Purpose of review

The relationships between bone vasculature and bone microstructure and strength remain incompletely understood. Addressing this gap will require in vivo imaging capabilities. We describe the relevant vascular anatomy of compact bone, review current magnetic resonance imaging (MRI)-based techniques that allow in vivo assessment of intracortical vasculature, and finally present preliminary studies that apply these techniques to investigate changes in intracortical vessels in aging and disease.

Recent findings

Ultra-short echo time MRI (UTE MRI), dynamic contrast-enhanced MRI (DCE-MRI), and susceptibility-weighted MRI techniques are able to probe intracortical vasculature. Applied to patients with type 2 diabetes, DCE-MRI was able to find significantly larger intracortical vessels compared to nondiabetic controls. Using the same technique, a significantly larger number of smaller vessels was observed in patients with microvascular disease compared to those without. Preliminary data on perfusion MRI showed decreased cortical perfusion with age.

Summary

Development of in vivo techniques for intracortical vessel visualization and characterization will enable the exploration of interactions between the vascular and skeletal systems, and further our understanding of drivers of cortical pore expansion. As we investigate potential pathways of cortical pore expansion, appropriate treatment and prevention strategies will be clarified.

Roux-en Y gastric bypass (RYGB) surgery is an effective treatment for obesity; however, it may negatively impact skeletal health by increasing fracture risk. This increase may be the result not only of decreased bone mineral density but also of changes in bone microstructure, for example, increased cortical porosity. Increased tibial and radial cortical porosity of patients undergoing RYGB surgery has been observed as early as 6 months postoperatively; however, local microstructural changes and associated biological mechanisms driving this increase remain unclear. To provide insight, we studied the spatial distribution of cortical porosity in 42 women and men (aged 46 ± 12 years) after RYGB surgery. Distal tibias and radii were evaluated with high-resolution peripheral quantitative computed tomography (HR-pQCT) preoperatively and at 12 months postoperatively. Laminar analysis was used to determine cortical pore number and size within the endosteal, midcortical, and periosteal layers of the cortex. Paired t tests were used to compare baseline versus follow-up porosity parameters in each layer. Mixed models were used to compare longitudinal changes in laminar analysis outcomes between layers. We found that the midcortical (0.927 ± 0.607 mm^-2 to 1.069 ± 0.654 mm^-2 , p = 0.004; 0.439 ± 0.293 mm^-2 to 0.509 ± 0.343 mm^-2 , p = 0.03) and periosteal (0.642 ± 0.412 mm^-2 to 0.843 ± 0.452 mm^-2 , p < 0.0001; 0.171 ± 0.101 mm^-2 to 0.230 ± 0.160 mm^-2 , p = 0.003) layers underwent the greatest increases in porosity over the 12-month period at the distal tibia and radius, respectively. The endosteal layer, which had the greatest porosity at baseline, did not undergo significant porosity increase over the same period (1.234 ± 0.402 mm^-2 to 1.259 ± 0.413 mm^-2 , p = 0.49; 0.584 ± 0.290 mm^-2 to 0.620 ± 0.299 mm^-2 , p = 0.35) at the distal tibia and radius, respectively. An alternative baseline-mapping approach for endosteal boundary definition confirmed that cortical bone loss was not primarily endosteal. These findings indicate that increases in cortical porosity happen in regions distant from the endosteal surface, suggesting that the underlying mechanism driving the increase in cortical porosity is not merely endosteal trabecularization. © 2022 American Society for Bone and Mineral Research (ASBMR).

Objective

Significant weight loss following treatments for obesity undermines bone metabolism and increases bone turnover and fracture incidence. High resolution peripheral quantitative computed tomography (HR-pQCT) is widely used in skeletal heath assessment research to provide noninvasive bone parameter measurement (e.g. volumetric bone mineral density (vBMD)) with minimal radiation exposure. However, variation in body composition among study groups or longitudinal variations within individuals undergoing significant weight change will generate artifacts and errors in HR-pQCT data. The purpose of this study is to determine the influence of these artifacts on the measurement of vBMD.

Methods

We designed a custom-made hydroxyapatite (HA)-polymer phantom surrounded by layers of reusable gel pack and hydrogenated fat to mimic the distal tibia and the surrounding lean and fat tissue. Four different thicknesses of fat were used to mimic the soft tissue of increasingly overweight individuals. We then evaluated how a change in soft tissue thickness influenced image quality and vBMD quantification within total, trabecular, and cortical bone compartments. Based on these data, we applied a data correction to previously acquired clinical data in a cohort of gastric bypass patients.

