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Identifying individuals at risk for short-term fracture is essential to offer prompt beneficial treatment, especially since many fractures occur in those without osteoporosis by DXA-aBMD. We evaluated whether deficits in bone microarchitecture and density predict short-term fracture risk independent of the clinical predictors, DXA-BMD and FRAX. We combined data from eight cohorts to conduct a prospective study of bone microarchitecture at the distal radius and tibia (by HR-pQCT) and 2-year incidence of fracture (non-traumatic and traumatic) in 7327 individuals (4824 women, 2503 men, mean 69 ± 9 years). We estimated sex-specific hazard ratios (HR) for associations between bone measures and 2-year fracture incidence, adjusted for age, cohort, height, and weight, and then additionally adjusted for FN aBMD or FRAX for major osteoporotic fracture. Only 7% of study participants had FN T-score ≤ -2.5, whereas 53% had T-scores between -1.0 and -2.5 and 37% had T-scores ≥-1.0. Two-year cumulative fracture incidence was 4% (296/7327). Each SD decrease in radius cortical bone measures increased fracture risk by 38%-76% for women and men. After additional adjustment for FN-aBMD, risks remained increased by 28%-61%. Radius trabecular measures were also associated with 2-year fracture risk independently of FN-aBMD in women (HRs range: 1.21 per SD for trabecular separation to 1.55 for total vBMD). Decreased failure load (FL) was associated with increased fracture risk in both women and men (FN-aBMD ranges of adjusted HR = 1.47-2.42). Tibia measurement results were similar to radius results. Findings were also similar when models were adjusted for FRAX. In older adults, FL and HR-pQCT measures of cortical and trabecular bone microarchitecture and density with strong associations to short-term fractures improved fracture prediction beyond aBMD and FRAX. Thus, HR-pQCT may be a useful adjunct to traditional assessment of short-term fracture risk in older adults, including those with T-scores above the osteoporosis range., (© The Author(s) 2024. Published by Oxford University Press on behalf of the American Society for Bone and Mineral Research. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

The basis for increased fracture risk in type 2 diabetes (T2DM) is not well understood. In this multi-ethnic, population-based study (n = 565), we investigated bone microstructure, trabecular plate/rod morphology, and mineralization in women with T2DM (n = 175) with and without fracture using a second-generation HRpQCT and individual trabecula segmentation and mineralization (ITS; ITM). Covariate-adjusted aBMD was 3.0%-6.5% higher at all sites (all p<.005) in T2DM vs controls. By HRpQCT, T2DM had higher covariate-adjusted trabecular vBMD (5.3%-6.4%) and number (3.8%-5.1%) and greater cortical area at the radius and tibia. Covariate-adjusted cortical porosity was 10.0% higher at the tibia only in T2DM vs controls, but failure load did not differ. Among women with T2DM, those with adult atraumatic fracture (n = 59) had 5.2%-8.5% lower adjusted aBMD at all sites by DXA compared with those without fracture (n = 103). By HRpQCT, those with fracture had lower adjusted total vBMD and smaller cortical area (10.2%-16.1%), lower cortical thickness (10.5-15.8%) and lower cortical vBMD associated with 18.1 and 17.2% lower failure load at the radius and tibia, respectively (all p<.05); plate volume and thickness were 5.7% and 4.7% lower, respectively, (p<.05) while rod volume fraction was 12.8% higher in the fracture group at the tibia only. Sodium glucose cotransporter 2 inhibitor users (SGLT2i; n = 19), tended to have lower radial rod tissue mineral density by ITS (p=.06). GLP1 agonist users (n = 19) had trabecular deficits at both sites and higher cortical porosity and larger pores at the distal tibia. In summary, T2DM is associated with increased cortical porosity while those with T2DM and fracture have more marked cortical deficits and fewer trabecular plates associated with lower failure load., (© The Author(s) 2024. Published by Oxford University Press on behalf of the American Society for Bone and Mineral Research. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Moderate- to high-impact exercise improves bone mineral density (BMD) across the lifespan, but its effects on bone structure, which predicts fracture independent of areal BMD, are unclear. This systematic review and meta-analysis investigated effects of impact exercise on volumetric BMD (vBMD) and bone structure. Four databases (PubMed, Embase, SPORTDiscus, Web of Science) were searched up to March 2022 for randomized controlled trials (RCTs) investigating the effects of impact exercise, with ground reaction forces equal to or greater than running, compared with sham or habitual activity, on bone vBMD and structure. Bone variables were measured by quantitative computed tomography or magnetic resonance imaging at the tibia, radius, lumbar spine, and femur. Percentage changes in bone variables were compared among groups using mean differences (MD) and 95% confidence intervals (CI) calculated via random effects meta-analyses. Subgroup analyses were performed in children/adolescents (<18 years), adults (18-50 years), postmenopausal women, and older men. Twenty-eight RCTs (n = 2985) were included. Across all studies, impact exercise improved trabecular vBMD at the distal tibia (MD = 0.54% [95% CI 0.17, 0.90%]), total vBMD at the proximal femur (3.11% [1.07, 5.14%]), and cortical thickness at the mid/proximal radius (1.78% [0.21, 3.36%]). There was no effect on vBMD and bone structure at the distal radius, femoral shaft, or lumbar spine across all studies or in any subgroup. In adults, impact exercise decreased mid/proximal tibia cortical vBMD (-0.20% [-0.24, -0.15%]). In postmenopausal women, impact exercise improved distal tibia trabecular vBMD (0.79% [0.32, 1.25%]). There was no effect on bone parameters in children/adolescents in overall analyses, and there were insufficient studies in older men to perform meta-analyses. Impact exercise may have beneficial effects on bone structure and vBMD at various skeletal sites, but additional high-quality RCTs in different age and sex subgroups are needed to identify optimal exercise protocols for improving bone health across the lifespan. © 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)., (© 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).)

Periosteosis refers to pathological woven bone formation beneath the cortical bone of the long bones. It is an imaging hallmark of primary hypertrophic osteoarthropathy (PHO) and also considered as one of the major diagnostic criteria of PHO patients. Up to date, detailed information on bone quality changes in long bones of PHO patients is still missing. This study aimed to evaluate bone microarchitecture and bone strength in PHO patients by using high-resolution peripheral quantitative computed tomography (HR-pQCT). The study comprised 20 male PHO patients with the average age of 27.0 years and 20 age- and sex-matched healthy controls. The areal bone mineral density (aBMD) was assessed at the lumbar spine (L 1 -L 4 ) and hip (total hip and femoral neck) by dual-energy X-ray absorptiometry (DXA). Bone geometry, volumetric bone mineral density (vBMD), and microstructure parameters at the distal tibia were evaluated by using HR-pQCT. Bone strength was evaluated by finite element analysis (FEA) based on HR-pQCT screening at distal tibia. Urinary prostaglandin E 2 (PGE 2 ), serum phosphatase (ALP), beta-C-telopeptides of type I collagen (β-CTX), soluble receptor activator of nuclear factor-κB ligand (sRANKL), osteoprotegerin (OPG), and neuronal calcitonin gene-related peptide (CGRP) were investigated. As compared with healthy controls, PHO patients had larger bone cross-sectional areas; lower total, trabecular, and cortical vBMD; compromised bone microstructures with more porous cortices, thinned trabeculae, reduced trabecular connectivity, and relatively more significant resorption of rod-like trabeculae at distal tibia. The apparent Young's modulus was significantly lower in PHO patients. The concentration of PGE 2 , biomarkers of bone resorption (β-CTX and sRANKL/OPG ratio), and the neuropeptide CGRP were higher in PHO patients versus healthy controls. PGE 2 level correlated negatively with vBMD and estimated bone strength and positively with bone geometry at distal tibia. The present HR-pQCT study is the first one illustrating the microarchitecture and bone strength features in long bones. © 2021 American Society for Bone and Mineral Research (ASBMR)., (© 2021 American Society for Bone and Mineral Research (ASBMR).)

Tumor-induced osteomalacia (TIO) is a rare paraneoplastic syndrome caused by excessive production of fibroblast growth factor 23 (FGF23) by a tumor. Previous studies have revealed generalized mineralization defects and low areal bone mineral density (aBMD) in TIO. However, data on the bone microarchitecture in TIO are limited. In this study, we evaluated the microarchitecture in the peripheral (distal radius and tibia) and axial (lumbar spine) skeleton using high-resolution peripheral quantitative computed tomography (HR-pQCT) and trabecular bone score (TBS) and investigated related factors in a large cohort of Chinese patients with TIO. A total of 186 patients with TIO who had undergone dual-energy X-ray absorptiometry (DXA) or HR-pQCT scans were enrolled. Compared with age-, sex-, and body mass index (BMI)-matched healthy controls, TIO patients (n = 113) had lower volumetric BMD, damaged microstructure, and reduced bone strength in the peripheral skeleton, especially at the tibia. The average TBS obtained from 173 patients was 1.15 ± 0.16. The proportion of patients with abnormal TBS (<1.35) was higher than that with low L 1 to L 4 aBMD Z-score (Z ≤ -2) (43.9% versus 89.6%, p < 0.001). Higher intact fibroblast growth factor 23 (iFGF23), intact parathyroid hormone (iPTH), alkaline phosphatase, and β-isomerized C-terminal telopeptide of type I collagen (β-CTx) levels, more severe mobility impairment, and a history of fracture were associated with poorer HR-pQCT parameters but not with lower TBS. However, greater height loss and longer disease duration were correlated with worse HR-pQCT parameters and TBS. Moreover, TBS was correlated with both trabecular and cortical HR-pQCT parameters in TIO. In conclusion, we revealed impaired bone microarchitecture in the axial and peripheral skeleton in a large cohort of Chinese TIO patients. HR-pQCT parameters and TBS showed promising advantages over aBMD for assessing bone impairment in patients with TIO. A longer follow-up period is needed to observe changes in bone microarchitecture after tumor resection. © 2021 American Society for Bone and Mineral Research (ASBMR)., (© 2021 American Society for Bone and Mineral Research (ASBMR).)

