In vivo discrimination of hip fracture with quantitative computed tomography: Results from the prospective European Femur Fracture Study (EFFECT)

In assessing osteoporotic fractures of the proximal femur, the main objective of this in vivo case‐control study was to evaluate the performance of quantitative computed tomography (QCT) and a dedicated 3D image analysis tool [Medical Image Analysis Framework—Femur option (MIAF‐Femur)] in differentiating hip fracture and non–hip fracture subjects. One‐hundred and seven women were recruited in the study, 47 women (mean age 81.6 years) with low‐energy hip fractures and 60 female non–hip fracture control subjects (mean age 73.4 years). Bone mineral density (BMD) and geometric variables of cortical and trabecular bone in the femoral head and neck, trochanteric, and intertrochanteric regions and proximal shaft were assessed using QCT and MIAF‐Femur. Areal BMD (aBMD) was assessed using dual‐energy X‐ray absorptiometry (DXA) in 96 (37 hip fracture and 59 non–hip fracture subjects) of the 107 patients. Logistic regressions were computed to extract the best discriminates of hip fracture, and area under the receiver characteristic operating curve (AUC) was calculated. Three logistic models that discriminated the occurrence of hip fracture with QCT variables were obtained (AUC = 0.84). All three models combined one densitometric variable—a trabecular BMD (measured in the femoral head or in the trochanteric region)—and one geometric variable—a cortical thickness value (measured in the femoral neck or proximal shaft). The best discriminant using DXA variables was obtained with total femur aBMD (AUC = 0.80, p = .003). Results highlight a synergistic contribution of trabecular and cortical components in hip fracture risk and the utility of assessing QCT BMD of the femoral head for improved understanding and possible insights into prevention of hip fractures. © 2011 American Society for Bone and Mineral Research.     

Differences in hip quantitative computed tomography (QCT) measurements of bone mineral density and bone strength between glucocorticoid-treated and glucocorticoid-naïve postmenopausal women

Chronic treatment with glucocorticoids (GCs) leads to significant bone loss and increased risk of fractures. In chronically GC-treated patients, hip fracture risk is nearly 50%. The purpose of this investigation was to determine if there are differences in the quantities of trabecular and cortical bone and bone strength of the hip between GC-treated osteoporotic patients and controls. Methods: Study subjects were GC-treated osteoporotic postmenopausal women, and controls were postmenopausal women, recruited for separate clinical trials. Quantitative computed tomography (QCT) and dual-energy X-ray absorptiometry (DXA) of the hip were obtained from all subjects. QCT outcome variables measured included total, cortical, and trabecular BMD of hip subregions (femoral neck and trochanter) and total hip. In addition, finite element modeling (FEM) was performed on a subset of 19 cases and 38 controls, matched on age (± 5 years), weight (± 5 kg), and history of hormone replacement (>1 year use) to assess failure load in stance and fall loading conditions. Generalized linear models were used to adjust the QCT variables for covariates between groups. Multiple regression was performed to identify independent predictors of bone strength from the QCT variables. Results: Compared with controls, GC-treated subjects were significantly (p<0.05) younger, weighed less, and had more years of hormone replacement. QCT of the hip in GC-treated subjects for total femoral integral, cortical, and trabecular BMD averaged 4.9–23.2% (p<0.002) less than controls, and similar results were seen by hip subregion including the trochanter and femoral neck. DXA of the total hip was 17% lower in GC subjects than controls (p<0.05). Compared with controls, FEM failure load in GC subjects was 15% (p<0.05) and 16% (p=0.07) lower for stance and fall loading conditions, respectively. Multiple regression analysis demonstrated that a combination of QCT measures was correlated with bone strength as measured by FEM. Conclusions: Chronic GC treatment in postmenopausal women resulted in significantly decreased BMD of the hip, measured by QCT, with loss of both trabecular and cortical bone. In addition, GC treatment decreased bone strength as determined by FEM. The reduced cortical and trabecular bone mass in the hip may contribute to the disproportionately high hip fracture rates observed in GC-treated subjects.This work was supported by grants from the NIH 1R01AG05407, 1R01AR40431, 1R01AR46197, the Doris Duke Clinical Research Fellowship (CRF) Program for Medical Students (#20000684) K24AR048841-02 and the Rosalind Russell Arthritis Foundation.     

