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IntroductionThe 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.MethodsA 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.ResultsAn 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.ConclusionThis 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.

High‐dose vitamin D supplementation (4000 or 10,000 IU/d) in vitamin D‐sufficient individuals results in a dose‐dependent decrease in radius and tibia total bone mineral density (Tt.BMD) compared with 400 IU/d. This exploratory analysis examined whether the response to high‐dose vitamin D supplementation depends on imaging modality and skeletal site. Participants were aged 55 to 70 years, not osteoporotic, with serum 25(OH)D 30 to 125 nM. Participants’ radius and tibia were scanned on high‐resolution peripheral quantitative computed tomography (HR‐pQCT) to measure Tt.BMD, trabecular bone volume fraction (Tb.BV/TV), trabecular separation (Tb.Sp), cortical thickness (Ct.Th), and finite element analysis (FEA) estimated failure load. Three‐dimensional image registration was used. Dual‐energy X‐ray absorptiometry (DXA) scans of the hip, spine, and radius measured areal BMD (aBMD) and trabecular bone score (TBS). Constrained linear mixed‐effects models determined treatment group‐by‐time and treatment group‐by‐time‐by‐sex interactions. The treatment group‐by‐time interaction previously observed for radial Tt.BMD was observed at both ultradistal (UD, p < 0.001) and 33% (p < 0.001) aBMD sites. However, the treatment group‐by‐time‐by‐sex interaction observed for radial Tt.BMD was not observed with aBMD at either the UD or 33% site, and the 4000 and 400 groups did not differ. Registered radial FEA results mirrored Tt.BMD. An increase in Tb.Sp and decrease in Ct.Th underpinned dose‐dependent changes in radial BMD and strength. We observed no effects in DXA‐based aBMD at the hip or spine or TBS. At the tibia, we observed a time‐by‐treatment group effect for Tb.BV/TV. Given that DXA measures at the radius did not detect sex differences or differences between the 4000 and 400 groups, HR‐pQCT at the radius may be more sensitive for examining bone changes after vitamin D supplementation. Although DXA did not reveal treatment effects at the hip or spine, whether that is a true skeletal site difference or a lack of modality sensitivity remains unclear. © 2022 The Authors. JBMR Plus published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research.

The osteopetroses are a group of rare genetic diseases caused by osteoclast dysfunction or absence. The hallmark of osteopetrosis is generalized increased bone mineral density (BMD). However, the bone is fragile and fractures are common. Autosomal recessive osteopetrosis is usually a severe disorder and often life‐threatening in childhood. We present male siblings with autosomal recessive osteopetrosis due to biallelic variants in TCIRG1 who survived childhood and underwent hematopoietic stem cell transplant (HSCT) in adulthood. One sibling died of posttransplant complications. After transplant, the other sibling had improvement of multiple clinical parameters, including some decline in BMD Z‐scores by dual‐energy X‐ray absorptiometry (DXA) and cessation of fractures. However, spine quantitative computed tomography 11 years after transplant demonstrated an anvil pattern of sclerosis with BMD Z‐score of +18.3. High‐resolution peripheral quantitative computed tomography (HR‐pQCT) of the tibia demonstrated near complete obliteration of the marrow space combined with an unusual cortical phenotype, suggesting extensive cortical porosity at the distal tibia. This case highlights that despite successful transplantation and subsequent improvement in clinical parameters, this patient continued to have significantly elevated bone density and decreased marrow space. Transplant‐associated increased cortical porosity is multifactorial and occurs in two‐thirds of non‐osteopetrotic patients undergoing HSCT. This finding after transplant in osteopetrosis may suggest particular sensitivity of the cortical bone to resorptive activity of transplanted osteoclasts. The case also suggests HR‐pQCT may be a useful modality for imaging and assessing the therapeutic effects on bone in individuals with osteopetrosis. © 2022 The Authors. JBMR Plus published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research. An adult male with autosomal recessive osteopetrosis due to variants in TCIRG1 underwent hematopoietic stem cell transplant in adulthood. After transplant, despite some decline in DXA BMD Z‐scores and cessation of fractures, spine quantitative computed tomography 11 years later demonstrated sclerosis with BMD Z‐score of +18.3. High‐resolution peripheral quantitative computed tomography (HR‐pQCT) of the tibia demonstrated in impressive cortical phenotype of high BMD, near complete obliteration of the marrow space, and extensive cortical porosity.

