Decreased Quantity and Quality of the Periarticular and Nonperiarticular Bone in Patients With Rheumatoid Arthritis: A Cross‐Sectional HR‐pQCT Study

Rheumatoid arthritis (RA) is a highly bone destructive disease. Although it is well established that RA leads to bone loss and increased fracture risk, current knowledge on the microstructural changes of bone in RA is still limited. The purpose of this study was to assess the microstructure of periarticular and nonperiarticular bone in female and male RA patients and compare it with respective healthy controls. We performed two high‐resolution peripheral quantitative computed tomography (HR‐pQCT; Xtreme‐CT) scans, one of the distal radius and one of the ultradistal radius in 90 patients with RA (60 females, 30 males) and 70 healthy controls (40 females, 30 males) matched for sex, age, and body mass index. Volumetric bone mineral density (vBMD), bone geometry, and bone microstructure including trabecular bone volume fraction (BV/TV), trabecular number (Tb.N), trabecular thickness (Tb.Th), cortical thickness (Ct.Th) and cortical porosity (Ct.Po) were assessed. At the distal and ultradistal radius, trabecular (p = 0.005 and p < 0.001) and cortical BMD (p < 0.001 and p < 0.001) were significantly decreased in male and female patients with RA, respectively. BV/TV was also decreased at both sites, based on lower Tb.N in female RA (p < 0.001 for both sites) and lower Tb.Th (p = 0.034 and p = 0.005) in male RA patients compared with respective healthy controls. Cortical thinning (p = 0.018 and p = 0.002) but not Ct.Po (p = 0.070 and p = 0.275) was pronounced in male and female RA patients at the distal radius. Cortical perimeter was increased in male and female RA patients at both sites. Multiple regression models showed that bone geometry (cortical perimeter) is predominantly influenced by age of the RA patient, cortical thickness by both age and disease duration, and trabecular microstructure predominantly by the disease duration. In summary, these data show profound deterioration of bone microstructure in the appendicular skeleton of RA patients at both periarticular and nonperiarticular sites. © 2014 American Society for Bone and Mineral Research.     

Age‐related patterns of trabecular and cortical bone loss differ between sexes and skeletal sites: A population‐based HR‐pQCT study

In this cross‐sectional study, we aimed to predict age‐related changes in bone microarchitecture and strength at the distal radius (DR) and distal tibia (DT) in 644 Canadian adults (n = 442 women and 202 men) aged 20 to 99 years. We performed a standard morphologic analysis of the DR and DT with high‐resolution peripheral quantitative computed tomography (pQCT) and used finite‐element analysis (FEA) to estimate bone strength (failure load) and the load distribution. We also calculated a DR load‐to‐strength ratio as an estimate of forearm fracture risk. Total bone area, which was 33% larger in young men at both sites, changed similarly with age in women and men at the DT but increased 17% more in men than in women at the DR (p < .001). Trabecular number and thickness (Tb.Th) were 7% to 20% higher in young men than in young women at both sites, and with the exception of Tb.Th at the DR, which declined more with age in men (?16%) than in women (?2%, p < .01), the age‐related decline in these outcomes was similar in women and in men. In the cortex, porosity (Ct.Po) was 31% to 44% lower in young women than in young men but increased 92% to 176% more with age in women than in men (p < .001). The DR cortex carried 14% more load in young women than in young men, and the percentage of load carried by the DR cortex did not change with age in women but declined by 17% in men (p < .01). FEA‐estimated bone strength was 34% to 47% greater in young men, but the predicted change with age was similar in both sexes. In contrast, the load‐to‐strength ratio increased 27% more in women than in men with age (p < .01). These results highlight important site‐ and sex‐specific differences in patterns of age‐related bone loss. In particular, the trends for less periosteal expansion, more porous cortices, and a greater percentage of load carried by the DR cortex in women may underpin sex differences in forearm fracture risk. © 2011 American Society for Bone and Mineral Research.     

