Recommendations for High-resolution Peripheral Quantitative Computed Tomography Assessment of Bone Density, Microarchitecture, and Strength in Pediatric Populations

Sadoughi S., Subramanian A., Ramil G., Burghardt A.J., Kazakia G.J.

ABSTRACTAlthough second‐generation high‐resolution peripheral quantitative computed tomography (XCTII) provides the highest‐resolution in vivo bone microstructure assessment, the manufacturer's standard image processing protocol omits fine features in both trabecular and cortical compartments. To optimize fine structure segmentation, we implemented a binarization approach based on a Laplace–Hamming (LH) segmentation and documented the reproducibility and accuracy of XCTII structure segmentation using both the standard Gaussian‐based binarization and the proposed LH segmentation approach. To evaluate reproducibility, 20 volunteers (9 women, 11 men; aged 23–75 years) were recruited, and three repeat scans of the radii and tibias were acquired using the manufacturer's standard in vivo protocol. To evaluate accuracy, cadaveric structure phantoms (14 radii, 6 tibias) were scanned on XCTII using the same standard in vivo protocol and on μCT at 24.5 μm resolution. XCTII images were analyzed twice—first, with the manufacturer's standard patient evaluation protocol and, second, with the proposed LH segmentation approach. The LH approach rescued fine features evident in the grayscale images but omitted or overrepresented (thickened) by the standard approach. The LH approach significantly reduced error in trabecular volume fraction (BV/TV) and thickness (Tb.Th) compared with the standard approach; however, higher error was introduced for trabecular separation (Tb.Sp). The LH approach improved the correlation between XCTII and μCT for cortical porosity (Ct.Po) and significantly reduced error in cortical pore diameter (Ct.Po.Dm) compared with the standard approach. The LH approach resulted in improved precision compared with the standard approach for BV/TV, Tb.Th, Ct.Po, and Ct.Po.Dm at the radius and for Ct.Po at the tibia. Our results suggest that the proposed LH approach produces substantially improved binary masks, reduces proportional bias, and provides greater accuracy and reproducibility in important outcome metrics, all due to more accurate segmentation of the fine features in both trabecular and cortical compartments. © 2023 The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research (ASBMR).

Zheng Y., Rostami Haji Abadi M., Ghafouri Z., Meira Goes S., Johnston J.(., Nour M., Kontulainen S.

Deficits in bone mineral and weaker bone structure in children with type 1 diabetes (T1D) may contribute to a lifelong risk of fracture. However, there is no meta-analysis comparing bone properties beyond density between children with T1D and typically developing children (TDC). This meta-analysis aimed to assess differences and related factors in bone mineral content (BMC), density, area, micro-architecture and estimated strength between children with T1D and TDC. We systematically searched MEDLINE, Embase, CINAHL, Web of Science, Scopus, Cochrane Library databases, and included 36 in the meta-analysis (2222 children and youth with T1D, 2316 TDC; mean age ≤18 yrs., range 1–24). We estimated standardized mean differences (SMD) using random-effects models and explored the role of age, body size, sex ratio, disease duration, hemoglobin A1c in relation to BMC and areal density (aBMD) SMD using meta-regressions. Children and youth with T1D had lower total body BMC (SMD: −0.21, 95% CI: −0.37 to −0.05), aBMD (−0.30, −0.50 to −0.11); lumbar spine BMC (−0.17, −0.28 to −0.06), aBMD (−0.20, −0.32 to −0.08), bone mineral apparent density (−0.30, −0.48 to −0.13); femoral neck aBMD (−0.21, −0.33 to −0.09); distal radius and tibia trabecular density (−0.38, −0.64 to −0.12 and −0.35, −0.51 to −0.18, respectively) and bone volume fraction (−0.33, −0.56 to −0.09 and −0.37, −0.60 to −0.14, respectively); distal tibia trabecular thickness (−0.41, −0.67 to −0.16); and tibia shaft cortical content (−0.33, −0.56 to −0.10). Advanced age was associated with larger SMD in total body BMC (−0.13, −0.21 to −0.04) and aBMD (−0.09; −0.17 to −0.01) and longer disease duration with larger SMD in total body aBMD (−0.14; −0.24 to −0.04). Children and youth with T1D have lower BMC, aBMD and deficits in trabecular density and micro-architecture. Deficits in BMC and aBMD appeared to increase with age and disease duration. Bone deficits may contribute to fracture risk and require attention in diabetes research and care. PROSPERO (CRD42020200819). • First meta-analysis of BMC and micro-architectural deficits in children with T1D • Meta-regressions indicated greater deficits in total body BMC and aBMD with age. • Deficits in trabecular bone thickness and density were pronounced in T1D. • Prospective, advanced imaging data of bone development in children with T1D needed

