operating characteristic curve (AUC) of 0.901 (95% CI, 0.852–0.950), the regression model combining TH aBMD, age, and trabecular vBMD predicted hip fracture significantly (p < 0.05) better than TH aBMD alone or TH aBMD plus age. These findings confirm that both cortical and trabecular bone contribute to hip fracture risk and highlight trabecular vBMD at the FN and TR as an independent risk factor. © 2012 American Society for Bone and Mineral Research.


Introduction

  1. Top of page
  2. Abstract
  3. Introduction
  4. Subjects and Methods
  5. Results
  6. Discussion
  7. Disclosures
  8. Acknowledgements
  9. References
  10. Supporting Information

The mechanical competence of bone is determined by its size and shape, and by the spatial distribution, organization, and intrinsic properties of the bone tissue.1–3 Areal bone mineral density (aBMD) measured by dual-energy X-ray absorptiometry (DXA) explains 50% to 80% of the mechanical strength of bone in vitro4–6 and is strongly associated with clinical fractures,7, 8 but it does not reflect the three-dimensional distribution of bone mass, cortical and trabecular microarchitecture, and intrinsic properties of the bone matrix. Quantitative computed tomography (QCT), on the other hand, measures cortical volumetric BMD (vBMD), trabecular vBMD, bone volume, cross-sectional area, and cortical thickness.5, 9–13 For these reasons, QCT has become an important clinical research tool that has been used to examine age-related changes,10, 11, 14–16 effects of drug therapy,17–19 mechanical unloading in the proximal femur,20 and association of femoral bone structure and strength with hip fracture.4, 21–27 In most such QCT studies, cortical, trabecular, and integral vBMD was measured in the whole femoral neck (FN), intertrochanter (IT), trochanter (TR), and total hip (TH). Other structural measures, such as moment of inertia, cortical thickness, and buckling ratio have also been estimated in certain but not all cross-sections of the FN, TR, and femoral shaft. Age-related bone loss has been found to be predominately on the superior aspect of the FN,10, 11, 28 and patients with fractured neck of femur have thinner cortex than those without fracture, particularly on the inferior aspect of the FN.29, 30 It is unclear whether there are such differences in other regions of the proximal femur.

The purpose of this study was to map the distribution of bone density in the proximal femur of older men and examine its association with hip fracture.

Subjects and Methods

  1. Top of page
  2. Abstract
  3. Introduction
  4. Subjects and Methods
  5. Results
  6. Discussion
  7. Disclosures
  8. Acknowledgements
  9. References
  10. Supporting Information

Study population and cohort selection

The Osteoporotic Fractures in Men (MrOS) study enrolled 5995 men from six U.S. cities, from March 2000 through April 2002, as described.31 Eligible participants were ≥65 years of age, able to walk without assistance, and had not had bilateral hip replacement surgery. At baseline, participants had aBMD measured at the hip by DXA (QDR 4500W; Hologic Inc., Bedford, MA, USA) and measurements of weight and height. A subset of 3633 participants (61% of the MrOS cohort) also had QCT of the hip at baseline. Questionnaires were mailed to participants every 4 months to obtain information about recent fractures. Reported hip fractures were validated by physician review of the radiology report or radiographs.

For this analysis we adopted a case-cohort design.32 Using a random selection procedure we selected 225 men from the 3663 participants with QCT to form the subcohort of the case-cohort. Forty-one incident hip fractures occurred as of February 2007 (average follow-up of 5.5 years) in men with available baseline QCT and four were in the subcohort. Sixteen participants were excluded from the analysis due to poor image quality, leaving 250 in the final analysis (210 no fracture, 40 cases).

QCT

The acquisition of QCT scans has been described.14 Briefly, participants were positioned supine and the pelvic region was scanned from just above the femoral head to 3.5 cm below the lesser trochanter. During scanning, a density calibration phantom (Image Analysis, Columbia, KY, USA) was placed beneath the patient between the hips. Scan parameters were 3-mm section thickness, 80 kVp, 280 mA, and 512 × 512 matrix in spiral reconstruction, with an in-plane pixel size of 0.94 mm. The CT images were archived to Digital Imaging and Communications in Medicine (DICOM) CD-ROM for further analysis.

Three-dimensional structural analysis of the hip

We analyzed the left hip scans, and researchers (AB, LY) who performed the analysis were blinded to who had incident hip fracture. As an post hoc analysis we also analyzed 37 out of 40 right hips of men with incident hip fracture (three right hips, all on the nonfractured side, were partly out of the QCT field of view) and compared the fractured side (n = 40) with the unfractured side (n = 37) for men with incident hip fracture.