Background We used High Resolution – peripheral Quantitative CT (HR-pQCT) imaging to examine peri-articular bone quality in early rheumatoid arthritis (RA) and explore whether bone quality improved over 12-months in individuals receiving care consistent with practice guidelines. Methods A 1-year longitudinal cohort study (Baseline and 12-months) evaluating individuals with early RA compared to age/sex-matched peers. Personal demographic and health and lifestyle information were collected for all. Whereas, active joint count (AJC 28 ), functional limitation, and RA medications were also collected for RA participants. HR-pQCT imaging analyses quantified bone density and microstructure in the Metacarpal Head (MH) and Ultra-Ultra-Distal (UUD) radius at baseline and 12-months. Analyses included a General Linear Modelling repeated measures analyses examined main effects for disease, time, and interaction on bone quality. Results Participants ( n  = 60, 30 RA/30 NRA); 80% female, mean age 53 (varying from 21 to 74 years). At baseline, RA participants were on average 7.7 months since diagnosis, presenting with few active joints (AJC 28 : 30% none, remaining 70% Median 4 active joints) and minimal self-reported functional limitation (mHAQ-DI 0–3 : 0.56). At baseline, 29 of 30 RA participants had received one or more non-biologic disease-modifying anti-rheumatic drugs (DMARD);13 in combination with glucocorticoid and 1 in combination with a biologic medication. One participant only received glucocorticoid medication. Four RA participants withdrew leaving 26 pairs ( n  = 52) at 12-months; 23 pairs ( n  = 46) with UUD and 22 pairs ( n  = 44) with MH baseline and 12-month images to compare. Notable RA/NRA differences ( p  < 0.05) in bone quality at all three sites included lower trabecular bone density and volume, more rod-like trabeculae, and larger and more variable spaces between trabeculae; fewer trabeculae at the UUD and MH2 sites; and lower cortical bone density and volume in the MH sites. Rate of change over 12-months did not differ between RA/NRA participants which meant there was also no improvement over the year in RA bone quality. Conclusions Early changes in peri-articular bone density and microstructure seen in RA are consistent with changes more commonly seen in aging bone and are slow or resistant to recover despite well controlled inflammatory joint symptoms with early DMARD therapy.

High-resolution peripheral computed tomography (HR-pQCT) was developed to image bone microarchitecture in vivo at peripheral skeletal sites. Since the introduction of HR-pQCT in 2005, clinical research to gain insight into pathophysiology of skeletal fragility and to improve prediction of fractures has grown. Meanwhile, the second-generation HR-pQCT device has been introduced, allowing novel applications such as hand joint imaging, assessment of subchondral bone and cartilage thickness in the knee, and distal radius fracture healing. This article provides an overview of the current clinical applications and guidance on interpretation of results, as well as future directions. Specifically, we provide an overview of (1) the differences and reference data for HR-pQCT variables by age, sex, and race/ethnicity; (2) fracture risk prediction using HR-pQCT; (3) the ability to monitor response of anti-osteoporosis therapy with HR-pQCT; (4) the use of HR-pQCT in patients with metabolic bone disorders and diseases leading to secondary osteoporosis; and (5) novel applications of HR-pQCT imaging. Finally, we summarize the status of the application of HR-pQCT in clinical practice and discuss future directions. From the clinical perspective, there are both challenges and opportunities for more widespread use of HR-pQCT. Assessment of bone microarchitecture by HR-pQCT improves fracture prediction in mostly normal or osteopenic elderly subjects beyond DXA of the hip, but the added value is marginal. The prospects of HR-pQCT in clinical practice need further study with respect to medication effects, metabolic bone disorders, rare bone diseases, and other applications such as hand joint imaging and fracture healing. The mostly unexplored potential may be the differentiation of patients with only moderately low BMD but severe microstructural deterioration, which would have important implications for the decision on therapeutical interventions.