Hosseinitabatabaei S., Mikolajewicz N., Zimmermann E.A., Rummler M., Steyn B., Julien C., Rauch F., Willie B.M.

Repositioning error in longitudinal high-resolution peripheral-quantitative computed tomography (HR-pQCT) imaging can lead to different bone volumes being assessed over time. To identify the same bone volumes at each time point, image registration is used. While cross-sectional area image registration corrects axial misalignment, 3D registration additionally corrects rotations. Other registration methods involving matched angle analysis (MA) or boundary transformations (3D-TB) can be used to limit interpolation error in 3D-registering micro-finite-element data. We investigated the effect of different image registration methods on short-term in vivo precision in adults with osteogenesis imperfecta, a collagen-related genetic disorder resulting in low bone mass, impaired quality, and increased fragility. The radii and tibiae of 29 participants were imaged twice on the same day with full repositioning. We compared the precision error of different image registration methods for density, microstructural, and micro-finite-element outcomes with data stratified based on anatomical site, motion status, and scanner generation. Regardless of the stratification, we found that image registration improved precision for total and trabecular bone mineral densities, trabecular and cortical bone mineral contents, area measurements, trabecular bone volume fraction, separation, and heterogeneity, as well as cortical thickness and perimeter. 3D registration marginally outperformed cross-sectional area registration for some outcomes, such as trabecular bone volume fraction and separation. Similarly, precision of micro-finite-element outcomes was improved after image registration, with 3D-TB and MA methods providing greatest improvements. Our regression model confirmed the beneficial effect of image registration on HR-pQCT precision errors, whereas motion had a detrimental effect on precision even after image registration. Collectively, our results indicate that 3D registration is recommended for longitudinal HR-pQCT imaging in adults with osteogenesis imperfecta. Since our precision errors are similar to those of healthy adults, these results can likely be extended to other populations, although future studies are needed to confirm this. © 2022 American Society for Bone and Mineral Research (ASBMR).

Simon M., Indermaur M., Schenk D., Hosseinitabatabaei S., Willie B.M., Zysset P.

Osteogenesis Imperfecta (OI) is an inherited form of bone fragility characterised by impaired synthesis of type I collagen, altered trabecular bone architecture and reduced bone mass. High resolution peripheral computed tomography (HR-pQCT) is a powerful method to investigate bone morphology at peripheral sites including the weight-bearing distal tibia. The resulting 3D reconstructions can be used as a basis of micro-finite element (FE) or homogenized finite element (hFE) models for bone strength estimation. The hFE scheme uses homogenized local bone volume fraction (BV/TV) and anisotropy information (fabric) to compute healthy bone strength within a reasonable computation time using fabric-elasticity relationships. However, it is unclear if these relationships quantified previously for healthy controls are valid for trabecular bone from OI patients. Thus, the aim of this study is to investigate fabric-elasticity relationships in OI trabecular bone compared to healthy controls.

Warden S.J., Liu Z., Fuchs R.K., van Rietbergen B., Moe S.M.