We developed a suite of Matlab programs (The Mathworks Inc., Natick, MA, USA) to analyze the QCT scans; this has been described.13, 33 The Hounsfield Unit of each voxel was converted to mineral density using the density calibration phantom. The outer contours of the proximal femur were determined slice-by-slice using an interactive program that combines density-thresholding at 100 mg/cm3, morphological operation, and manual tracing. From this point onward, all image processing and calculations were performed automatically. The FN and shaft axes were identified and the femora were digitally rotated to a standard orientation using nearest interpolation so that the FN and shaft axes were in the frontal plane. A series of cross-sections were defined from proximal to distal and perpendicular to the FN axis in the FN, and perpendicular to the femoral shaft axis in the IT and TR. The cross-sectional images were enlarged by four times using bilinear interpolation. The cross-sections were further divided into four quadrants, namely the inferoanterior (IA), superoanterior (SA), superoposterior (SP), and inferoposterior (IP) quadrants for the FN and medioanterior (MA), lateroanterior (LA), lateroposterior (LP), and medioposterior (MP) quadrants for the IT and TR (Fig. 1). The quadrant origin was at the geometrical centre of the cross-section except for the cross-sections in the IT, where the origin was defined by the femoral shaft axis. The IT cross-sections were not complete medially because they were bounded by the femoral neck. A 22-degree rotation of the axes of the FN cross-sections was introduced to account for the incident angle of the femoral anterior surface at stance phase.34 A 15-degree external rotation of the axes of the trochanter cross-sections was introduced to account for the FN anteversion (clockwise rotation in Fig. 1C and D). To define cortical bone in each cross-section, we developed and validated a method specifically for clinical hip QCT scans with an in-plane pixel resolution of about 1 mm33 (see Supporting Information for details; Table S1, Fig. S1). A threshold of 100 mg/cm3 was used to identify trabecular bone and exclude marrow. For each quadrant of each cross-section we calculated cortical, trabecular, and integral bone mineral content, bone volume, vBMD, and cortical thickness as described.13, 33 We used these cross-sectional data by quadrants to investigate density distribution. To account for differences in the number of cross-sections for different men, we normalized the measurements by interpolating each measurement linearly along the FN, IT, and TR, and obtained values at 2% length intervals from the proximal to distal.

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Figure 1. (A) Regions of interest for analysis of volumetric BMD and cortical thickness in the proximal femur. (B) Quadrants of cross-sections in the femoral neck. (C) Quadrants of cross-sections in the intertrochanter. Notice that the cross-sections are not complete medially because it is bounded by the femoral neck. (D) Quadrants of cross-section in the trochanter: the left image shows a cross-section in the proximal trochanter and the right image a cross-section at the lesser trochanter. The black lines inside the bone cross-sections separate cortical and trabecular bone. IA = inferoanterior; IP = inferoposterior; SA = superoanterior; SP = superoposterior. MA = medioanterior; LA = lateroanterior; MP = medioposterior.

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To determine the association between QCT measurements and hip fracture, we calculated cortical, trabecular, and integral vBMDs and averaged cortical thickness for the inferomedial (inferoanterior plus inferoposterior) and superolateral (superoanterior plus superoposterior) halves of the FN, and medial (medioanterior plus medioposterior) and lateral (lateroanterior plus lateroposterior) halves of the IT and TR. The justification for this was the apparent differences in loading conditions and cortical bone distribution: the medial side of the femur is mainly in tension in a sideways fall and has a thicker cortex, whereas the lateral side is in compression and the cortex is thinner.10, 11, 28, 35–38 We also calculated vBMDs, cortical thickness (CtTh), cross-sectional area (CSA), and polar moment of inertia (PMI) at the whole FN, whole IT, and whole TR, and vBMDs only at the whole proximal femur. A total of 46 QCT measurements were examined for their association with hip fracture.

We assessed the intraobserver reproducibility of the analysis by analyzing 16 randomly selected scans three times. The coefficients of variation were 0.6% to 2.5% for vBMD, 1.1% to 4.9% for cortical thickness, 0.6% to 1.0% for CSA, and 3.3% to 6.5% for PMI (Table 1).

