Trabecular Bone Structure Analysis in the Osteoporotic Spine Using a Clinical In Vivo Setup for 64‐Slice MDCT Imaging: Comparison to μCT Imaging and μFE Modeling

Assessment of trabecular microarchitecture may improve estimation of biomechanical strength, but visualization of trabecular bone structure in vivo is challenging. We tested the feasibility of assessing trabecular microarchitecture in the spine using multidetector CT (MDCT) on intact human cadavers in an experimental in vivo–like setup. BMD, bone structure (e.g., bone volume/total volume = BV/TV; trabecular thickness = Tb.Th; structure model index = SMI) and bone texture parameters were evaluated in 45 lumbar vertebral bodies using MDCT (mean in‐plane pixel size, 274 μm²; slice thickness, 500 μm). These measures were correlated with structure measures assessed with μCT at an isotropic spatial resolution of 16 μm and to microfinite element models (μFE) of apparent modulus and stiffness. MDCT‐derived BMD and structure measures showed significant correlations to the density and structure obtained by μCT (BMD, R² = 0.86, p < 0.0001; BV/TV, R² = 0.64, p < 0.0001; Tb.Th, R² = 0.36, p < 0.01). When comparing μCT‐derived measures with μFE models, the following correlations (p < 0.001) were found for apparent modulus and stiffness, respectively: BMD (R² = 0.58 and 0.66), BV/TV (R² = 0.44 and 0.58), and SMI (R² = 0.44 and 0.49). However, the overall highest correlation (p < 0.001) with μFE app. modulus (R² = 0.75) and stiffness (R² = 0.76) was achieved by the combination of QCT‐derived BMD with the bone texture measure Minkowski Dimension. In summary, although still limited by its spatial resolution, trabecular bone structure assessment using MDCT is overall feasible. However, when comparing with μFE‐derived bone properties, BMD is superior compared with single parameters for microarchitecture, and correlations further improve when combining with texture measures.     

Use of high resolution dual‐energy x‐ray absorptiometry‐region free analysis (DXA‐RFA) to detect local periprosthetic bone remodeling events

Dual‐energy x‐ray absorptiometry (DXA) is the gold standard method for measuring periprosthetic bone remodeling, but relies on a region of interest (ROI) analysis approach. While this addresses issues of anatomic variability, it is insensitive to bone remodeling events at the sub‐ROI level. We have validated a high‐spatial resolution tool, termed DXA‐region free analysis (DXA‐RFA) that uses advanced image processing approaches to allow quantitation of bone mineral density (BMD) at the individual pixel (data‐point) level. Here we compared the resolution of bone remodeling measurements made around a stemless femoral prosthesis in 18 subjects over 24 months using ROI‐based analysis versus that made using DXA‐RFA. Using the ROI approach the regional pattern of BMD change varied by region, with greatest loss in ROI5 (20%, p < 0.001), and largest gain in ROI4 (6%, p < 0.05). Analysis using DXA‐RFA showed a focal zone of increased BMD localized to the prosthesis–bone interface (30–40%, p < 0.001) that was not resolved using conventional DXA analysis. The 20% bone loss observed in ROI5 with conventional DXA was resolved to a focal area adjacent to the cut surface of the infero‐medial femoral neck (up to 40%, p < 0.0001). DXA‐RFA enables high resolution analysis of DXA datasets without the limitations incurred using ROI‐based approaches. © 2015 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 33:712–716, 2015.     

The Contribution of Cortical and Cancellous Bone to Dual-Energy X-ray Absorptiometry Measurements in the Female Proximal Femur

Dual-energy X-ray absorptiometry (DXA) is the most common method for determining bone mineral density (BMD) in the proximal femur. However, there remain questions concerning the contribution of cortical and cancellous bone to this technology in the proximal femur. The purpose of this investigation was to identify structural and compositional characteristics of human bone in the proximal femur that significantly influence DXA BMD measurements. Twenty-four femora were obtained at autopsy from Caucasian females ranging in age from 17 to 92 years (mean ± SD, 61 ± 25 years). DXA scans were performed on each specimen with a Hologic QDR-2000 densitometer. Direct measurements were determined from proximal femoral sections for cancellous bone (volume fraction, ash fraction, cancellous cross-sectional area and percent cancellous cross-sectional area), cortical bone (thickness, ash fraction, porosity, cortical cross-sectional area and percent cortical cross-sectional area) and anteroposterior thickness. These parameters were compared with the associated DXA measurements by means of simple and multiple regressions. Cancellous volume fraction was the best predictor of variability of DXA measurements for both the neck and trochanter, with an R ² of 0.87 and 0.76, respectively (p<0.0001). There was only a minor influence of cortical factors such as thickness (neck and trochanter R ²= 0.51 and 0.42, respectively, p<0.001) and trochanteric cross-sectional area (R ²= 0.21, p<0.05). Although the accuracy for determining specific components of the proximal femur was low, the DXA BMD measurement was a strong predictor of cancellous bone factors, but not cortical bone factors that have been shown to change significantly with age. Received: 2 February 2000 / Accepted: 7 September 2000     

