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J Clin Endocrinol Metab. Nov 2010; 95(11): 5045–5055.
Published online Aug 18, 2010. doi:  10.1210/jc.2010-0226
PMCID: PMC2968722

High-Resolution Peripheral Quantitative Computed Tomographic Imaging of Cortical and Trabecular Bone Microarchitecture in Patients with Type 2 Diabetes Mellitus

Abstract

Context: Cross-sectional epidemiological studies have found that patients with type 2 diabetes mellitus (T2DM) have a higher incidence of certain fragility fractures despite normal or elevated bone mineral density (BMD).

Objective: In this study, high-resolution peripheral quantitative computed tomography was applied to characterize cortical and trabecular microarchitecture and biomechanics in the peripheral skeleton of female patients with T2DM.

Design and Setting: A cross-sectional study was conducted in patients with T2DM recruited from a diabetic outpatient clinic.

Participants: Elderly female patients (age, 62.9 ± 7.7 yr) with a history of T2DM (n = 19) and age- and height-matched controls (n = 19) were recruited.

Outcome Measures: Subjects were imaged using high-resolution peripheral quantitative computed tomography at the distal radius and tibia. Quantitative measures of volumetric (BMD), cross-sectional geometry, trabecular and cortical microarchitecture were calculated. Additionally, compressive mechanical properties were determined by micro-finite element analysis.

Results: Compared to the controls, the T2DM cohort had 10% higher trabecular volumetric BMD (P < 0.05) adjacent to the cortex and higher trabecular thickness in the tibia (13.8%; P < 0.05). Cortical porosity differences alone were consistent with impaired bone strength and were significant in the radius (>+50%; P < 0.05), whereas pore volume approached significance in the tibia (+118%; P = 0.1).

Conclusion: The results of this pilot investigation provide a potential explanation for the inability of standard BMD measures to explain the elevated fracture incidence in patients with T2DM. The findings suggest that T2DM may be associated with impaired resistance to bending loads due to inefficient redistribution of bone mass, characterized by loss of intracortical bone offset by an elevation in trabecular bone density.

Type 2 diabetes mellitus (T2DM) is a chronic metabolic disorder associated with impaired glucose metabolism that is often accompanied by a range of systemic complications. A number of cohort studies and recent meta-analyses have found an increased risk of fragility fractures in the humerus, femur, and the distal lower extremity of patients with T2DM (1,2,3,4,5,6,7,8). Schwartz et al. (6) found that insulin-treated type 2 diabetics had more than double the risk of foot fractures compared with nondiabetics. These fractures are a serious and well-recognized complication of diabetes mellitus that may significantly impair clinical outcomes for such patients (9). Although factors related to the risk of falling (visual deficits, peripheral neuropathy, etc.) may be important discriminants for this population (1), increased bone fragility may also contribute to the elevated risk of fracture. Determination of fracture risk in postmenopausal osteoporosis is primarily based on measures of areal bone mineral density (aBMD) obtained by dual x-ray absorptiometry (DXA). However, cross-sectional epidemiological studies have generally found that, despite the elevated incidence of certain types of fragility fractures, type 2 diabetics generally have equivalent (10,11,12) or even higher (2,13,14,15,16,17,18) aBMD compared with matched controls (CTRLs). Therefore, bone mineral density (BMD) is of limited utility for assessing fracture risk in this patient population, and new investigational methods for exploring fracture etiology related to diabetes mellitus are critically needed. Specifically, there is a need to measure bone quality factors related to bone strength that are not captured by projectional x-ray techniques. These include volumetric density, cross-sectional geometry, cortical and trabecular microarchitecture, and tissue composition. In this context, high-resolution quantitative three-dimensional (3D) imaging techniques are particularly well suited as a clinical research tool to investigate bone quality in patients with T2DM.

