Structural alterations during fracture healing lead to void spaces developing in surrounding bone microarchitecture

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 L1 to L4 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).

Limited prospective evidence exists regarding bone microarchitectural deterioration. We report annual changes in trabecular and cortical bone microarchitecture at the distal radius and tibia in postmenopausal women. Lost trabeculae with corresponding increase in trabecular thickness at the radius and thinning tibial cortex indicated trabecularization of the cortex at both sites. Osteoporosis is characterized by low bone mass and the deterioration of bone microarchitecture. However, limited prospective evidence exists regarding bone microarchitectural changes in postmenopausal women: a population prone to sustaining osteoporotic fractures. Our primary objective was to characterize the annual change in bone area, density, and microarchitecture at the distal radius and distal tibia in postmenopausal women. Distal radius and tibia were measured using high-resolution peripheral quantitative computed tomography (HR-pQCT) at baseline and 1 year later in 51 women (mean age ± SD, 77 ± 7 years) randomly sampled from the Saskatoon cohort of the Canadian Multicentre Osteoporosis Study (CaMos). We used repeated measures analysis of variance (ANOVA) with Bonferroni adjustment for multiple comparisons to characterize the mean annual change in total density, cortical perimeter, trabecular and cortical bone area, density, content, and microarchitecture. Significant changes were accepted at P < 0.05. At the distal radius in women without bone-altering drugs, total density (-1.7%) and trabecular number (-6.4%) decreased, while trabecular thickness (+6.0%), separation (+8.6%), and heterogeneity (+12.1%) increased. At their distal tibia, cortical area (-4.5%), density (-1.9%), content (-6.3%), and thickness (-4.4%) decreased, while trabecular area (+0.4%) increased. The observed loss of trabeculae with concomitant increase in trabecular size at the distal radius and the declined cortical thickness, density, and content at the distal tibia indicated a site-specific trabecularization of the cortical bone in postmenopausal women.

The association between body mass index (BMI) and functional outcomes is unknown in elderly individuals with distal radius fracture (DRF). The aim of this study is to evaluate if there is association between BMI and functional outcomes in patients older than 60years with DRF treated conservatively. A prospective observational study was performed. A total of 228 patients with extra-articular DRF were prospectively recruited. All patients were categorized by their BMI as normal, overweight, or obese. Functional outcomes were assessed after cast removal and at 1-year follow-up. The Disabilities of the Arm, Shoulder and Hand Outcome Measure (DASH), and Patient-Rated Wrist Evaluation (PRWE) questionnaires were used to assess upper limb and wrist/hand function, respectively, while the Jamar Dynamometer was used to assess grip strength. Of the total number of patients, 184 were female (80.7%), 87 were overweight (38.2%), and 111 were obese (48.7%). After cast removal, the correlations between BMI and functional outcomes were DASH 0.06 (p = 0.578), PRWE 0.04 (p = 0.692), and grip strength -0.02 (p = 0.763). At 1-year follow-up, the correlations were DASH 0.55 (p = 0.036), PRWE 0.32 (p = 0.041), and grip strength -0.21 (p = 0.043). This study suggests that at 1-year follow-up, there was a low-to-moderate association between BMI and poor functional outcomes in elderly patients with extra-articular DRF treated conservatively. Level IV, observational prospective study.

Chronic kidney disease (CKD) may be complicated by mineral and bone disorders (CKD-MBD). Data on the association between estimated glomerular filtration rate (eGFR) and bone microarchitecture are limited. We studied the link between eGFR and bone microarchitecture (baseline, changes) assessed by high resolution peripheral quantitative computed tomography (HR-pQCT) in older men followed for 8 years. In 826 men aged ≥60, eGFR was calculated using three equations based on creatinin and cystatin C: CKDEPI-2012, EKFC without race and sex, CKDEPI-2021 without race. Bone microarchitecture was assessed at the distal radius and distal tibia by HR-pQCT at baseline, then after 4 and 8 years. Reaction force and failure load were estimated by microfinite element analysis. Changes in bone measures across the eGFR classes were explored using linear mixed effect models. At baseline, distal radius bone microarchitecture did not differ across the eGFR groups (CKDEPI-2012), whereas distal tibia trabecular measures and failure load were higher in men with decreased eGFR. During the follow-up, lower eGFR was associated with more rapid decrease in total bone mineral density (Tt.BMD), cortical area (Ct.Ar) and BMD (Ct.BMD), trabecular BMD (Tb.BMD), and failure load at the distal radius. Low eGFR was also associated with faster increase in trabecular area (Tb.Ar) and trabecular distribution heterogeneity (Tb.1/N.SD). At the distal tibia, low eGFR was associated with more rapid decrease in Tt.BMD, Ct.Ar, Ct.BMD, Tb.1/N.SD, and failure load as well as with faster increase in Tb.Ar. The patterns were similar for changes expressed as percentages. The patterns were similar for two other equations. Lower eGFR is associated with faster decline in cortical bone microarchitecture and bone strength at the distal radius and tibia in older men. This phenomenon may contribute to the higher fracture risk in older adults with CKD.