Effect of cavity preparation and bone mineral density on bone‐interface densification and bone‐implant contact during press‐fit implantation of hip stems

Implant loosening and periprosthetic fracture are two major revision causes for uncemented hip stems. The chosen method of cavity preparation could play a key role for both failure mechanisms. The aim of this study was to determine the dependence of the broach type as well as patient bone mineral density (BMD) on densification and contact conditions at the bone‐implant interface. Hip stems were implanted into cadaveric femora using compaction, blunt extraction or sharp extraction broaches with computed tomography scans performed prior to broaching, after broaching and after stem implantation. Proximal periprosthetic bone densification as well as press‐fit, contact area and stem seating relative to the last broach were determined. Median bone densification was higher with the compaction and blunt extraction broaches compared to sharp extraction broaches (181% and 177%, respectively, p = 0.002). The bone densification of femora prepared with compaction broaching increased with higher BMD (R² = 0.183, p = 0.037), while stem seating decreased with higher BMD for all broach types (R² = 0.259, p = 0.001). Incomplete seated prostheses were associated with smaller press‐fit and bone‐implant contact area (R² = 0.249, p = 0.001; R² = 0.287, p < 0.001). Clinical Significance: The results suggest that compaction broaching maximizes bone densification in patients with higher bone density. However, there appears to be an increased risk of insufficient stem seating in high‐density bone that could limit the benefits for primary stability. For lower quality bone, the broach type appears to play a lesser role, but care must be taken to limit extensive stem seating which might increase periprosthetic fracture risk. © 2019 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 37:1580–1589, 2019.     

Application of High‐Resolution Skeletal Imaging to Measurements of Volumetric BMD and Skeletal Microarchitecture in Chinese‐American and White Women: Explanation of a Paradox

Asian women have lower rates of hip and forearm fractures despite lower areal BMD (aBMD) by DXA compared with white women and other racial groups. We hypothesized that the lower fracture rates may be explained by more favorable measurements of volumetric BMD (vBMD) and microarchitectural properties, despite lower areal BMD. To address this hypothesis, we used high‐resolution pQCT (HRpQCT), a new method that can provide this information noninvasively. We studied 63 premenopausal Chinese‐American (n = 31) and white (n = 32) women with DXA and HRpQCT. aBMD by DXA did not differ between groups for the lumbar spine (1.017 ± 0.108 versus 1.028 ± 0.152 g/cm²; p = 0.7), total hip (0.910 ± 0.093 versus 0.932 ± 0.134 g/cm²; p = 0.5), femoral neck (0.788 ± 0.083 versus 0.809 ± 0.129 g/cm²; p = 0.4), or one‐third radius (0.691 ± 0.052 versus 0.708 ± 0.047 g/cm²; p = 0.2). HRpQCT at the radius indicated greater trabecular (168 ± 41 versus 137 ± 33 mg HA/cm³; p = <0.01) and cortical (963 ± 46 versus 915 ± 42 mg HA/cm³; p < 0.0001) density; trabecular bone to tissue volume (0.140 ± 0.034 versus 0.114 ± 0.028; p = <0.01); trabecular (0.075 ± 0.013 versus 0.062 ± 0.009 mm; p < 0.0001) and cortical thickness (0.98 ± 0.16 versus 0.80 ± 0.14 mm; p < 0.0001); and lower total bone area (197 ± 34 versus 232 ± 33 mm²; p = <0.001) in the Chinese versus white women and no difference in trabecular number, spacing, or inhomogeneity before adjustment for covariates. Similar results were observed at the weight‐bearing tibia. At the radius, adjustment for covariates did not change the direction or significance of differences except for bone, which became similar between the groups. However, at the tibia, adjustment for covariates attenuated differences in cortical BMD and bone area and accentuated differences in trabecular microarchitecture such that Chinese women additionally had higher trabecular number and lower trabecular spacing, as well as inhomogeneity after adjustment. Using the high‐resolution technology, the results provide a mechanistic explanation for why Chinese women have fewer hip and forearm fractures than white women.     