Results

In the phantom measurements, total, trabecular, and cortical vBMD increased as soft tissue thickness decreased. The impact of soft tissue thickness on vBMD varied by anatomic quadrant. When applying the soft tissue data correction to a set of clinical data, we found that soft tissue reduction following bariatric surgery can lead to a clinically significant underestimation of bone loss in longitudinal data, and that the effect is most severe in the cortical compartment.

Conclusion

HR-pQCT-based vBMD measurement accuracy is influenced by soft tissue thickness and is spatially inhomogeneous. Our results suggest that variations in soft tissue thickness must be considered in HR-pQCT studies, particularly in studies enrolling cohorts with differing body composition or in studies of longitudinal weight change.

Cortical bone microstructure deficits may increase fracture risk in individuals with cardiovascular disease and diabetes. High resolution peripheral quantitative computed tomography (HR-pQCT) enables in vivo microstructure characterization but is limited in its ability to visualize important biological features. We conducted histological analyses and HR-pQCT imaging of distal tibia bone samples from 6 donors with cardiovascular disease (CVD) and type 2 diabetes mellitus (T2D). Histology but not HR-pQCT identified previously undocumented morphopathological deficits that may contribute to cortical bone fragility. These observations may provide guidance for improved HR-pQCT microstructural characterization as well as insight into mechanisms of cortical bone degradation.

Background

Cortical bone porosity is a major determinant of bone strength. Despite the biomechanical importance of cortical bone porosity, the biological drivers of cortical porosity are unknown. The content of cortical pore space can indicate pore expansion mechanisms; both of the primary components of pore space, vessels and adipocytes, have been implicated in pore expansion. Dynamic contrast-enhanced MRI (DCE-MRI) is widely used in vessel detection in cardiovascular studies, but has not been applied to visualize vessels within cortical bone. In this study, we have developed a multimodal DCE-MRI and high resolution peripheral QCT (HR-pQCT) acquisition and image processing pipeline to detect vessel-filled cortical bone pores.

Methods

For this in vivo human study, 19 volunteers (10 males and 9 females; mean age =63±5) were recruited. Both distal and ultra-distal regions of the non-dominant tibia were imaged by HR-pQCT (82 µm nominal resolution) for bone structure segmentation and by 3T DCE-MRI (Gadavist; 9 min scan time; temporal resolution =30 sec; voxel size 230×230×500 µm³) for vessel visualization. The DCE-MRI was registered to the HR-pQCT volume and the voxels within the MRI cortical bone region were extracted. Features of the DCE data were calculated and voxels were categorized by a 2-stage hierarchical kmeans clustering algorithm to determine which voxels represent vessels. Vessel volume fraction (volume ratio of vessels to cortical bone), vessel density (average vessel count per cortical bone volume), and average vessel volume (mean volume of vessels) were calculated to quantify the status of vessel-filled pores in cortical bone. To examine spatial resolution and perform validation, a virtual phantom with 5 channel sizes and an applied pseudo enhancement curve was processed through the proposed image processing pipeline. Overlap volume ratio and Dice coefficient was calculated to measure the similarity between the detected vessel map and ground truth.

Results

In the human study, mean vessel volume fraction was 2.2%±1.0%, mean vessel density was 0.68±0.27 vessel/mm³, and mean average vessel volume was 0.032±0.012 mm³/vessel. Signal intensity for detected vessel voxels increased during the scan, while signal for non-vessel voxels within pores did not enhance. In the validation phantom, channels with diameter 250 µm or greater were detected successfully, with volume ratio equal to 1 and Dice coefficient above 0.6. Both statistics decreased dramatically for channel sizes less than 250 µm.

Conclusions

We have a developed a multi-modal image acquisition and processing pipeline that successfully detects vessels within cortical bone pores. The performance of this technique degrades for vessel diameters below the in-plane spatial resolution of the DCE-MRI acquisition. This approach can be applied to investigate the biological systems associated with cortical pore expansion.

Purpose

In adults with long-term HIV infection, low bone density and increased fracture risk have emerged as significant comorbidities. Our aim was to assess the association of exercise, nutrition, and medications with bone quality in adults with long-term HIV infection.