Bone Geometry,Volumetric Density,Microarchitecture, and Estimated Bone Strength Assessed by HR‐pQCT in Adult Patients With Hypophosphatemic Rickets

Hypophosphatemic rickets (HR) is characterized by a generalized mineralization defect. Although densitometric studies have found the patients to have an elevated bone mineral density (BMD), data on bone geometry and microstructure are scarce. The aim of this cross‐sectional in vivo study was to assess bone geometry, volumetric BMD (vBMD), microarchitecture, and estimated bone strength in adult patients with HR using high‐resolution peripheral quantitative computed tomography (HR‐pQCT). Twenty‐nine patients (aged 19 to 79 years; 21 female, 8 male patients), 26 of whom had genetically proven X‐linked HR, were matched with respect to age and sex with 29 healthy subjects. Eleven patients were currently receiving therapy with calcitriol and phosphate for a median duration of 29.1 years (12.0 to 43.0 years). Because of the disproportionate short stature in HR, the region of interest in HR‐pQCT images at the distal radius and tibia were placed in a constant proportion to the entire length of the bone in both patients and healthy volunteers. In age‐ and weight‐adjusted models, HR patients had significantly higher total bone cross‐sectional areas (radius 36%, tibia 20%; both p < 0.001) with significantly higher trabecular bone areas (radius 49%, tibia 14%; both p < 0.001) compared with controls. In addition, HR patients had lower total vBMD (radius ?20%, tibia ?14%; both p < 0.01), cortical vBMD (radius ?5%, p < 0.001), trabecular number (radius ?13%, tibia ?14%; both p < 0.01), and cortical thickness (radius ?19%; p < 0.01) compared with controls, whereas trabecular spacing (radius 18%, tibia 23%; p < 0.01) and trabecular network inhomogeneity (radius 29%, tibia 40%; both p < 0.01) were higher. Estimated bone strength was similar between the groups. In conclusion, in patients with HR, the negative impact of lower vBMD and trabecular number on bone strength seems to be compensated by an increase in bone diameter, resulting in HR patients having normal estimates of bone strength. © 2014 American Society for Bone and Mineral Research.     

Sex Differences and Growth‐Related Adaptations in Bone Microarchitecture,Geometry, Density,and Strength From Childhood to Early Adulthood: A Mixed Longitudinal HR‐pQCT Study

Sex differences in bone strength and fracture risk are well documented. However, we know little about bone strength accrual during growth and adaptations in bone microstructure, density, and geometry that accompany gains in bone strength. Thus, our objectives were to (1) describe growth related adaptations in bone microarchitecture, geometry, density, and strength at the distal tibia and radius in boys and girls; and (2) compare differences in adaptations in bone microarchitecture, geometry, density, and strength between boys and girls. We used HR‐pQCT at the distal tibia (8% site) and radius (7% site) in 184 boys and 209 girls (9 to 20 years old at baseline). We aligned boys and girls on a common maturational landmark (age at peak height velocity [APHV]) and fit a mixed effects model to these longitudinal data. Importantly, boys showed 28% to 63% greater estimated bone strength across 12 years of longitudinal growth. Boys showed 28% to 80% more porous cortices compared with girls at both sites across all biological ages, except at the radius at 9 years post‐APHV. However, cortical density was similar between boys and girls at all ages at both sites, except at 9 years post‐APHV at the tibia when girls’ values were 2% greater than boys’. Boys showed 13% to 48% greater cortical and total bone area across growth. Load‐to‐strength ratio was 26% to 27% lower in boys at all ages, indicating lower risk of distal forearm fracture compared with girls. Contrary to previous HR‐pQCT studies that did not align boys and girls at the same biological age, we did not observe sex differences in Ct.BMD. Boys’ superior bone size and strength compared with girls may confer them a protective advantage. However, boys’ consistently more porous cortices may contribute to their higher fracture incidence during adolescence. Large prospective studies using HR‐pQCT that target boys and girls who have sustained a fracture are needed to verify this. © 2016 American Society for Bone and Mineral Research.     