Quantitating the effect of prosthesis design on femoral remodeling using high‐resolution region‐free densitometric analysis (DXA‐RFA)

Dual energy X‐ray absorptiometry (DXA) is the reference standard method used to study bone mineral density (BMD) after total hip arthroplasty (THA). However, the subtle, spatially complex changes in bone mass due to strain‐adaptive bone remodeling relevant to different prosthesis designs are not readily resolved using conventional DXA analysis. DXA region free analysis (DXA RFA) is a novel computational image analysis technique that provides a high‐resolution quantitation of periprosthetic BMD. Here, we applied the technique to quantitate the magnitude and areal size of periprosthetic BMD changes using scans acquired during two previous randomized clinical trials (2004 to 2009); one comparing three cemented prosthesis design geometries, and the other comparing a hip resurfacing versus a conventional cementless prosthesis. DXA RFA resolved subtle differences in magnitude and area of bone remodeling between prosthesis designs not previously identified in conventional DXA analyses. A mean bone loss of 10.3%, 12.1%, and 11.1% occurred for the three cemented prostheses within a bone area fraction of 14.8%, 14.4%, and 6.2%, mostly within the lesser trochanter (p < 0.001). For the cementless prosthesis, a diffuse pattern of bone loss (−14.3%) was observed at the shaft of femur in a small area fraction of 0.6% versus no significant bone loss for the hip resurfacing prosthesis (p < 0.001). BMD increases were observed consistently at the greater trochanter for all prostheses except the hip‐resurfacing prosthesis, where BMD increase was widespread across the metaphysis (p < 0.001). DXA RFA provides high‐resolution insights into the effect of prosthesis design on the local strain environment in bone. © 2017 The Authors Journal of Orthopaedic Research published by Wiley Periodicals, Inc. on behalf of Orthopaedic Research Society. J Orthop Res 35:2203–2210, 2017.

     

Effect of Surgery Versus Observation: Skeletal 5‐Year Outcomes in a Randomized Trial of Patients With Primary HPT (the SIPH Study)

Mild primary hyperparathyroidism (PHPT) is known to affect the skeleton, even though patients usually are asymptomatic. Treatment strategies have been widely discussed. However, long‐term randomized studies comparing parathyroidectomy to observation are lacking. The objective was to study the effect of parathyroidectomy (PTX) compared with observation (OBS) on bone mineral density (BMD) in g/cm² and T‐scores and on biochemical markers of bone turnover (P1NP and CTX‐1) in a prospective randomized controlled study of patients with mild PHPT after 5 years of follow‐up. Of 191 patients with mild PHPT randomized to either PTX or OBS, 145 patients remained for analysis after 5 years (110 with validated DXA scans). A significant decrease in P1NP (p < 0.001) and CTX‐1 (p < 0.001) was found in the PTX group only. A significant positive treatment effect of surgery compared with observation on BMD (g/cm²) was found for the lumbar spine (LS) (p = 0.011), the femoral neck (FN) (p < 0.001), the ultradistal radius (UDR) (p = 0.042), and for the total body (TB) (p < 0.001) but not for the radius 33% (Rad33), where BMD decreased significantly also in the PTX group (p = 0.012). However, compared with baseline values, there was no significant BMD increase in the PTX group, except for the lumbar spine. In the OBS group, there was a significant decrease in BMD (g/cm²) for all compartments (FN, p < 0.001; Rad33, p = 0.001; UDR, p = 0.006; TB, p < 0.001) with the exception of the LS, where BMD was stable. In conclusion, parathyroidectomy improves BMD and observation leads to a small but statistically significant decrease in BMD after 5 years. Thus, bone health appears to be a clinical concern with long‐term observation in patients with mild PHPT. © 2017 American Society for Bone and Mineral Research.     

Contribution of Trabecular and Cortical Components to Biomechanical Behavior of Human Vertebrae: An Ex Vivo Study

Whereas there is clear evidence for a strong influence of bone quantity (i.e., bone mass or bone mineral density) on vertebral mechanical behavior, there are fewer data addressing the relative influence of cortical and trabecular bone microarchitecture. The aim of this study was to determine the relative contributions of bone mass, trabecular microarchitecture, and cortical thickness and curvature to the mechanical behavior of human lumbar vertebrae. Thirty‐one L3 vertebrae (16 men, 15 women, aged 75 ± 10 years and 76 ± 10 years, respectively) were obtained. Bone mineral density (BMD) of the vertebral body was assessed by lateral dual energy X‐ray absorptiometry (DXA), and 3D trabecular microarchitecture and anterior cortical thickness and curvature was assessed by micro‐computed tomography (µCT). Then compressive stiffness, work to failure, and failure load were measured on the whole vertebral body. BMD was correlated with compressive stiffness (r = 0.60), failure load (r = 0.70), and work to failure (r = 0.55). Except for the degree of anisotropy, all trabecular and cortical parameters were correlated with mechanical behavior (r = 0.36 to 0.58, p = .05 to .001, and r = 0.36 to 0.61, p = .05 to .0001, respectively). Stepwise and multiple regression analyses indicated that the best predictor of (1) failure load was the combination of BMD, structural model index (SMI), and trabecular thickness (Tb.Th) (R = 0.80), (2) stiffness was the combination of BMD, Tb.Th, and curvature of the anterior cortex (R = 0.82), and (3) work to failure was the combination of anterior cortical thickness and BMD (R = 0.68). Our data imply that measurements of cortical thickness and curvature may enhance prediction of vertebral fragility and that therapies that improve both vertebral cortical and trabecular bone properties may provide a greater reduction in fracture risk. © 2010 American Society for Bone and Mineral Research     