High-resolution peripheral quantitative computed tomography (HR-pQCT) is a powerful tool to assess bone health. To determine how an individual’s or population of interest’s HR-pQCT outcomes compare to expected, reference data are required. This study provides reference data for HR-pQCT measures acquired in a population of White adults. To provide age- and sex-specific reference data for high-resolution peripheral quantitative computed tomography (HR-pQCT) measures of the distal and diaphyseal radius and tibia acquired using a second-generation scanner and percent-of-length offsets proximal from the end of the bone. Data were acquired in White adults (aged 18–80 years) living in the Midwest region of the USA. HR-pQCT scans were performed at the 4% distal radius, 30% diaphyseal radius, 7.3% distal tibia, and 30% diaphyseal tibia. Centile curves were fit to the data using the LMS approach. Scans of 867 females and 317 males were included. The fitted centile curves reveal HR-pQCT differences between ages, sexes, and sites. They also indicate differences when compared to data obtained by others using fixed length offsets. Excel-based calculators based on the current data were developed and are provided to enable computation of subject-specific percentiles, z-scores, and t-scores and to plot an individual’s outcomes on the fitted curves. In addition, regression equations are provided to convert estimated failure load acquired with the conventional criteria utilized with first-generation scanners and those specifically developed for second-generation scanners. The current study provides unique data and resources. The combination of the reference data and calculators provide clinicians and investigators an ability to assess HR-pQCT outcomes in an individual or population of interest, when using the described scanning and analysis procedure. Ultimately, the expectation is these data will be expanded over time so the wealth of information HR-pQCT provides becomes increasingly interpretable and utilized.

Mikolajewicz N., Zimmermann E.A., Rummler M., Hosseinitabatabaei S., Julien C., Glorieux F.H., Rauch F., Willie B.M.

For high-resolution peripheral quantitative computed tomography (HR-pQCT) to be used in longitudinal multi-center studies to assess disease and treatment effects, data must be aggregated across multiple timepoints and scanners. This requires an understanding of the factors contributing to scanner precision, and multi-scanner cross-calibration procedures, especially for clinical populations with severe phenotypes, like osteogenesis imperfecta (OI). To address this, we first evaluated single- and multi-center short- and long-term precision errors of standard HR-pQCT parameters. Two imaging phantoms were circulated among 13 sites (7 XtremeCT and 6 XtremeCT2) and scanned in triplicate at 3 timepoints/site. Additionally, duplicate in vivo radial and tibial scans were acquired in 29 individuals with OI. Secondly , we investigated subject- and scanner-related factors that contribute to precision errors using regression analysis. Thirdly , we proposed a reference site selection criterion for multisite cross-calibration and demonstrated the external validity of phantom-based calibrations. Our results show excellent short-term single-site precision in both phantoms ( CV % < 0.5%) and in density, microarchitecture and finite element parameters of OI participants ( CV % = 0.75 to 1.2%). In vivo reproducibility significantly improved with ( i ) cross sectional area image registration versus no registration and ( ii ) scans with no motion artifacts. While reproducibility was similar across OI subtypes and anatomical sites, XtremeCT2 scanners achieved ~2.5% better precision than XtremeCT for trabecular parameters. Finally , we demonstrate that multisite longitudinal precision errors resulting from inconsistencies between scanners can be partially corrected through scanner cross-calibration. This study is the first to assess long-term reproducibility and cross-calibration in a study using first and second generation HR-pQCT scanners. The results presented in this context provide timely guidelines for future use of this powerful clinical imaging modality in multi-center longitudinal clinical trials. • Our study provides short- and long-term reproducibility measurements in the context of a multi-center clinical study reporting HR-pQCT outcomes from different scanner generations and in the osteogenesis imperfecta population. • We provide recommendations on reporting practices, imaging phantom selection and design, and reference site selection criteria. • We present XcalRep, an open-sourced R package ( https://github.com/NMikolajewicz/XcalRep ), that implements methods for cross-calibration and precision analysis of HR-pQCT.

Lahham A., Issa A.

This work deals with the evaluation of radiation doses from chest x rays for 240 male and female pediatric patients selected randomly from four Palestinian hospitals. The patient population was divided into five age groups: Newborn, 1, 5, 10, and 15 y old. Doses were theoretically calculated by using Monte Carlo based codes: CALDOSE-X5 and PCXMC-2.0. Patients' data and type of radiographic systems used as well as exposure factors were provided by the administrations of the selected hospitals. Absorbed organ doses from AP and PA projections were evaluated for 76 pediatric patients selected from one hospital in East Jerusalem. The highest mean organ dose for these patients was 0.085 mGy to the breast in AP projection. Effective doses were estimated for the five age groups for all patients. The highest average effective dose was found for patients in the age group of 10 y and was about 0.13 mSv, while the lowest average effective dose was found for the 5-y age group, about 0.06 mSv. The mean effective dose for all investigated patients in the five age categories was about 0.08 mSv. Variations in effective doses for the same age group and x-ray examination among involved hospitals are remarkable.