Bone Geometry,Volumetric Density,Microarchitecture, and Estimated Bone Strength Assessed by HR‐pQCT in Adult Patients With Type 1 Diabetes Mellitus

The primary goal of this cross‐sectional in vivo study was to assess peripheral bone microarchitecture, bone strength, and bone remodeling in adult type 1 diabetes (T1D) patients with and without diabetic microvascular disease (MVD+ and MVD–, respectively) and to compare them with age‐, gender‐, and height‐matched healthy control subjects (CoMVD+ and CoMVD–, respectively). The secondary goal was to assess differences in MVD– and MVD+ patients. Fifty‐five patients with T1DM (MVD+ group: n = 29) were recruited from the Funen Diabetes Database. Dual‐energy X‐ray absorptiometry (DXA), high‐resolution peripheral quantitative computed tomography (HR‐pQCT) of the ultradistal radius and tibia, and biochemical markers of bone turnover were performed in all participants. There were no significant differences in HR‐pQCT parameters between MVD– and CoMVD– subjects. In contrast, MVD+ patients had larger total and trabecular bone areas (p = 0.04 and p = 0.02, respectively), lower total, trabecular, and cortical volumetric bone mineral density (vBMD) (p < 0.01, p < 0.04, and p < 0.02, respectively), and thinner cortex (p = 0.03) at the radius, and lower total and trabecular vBMD (p = 0.01 and p = 0.02, respectively) at the tibia in comparison to CoMVD+. MVD+ patients also exhibited lower total and trabecular vBMD (radius p = 0.01, tibia p < 0.01), trabecular thickness (radius p = 0.01), estimated bone strength, and greater trabecular separation (radius p = 0.01, tibia p < 0.01) and network inhomogeneity (radius p = 0.01, tibia p < 0.01) in comparison to MVD– patients. These differences remained significant after adjustment for age, body mass index, gender, disease duration, and glycemic control (average glycated hemoglobin over the previous 3 years). Although biochemical markers of bone turnover were significantly lower in MVD+ and MVD– groups in comparison to controls, they were similar between the MVD+ and MVD– groups. The results of our study suggest that the presence of MVD was associated with deficits in cortical and trabecular bone vBMD and microarchitecture that could partly explain the excess skeletal fragility observed in these patients. © 2015 American Society for Bone and Mineral Research.     

A comparison of bone quality at the distal radius between Asian and white adolescents and young adults: An HR‐pQCT study

Paradoxically, Asians have lower areal bone mineral density (aBMD), but their rates of hip and wrist fractures are lower than whites. Therefore, we used high‐resolution pQCT (HR‐pQCT) to determine whether differences in bone macrostructure and microstructure, BMD, and bone strength at the distal radius were apparent in Asian (n = 91, 53 males, 38 females, [mean ± SD] 17.3 ± 1.5 years) and white (n = 89, 46 males, 43 females, 18.1 ± 1.8 years) adolescents and young adults. HR‐pQCT outcomes included total BMD (Tt.BMD), trabecular bone volume fraction (BV/TV), and trabecular number (Tb.N), thickness (Tb.Th), and separation (Tb.Sp). We used an automated segmentation algorithm to determine total bone area (Tt.Ar), and cortical BMD (Ct.BMD), porosity (Ct.Po), and thickness (Ct.Th), and we applied finite element (FE) analysis to HR‐pQCT scans to estimate bone strength. We fit sex‐specific multivariable regression models to compare bone outcomes between Asians and whites, adjusting for age, age at menarche (girls), lean mass, ulnar length, dietary calcium intake, and physical activity. In males, after adjusting for covariates, Asians had 11% greater Tt.BMD, 8% greater Ct.BMD, and 25% lower Ct.Po than whites (p < 0.05). Also, Asians had 9% smaller Tt.Ar and 27% greater Ct.Th (p < 0.01). In females, Asians had smaller Tt.Ar than whites (16%, p < 0.001), but this difference was not significant after adjusting for covariates. Asian females had 5% greater Ct.BMD, 12% greater Ct.Th, and 11% lower Tb.Sp than whites after adjusting for covariates (p < 0.05). Estimated bone strength did not differ between Asian and white males or females. Our study supports the notion of compensatory elements of bone structure that sustain bone strength; smaller bones as observed between those of Asian origin compared with white origin have, on average, more dense, less porous, and thicker cortices. Longitudinal studies are needed to determine whether ethnic differences in bone structure exist in childhood, persist into old age, and whether they influence fracture risk.     