Prediction of Human Femoral Bone Strength Using Ultrasound Velocity and BMD: An In Vitro Study

The stiffness and strength of cancellous bone are important in the management of skeletal diseases such as osteoporosis. These properties are a function not only of bone density but also of bone architecture, some measure of which can be provided by quantitative ultrasound. The ability of quantitative ultrasound and bone mineral density (BMD) to predict stiffness and strength of human femoral heads removed from live subjects during hip replacement was assessed. Stiffness and strength were measured using a uniaxial compression test. Ultrasound velocity was measured using the pulse-submersion technique (McClue CUBAResearch) and BMD using DXA (Lunar DPX-L). Ultrasound velocity (quantitative ultrasound) and stiffness varied with the three orthogonal directions, the highest significance being between the proximo-distal (PD) and antero-posterior (AP) directions (p < 0.0001) for stiffness and p = 0.0003 for velocity). Ultrasound velocity was significantly correlated with compressive bone strength (r = 0.76, p < 0.0001) and stiffness (r = 0.79–0.83, p < 0.0001). BMD was also significantly correlated with compressive strength (r = 0.82, p < 0.0001) and stiffness (r = 0.66–0.81, p < 0.001). Using multiple regression analysis both BMD and velocity were significant predictors of strength (r = 0.88, p = 0.0004 and 0.0054 respectively) and stiffness r = 0.92, p = 0.0001 and 0.0003 respectively). BMD and velocity were still independent significant predictors of both stiffness (r = 0.93, p < 0.0001 and 0.0001 respectively) and strength (r = 0.89, p < 0.0001 and 0.02) when they combined as a product (BMDⁿ*V^m). This suggests that BMD measured using DXA, if used in conjunction with ultrasound velocity, may be able to improve osteoporosis risk assessment. The information about femur anisotropy may also be important for hip prosthesis and in vivo modelling.     

In Vivo Magnetic Resonance Detects Rapid Remodeling Changes in the Topology of the Trabecular Bone Network After Menopause and the Protective Effect of Estradiol

Introduction : Estrogen depletion after menopause is accompanied by bone loss and architectural deterioration of trabecular bone. The hypothesis underlying this work is that the μMRI‐based virtual bone biopsy can capture the temporal changes of scale and topology of the trabecular network and that estrogen supplementation preserves the integrity of the trabecular network. Materials and Methods : Subjects studied were early postmenopausal women, 45–55 yr of age (N = 65), of whom 32 were on estrogen (estradiol group), and the remainder were not (control group). Early menopause was defined by amenorrhea for 6–24 mo and elevated serum follicle‐stimulating hormone (FSH) concentration. The subjects were evaluated with three imaging modalities at baseline and 12 and 24 mo to determine the temporal changes in trabecular and cortical architecture and density. μMRI of the distal radius and tibia was performed at 137 × 137 × 410‐μm³ voxel size. The resulting bone volume fraction maps were Fourier interpolated to a final voxel size of 45.7 × 45.7 × 136.7 μm³, binarized, skeletonized, and subjected to 3D digital topological analysis (DTA). Skeletonization converts trabecular rods to curves and plates to surfaces. Parameters quantifying scale included BV/TV, whereas DTA parameters included the volume densities of curves (C) and surface (S)‐type voxels, as well as composite parameters: the surface/curve ratio (S/C), and erosion index (EI, ratio of the sum of parameters expected to increase with osteoclastic resorption divided by the sum of those expected to decrease). For comparison, pQCT of the same peripheral locations was conducted, and trabecular density and cortical structural parameters were measured. Areal BMD of the lumbar vertebrae and hip was also measured. Results : Substantial changes in trabecular architecture of the distal tibia, in particular as they relate to topology of the network, were detected after 12 mo in the control group. S/C decreased 5.6% (p < 0.0005), and EI increased 7.1% (p < 0.0005). Most curve‐ and profile‐type voxels (representative of trabecular struts), increased significantly (p < 0.001). Curve and profile edges resulting from disconnection of rod‐like trabeculae increased by 9.8% and 5.1% (p = 0.0001 and <0.001, respectively). Similarly, DXA BMD in the spine and hip decreased 2.6% and 1.3% (p < 0.0001 and <0.005, respectively), and pQCT cortical area decreased 3.6% (p = 0.0001). However, neither trabecular density nor BV/TV changed. Furthermore, none of the parameters measured in the estradiol group were significantly different after 12 mo. Substantial differences in the mean changes from baseline between the estradiol treatment and control groups, in particular after 24 mo, were observed, with relative group differences as large as 13% (S/C, p = 0.005), and the relative changes in the two groups had the opposite sign for most parameters. The observed temporal alterations in architecture are consistent with remodeling changes that involve gradual conversion of plate‐like to rod‐like trabecular bone along with disconnection of trabecular elements, even in the absence of a net loss of trabecular bone. The high‐resolution 3D rendered images provide direct evidence of the above remodeling changes in individual subjects. The radius structural data indicated similar trends but offered no definitive conclusions. Conclusions : The short‐term temporal changes in trabecular architecture after menopause, and the protective effects of estradiol ensuring maintenance of a more plate‐like TB architecture, reported here, have not previously been observed in vivo. This work suggests that MRI‐based in vivo micromorphometry of trabecular bone has promise as a tool for monitoring osteoporosis treatment.     