Given prior work showing associations between remodeling and external bone size, we tested the hypothesis that wide bones would show a greater negative correlation between whole-bone strength and age compared with narrow bones. Cadaveric male radii (n = 37 pairs, 18 to 89 years old) were evaluated biomechanically, and samples were sorted into narrow and wide subgroups using height-adjusted robustness (total area/bone length). Strength was 54% greater (p < 0.0001) in wide compared with narrow radii for young adults (<40 years old). However, the greater strength of young-adult wide radii was not observed for older wide radii, as the wide (R 2  = 0.565, p = 0.001), but not narrow (R 2  = 0.0004, p = 0.944) subgroup showed a significant negative correlation between strength and age. Significant positive correlations between age and robustness (R 2  = 0.269, p = 0.048), cortical area (Ct.Ar; R 2  = 0.356, p = 0.019), and the mineral/matrix ratio (MMR; R 2  = 0.293, p = 0.037) were observed for narrow, but not wide radii (robustness: R 2  = 0.015, p = 0.217; Ct.Ar: R 2  = 0.095, p = 0.245; MMR: R 2  = 0.086, p = 0.271). Porosity increased with age for the narrow (R 2  = 0.556, p = 0.001) and wide (R 2  = 0.321, p = 0.022) subgroups. The wide subgroup (p < 0.0001) showed a significantly greater elevation of a new measure called the Cortical Pore Score, which quantifies the cumulative effect of pore size and location, indicating that porosity had a more deleterious effect on strength for wide compared with narrow radii. Thus, the divergent strength-age regressions implied that narrow radii maintained a low strength with aging by increasing external size and mineral content to mechanically offset increases in porosity. In contrast, the significant negative strength-age correlation for wide radii implied that the deleterious effect of greater porosity further from the centroid was not offset by changes in outer bone size or mineral content. Thus, the low strength of elderly male radii arose through different biomechanical mechanisms. Consideration of different strength-age regressions (trajectories) may inform clinical decisions on how best to treat individuals to reduce fracture risk. © 2019 American Society for Bone and Mineral Research., (© 2019 American Society for Bone and Mineral Research.)

Leisure-time physical activity (LTPA) is widely recommended for the prevention of osteoporosis and fractures in older populations. However, whether the beneficial effects of LTPA on bone accumulate across life and are maintained even after reduction or cessation of regular PA in later life is unknown. We examined whether LTPA across adulthood was cumulatively associated with volumetric and areal bone mineral density (vBMD, aBMD) at ages 60 to 64 and whether associations were mediated by lean mass. Up to 1498 participants from the Medical Research Council National Survey of Health and Development were included in analyses. LTPA was self-reported at ages 36, 43, 53, and 60 to 64, and responses summed to generate a cumulative score (range 0 = inactive at all four ages to 8 = most active at all four ages). Total and trabecular vBMD were measured at the distal radius using pQCT and aBMD at the total hip and lumbar spine (L1 to L4) using DXA. Linear regression was used to test associations of the cumulative LTPA score with each bone outcome. After adjustment for height and weight, a 1-unit increase in LTPA score (95% CI) in men was associated with differences of 1.55% (0.78% to 2.31%) in radial trabecular vBMD, 0.83% (0.41% to 1.25%) in total hip aBMD, and 0.97% (0.44% to 1.49%) in spine aBMD. Among women, positive associations were seen for radial trabecular vBMD and total hip aBMD, but only among those of greater weight (LTPA × weight interaction p ≤ 0.01). In men, there was evidence to suggest that lean mass index may partly mediate these associations. These findings suggest that there are cumulative benefits of LTPA across adulthood on BMD in early old age, especially among men. The finding of weaker associations among women suggests that promotion of specifıc types of LTPA may be needed to benefit bone health in women. © 2018 The Authors. Journal of Bone and Mineral Research Published by Wiley Periodicals, Inc., (© 2018 The Authors. Journal of Bone and Mineral Research Published by Wiley Periodicals, Inc.)

Annual gains in BMC and areal bone mineral density (aBMD) in children vary with age, pubertal status, height-velocity, and lean body mass accrual (LBM velocity). Evaluating bone accrual in children with bone health-threatening conditions requires consideration of these determinants. The objective of this study was to develop prediction equations for calculating BMC/aBMD velocity SD scores (velocity-Z) and to evaluate bone accrual in youth with health conditions. Bone and body compositions via DXA were obtained for up to six annual intervals in healthy youth (n = 2014) enrolled in the Bone Mineral Density in Childhood Study (BMDCS) . Longitudinal statistical methods were used to develop sex- and pubertal-status-specific reference equations for calculating velocity-Z for total body less head-BMC and lumbar spine (LS), total hip (TotHip), femoral neck, and 1/3-radius aBMD. Equations accounted for (1) height velocity, (2) height velocity and weight velocity, or (3) height velocity and LBM velocity. These equations were then applied to observational, single-center, 12-month longitudinal data from youth with cystic fibrosis (CF; n = 65), acute lymphoblastic leukemia (ALL) survivors (n = 45), or Crohn disease (CD) initiating infliximab (n = 72). Associations between BMC/aBMD-Z change (conventional pediatric bone health monitoring method) and BMC/aBMD velocity-Z were assessed. The BMC/aBMD velocity-Z for CF, ALL, and CD was compared with BMDCS. Annual changes in the BMC/aBMD-Z and the BMC/aBMD velocity-Z were strongly correlated, but not equivalent; LS aBMD-Z = 1 equated with LS aBMD velocity-Z = -3. In CF, BMC/aBMD velocity-Z was normal. In posttherapy ALL, BMC/aBMD velocity-Z was increased, particularly at TotHip (1.01 [-.047; 1.7], p < 0.0001). In CD, BMC/aBMD velocity-Z was increased at all skeletal sites. LBM-velocity adjustment attenuated these increases (eg, TotHip aBMD velocity-Z: 1.13 [0.004; 2.34] versus 1.52 [0.3; 2.85], p < 0.0001). Methods for quantifying the BMC/aBMD velocity that account for maturation and body composition changes provide a framework for evaluating childhood bone accretion and may provide insight into mechanisms contributing to altered accrual in chronic childhood conditions. © 2018 American Society for Bone and Mineral Research., (© 2018 American Society for Bone and Mineral Research.)

Accelerated bone loss (ABL) shown on routine dual-energy X-ray absorptiometry (DXA) may be accompanied by microarchitectural changes, increased cortical porosity, and lower bone strength. To test this hypothesis, we performed a cross-sectional study and used high-resolution peripheral quantitative computed tomography (HR-pQCT) scans (Scanco Medical AG, Brüttisellen, Switzerland) to measure estimated bone strength and microarchitecture in the distal radius and distal and diaphyseal tibia. We studied 1628 men who attended the year 14 exam of the Osteoporotic Fractures in Men (MrOS) study. We retrospectively characterized areal bone mineral density (aBMD) change from the year 7 to year 14 exam in three categories: "accelerated" loss, ≥10% loss at either the total hip or femoral neck (n = 299, 18.4%); "expected" loss, <10% (n = 1061, 65.2%), and "maintained" BMD, ≥0% (n = 268, 16.5%). The ABL cut-off was a safety alert established for MrOS. We used regression models to calculate adjusted mean HR-pQCT parameters in men with ABL, expected loss, or maintained BMD. Men who experienced ABL were older and had a lower body mass index and aBMD and experienced greater weight loss compared with other men. Total volumetric BMD and trabecular and cortical volumetric BMD were lower in men with ABL compared with the expected or maintained group. Men with ABL had significantly lower trabecular bone volume fraction (BV/TV), fewer trabeculae, and greater trabecular separation at both the distal radius and tibia than men with expected loss or who maintained aBMD, all p trend <0.001. Men with ABL had lower cortical thickness and lower estimated bone strength, but there was no difference in cortical porosity except at the tibia diaphyseal site. In summary, men with ABL have lower estimated bone strength, poorer trabecular microarchitecture, and thinner cortices than men without ABL but have similar cortical porosity. These impairments may lead to an increased risk of fracture. © 2018 American Society for Bone and Mineral Research., (© 2018 American Society for Bone and Mineral Research.)

Weight loss in older adults is associated with increased bone loss and fracture. Little is known about the potential impact of weight loss on cortical and trabecular bone density, microarchitecture, and strength. In this study, participants were members of the Framingham Offspring Cohort (769 women, 595 men; mean age 70 ± 8 years), who underwent high-resolution peripheral quantitative computed tomography (HR-pQCT) scanning at the tibia and radius in 2012 to 2016. Weight measurements taken every 4 to 6 years were used to assess recent weight change over 6 years and long-term change over 40 years. General linear models, adjusting for age, sex, height, smoking, and diabetes, were used to evaluate the association between HR-pQCT indices and relative long-term and recent weight change. We found that long-term and recent weight loss were associated with lower cortical density and thickness, higher cortical porosity, and lower trabecular density and number. Associations were stronger for the tibia than radius. Failure load was lower in those individuals with long-term but not short-term weight loss. Deterioration in both cortical and trabecular indices, especially at the weight-bearing skeleton, characterizes bone fragility associated with long-term and recent weight loss in older adults. © 2018 American Society for Bone and Mineral Research., (© 2018 American Society for Bone and Mineral Research.)

Low muscle mass and strength are associated with poor bone microarchitecture. We studied the association of muscle mass and strength with changes in bone microarchitecture of distal radius in 821 older men during an 8-year prospective follow-up. Bone microarchitecture was assessed by high resolution peripheral quantitative computed tomography (XtremeCT-1, Scanco) at baseline, then after 4 and 8 years. Relative appendicular lean mass of the upper limbs (RALM-u.l.) was calculated as DXA-measured lean mass of upper limbs divided by (height) 2 . Relative grip strength was calculated as grip strength divided by height. Decrease in bone mineral content (BMC), total volumetric bone mineral density (Tt.vBMD), cortical thickness (Ct.Th), cortical area (Ct.Ar) and cortical vBMD (Ct.vBMD) accelerated with age. Trabecular area (Tb.Ar) expansion and trabecular bone deterioration accelerated with age. Men in the first RALM-u.l. quartile had more rapid loss of BMC, Tt.vBMD, Ct.Th, Ct.vBMD and Ct.Ar vs. the highest quartile. They had more rapid increase in Tb.Ar. Men in the lowest quartile of grip strength had greater decrease in BMC, Tt.vBMD, Ct.Th, Ct.vBMD, Ct.Ar, and greater increase in Tb.Ar vs. the highest quartile. In the models including ALM-u.l. and grip strength (not corrected for height), both muscle-related variables were associated with more rapid bone microarchitectural deterioration (slightly more so for grip strength). Trabecular vBMD (Tb.vBMD) and Central.Tb.vBMD increased in men having higher muscle mass and strength. Trends in trabecular number and thickness did not differ across the groups in all the analyses. Thus, in men, aging-related deterioration of bone microarchitecture was most rapid after the age of 80. Low grip strength (and slightly more weakly low RALM-u.l.) is associated with the more rapid decrease in Tt.vBMD and cortical variables, and with greater Tb.Ar expansion. In conclusion, dynapenia and sarcopenia contribute to the deterioration of bone microarchitecture in older men. © 2018 American Society for Bone and Mineral Research., (© 2018 American Society for Bone and Mineral Research.)