Persistent immunoglobulin E (IgE)-mediated cow's milk allergy (CMA) may impair bone parameters and increase the risk of fractures. High-resolution peripheral quantitative computed tomography (HR-pQCT) is a novel methodology that not only assesses trabecular and cortical bone compartments and volumetric density measurements, but also evaluates bone microarchitecture and estimates biomechanical properties through finite element analysis (FEA). Both HR-pQCT and bone strength parameters derived from FEA have shown a strong correlation with fracture risk. To assess the bone density, microarchitecture, and bone strength of adolescents with persistent IgE-mediated CMA (IgE-CMA). This was an observational, cross-sectional study with female adolescents with persistent IgE-CMA and healthy control participants matched by female sex and sexual maturation. Bone parameters were assessed by areal bone mineral density (aBMD) through dual-energy X-ray absorptiometry (DXA), bone microarchitecture by HR-pQCT at the radius and tibia, and laboratory markers related to bone metabolism. The median age of adolescents with persistent IgE-CMA (n = 26) was 13.0years (interquartile range (IQR) 11.4-14.7) and of healthy control participants (n = 28) was 13.6years (IQR 11.9-14.9). Adolescents with IgE-CMA ingested 27.4% less calcium (p = 0.012) and 28.8% less phosphorus (p = 0.009) than controls. Adolescents with IgE-CMA had lower bone mineral content (BMC) (38.83g vs. 44.50g) and aBMD (0.796g/cm2 vs. 0.872g/cm2) at lumbar spine, and lower BMC (1.11kg vs. 1.27kg) and aBMD (0.823g/cm2 vs. 0.877g/cm2) at total body less head (TBLH) (p < 0.05). However, Z-scores BMC and Z-scores aBMD at lumbar spine and TBLH, when adjusted for Z-score height/age, were not significantly different between the groups. Moreover, CMA adolescents had lower bone strength at the distal tibia (S 169 kN/mm vs. 194 kN/mm; F Load 8030 N vs. 9223 N) (p < 0.05). Pairing of groups by the presence of menarche showed compromised parameters at the tibia-lower total volumetric BMD (Tt.vBMD) (293.9mg HA/cm3 vs. 325.9mg HA/cm3) and trabecular vBMD (Tb.vBMD) (170.8mg HA/cm3 vs. 192.2mg HA/cm3), along with lower cortical thickness (Ct.th) (1.02mm vs. 1.16mm) and bone strength (S 174 kN vs. 210 kN; F Load 8301 N vs. 9950 N)-and at the radius (S 61 kN/mm vs. 71 kN/mm; F Load 2920 N vs. 3398 N) (p < 0.05) among adolescents with IgE-CMA. Adolescents with IgE-CMA on a total exclusion diet (n = 12) showed greater impairment of bone features than those on a partial exclusion diet (n = 14), with lower lumbar spine Z-score BMC (- 0.65 vs. 0.18; p = 0.013), lumbar spine trabecular bone score (TBS) (1.268 vs. 1.383; p = 0.005), Z-score TBS (0.03 vs. 1.14; p = 0.020), TBLH Z-score BMC (- 1.17 vs. - 0.35; p = 0.012), TBLH Z-score aBMD (- 1.13 vs. - 0.33; p = 0.027), Tt.vBMD at the tibia (259.0mg HA/cm3 vs. 298.7mg HA/cm3; p = 0.021), Ct.th at the tibia (0.77mm vs. 1.04mm; p = 0.015) and Ct.th at the radius (0.16mm vs. 0.56mm; p = 0.033). Adolescents with persistent IgE-CMA had lower aBMD and compromised microarchitecture (impaired trabecular microarchitecture and lower bone strength). Adolescents on a partial exclusion diet had better bone parameters than those on a total exclusion diet.