SummaryHigh-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.PurposeTo 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.MethodsData 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.ResultsScans 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.ConclusionThe 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.

In 2011 over 1.7 million people were hospitalized because of a fragility fracture, and direct costs associated with osteoporosis treatment exceeded 70 billion dollars in the United States. Failure to reach and maintain optimal peak bone mass during adulthood is a critical factor in determining fragility fracture risk later in life. Physical activity is a widely accessible, low cost, and highly modifiable contributor to bone health. Exercise is especially effective during adolescence, a time period when nearly 50% of peak adult bone mass is gained. Here, we review the evidence linking exercise and physical activity to bone health in women. Bone structure and quality will be discussed, especially in the context of clinical diagnosis of osteoporosis. We review the mechanisms governing bone metabolism in the context of physical activity and exercise. Questions such as, when during life is exercise most effective, and what specific types of exercises improve bone health, are addressed. Finally, we discuss some emerging areas of research on this topic, and summarize areas of need and opportunity.

Impaired bone microarchitecture, assessed by high-resolution peripheral quantitative computed tomography (HR-pQCT), may contribute to bone fragility in type 2 diabetes (T2DM) but data on men are lacking. To investigate the association between T2DM and HR-pQCT parameters in older men. HR-pQCT scans were acquired on 1794 participants in the Osteoporotic Fractures in Men study. T2DM was ascertained by self-report or medication use. Linear regression models, adjusted for age, race, body mass index, limb length, clinic site, and oral corticosteroid use, were used to compare HR-pQCT parameters by diabetes status. Among 1777 men, 290 had T2DM (mean age, 84.4 years). T2DM men had smaller total cross-sectional area at the distal tibia (P = .028) and diaphyseal tibia (P = .025), and smaller cortical area at the distal (P = .009) and diaphyseal tibia (P = .023). Trabecular indices and cortical porosity were similar between T2DM and non-T2DM. Among men with T2DM, in a model including HbA1c, diabetes duration, and insulin use, diabetes duration ≥ 10 years, compared with <10 years, was significantly associated with higher cortical porosity but with higher trabecular thickness at the distal radius. Insulin use was significantly associated with lower cortical area and thickness at the distal radius and diaphyseal tibia and lower failure load at all 3 scan sites. Lower cortical area, cortical thickness, total bone mineral density, cortical bone mineral density, and failure load of the distal sites were associated with increased risk of incident nonvertebral fracture in T2DM. Older men with T2DM have smaller bone size compared to those without T2DM, which may contribute to diabetic skeletal fragility. Longer diabetes duration was associated with higher cortical porosity and insulin use with cortical bone deficits and lower failure load.

The finite element (FE) method based on high-resolution peripheral quantitative computed tomography (HR-pQCT) use a variety of tissue constitutive properties and boundary conditions at different laboratories making comparison of mechanical properties difficult. Furthermore, the advent of a second-generation HR-pQCT poses challenges due to improved resolution and a larger region of interest (ROI). This study addresses the need to harmonize results across FE models. The aims are to establish the relationship between FE results as a function of boundary conditions and a range of tissue properties for the first-generation HR-pQCT system, and to determine appropriate model parameters for the second-generation HR-pQCT system. We implemented common boundary conditions and tissue properties on a large cohort (N = 1371), and showed the relationships were highly linear (R2 > 0.99) for yield strength and reaction force between FE models. Cadaver radii measured on both generation HR-pQCT with matched ROIs were used to back-calculate a tissue modulus that accounts for the increased resolution (61 µm versus 82 µm), resulting in a modulus of 8748 MPa for second-generation HR-pQCT to produce bone yield strength and reaction force equivalent to using 6829 MPa for first-generation HR-pQCT. Finally, in vivo scans (N = 61) conducted on both generations demonstrated that the larger ROI in the second-generation system results in stronger bone outcome measures, suggesting it is not advisable to convert FE results across HR-pQCT generations without matching ROIs. Together, these findings harmonize FE results by providing a means to compare findings with different boundary conditions and tissue properties, and across scanner generations.

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.