Quantitative computed tomography (QCT) of the forearm using general purpose spiral whole-body CT scanners: Accuracy,precision and comparison with dual-energy X-ray absorptiometry (DXA)

BackgroundDual-energy X-ray absorptiometry (DXA) allows clinically relevant measurement of bone mineral density (BMD) at central and appendicular skeletal sites, but DXA has a limited ability to assess bone geometry and cannot distinguish between the cortical and trabecular bone compartments. Quantitative computed tomography (QCT) can supplement DXA by enabling geometric and compartmental bone assessments. Whole-body spiral CT scanners are widely available and require only seconds per scan, in contrast to peripheral QCT scanners, which have restricted availability, limited spatial resolution, and require several minutes of scanning time.This study evaluated the accuracy and precision of whole-body spiral CT scanners for quantitatively assessing the distal radius, a common site of non-vertebral osteoporosis-related fractures, and compared the CT-measured densitometric values with those obtained from dual-energy-X-ray absorptiometry.Subjects and methodsA total of 161 postmenopausal women with baseline lumbar spine BMD T-scores between ? 1.0 and ? 2.5 underwent left forearm QCT using whole-body spiral CT scanners twice, 1 month apart. QCT volumes of interest were defined and analyzed at 3 specific radial regions: the ultradistal region by using slices at 8, 9, and 10 mm proximal to the ulnar styloid tip; the distal region by a slice 20 mm proximal; and the middle region by a slice 40 mm proximal. BMD, bone mineral content (BMC), volume, and average cortical thickness and circumference were measured. We evaluated QCT accuracy and precision and also report correlations between QCT and DXA for BMD and BMC.ResultsOverall accuracy and precision errors for BMD, BMC and volume were consistent with known skeletal QCT technology precision and were generally less than 3%. BMD and BMC assessed by QCT and DXA were correlated (r = 0.55 to 0.80).DiscussionWhole-body spiral CT scanners allow densitometric evaluations of the distal radius with good accuracy and very good precision. This original and convenient method provides a tool to further investigate cortical and trabecular bone variables in the peripheral skeleton in osteoporotic patients. These assessments, coupled with evaluation of the effects on cortical and trabecular bone measured in response to therapies for osteoporosis, may advance our understanding of the contributors to non-vertebral fracture occurrence.     

Experimental hip fracture load can be predicted from plain radiography by combined analysis of trabecular bone structure and bone geometry

Summary Computerized analysis of the trabecular structure was used to test whether femur failure load can be estimated from radiographs. The study showed that combined analysis of trabecular bone structure and geometry predicts in vitro failure load with similar accuracy as DXA. Introduction Since conventional radiography is widely available with low imaging cost, it is of considerable interest to discover how well bone mechanical competence can be determined using this technology. We tested the hypothesis that the mechanical strength of the femur can be estimated by the combined analysis of the bone trabecular structure and geometry. Methods The sample consisted of 62 cadaver femurs (34 females, 28 males). After radiography and DXA, femora were mechanically tested in side impact configuration. Fracture patterns were classified as being cervical or trochanteric. Computerized image analysis was applied to obtain structure-related trabecular parameters (trabecular bone area, Euler number, homogeneity index, and trabecular main orientation), and set of geometrical variables (neck-shaft angle, medial calcar and femoral shaft cortex thicknesses, and femoral neck axis length). Multiple linear regression analysis was performed to identify the variables that best explain variation in BMD and failure load between subjects. Results In cervical fracture cases, trabecular bone area and femoral neck axis length explained 64% of the variability in failure loads, while femoral neck BMD also explained 64%. In trochanteric fracture cases, Euler number and femoral cortex thickness explained 66% of the variability in failure load, while trochanteric BMD explained 72%. Conclusions Structural parameters of trabecular bone and bone geometry predict in vitro failure loads of the proximal femur with similar accuracy as DXA, when using appropriate image analysis technology.     

Cortical and trabecular bone in the femoral neck both contribute to proximal femur failure load prediction

Summary  We examined the contributions of femoral neck cortical and trabecular bone to proximal femur failure load. We found that trabecular bone mineral density explained a significant proportion of variance in failure load after accounting for total bone size and cortical bone mineral content or cortical area. Introduction  The relative contribution of femoral neck trabecular and cortical bone to proximal femur failure load is unclear. Objectives  Our primary objective was to determine whether trabecular bone mineral density (TbBMD) contributes to proximal femur failure load after accounting for total bone size and cortical bone content. Our secondary objective was to describe regional differences in the relationship among cortical bone, trabecular bone, and failure load within a cross-section of the femoral neck. Materials and methods  We imaged 36 human cadaveric proximal femora using quantitative computed tomography (QCT). We report total bone area (ToA), cortical area (CoA), cortical bone mineral content (CoBMC), and TbBMD measured in the femoral neck cross-section and eight 45° regions. The femora were loaded to failure. Results and observations  Trabecular bone mineral density explained a significant proportion of variance in failure load after accounting for ToA and then either CoBMC or CoA respectively. CoBMC contributed significantly to failure load in all regions of the femoral neck except the posterior region. TbBMD contributed significantly to failure load in all regions of the femoral neck except the inferoanterior, superoposterior, and the posterior regions. Conclusion  Both cortical and trabecular bone make significant contributions to failure load in ex vivo measures of bone strength.