High-resolution peripheral quantitative computed tomography (HR-pQCT) has recently been introduced as a noninvasive method for in vivo 3D characterization of bone in the peripheral skeleton (distal radius and tibia). Similar to traditional quantitative computed tomography (QCT), HR-pQCT provides the ability to quantitatively assess volumetric BMD (vBMD) independently in cortical and trabecular compartments. Additionally, due to the high isotropic nominal resolution of this modality (82 μm), the ability to quantify geometric, microarchitectural, and mechanical features of cortical and trabecular bone has also been established (19,20,21). This imaging technique has been applied in a number of cross-sectional studies to characterize aging effects (22,23,24,25,26,27), fracture discrimination (28,29,30,31), and various pathologies (32,33,34) frequently, but not exclusively, in the context of postmenopausal bone loss in women.

In this pilot study, HR-pQCT was applied to image the peripheral skeleton of postmenopausal women with T2DM. This population was selected because the increase in nonvertebral fracture risk associated with T2DM has been more definitively established compared with men (35). T2DM-related changes in bone quality, coincident with estrogen-deficient bone loss, may compound fracture risk, and therefore this is a particularly important population to characterize. Our hypothesis was that type 2 diabetics have unique structural deficiencies that result in compromised bone strength, compared with CTRLs without diabetes. This would suggest that the discrepancy between fracture incidence and DXA findings in the T2DM epidemiological literature can be attributed, in part, to differences in bone quality not detected by aBMD. To that end, we calculated measures of density, cross-sectional geometry, trabecular microarchitecture, cortical porosity, and compressive biomechanics from the HR-pQCT image data acquired for our T2DM cohort and an age-, height-, and ethnicity-matched CTRL cohort.

Subjects and Methods

Subjects

For this cross-sectional study, postmenopausal female patients with T2DM (n = 19) were recruited from a local diabetic outpatient clinic by a coinvestigator of the study (U.M.). Inclusion criteria required patients to have a history of diabetes for a minimum of 5 yr and a body mass index (BMI) between 19 and 35 kg/m2, to be fully ambulatory at the time of the exam, and to not have a recent history of long periods of inactivity. In accordance with the American Diabetes Association criteria, diabetes was defined as self-report of diabetes previously diagnosed by a physician, use of hypoglycemic medications, or a fasting glucose greater than 126 mg/dl (7.0 mm). Age, ethnicity, and height-matched CTRLs were recruited through public media and posted flyers. Additionally, eight subjects matching the inclusion/exclusion criteria were cross-enrolled from a normative cross-sectional study (36) to equalize the number of subjects in the CTRL group (n = 19 total). Exclusion criteria were as follows: history of severe neuropathic disease, alcoholism, chronic drug use, chronic gastrointestinal disease, renal or hepatic impairment, unstable cardiovascular disease, high-energy trauma, and pathological skeletal fractures. Patients with a history of treatment with the following medications were also excluded: rosiglitazone, pioglitazone, adrenal or anabolic steroids, anticonvulsants, anticoagulants, fluoride, bisphosphonates, calcitonin, or tamoxifen. The University of California, San Francisco Committee of Human Research approved the study protocol, and all patients gave written, informed consent before participation.

HR-pQCT imaging

All subjects were imaged in a clinical HR-pQCT system (XtremeCT; Medical AG, Brüttisellen, Switzerland) using a standard in vivo protocol described in previous patient studies (15,16,17). The subject’s nondominant forearm and leg were immobilized in a carbon fiber cast that was fixed within the gantry of the scanner. If the subject reported a previous extremity fracture at that site, the contralateral forearm or leg was examined. A single dorsal-palmar projection image of the distal radius/tibia was acquired to define the tomographic scan region (Fig. 11,, A and B). This region spanned 9.02 mm in length (110 slices) and was fixed starting at 9.5 mm and 22.5 mm (for the radius and tibia, respectively) proximal from the mid-jointline, and extending proximally. For tomography, 750 projections were acquired over 180° with a 100-msec integration time at each angular position. The 12.6-cm field of view was reconstructed across a 1536 × 1536 matrix using a modified Feldkamp algorithm, yielding 82-μm voxels (37). Total scan time was 2.8 min, with an effective dose of approximately 4.2 μSv for each site, comparable to the dose received from a standard chest x-ray or DXA procedure. The images were calibrated to hydroxyapatite (HA) concentration based on a separate measurement of a phantom comprised of several rods with a range of mixtures of HA and a soft tissue equivalent organic resin. This calibration procedure is based on the methods originally established for desktop microtomography (38).