Type 2 diabetes (T2D) patients have an increased fracture risk, which may be partly explained by compromised bone microarchitecture within the cortical bone compartment. Data on trabecular bone parameters in T2D are contradictory. By high-resolution peripheral quantitative computed tomography (HR-pQCT), trabecular microarchitecture is preserved, yet larger trabecular holes are detected in T2D by MRI and DXA-based trabecular bone scores are abnormal. To determine if there are differences in trabecular microstructure, connectivity, and alignment in postmenopausal women with T2D as compared with controls, we performed an individual trabecula segmentation (ITS) analysis on HR-pQCT scans of the distal radius and tibia in 92 women with (n = 42) and without (n = 50) T2D. Unadjusted analyses showed that T2D subjects had greater total trabecular bone volume, trabecular plate volume fraction, plate number density, plate junction density, and axial alignment at the radius and tibia, and increased plate tissue fraction, but decreased rod tissue fraction and rod length at the radius (p < 0.05 for all). After adjustments for clinical covariates, plate number density and plate junction density remained higher at the radius and tibia, whereas total trabecular bone volume was increased and trabecular rod length was decreased at the radius. These differences remained significant after adjustment for hip BMD and trabecular volumetric bone density. Notably, the increased plate-like ITS qualities were seen in those with T2D duration of <10 years, whereas ITS parameters in subjects with T2D duration ≥10 years did not differ from those of control subjects. In conclusion, postmenopausal women with early T2D had a greater plate-like and less rod-like trabecular network. This early advantage in trabecular plate quality does not explain the well-established increased fracture risk in these patients and does not persist in the later stage of T2D. © 2018 American Society for Bone and Mineral Research., (© 2018 American Society for Bone and Mineral Research.)

Areal bone mineral density (aBMD) poorly identifies men at high fracture risk. Our aim was to assess prediction of fractures in men by bone microarchitectural measures. At baseline, 825 men aged 60 to 87 years had the assessment of bone microarchitecture at distal radius and distal tibia by high-resolution peripheral QCT (HR-pQCT; XtremeCT-I, Scanco Medical, Brüttisellen, Switzerland). Bone strength was estimated by micro-finite element analysis. During the prospective 8-year follow-up, 105 men sustained fractures (59 vertebral fractures in 49 men and 70 nonvertebral fractures in 68 men). After adjustment for age, body mass index (BMI), prior falls, and fractures, most HR-pQCT measures at both skeletal sites predicted fractures. After further adjustment for aBMD, low distal radius trabecular number (Tb.N) was most strongly associated with higher fracture risk (hazard ratio [HR] = 1.63 per SD, 95% confidence interval [CI] 1.31-2.03, p < 0.001). In similar models, low Tb.N was associated with higher risk of major osteoporotic fracture (HR = 1.80 per SD, p < 0.001), vertebral fracture (HR = 1.78 per SD, p < 0.01) and nonvertebral fracture (HR = 1.46 per SD, p < 0.01). In comparison with the reference model (age, BMI, falls, fractures, aBMD), the adjustment for distal radius Tb.N increased the estimated fracture probability in men who sustained fractures versus those who did not have ones (difference = 4.1%, 95% CI 1.9-6.3%, p < 0.001). However, the adjustment for distal radius Tb.N did not increase the area under the curve (AUC, p = 0.37). Similar results were found for distal radius trabecular separation (Tb.Sp) and connectivity density (Conn. D). They were predictive of all fracture types and increased the estimated fracture risk, but not AUC, in men who had incident fractures. Thus, poor distal radius trabecular microarchitecture is predictive of fracture after adjustment for age, BMI, falls, fractures, and aBMD. Although distal radius Tb.N, Conn. D, and Tb.Sp improve the discrimination between men who will or who will not have fracture, they do not provide clinically relevant improvement of fracture prediction in older men. © 2018 American Society for Bone and Mineral Research., (© 2018 American Society for Bone and Mineral Research.)

Reduced bone mineral density (BMD) may be due to reduced mineralized bone matrix volume, incomplete secondary mineralization, or reduced primary mineralization. Because bone biopsy is invasive, we hypothesized that noninvasive image acquisition at high resolution can accurately quantify matrix mineral density (MMD). Quantification of MMD was confined to voxels attenuation photons above 80% of that produced by fully mineralized bone matrix because attenuation at this level is due to variation in mineralization, not porosity. To assess accuracy, 9 cadaveric distal radii were imaged at a voxel size of 82 microns using high-resolution peripheral quantitative computed tomography (HR-pQCT; XtremeCT, Scanco Medical AG, Bruttisellen, Switzerland) and compared with VivaCT 40 (µCT) at 19-micron voxel size. Associations between MMD and porosity were studied in 94 healthy vitamin D-replete premenopausal women, 77 postmenopausal women, and in a 27-year-old woman with vitamin D-dependent rickets (VDDR). Microstructure and MMD were quantified using StrAx (StraxCorp, Melbourne, Australia). MMD measured by HR-pQCT and µCT correlated (R = 0.87; p < 0.0001). The precision error for MMD was 2.43%. Cortical porosity and MMD were associated with age (r 2  = 0.5 and -0.4, respectively) and correlated inversely in pre- and postmenopausal women (both r 2  = 0.9, all p < 0.001). Porosity was higher, and MMD was lower, in post- than in premenopausal women (porosity 40.3% ± 7.0 versus 34.7% ± 3.5, respectively; MMD 65.4% ± 1.8 versus 66.6% ± 1.4, respectively, both p < 0.001). In the woman with VDDR, MMD was 5.6 SD lower and porosity was 5.6 SD higher than the respective trait means in premenopausal women. BMD was reduced (Z-scores femoral neck -4.3 SD, lumbar spine -3.8 SD). Low-radiation HR-pQCT may facilitate noninvasive quantification of bone's MMD and microstructure in health, disease, and during treatment. © 2018 American Society for Bone and Mineral Research., (© 2018 American Society for Bone and Mineral Research.)

Nonsurgical hypoparathyroidism (Ns-HypoPT) and pseudohypoparathyroidism (PHP) are both rare diseases, characterized by hypocalcemia. In Ns-HypoPT, PTH levels are low, whereas patients with PHP often have very high levels due to receptor-insensitivity to PTH (PTH-resistance). Accordingly, we hypothesized that indices of bone turnover and bone mineralization/architecture are similar in Ns-HypoPT and PHP despite marked differences in PTH levels. We studied 62 patients with Ns-HypoPT and 31 with PHP as well as a group of age- and sex-matched healthy controls. We found a significantly higher areal BMD (aBMD) by DXA among patients with Ns-HypoPT, both compared with PHP and the background population. Compared with Ns-HypoPT, PHP patients had significantly lower total and trabecular volumetric BMD (vBMD) assessed by quantitative computed tomography (QCT) scans at the spine and hip. High-resolution peripheral quantitative computed tomography (HRpQCT) scans showed a lower trabecular area and vBMD as well as a lower trabecular number at the tibia in PHP compared to Ns-HypoPT and matched controls. In PHP, PTH levels correlated with levels of markers of bone formation (osteocalcin, bone-specific alkaline phosphatase, P1NP), and bone resorption (CTx). In adult males, levels of bone markers were significantly higher in PHP compared with Ns-HypoPT. Levels of procalcitonin and calcitonin were significantly higher in PHP compared with Ns-HypoPT. In conclusion, indices of bone turnover, density, and microarchitecture differ between patients with Ns-HypoPT and PHP. Our data suggest that patients with PHP do not have a complete skeletal resistance to PTH and that the effects of chronically high PTH levels in PHP are mostly confined to the trabecular tissue. © 2017 American Society for Bone and Mineral Research., (© 2017 American Society for Bone and Mineral Research.)

A majority of low-trauma fractures occur in subjects with only moderate decrease of areal bone mineral density (aBMD), ie, osteopenia, assessed by dual-energy X-ray absorptiometry (DXA) or low fracture probability assessed by FRAX. We investigated whether peripheral bone microstructure and estimated strength improve the prediction of incident fractures beyond central DXA and FRAX. In this population-based study of 740 postmenopausal women (aged 65.0 ± 1.4 years) from the Geneva Retirees Cohort (ISRCTN registry 11865958), we assessed at baseline cortical (Ct) and trabecular (Tb) volumetric bone mineral density (vBMD) and microstructure by peripheral quantitative computed tomography (HR-pQCT); bone strength by micro-finite element analysis; aBMD and trabecular bone score (TBS) by DXA; and FRAX fracture probability. Eighty-five low-trauma fractures occurred in 68 women over a follow-up of 5.0 ± 1.8 years. Tb and Ct vBMD and microstructure predicted incident fractures, independently of each other and of femoral neck (FN) aBMD and FRAX (with BMD ± TBS). However, the associations were markedly attenuated after adjustment for ultra-distal radius aBMD (same bone site). The best discrimination between women with and without fracture was obtained at the radius with total vBMD, the combination of a Tb with a Ct parameter, or with failure load, which improved the area under the curve (AUC) for major osteoporotic fracture when added to FN aBMD (0.760 versus 0.695, p = 0.022) or to FRAX-BMD (0.759 versus 0.714, p = 0.015). The replacement of failure load by ultra-distal aBMD did not significantly decrease the AUC (0.753, p = 0.747 and 0.750, p = 0.509, respectively). In conclusion, peripheral bone microstructure and strength improve the prediction of fractures beyond central DXA and FRAX but are partially captured in aBMD measured by DXA at the radius. Because HR-pQCT is not widely available for clinical purposes, assessment of ultra-distal radius aBMD by DXA may meanwhile improve fracture risk estimation. © 2017 American Society for Bone and Mineral Research., (© 2017 American Society for Bone and Mineral Research.)

Obese adolescents have increased fracture risk, but effects of alterations in adiposity on bone accrual and strength in obese adolescents are not understood. We evaluated 12-month changes in trabecular and cortical volumetric bone mineral density (vBMD) and cortical geometry in obese adolescents undergoing a randomized weight management program, and investigated the effect of body composition changes on bone outcomes. Peripheral quantitative computed tomography (pQCT) of the radius and tibia, and whole-body dual-energy X-ray absorptiometry (DXA) scans were obtained at baseline, 6 months, and 12 months in 91 obese adolescents randomized to standard care versus behavioral intervention for weight loss. Longitudinal models assessed effects of body composition changes on bone outcomes, adjusted for age, bone length, and African-American ancestry, and stratified by sex. Secondary analyses included adjustment for physical activity, maturation, vitamin D, and inflammatory biomarkers. Baseline body mass index (BMI) was similar between intervention groups. Twelve-month change in BMI in the standard care group was 1.0 kg/m 2 versus -0.4 kg/m 2 in the behavioral intervention group (p < 0.01). Intervention groups were similar in bone outcomes, so they were combined for subsequent analyses. For the tibia, BMI change was not associated with change in vBMD or structure. Greater baseline lean body mass index (LBMI) associated with higher cortical vBMD in males, trabecular vBMD in females, and polar section modulus (pZ) and periosteal circumference (Peri-C) in both sexes. In females, change in LBMI positively associated with gains in pZ and Peri-C. Baseline visceral adipose tissue (VFAT) was inversely associated with pZ in males and cortical vBMD in females. Change in VFAT did not affect bone outcomes. For the radius, BMI and LBMI changes positively associated with pZ in males. Thus, in obese adolescents, weight loss intervention with modest changes in BMI was not detrimental to radius or tibia bone strength, and changes in lean, but not adiposity, measures were beneficial to bone development. © 2017 American Society for Bone and Mineral Research., (© 2017 American Society for Bone and Mineral Research.)