Simulated increases in body fat and errors in bone mineral density measurements by DXA and QCT

Major alterations in body composition, such as with obesity and weight loss, have complex effects on the measurement of bone mineral density (BMD) by dual‐energy X‐ray absorptiometry (DXA). The effects of altered body fat on quantitative computed tomography (QCT) measurements are unknown. We scanned a spine phantom by DXA and QCT before and after surrounding with sequential fat layers (up to 12 kg). In addition, we measured lumbar spine and proximal femur BMD by DXA and trabecular spine BMD by QCT in 13 adult volunteers before and after a simulated 7.5 kg increase in body fat. With the spine phantom, DXA BMD increased linearly with sequential fat layering at the normal (p < 0.01) and osteopenic (p < 0.01) levels, but QCT BMD did not change significantly. In humans, fat layering significantly reduced DXA spine BMD values (mean ± SD: ?2.2 ± 3.7%, p = 0.05) and increased the variability of measurements. In contrast, fat layering increased QCT spine BMD in humans (mean ± SD: 1.5 ± 2.5%, p = 0.05). Fat layering did not change mean DXA BMD of the femoral neck or total hip in humans significantly, but measurements became less precise. Associations between baseline and fat‐simulation scans were stronger for QCT of the spine (r² = 0.97) than for DXA of the spine (r² = 0.87), total hip (r² = 0.80), or femoral neck (r² = 0.75). Bland‐Altman plots revealed that fat‐associated errors were greater for DXA spine and hip BMD than for QCT trabecular spine BMD. Fat layering introduces error and decreases the reproducibility of DXA spine and hip BMD measurements in human volunteers. Although overlying fat also affects QCT BMD measurements, the error is smaller and more uniform than with DXA BMD. Caution must be used when interpreting BMD changes in humans whose body composition is changing. © 2012 American Society for Bone and Mineral Research     

Changes in bone density during childhood and adolescence: an approach based on bone's biological organization.

Bone densitometry has great potential to improve our understanding of bone development. However, densitometric data in children rarely are interpreted in light of the biological processes they reflect. To strengthen the link between bone densitometry and the physiology of bone development, we review the literature on physiological mechanisms and structural changes determining bone mineral density (BMD). BMD (defined as mass of mineral per unit volume) is analyzed in three levels: in bone material (BMD(material)), in a bone's trabecular and cortical tissue compartments (BMD(compartment)), and in the entire bone (BMD(total)). BMD(material) of the femoral midshaft cortex decreases after birth to a nadir in the first year of life and thereafter increases. In iliac trabecular bone, BMD(material) also increases from infancy to adulthood, reflecting the decrease in bone turnover. BMD(material) cannot be determined with current noninvasive techniques because of insufficient spatial resolution. BM(compartment) of the femoral midshaft cortex decreases in the first months after birth followed by a rapid increase during the next 2 years and slower changes thereafter, reflecting changes in both relative bone volume and BMD(material). Trabecular BMD(compartment) increases in vertebral bodies but not at the distal radius. Quantitative computed tomography (QCT) allows for the determination of both trabecular and cortical BMD(compartment), whereas projectional techniques such as dual-energy X-ray absorptiometry (DXA) can be used only to assess cortical BMD(compartment) of long bone diaphyses. BMD(total) of long bones decreases by about 30% in the first months after birth, reflecting a redistribution of bone tissue from the endocortical to the periosteal surface. In children of school age and in adolescents, changes in BMD(total) are site-specific. There is a marked rise in BMD(total) at locations where relative cortical area increases (metacarpal bones, phalanges, and forearm), but little change at the femoral neck and midshaft. BMD(total) can be measured by QCT at any site of the skeleton, regardless of bone shape. DXA allows the estimation of BMD(total) at skeletal sites, which have an approximately circular cross-section. The system presented here may help to interpret densitometric results in growing subjects on a physiological basis.     

Quantitative ultrasound of cortical bone in the femoral neck predicts femur strength: Results of a pilot study

A significant risk of femoral neck (FN) fracture exists for men and women with an areal bone mineral density (aBMD) higher than the osteoporotic range, as measured with dual‐energy X‐ray absorptiometry (DXA). Separately measuring the cortical and trabecular FN compartments and combining the results would likely be a critical aspect of enhancing the diagnostic capabilities of a new technique. Because the cortical shell determines a large part of FN strength a novel quantitative ultrasound (QUS) technique that probes the FN cortical compartment was implemented. The sensitivity of the method to variations of FN cortical properties and FN strength was tested. Nine femurs (women, mean age 83 years) were subjected to QUS to measure the through transmission time‐of‐flight (TOF) at the FN and mechanical tests to assess strength. Quantitative computed tomography (QCT) scans were performed to enable analysis of the dependence of TOF on bone parameters. DXA was also performed for reference. An ultrasound wave propagating circumferentially in the cortical shell was measured in all specimens. Its TOF was not influenced by the properties of the trabecular compartment. Averaged TOF for nine FN measurement positions/orientations was significantly correlated to strength (R² = 0.79) and FN cortical QCT variables: total BMD (R² = 0.54); regional BMD in the inferoanterior (R² = 0.90) and superoanterior (R² = 0.57) quadrants; and moment of inertia (R² = 0.71). The results of this study demonstrate that QUS can perform a targeted measurement of the FN cortical compartment. Because the method involves mechanical guided waves, the QUS variable is related to the geometric and material properties of the cortical shell (cortical thickness, tissue elasticity, and porosity). This work opens the way to a multimodal QUS assessment of the proximal femur, combining our approach targeting the cortical shell with the existing modality sensitive to the trabecular compartment. In vivo feasibility of our approach has to be confirmed with experimental data in patients. © 2013 American Society for Bone and Mineral Research     