Figure 1
Representative scout radiographs for the radius (A) and tibia (B) illustrating the localization for the tomographic acquisition (filled green).

Image analysis

HR-pQCT images were evaluated using the standard clinical evaluation protocol, adapted from methods developed for a previous peripheral QCT device (39,40). Trabecular bone volume fraction [bone volume/tissue volume (BV/TV)] was derived from the vBMD of the trabecular compartment (Tb.vBMD) using the assumption that compact bone has a matrix mineral density of 1200 mg HA/cm3, whereas the marrow background is equivalent to 0 mg HA/cm3. Tb.vBMD was also calculated for two concentric subregions: a peripheral region adjacent to the cortex (pTb.vBMD) and a central medullary region (mTb.vBMD) (Fig. 22,, A and B). The peripheral region was defined such that it extended from the endosteal boundary centrally, covering 40% of the cross-sectional area (CSA). In addition to vBMD measures, aBMD was calculated for the distal radius from the HR-pQCT images using an automated approach (41). The trabecular structure was extracted using a Laplace-Hamming filter—which effectively smoothes the image and enhances edges—followed by a fixed global threshold (42). From the binary image, trabecular number (Tb.N) and its distribution (Tb.1/N.SD) were measured using direct 3D methods (43,44). Based on the densitometric BV/TV and direct Tb.N, trabecular thickness (Tb.Th) and trabecular separation (Tb.Sp) were derived using traditional plate model assumptions. The reproducibility of density-based measures is generally less than 1% and typically between 3 and 5% for bone structure parameters (22,45,46,47).

Figure 2
Two-dimensional illustration of the segmented compartments included in the quantitative image analysis of the radius (A) and tibia (B): cortical bone (black), peripheral trabecular bone (dark gray), and medullary trabecular bone (light gray).

As reported previously, the default cortical bone analysis provided with this HR-pQCT device performs poorly for subjects with thin or porous cortices (45,48). Accordingly, a fully automated cortical compartment segmentation technique adapted from the method described originally by Buie et al. (48,49) was applied. Based on this segmentation, cortical vBMD (Ct.vBMD) and cortical tissue mineral density (Ct.TMD) were calculated. Ct.vBMD was simply the mean mineralization of all voxels in the cortical volume of interest (VOI), whereas Ct.TMD was calculated as the mean of only mineralized voxels in the cortical VOI (i.e. based on the same segmentation of mineralized voxels used for the trabecular structure analysis). Additionally, for Ct.TMD, partial volume contributions were suppressed by peeling two voxels from all surfaces. The average maximal second moment of inertia (MOI) for the cortex (Ct.MOI) and total cross-section were calculated from the segmented binary images to provide an estimate of bending strength. A volumetric index of cortical porosity, denoted Ct.Po, was calculated as previously described by Burghardt et al. (36,50) based on the cortical pore volume (Ct.PoV) and the mineralized cortical bone volume (Ct.BV):

equation M1

Based on this segmentation, a direct 3D calculation (43) of cortical thickness (Ct.Th) was performed on the composite segmentations of the mineralized cortex and porosity, thereby disregarding intracortical pore surfaces in the local distance calculations. This index represents a direct, 3D measure of endosteal-periosteal distance. The least significant change and root-mean-square coefficient of variation for these parameters are described in Table 11 from reproducibility measurements in 27 postmenopausal women (50).