Type 2 diabetes mellitus (T2DM) is associated with an increased risk of fractures according to several studies. The underlying mechanisms remain unclear, although small case-control studies indicate poor quality of the cortical bone. We have studied a population-based sample of women aged 75 to 80 years in Gothenburg, randomly invited from the population register. Areal bone mineral density (aBMD) was measured by dual-energy X-ray absorptiometry (Hologic Discovery A), bone microarchitecture by high-resolution peripheral quantitative computed tomography (HR-pQCT; ExtremeCT from Scanco Medical AG), and reference point indentation was performed with Osteoprobe (Active Life Scientific). Women with T2DM (n = 99) had higher aBMD compared to controls (n = 954). Ultradistal tibial and radial trabecular bone volume fraction (+11% and +15%, respectively), distal cortical volumetric BMD (+1.6% and +1.7%), cortical area (+11.5% and +9.3%), and failure load (+7.7% and +12.9%) were higher in diabetics than in controls. Cortical porosity was lower (mean ± SD: 1.5% ± 1.1% versus 2.0% ± 1.7%, p = 0.001) in T2DM in the distal radius but not in the ultradistal radius or the tibia. Adjustment for covariates (age, body mass index, glucocorticoid treatment, smoking, physical activity, calcium intake, bone-active drugs) eliminated the differences in aBMD but not in HR-pQCT bone variables. However, bone material strength index (BMSi) by reference point indentation was lower in T2DM (74.6 ± 7.6 versus 78.2 ± 7.5, p < 0.01), also after adjustment, and women with T2DM performed clearly worse in measures of physical function (one leg standing: -26%, 30-s chair-stand test: -7%, timed up and go: +12%, walking speed: +8%; p < 0.05-0.001) compared to controls. In conclusion, we observed a more favorable bone microarchitecture but no difference in adjusted aBMD in elderly women with T2DM in the population compared to nondiabetics. Reduced BMSi and impaired physical function may explain the increased fracture risk in T2DM. © 2016 American Society for Bone and Mineral Research., (© 2016 American Society for Bone and Mineral Research.)

Chronic immune activation associated with human immunodeficiency virus (HIV) infection may have negative consequences on bone acquisition in individuals infected with HIV early in life. Bone mineral density (BMD) and microarchitecture were characterized in 38 HIV-infected men on antiretroviral therapy (18 perinatally-infected, 20 adolescence-infected) and 20 uninfected men age 20 to 25 years by dual-energy X-ray absorptiometry (DXA), high-resolution peripheral quantitative computed tomography (HRpQCT). Flow cytometry was utilized to measure CD4+/CD8+ activation (HLADR+CD38+) and senescence (CD28-CD57+) and to quantify circulating osteogenic precursor (COP) cells in peripheral blood mononuclear cells using antibodies to RUNX2 and osteocalcin (OCN). Telomere lengths were measured in sorted COP cells using qPCR. DXA-derived areal BMD Z-scores and HRpQCT-derived volumetric BMD (vBMD) measures were lower in HIV-infected than uninfected men. Proportion of activated and senescent CD4+ and CD8+ T cells were higher in HIV-infected than uninfected men. The percentage of COP cells (mean ± SE) was lower in HIV-infected than uninfected (0.19% ± 0.02% versus 0.43% ± 0.06%; p < 0.0001) men, and also lower in perinatally-infected than adolescence-infected men (0.15% ± 0.02% versus 0.22% ± 0.03%; p < 0.04). A higher proportion of COP cells correlated with higher bone stiffness, a measure of bone strength, whereas a higher proportion of activated CD4+ T cells correlated with lower BMD and stiffness and lower proportion of COP cells. T cell activation with HIV-infection was associated with decreased numbers of osteogenic precursors as well as lower peak bone mass and bone strength. © 2016 American Society for Bone and Mineral Research., (© 2016 American Society for Bone and Mineral Research.)

Because single-center studies have reported conflicting associations between microarchitecture and fracture prevalence, we included high-resolution peripheral quantitative computed tomography (HR-pQCT) data from five centers worldwide into a large multicenter analysis of postmenopausal women with and without fracture. Volumetric BMD (vBMD) and microarchitecture were assessed at the distal radius and tibia in 1379 white postmenopausal women (age 67 ± 8 years); 470 (34%) had at least one fracture including 349 with a major fragility fracture. Age, height, weight, and total hip T-score differed across centers and were employed as covariates in analyses. Women with fracture had higher BMI, were older, and had lower total hip T-score, but lumbar spine T-score was similar between groups. At the radius, total and trabecular vBMD and cortical thickness were significantly lower in fractured women in three out of five centers, and trabecular number in two centers. Similar results were found at the tibia. When data from five centers were combined, however, women with fracture had significantly lower total, trabecular, and cortical vBMD (2% to 7%), lower trabecular number (4% to 5%), and thinner cortices (5% to 6%) than women without fracture after adjustment for covariates. Results were similar at the radius and tibia. Similar results were observed with analysis restricted to major fragility fracture, vertebral and hip fractures, and peripheral fracture (at the radius). When focusing on osteopenic women, each SD decrease of total and trabecular vBMD was associated with a significantly increased risk of major fragility fracture (OR = 1.55 to 1.88, p < 0.01) after adjustment for covariates. Moreover, trabecular architecture modestly improved fracture discrimination beyond peripheral total vBMD. In conclusion, we observed differences by center in the magnitude of fracture/nonfracture differences at both the distal radius and tibia. However, when data were pooled across centers and the sample size increased, we observed significant and consistent deficits in vBMD and microarchitecture independent of total hip T-score in all postmenopausal white women with fracture and in the subgroup of osteopenic women, compared to women who never had a fracture. © 2016 American Society for Bone and Mineral Research., (© 2016 American Society for Bone and Mineral Research.)

Fracture healing is characterized by an intense increase in modeling and remodeling of bone, which allows removal of the cast after a stable distal radius fracture within 3 to 5 weeks. However, at that time, bone strength has not recovered yet. We studied the changes in bone mineral density (BMD), microarchitecture, and bone stiffness after a distal radius fracture during a 2-year follow-up in comparison to the contralateral side and the association between the 2-year stiffness and baseline BMD, microarchitecture, and early changes in these parameters. The fractured side of 14 postmenopausal women (mean age 64 ± 8 years) with a conservatively treated distal radius fracture was scanned by high-resolution peripheral quantitative computed tomography (HRpQCT) at 1 to 2, 3 to 4, 6 to 8, and 12 weeks and 2 years postfracture. The same region contralaterally was scanned as well at the 2-year visit. BMD, microarchitecture, and stiffness parameters were determined and the fracture side was compared with the contralateral side using a linear mixed-effect model. Spearman's correlation was used to correlate the 2-year bone stiffness with baseline BMD, microarchitecture, and early 3-month changes in these parameters. Two years postfracture, cortical and trabecular thickness and torsional and bending stiffness were significantly higher at the fractured side compared with the nonfractured side (21%, 55%, 31%, and 29%, respectively, p < 0.05), whereas BMD was similar. Two-year torsional and bending stiffness correlated significantly with baseline BMD and cortical perimeter (|rho| ≥ 0.63, p < 0.016) but not with early changes in bone parameters. Using HRpQCT, this study illustrates that fracture healing is not completed by the time the cast is removed. We showed that from 6 weeks to 2 years postfracture, large changes occur in BMD, microarchitecture, and biomechanical parameters at the fractured side, which were fully recovered after 2 years in comparison to the nonfractured contralateral side. Interestingly, higher 2-year torsional and bending stiffness were associated with lower BMD and higher cortical perimeter at baseline. © 2015 American Society for Bone and Mineral Research., (© 2015 American Society for Bone and Mineral Research.)

The aim of this case study is to describe changes in areal bone mineral density (aBMD) by dual-energy X-ray absorptiometry (DXA) scan, as well as volumetric bone density and microarchitecture by high-resolution peripheral quantitative computed tomography (HR-pQCT) in two patients with autosomal dominant osteopetrosis (ADO) and compare with 20 healthy subjects. We describe a 44-year-old male patient with six low-impact fractures since he was age 16 years, and a 32-year-old female patient with four low-impact fractures on her past history. Radiographic changes were typical of ADO. Consistent with the much higher aBMD, total volumetric BMD (average bone density of the whole bone, including trabecular and cortical compartments) at distal radius and tibia (HR-pQCT) was more than twice the mean values found in healthy subjects in both patients. Trabecular number and thickness were higher, leading to an evident increase in trabecular bone volume to tissue volume. Also, an enormous increase in cortical thickness was found. Most important, a great heterogeneity in bone microstructure of the affected patients was evident on HR-pQCT images: islets of very dense bone were interposed with areas with apparent normal density. The increase in aBMD, volumetric BMD, and most indices of trabecular and cortical bone, associated with the great heterogeneity on bone tridimensional microarchitecture, reflect the accumulation of old and fragile bone randomly distributed along the skeleton. These alterations in bone microstructure probably compromise bone quality, which might justify the high prevalence of low-impact fractures in patients with ADO, despite abnormally elevated BMD., (© 2015 American Society for Bone and Mineral Research.)

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.)

RECQ DNA helicases play critical roles in maintaining genomic stability, but their role in development has been less well studied. Rothmund-Thomson syndrome, RAPADILINO, and Baller-Gerold syndrome are rare genetic disorders caused by mutations in the RECQL4 gene. These patients have significant skeletal developmental abnormalities including radial ray, limb and craniofacial defects. To investigate the role of Recql4 in the developing skeletal system, we generated Recql4 conditional knockout mice targeting the skeletal lineage. Inactivation of Recql4 using the Prx1-Cre transgene led to limb abnormalities and craniosynostosis mimicking the major bone findings in human RECQL4 patients. These Prx1-Cre(+) ;Recql4(fl/fl) mice as well as Col2a1-Cre(+) ;Recql4(fl/fl) mice exhibited growth plate defects and an increased p53 response in affected tissues. Inactivation of Trp53 in these Recql4 mutants resulted in genetic rescue of the skeletal phenotypes, indicating an in vivo interaction between Recql4 and Trp53, and p53 activation as an underlying mechanism for the developmental bone abnormalities in RECQL4 disorders. Our findings show that RECQL4 is critical for skeletal development by modulating p53 activity in vivo., (© 2015 American Society for Bone and Mineral Research.)