Table 1. Intraobserver Reproducibility of vBMD (%CV)
 Cortical vBMDTrabecular vBMDIntegral vBMDCortical thicknessCSAPMI
  1. vBMD = volumetric BMD; CV = coefficient of variation; CSA = cross-sectional area; PMI = polar moment of inertia.

Femoral neck
 Inferomedial2.01.51.84.9
 Anterior0.91.60.92.7
 Superolateral0.82.41.01.8
 Posterior2.02.62.13.9
 Total1.21.21.20.96.5
Intertrochanter
 Medial2.12.52.24.3
 Anterior1.21.21.11.7
 Lateral1.00.70.61.1
 Posterior2.91.52.01.2
 Total0.80.60.61.03.3
Trochanter
 Medial1.41.71.21.8
 Anterior1.41.81.73.6
 Lateral2.02.01.93.0
 Posterior1.01.71.01.6
 Total0.81.20.90.64.6
Total hip0.70.50.6

Statistical analysis

We used the two-sample t test to compare the means for each measurement at each 2% length interval of the interpolated data between the fracture cases and subcohort. We tested the association between hip fracture and QCT measurements by performing Cox proportional hazard regression; the time to incident hip fracture was modeled with Prentice weighting and robust variance estimation (as recommended for case-cohort analysis).32 Each QCT measurement was included in a separate model of time to first hip fracture to estimate the relative increase in hazard of hip fracture for 1 SD change in its value. Age, body mass index (BMI), clinical site, and TH aBMD were sequentially added to the regression model to assess their effects on the hazard ratio (HR). To account for multiple comparisons of 46 variables, we set statistical significance level for HR at 0.001 based on Bonferroni correction. To examine the ability of QCT measurements to predicting incident hip fracture, we performed stepwise logistic regression that included the QCT measurements only, the QCT measurements plus age, and the QCT measurements plus age and TH aBMD. The ability of the resulting multicovariate regression models to predict incident fracture were compared in terms of the area under the receiver operating characteristic (ROC) curve (AUC) against the models that included TH aBMD alone and TH aBMD plus age.

Results

  1. Top of page
  2. Abstract
  3. Introduction
  4. Subjects and Methods
  5. Results
  6. Discussion
  7. Disclosures
  8. Acknowledgements
  9. References
  10. Supporting Information

Baseline characteristics

The baseline characteristics of the subcohort were very similar to the whole MrOS cohort (Table 2), confirming the validity of the random selection. Participants in the case group were significantly older and lighter and with significantly lower TH aBMD (Table 2).

Table 2. Comparison of Baseline Characteristics
 Case group (n = 38)Subcohort (n = 212)Full MrOS (n = 5995)
  1. MrOS = Osteoporotic Fractures in Men study; BMI = body mass index; TH = total hip; aBMD = areal bone mineral density.

  2. *Significant difference between cases and subcohort (p < 0.0005).

  3. **Significant difference between cases and subcohort (p < 0.05).

Age (years)78.6 (6.0)*73.2 (5.6)73.7 (5.9)
Height (cm)172.4 (5.8)174.5 (7.5)174.1 (6.8)
Weight (kg)78.4 (12.7)**83.5 (13.5)83.1(13.3)
BMI (kg/m2)26.3 (3.3)27.3 (3.6)27.4 (3.8)
TH aBMD (g/cm2)0.79 (0.12)*0.95 (0.13)0.96 (0.14)

vBMD

The patterns of variation in vBMD along the FN were similar for both the case and subcohort (Fig. 2). vBMDs in quadrants were more or less constant from proximal to distal (variation in mean vBMD less than 0.10 g/cm3 and 40%) except for cortical and integral vBMDs in the inferomedial (IA and IP) quadrants of the FN that increased markedly from the proximal to the distal (average increases of 0.46 g/cm3 or 154% and 0.24 g/cm3 or 78% in cortical and integral vBMD, respectively). On average, cortical and trabecular vBMDs in the inferomedial (IA and IP) quadrants were 95% and 54% higher than those in the superolateral (SA and SP) quadrants (p < 0.001), respectively. In comparison to men in the subcohort, the case group had significantly (p < 0.05) lower cortical, trabecular, and integral vBMD in all quadrants and along the most of the FN length. Averaged vBMD over the quadrant was 10% to 20% lower in the case group compared to the subcohort (p < 0.001).

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Figure 2. Mean (95% CI) cortical, trabecular and integral vBMD (mg/cm3) along the femoral neck by quadrant and fracture status. The numbers represent the mean ± SD over the entire length, the t test p value for comparison of means, and percentage difference in means.