Mechanical strength of the proximal femur as predicted from geometric and densitometric bone properties at the lower limb versus the distal radius.

This experimental study compares geometric and densitometric properties of cortical and trabecular bone at the lower limb and the distal radius with those at the femoral neck, and evaluates their ability to predict mechanical failure loads of the proximal femur. One hundred five cadavers were examined with peripheral quantitative computed tomography (LpQCT), with measurements being performed in situ at the distal radius (4%, 20%, 33%), at the distal and proximal tibia, at the tibial and femoral shaft, and at the distal femur. Ex situ measurements were obtained at the femoral neck and at the proximal femoral shaft. Pairs of femora were mechanically tested in a vertical loading and a side impact (fall) configuration. The total (cross-sectional) bone mineral content and trabecular density, but not the cortical properties, displayed a higher association between the femoral neck and the peripheral lower limb than between the neck and the distal radius. Approximately 50%-60% of the variability of femoral failure loads (and >80% of trochanteric side impact fractures) were predicted by in vitro measurements at the neck. Geometric cortical parameters and density contributed independently and significantly to femoral strength. Measurements at the peripheral skeleton explained, however, only 30%-45% of the variability of femoral failure, with no significant difference between the lower limb and the distal radius. At peripheral sites, a combination of geometric and densitometric variables was slightly superior to bone mineral content alone in predicting failure in vertical loading, but this was less evident for cervical side impact fractures. The results show that a stronger association of total bone mineral content and trabecular density between the femoral neck and the lower limb does not translate into improved prediction of femoral strength from measurements at the lower limb vs. those at the distal radius.     

Effect of once-yearly zoledronic acid on the spine and hip as measured by quantitative computed tomography: results of the HORIZON Pivotal Fracture Trial

Summary

Changes in bone mineral density and bone strength following treatment with zoledronic acid (ZOL) were measured by quantitative computed analysis (QCT) or dual-energy X-ray absorptiometry (DXA). ZOL treatment increased spine and hip BMD vs placebo, assessed by QCT and DXA. Changes in trabecular bone resulted in increased bone strength.

Introduction

To investigate bone mineral density (BMD) changes in trabecular and cortical bone, estimated by quantitative computed analysis (QCT) or dual-energy X-ray absorptiometry (DXA), and whether zoledronic acid 5 mg (ZOL) affects bone strength.

Methods

In 233 women from a randomized, controlled trial of once-yearly ZOL, lumbar spine, total hip, femoral neck, and trochanter were assessed by DXA and QCT (baseline, Month 36). Mean percentage changes from baseline and between-treatment differences (ZOL vs placebo, t-test) were evaluated.

Results

Mean between-treatment differences for lumbar spine BMD were significant by DXA (7.0%, p?<?0.01) and QCT (5.7%, p?<?0.0001). Between-treatment differences were significant for trabecular spine (p?=?0.0017) [non-parametric test], trabecular trochanter (10.7%, p?<?0.0001), total hip (10.8%, p?<?0.0001), and compressive strength indices at femoral neck (8.6%, p?=?0.0001), and trochanter (14.1%, p?<?0.0001).

Conclusions

Once-yearly ZOL increased hip and spine BMD vs placebo, assessed by QCT vs DXA. Changes in trabecular bone resulted in increased indices of compressive strength.     

Quantitative Computed Tomography in the Evaluation of Spinal Osteoporosis Following Spinal Cord Injury

Disuse osteoporosis occurs in the lower extremities of patients with spinal cord injury (SCI). However, spinal osteoporosis is not usually observed in these patients. We investigated lumbar spine bone mineral density (BMD) in SCI patients using single energy quantitative computed tomography (QCT) and dual-energy X-ray absorptiometry (DXA). Our study population consisted of 64 patients with long-standing SCI. Spine BMD (g/cm³) was assessed by QCT at four vertebrae ranging from T11 to L4 with single midvertebral CT slices 1 cm thick parallel to the vertebral end-plates. Confounding variables affecting normal trabecular bone pattern, such as compression fractures, surgical hardware or fat replacement, were excluded. For a subset of 29 patients, DXA values of the spine and femoral neck were also measured, and QCT and DXA Z-scores were compared On the average, the 64 SCI patients had Z-scores 2.0 ± 1.2 below those of age-matched controls. In the subset of 29 patients with both QCT and DXA measurements, the QCT and DXA Z-scores were 2.4 ± 1.1 below and 1.3 ± 2.3 above the mean, respectively (p<0.0001). Our results indicate that QCT reveals osteoporosis of the spine after SCI, in contrast to DXA. We postulate that QCT is more valuable for evaluating spinal osteoporosis following SCI than DXA and thus recommend QCT for spinal BMD studies in SCI. Received: 20 December 1999 / Accepted: 17 April 2000     

