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Femoral neck areal bone mineral density (FN aBMD) is a key determinant of fracture risk in older adults; however, the majority of individuals who have a hip fracture are not considered osteoporotic according to their FN aBMD. This study uses novel tools to investigate the characteristics of bone microarchitecture that underpin bone fragility. Recent hip fracture patients (n = 108, 77% female) were compared with sex- and age-matched controls (n = 216) using high-resolution peripheral quantitative computed tomography (HR-pQCT) imaging of the distal radius and tibia. Standard morphological analysis of bone microarchitecture, micro-finite element analysis, and recently developed techniques to identify void spaces in bone microarchitecture were performed to evaluate differences between hip fracture patients and controls. In addition, a new approach for phenotyping bone microarchitecture was implemented to evaluate whether hip fractures in males and females occur more often in certain bone phenotypes. Overall, hip fracture patients had notable deterioration of bone microarchitecture and reduced bone mineral density compared with controls, especially at weight-bearing sites (tibia and femoral neck). Hip fracture patients were more likely to have void spaces present at either site and had void spaces that were two to four times larger on average when compared with non-fractured controls (p 0.01). Finally, bone phenotyping revealed that hip fractures were significantly associated with the low density phenotype (p 0.01), with the majority of patients classified in this phenotype (69%). However, female and male hip fracture populations were distributed differently across the bone phenotype continuum. These findings highlight how HR-pQCT can provide insight into the underlying mechanisms of bone fragility by using information about bone phenotypes and identification of microarchitectural defects (void spaces). The added information suggests that HR-pQCT can have a beneficial role in assessing the severity of structural deterioration in bone that is associated with osteoporotic hip fractures. © 2022 The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research (ASBMR).

High resolution peripheral quantitative computed tomography (HR-pQCT) was designed to study bone mineral density (BMD) and microarchitecture in peripheral sites at the distal radius and tibia. With the introduction of the second generation HR-pQCT scanner (XtremeCT II, Scanco Medical) that has a larger, longer gantry it is now possible to study the human knee in vivo using HR-pQCT. Previous validation of HR-pQCT measurements at the distal radius and tibia against micro-CT is not representative of the knee because the increased cross-sectional area, greater amount of soft tissue surrounding the scan region, and different imaging protocol result in potentially increased beam hardening effects and photon scatter and different signal-to-noise ratio. The objective of this study is to determine the accuracy of density and microarchitecture measurements in the human knee measured by HR-pQCT using an in vivo protocol. Twelve fresh-frozen cadaver knees were imaged using in vivo HR-pQCT (60.7 µm) protocol. Subsequentially, distal femurs were extracted and imaged using a higher resolution (30.3 µm) ex vivo protocol, replicating micro-CT imaging. Scans were registered so that agreement of density and bone microarchitecture measurements could be determined using linear regression and Bland-Altman plots. All density and microarchitecture outcomes were highly correlated between the 2 protocols (R2 > 0.89) albeit with statistically significant differences between absolute measures based on paired t tests. All parameters showed accuracy between 4.5% and 8.7%, and errors were highly systematic, particularly for trabecular BMD and trabecular thickness (R2 > 0.93). We found that BMD and microarchitecture measurements in the distal femur obtained using an in vivo HR-pQCT knee protocol contained systematic errors, and accurately represented measurements obtained using a micro-CT equivalent imaging protocol. This work establishes the validity and limitations of using HR-pQCT to study the BMD and microarchitecture of human knees in future clinical studies.

Injury to the ACL significantly increases the risk of developing post-traumatic osteoarthritis. Following injury, considerable focus is placed on visualizing soft tissue changes using MRI, but there is less emphasis on the alterations to the underlying bone. It has recently been shown using high-resolution peripheral quantitative computed tomography (HR-pQCT) that significant reductions in bone quality occur in the knee post ACL-injury. Despite the ability of HR-pQCT to show these changes, the availability of scanners and computational time requirements required to assess bone stiffness and strength with HR-pQCT limit its widespread clinical use. As such, the objective of this study was to determine if clinical quantitative CT (QCT) finite element models (QCT-FEMs) can accurately replicate HR-pQCT FEM proximal tibial stiffness and strength. From FEMs of 30 participants who underwent both QCT and HR-pQCT bilateral imaging, QCT-FEMs were strongly correlated with HR-pQCT FEM stiffness (R2 = 0.79). When QCT-FEM bone strength was estimated using the reaction force at 1% apparent strain, strong correlations were observed (R2 = 0.81), with no bias between HR-pQCT FEMs and non-linear QCT-FEMs. These results indicate that QCT-FEMs can accurately replicate HR-pQCT FEM stiffness and strength in the proximal tibia. Although these models are not able to replicate the trabecular structure or tissue-level strains, they require significantly reduced computational time and use widely available clinical-CT images as input, which make them an attractive choice to monitor bone density, stiffness and strength alterations, such as those that occur post ACL-injury.