The Estimation of Second‐Generation HR‐pQCT From First‐Generation HR‐pQCT Using In Vivo Cross‐Calibration

Second‐generation high‐resolution peripheral quantitative computed tomography (HR‐pQCT) provides the highest resolution in vivo to assess bone density and microarchitecture in 3D. Although strong agreement of most outcomes measured with first‐ (XCTI) and second‐ (XCTII) generation HR‐pQCT has been demonstrated, the ability to use the two systems interchangeably is unknown. From in vivo measurements, we determined the limits of estimating XCTII data from XCTI scans conducted in vivo and whether that estimation can be improved by linear cross‐calibration equations. These data are crucial as the research field transitions to the new technology. Our study design established cross‐calibration equations by scanning 62 individuals on both systems on the same day and then tested those cross‐calibrations on the same cohort 6 months later so that estimated (denoted as XCTII*) and “true” XCTII parameters could be compared. We calculated the generalized least‐significant change (GLSC) for those predictions. There was strong agreement between both systems for density (R² > 0.94), macroarchitecture (R² > 0.95), and most microarchitecture outcomes with the exception of trabecular thickness (Tb.Th, R² = 0.51 to 0.67). Linear regression equations largely eliminated the systematic error between XCTII and XCTII* and produced a good estimation of most outcomes, with individual error estimates between 0.2% and 3.4%, with the exception of Tt.BMD. Between‐system GLSC was similar to within‐XCTI LSC (eg, 8.3 to 41.9 mg HA/cm³ for density outcomes). We found that differences between outcomes assessed with XCTI and XCTII can be largely eliminated by cross‐calibration. Tb.Th is poorly estimated because it is measured more accurately by XCTII than XCTI. It may be possible to use cross‐calibration for most outcomes when both scanner generations are used for multicenter and longitudinal studies. © 2017 American Society for Bone and Mineral Research.     

Longitudinal HR‐pQCT and Image Registration Detects Endocortical Bone Loss in Kidney Transplantation Patients

Patients with chronic kidney disease (CKD) who undergo kidney transplantation experience bone loss and increased risk of fracture. However, the mechanisms of this bone loss are unclear. Our objective was to use image registration to define the cortex to assess changes in cortical porosity (Ct.Po) in patients undergoing first‐time kidney transplantation. We obtained serial measurements of parathyroid hormone (PTH) and bone turnover markers and used high‐resolution peripheral quantitative computed tomography (HR‐pQCT) to scan the distal radius and tibia in 31 patients (21 men, 10 women; aged 51.9 ± 13.4 years) at transplant and after 1 year. Baseline and 1‐year images were aligned using a fully automated, intensity‐based image registration framework. We compared three methods to define the cortical region of interest (ROI) and quantify the changes: 1) cortical bone was independently defined in baseline and follow‐up scans; 2) cortical bone was defined as the common cortical ROI; and 3) the cortical ROI at baseline was carried forward to 1‐year follow‐up (baseline‐indexed). By the independently defined ROI, Ct.Po increased 11.7% at the radius and 9.1% at the tibia, whereas by the common ROI, Ct.Po increased 14.6% at the radius and 9.1% at the tibia. By the baseline‐indexed ROI, which provides insight into changes at the endocortical region, Ct.Po increased 63.4% at the radius and 17.6% at the tibia. We found significant relationships between changes in Ct.Po and bone formation and resorption markers at the radius. The strongest associations were found between markers and Ct.Po using the baseline‐index method. We conclude that Ct.Po increases throughout the cortex after kidney transplant, and this increase is particularly marked at the endocortical surface. These methods may prove useful for all HR‐pQCT longitudinal studies, particularly when changes are expected at the endocortical region. © 2014 American Society for Bone and Mineral Research.     