Fracture healing is an active process with early changes in bone and inflammation. We performed an exploratory study evaluating the association between early changes in densitometric, structural, biomechanical, and biochemical bone parameters during the first weeks of fracture healing and wrist-specific pain and disability at 12 weeks in postmenopausal women with a conservatively treated distal radius fracture. Eighteen patients (aged 64 ± 8 years) were evaluated at 1 to 2 and 3 to 4 weeks postfracture, using high-resolution peripheral quantitative computed tomography (HR-pQCT), micro-finite element analysis, serum procollagen type-I N-terminal propeptide (P1NP), carboxy-terminal telopeptide of type I collagen (ICTP), and high-sensitive C-reactive protein (hsCRP). After 12 weeks, patients rated their pain and disability using Patient Rated Wrist Evaluation (PRWE) questionnaire. Additionally, Quick Disability of the Arm Shoulder and Hand (QuickDASH) questionnaire and active wrist range of motion was evaluated. Linear regression models were used to study the relationship between changes in bone parameters and in hsCRP from visit 1 to 2 and PRWE score after 12 weeks. A lower PRWE outcome, indicating better outcome, was significantly related to an early increase in trabecular bone mineral density (BMD) (β -0.96 [95% CI -1.75 to -0.16], R(2)  = 0.37), in torsional stiffness (-0.14 [-0.28 to -0.004], R(2)  = 0.31), and to an early decrease in trabecular separation (209 [15 to 402], R(2)  = 0.33) and in ICTP (12.1 [0.0 to 24.1], R(2)  = 0.34). Similar results were found for QuickDASH. Higher total dorsal and palmar flexion range of motion was significantly related to early increase in hsCRP (9.62 [3.90 to 15.34], R(2)  = 0.52). This exploratory study indicates that the assessment of early changes in trabecular BMD, trabecular separation, calculated torsional stiffness, bone resorption marker ICTP, and hsCRP after a distal radius fracture provides valuable information regarding the 12-week clinical outcome in terms of pain, disability, and range of motion and validates its use in studies on the process of early fracture healing. © 2014 American Society for Bone and Mineral Research., (© 2014 American Society for Bone and Mineral Research.)

In this cross-sectional study, we investigated volumetric bone mineral density (vBMD), bone microstructure, and biomechanical competence of the distal radius in male patients with rheumatoid arthritis (RA). The study cohort comprised 50 male RA patients of average age of 61.1 years and 50 age-matched healthy males. Areal BMD (aBMD) of the hip, lumbar spine, and distal radius was measured by dual-energy X-ray absorptiometry. High-resolution peripheral quantitative computed tomography (HR-pQCT) of the distal radius provided measures of cortical and trabecular vBMD, microstructure, and biomechanical indices. aBMD of the hip but not the lumbar spine or ultradistal radius was significantly lower in RA patients than controls after adjustment for body weight. Total, cortical, and trabecular vBMD at the distal radius were, on average, -3.9% to -23.2% significantly lower in RA patients, and these differences were not affected by adjustment for body weight, testosterone level, or aBMD at the ultradistal radius. Trabecular microstructure indices were, on average, -8.1% (trabecular number) to 28.7% (trabecular network inhomogeneity) significantly inferior, whereas cortical pore volume and cortical porosity index were, on average, 80.3% and 63.9%, respectively, significantly higher in RA patients. RA patients also had significantly lower whole-bone stiffness, modulus, and failure load, with lower and more unevenly distributed cortical and trabecular stress. Density and microstructure indices significantly correlated with disease activity, severity, and levels of pro-inflammatory cytokines (interleukin [IL] 12p70, tumor necrosis factor, IL-6 and IL-1β). Ten RA patients had focal periosteal bone apposition most prominent at the ulnovolar aspect of the distal radius. These patients had shorter disease duration and significantly higher cortical porosity. In conclusion, HR-pQCT reveals significant alterations of bone density, microstructure, and strength of the distal radius in male RA patients and provides new insight into the microstructural basis of bone fragility accompanying chronic inflammation., (© 2014 American Society for Bone and Mineral Research.)

More accurate techniques to estimate fracture risk could help reduce the burden of fractures in postmenopausal women. Although micro-finite element (µFE) simulations allow a direct assessment of bone mechanical performance, in this first clinical study we investigated whether the additional information obtained using geometrically and materially nonlinear µFE simulations allows a better discrimination between fracture cases and controls. We used patient data and high-resolution peripheral quantitative computed tomography (HRpQCT) measurements from our previous clinical study on fracture risk, which compared 100 postmenopausal women with a distal forearm fracture to 105 controls. Analyzing these data with the nonlinear µFE simulations, the odds ratio (OR) for the factor-of-risk (yield load divided by the expected fall load) was marginally higher (1.99; 95% confidence interval [CI], 1.41-2.77) than for the factor-of-risk computed from linear µFE (1.89; 95% CI, 1.37-2.69). The yield load and the energy absorbed up to the yield point as computed from nonlinear µFE were highly correlated with the initial stiffness (R(2)  = 0.97 and 0.94, respectively) and could therefore be derived from linear simulations with little loss in precision. However, yield deformation was not related to any other measurement performed and was itself a good predictor of fracture risk (OR, 1.89; 95% CI, 1.39-2.63). Moreover, a combined risk score integrating information on relative bone strength (yield load-based factor-of-risk), bone ductility (yield deformation), and the structural integrity of the bone under critical loads (cortical plastic volume) improved the separation of cases and controls by one-third (OR, 2.66; 95% CI, 1.84-4.02). We therefore conclude that nonlinear µFE simulations provide important additional information on the risk of distal forearm fractures not accessible from linear µFE nor from other techniques assessing bone microstructure, density, or mass., (© 2013 American Society for Bone and Mineral Research.)

Osteoporosis is frequently seen in patients with chronic obstructive pulmonary disease (COPD). Because research on bone structure and bone strength in COPD patients is limited, the objectives of this pilot study were as follows: (1) to compare bone structure, stiffness, and failure load, measured at the peripheral skeleton, between men with and without COPD after stratification for areal bone mineral density (aBMD); and (2) to relate clinical parameters with bone stiffness and failure load in men with COPD. We included 30 men with COPD (normal aBMD, n = 18; osteoporosis, n = 12) and 17 men without COPD (normal aBMD, n = 9; osteoporosis, n = 8). We assessed pack-years of smoking, body mass index (BMI), fat free mass index (FFMI), pulmonary function (forced expiratory volume in 1 second [FEV1 ], FEV1 /forced vital capacity [FVC], diffusion capacity for carbon monoxide [DLCO], and transfer coefficient for carbon monoxide [KCO]), and extent of emphysema. Bone structure of the distal radius and tibia was assessed by high-resolution peripheral quantitative computed tomography (HR-pQCT), and bone stiffness and failure load of the distal radius and tibia were estimated from micro finite element analysis (µFEA). After stratification for aBMD and COPD, men with osteoporosis showed abnormal bone structure (p < 0.01), lower bone stiffness (p < 0.01), and lower failure load (p < 0.01) compared with men with normal aBMD, and men with COPD had comparable bone structure, stiffness, and failure load compared with men without COPD. In men with COPD, lower FFMI was related with lower bone stiffness, and failure load of the radius and tibia and lower DLCO and KCO were related with lower bone stiffness and failure load of the tibia after normalization with respect to femoral neck aBMD. Thus, this pilot study could not detect differences in bone structure, stiffness, and failure load between men with and without COPD after stratification for aBMD. FFMI and gas transfer capacity of the lung were significantly related with bone stiffness and failure load in men with COPD after normalization with respect to femoral neck aBMD., (© 2013 American Society for Bone and Mineral Research.)

Taller women are at increased risk for fracture despite having wider bones that better tolerate bending. Because wider bones require less material to achieve a given bending strength, we hypothesized that taller women assemble bones with relatively thinner and more porous cortices because excavation of a larger medullary canal may be accompanied by excavation of more intracortical canals. Three-dimensional images of distal tibia, fibula, and radius were obtained in vivo using high-resolution peripheral quantitative computed tomography (HRpQCT) in a twin study of 345 females aged 40 to 61 years, 93 with at least one fracture. Cortical porosity <100 µm as well as >100 µm, and microarchitecture, were quantified using Strax1.0, a new algorithm. Multivariable linear and logistic regression using generalized estimating equation (GEE) methods quantified associations between height and microarchitecture and estimated the associations with fracture risk. Each standard deviation (SD) greater height was associated with a 0.69 SD larger tibia total cross-sectional area (CSA), 0.66 SD larger medullary CSA, 0.50 SD higher medullary CSA/total CSA (i.e., thinner cortices relative to the total CSA due to a proportionally larger medullary area), and 0.42 SD higher porosity (all p < 0.001). Cortical area was 0.45 SD larger in absolute terms but 0.50 SD smaller in relative terms. These observations were confirmed by examining trait correlations in twin pairs. Fracture risk was associated with height, total CSA, medullary CSA/total CSA, and porosity in univariate analyses. In multivariable analyses, distal tibia, medullary CSA/total CSA, and porosity predicted fracture independently; height was no longer significant. Each 1 SD greater porosity was associated with fracture; odds ratios (ORs) and 95% confidence intervals (CIs) are as follows: distal tibia, OR = 1.55 (95% CI, 1.11-2.15); distal fibula, OR = 1.47 (95% CI, 1.14-1.88); and distal radius, OR = 1.22 (95% CI, 0.96-1.55). Taller women assemble wider bones with relatively thinner and more porous cortices predisposing to fracture., (Copyright © 2013 American Society for Bone and Mineral Research.)

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., (Copyright © 2013 American Society for Bone and Mineral Research.)

Whereas the beneficial effects of intermittent treatment with parathyroid hormone (PTH) (intact PTH 1-84 or fragment PTH 1-34, teriparatide) on vertebral strength is well documented, treatment may not be equally effective in the peripheral skeleton. We used high-resolution peripheral quantitative computed tomography (HR-pQCT) to detail effects on compartmental geometry, density, and microarchitecture as well as finite element (FE) estimated integral strength at the distal radius and tibia in postmenopausal osteoporotic women treated with PTH 1-34 (20 µg sc daily, n = 18) or PTH 1-84 (100 µg sc daily, n = 20) for 18 months in an open-label, nonrandomized study. A group of postmenopausal osteoporotic women receiving zoledronic acid (5 mg infusion once yearly, n = 33) was also included. Anabolic therapy increased cortical porosity in radius (PTH 1-34 32 ± 37%, PTH 1-84 39 ± 32%, both p < 0.001) and tibia (PTH 1-34 13 ± 27%, PTH 1-84 15 ± 22%, both p < 0.001) with corresponding declines in cortical density. With PTH 1-34, increases in cortical thickness in radius (2.0 ± 3.8%, p < 0.05) and tibia (3.8 ± 10.4%, p < 0.01) were found. Trabecular number increased in tibia with both PTH 1-34 (4.2 ± 7.1%, p < 0.05) and PTH 1-84 (5.3 ± 8.3%, p < 0.01). Zoledronic acid did not impact cortical porosity at either site but increased cortical thickness (3.0 ± 3.5%, p < 0.01), total (2.7 ± 2.5%, p < 0.001) and cortical density (1.5 ± 2.0%, p < 0.01) in tibia as well as trabecular volume fraction in radius (2.5 ± 5.1%, p < 0.05) and tibia (2.2 ± 2.2%, p < 0.01). FE estimated bone strength was preserved, but not increased, with PTH 1-34 and zoledronic acid at both sites, whereas it decreased with PTH 1-84 in radius (-2.8 ± 5.8%, p < 0.05) and tibia (-3.9 ± 4.8%, p < 0.001). Conclusively, divergent treatment-specific effects in cortical and trabecular bone were observed with anabolic and zoledronic acid therapy. The finding of decreased estimated strength with PTH 1-84 treatment was surprising and warrants confirmation., (Copyright © 2013 American Society for Bone and Mineral Research.)