Figure skaters typically have higher bone mineral density (BMD) than the general population. However, the current literature is limited to cross-sectional studies. The objective of this study was to determine two-year changes in volumetric BMD, bone microarchitecture, and estimated bone strength in elite national and development level Canadian figure skaters. Eleven female figure skaters aged 14+ years were recruited for this longitudinal study. Measurements occurred annually. High-resolution peripheral quantitative computed tomography (HR-pQCT) scans of the radius and tibia underwent three-dimensional image registration. Total (Tt), cortical (Ct) and trabecular (Tb) volumetric BMD (mg HA/cm3), trabecular thickness (TbTh, mm) and cortical thickness (CtTh, mm) were determined. Finite element analysis estimated bone strength. Linear mixed effects models with subject random intercept and time×level interaction evaluated the influence of TtBMD over two-years. Eleven figure skaters completed baseline and one-year data collection, and nine completed the two-year study. All skaters were included in our models and were either national (n=5, 18.6–28.1 years) or development (n=6; 14.4–17.7 years) athletes. Significant time-by-level status (development or national) interactions indicated increases over time in development level athletes only for TtBMD, CtBMD, CtTh and bone strength at the radius and TtBMD, TbBMD, TbTh and bone strength at the tibia (p<0.01 for all). Bone outcomes did not change significantly over the two years in national level figure skaters. Changes in bone density, microarchitecture and strength were only observed in the younger, development level athletes. Given the differences in age between development and national level figure skaters, these results are understandable.

Diabetes mellitus (T1DM) is associated with increased fracture risk that cannot be fully explained by traditional bone mineral density (BMD) measurements. Emerging evidence suggests that diabetes-induced alterations in bone microarchitecture, remodeling, and mechanoregulation contribute to skeletal fragility. However, the specific structural and functional changes in bone differ between T1DM and T2DM, and the mechanisms underlying these differences remain incompletely understood.Innovation in medical imaging and increasingly accessible computational power have made it possible to monitor changes in bone microarchitecture and measure the mechanical properties of bone via image-based finite element analysis. Moreover, longitudinal clinical studies have also shown that the combined use of high-resolution peripheral quantitative computed tomography (HR-pQCT) and micro-finite element analysis can be used to measure load-driven bone remodelling in vivo.This talk will present findings from a meta-analysis of high-resolution peripheral quantitative computed tomography (HR-pQCT) studies assessing diabetes-related differences in bone structure and a longitudinal cohort study, conducted with partners from the FIDELIO – Bone Health in Diabetes Innovative Training Network, examining bone remodeling and mechanoregulation in individuals with type 1 diabetes mellitus (T1DM).The meta-analysis synthesized data from 16 studies, encompassing 743 individuals with diabetes and 3,472 controls, to characterize the impact of T1DM and type 2 diabetes mellitus (T2DM) on bone microarchitecture. Results revealed that T1DM is predominantly associated with adverse trabecular characteristics, whereas T2DM is linked to cortical deficits, with more pronounced deterioration at the radius than at the weight-bearing tibia. These findings suggest that mechanical loading may mitigate some diabetes-associated skeletal changes, emphasizing the role of mechanoregulation in bone fragility.Complementing these insights, a four-year longitudinal cohort study investigated bone remodeling dynamics and responsiveness to mechanical stimuli in individuals with T1DM and diabetic neuropathy. By integrating HR-pQCT imaging with micro-finite element analysis, the study found that T1DM is characterized by lower trabecular bone formation (47% reduction) and resorption (59% reduction) compared to controls. Furthermore, impaired mechanoregulation was evidenced by a reduced likelihood of bone formation and resorption in response to mechanical strain, with these deficits correlating with nerve conduction amplitude and glycated hemoglobin levels.Together, these studies provide a mechanistic understanding of diabetes-associated skeletal fragility, highlighting distinct microarchitectural vulnerabilities in T1DM and T2DM and the role of neuropathy and metabolic control in bone remodeling.