Synovium‐Derived MicroRNAs Regulate Bone Pathways in Rheumatoid Arthritis

Articular bone erosion in rheumatoid arthritis (RA) is mediated by the interaction between inflammation and pathways regulating bone metabolism. Inflammation promotes osteoclastogenesis and also inhibits osteoblast function, further contributing to the persistence of erosions. MicroRNAs (miRNAs) are important regulators of skeletal remodeling and play a role in RA pathogenesis. We therefore determined the expression of miRNAs in inflamed synovial tissue and the role they play in pathways regulating osteoblast and osteoclast function. Using the serum transfer mouse model of RA in C57BL/6 mice, we performed Fluidigm high‐throughput qPCR‐based screening of miRNAs from nonarthritic and arthritic mice. Global gene expression profiling was also performed on Affymetrix microarrays from these same synovial samples. miRNA and mRNA expression profiles were subjected to comparative bioinformatics. A total of 536 upregulated genes and 417 downregulated genes were identified that are predicted targets of miRNAs with reciprocal expression changes. Gene ontology analysis of these genes revealed significant enrichment in skeletal pathways. Of the 22 miRNAs whose expression was most significantly changed (p < 0.01) between nonarthritic and arthritic mice, we identified their targets that both inhibit and promote bone formation. These miRNAs are predicted to target Wnt and BMP signaling pathway components. We validated miRNA array findings and demonstrated that secretion of miR‐221‐3p in exosomes was upregulated by synovial fibroblasts treated with the proinflammatory cytokine TNF. Overexpression of miR‐221‐3p suppressed calvarial osteoblast differentiation and mineralization in vitro. These results suggest that miRNAs derived from inflamed synovial tissues may regulate signaling pathways at erosion sites that affect bone loss and potentially also compensatory bone formation. © 2016 American Society for Bone and Mineral Research.     

Structure and strength of the distal radius in female patients with rheumatoid arthritis: A case‐control study

The purpose of this work was to investigate the volumetric bone mineral density (vBMD), bone microstructure, and mechanical indices of the distal radius in female patients with rheumatoid arthritis (RA). We report a cross‐sectional study of 66 middle‐aged female RA patients and 66 age‐matched healthy females. Areal BMD (aBMD) of the hip, lumbar spine, and distal radius was measured by dual‐energy X‐ray absorptiometry (DXA). High‐resolution peripheral quantitative computed tomography (HR‐pQCT) was performed at the distal radius, yielding vBMD, bone microstructure, and mechanical indices. Cortical and trabecular vBMD were 3.5% and 10.7% lower, respectively, in RA patients than controls, despite comparable aBMD. Trabecular microstructural indices were –5.7% to –23.1% inferior, respectively, in RA patients compared to controls, with significant differences in trabecular bone volume fraction, separation, inhomogeneity, and structural model index. Cortical porosity volume and percentage were 128% and 93% higher, respectively, in RA patients, with stress being distributed more unevenly. Fourteen RA patients had exaggerated periosteal bone apposition primarily affecting the ulnovolar aspect of the distal radius. These particular patients were more likely to have chronic and severe disease and coexisting wrist deformity. The majority of the differences in density and microstructure between RA patients and controls did not depend on menstrual status. Recent exposure to glucocorticoids did not significantly affect bone density and microstructure. HR‐pQCT provides new insight into inflammation‐associated bone fragility in RA. It detects differences in vBMD, bone microstructure, and mechanical indices that are not captured by DXA. At the distal radius, deterioration in density and microstructure in RA patients involved both cortical and trabecular compartments. Excessive bone resorption appears to affect cortical more than trabecular bone at distal radius, particularly manifested as increased cortical porosity. Ulnovolar periosteal apposition of the distal radius is a feature of chronic, severe RA with wrist deformity. © 2013 American Society for Bone and Mineral Research.     

Trabecular and cortical bone density and architecture in women after 60 days of bed rest using high‐resolution pQCT: WISE 2005