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Figure 3 shows bone density distribution in the intertrochanter for both cases and subcohort. Intertrochanteric vBMD was not measured in the proximal 10% of the medial (MA and MP) quadrants because these regions did not contain any bone. Cortical vBMD in all quadrants increased from proximal to distal, 0.55 g/cm3 or 260% on average in the anterior (MA and LA) quadrants and 0.21 g/cm3 or 76% on average in the posterior (MP and LP) quadrants. Trabecular and integral vBMD were lowest in the central third of the intertrochanter. Cortical and integral vBMD was 7% to 19% lower in the case group compared to the subcohort (p < 0.001) except for integral vBMD in the MA quadrant.

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Figure 3. Mean (95% CI) cortical, trabecular, and integral vBMD (mg/cm3) along the intertrochanter by quadrant and fracture status. The numbers represent the mean ± SD over the entire length, the t test p value for comparison of means, and percentage difference in means.

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At the trochanter, cortical vBMD changed little from proximal to distal in the MA and MP quadrants, whereas it increased in the LA and LP quadrants by 0.29 g/cm3 or 55% on average for both cases and the subcohort (Fig. 4). The highest cortical vBMD was in the MA, and the lowest vBMD was in the MP quadrant (which includes the lesser trochanter). Unlike the cortical and integral measurements, trabecular vBMD did not differ significantly between groups except in the MP quadrant, where it was 18% lower in men with fracture (p < 0.000).

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Figure 4. Mean cortical, trabecular, and integral vBMD (mg/cm3) along the trochanter by quadrant and fracture status. The numbers represent the mean ± SD over the entire length, the t test p value for comparison of means, and percentage difference in means.

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Cortical thickness

For both cases and the subcohort, cortical thickness increased from <1 mm proximally to over 3 mm distally in the inferomedial (IA and IP) quadrants of the FN and the anterior (MA and LA) quadrants of the intertrochanter, whereas it remained <1.0 mm in the superior (SA and SP) quadrants of the FN and the MP quadrant of the intertrochanter (Fig. 5). In the trochanter, cortical thickness was always greater than 2 mm in the anterior (MA and LA) quadrants with changes around 1 mm along the length: decreases in MA and increases in LA quadrants. It increased in LP from 1.5 mm to 3 to 5 mm, whereas it remained at 1 to 1.5 mm in the MP quadrant.

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Figure 5. Mean (95% CI) cortical thickness (mm) along the femoral neck, intertrochanter, and trochanter by quadrant and fracture status. The numbers represent the mean ± SD over the entire length, the t test p value for comparison of means, and percentage difference in means.

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Men in the case group had significantly thinner cortex than the subcohort throughout the proximal femur and the percentage differences in mean thickness ranged from 14% to 30%.

Cross-sectional area and PMI

Mean cross-sectional area of the fracture cases was 12.9 (95% confidence interval [CI], 12.3–13.5) cm2 at the FN, 18.2 (95% CI, 17.2–19.3) cm2 at the IT, and 20.7 (95% CI, 19.7–21.8) cm2 at the TR, which were not significantly greater than the subcohort's values of 12.4 (95% CI, 12.1–12,6) cm2 at the FN (p = 0.09), 17.2 (95% CI, 16.8–17.6) cm2 at the IT (p = 0.06), but significantly larger than 19.5 (95% CI, 19.1–20.0) cm2 at the TR (p = 0.04), respectively. PMI at the FN was significantly (p = 0.001) lower in cases (mean, 47.4; 95% CI, 41.2–53.6 cm4) than in the subcohort (mean, 60.2; 95% CI, 55.9–64.6 cm4), whereas they were similar at the IT (mean = 492; 95% CI, 419–567 versus mean = 569; 95% CI, 529–610 cm4, p = 0.07) and TR (mean = 375; 95% CI, 337–413 versus mean, 384; 95% CI, 365–404, p = 0.66).

Associations with hip fracture

HRs for 1 SD increase in age and decreases in BMI and TH aBMD were 2.69 (95% CI, 1.79–4.04), 1.46 (95% CI, 1.00–2.14), and 5.18 (95% CI, 2.76–9.72), respectively.