High-resolution peripheral quantitative computed tomography (HR-pQCT) is a noninvasive imaging modality for assessing volumetric bone mineral density (vBMD) and microarchitecture of cancellous and cortical bone. The objective was to (1) assess fracture-associated differences in HR-pQCT bone parameters; and (2) to determine if HR-pQCT is sufficiently precise to reliably detect these differences in individuals. We systematically identified 40 studies that used HR-pQCT (39/40 used XtremeCT scanners) to assess 1291 to 3253 and 3389 to 10,687 individuals with and without fractures, respectively, ranging in age from 10.9 to 84.7 years with no comorbid conditions. Parameters describing radial and tibial bone density, microarchitecture, and strength were extracted and percentage differences between fracture and control subjects were estimated using a random effects meta-analysis. An additional meta-analysis of short-term in vivo reproducibility of bone parameters assessed by XtremeCT was conducted to determine whether fracture-associated differences exceeded the least significant change (LSC) required to discern measured differences from precision error. Radial and tibial HR-pQCT parameters, including failure load, were significantly altered in fracture subjects, with differences ranging from -2.6% (95% confidence interval [CI] -3.4 to -1.9) in radial cortical vBMD to -12.6% (95% CI -15.0 to -10.3) in radial trabecular vBMD. Fracture-associated differences reported by prospective studies were consistent with those from retrospective studies, indicating that HR-pQCT can predict incident fracture. Assessment of study quality, heterogeneity, and publication biases verified the validity of these findings. Finally, we demonstrated that fracture-associated deficits in total and trabecular vBMD and certain tibial cortical parameters can be reliably discerned from HR-pQCT-related precision error and can be used to detect fracture-associated differences in individual patients. Although differences in other HR-pQCT measures, including failure load, were significantly associated with fracture, improved reproducibility is needed to ensure reliable individual cross-sectional screening and longitudinal monitoring. In conclusion, our study supports the use of HR-pQCT in clinical fracture prediction. © 2019 American Society for Bone and Mineral Research.

Contra-lateral bone loss at the distal radius in postmenopausal women after a distal radius fracture: A two-year follow-up HRpQCT study

Accuracy and precision of segmentation and quantification of wrist bone microarchitecture using photon-counting computed tomography ex vivo.

The purpose of this study was to compare changes in bone density and microarchitecture in peri- and post-menopausal women over 6years. Peri- (n=26) and post- (n=65) menopausal women were selected from the Canadian Multicenter Osteoporosis Study. Caucasian women were scanned on dual x-ray absorptiometry (DXA) and high-resolution peripheral quantitative computed tomography (HR-pQCT) at baseline and follow-up, an average 6years later. To compare repeat scans, automated 3D image registration was conducted. At the radius and tibia, total volumetric BMD (Tt.BMD), total bone area (Tt.Ar) and cortical porosity (Ct.Po) were assessed, and finite element analysis estimated apparent bone strength. At the tibia, the rate of change for Ct.Po and Tt.Ar was different between groups. Peri-menopausal women had a+9% per year increase in Ct.Po, but this increase was slower for post-menopausal women at +6% per year (p=0.049). In addition, post-menopausal women had an increase in Tt.Ar of +0.13% per year compared with a slower increase of +0.06% per year for peri-menopausal women (p=0.017). The rate of change of density between groups was not significantly different and was approximately -1% per year at the hip by DXA, and -1% per year at the radius and -0.5% per year tibia by HR-pQCT. This is a 6-year prospective HR-pQCT study exploring rate of change in Caucasian peri- and post-menopausal women. The microarchitectural features represented by Ct.Po and Tt.Ar changed at a significantly different rate between groups, but group differences were not detected by density measures.