Table 1
Least significant change and root-mean-square coefficient of variation of quantitative cortical bone measures

Micro-finite element (μFE) analysis

Linear micro-finite element (μFE) analysis was applied to calculate apparent biomechanical properties under uniaxial compression. Homogeneous mechanical properties were assumed for all bone elements. The binary image data set was converted to a mesh of isotropic brick elements using a voxel conversion technique (51), and each element was assigned an elastic modulus of 10 GPa (52) and a Poisson’s ratio of 0.3 (53). Cortical and trabecular bone elements were labeled as different materials, with identical material properties to facilitate calculation of compartmental load distribution. A uniaxial compression test in the axial direction (superior-inferior) was performed with an applied strain of 1%. An iterative solver (Scanco FE Software v1.12; Scanco Medical AG) was used to compute reaction forces at the proximal and distal ends of the scan region for the prescribed displacements. For each model, stiffness (K), apparent modulus (E), and the load fraction for the cortical compartment (Ct.LF) at the distal boundary were calculated. Furthermore, failure load (F) was estimated using methods previously described by Pistoia et al. (54). Differential biomechanical indices related to Ct.Po were also calculated by running a second model for each specimen with the intracortical pore spaces digitally occluded (36). Specifically, the deficit in stiffness (ΔK), apparent modulus (ΔE), and failure load (ΔF) due to the resolvable Ct.Po were calculated as the difference in the respective parameter between the occluded and original models, and normalized by the original. These indices were reported as a percentage. The fractional load (ΔCt.LF) shifted from the cortex to the trabecular bone was calculated simply as the difference between occluded and original Ct.LF.

Statistical analysis

Mean and sd were calculated for all indices and were determined for each site (radius and tibia) and study group (CTRL and T2DM). Because the Shapiro-Wilk W test revealed that multiple parameters were not normally distributed, group-wise differences were evaluated for statistically significant differences using the Wilcoxon rank sum test with α = 0.05. Because the mean weight of the T2DM group was statistically greater than the CTRL group (P < 0.05), analysis of covariance (ANCOVA) was additionally applied to test for statistical significance after correcting for weight as a covariate. The interaction between weight and T2DM status was tested for each measure, and because the slopes were not statistically different between T2DM and CTRL, the ANCOVA was performed assuming covariate homogeneity between groups (i.e. equal slopes).

Results

Subjects

A summary of the characteristics of patients recruited for this study is presented in Table 22.. The CTRL group was comprised of six Caucasian, one African-American, six Hispanic, and six Asian subjects, whereas the T2DM group was comprised of six Caucasian, five African-American, four Hispanic, and four Asian subjects. As expected, given height and age matching, the T2DM cohort had a higher average body mass and BMI compared with the CTRL group (P < 0.05). As a result, statistical correction for weight was performed in addition to standard ANOVA for T2DM and CTRL comparisons. Because ANCOVA did not significantly change the results, the uncorrected results (Wilcoxon rank sum test) are reported in detail, and corrected differences are noted where appropriate. Of the 19 patients with T2DM, two had previous fractures. One patient had a history of fracture at the femoral head and ankle. The second patient had a previous proximal humerus fracture and a grade II fracture of the L5 vertebrae, as determined from radiographic analysis using the semiquantitative method of Genant et al. (55).

Table 2
Descriptive data of study participants

HR-pQCT imaging

Representative HR-pQCT images of the distal radius and tibia for the median (by vBMD) CTRL, T2DM, and T2DM with fracture subjects are shown in Figs. 33 and 44.. The fracture subjects in particular showed dramatic levels of intracortical porosity in the distal radius and tibia as well as extremely dense trabecular bone in the peripheral region adjacent to the cortex. Additionally, the presence of severe arterial calcifications in the soft tissue surrounding the bone was observed in five T2DM subjects (26%), including both fracture subjects (Fig. 55).). Arterial calcifications were not observed in the CTRL group.

Figure 3
Median (by total vBMD) HR-pQCT images of the distal radius from CTRL (top), T2DM (middle), and T2DM with fracture (bottom): distal-most slices (A, E, I); proximal-most slices (B, F, J); 3D visualization of the mineralized bone structure (C, G, K); and ...
Figure 4
Median (by total vBMD) HR-pQCT images of the distal tibia from CTRL (top), T2DM (middle), and T2DM with fracture (bottom): distal-most slices (A, E, I); proximal-most slices (B, F, J); 3D visualization of the mineralized bone structure (C, G, K); and ...
Figure 5
HR-pQCT images illustrating arterial calcifications in the distal radius (A) and distal tibia (B) of a subject with T2DM and a history of lower extremity fragility fracture.