Prolonged bed rest is used to simulate the effects of spaceflight and causes disuse‐related loss of bone. While bone density changes during bed rest have been described, there are no data on changes in bone microstructure. Twenty‐four healthy women aged 25 to 40 years participated in 60 days of strict 6‐degree head‐down tilt bed rest (WISE 2005). Subjects were assigned to either a control group (CON, n = 8), which performed no countermeasures; an exercise group (EXE, n = 8), which undertook a combination of resistive and endurance training; or a nutrition group (NUT, n = 8), which received a high‐protein diet. Density and structural parameters of the distal tibia and radius were measured at baseline, during, and up to 1 year after bed rest by high‐resolution peripheral quantitative computed tomography (HR‐pQCT). Bed rest was associated with reductions in all distal tibial density parameters (p < 0.001), whereas only distal radius trabecular density decreased. Trabecular separation increased at both the distal tibia and distal radius (p < 0.001), but these effects were first significant after bed rest. Reduction in trabecular number was similar in magnitude at the distal radius (p = 0.021) and distal tibia (p < 0.001). Cortical thickness decreased at the distal tibia only (p < 0.001). There were no significant effects on bone structure or density of the countermeasures (p ≥ 0.057). As measured with HR‐pQCT, it is concluded that deterioration in bone microstructure and density occur in women during and after prolonged bed rest. The exercise and nutrition countermeasures were ineffective in preventing these changes. © 2011 American Society for Bone and Mineral Research     

Age‐ and Sex‐Dependent Changes of Intra‐articular Cortical and Trabecular Bone Structure and the Effects of Rheumatoid Arthritis

The objective of this cross‐sectional study was to define normal sex‐ and age‐dependent values of intra‐articular bone mass and microstructures in the metacarpal heads of healthy individuals by high‐resolution peripheral quantitative computed tomography (HR‐pQCT) and test the effect of rheumatoid arthritis (RA) on these parameters. Human cadaveric metacarpal heads were used to exactly define intra‐articular bone. Healthy individuals of different sex and age categories and RA patients with similar age and sex distribution received HR‐pQCT scans of the second metacarpal head and the radius. Total, cortical, and trabecular bone densities as well as microstructural parameters were compared between 1) the different ages and sexes in healthy individuals; 2) between metacarpal heads and the radius; and 3) between healthy individuals and RA patients. The cadaveric study allowed exact definition of the intra‐articular (intracapsular) bone margins. These data were applied in measuring intra‐articular and radial bone parameters in 214 women and men (108 healthy individuals, 106 RA patients). Correlations between intra‐articular and radial bone parameters were good (r = 0.51 to 0.62, p < 0.001). In contrast to radial bone, intra‐articular bone remained stable until age 60 years (between 297 and 312 mg HA/cm³) but decreased significantly (p < 0.001) in women thereafter (237.5 ± 44.3) with loss of both cortical and trabecular bone. Similarly, RA patients showed significant (p < 0.001) loss of intra‐articular total (263.0 ± 44.8), trabecular (171.2 ± 35.6), and cortical bone (610.2 ± 62.0) compared with sex‐ and age‐adjusted controls. Standard sex‐ and age‐dependent values for physiological intra‐articular bone were defined. Postmenopausal state and RA led to significant decrease of intra‐articular bone. © 2016 American Society for Bone and Mineral Research.     

Milk Fat Globule‐Epidermal Growth Factor 8 (MFG‐E8) Is a Novel Anti‐inflammatory Factor in Rheumatoid Arthritis in Mice and Humans

Milk fat globule‐epidermal growth factor 8 (MFG‐E8) is an anti‐inflammatory glycoprotein that mediates the clearance of apoptotic cells and is implicated in the pathogenesis of autoimmune and inflammatory diseases. Because MFG‐E8 also controls bone metabolism, we investigated its role in rheumatoid arthritis (RA), focusing on inflammation and joint destruction. The regulation of MFG‐E8 by inflammation was assessed in vitro using osteoblasts, in arthritic mice and in patients with RA. K/BxN serum transfer arthritis (STA) was applied to MFG‐E8 knock‐out mice to assess its role in the pathogenesis of arthritis. Stimulation of osteoblasts with lipopolysaccharide (LPS) and tumor necrosis factor (TNF)‐α downregulated the expression of MFG‐E8 by 30% to 35%. MFG‐E8‐deficient osteoblasts responded to LPS with a stronger production of pro‐inflammatory cytokines. In vivo, MFG‐E8 mRNA levels were 52% lower in the paws of collagen‐induced arthritic (CIA) mice and 24% to 42% lower in the serum of arthritic mice using two different arthritis models (CIA and STA). Similarly, patients with RA (n = 93) had lower serum concentrations of MFG‐E8 (–17%) compared with healthy controls (n = 140). In a subgroup of patients who had a moderate to high disease activity (n = 21), serum concentrations of MFG‐E8 rose after complete or partial remission had been achieved (+67%). Finally, MFG‐E8‐deficient mice subjected to STA exhibited a stronger disease burden, an increased number of neutrophils in the joints, and a more extensive local and systemic bone loss. This was accompanied by an increased activation of osteoclasts and a suppression of osteoblast function in MFG‐E8‐deficient mice. Thus, MFG‐E8 is a protective factor in the pathogenesis of RA and subsequent bone loss. Whether MFG‐E8 qualifies as a novel biomarker or therapeutic target for the treatment of RA is worth addressing in further studies. © 2015 American Society for Bone and Mineral Research.     