Methods

Forty-three adults with HIV infection were enrolled (median BMI 25.7, range 18.2-35.6 kg/m²; median age 57, range 50-69 years). Participants underwent ultradistal radius and tibia high-resolution peripheral quantitative CT (HR-pQCT). Questionnaires included the revised Community Healthy Activities Model Program for Seniors (CHAMPS), the Mini Nutritional Assessment (MNA) as well as medication assessments. Multivariable linear regression models were used to evaluate the association of exercise, nutritional status, tenofovir disoproxil fumarate (TDF) and protease inhibitor (PI) use with bone density and microstructure, adjusting for demographic risk factors.

Results

In regression models, higher nutrition scores were associated with higher tibia cortical thickness (R² = 0.23; β = 0.03; p = 0.044) and higher radius cortical BMD (R² = 0.43; β = 8.4; p = 0.026). Higher weekly frequency of all physical activities was significantly associated with higher radius trabecular BMD (R² = 0.38; β = 0.96; p = 0.050), higher radius trabecular number (R² = 0.31; β = 0.01; p = 0.026), lower tibia and radius trabecular separation (tibia: R² = 0.30; β = -0.003; p = 0.038; radius: R² = 0.35; β = -0.003; p = 0.021), and higher radius bone stiffness (R² = 0.45; β = 0.38; p = 0.047). Higher frequency of bone loading physical activities was significantly associated with higher tibia trabecular density (R² = 0.44; β = 4.06; p = 0.036), higher tibia bone stiffness (R² = 0.46; β = 3.06; p = 0.050), and higher tibia estimated failure load (R² = 0.46; β = 0.17; p = 0.049). TDF used in combination with a PI was associated with lower radius trabecular BMD (R² = 0.39; β = -41.2; p = 0.042), lower radius trabecular number (R² = 0.34; β = -0.44; p = 0.009) and greater radius trabecular separation (R² = 0.42; β = 0.16; p = 0.002), while TDF use without a PI was not associated with reduced bone quality.

Conclusions

In adults with HIV infection, malnutrition is associated with poor cortical bone quality, while reduced frequency of physical activities and specifically reduced frequency of mechanical loading activities are associated with deficient trabecular bone structure and reduced estimates of bone strength. TDF use in combination with a PI is associated with deleterious effects on trabecular bone structure.

Mechanical unloading causes rapid loss of bone structure and strength, which gradually recovers after resuming normal loading. However, it is not well established how this adaptation to unloading and reloading changes with age. Clinically, elderly patients are more prone to musculoskeletal injury and longer periods of bedrest, therefore it is important to understand how periods of disuse will affect overall skeletal health of aged subjects. Bone also undergoes an age-related decrease in osteocyte density, which may impair mechanoresponsiveness. In this study, we examined bone adaptation during unloading and subsequent reloading in mice. Specifically, we examined the differences in bone adaptation between young mice (3-month-old), old mice (18-month-old), and transgenic mice that exhibit diminished osteocyte density at a young age (3-month-old BCL-2 transgenic mice). Mice underwent 14 days of hindlimb unloading followed by up to 14 days of reloading. We analyzed trabecular and cortical bone structure in the femur, mechanical properties of the femoral cortical diaphysis, osteocyte density and cell death in cortical bone, and serum levels of inflammatory cytokines. We found that young mice lost ~10% cortical bone volume and 27-42% trabecular bone volume during unloading and early reloading, with modest recovery of metaphyseal trabecular bone and near total recovery of epiphyseal trabecular bone, but no recovery of cortical bone after 14 days of reloading. Old mice lost 12-14% cortical bone volume and 35-50% trabecular bone volume during unloading and early reloading but had diminished recovery of trabecular bone during reloading and no recovery of cortical bone. In BCL-2 transgenic mice, no cortical bone loss was observed during unloading or reloading, but 28-31% trabecular bone loss occurred during unloading and early reloading, with little to no recovery during reloading. No significant differences in circulating inflammatory cytokine levels were observed due to unloading and reloading in any of the experimental groups. These results illustrate important differences in bone adaptation in older and osteocyte deficient mice, suggesting a possible period of vulnerability in skeletal health in older subjects during and following a period of disuse that may affect skeletal health in elderly patients.