Table 3 shows the HR of incident hip fracture, adjusted for age, BMI, and clinical site, for 1 SD decrease in vBMD, cortical thickness, and PMI, and 1 SD increase in PMI. Significance level for HR was set at 0.001, the Bonferroni-corrected alpha for multiple comparison. Except cortical vBMD at the inferomedial FN and trabecular and integral vBMDs at the medial IT, all vBMDs at the FN and IT were significantly associated with hip fracture, the HR adjusted for age, BMI, and clinical site for 1 SD decrease ranged between 2.28 (95% CI, 1.44–3.63) for cortical vBMD at the medial IT and 6.54 (95% CI, 3.35–12.77) for trabecular vBMD at the whole FN (Table 3). At the TR, trabecular and integral vBMDs at the medial side and cortical and integral vBMDs at the whole TR were significantly associated with hip fracture, whereas all vBMDs at the lateral side were not. Cortical thickness in all regions but the superolateral FN was significantly associated with hip fracture. The vBMD and cortical thickness at the lateral sides of the FN and IT had higher HRs than the medial side, whereas trabecular vBMD at the whole FN and IT had the highest HRs. However, these differences were not statistically significant (p > 0.05). Cross-sectional area and PMI were not significantly associated with hip fracture.

Table 3. Hazard Ratio (95% CI) for 1 SD Decrease in vBMD and Cortical Thickness
 Inferomedial femoral neckMedial intertrochanterMedial trochanter 
  1. Values adjusted for age, BMI, and study site.

  2. CI = confidence interval; PMI = polar moment of inertia; vBMD = volumetric bone mineral density; BMI = body mass index.

Cortical vBMD1.98 (1.26–3.10); p = 0.00302.28 (1.44–3.63); p = 0.00052.01 (1.26–3.20); p = 0.0034 
Trabecular vBMD4.65 (2.64–8.20); p < 0.00012.33 (1.274.26); p = 0.00606.91 (3.11–15.35); p < 0.0001 
Integral vBMD2.83 (1.71–4.67); p < 0.00012.17 (1.34–3.53); p = 0.00173.70 (2.04–6.71); p < 0.0001 
Cortical thickness2.89 (1.65–5.05); p = 0.00023.18 (1.74–5.81); p = 0.00023.44 (1.70–6.98); p = 0.0006 
 Superolateral femoral neckLateral intertrochanterLateral trochanter 
Cortical vBMD2.87 (1.55–5.30); p = 0.00083.45 (1.90–6.26); p < 0.00012.60 (1.44–4.70); p = 0.0015 
Trabecular vBMD5.45 (2.85–10.44); p < 0.00012.80 (1.61–4.84); p = 0.00021.00 (0.64–1.55); p = 0.9874 
Integral vBMD3.90 (2.12–7.16); p < 0.00012.71 (1.56–4.71); p = 0.00041.86 (0.96–3.60); p = 0.0651 
Cortical thickness5.13 (1.91–13.72); p = 0.00113.68 (1.77–7.66); p = 0.00052.60(1.54–4.38); p = 0.0004 
 Femoral neckIntertrochanterTrochanterTotal hip
Cortical vBMD2.36 (1.46–3.82); p = 0.00053.09 (1.80–5.30); p < 0.00012.45 (1.45–4.12); p = 0.00082.61 (1.60–4.27); p = 0.0001
Trabecular vBMD6.54 (3.35–12.77); p < 0.00014.02 (2.01–8.05); p < 0.00012.74 (1.43–5.29); p = 0.00254.92 (2.55–9.50); p < 0.0001
Integral vBMD3.34 (1.95–5.71); p < 0.00012.86 (1.68–4.86); p = 0.00013.53 (1.87–6.67); p = 0.00013.23 (1.82–5.72); p < 0.0001
Cortical thickness3.49 (1.82–6.71); p = 0.00023.67 (1.86–7.25); p = 0.00023.09 (1.69–5.66); p = 0.0003
Cross-section area1.10 (0.76–1.58); p = 0.62601.07 (0.65–1.74); p = 0.79011.05 (0.65–1.70); p = 0.8373
PMI2.73 (1.43–5.20); p = 0.00222.35 (1.27–4.33); p = 0.00631.45 (0.94–2.23); p = 0.09582.54 (1.59–4.05); p < 0.0001

After adjustment for age, BMI, clinical site, and TH aBMD, trabecular vBMDs at the medial, lateral, and whole FN, medial TR, whole TR, and TH were still significantly associated with hip fracture; the HRs ranged from 3.21 (95% CI, 1.65–6.24) for the superolateral FN to 6.20 (95% CI, 2.71–14.18) for medial TR (Table 4).