Trabecular and Cortical Microstructure and Fragility of the Distal Radius in Women

Fragility fractures commonly involve metaphyses. The distal radius is assembled with a thin cortex formed by fusion (corticalization) of trabeculae arising from the periphery of the growth plate. Centrally positioned trabeculae reinforce the thin cortex and transfer loads from the joint to the proximal thicker cortical bone. We hypothesized that growth‐ and age‐related deficits in trabecular bone disrupt this frugally assembled microarchitecture, producing bone fragility. The microarchitecture of the distal radius was measured using high‐resolution peripheral quantitative computed tomography in 135 females with distal radial fractures, including 32 girls (aged 7 to 18 years), 35 premenopausal women (aged 18 to 44 years), and 68 postmenopausal women (aged 50 to 76 years). We also studied 240 fracture‐free controls of comparable age and 47 healthy fracture‐free premenopausal mother‐daughter pairs (aged 30 to 55 and 7 to 20 years, respectively). In fracture‐free girls and pre‐ and postmenopausal women, fewer or thinner trabeculae were associated with a smaller and more porous cortical area (r = 0.25 to 0.71 after age, height, and weight adjustment, all p < 0.05). Fewer and thinner trabeculae in daughters were associated with higher cortical porosity in their mothers (r = 0.30 to 0.47, all p < 0.05). Girls and premenopausal and postmenopausal women with forearm fractures had 0.3 to 0.7 standard deviations (SD) fewer or thinner trabeculae and higher cortical porosity than controls in one or more compartment; one SD trait difference conferred odds ratio (95% confidence interval) for fracture ranging from 1.56 (1.01–2.44) to 4.76 (2.86–7.69). Impaired trabecular corticalization during growth, and cortical and trabecular fragmentation during aging, may contribute to the fragility of the distal radius. © 2014 American Society for Bone and Mineral Research.     

Differences in Trabecular Microstructure Between Black and White Women Assessed by Individual Trabecular Segmentation Analysis of HR‐pQCT Images

Black women have lower fracture risk compared with white women, which may be partly explained by improved volumetric bone mineral density (vBMD) and bone microarchitecture primarily within the cortical bone compartment. To determine if there are differences in trabecular microstructure, connectivity, and alignment according to race/ethnicity, we performed individual trabecular segmentation (ITS) analyses on high‐resolution peripheral quantitative computed tomography (HR‐pQCT) scans of the distal radius and tibia in 273 peri‐ and postmenopausal black (n = 100) and white (n = 173) women participating in the Study of Women's Health Across the Nation in Boston. Unadjusted analyses showed that black women had greater trabecular plate volume fraction, plate thickness, plate number density, and plate surface area along with greater axial alignment of trabeculae, whereas white women had greater trabecular rod tissue fraction (p < 0.05 for all). Adjustment for clinical covariates augmented these race/ethnicity‐related differences in plates and rods, such that white women had greater trabecular rod number density and rod‐rod connectivity, whereas black women continued to have superior plate structural characteristics and axial alignment (p < 0.05 for all). These differences remained significant after adjustment for hip BMD and trabecular vBMD. In conclusion, black women had more plate‐like trabecular morphology and higher axial alignment of trabeculae, whereas white women had more rod‐like trabeculae. These differences may contribute to the improved bone strength and lower fracture risk observed in black women. © 2016 American Society for Bone and Mineral Research.     