The aim was to study the association between bone microarchitecture and muscle mass and strength in older men. Volumetric bone mineral density (vBMD) and bone microarchitecture were assessed in 810 men aged ≥60 years at the distal radius by high-resolution peripheral computed tomography (HR-pQCT). Areal bone mineral density (aBMD) and appendicular muscle mass (ASM) were assessed by dual-energy X-ray absorptiometry (DXA). Relative ASM of the upper limbs (RASM-u.l.) was calculated as ASM of the upper limbs/(height)(2). Grip strength was measured by dynanometry. In multivariable models, men in the lowest RASM-u.l. quartile had lower cross-sectional area (CSA), cortical area (Ct.Ar), cortical thickness (Ct.Th), and trabecular area (Tb.Ar) at distal radius compared with men in the highest quartile. The trends remained significant after adjustment for grip strength. Men in the lowest quartile of the normalized grip strength (grip strength/[height](2)) had lower aBMD, total vBMD, Ct.Ar, Ct.Th, Tb.vBMD, and Tb.N, and higher Tb.Sp and Tb.Sp.SD. The associations for Ct.Ar, total vBMD, Ct.Th, Tb.vBMD, and Tb.Sp remained significant after adjustment for RASM-u.l. In the models including RASM-u.l. and normalized grip strength, CSA and Tb.Ar were associated with RASM-u.l. but not with the strength. Lower Ct.Th, Tb.vBMD, and Tb.N were associated with lower grip strength but not with RASM-u.l. Lower Ct.Ar was associated with lower grip strength and with lower RASM-u.l. In conclusion, in older men, low RASM-u.l. and low grip strength are associated with poor cortical and trabecular microarchitecture partly independently of each other, after adjustment for confounders., (Copyright © 2013 American Society for Bone and Mineral Research.)

It has previously been shown that smoking is associated with reduced bone mass and increased fracture risk, but no longitudinal studies have been published investigating altered smoking behavior at the time of bone mass acquisition. The aim of this study was to investigate the development of bone density and geometry according to alterations in smoking behavior in a 5-year, longitudinal, population-based study of 833 young men, age 18 to 20 years (baseline). Furthermore, we aimed to examine the cross-sectional, associations between current smoking and parameters of trabecular microarchitecture of the radius and tibia, using high-resolution peripheral quantitative computed tomography (HR-pQCT), in young men aged 23 to 25 years (5-year follow-up). Men who had started to smoke since baseline had considerably smaller increases in areal bone mineral density (aBMD) at the total body (mean ± SD, 0.020 ± 0.047 mg/cm(2) versus 0.043 ± 0.040 mg/cm(2) , p < 0.01) and lumbar spine (0.027 ± 0.062 mg/cm(2) versus 0.052 ± 0.065 mg/cm(2) , p = 0.04), and substantially greater decreases in aBMD at the total hip (-0.055 ± 0.058 mg/cm(2) versus -0.021 ± 0.062 mg/cm(2) , p < 0.01) and femoral neck (-0.077 ± 0.059 mg/cm(2) versus -0.042 ± 0.070 mg/cm(2) , p < 0.01) than men who were nonsmokers at both the baseline and follow-up visits. At the tibia, subjects who had started to smoke had a smaller increment of the cortical cross-sectional area (CSA) than nonsmokers (8.1 ± 4.3 mm(2) versus 11.5 ± 8.9 mm(2) , p = 0.03), and a larger decrement of trabecular volumetric BMD (vBMD) than nonsmokers (-13.9 ± 20.5 mg/mm(3) versus -4.1 ± 13.9 mg/mm(3) , p < 0.001). In the cross-sectional analysis at follow-up (23-25 years of age), smokers had significantly lower trabecular vBMD at the tibia (7.0%, p < 0.01) due to reduced trabecular thickness (8.9%, p < 0.001), as assessed using HR-pQCT, than nonsmokers. In conclusion, this study is the first to report that men who start to smoke in young adulthood have poorer development of their aBMD at clinically important sites such as the spine and hip than nonsmokers, possibly due to augmented loss of trabecular density and impaired growth of cortical cross-sectional area., (Copyright © 2012 American Society for Bone and Mineral Research.)

Although bone mass appear ample for bone size in Turner syndrome (TS), epidemiological studies have reported an increased risk of fracture in TS. We used high-resolution peripheral quantitative computed tomography (HR-pQCT) to measure standard morphological parameters of bone geometry and microarchitecture, as well as estimated bone strength by finite element analysis (FEA) to assess bone characteristics beyond bone mineral density (BMD) that possibly contribute to the increased risk of fracture. Thirty-two TS patients (median age 35, range 20-61 years) and 32 healthy control subjects (median age 36, range 19-58 years) matched with the TS participants with respect to age and body-mass index were studied. A full region of interest (ROI) image analysis and a height-matched ROI analysis adjusting for differences in body height between groups were performed. Mean bone cross-sectional area was lower in TS patients in radius (-15%) and tibia (-13%) (both p < 0.01) whereas cortical thickness was higher in TS patients in radius (18%, p < 0.01) but not in tibia compared to controls. Cortical porosity was lower in TS patients at both sites (-32% in radius, -36% in tibia, both p < 0.0001). Trabecular integrity was compromised in TS patients with lower bone volume per tissue volume (BV/TV) (-27% in radius, -22% in tibia, both p < 0.0001), trabecular number (-27% in radius, -12% in tibia, both p < 0.05), and higher trabecular spacing (54% in radius, 23% in tibia, both p < 0.01). In the height-matched ROI analysis, differences remained significant apart from total area at both sites, cortical thickness in radius, and trabecular number in tibia. FEA estimated failure load was lower in TS patients in both radius (-11%) and tibia (-16%) (both p < 0.01) and remained significantly lower in the height-matched ROI analysis. Conclusively, TS patients had compromised trabecular microarchitecture and lower bone strength at both skeletal sites, which may partly account for the increased risk of fracture observed in these patients., (Copyright © 2012 American Society for Bone and Mineral Research.)

Osteogenesis imperfecta (OI) is a hereditary disorder characterized by decreased biosynthesis or impaired morphology of type I collagen that leads to decreased bone mass and increased bone fragility. We hypothesized that patients with OI have altered bone microstructure and bone geometry. In this cross-sectional study we compared patients with type I OI to age- and gender-matched healthy controls. A total of 39 (13 men and 26 women) patients with OI, aged 53 (range, 21-77) years, and 39 controls, aged 53 (range, 21-77) years, were included in the study. Twenty-seven of the patients had been treated with bisphosphonates. High-resolution peripheral quantitative computed tomography (HR-pQCT) at the distal radius and distal tibia and dual-energy X-ray absorptiometry of total hip, femoral neck, trochanteric region, and the lumbar spine (L1-L4) were performed. The patients were shorter than the controls (159 ± 10 cm versus 170 ± 9 cm, p < 0.001), but had similar body weight. In OI, areal bone mineral density (aBMD) was 8% lower at the hip (p < 0.05) and 13% lower at the spine (p < 0.001) compared with controls. The trabecular volumetric bone mineral density (vBMD) was 28% lower in radius (p < 0.001) and 38% lower in tibia (p < 0.001) in OI compared with controls. At radius, total bone area was 5% lower in OI than in controls (p < 0.05). In the tibia, cortical bone area was 18% lower in OI (p < 0.001). In both radius and tibia the number of trabeculae was lower in patients compared to the controls (35% and 38%, respectively, p < 0.001 at both sites). Furthermore, trabecular spacing was 55% higher in OI in both tibia and radius (p < 0.001 at both sites) when compared with controls. We conclude that patients with type I OI have lower aBMD, vBMD, bone area, and trabecular number when compared with healthy age- and gender-matched controls., (Copyright © 2012 American Society for Bone and Mineral Research.)

Areal bone mineral density (aBMD) measured by dual-energy X-ray absorptiometry (DXA) identifies 20% of men who will sustain fragility fractures. Thus we need better fracture predictors in men. We assessed the association between the low-trauma prevalent fractures and bone microarchitecture assessed at the distal radius and tibia by high-resolution peripheral quantitative computed tomography (HR-pQCT) in 920 men aged 50 years of older. Ninety-eight men had vertebral fractures identified on the vertebral fracture assessment software of the Hologic Discovery A device using the semiquantitative criteria, whereas 100 men reported low-trauma peripheral fractures. Men with vertebral fractures had poor bone microarchitecture. However, in the men with vertebral fractures, only cortical volumetric density (D.cort) and cortical thickness (C.Th) remained significantly lower at both the radius and tibia after adjustment for aBMD of ultradistal radius and hip, respectively. Low D.cort and C.Th were associated with higher prevalence of vertebral fractures regardless of aBMD. Severe vertebral fractures also were associated with poor trabecular microarchitecture regardless of aBMD. Men with peripheral fractures had poor bone microarchitecture. However, after adjustment for aBMD, all microarchitectural parameters became nonsignificant. In 15 men with multiple peripheral fractures, trabecular spacing and distribution remained increased after adjustment for aBMD. Thus, in men, vertebral fractures and their severity are associated with impaired cortical bone, even after adjustment for aBMD. The association between peripheral fractures and bone microarchitecture was weaker and nonsignificant after adjustment for aBMD. Thus bone microarchitecture may be a determinant of bone fragility in men, which should be investigated in prospective studies., (Copyright © 2011 American Society for Bone and Mineral Research.)

Bone adapts to mechanical loads applied on it. During aging, loads decrease to a greater extent at those skeletal sites where loads increase most in earlier life. Thus, the loss of bone may occur preferentially at sites where most bone has been deposited previously; ie, bone loss could be the directional reversal of accrual. To test this hypothesis, we compared the bone mass distribution at weight-bearing (tibia) and non-weight-bearing (radius) bones among 18-year-old girls, their premenopausal mothers, and their postmenopausal maternal grandmothers. Bone and muscle properties were measured by pQCT, and polar distribution of bone mass was obtained in 55 girl-mother-maternal grandmother trios. Site-matched differences in bone mass were compared among three generations. The differences between girls and mothers and between mothers and grandmothers were used to represent the patterns of bone mass accrual from early adulthood to middle age and bone loss from middle to old age, respectively. Compared to the mothers, 18-year old girls had less bone mass in the anterior and medial-posterior regions of the tibial shaft, while the grandmothers had less bone in the anterior and posterior regions. In contrast, the bone mass differences in the radial shaft between girls and mothers and mothers and grandmothers were relatively uniform. We conclude that both bone accrual and loss are direction-specific in weight-bearing bones but relatively uniform in non-weight-bearing bones. Bone loss in old age is largely, but not completely, a reversal of the preferential deposition of bone in the most highly loaded regions during early life., (Copyright © 2011 American Society for Bone and Mineral Research.)