Poor vitamin D status and high parathyroid hormone (PTH) level are associated with impaired bone microarchitecture, but these data are mainly cross-sectional. We studied the association of the baseline PTH and 25-hydroxycholecalciferol (25OHD) levels with the prospectively assessed deterioration of bone microarchitecture and in estimated bone strength in older men. Distal radius and tibia bone microarchitecture was assessed by high-resolution peripheral quantitative computed tomography (HR-pQCT) at baseline, then after 4 and 8 years in 826 men aged 60-87 years. At distal radius, total bone mineral density (Tt.BMD), cortical thickness (Ct.Th

There are currently no population-based reference data sets available for volumetric bone mineral density and microarchitecture parameters measured using the second-generation high-resolution peripheral quantitative computed tomography (HR-pQCT), yet the technology is rapidly becoming a standard for studies of bone microarchitecture. Although cross-calibrated data sets from the first-generation HR-pQCT have been reported, they are not suitable for second-generation bone microarchitecture properties because of fundamental differences between scanner generations. This study provides site- and sex-specific centile curves across the adult life span for second-generation HR-pQCT properties. A total of 1236 adult participants (768 female and 468 male) from the Calgary area between the ages of 18 and 90 years were scanned at the distal tibia and radius using the second-generation HR-pQCT. Bone densities, microarchitectural properties, and failure load estimated using finite element analysis were determined using standard in vivo protocol. Site- and sex-specific centile curves were generated using the generalized additive models for location, scale, and shape (GAMLSS) method. These data provide reference curves appropriate for predominantly white male and female adults, which can be used as a tool to assess patient- or cohort-specific bone health. © 2020 American Society for Bone and Mineral Research.

Prevalence of osteoporosis is more than 50% in older adults, yet current clinical methods for diagnosis that rely on areal bone mineral density (aBMD) fail to detect most individuals who have a fragility fracture. Bone fragility can manifest in different forms, and a "one-size-fits-all" approach to diagnosis and management of osteoporosis may not be suitable. High-resolution peripheral quantitative computed tomography (HR-pQCT) provides additive information by capturing information about volumetric density and microarchitecture, but interpretation is challenging because of the complex interactions between the numerous properties measured. In this study, we propose that there are common combinations of bone properties, referred to as phenotypes, that are predisposed to different levels of fracture risk. Using HR-pQCT data from a multinational cohort (n = 5873, 71% female) between 40 and 96 years of age, we employed fuzzy c-means clustering, an unsupervised machine-learning method, to identify phenotypes of bone microarchitecture. Three clusters were identified, and using partial correlation analysis of HR-pQCT parameters, we characterized the clusters as low density, low volume, and healthy bone phenotypes. Most males were associated with the healthy bone phenotype, whereas females were more often associated with the low volume or low density bone phenotypes. Each phenotype had a significantly different cumulative hazard of major osteoporotic fracture (MOF) and of any incident osteoporotic fracture (p 0.05). After adjustment for covariates (cohort, sex, and age), the low density followed by the low volume phenotype had the highest association with MOF (hazard ratio = 2.96 and 2.35, respectively), and significant associations were maintained when additionally adjusted for femoral neck aBMD (hazard ratio = 1.69 and 1.90, respectively). Further, within each phenotype, different imaging biomarkers of fracture were identified. These findings suggest that osteoporotic fracture risk is associated with bone phenotypes that capture key features of bone deterioration that are not distinguishable by aBMD. © 2021 American Society for Bone and Mineral Research (ASBMR).

Due to difficulty assessing healing of distal radius fractures using conventional radiography, there is interest in using high resolution peripheral quantitative computed tomography (HR-pQCT) to track healing at the microarchitectural level. Unfortunately, the plaster-of-Paris and fiberglass casts used to immobilize fractures affect HR-pQCT measurements due to beam hardening, and increased noise. The challenge is compounded because casts have variable thickness, and an individual patient will often have their cast changed 2-3 times during the course of treatment. This study quantifies the effect of casts within a clinically relevant range of thicknesses on measured bone parameters at the distal radius, and establishes conversion equations to correct for systematic error in due to cast presence. Eighteen nonfractured participants were scanned by HR-pQCT in three conditions: no cast, plaster-of-Paris cast, and fiberglass cast. Measured parameters were compared between the baseline scan (no cast) and each cast scan to evaluate if systematic error exists due to cast presence. A linear regression model was used to determine an appropriate conversion for parameters that were found to have systematic error. Plaster-of-Paris casts had a greater range of thicknesses (3.2-9.5 mm) than the fiberglass casts (3.0-5.4 mm), and induced a greater magnitude of systematic error overall. Key parameters of interest were bone mineral density (total, cortical, and trabecular) and trabecular bone volume fraction, all of which were found to have systematic error due to presence of either cast type. Linear correlations between baseline and cast scans for these parameters were excellent (R2 > 0.98), and appropriate conversions could be determined within a margin of error less than a ±6% for the plaster-of-Paris cast, and ±4% for the fiberglass cast. We have demonstrated the effects of cast presence on bone microarchitecture measurements, and presented a method to correct for systematic error, in support of future use of HR-pQCT to study fracture healing.