Physical Activity,Sedentary Time,and Bone Strength From Childhood to Early Adulthood: A Mixed Longitudinal HR‐pQCT study

Bone strength is influenced by bone geometry, density, and bone microarchitecture, which adapt to increased mechanical loads during growth. Physical activity (PA) is essential for optimal bone strength accrual; however, less is known about how sedentary time influences bone strength and its determinants. Thus, our aim was to investigate the prospective associations between PA, sedentary time, and bone strength and its determinants during adolescence. We used HR‐pQCT at distal tibia (8% site) and radius (7% site) in 173 girls and 136 boys (aged 9 to 20 years at baseline). We conducted a maximum of four annual measurements at the tibia (n = 785 observations) and radius (n = 582 observations). We assessed moderate‐to‐vigorous PA (MVPA) and sedentary time with accelerometers (ActiGraph GT1M). We aligned participants on maturity (years from age at peak height velocity) and fit a mixed‐effects model adjusting for maturity, sex, ethnicity, leg muscle power, lean mass, limb length, dietary calcium, and MVPA in sedentary time models. MVPA was a positive independent predictor of bone strength (failure load [F.Load]) and bone volume fraction (BV/TV) at the tibia and radius, total area (Tt.Ar) and cortical porosity (Ct.Po) at the tibia, and negative predictor of load‐to‐strength ratio at the radius. Sedentary time was a negative independent predictor of Tt.Ar at both sites and Ct.Po at the tibia and a positive predictor of cortical thickness (Ct.Th), trabecular thickness (Tb.Th), and cortical bone mineral density (Ct.BMD) at the tibia. Bone parameters demonstrated maturity‐specific associations with MVPA and sedentary time, whereby associations were strongest during early and mid‐puberty. Our findings support the importance of PA for bone strength accrual and its determinants across adolescent growth and provide new evidence of a detrimental association of sedentary time with bone geometry but positive associations with microarchitecture. This study highlights maturity‐specific relationships of bone strength and its determinants with loading and unloading. Future studies should evaluate the dose‐response relationship and whether associations persist into adulthood. © 2017 American Society for Bone and Mineral Research.     

Age‐ and Sex‐Related Changes in Bone Microarchitecture and Estimated Strength: A Three‐Year Prospective Study Using HRpQCT

Although projections from cross‐sectional studies have shown that bone loss leading to osteoporosis begins around menopause in women and later in life in men, this has not been examined longitudinally in population‐based studies using high‐resolution technology capable of distinguishing cortical (Ct) and trabecular (Tb) bone microarchitecture. The aim of this 3‐year prospective study was to investigate age‐ and sex‐related changes in bone compartment–specific geometry, volumetric bone mineral density (vBMD), microarchitecture, and estimated strength. The distal radius and tibia were imaged at baseline and after 3 years (median 3.0; range, 2.7 to 3.9 years) using high‐resolution peripheral computed tomography (HRpCT) in an age‐ and sex‐stratified, population‐based, random sample of white men and women (n = 260) aged 21 to 82 years. In general, at the radius and tibia there was a moderate annual increase in cortical thickness (Ct.Th) that seemed to offset the increase in cortical porosity (Ct.Po), resulting in net annual increase in cortical vBMD (Ct.vBMD) in premenopausal women and young men. With advancing age, postmenopausal women displayed significant bone loss with decreased trabecular vBMD (Tb.vBMD) (due to loss of entire trabeculae) and Ct.vBMD (manifested as increase in Ct.Po and decrease in Ct.Th) at the radius, and a decline in Ct.vBMD (with increasing Ct.Po) at the tibia, resulting in loss of estimated bone strength. In contrast, men had a lower rate of bone loss with advancing age with smaller increases in Ct.Po at both the skeletal sites. In summary, the pattern of bone loss in men and women was discrepant, with women losing more bone than men with aging, although with a dominance of cortical over trabecular bone loss at the peripheral sites in both sexes. This conforms to epidemiological evidence that most fractures occurring in old age are predominantly at cortical peripheral sites, with women having a higher incidence of fractures than men at any given age. © 2016 American Society for Bone and Mineral Research.