Image analysis

Of the 38 total datasets, the automated cortical bone compartment segmentation was qualitatively acceptable for all but the two fracture subjects. In these subjects, extensive Ct.Po and endocortical trabecularization was evident and led to poor detection of the endocortical boundary. As a result, manual adjustments to the endocortical contour were required for both the radius and tibia scans of these subjects. The mean and sd for all density, cross-sectional geometry, microarchitectural, and biomechanical indices are reported in Table 33.. The percentage difference between T2DM and CTRL groups is also reported, with statistically significant differences indicated where appropriate.

Table 3
Density, cross-sectional geometry, microarchitectural, and biomechanical parameters for controls and T2DM patients

At both sites, the majority of bone quality markers were found to be consistent with equivalent or greater estimates of bone strength for the T2DM cohort compared with CTRL. aBMD of the distal radius was effectively the same between groups. In the distal tibia, vBMD was significantly higher (P < 0.05) in the T2DM group. This was primarily due to a 10% greater trabecular density (P < 0.05) in the peripheral region adjacent to the cortex (pTb.vBMD).

Minor differences in cross-sectional geometry were observed and were generally muted when corrected for weight. After statistical correction for weight, total and cortical maximal MOI tended to be lower for the T2DM cohort, although these trends did not reach statistical significance. In the distal tibia, Tb.Th was significantly higher in the T2DM group (+13.8%; P < 0.05). Estimates of bone strength determined by μFE modeling of an axial compressive load tended to be higher for T2DM subjects, with apparent modulus reaching statistical significance (+10.6%; P < 0.05).

The only measures indicating compromised bone quality were related to Ct.Po, where Ct.PoV and Ct.Po were 151 and 124% higher, respectively, in the radius of the T2DM cohort. In the tibia, the trends were similar (118 and 36%, respectively) but were shy of statistical significance. Porosity in the distal radius of these subjects was specifically associated with a 2.5–3.0% deficit in compressive biomechanical properties, compared with a 1.7–1.9% deficit in the CTRL cohort (P < 0.05). After statistical correction for weight, the group-wise differences generally decreased, although the relative effects exhibited similar trends to the uncorrected differences.

Discussion

A number of cross-sectional studies have documented the increased fracture incidence of individuals with T2DM (1,2,3,4,5,6,7,8) despite equivalent or higher aBMD measures compared with matched CTRLs (2,10,11,12,13,14,15,16,17,18). This is often attributed to a greater risk for falls due to visual deficiencies, peripheral neuropathy, and other complications commonly associated with T2DM (1). Another possible explanation for this discrepancy is that bone quality factors not captured by two-dimensional projectional densitometry may compromise bone strength in this population. In this pilot investigation, we have used HR-pQCT to characterize 3D bone density, geometry, microarchitecture, and compressive biomechanics in a limited cohort of postmenopausal female patients with T2DM and compared with age- and height-matched CTRLs.

In general, the density, geometric, microarchitectural, and biomechanical differences between the T2DM and CTRL cohorts were consistent with comparable or even greater bone quality and compressive strength in the T2DM cohort. When statistically corrected for body mass, these differences were generally more muted. The observed trend toward higher Tb.vBMD in T2DM subjects is in agreement with other recent imaging studies based on lower resolution modalities (14,56). Ct.Po-related measures alone were significant indicators of compromised bone quality. This is an important observation because the cortical ultra- and microarchitecture are important determinants of bone strength (57), and specifically, are critical to fracture initiation and propagation under bending loads (58). Although it is not possible to realistically simulate bending loads from HR-pQCT scans that span only 1 cm along the length of the bone, the cross-sectional MOI parameters were reported as surrogates for bending strength. After correction for body mass, total and cortical maximal MOI tended to be lower in T2DM subjects relative to CTRL. Although these differences failed to reach statistical significance in our limited cohort (n = 19 per group), they are consistent with a deleterious effect on bending strength.