Context High fracture risk in individuals with low muscle strength is attributed to high risk of falls. Objective This work aims to study the association of muscle mass and physical performance with bone microarchitecture decline and risk of fall and nonvertebral fracture in men. Methods A prospective, 8-year follow-up of a cohort was conducted among the general population. A total of 821 volunteer men aged 60 and older participated. Hip areal bone mineral density (aBMD) and appendicular lean mass (ALM) were assessed at baseline by dual x-ray absorptiometry. Lower-limb relative ALM (RALM-LL) is ALM-LL/(leg length)2. The physical performance score reflects the ability to perform chair stands and static and dynamic balance. Bone microarchitecture was assessed by high-resolution peripheral quantitative computed tomography (HR-pQCT) at baseline and after 4 and 8 years. Statistical analyses were adjusted for shared risk factors. Outcome measurements included the rate of change in the HR-pQCT indices, incident falls, and fractures. Results Cortical bone loss and estimated bone strength decline were faster in men with low vs normal RALM-LL (failure load: –0.74 ± 0.09 vs –0.43 ± 0.10%/year; P Conclusion Rapid decline of bone microarchitecture and estimated strength in men with poor physical performance and low RALM-LL may contribute to higher fracture risk.

Injury to the ACL significantly increases the risk of developing post-traumatic osteoarthritis. Following injury, considerable focus is placed on visualizing soft tissue changes using MRI, but there is less emphasis on the alterations to the underlying bone. It has recently been shown using high-resolution peripheral quantitative computed tomography (HR-pQCT) that significant reductions in bone quality occur in the knee post ACL-injury. Despite the ability of HR-pQCT to show these changes, the availability of scanners and computational time requirements required to assess bone stiffness and strength with HR-pQCT limit its widespread clinical use. As such, the objective of this study was to determine if clinical quantitative CT (QCT) finite element models (QCT-FEMs) can accurately replicate HR-pQCT FEM proximal tibial stiffness and strength. From FEMs of 30 participants who underwent both QCT and HR-pQCT bilateral imaging, QCT-FEMs were strongly correlated with HR-pQCT FEM stiffness (R

Finite element analysis (FE) coupled with high-resolution peripheral quantitative computed tomography (HR-pQCT) allows for noninvasive in vivo assessment of fracture stiffness at peripheral locations including the distal radius. Previous studies have reported the ability of FE analysis to capture significant longitudinal changes in fracture stiffness. We hypothesized that continuum-based FE methods are necessary to capture significant changes in FE-estimated stiffness in men and women, with closed reductions and casting, over the course of their fracture healing process. The primary aim of the study was to evaluate the performance of 3 micro-FE (μFE) methods, 2 density-based (continuum) methods, and a homogeneous method. A total of 30 participants with stable distal radius fractures completed follow-ups at 2, 4, 6, 8, 12, and 26 weeks postfracture. Participants had their fractured wrist scanned using HR-pQCT at each follow-up; the contralateral wrist was also scanned at the initial assessment to represent baseline conditions. Images were used to generate continuum and homogeneous µFE models. Uniaxial compression and torsional tests were completed, with apparent stiffness determined as the primary outcome measure. Stiffness of the fractured wrist was compared to stiffness of the uninjured contralateral wrist to quantify the change in stiffness. Days since fracture significantly predicted change in stiffness for continuum and homogeneous µFE methods (p < 0.05). Continuum µFE methods appeared to account for partially mineralized tissues, resulting in a graduated recovery of stiffness (1% per week). Homogeneous µFE methods were more sensitive to stages of healing progression, resulting in a faster recovery of stiffness (3% per week). Our findings demonstrate the capability of µFE to capture the restoration of stiffness at the fractured side to prefracture stiffness in men and women, up to 6 months postfracture.