Abdominal Aortic Calcification,BMD, and Bone Microstructure: A Population‐Based Study

To better define the relationship between vascular calcification and bone mass/structure, we assessed abdominal aortic calcification (AAC), BMD, and bone microstructure in an age‐stratified, random sample of 693 Rochester, MN, residents. Participants underwent QCT of the spine and hip and high‐resolution pQCT (HRpQCT) of the radius to define volumetric BMD (vBMD) and microstructural parameters. AAC was quantified with the Agatston scoring method. In men, AAC correlated with lower vertebral trabecular and femoral neck vBMD (p < 0.001), but not after age or multivariable (age, body mass index, smoking status) adjustment. Separation into <50 and ≥50 yr showed this pattern only in the older men. BV/TV and Tb.Th inversely correlated with AAC in all men (p < 0.001), and Tb.Th remained significantly correlated after age adjustment (p < 0.05). Tb.N positively correlated with AAC in younger men (p < 0.001) but negatively correlated in older men (p < 0.001). The opposite was true with Tb.Sp (p = 0.01 and p < 0.001, respectively). Lower Tb.N and higher Tb.Sp correlated with AAC in older men even after multivariable adjustment. Among all women and postmenopausal women, AAC correlated with lower vertebral and femoral neck vBMD (p < 0.001) but not after adjustment. Lower BV/TV and Tb.Th correlated with AAC (p = 0.03 and p = 0.04, respectively) in women, but not after adjustment. Our findings support an age‐dependent association between AAC and vBMD. We also found that AAC correlates with specific bone microstructural parameters in older men, suggesting a possible common pathogenesis for vascular calcification and deterioration in bone structure. However, sex‐specific differences exist.     

Bone Density,Microstructure and Strength in Obese and Normal Weight Men and Women in Younger and Older Adulthood

Obesity is associated with greater areal BMD (aBMD) and is considered protective against hip and vertebral fracture. Despite this, there is a higher prevalence of lower leg and proximal humerus fracture in obesity. We aimed to determine if there are site‐specific differences in BMD, bone structure, or bone strength between obese and normal‐weight adults. We studied 100 individually‐matched pairs of normal (body mass index [BMI] 18.5 to 24.9 kg/m²) and obese (BMI >30 kg/m²) men and women, aged 25 to 40 years or 55 to 75 years. We assessed aBMD at the whole body (WB), hip (TH), and lumbar spine (LS) with dual‐energy X‐ray absorptiometry (DXA), LS trabecular volumetric BMD (Tb.vBMD) by quantitative computed tomography (QCT), and vBMD and microarchitecture and strength at the distal radius and tibia with high‐resolution peripheral QCT (HR‐pQCT) and micro–finite element analysis. Serum type 1 procollagen N‐terminal peptide (P1NP) and collagen type 1 C‐telopeptide (CTX) were measured by automated electrochemiluminescent immunoassay (ECLIA). Obese adults had greater WB, LS, and TH aBMD than normal adults. The effect of obesity on LS and WB aBMD was greater in older than younger adults (p < 0.01). Obese adults had greater vBMD than normal adults at the tibia (p < 0.001 both ages) and radius (p < 0.001 older group), thicker cortices, higher cortical BMD and tissue mineral density, lower cortical porosity, higher trabecular BMD, and higher trabecular number than normal adults. There was no difference in bone size between obese and normal adults. Obese adults had greater estimated failure load at the radius (p < 0.05) and tibia (p < 0.01). Differences in HR‐pQCT measurements between obese and normal adults were seen more consistently in the older than the younger group. Bone turnover markers were lower in obese than in normal adults. Greater BMD in obesity is not an artifact of DXA measurement. Obese adults have higher BMD, thicker and denser cortices, and higher trabecular number than normal adults. Greater differences between obese and normal adults in the older group suggest that obesity may protect against age‐related bone loss and may increase peak bone mass. © 2014 American Society for Bone and Mineral Research.     