Finite Element Analysis Based on In Vivo HR‐pQCT Images of the Distal Radius Is Associated With Wrist Fracture in Postmenopausal Women

BMD, bone microarchitecture, and bone mechanical properties assessed in vivo by finite element analysis were associated with wrist fracture in postmenopausal women. Introduction: Many fractures occur in individuals with normal BMD. Assessment of bone mechanical properties by finite element analysis (FEA) may improve identification of those at high risk for fracture. Materials and Methods: We used HR‐pQCT to assess volumetric bone density, microarchitecture, and μFE‐derived bone mechanical properties at the radius in 33 postmenopausal women with a prior history of fragility wrist fracture and 33 age‐matched controls from the OFELY cohort. Radius areal BMD (aBMD) was also measured by DXA. Associations between density, microarchitecture, mechanical parameters and fracture status were evaluated by univariate logistic regression analysis and expressed as ORs (with 95% CIs) per SD change. We also conducted a principal components (PCs) analysis (PCA) to reduce the number of parameters and study their association (OR) with wrist fracture. Results: Areal and volumetric densities, cortical thickness, trabecular number, and mechanical parameters such as estimated failure load, stiffness, and the proportion of load carried by the trabecular bone at the distal and proximal sites were associated with wrist fracture (p < 0.05). The PCA revealed five independent components that jointly explained 86.2% of the total variability of bone characteristics. The first PC included FE‐estimated failure load, areal and volumetric BMD, and cortical thickness, explaining 51% of the variance with an OR for wrist fracture = 2.49 (95% CI, 1.32–4.72). Remaining PCs did not include any density parameters. The second PC included trabecular architecture, explaining 12% of the variance, with an OR = 1.82 (95% CI, 0.94–3.52). The third PC included the proportion of the load carried by cortical versus trabecular bone, assessed by FEA, explaining 9% of the variance, and had an OR = 1.61 (95% CI, 0.94–2.77). Thus, the proportion of load carried by cortical versus trabecular bone seems to be associated with wrist fracture independently of BMD and microarchitecture (included in the first and second PC, respectively). Conclusions: These results suggest that bone mechanical properties assessed by μFE may provide information about skeletal fragility and fracture risk not assessed by BMD or architecture measurements alone and are therefore likely to enhance the prediction of wrist fracture risk.     

Automated 3D trabecular bone structure analysis of the proximal femur—prediction of biomechanical strength by CT and DXA

Summary

The standard diagnostic technique for assessing osteoporosis is dual X-ray absorptiometry (DXA) measuring bone mass parameters. In this study, a combination of DXA and trabecular structure parameters (acquired by computed tomography [CT]) most accurately predicted the biomechanical strength of the proximal femur and allowed for a better prediction than DXA alone.

Introduction

An automated 3D segmentation algorithm was applied to determine specific structure parameters of the trabecular bone in CT images of the proximal femur. This was done to evaluate the ability of these parameters for predicting biomechanical femoral bone strength in comparison with bone mineral content (BMC) and bone mineral density (BMD) acquired by DXA as standard diagnostic technique.

Methods

One hundred eighty-seven proximal femur specimens were harvested from formalin-fixed human cadavers. BMC and BMD were determined by DXA. Structure parameters of the trabecular bone (i.e., morphometry, fuzzy logic, Minkowski functionals, and the scaling index method [SIM]) were computed from CT images. Absolute femoral bone strength was assessed with a biomechanical side-impact test measuring failure load (FL). Adjusted FL parameters for appraisal of relative bone strength were calculated by dividing FL by influencing variables such as body height, weight, or femoral head diameter.

Results

The best single parameter predicting FL and adjusted FL parameters was apparent trabecular separation (morphometry) or DXA-derived BMC or BMD with correlations up to r?=?0.802. In combination with DXA, structure parameters (most notably the SIM and morphometry) added in linear regression models significant information in predicting FL and all adjusted FL parameters (up to R _adj?=?0.872) and allowed for a significant better prediction than DXA alone.

Conclusion

A combination of bone mass (DXA) and structure parameters of the trabecular bone (linear and nonlinear, global and local) most accurately predicted absolute and relative femoral bone strength.     