The dense trabecular bone in the peripheral cancellous compartment and elevated pTb.vBMD of T2DM patients did not visually appear to be due to endocortical trabecularization artifactually included in the cancellous VOI. Despite significant intracortical erosion in these subjects, the extant endocortical boundary is still visually discernable (Fig. 44).). The manual adjustments made to the automated endocortical contour generated during the segmentation process ensured that these features were appropriately assigned to the trabecular compartment. Instead, this hyperdense structure is likely the result of trabecular thickening in this region, possibly a compensatory adaptation for the loss of bone mass in the cortex. This adaptation would be particularly necessary in a habitually loaded skeletal site such as the tibia to provide sufficient compressive rigidity to support the greater weight of a diabetic individual, but it would be less efficient with respect to bending loads.

In a subcohort of the Osteoporotic Fractures in Men (MrOS) study using pQCT, Petit et al. (56) reported that men with T2DM had cortical bone geometry deficits despite higher aBMD compared with CTRLs. Whereas they found smaller CSA in T2DM men compared with CTRLs (significant after correction for weight), the results of this study indicated a trend toward greater CSA for a female T2DM cohort (not statistically significant). They proposed that the smaller CSA is a possible explanation for the observed elevated aBMD, compared with matched CTRLs. In a small cross-sectional QCT study that included men and women with T2DM, Melton et al. (14) observed differences related to diabetes within each gender cohort consistent with the results of both MrOS and the present study. Several studies in small animal models of hyperglycemic T2DM have found reduced cross-sectional geometric properties and compromised bending strength compared with control animals (59,60,61). However, it is difficult to draw direct comparisons with respect to cortical structure because rodents lack the intracortical Haversian remodeling surfaces that give rise to the porosity observed in this study in humans.

The use of a high-resolution in vivo clinical imaging device with a spatial resolution at the trabecular level was a particular strength of this study. This advantage allowed a more detailed evaluation of both trabecular and cortical microarchitecture not previously possible with lower-resolution in vivo modalities (14,56). Specifically, increased Ct.Po was identified as a possible explanation for the increased peripheral fracture incidence for T2DM women, compared with matched CTRLs, despite favorable aBMD scores. The μFE results support the deleterious biomechanical impact of Ct.Po in this cohort; whereas absolute estimates of compressive bone strength were equivalent or even greater than CTRL, porosity-specific biomechanical deficits were significantly higher in the T2DM cohort and offset by higher Tb.vBMD.

Notably, the porosity-related parameters have substantially greater variability compared with CTRL. In part, this can be attributed to the contribution of the two fracture subjects that were found to have Ct.Po 2-fold greater than the mean for the T2DM group. Nevertheless, when these subjects were excluded from the statistical analysis, the variability of the T2DM group remained somewhat greater than CTRL. Additionally, whereas excluding the fracture subjects reduced the porosity-related differences between T2DM and CTRL, the trends for higher porosity and associated biomechanical deficits generally remained significant or approaching significance. The greater variability in cortical microarchitecture of the T2DM cohort may be associated with a number of important covariates such as the age of onset of T2DM, disease severity, duration, and treatment. Furthermore, the two fracture subjects may represent a subset of the T2DM population that manifests significant architectural deterioration due to secondary causes associated with diabetes. Higher-powered epidemiological HR-pQCT studies are needed to address these questions more explicitly.

There are several limitations to this study to acknowledge. First, the limited number of subjects successfully recruited for this study (n = 38 total) precluded a direct examination and/or control for other potential covariates for the bone quality measures considered. This includes ethnicity, the age of onset of T2DM, the duration and severity of T2DM, treatment for T2DM, and the effect of other systemic complications related to diabetes. Furthermore, because only two of our T2DM patients had a history of fragility fracture, our results cannot directly address the question of fracture risk. It should be noted that although there were somewhat more African-American subjects in the T2DM group, vBMD, Ct.Th, and Tb.vBMD were not significantly different between African-American T2DM and the other pooled T2DM patients. Large cross-sectional case-control studies and prospective studies should be pursued to more rigorously investigate the relationship between bone quality measures and fracture risk in T2DM populations.