Few studies have investigated bone microarchitecture and biomechanical properties in men. This study assessed in vivo both aspects in a population of 185 men (aged 71 ± 10 years) with prevalent fragility fractures, compared to 185 controls matched for age, height, and weight, from the Structure of the Aging Men's Bones (STRAMBO) cohort. In this case-control study, areal BMD (aBMD) was measured by DXA, bone microarchitecture was assessed by high resolution (HR)-pQCT, and finite element (µFE) analysis was based on HR-pQCT images of distal radius and tibia. A principal component (PC) analysis (PCA) was used to study the association of synthetic PCs with fracture by computing their odds ratio (OR [95%CI]) per SD change. Specific associations with vertebral fracture (n = 100), and nonvertebral fracture (n = 85) were also computed. At both sites, areal and volumetric BMD, cortical thickness and trabecular number, separation, and distribution were significantly worse in cases than in controls, with differences ranging from -6% to 15%. µFE-derived stiffness and failure load were 8% to 9% lower in fractures (p < .01). No difference in load distribution was found between the two groups. After adjustment for aBMD, only differences of µFE-derived stresses, stiffness, and failure load at the tibia remained significant (p < .05). PCA resulted in defining 4 independent PCs, explaining 83% of the total variability of bone characteristics. Nonvertebral fractures were associated with PC1, reflecting bone quantity and strength at the radius (tibia) with OR = 1.64 [1.27-2.12] (2.21 [1.60-3.04]), and with PC2, defined by trabecular microarchitecture, with OR = 1.27 [1.00-1.61]. Severe vertebral fractures were associated with PC1, with OR = 1.56 [1.16-2.09] (2.21 [1.59-3.07]), and with PC2, with OR = 1.55 [1.17-2.06] (1.45 [1.06-1.98]). In conclusion, microarchitecture and biomechanical properties derived from µFE were associated with all types of fractures in men, showing that radius and tibia mechanical properties were relatively representative of distant bone site properties., (Copyright © 2011 American Society for Bone and Mineral Research.)

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.)

Measurement of areal bone mineral density (aBMD) by dual-energy x-ray absorptiometry (DXA) has been shown to predict fracture risk. High-resolution peripheral quantitative computed tomography (HR-pQCT) yields additional information about volumetric BMD (vBMD), microarchitecture, and strength that may increase understanding of fracture susceptibility. Women with (n = 68) and without (n = 101) a history of postmenopausal fragility fracture had aBMD measured by DXA and trabecular and cortical vBMD and trabecular microarchitecture of the radius and tibia measured by HR-pQCT. Finite-element analysis (FEA) of HR-pQCT scans was performed to estimate bone stiffness. DXA T-scores were similar in women with and without fracture at the spine, hip, and one-third radius but lower in patients with fracture at the ultradistal radius (p < .01). At the radius fracture, patients had lower total density, cortical thickness, trabecular density, number, thickness, higher trabecular separation and network heterogeneity (p < .0001 to .04). At the tibia, total, cortical, and trabecular density and cortical and trabecular thickness were lower in fracture patients (p < .0001 to .03). The differences between groups were greater at the radius than at the tibia for inner trabecular density, number, trabecular separation, and network heterogeneity (p < .01 to .05). Stiffness was reduced in fracture patients, more markedly at the radius (41% to 44%) than at the tibia (15% to 20%). Women with fractures had reduced vBMD, microarchitectural deterioration, and decreased strength. These differences were more prominent at the radius than at the tibia. HR-pQCT and FEA measurements of peripheral sites are associated with fracture prevalence and may increase understanding of the role of microarchitectural deterioration in fracture susceptibility. © 2010 American Society for Bone and Mineral Research., (Copyright © 2010 American Society for Bone and Mineral Research.)

Patients with primary hyperparathyroidism (PHPT) have continuously elevated parathyroid hormone (PTH) and consequently increased bone turnover with negative effects on cortical (Ct) bone with preservation of trabecular (Tb) bone. High-resolution peripheral quantitative computed tomography (HR-pQCT) is a new technique for in vivo assessment of geometry, volumetric density, and microarchitecture at the radius and tibia. In this study we aimed to evaluate bone status in women with PHPT compared with controls using HR-pQCT. The distal radius and tibia of 54 women--27 patients with PHPT (median age 60, range 44-75 years) and 27 randomly recruited age-matched healthy controls (median age 60, range 44-76 years)--were imaged using HR-pQCT along with areal bone mineral density (aBMD) by dual-energy X-ray absorptiomentry (DXA) of the ultradistal forearm, femoral neck, and spine (L1-L4). Groups were comparable regarding age, height, and weight. In the radius, patients had reduced Ct area (Ct.Ar) (p = .008), Ct thickness (Ct.th) (p = .01) along with reduced total (p = .002), Ct (p = .02), and Tb (p = .02) volumetric density and reduced Tb number (Tb.N) (p = .04) and increased Tb spacing (Tb.sp) (p = .05). Ct porosity did not differ. In the tibia, no differences in HR-pQCT parameters were found. Moreover, patients had lower ultradistal forearm (p = .005), spine (p = .04), and femoral neck (p = 0.04) aBMD compared with controls. In conclusion, a negative bone effect of continuously elevated PTH with alteration of HR-pQCT assessed geometry, volumetric density, and both trabecular and cortical microarchitecture in radius but not tibia was found along with reduced aBMD by DXA at all sites in female patients with PHPT. © 2010 American Society for Bone and Mineral Research.

Increases in cortical porosity (Ct.Po) and decreases in cortical thickness (Ct.Th) are associated with increased bone fragility. The purpose of this study was to validate an autosegmentation method for high-resolution peripheral quantitative computed tomography (HR-pQCT) scans to measure Ct.Po and Ct.Th and use it to compare Ct.Po and Ct.Th between pre- and postmenopausal women with normal, osteopenic, and osteoporotic areal bone mineral density (aBMD). The Ct.Po and Ct.Th measurements were validated using cadaver forearms (n = 10) and micro-computed tomography (microCT) as the gold standard. The analysis was applied to distal radius and tibia HR-pQCT scans from a subset of participants from the Calgary, Alberta, cohort of the Canadian Multicentre Osteoporosis Study (n = 280, 18 to 90 years). Analysis of covariance compared Ct.Po and Ct.Th outcomes between 63 normal premenopausal (dual-energy X-ray absorptiometry femoral neck T-score > -1), 87 normal postmenopausal, 121 osteopenic postmenopausal, and 9 osteoporotic postmenopausal women. Linear regression analysis and Bland-Altman plots were used to assess the agreement between the HR-pQCT and microCT measurements, resulting in r(2) values of 0.80 for Ct.Po and 0.98 for Ct.Th. At both sites, Ct.Po was higher in postmenopausal (all groups) than in premenopausal women (3.2% to 12.9%, p < .001). Ct.Th was not significantly different between normal premenopausal and postmenopausal women at either site; however, both osteopenic and osteoporotic women had thinner (-12.8% to -30.3%, p < .01), more porous (2.1% to 8.1%, p < .001) cortices than normal postmenopausal women. Our method offers promise as a valuable tool to measure Ct.Po and Ct.Th in vivo and investigate associations among cortical bone structure, age, and disease status., (Copyright 2010 American Society for Bone and Mineral Research.)

Patients with vertebral fractures (VFx) have trabecular architectural disruption on iliac biopsies. Because cortical bone is an important determinant of bone strength, we assessed cortical and trabecular microarchitecture at peripheral sites in patients with VFx of varying number (N) and severity (S). Bone architecture and volumetric density (vBMD) were assessed at the distal radius and tibia with HR-pQCT (XTreme CT; Scanco Medical, Bassersdorf, Switzerland) in 100 women with VFx (age, 74 +/- 9 yr) of different S (GI, n = 23; GII, n = 35 ; GIII, n = 42) and in 362 women (age, 69 +/- 7 yr) without peripheral or VFx (G0) from the OFELY study. Spine areal BMD (aBMD) was assessed by DXA. Among all women, at the radius and after adjustment for age and aBMD, there were significant trends in lower vBMD, cortical thickness (Cort.Th), trabecular number (Tb.N) and thickness (Tb.Th), higher trabecular separation (Tb.Sp), and distribution of separation (Tb.Sp.SD) with greater VFx S and N. Among women with VFx, lower Cort.Th and cortical vBMD (D.Cort) were associated with severe (GIII) and multiple (n > 2) VFx (p < 0.05). The age-adjusted OR for each SD decrease of Cort.Th was 2.04 (95% CI, 1.02-4.00) after adjustment for aBMD. At the tibia, there were trends for lower vBMD, Tb.N, Tb.Th, and higher Tb.Sp and Tb.Sp.SD with greater VFx S and N (p < 0.001). Among women with VFx, lower Cort.Th and D.Cort were associated with severe and multiple (n > 3) VFx (p < 0.01). In postmenopausal women, VFx are associated with low vBMD and architectural decay of trabecular and cortical bone at the radius and tibia, independently of spine aBMD. Severe and multiple VFx are associated with even more alterations of cortical bone.

Unlabelled: In postmenopausal women with a wide range of vertebral deformities, MRI-based structural measures of topology and scale at the distal radius are shown to account for as much as 30% of vertebral deformity, independent of integral vertebral BMD., Introduction: Trabecular bone architecture has been postulated to contribute to overall bone strength independent of vertebral BMD measured by DXA. However, there has thus far been only sparse in vivo evidence to support this hypothesis., Materials and Methods: Postmenopausal women, 60-80 yr of age, were screened by DXA, and those with T-scores at either the hip or spine falling within the range of -2.5 +/- 1.0 were studied with the MRI-based virtual bone biopsy, along with heel broadband ultrasound absorption and pQCT of the tibia. The data from 98 subjects meeting the enrollment criteria were subjected to microMRI at the distal tibia and radius, and measures of topology and scale of the trabecular bone network were computed. A spinal deformity index (SDI) was obtained from morphometric measurements in midline sagittal MR images of the thoracic and lumbar spine to evaluate associations between structure and deformity burden., Results: A number of structural indices obtained at the distal radius were correlated with the SDI. Among these were the topological surface density (a measure of trabecular plates) and trabecular bone volume fraction, which were inversely correlated with SDI (p < 0.0001). Combinations of two structural parameters accounted for up to 30% of the variation in SDI (p < 0.0001) independent of spinal BMD, which was not significantly correlated. pQCT trabecular BMD was also weakly associated, whereas broadband ultrasound absorption was not. No significant association between SDI and structural indices were found at the tibia., Conclusions: Structural measures at the distal radius obtained in vivo by microMRI explained a significant portion of the variation in total spinal deformity burden in postmenopausal women independent of areal BMD.