Association of 3D Geometric Measures Derived From Quantitative Computed Tomography With Hip Fracture Risk in Older Men

We investigated the associations of 3D geometric measures and volumetric bone mineral density (vBMD) of the proximal femur assessed by quantitative computed tomography (QCT) with hip fracture risk among elderly men. This study was a prospective case‐cohort design nested within the Osteoporotic Fractures in Men Study (MrOS) cohort. QCT scans of 230 men (65 with confirmed hip fractures) were evaluated with Mindways' QCTPRO‐BIT software. Measures that are indicative of bone strength for the femoral neck (FN) and for the trochanteric region (TR) were defined. Bending strength measures were estimated by minimum section modulus, buckling strength by buckling ratio, and a local thinning index (LTI). Integral and trabecular vBMD measures were also derived. Areal BMD (aBMD) of the total proximal femur from dual‐energy X‐ray absorptiometry (DXA) is presented for comparison. Associations of skeletal measures with incident hip fracture were estimated with hazard ratios (HR) per standard deviation and their 95% confidence intervals (CI) from Cox proportional hazard regression models with adjustment for age, body mass index (BMI), site, and aBMD. Men with hip fractures were older than men without fracture (77.1 ± 6.0 years versus 73.3 ± 5.7 years, p < 0.01). Age, BMI, and site‐adjusted HRs were significant for all measures except TR_LTI. Total femural BMD by DXA (HR = 4.9, 95% CI 2.5–9.9) and QCT (HR = 5.5, 95% CI 2.5–11.7) showed the strongest association followed by QCT FN integral vBMD (HR = 3.6, 95% CI 1.8–6.9). In models that additionally included aBMD, FN buckling ratio (HR = 1.9, 95% CI 1.1–3.2) and trabecular vBMD of the TR (HR = 2.0, 95% CI 1.2–3.4) remained associated with hip fracture risk, independent of aBMD. QCT‐derived 3D geometric indices of instability of the proximal femur were significantly associated with incident hip fractures, independent of DXA aBMD. Buckling of the FN is a relevant failure mode not entirely captured by DXA. Further research to study these relationships in women is warranted. © 2016 American Society for Bone and Mineral Research.     

Distribution of bone density and cortical thickness in the proximal femur and their association with hip fracture in postmenopausal women: a quantitative computed tomography study

Summary

The quantitative computed tomography (QCT) scans in an individually matched case–control study of women with hip fracture were analysed. There were widespread deficits in the femoral volumetric bone mineral density (vBMD) and cortical thickness of cases, and cortical vBMD and thickness discriminated hip fracture independently of BMD by dual-energy X-ray absorptiometry (DXA).

Introduction

Acknowledging the limitations of QCT associated with partial volume effects, we used QCT in an individually matched case–control study of women with hip fracture to better understand its structural basis.

Methods

Fifty postmenopausal women (55–89 years) who had sustained hip fractures due to low-energy trauma underwent QCT scans of the contralateral hip within 3 months of the fracture. For each case, postmenopausal women, matched by age (±5 years), weight (±5 kg) and height (±5 cm), were recruited as controls. We quantified cortical, trabecular and integral vBMD and apparent cortical thickness (AppCtTh) in four quadrants of cross-sections along the length of the femoral head (FH), femoral neck (FN), intertrochanter and trochanter and examined their association with hip fracture.

Results

Women with hip or intracapsular (IC) fracture had significantly (p?<?0.05) lower vBMD and AppCtTh than the controls in the majority of cross-sections and quadrants of the proximal femur, and both cortical and trabecular compartments are involved. Cortical vBMD and AppCtTh in the FH and FN were associated with hip and IC fractures independent of hip areal BMD (aBMD). The combination of AppCtTh and trabecular or integral vBMD discriminated hip fracture, whereas the combination of FH and FN AppCtTh discriminated IC fracture significantly (p?<?0.05) better than the hip aBMD.

Conclusion

Deficits in vBMD and AppCtTh in cases were widespread in the proximal femur, and cortical vBMD and AppCtTh discriminated hip fracture independently of aBMD by DXA.     

Effect of Low‐Magnitude Mechanical Stimuli on Bone Density and Structure in Pediatric Crohn's Disease: A Randomized Placebo‐Controlled Trial