Additionally, the imaging sites were limited to 1-cm sections of the ultra distal end of the radius and tibia where a majority of the bone mass is cancellous, not cortical bone. This site was selected to be consistent with the manufacturer’s default protocol, which has been applied in the vast majority of cross-sectional studies related to osteopenia and osteoporosis (22,23,29,45). In the radius, bone strength estimates at this location have been shown to be well correlated to experimental mechanical behavior and approximately correspond spatially to the common Colles’ fracture location (26). Although it is not possible to acquire mid-diaphyseal scans at the radius or tibia with this device, future studies could reliably include acquisitions up to 2 cm more proximal where the relative bone mass is dominated by cortical bone (26,62).

Finally, the standard trabecular bone analysis applied in this study employs several assumptions about bone matrix mineral density and marrow composition to calculate BV/TV which, in turn, is used to derive Tb.Th and Tb.Sp: namely, that both marrow composition and bone matrix mineral density are constant. Although variability in marrow composition is not likely a major source of error for peripheral skeletal sites, it is less clear how the degree of variability in bone matrix mineralization between these populations may be affected. In the cortex, our results indicate no significant difference in tissue level mineralization (Ct.TMD); however, this does not account for possible differences in microporosity not resolved by HR-pQCT. Furthermore, our analysis does not address the effect of matrix level differences in the organic phase of bone, which has been shown to be altered in association with T2DM (63).

In this study, we have characterized microarchitectural and biomechanical abnormalities in postmenopausal women with T2DM using noninvasive, high-resolution 3D imaging. The results of this pilot investigation provide a potential explanation for the inability of standard BMD measures to explain the elevated fracture incidence in patients with T2DM. Specifically, the findings suggest that T2DM may be associated with an inefficient redistribution of bone mass and insufficient compensation for increased body mass, which may result in impaired bending strength. These observations highlight the need for large, controlled, cross-sectional and longitudinal studies of bone quality in T2DM cohorts as well as prospective studies of fracture risk in this population. Collectively, this study has used HR-pQCT to identify microarchitectural deficits in the cortical bone of patients with T2DM compared with normal CTRLs.

Acknowledgments

The authors thank Thelma Munoz, Jingyi Yu, Nicole Cheng, Melissa Guan, and Ayako Suzuki for contributions in recruiting subjects, image acquisition, and database management. The authors additionally thank Dr. Andres Laib and Scanco Medical AG for providing software development documentation and resources and for countless helpful technical discussions.

Footnotes

This work was supported by National Institutes of Health (NIH)/National Center for Research Resources (NCRR), University of California, San Francisco (UCSF)-Clinical and Translational Science Institute Grant UL1 RR024131-01 (to A.J.B.), NIH Grant R01 AG17762 (to S.M.), NIH Grant RC1 AR058405-01 (to T.M.L.), and a UCSF Research Evaluation and Allocation Committee Grant (to T.M.L.).

Disclosure Summary: The authors have no financial disclosures or conflicts of interest.

First Published Online August 18, 2010

Abbreviations: aBMD, Areal BMD; ANCOVA, analysis of covariance; BMD, bone mineral density; BMI, body mass index; BV/TV, bone volume/tissue volume; CSA, cross-sectional area; Ct.LF, cortical load fraction; Ct.MOI, cortical MOI; Ct.Po, volumetric index of cortical porosity; Ct.PoV, cortical pore volume; Ct.Th, cortical thickness; CTRL, control; Ct.TMD, cortical tissue mineral density; Ct.vBMD, cortical vBMD; 3D, three-dimensional; DXA, dual x-ray absorptiometry; μFE, micro-finite element; HA, hydroxyapatite; HR-pQCT, high-resolution peripheral QCT; MOI, moment of inertia; mTb.vBMD; medullary Tb.vBMD; pTb.vBMD, peripheral Tb.vBMD; QCT, quantitative computed tomography; Tb.1/N.SD, trabecular number distribution; Tb.N, trabecular number; Tb.Sp, trabecular separation; Tb.Th, trabecular thickness; Tb.vBMD, trabecular vBMD; T2DM, type 2 diabetes mellitus; vBMD, volumetric BMD; VOI, volume of interest.

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