Whittier D.E., Burt L.A., Hanley D.A., Boyd S.K.

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.

Fennimore D.J., Digby M., Paggiosi M., Arundel P., Bishop N.J., Dimitri P., Offiah A.C.

Bone health in children with osteogenesis imperfecta is monitored using radiographs and dual-energy X-ray absorptiometry, which have limitations. High-resolution peripheral quantitative CT can non-invasively derive bone microarchitectural data. Children with severe osteogenesis imperfecta have fragile deformed bones, and positioning for this scan can be difficult. We assessed the feasibility of high-resolution peripheral quantitative CT in nine children aged 9–15 years with osteogenesis imperfecta and compared results with dual-energy X-ray absorptiometry and with healthy controls. All nine recruited children were successfully scanned and showed no preference for either modality. It therefore appears feasible to perform high-resolution peripheral quantitative CT in children with osteogenesis imperfecta aged 9 years and older. Future studies should focus on understanding the clinical implications of the technology in this patient cohort.

Whittier D.E., Boyd S.K., Burghardt A.J., Paccou J., Ghasem-Zadeh A., Chapurlat R., Engelke K., Bouxsein M.L.

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.

Kemp T.D., de Bakker C.M., Gabel L., Hanley D.A., Billington E.O., Burt L.A., Boyd S.K.

Longitudinal studies of bone using high-resolution medical imaging may result in non-physiological measurements of longitudinal changes. In this study, we determined that three-dimensional image processing techniques best capture realistic longitudinal changes in bone density and should therefore be used with high-resolution imaging when studying bone changes over time. The purpose of this study was to determine which longitudinal analysis technique (no registration (NR), slice-match (SM) registration, or three-dimensional registration (3DR)) produced the most realistic longitudinal changes in a 3-year study of bone density and structure using high-resolution peripheral quantitative computed tomography (HR-pQCT). We assessed HR-pQCT scans of the distal radius and tibia for men and women (N = 40) aged 55–70 years at baseline and 6, 12, 24, and 36 months. To evaluate which longitudinal analysis technique (NR, SM, or 3DR) best captured physiologically reasonable 3-year changes, we calculated the standard deviation of the absolute rate of change in each bone parameter. The data were compared between longitudinal analysis techniques using repeated measures ANOVA and post hoc analysis. As expected, both SM and 3DR better captured physiological longitudinal changes than NR. At the tibia, there were no differences between SM and 3DR; however, at the radius where precision was lower, 3DR produced better results for total bone mineral density. At least SM or 3DR should be implemented in longitudinal studies using HR-pQCT. 3DR is preferable, particularly at the radius, to ensure that physiological changes in bone density are observed.

Varga P., Willie B.M., Stephan C., Kozloff K.M., Zysset P.K.

As a dedicated experimentalist, John Currey praised the high potential of finite element (FE) analysis but also recognized its critical limitations. The application of the FE methodology to bone tissue is reviewed in the light of his enthusiastic and colorful statements. In the past decades, FE analysis contributed substantially to the understanding of structure-function properties in the hierarchical organization of bone and to the simulation of bone adaptation. The systematic experimental validation of FE analysis of bone strength in anatomical locations at risk of fracture led to its application in clinical studies to evaluate efficacy of antiresorptive or anabolic treatment of bone fragility. Beyond the successful analyses of healthy or osteoporotic bone, FE analysis becomes increasingly involved in the investigation of other fragility-related bone diseases. The case of osteogenesis imperfecta (OI) is exposed, the multiscale alterations of the bone tissue and the effect of treatment summarized. A few FE analyses attempting to answer open questions in OI are then reported. An original study is finally presented that explored the structural properties of the Brtl/+ murine model of OI type IV subjected to sclerostin neutralizing antibody treatment using microFE analysis. The use of identical material properties in the four-point bending FE simulations of the femora reproduced not only the experimental values but also the statistical comparisons examining the effect of disease and treatment. Further efforts are needed to build upon the extraordinary legacy of John Currey and clarify the impact of different bone diseases on the hierarchical mechanical properties of bone.