Table 4. Hazard Ratio (95% CI) for 1 SD Decrease in vBMD and Cortical Thickness
 Inferomedial femoral neckMedial intertrochanterMedial trochanter 
  1. Values adjusted for age, BMI, study site, and hip aBMD.

  2. CI = confidence interval; vBMD = volumetric bone mineral density; PMI = polar moment of inertia; BMI = body mass index; aBMD = areal bone mineral density.

  3. *Significant at p < 0.001.

Cortical vBMD1.31 (0.66–2.57)1.29 (0.70–2.39)1.09 (0.63–1.87) 
Trabecular vBMD3.44 (1.77–6.69)*1.81 (0.82–3.99)6.20 (2.71–14.18)* 
Integral vBMD1.99 (1.06–3.75)1.21 (0.65–2.27)1.99 (1.01–3.93) 
Cortical thickness1.82 (0.91–3.63)1.26 (0.57–2.77)1.86, 0.87–3.94) 
 Superolateral femoral neckLateral intertrochanterLateral trochanter 
Cortical vBMD1.38 (0.66–2.90)1.76 (0.81–3.82)1.29 (0.58–2.87) 
Trabecular vBMD3.21 (1.65–6.24)*1.72 (0.89–3.34)1.73 (0.96–3.09) 
Integral vBMD2.03 (1.04–3.97)1.57 (0.81–3.05)1.42 (0.67–3.03) 
Cortical thickness1.55 (0.50–4.81)1.93 (0.84–4.45)1.25 (0.61–2.57) 
 Femoral neckIntertrochanterTrochanterTotal hip
Cortical vBMD1.41 (0.74–2.70)1.62 (0.81–3.27)1.20 (0.62–2.32)1.19 (0.61–2.33)
Trabecular vBMD4.27 (2.00–9.08)*2.44 (1.05–5.68)4.08 (1.88–8.87)*3.89 (1.83–8.30)*
Integral vBMD2.11 (1.10–4.03)1.63 (0.86–3.08)1.93 (0.96–3.88)1.67 (0.87–3.18)
Cortical thickness1.88 (0.89–3.97)1.69 (0.75–3.80)1.52 (0.72–3.24)1.49 (0.85–2.61)
Cross-section area0.95 (0.62–1.48)0.97 (0.54–1.72)0.68 (0.89–1.56) 
PMI2.66 (1.08–6.56)1.52 (0.68–3.44)0.98 (0.63–1.52) 

TH aBMD alone predicted hip fracture with an AUC of 0.829 (95% CI, 0.756–0.902) and adding age improved the prediction slightly (AUC, 0.863; 95% CI, 0.797–0.929). QCT parameters alone or in combination did not predict fracture significantly better than TH aBMD alone; the AUC ranged from 0.675 (95% CI, 0.577–0.773) for cortical vBMD at the inferomedial FN to 0.880 (95% CI, 0.832–0.929) for a regression model that included trabecular vBMDs at the superolateral FN, medial IT, and medial TR. A regression model combining age and trabecular vBMD at the superolateral FN and medial TR had an AUC of 0.896 (95% CI, 0.849–0.944), which was significantly larger than that of TH aBMD alone but not significantly greater than TH aBMD plus age. Adding TH aBMD to the model produced an AUC of 0.901 (95% CI, 0.852–0.950), which was significantly (p < 0.005) larger than TH aBMD alone and TH aBMD plus age.

Comparison between fractured and contralateral sides

All QCT measures were not significantly (p > 0.12) different between the fractured and contralateral side for men who sustained an incident hip fracture (Table 5).

Table 5. Side Differences (95% CI) in QCT Measures for Men With Incident Hip Fracture
 Inferomedial femoral neckMedial intertrochanterMedial trochanter 
  1. Values are nonfractured side minus fractured side; vBMD in mg/cm3, cortical thickness in mm, cross-section area in mm2, and PMI in cm4.