Effect of Total Hip Bone Area on Osteoporosis Diagnosis and Fractures

DXA is affected by skeletal size, with smaller bones giving lower areal BMD despite equal material density. Whether this size effect confounds the use of BMD as a diagnostic and fracture risk assessment tool is unclear. We identified 16,205 women of white ethnicity ≥50 yr of age undergoing baseline hip assessment with DXA (1998–2002) from a population‐based database that contains all clinical DXA test results for the Province of Manitoba, Canada. Total hip measurements were categorized according to quartile in total hip bone area (Q1 = smallest, Q4 = largest). Longitudinal health service records were assessed for the presence of nontraumatic osteoporotic fracture codes during a mean of 3.2 yr of follow‐up after BMD testing (757 osteoporotic fractures, 186 hip fractures). Total hip bone area strongly affected osteoporosis diagnosis with much higher rates in Q1 (14.4%) than Q4 (8.9%). However, incident fracture rates were constant across all area quartiles, and prevalent fractures were paradoxically fewer in smaller area quartiles (p < 0.001 for trend). Age was a potential confounder that correlated positively with area (r = 0.12, p < 0.0001). When age was not included in a Cox regression model, Q1 seemed to have a lower rate of incident osteoporotic fractures (HR = 0.80, 95% CI = 0.66–0.98, reference Q4) and hip fractures (HR = 0.63, 95% CI = 0.43–0.94) for a given level of BMD. In age‐adjusted regression models, total hip BMD was strongly predictive of incident osteoporotic fractures (HR per SD = 1.83, 95% CI = 1.68–1.99) and hip fractures (HR per SD = 2.80, 95% CI = 2.33–3.35), but there was no independent effect of bone area (categorical or continuous). Nested matched subgroup analysis and ROC analysis confirmed that bone area had no appreciable effect on incident fractures. We conclude that total hip areal BMD categorizes a substantially higher fraction of women with smaller bone area as being osteoporotic despite younger age. Incident fracture rates correlate equally well with BMD across all bone area quartiles when adjusted for age.     

Deleterious Effect of Late Menarche on Distal Tibia Microstructure in Healthy 20‐Year‐Old and Premenopausal Middle‐Aged Women

Late menarche is a risk factor for fragility fractures. We hypothesized that pubertal timing–dependent alterations in bone structural components would persist from peak bone mass to menopause, independent of premenopausal bone loss. We studied the influence of menarcheal age (MENA) on femoral neck BMD (FN aBMD) by DXA and microstructure of distal tibia by HR‐pQCT in healthy young adult (YAD; 20.4 ± 0.6 [SD] yr, n = 124) and premenopausal middle‐aged (PREMENO; 45.8 ± 3.4 yr, n = 120) women. Median of MENA was 13.0 ± 1.2 and 13.1 ± 1.7 yr in YAD and PREMENO, respectively. In YAD and PREMENO (n = 244), FN aBMD (R = ?0.29, p = 0.013), as well as total volumetric BMD (Dtot; R = ?0.23, p = 0.006) and cortical thickness (Ct.Th; R = ?0.18, p = 0.011) of distal tibia were inversely correlated to MENA. After segregation by the median of MENA in EARLY and LATE subgroups, the significant influences of both MENA (p = 0.004) and chronological age (p < 0.0001) were observed for FN aBMD and trabecular bone volume fraction of the distal tibia with similar differences in T‐scores between LATE and EARLY subgroups in YAD (?0.36 and ?0.31 T‐scores) and PREMENO (?0.35 and ?0.42 T‐scores) women. Ct.Th was negatively influenced by MENA, whereas trabecular thickness (Tb.Th) was negatively influenced by chronological age. There was a striking inverse relationship between cross‐sectional area and Ct.Th (R = ?0.57, p < 0.001). In conclusion, the negative influence of late menarcheal age at weight‐bearing sites as observed by the end of skeletal growth remains unattenuated a few years before menopause and is independent of premenopausal bone loss. Alterations in both bone mineral mass and microstructural components may explain the increased risk of fragility fractures associated with later menarcheal age.     