&lt;p dir="ltr"&gt;&lt;u&gt;Objective&lt;/u&gt;: To determine whether type 1 diabetes and its complications are associated with bone geometry and microarchitecture.&lt;/p&gt;&lt;p dir="ltr"&gt;&lt;u&gt;Research Design and Methods&lt;/u&gt;: Cross-sectional study embedded in a long-term observational study. High-resolution peripheral quantitative computed tomography (HR-pQCT) scans of distal radius and distal and diaphyseal tibia were performed in a subset of 183 type 1 diabetes participants from the Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications (DCCT/EDIC) and 94 controls without diabetes. HbA1c, skin advanced glycation end products (AGEs), and diabetes-related complications were assessed in EDIC participants with &gt;30 years of follow-up.&lt;/p&gt;&lt;p dir="ltr"&gt;&lt;u&gt;Results&lt;/u&gt;: Compared to controls (60±8 years-old, 65% female), EDIC participants (60±7 years-old, diabetes duration 38±5 years, 51% female) had lower total bone mineral density (BMD) at distal radius (-7.9%, 95%CI:(-15.2%,-0.6%), p=0.030) and distal tibia (-11.3%, 95%CI:(-18.5%,-4.2%), p=0.001); larger total area at all sites (distal radius +4.7%, 95%CI:(+0.5%,+8.8%), p=0.030; distal tibia +5.9%, 95%CI:(+2.1%,+9.8%), p=0.003; diaphyseal tibia +3.4%, 95%CI (+0.8%,+6.1%), p=0.011); and poorer radius trabecular and cortical microarchitecture. Estimated failure load was similar between two groups. Among EDIC, higher HbA1c, AGE and macroalbuminuria were associated with lower total BMD. Macroalbuminuria was associated with larger total area and lower cortical thickness at distal radius. Higher HbA1c and AGE, lower glomerular filtration rate, peripheral neuropathy and retinopathy were associated with deficits in trabecular microarchitecture.&lt;/p&gt;&lt;p dir="ltr"&gt;&lt;u&gt;Conclusions&lt;/u&gt;: Type 1 diabetes is associated with lower BMD, larger bone area and poorer trabecular microarchitecture. Among 1 diabetes, suboptimal glycemic control, AGE accumulation and microvascular complications are associated with deficits in bone microarchitecture and lower BMD.&lt;/p&gt;

BackgroundThe Patient-Rated Wrist Evaluation (PRWE) was developed as a wrist joint specific measure of pain and disability and evidence of sound validity has been accumulated through classical psychometric methods. Rasch analysis (RA) has been endorsed as a newer method for analyzing the clinical measurement properties of self-report outcome measures. The purpose of this study was to evaluate the PRWE using Rasch modeling.MethodsWe employed the Rasch model to assess overall fit, response scaling, individual item fit, differential item functioning (DIF), local dependency, unidimensionality and person separation index (PSI). A convenience sample of 382 patients with distal radius fracture was recruited from the hand and upper limb clinic at large academic healthcare organization, London, Ontario, Canada, 6-month post-injury scores of the PRWE was used. RA was conducted on the 3 subscales (pain, specific activities, and usual activities) of the PRWE separately.ResultsThe pain subscale adequately fit the Rasch model when item 4 “Pain - When it is at its worst” was deleted to eliminate non-uniform DIF by age group, and item 5 “How often do you have pain” was rescored by collapsing into 8 intervals to eliminate disordered thresholds. Uniform DIF for “Use my affected hand to push up from the chair” (by work status) and “Use bathroom tissue with my affected hand” (by injured hand) was addressed by splitting the items for analysis. After background rescoring of 2 items in pain subscale, 2 items in specific activities and 3 items in usual activities, all three subscales of the PRWE were well targeted and had high reliability (PSI = 0.86). These changes provided a unidimensional, interval-level scaled measure.ConclusionLike a previous analysis of the Patient-Rated Wrist and Hand Evaluation, this study found the PRWE could be fit to the Rasch model with rescoring of multiple items. However, the modifications required to achieve fit were not the same across studies, our fit statistics also suggested one of the pain items should be deleted. This study adds to the pool of evidence supporting the PRWE, but cannot confidently provide a Rasch-based scoring algorithm.

Responsiveness of the short form-36, disability of the arm, shoulder, and hand questionnaire, patient-rated wrist evaluation, and physical impairment measurements in evaluating recovery after a distal radius fracture.

BackgroundAnkylosing spondylitis (AS) is associated with high risk of fractures. BMD, bone microarchitecture and strength are negatively affected in AS. TNF inhibitors such as etanercept, adalimumab, golimumab and infliximab are...