Pediatric Crohn's Disease (CD) is associated with low trabecular bone mineral density (BMD), cortical area, and muscle mass. Low‐magnitude mechanical stimulation (LMMS) may be anabolic. We conducted a 12‐month randomized double‐blind placebo‐controlled trial of 10 minutes daily exposure to LMMS (30 Hz frequency, 0.3 g peak‐to‐peak acceleration). The primary outcomes were tibia trabecular BMD and cortical area by peripheral quantitative CT (pQCT) and vertebral trabecular BMD by QCT; additional outcomes included dual‐energy X‐ray absorptiometry (DXA) whole body, hip and spine BMD, and leg lean mass. Results were expressed as sex‐specific Z‐scores relative to age. CD participants, ages 8 to 21 years with tibia trabecular BMD <25th percentile for age, were eligible and received daily cholecalciferol (800 IU) and calcium (1000 mg). In total, 138 enrolled (48% male), and 121 (61 active, 60 placebo) completed the 12‐month trial. Median adherence measured with an electronic monitor was 79% and did not differ between arms. By intention‐to‐treat analysis, LMMS had no significant effect on pQCT or DXA outcomes. The mean change in spine QCT trabecular BMD Z‐score was +0.22 in the active arm and –0.02 in the placebo arm (difference in change 0.24 [95% CI 0.04, 0.44]; p = 0.02). Among those with >50% adherence, the effect was 0.38 (95% CI 0.17, 0.58, p < 0.0005). Within the active arm, each 10% greater adherence was associated with a 0.06 (95% CI 0.01, 1.17, p = 0.03) greater increase in spine QCT BMD Z‐score. Treatment response did not vary according to baseline body mass index (BMI) Z‐score, pubertal status, CD severity, or concurrent glucocorticoid or biologic medications. In all participants combined, height, pQCT trabecular BMD, and cortical area and DXA outcomes improved significantly. In conclusion, LMMS was associated with increases in vertebral trabecular BMD by QCT; however, no effects were observed at DXA or pQCT sites. © 2016 American Society for Bone and Mineral Research.     

Proximal Femoral Structure and the Prediction of Hip Fracture in Men: A Large Prospective Study Using QCT

The structure of the femoral neck contributes to hip strength, but the relationship of specific structural features of the hip to hip fracture risk is unclear. The objective of this study is to determine the contribution of structural features and volumetric density of both trabecular and cortical bone in the proximal femur to the prediction of hip fracture in older men. Baseline QCT scans of the hip were obtained in 3347 men ≥65 yr of age enrolled in the Osteoporotic Fractures in Men Study (MrOS). All men were followed prospectively for an average of 5.5 yr. Areal BMD (aBMD) by DXA was also assessed. We determined the associations between QCT‐derived measures of femoral neck structure, volumetric bone density, and hip fracture risk. Forty‐two men sustained incident hip fractures during follow‐up: an overall rate of 2.3/1000 person‐years. Multivariable analyses showed that, among the QCT‐derived measures, lower percent cortical volume (hazard ratio [HR] per SD decrease: 3.2; 95% CI: 2.2–4.6), smaller minimal cross‐sectional area (HR: 1.6; 95% CI: 1.2–2.1), and lower trabecular BMD (HR: 1.7; 95% CI: 1.2–2.4) were independently related to increased hip fracture risk. Femoral neck areal BMD was also strongly related to hip fracture risk (HR: 4.1; 95% CI: 2.7–6.4). In multivariable models, percent cortical volume and minimum cross‐sectional area remained significant predictors of hip fracture risk after adjustment for areal BMD, but overall prediction was not improved by adding QCT parameters to DXA. Specific structural features of the proximal femur were related to an increased risk of hip fracture. Whereas overall hip fracture prediction was not improved relative to aBMD, by adding QCT parameters, these results yield useful information concerning the causation of hip fracture, the evaluation of hip fracture risk, and potential targets for therapeutic intervention.     

Effect of aging on trabecular and compact bone components of proximal and ultradistal radius

Bone densitometry has become a major tool for osteoporosis risk assessment. The traditional dual-energy X-ray absorptiometry (DXA) methods are able to evaluate the bone mineral content (BMC; mg/cm) and the areal density (BMD; mg/cm²), but only quantitative computed tomography (QCT) has the potential to measure the true volumetric bone density in the sense of mass per unit volume (mg/cm³). Peripheral QCT (pQCT) measurements were carried out at the non-dominant radius using a Stratec XCT 960 (Unitrem, Roma) in 241 postmenopausal and 29 premenopausal women. The sites of evaluation were both the ultradistal and the proximal radius. The technique used has a coefficient of variation of 2% and it allows separation of the bone section into trabecular and cortical bone on the basis of density threshold. Bone mass of radius, hip and spine was also evaluated by DXA procedures. The bone density data obtained by pQCT were significantly correlated with all DXA measurements. The correlation coefficients between their respective BMD values ranged from 0.48 to 0.75, but for the BMC values of the radius the correlation coefficients ranged from 0.82 to 0.93. The BMD values measured by DXA, but not by pQCT, were positively related with patient heights. All pQCT density measurements, including those obtained at the proximal radius and containing exclusively cortical bone, where negatively related with age and years since menopause. A partial volume effect, which is increasingly relevant the thinner are the bone cortices, might explain that. However, by applying increasing density thresholds, cortical bone density seems to decrease with age as a consequence of a gradual density diminution from the inner part of the bone cortex outwards. Trabecular bone density decreases with aging, but its overall mass does not change as a consequence of an age-related enlargement of trabecular area. Thus, the proportion of trabecular bone over total bone rises, and this might be relevant for our understanding of the age-related changes in bone turnover and rate of bone loss.     