Naturally Occurring Stable Calcium Isotope Ratios in Body Compartments Provide a Novel Biomarker of Bone Mineral Balance in Children and Young Adults

Serum calcium (Ca), bone biomarkers, and radiological imaging do not allow accurate evaluation of bone mineral balance (BMB), a key determinant of bone mineral density (BMD) and fracture risk. We studied naturally occurring stable (non-radioactive) Ca isotopes in different body pools as a potential biomarker of BMB. ⁴²Ca and ⁴⁴Ca are absorbed from our diet and sequestered into different body compartments following kinetic principles of isotope fractionation; isotopically light ⁴²Ca is preferentially incorporated into bone, whereas heavier ⁴⁴Ca preferentially remains in blood and is excreted in urine and feces. Their ratio (δ^44/42Ca) in serum and urine increases during bone formation and decreases with bone resorption. In 117 healthy participants, we measured Ca isotopes, biomarkers, and BMD by dual-energy X-ray absorptiometry (DXA) and tibial peripheral quantitative CT (pQCT). ⁴⁴Ca and ⁴²Ca were measured by multi-collector ionization-coupled plasma mass-spectrometry in serum, urine, and feces. The relationship between bone Ca gain and loss was calculated using a compartment model. δ^44/42Ca_serum and δ^44/42Ca_urine were higher in children (n = 66, median age 13 years) compared with adults (n = 51, median age 28 years; p < 0.0001 and p = 0.008, respectively). δ^44/42Ca_serum increased with height in boys (p < 0.001, R² = 0.65) and was greatest at Tanner stage 4. δ^44/42Ca_serum correlated positively with biomarkers of bone formation (25-hydroxyvitaminD [p < 0.0001, R² = 0.37] and alkaline phosphatase [p = 0.009, R² = 0.18]) and negatively with bone resorption marker parathyroid hormone (PTH; p = 0.03, R² = 0.13). δ^44/42Ca_serum strongly positively correlated with tibial cortical BMD Z-score (n = 62; p < 0.001, R² = 0.39) but not DXA. Independent predictors of tibial cortical BMD Z-score were δ^44/42Ca_serum (p = 0.004, β = 0.37), 25-hydroxyvitaminD (p = 0.04, β = 0.19) and PTH (p = 0.03, β = −0.13), together predicting 76% of variability. In conclusion, naturally occurring Ca isotope ratios in different body compartments may provide a novel, non-invasive method of assessing bone mineralization. Defining an accurate biomarker of BMB could form the basis of future studies investigating Ca dynamics in disease states and the impact of treatments that affect bone homeostasis. © 2020 The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research (ASBMR).     

Using vertebral bone densitometry to determine aortic calcification in patients with chronic kidney disease

Background: Vascular calcification (VC) is a major contributor to increased cardiovascular (CV) disease in chronic kidney disease (CKD) and an independent predictor of mortality. VC is inversely correlated with bone mineral density (BMD). Screening for VC may be useful to determine those at greater CV risk and dual‐energy X‐ray absorptiometry (DXA) may have a dual role in providing VC measurement as well as BMD. Methods: We report cross‐sectional data on 44 patients with CKD stages 3–4 and aim to determine and validate measurement of VC using DXA. Patients had computed tomography (CT) of abdominal aorta and DXA of lateral lumbar spine, to determine both aortic VC and BMD. Semi‐quantitative measurement of VC from DXA was determined (blinded) using previously validated 8‐ and 24‐point scales, and compared with VC from CT. BMD determination from L2 to L4 vertebrae on CT was compared with DXA‐reported BMD. Results: Patients 66% male, 57% diabetic, had mean age 63.4 years and mean estimated glomerular filtration rate 31.4 ± 12 mL/min. Aortic VC was present in 95% on CT, mean 564.9 ± 304 Hounsfield units (HU). Aortic VC was seen in 68% on lateral DXA, mean scores 5.1 ± 5.9 and 1.9 ± 1.9 using 24‐ and 8‐point scales, respectively. Strong correlation of VC measurement was present between CT and DXA (r 0.52, P < 0.001). For DXA VC 24‐point score, intraclass correlations for intra‐rater and inter‐rater agreement were 0.91 and 0.64, respectively (8‐point scale, intraclass correlations 0.90 and 0.69). Vertebral BMD measured by CT (mean 469.3 HU L2–4) also significantly correlated with lateral DXA‐reported BMD (mean spine T‐score –0.67 ± 1.6) (r 0.56, P < 0.001). Conclusion: Despite limitations in CKD, DXA may be useful as lateral DXA images provide concurrent assessment of aortic calcification as well as lumbar spine BMD, both correlating significantly with CT measurements. Lateral DXA may provide VC screening to determine patients at greater CV risk although more studies are needed to evaluate their potential role.     