Unlabelled: Healing of fractures is dependent on vascularization of bone, which is in turn promoted by VEGF. It was shown that 0.1 and 1 mg of pVEGF165-GAM led to a significant increase in vascularization and bone regeneration in defects that would otherwise have led to atrophic nonunions., Introduction: One reason for lack of bone healing in nonunions is the absence of vascularization. In skeletogenesis, which is tightly linked to angiogenesis, vascular endothelial growth factor (VEGF) promotes the vascularization of the growth plate and transformation of cartilage to bone. We postulate that a gene-activated matrix (GAM), created with a plasmid coding for human VEGF165, coated on a collagen sponge could efficiently accelerate bone healing in large segmental defects., Materials and Methods: Sixty New Zealand white rabbits received a 15-mm critical size defect on one radius, which was filled with either 0.1 or 1 mg plasmid-DNA as GAM. Radiographs were obtained every 3 weeks. After 6 or 12 weeks, animals were killed. New bone was measured by microCT scans. Vascularity was measured using anti-CD31 staining of endothelial cells in 18 regions of interest per implant., Results: Scaffold and control plasmid showed no defect healing, whereas most of the animals in the VEGF groups showed partial or total bone regeneration. Significantly more bone was found in the VEGF groups, with no significant differences between the 0.1- and 1-mg groups. Immunohistochemical staining of endothelial cells revealed that the VEGF groups showed two to three times the number of vessels and a significantly larger endothelial area after 6 weeks. Twelve weeks after surgery, the amount of vascularization decreased, whereas more new bone was detectable., Conclusions: The rabbit critical size defect was appropriate in size to produce atrophic nonunions. We showed that angiogenesis and osteogenesis can be promoted by a VEGF165-GAM that is an appropriate tool to induce bone healing in atrophic nonunions.

Unlabelled: A population-based British cohort study, including approximately 6% of the population, was used to derive age- and sex-specific incidence rates of fractures during childhood. Fractures were more common among boys than girls, with peak incidences at 14 and 11 years of age, respectively. At childhood peak, incidence rates were only surpassed later in life at 85 years of age among women and never among men., Introduction: Fractures account for 25% of accidents and injuries in childhood; however, the descriptive epidemiology of childhood fractures remains uncertain., Materials and Methods: Age- and sex-specific incidence rates for fractures at various skeletal sites were derived from the General Practice Research Database (a population-based British cohort containing computerized medical records of approximately 7,000,000 residents) between 1988 and 1998., Results: A total of 52,624 boys and 31,505 girls sustained one or more fractures over the follow-up period, for a rate of 133.1/10,000 person-years. Fractures were more common in boys (161.6/10,000 person-years) than girls (102.9/10,000 person-years). The most common fracture in both sexes was that of the radius/ulna (30%). Fracture incidence was greater among boys than girls at all ages, with the peak incidence at 14 years of age among boys and 11 years of age among girls. Marked geographic variation was observed in standardized fracture incidence, with significantly (p < 0.01) higher rates observed in Northern Ireland, Wales, and Scotland compared with southeast England., Conclusions: Fractures are a common problem in childhood, with around one-third of boys and girls sustaining at least one fracture before 17 years of age. Rates are higher among boys than girls, and male incidence rates peak later than those among females. At their childhood peak, the incidence of fractures (boys, 3%; girls, 1.5%) is only surpassed at 85 years of age among women and never among men. The most common site affected in both genders is the radius/ulna. Studies to clarify the pathogenesis of these fractures, emphasizing bone fragility, are now required.

Unlabelled: In a population-based, cross-sectional study, we assessed age- and sex-specific changes in bone structure by QCT. Over life, the cross-sectional area of the vertebrae and proximal femur increased by approximately 15% in both sexes, whereas vBMD at these sites decreased by 39-55% and 34-46%, respectively, with greater decreases in women than in men., Introduction: The changes in bone structure and density with aging that lead to fragility fractures are still unclear., Materials and Methods: In an age- and sex-stratified population sample of 373 women and 323 men (age, 20-97 years), we assessed bone geometry and volumetric BMD (vBMD) by QCT at the lumbar spine, femoral neck, distal radius, and distal tibia., Results: In young adulthood, men had 35-42% larger bone areas than women (p < 0.001), consistent with their larger body size. Bone area increased equally over life in both sexes by approximately 15% (p < 0.001) at central sites and by approximately 16% and slightly more in men at peripheral sites. Decreases in trabecular vBMD began before midlife and continued throughout life (p < 0.001), whereas cortical vBMD decreases began in midlife. Average decreases in trabecular vBMD were greater in women (-55%) than in men (-46%, p < 0.001) at central sites, but were similar (-24% and -26%, respectively) at peripheral sites. With aging, cortical area decreased slightly, and the cortex was displaced outwardly by periosteal and endocortical bone remodeling. Cortical vBMD decreased over life more in women ( approximately 25%) than in men (approximately 18%, p < 0.001), consistent with menopausal-induced increases in bone turnover and bone porosity., Conclusions: Age-related changes in bone are complex. Some are beneficial to bone strength, such as periosteal apposition with outward cortical displacement. Others are deleterious, such as increased subendocortical resorption, increased cortical porosity, and, especially, large decreases in trabecular vBMD that may be the most important cause of increased skeletal fragility in the elderly. Our findings further suggest that the greater age-related decreases in trabecular and cortical vBMD and perhaps also their smaller bone size may explain, in large part, why fragility fractures are more common in elderly women than in elderly men.

Bone characteristics of the humeral shaft and distal radius were measured from 64 female tennis and squash players and their 27 age-, height-, and weight-matched controls with peripheral quantitative tomography (pQCT) and dual energy X-ray absorptiometry (DXA). The players were divided into two groups according to the starting age of their tennis or squash training (either before or after menarche) to examine the possible differences in the loading-induced changes in bone structure and volumetric density. The following pQCT variables were used: bone mineral content, total cross-sectional area of bone (TotA), cross-sectional area of the marrow cavity (CavA) and that of the cortical bone (CoA), cortical wall thickness (CWT), volumetric density of the cortical bone (CoD) and trabecular bone (TrD), and torsional bone strength index for the shaft (BSIt) and compressional bone strength index for the bone end (BSIc). These bone strength indices were compared with the DXA-derived areal bone mineral density (aBMD) to assess how well the latter represents the effect of mechanical loading on apparent bone strength. At the humeral shaft, the loaded arm's greater bone mineral content (an average 19% side-to-side difference in young starters and 9% in old starters), was caused by an enlarged cortex (CoA; side-to-side differences 20% and 9%, respectively). The loaded humerus seemed to have grown periosteally (the CavA did not differ between the sites), leading to 26% and 11% side-to-side BSIt differences in the young and old starters, respectively. CoD was equal between the arms (-1% difference in both player groups). The side-to-side differences in the young starters' bone mineral content, CoA, TotA, CWT, and BSIt were 8-22% higher than those of the controls and 8-14% higher than those of the old starters. Old starters' bone mineral content, CoA, and BSIt side-to-side differences were 6-7% greater than those in the controls. The DXA-derived side-to-side aBMD difference was 7% greater in young starters compared with that of the old starters and 14% compared with that in controls, whereas the difference between old starters and controls was 6%, in favor of the former. All these between-group differences were statistically significant. At the distal radius, the player groups differed significantly from controls in the side-to-side bone mineral content, TrD, and aBMD differences only: the young starters' bone mineral content difference was 9% greater, TrD and aBMD differences were 5% greater than those in the controls, and the old starters' TrD and aBMD differences were both 7% greater than those in the controls. In summary, in both of the female player groups, the structural adaptation of the humeral shaft to long-term loading seemed to be achieved through periosteal enlargement of the bone cortex, although this adaptation was clearly better in the young starters. Exercise-induced cortical enlargement was not so clear at the distal radius (a trabecular bone site), and the study suggested that at long bone ends, the trabecular density could be a modifiable factor to built a stronger bone structure. Conventional DXA-based aBMD measurement detected the intergroup differences in the exercise-induced bone gains, although, because it measured two dimensions of bone only, it seemed to underestimate the effect of exercise on the apparent bone strength, especially if the playing had been started during the growing years.

A large number of children sustain fractures after relatively minor trauma and several investigators have associated these fractures to a deficient accumulation of bone during growth. This study was conducted to better characterize the skeletal phenotype associated with low-energy impact fractures of the forearm in girls. The densities of cancellous, cortical, and integral bone and the cross-sectional area were measured in the radius of 100 healthy white girls (aged 4-15 years) using computed tomography (CT); 50 girls had never fractured and 50 girls had sustained a forearm fracture within the previous month. Fractured and nonfractured groups were matched for age, height, weight, and Tanner stage of sexual development. Compared with controls, girls with fractures had, on average, 8% smaller cross-sectional area at the distal radius (1.82 +/- 0.50 cm2 vs. 1.97 +/- 0.42 cm2; p < 0.0001) but similar cancellous, integral, and cortical bone densities. Neither radial length nor the amount of fat or muscle at the midshaft of the radius differed between girls with and without fractures. Both study subjects and matched controls were overweight. Although mean height was at the 50th percentile, mean weight was at the 90th percentile for age-adjusted normal values. Girls who sustain forearm fractures after minor trauma have small cross-sectional dimensions of the radius and tend to be overweight. The smaller cross-sectional area confers a biomechanical disadvantage that, coupled with the greater body weight, increases the vulnerability to fracture after a fall.

Fracture and immobilization of an extremity lead to bone loss at the fracture and at adjacent sites. We conducted a 1-year, single-center, prospective, randomized, double-blind study to determine whether bone loss would occur in the distal radius after a Colles' fracture and whether this loss could be prevented using an antiresorptive drug (alendronate). Thirty-seven women with a recent fracture of the distal forearm and low bone mineral density (BMD) of the lumbar spine were randomized to receive either 10 mg alendronate daily or placebo. BMD of both forearms was measured at baseline and after 3, 6, and 12 months. The results of four women who developed reflex sympathetic dystrophy were not included in the analysis. In the placebo group, there was a significant reduction at 3 months and 6 months in BMD of total radius (p < 0.01), one-third distal radius (p < 0.01), middistal radius (p < 0.05), and ultradistal radius (p < 0.01) on the fractured side. The loss in BMD at one-third distal radius remained significant at month 12 (p < or = 0.001). In the alendronate group BMD of total distal radius, one-third distal radius, and middistal radius at the fractured side remained unchanged. BMD of ultradistal radius increased significantly at months 3, 6, and 12, compared with baseline (p < 0.05). The difference between the two treatment groups was significant at 3 months and 6 months and borderline significant (p = 0.054) after 1 year in total distal radius. In ultradistal radius the differences were significant at all time points. We conclude that BMD of the distal radius of a recently fractured forearm decreases significantly in the 6 months after fracture and the resulting deficit remains evident at least 1 year after fracture. This bone loss can be prevented by alendronate.