Mechanical strength of the thoracolumbar spine in the elderly: prediction from in situ dual-energy X-ray absorptiometry,quantitative computed tomography (QCT), upper and lower limb peripheral QCT,and quantitative ultrasound

The objective of this study was to compare the ability of clinically available densitometric measurement techniques for evaluating vertebral strength in elderly individuals. Measurements were related to experimentally determined failure strength in the thoracic and lumbar spine. In 127 specimens (82 women and 45 men, age 80 +/- 10 years), dual-energy X-ray absorptiometry (DXA) was performed at the lumbar spine, femur, radius, and total body, and peripheral-quantitative computed tomography (pQCT) at the distal radius, tibia, and femur under in situ conditions with intact soft tissues. Spinal QCT and calcaneal ultrasound parameters were performed ex situ in degassed specimens. Mechanical failure loads of thoracic vertebrae 6 and 10 (T-6 and -10), and lumbar vertebra 3 (L-3) were determined in axial compression on functional three-segment units. In situ anteroposterior DXA and QCT of the lumbar spine explained approximately 65% of the variability of thoracolumbar failure. A combination of cortical and trabecular density (QCT) provided the best prediction in the lumbar spine. However, this was not the case in the thoracic spine, for which lumbar cortical density (QCT) and DXA provided significantly better estimates than trabecular density (QCT). pQCT was significantly less correlated with the strength of lumbar and thoracic vertebrae (r(2) = 40%), but was equivalent to femoral or radial DXA. pQCT measurements in the lower limb showed no advantage over those at the distal radius. Ultrasound explained approximately 25% of the variability of vertebral failure strength and added independent information to spinal QCT, but not to spinal DXA. These experimental results advocate site-specific assessment of vertebral strength by either spinal DXA or QCT.     

Femoral Neck Trabecular Bone: Loss With Aging and Role in Preventing Fracture

Hip fracture risk rises 100‐ to 1000‐fold over six decades of age, but only a minor part of this increase is explained by declining BMD. A potentially independent cause of fragility is cortical thinning predisposing to local crushing, in which bone tissue's material disintegrates at the microscopic level when compressed beyond its capacity to maintain integrity. Elastic instability or buckling of a much thinned cortex might alternatively occur under compression. In a buckle, the cortex moves approximately at right angles to the direction of load, thereby distorting its microstructure, eventually to the point of disintegration. By resisting buckling movement, trabecular buttressing would protect the femoral neck cortex against this type of failure but not against crushing. We quantified the effect of aging on trabecular BMD in the femoral neck and assessed its contribution to cortical elastic stability, which determines resistance to buckling. Using CT, we measured ex vivo the distribution of bone in the midfemoral necks of 35 female and 33 male proximal femurs from cases of sudden death in those 20–95 yr of age. We calculated the critical stress σ_cr, at which the cortex was predicted to buckle locally, from the geometric properties and density of the cortical zone most highly loaded in a sideways fall. Using long‐established engineering principles, we estimated the amount by which stability or buckling resistance was increased by the trabecular bone supporting the most stressed cortical sector in each femoral neck. We repeated these measurements and calculations in an age‐ and sex‐matched series of femoral necks donated by women who had suffered intracapsular hip fracture and controls, using histological measurements of cortical thickness to improve accuracy. With normal aging, trabecular BMD declined asymmetrically, fastest in the supero‐lateral one‐half (in antero‐posterior projection) of the trabecular compartment. When viewed axially with respect to the femoral neck, the most rapid loss of trabecular bone occurred in the posterior part of this region (supero‐posterior [S‐P]), amounting to a 42% reduction in women (34% in men) over five decades of adult age. Because local cortical bone thickness declined comparably, age had no significant effect on the relative contributions of cortical and trabecular bone to elastic stability, and trabecular bone was calculated to contribute 40% (in men) and 43% (in women) to the S‐P cortex of its overall elastic stability. Hip fracture cases had reduced elastic stability compared with age‐matched controls, with a median reduction of 49% or 37%, depending on whether thickness was measured histologically or by CT (pQCT; p < 0.002 for both). This effect was because of reduced cortical thickness and density. Trabecular BMD was similar in hip fracture cases and controls. The capacity of the femur to resist fracture in a sideways fall becomes compromised with normal aging because cortical thickness and trabecular BMD in the most compressed part of the femoral neck both decline substantially. This decline is relatively more rapid than that of femoral neck areal BMD. If elastic instability rather than cortical crushing initiates the fracture event, interventions that increase trabecular bone in the proximal femur have great potential to reduce fracture risk because the gradient defining the increase in elastic stability with increasing trabecular BMD is steep, and most hip fracture cases have sufficient trabecular bone for anabolic therapies to build on.