Mitchell D.M., Caksa S., Joseph T., Bouxsein M.L., Misra M.

Abstract Context Skeletal fragility is a significant complication of type 1 diabetes (T1D), with an increased risk of fracture observed starting in childhood. Altered bone accrual and microarchitectural development during the critical peripubertal years may contribute to this fragility. Objective To evaluate differences in skeletal microarchitecture between girls with T1D and controls and to assess factors associated with these differences. Design Cross-sectional comparison. Participants Girls ages 10–16 years, 62 with T1D and 61 controls. Results Areal bone mineral density (BMD) measured by dual-energy x-ray absorptiometry did not differ between girls with and without T1D. At the distal tibia, trabecular BMD was 7.3 ± 2.9% lower in T1D (P = 0.013), with fewer plate-like and axially-aligned trabeculae. Cortical porosity was 21.5 ± 10.5% higher, while the estimated failure load was 4.7 ± 2.2% lower in T1D (P = 0.043 and P = 0.037, respectively). At the distal radius, BMD and microarchitecture showed similar differences between the groups but did not reach statistical significance. After stratifying by HbA1c, only those girls with T1D and HbA1c &gt; 8.5% differed significantly from controls. P1NP, a marker of bone formation, was lower in T1D while CTX and TRAcP5b, markers of bone resorption and osteoclast number, respectively, did not differ. The insulin-like growth factor 1 (IGF-1) Z-score was lower in T1D, and after adjustment for the IGF-1 Z-score, associations between T1D status and trabecular microarchitecture were largely attenuated. Conclusions Skeletal microarchitecture is altered in T1D early in the course of disease and among those with higher average glycemia. Suppressed bone formation and lower circulating IGF-1 likely contribute to this phenotype.

Mikolajewicz N., Bishop N., Burghardt A.J., Folkestad L., Hall A., Kozloff K.M., Lukey P.T., Molloy‐Bland M., Morin S.N., Offiah A.C., Shapiro J., Rietbergen B., Wager K., Willie B.M., Komarova S.V., et. al.

HR‐pQCT is a non‐invasive imaging modality for assessing volumetric bone mineral density (vBMD) and microarchitecture of cancellous and cortical bone. The objective was to (i) assess fracture‐associated differences in HR‐pQCT bone parameters and (ii) to determine if HR‐pQCT is sufficiently precise to reliably detect these differences in individuals. We systematically identified 40 studies that used HR‐pQCT (39/40 used XtremeCT scanners) to assess 1291‐3253 and 3389‐10,687 individuals with and without fractures, respectively, ranging in age from 10.9 to 84.7 years with no comorbid conditions. Parameters describing radial and tibial bone density, microarchitecture, and strength were extracted and percentage differences between fracture and control subjects were estimated using a random effects meta‐analysis. An additional meta‐analysis of short‐term in vivo reproducibility of bone parameters assessed by XtremeCT was conducted to determine whether fracture‐associated differences exceeded the least significant change (LSC) required to discern measured differences from precision error. Radial and tibial HR‐pQCT parameters, including failure load, were significantly altered in fracture subjects, with differences ranging from −2.6% (95% CI: −3.4 to −1.9) in radial cortical vBMD to −12.6% (95% CI: −15.0 to −10.3) in radial trabecular vBMD. Fracture‐associated differences reported by prospective studies were consistent with those from retrospective studies, indicating that HR‐pQCT can predict incident fracture. Assessment of study quality, heterogeneity and publication biases verified the validity of these findings. Finally, we demonstrated that fracture‐associated deficits in total and trabecular vBMD, and certain tibial cortical parameters, can be reliably discerned from HR‐pQCT‐related precision error and can be used to detect fracture‐associated differences in individual patients. Although differences in other HR‐pQCT measures, including failure load, were significantly associated with fracture, improved reproducibility is needed to ensure reliable individual cross‐sectional screening and longitudinal monitoring. In conclusion, our study supports the use of HR‐pQCT in clinical fracture prediction.

Bunyamin A., Björkman K., Kawalilak C., Hosseinitabatabaei S., Teare A., Johnston J., Kontulainen S.