The application of high-resolution peripheral quantitative computed tomography (HR-pQCT) to assess bone microarchitecture has grown rapidly since its introduction in 2005. As the use of HR-pQCT for clinical research continues to grow, there is an urgent need to form a consensus on imaging and analysis methodologies so that studies can be appropriately compared. In addition, with the recent introduction of the second-generation HrpQCT, which differs from the first-generation HR-pQCT in scan region, resolution, and morphological measurement techniques, there is a need for guidelines on appropriate reporting of results and considerations as the field adopts newer systems. A joint working group between the International Osteoporosis Foundation, American Society of Bone and Mineral Research, and European Calcified Tissue Society convened in person and by teleconference over several years to produce the guidelines and recommendations presented in this document. An overview and discussion is provided for (1) standardized protocol for imaging distal radius and tibia sites using HR-pQCT, with the importance of quality control and operator training discussed; (2) standardized terminology and recommendations on reporting results; (3) factors influencing accuracy and precision error, with considerations for longitudinal and multi-center study designs; and finally (4) comparison between scanner generations and other high-resolution CT systems. This article addresses the need for standardization of HR-pQCT imaging techniques and terminology, provides guidance on interpretation and reporting of results, and discusses unresolved issues in the field.

Manual correction of automatically generated contours for high-resolution peripheral quantitative computed tomography can be time consuming and introduces precision error. However, bias related to the automated protocol is unknown. This study provides insight into error bias that is present when using uncorrected contours and inter-operator precision error based on operator training. High-resolution peripheral quantitative computed tomography workflow includes manually correcting contours generated by the manufacturer’s automated protocol. There is interest in minimizing corrections to save time and reduce precision error; however, bias related to the automated protocol is unknown. This study quantifies error bias when contours are uncorrected and identifies the impact of operator training on bias and precision error. Forty-five radii and tibiae scans across a representative range of bone density were analyzed using the automated and manually corrected contours of three operators, with training ranging from beginner to expert, and compared with a “ground truth” to estimate bias. Inter-operator precision was measured across operators. The tibia had greater error bias than the radius when contours were uncorrected, with compartmental bone mineral densities and cortical microarchitecture having greatest biases, which could have significant implications for interpretation of studies using this skeletal site. Bias and precision error were greatest when contours were corrected by the beginner operator; however, when this operator was removed, bias was no longer present and inter-operator precision was between 0.01 and 3.74% for all parameters except cortical porosity. These findings establish the need for manual correction and provide guidance on operator training needed to maximize workflow efficiency.

The application of high resolution peripheral quantitative computed tomography (HR-pQCT) for the study of bone health has provided valuable insight into the role bone microarchitecture has in determining bone strength and fracture risk. However, conventional density and morphological parameters struggle to distinguish whether localized bone loss is present, visible as heterogeneous deterioration in the trabecular network. This is because current HR-pQCT parameters quantify a global average of properties in the cortical or trabecular compartment. This study proposes a new metric we term "void space" that segments volumes of localized deterioration in the trabecular bone network from HR-pQCT scans and quantifies void space as the void space to total volume ratio (VS/TV, %). A simple and fully automated protocol for segmenting and quantifying void space in HR-pQCT scans is presented, along with the assessment of accuracy, precision, and cross-calibration between generations of HR-pQCT systems. Finally, prevalence of void space and the association with standard HR-pQCT parameters is demonstrated using a large population-based cohort (n = 1236). Void space detection was found to be highly reproducible (accuracy95%, least significant change1.76% VS/TV) and correlation between scanner generations was strong (R

Purpose of Review Diabetes mellitus is defined by elevated blood glucose levels caused by changes in glucose metabolism and, according to its pathogenesis, is classified into type 1 (T1DM) and type 2 (T2DM) diabetes mellitus. Diabetes mellitus is associated with multiple degenerative processes, including structural alterations of the bone and increased fracture risk. High-resolution peripheral computed tomography (HR-pQCT) is a clinically applicable, volumetric imaging technique that unveils bone microarchitecture in vivo. Numerous studies have used HR-pQCT to assess volumetric bone mineral density and microarchitecture in patients with diabetes, including characteristics of trabecular (e.g. number, thickness and separation) and cortical bone (e.g. thickness and porosity). However, study results are heterogeneous given different imaging regions and diverse patient cohorts. Recent Findings This meta-analysis assessed T1DM- and T2DM-associated characteristics of bone microarchitecture measured in human populations in vivo reported in PubMed- and Embase-listed publications from inception (2005) to November 2021. The final dataset contained twelve studies with 516 participants with T2DM and 3067 controls and four studies with 227 participants with T1DM and 405 controls. While T1DM was associated with adverse trabecular characteristics, T2DM was primarily associated with adverse cortical characteristics. These adverse effects were more severe at the radius than the load-bearing tibia, indicating increased mechanical loading may compensate for deleterious bone microarchitecture changes and supporting mechanoregulation of bone fragility in diabetes mellitus. Summary Our meta-analysis revealed distinct predilection sites of bone structure aberrations in T1DM and T2DM, which provide a foundation for the development of animal models of skeletal fragility in diabetes and may explain the uncertainty of predicting bone fragility in diabetic patients using current clinical algorithms., Current Osteoporosis Reports, 20 (6), ISSN:1544-2241, ISSN:1544-1873