  2. CI = confidence interval; vBMD = volumetric bone mineral density; PMI = polar moment of inertia.

Cortical vBMD–14 (–64 to 34)–11 (–55 to 33)6 (–45 to 58) 
Trabecular vBMD–4 (-20 to 12)0 (–13 to 14)–4 (–15 to 7) 
Integral vBMD–9 (–39 to 20)–3 (–24 to 19)0 (–25 to 24) 
Cortical thickness0.0 (–0.2 to 0.1)0.0 (–0.1 to 0.1)0.0 (–0.2 to 0.2) 
 Superolateral femoral neckLateral intertrochanterLateral trochanter 
Cortical vBMD7 (–19 to 32)–4 (–35 to 26)4 (–54 to 62) 
Trabecular vBMD5 (–9 to 18)–3 (–14 to 8)0 (–16 to 16) 
Integral vBMD4 (–11 to 20)–4 (–20 to 11)–2 (–40 to 35) 
Cortical thickness0.0 (–0.0 to 0.1)0.0 (–0.1 to 0.1)0.0 (–0.4 to 0.4) 
 Femoral neckIntertrochanterTrochanterTotal hip
Cortical vBMD–5 (–42 to 32)–6 (–39 to 27)5 (–46 to 57)1 (–38 to 41)
Trabecular vBMD–2 (–14 to 10)–2 (12 to 9)–2 (–12 to 7)–2 (−11 to 7)
Integral vBMD–4 (–25 to 16)–4 (–20 to 12)0 (–27 to 26)–2 (–20 to 16)
Cortical thickness0.0 (–0.1 to 0.1)0.0 (–0.1 to 0.1)–0.0 (–0.3 to 0.2) 
Cross-section area–38 (–117 to 42)–52 (–182 to 77)–94 (–222 to 34) 
PMI–4.9 (–12 to 2)–31 (–124 to 63)–19 (–69 to 31)0.0 (–0.2 to 0.2)

Discussion

  1. Top of page
  2. Abstract
  3. Introduction
  4. Subjects and Methods
  5. Results
  6. Discussion
  7. Disclosures
  8. Acknowledgements
  9. References
  10. Supporting Information

In this prospective case-cohort study we used QCT to quantify the distribution of bone density in the proximal femur of older men with and without incident hip fracture. We measured cortical, trabecular, and integral vBMD and cortical thickness in four quadrants of all cross-sections and examined the pattern of their variations along the FN, IT, and TR. No other studies have described these so comprehensively. We found that although the pattern of bone density distribution was similar in men with and without hip fracture, there were significant deficits in vBMD and cortical thickness in men with hip fracture, which existed not only in the FN but also other regions of the proximal femur. Lower vBMD and cortical thickness in the FN, IT, and TR were all significantly associated with hip fracture, but only trabecular vBMD at the FN and medial aspect of the TR predicted hip fracture independently of aBMD, age, and BMI.

The relative contribution of cortical and trabecular bone to the femoral strength and hip fracture risk is important for understanding bone fragility and effects of therapeutic treatment of osteoporosis. Mechanical testing of ex vivo specimens and finite element analysis demonstrate that both cortical and trabecular bone contribute to femoral strength proportionate to their mass.4, 36, 38, 39 Cortical and trabecular vBMD at the FN decline with age11, 15, 40 and are associated with hip fracture.4, 23–27 We confirmed in this study that there are significant deficits in both cortical and trabecular vBMD in men with hip fracture across the whole of the proximal femur. We demonstrated that whereas the vBMD deficit was more widely present in the cortical than the trabecular compartments (particularly in the IT and TR), the percentage differences in mean vBMD between those with and without hip fracture over the whole quadrant were similar in both compartments. Furthermore, the HRs for cortical and trabecular vBMD were statistically similar after adjusting for age, BMI, and study site. These results suggest that both cortical and trabecular bone deficits across the whole proximal femur contribute to the bone fragility and hip fracture risk.

In vivo and in vitro analyses of a standard region of the FN show that age-related cortical thinning is concentrated in the superolateral aspect,10, 11 whereas in patients with fracture, the cortex is mainly thinner in the inferomedial aspect29, 30, 41; the thinner cortex is probably due to increased cortical remodeling and trabecularization42, 43 in that region. Our FN data corroborate the evidence from these studies. Furthermore, we also observed significantly thinner cortex at the IT and TR in men with than men without incident hip fracture, which suggests that cortical remodeling and trabecularization is not limited to the FN and occurs throughout the proximal femur.