High-resolution peripheral quantitative computed tomography (HR-pQCT) imaging, together with computational finite element analysis (FEA), offers an attractive, noninvasive tool to quantify bone strength development in pediatric studies. Evidence of annual changes and errors in repeated HR-pQCT measures is limited, and time intervals required to reliably capture changes in children's bone strength or microarchitecture have not yet been defined. Our objectives were: (1) to quantify annual changes in bone strength and microarchitectural properties; (2) to define precision errors for pediatric bone strength outcomes; (3) to characterize annual changes in contrast to pediatric precision errors; and (4) to estimate monitoring time intervals (MTIs) required to reliably characterize bone development at the distal radius and tibia. We obtained distal radius (7% of ulnar length) and tibia (8%) bone properties using HR-pQCT and FEA from 38 follow-up study participants (21 girls) at baseline (mean age 10.6 years, SD 1.7 years) and after 1 year; and from 32 precision study participants (16 girls) at baseline (mean age 11.3 years, SD 1.6 years) and after 1 week. We characterized mean annual changes (paired t tests) contrasted to pediatric precision errors (CV%RMS ) and estimated MTIs. Annual increases in bone strength, total area, cortical thickness, and density ranged between 3.0% and 25.3% and 2.4% and 15.6% at the distal radius and tibia, respectively. Precision errors for all bone strength outcomes were ≤6.8% and ≤5.1% at the distal radius and tibia, respectively, and appeared lower than annual gains in bone strength at both sites. Cortical porosity decreased 19.6% at the distal radius and 6.6% at the distal tibia; these changes exceeded respective precision errors, indicating cortical bone consolidation. MTIs ranged between 0.5 years and infinity at the distal radius and 0.5 and 5.9 years at the distal tibia. Estimated MTIs suggest that pediatric bone strength, cortical bone density, and porosity development can be reliably monitored with annual measurements. © 2019 American Society for Bone and Mineral Research.

Gera S., Guo M., Xie Y., Pollock N., Song M., Weber D.R., Denburg M., Zemel B., Mostoufi-Moab S.

Azlağ Pekince K., Pekince A.

The purpose of this study was to investigate changes in bone trabecular structure during adolescence using the fractal analysis (FA) method on hand–wrist radiographs (HWRs) and to evaluate the relationship of these changes with pubertal growth stages. HWRs of healthy individuals aged 8–18 years were included (N = 600). Pubertal stages were determined by the Fishman method and divided into 10 groups (early puberty [EP], pre-peak [PRPK], peak [PK], post-peak [PTPK], late puberty [LP]). FA was performed using FIJI (ImageJ) software and the BoneJ plugin on circular regions of interest (ROIs) selected from the first metacarpal bone head and distal radius. Image processing steps were applied according to the White and Rudolph method. Differences between groups were statistically evaluated. Fractal dimension (FD) values of the distal radius (RAFAM) and metacarpal bone head (MAFAM) showed significant differences according to pubertal growth stages (p < 0.05). The highest FD value was observed in the LP group, and the lowest FD value was observed in the EP group (except MAFAM in females). FD generally increased from EP to LP in the whole population, but a significant decrease was observed in all groups during the PK period. This decrease was more pronounced in RAFAM of males. These findings suggest a potential decrease of bone mechanical properties in the PK, which is found the be more suitable for orthodontic treatment in the literature. FA on HWRs is a useful and sensitive tool for quantitatively assessing pubertal changes in trabecular bone microarchitecture. The findings demonstrate a significant decrease in FD in both bone regions during the pubertal growth spurt, particularly at the peak period. This may indicate a temporary reduction in bone mechanical strength during this critical stage and could contribute to increased distal radius fracture incidence. Clinically, the relationship between FD and pubertal stages suggests this method could serve as a valuable biomarker in orthodontic treatment planning, allowing for optimized timing of interventions. Furthermore, it may aid in pediatric fracture risk assessment, potentially leading to preventative strategies for high-risk individuals.

Boyd S.K.