In Vivo Assessment of Bone Quality in Postmenopausal Women With Type 2 Diabetes

Although patients with type 2 diabetes (T2D) are at significant risk for well‐recognized diabetic complications, including macrovascular disease, retinopathy, nephropathy, and neuropathy, it is also clear that T2D patients are at increased risk for fragility fractures. Furthermore, fragility fractures in patients with T2D occur at higher bone mineral density (BMD) values compared to nondiabetic controls, suggesting abnormalities in bone material strength (BMS) and/or bone microarchitecture (bone “quality”). Thus, we performed in vivo microindentation testing of the tibia to directly measure BMS in 60 postmenopausal women (age range, 50–80 years) including 30 patients diagnosed with T2D for >10 years and 30 age‐matched, nondiabetic controls. Regional BMD was measured by dual‐energy X‐ray absorptiometry (DXA); cortical and trabecular bone microarchitecture was assessed from high‐resolution peripheral quantitative computed tomography (HRpQCT) images of the distal radius and tibia. Compared to controls, T2D patients had significantly lower BMS: unadjusted (?11.7%; p < 0.001); following adjustment for body mass index (BMI) (?10.5%; p < 0.001); and following additional adjustment for age, hypertension, nephropathy, neuropathy, retinopathy, and vascular disease (?9.2%; p = 0.022). By contrast, after adjustment for confounding by BMI, T2D patients had bone microarchitecture and BMD that were not significantly different than controls; however, radial cortical porosity tended to be higher in the T2D patients. In addition, patients with T2D had significantly reduced serum markers of bone turnover (all p < 0.001) compared to controls. Of note, in patients with T2D, the average glycated hemoglobin level over the previous 10 years was negatively correlated with BMS (r = ?0.41; p = 0.026). In conclusion, these findings represent the first demonstration of compromised BMS in patients with T2D. Furthermore, our results confirm previous studies demonstrating low bone turnover in patients with T2D and highlight the potential detrimental effects of prolonged hyperglycemia on bone quality. Thus, the skeleton needs to be recognized as another important target tissue subject to diabetic complications. © 2014 American Society for Bone and Mineral Research.     

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     

Ultrasound and densitometry of the calcaneus correlate with the failure loads of cadaveric femurs

We assessed the bone mineral density (BMD) of 16 matched sets of cadaveric proximal femurs and feet using dual-energy x-ray absorptiometry (DXA). We also estimated the femoral neck length from the DXA scans. Quantitative ultrasound densitometry was used to measure the velocity of sound and broadband ultrasound attenuation (BUA) in the calcaneus of each foot. The proximal femurs were then tested to failure in a loading configuration designed to simulate a fall with impact to the greater trochanter. Femoral neck BMD and trochanteric BMD were strongly associated with the femoral failure load (r²=0.79 and 0.81, respectively; P<0.001), whereas femoral neck length was modestly correlated with femoral failure load (r²=0.27, P=0.04). Calcaneal BMD (r²=0.63, P<0.001) and BUA (r²=0.51, P=0.002) were also significantly associated with femoral failure load. Given the small sample size, we were unable to detect differences in the strength of the correlations between the independent parameters and femoral failure load. Using linear multiple regression analyses, the strongest predictor of femoral failure load was a combination of femoral neck BMD and femoral neck length (R²=0.85, P<0.001). Thus, it appears that both femoral and calcaneal bone mineral properties may be useful for identifying those persons at greatest risk for hip fracture.     

Mechanical implications of estrogen supplementation in early postmenopausal women

Whereas the structural implications of drug intervention are well established, there are few data on the possible mechanical consequences of treatment. In this work we examined the changes in elastic and shear moduli (EM and SM) in a region of trabecular bone in the distal radius and distal tibia of early postmenopausal women on the basis of MRI‐based micro‐finite‐element (µFE) analysis. Whole‐section axial stiffness (AS) encompassing both trabecular and cortical compartments was evaluated as well. The study was conducted on previously acquired high‐resolution images at the two anatomic sites. Images were processed to yield a 3D voxel array of bone‐volume fraction (BVF), which was converted to a µFE model of hexahedral elements in which tissue modulus was set proportional to voxel BVF. The study comprised 65 early postmenopausal women (age range 45 to 55 years), of whom 32 had chosen estrogen supplementation (estradiol group); the remainder had not (control group). Subjects had been scanned at baseline and 12 and 24 months thereafter. At the distal tibia, EM and SM were reduced by 2.9% to 5.5% in the control group (p < .05 to <.005), but there was no change in the estradiol subjects. AS decreased 3.9% (4.0%) in controls (p < .005) and increased by 5.8% (6.2%) in estradiol group subjects (p < .05) at 12 (24) months. At the distal radius, EM and SM changes from baseline were not significant, but at both time points AS was increased in estradiol group subjects and decreased in controls (p < .005 to <.05), albeit by a smaller margin than at the tibia. EM and SM were strongly correlated with BV/TV (r² = 0.44 to 0.92) as well as with topologic parameters expressing the ratio of plates to rods (r² = 0.45 to 0.82), jointly explaining up to 96% of the variation in the mechanical parameters. Finally, baseline AS was strongly correlated between the two anatomic sites (r² = 0.58), suggesting that intersubject variations in the bone's mechanical competence follows similar mechanisms. In conclusion, the results demonstrate that micro‐MRI‐based µFE models are suited for the study of the mechanical implications of antiresorptive treatment. The data further highlight the anabolic effect of short‐term estrogen supplementation. © 2010 American Society for Bone and Mineral Research