Some QCT studies report better prediction of hip fracture risk using QCT measures in combination with aBMD4, 26 compared to aBMD alone, but this was not replicated in all studies.25, 44 Our results support the rationale for using vBMD measured by QCT, as the latter includes separate measurements of the cortical and trabecular compartments and thus captures information that is more relevant to bone strength. However, the improvement over aBMD was not large enough to justify substituting QCT for DXA in wider clinical use due to very small improvement in prediction with the combination of DXA and QCT measures versus DXA alone, the limited availability of QCT, the higher radiation dose, and the higher financial cost compared to DXA. On the other hand, QCT is valuable as a research tool to promote better understanding of the pathophysiology of hip fracture and to monitor the treatment effects of osteoporosis drugs. In addition to bone measurements, QCT can also be used to assess other factors that may influence the risk of hip fracture. These include factors related to physical function (such as muscle cross-sectional area and adiposity) or to impact force attenuation (such as, for example, trochanteric soft tissue thickness).45–47

Our study had some limitations. The study population was small in relation to the number of variables studied that precludes analysis of FN and extracapsular fractures separately. Secondly, there is an inherent limitation to the accuracy of cortical vBMD and thickness measurement using QCT, particularly at the superolateral aspect of the FN where cortex is thin. Hangartner and Gilsanz48 demonstrated that, with a pixel size of 0.6 × 0.6 mm and true cortical thickness of 1 mm, cortical vBMD could be underestimated by 30% and cortical thickness overestimated by 70% using the full-width half-maximum method. Prevrhal and colleagues49 pointed out that oblique orientation of bone surface relative to the CT acquisition plane causes further overestimation of cortical thickness. We estimated cortical thickness using a density-weighted method that took into account the influence of partial volume effects to some extent, and our results are comparable with others obtained using higher-resolution QCT.11, 26 However, the effect of bone-surface orientation was not accounted for. Furthermore, we digitally rotate the femur in a standard orientation by interpolation, which may affect the QCT measurements. However, limitations in accuracy should have little effect on the significant differences between hip fracture cases and non-cases. Recently, Treece and colleagues12 developed a method to accurately measure the femoral cortical thickness with QCT and map the thickness to cortical surface, and Poole and colleagues50 demonstrated its value in examine the effect of parathyroid hormone (PTH) treatment for severe osteoporosis. Finally, this study was performed in a largely white, male population, so the results may not be fully generalizable to other populations.

In conclusion, we examined the patterns of variation in cortical and trabecular bone density and cortical thickness in the proximal femur comprehensively and found that they were similar between hip fracture cases and cohorts. However, throughout the proximal femur, bone density and cortical thickness were lower in men who experienced incident fracture compared with unfractured men. The differences between groups were more frequent in cortical regions, but the percentage differences were similar in both cortical and trabecular compartments. All cortical and trabecular measures at the FN, IT, and TR were highly associated with hip fracture after adjustment for clinical site, age, and BMI, and trabecular vBMD in the FN and TR were still associated with fracture after further adjustment for total hip aBMD.

Acknowledgements

  1. Top of page
  2. Abstract
  3. Introduction
  4. Subjects and Methods
  5. Results
  6. Discussion
  7. Disclosures
  8. Acknowledgements
  9. References
  10. Supporting Information

This study is supported by Medical Research Council, UK and the National Institute for Health Research via its Biomedical Research Units funding scheme. The views expressed in this publication are those of the author(s) and not necessarily those of the NHS, the NIHR or the Department of Health. We acknowledge the editorial board of the Sheffield NIHR Biomedical Research Unit for Musculoskeletal Deceases for their help in preparing this manuscript. The MrOS Study is supported by National Institutes of Health funding. The following institutes provide support: the National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS), the National Institute on Aging (NIA), the National Center for Research Resources (NCRR), and NIH Roadmap for Medical Research under the following grant numbers: U01 AR45580, U01 AR45614, U01 AR45632, U01 AR45647, U01 AR45654, U01 AR45583, U01 AR052234, U01 AG18197, U01-AG027810, and UL1 RR024140. Additional support for these analyses was provided by Merck & Co., Eli Lilly, and Amgen, and by NIH Grant AR049828.

Authors' roles: Study design: EO, CN, LY, and RE. Study conduct: AB and LY. Data collection: AB and LY. Data analysis: AB, LY, MB, and CN. Data interpretation: All authors. Drafting manuscript: LY. Revising manuscript content: All authors. Approving final version of manuscript: LY. LY takes responsibility for the integrity of the data analysis.

References

  1. Top of page
  2. Abstract
  3. Introduction
  4. Subjects and Methods
  5. Results
  6. Discussion
  7. Disclosures
  8. Acknowledgements
  9. References
  10. Supporting Information

Supporting Information

  1. Top of page
  2. Abstract
  3. Introduction
  4. Subjects and Methods
  5. Results
  6. Discussion
  7. Disclosures
  8. Acknowledgements
  9. References
  10. Supporting Information

Additional Supporting Information may be found in the online version of this article.

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