AbstractTwenty years have passed since the introduction of high-resolution peripheral quantitative computed tomography (HR-pQCT) to assess human bone microarchitecture. During that time, the technique has emerged as an important research tool used by clinicians and scientists to learn about the pathophysiology of bone adaptation in the context of osteoporosis and many other bone-affected conditions. Its rich three-dimensional data is well suited for precise longitudinal monitoring of bone microarchitecture and associated patient-specific estimated bone strength.However, uptake of HR-pQCT as a clinical diagnostic tool has been limited, in part due to challenges such as availability, regulatory approvals, and demonstrated cost effectiveness. New research suggests fracture risk assessment using HR-pQCT is comparable with current standards based on traditional bone densitometry, but its contribution to clinical care is best suited to two areas: (1) leveraging microarchitectural information to assist in treatment decisions for the large subset of patients who lie in the so-called gray zone by current fracture risk assessment, and (2) longitudinal monitoring that establishes highly refined trajectories of bone adaptation and can inform decisions to initiate treatment, monitor treatment effects, and inform cessation.

Yang K.G., Lee W.Y., Hung A.L., Kumar A., Chui E.C., Hung V.W., Cheng J.C., Lam T., Lau A.Y.

Abstract Low bone mineral density and impaired bone qualities have been shown to be important prognostic factors for curve progression in Adolescent Idiopathic Scoliosis (AIS). There is no evidence-based integrative interpretation method to analyse high-resolution peripheral quantitative computed tomography (HR-pQCT) data in AIS. This study aimed to (a) utilize unsupervised machine learning to cluster bone microarchitecture phenotypes on HR-pQCT parameters in AIS girls, (b) assess the phenotypes’ risk of curve progression and progression to surgical threshold at skeletal maturity (primary cohort), and (c) investigate risk of curve progression in a separate cohort of mild AIS girls whose curve severity did not reach bracing threshold at recruitment (secondary cohort). Patients were followed up prospectively for 6.22 ± 0.33 years in the primary cohort (N = 101). Three bone microarchitecture phenotypes were clustered by Fuzzy C-Means at time of peripubertal peak height velocity (PHV). Phenotype-1 had normal bone characteristics. Phenotype-2 was characterized by low bone volume and high cortical bone density, and Phenotype-3 had low cortical and trabecular bone density and impaired trabecular microarchitecture. The difference in bone qualities amongst the phenotypes was significant at peripubertal PHV and continued to skeletal maturity. Phenotype-3 had significantly increased risk of curve progression to surgical threshold at skeletal maturity (Odd Ratios (OR) = 4.88; 95% Confidence Interval (CI): 1.03-28.63). In the secondary cohort (N = 106), both Phenotype-2 (adjusted OR = 5.39; 95%CI: 1.47-22.76) and Phenotype-3 (adjusted OR = 3.67; 95%CI: 1.05-14.29) had increased risk of curve progression ≥6° with mean follow-up of 3.03 ± 0.16 years. In conclusion, three distinct bone microarchitecture phenotypes could be clustered by unsupervised machine learning on HR-pQCT generated bone parameters at peripubertal PHV in AIS. The bone qualities reflected by these phenotypes were found to have significant differentiating risk of curve progression and progression to surgical threshold at skeletal maturity in AIS.

Rodrick E., Kindler J.M.

Purpose of review Bone accrual during childhood and adolescence is critical for the attainment of peak bone mass and is a major contributing factor towards osteoporosis in later life. Bone mass accrual is influenced by nonmodifiable factors, such as genetics, sex, race, ethnicity, and puberty, as well as modifiable factors, such as physical activity and diet. Recent progress in bone imaging has allowed clinicians and researchers to better measure the morphology, density, and strength of the growing skeleton, thereby encompassing key characteristics of peak bone strength. In this review, the patterning of bone accrual and contributors to these changes will be described, as well as new techniques assessing bone mass and strength in pediatric research and clinical settings. Recent findings This review discusses factors influencing peak bone mass attainment and techniques used to assess the human skeleton. Summary The rate of bone accrual and the magnitude of peak bone mass attainment occurs in specific patterns varying by sex, race, ethnicity, longitudinal growth, and body composition. Physical activity, diet, and nutritional status impact these processes. There is a need for longitudinal studies utilizing novel imaging modalities to unveil factors involved in the attainment and maintenance of peak bone strength.