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Vertebral fracture (VF) locations are bimodally distributed in the spine. The association between VF and bone attenuation (BA) measured on chest CT scans varied according to the location of VFs, indicating that other factors than only BA play a role in the bimodal distribution of VFs.INTRODUCTION: Vertebral fractures (VFs) are associated with low bone mineral density but are not equally distributed throughout the spine and occur most commonly at T7-T8 and T11-T12 ("cVFs") and less commonly at T4-T6 and T9-T10 ("lcVF"). We aimed to determine whether associations between bone attenuation (BA) and VFs vary between subjects with cVFs only, with lcVFs only and with both cVFs and lcVFs.METHODS: Chest CT images of T4-T12 in 1237 smokers with and without COPD were analysed for prevalent VFs according to the method described by Genant (11,133 vertebrae). BA (expressed in Hounsfield units) was measured in all non-fractured vertebrae (available for 10,489 vertebrae). Linear regression was used to compare mean BA, and logistic regression was used to estimate the association of BA with prevalent VFs (adjusted for age and sex).RESULTS: On vertebral level, the proportion of cVFs was significantly higher than of lcVF (5.6% vs 2.0%). Compared to subjects without VFs, BA was 15% lower in subjects with cVFs (p < 0.0001), 25% lower in subjects with lcVFs (p < 0.0001) and lowest in subjects with cVFs and lcVFs (- 32%, p < 0.0001). The highest ORs for presence of VFs per - 1SD BA per vertebra were found in subjects with both cVFs and lcVFs (3.8 to 4.6).CONCLUSIONS: The association between VFs and BA differed according to VF location. ORs increased from subjects with cVFs to subjects with lcVFs and were highest in subjects with cVFs and lcVFs, indicating that other factors than only BA play a role in the bimodal VF distribution.TRIAL REGISTRATION: Clinicaltrials.gov identifier: NCT00292552.

Vitamin D is an important factor in bone metabolism. Animal studies have shown a positive effect of vitamin D-3 supplementation on fracture healing, but evidence from clinical trials is inconclusive. A randomized controlled trial was performed to assess the effects of vitamin D-3 supplementation on fracture healing using HR-pQCT-based outcome parameters. Thirty-two postmenopausal women with a conservatively treated distal radius fracture were included within 2 weeks postfracture and randomized to a low-dose (N = 10) and a high-dose (N = 11) vitamin D intervention group receiving a 6-week bolus dose, equivalent to 700 and 1800 IU vitamin D-3 supplementation per day, respectively, in addition to a control group (N = 11) receiving no supplementation. After the baseline visit 1-2 weeks postfracture, follow-up visits were scheduled at 3-4, 6-8, and 12 weeks postfracture. At each visit, HR-pQCT scans of the fractured radius were performed. Cortical and trabecular bone density and microarchitectural parameters and microfinite element analysis-derived torsion, compression, and bending stiffness were assessed. Additionally, serum markers of bone resorption (CTX) and bone formation (PINP) were measured. Baseline serum levels of 25OHD(3) were

BACKGROUND: Computed tomography (CT), magnetic resonance imaging, and bone scintigraphy are second-line imaging techniques that are frequently used for the evaluation of patients with a clinically suspected scaphoid fracture. However, as a result of varying diagnostic performance results, no true reference standard exists for scaphoid fracture diagnosis. We hypothesized that the use of high-resolution peripheral quantitative CT (HR-pQCT) in patients with a clinically suspected scaphoid fracture could improve scaphoid fracture detection compared with conventional CT in the clinical setting.METHODS: The present study included 91 consecutive patients (≥18 years of age) who presented to the emergency department with a clinically suspected scaphoid fracture between December 2017 and October 2018. All patients were clinically reassessed within 14 days after first presentation, followed by CT and HR-pQCT. If a scaphoid fracture was present, the fracture type was determined according to the Herbert classification system and correlation between CT and HR-pQCT was estimated with use of the Kendall W statistic or coefficient of concordance (W) (the closer to 1, the higher the correlation).RESULTS: The cohort included 45 men and 46 women with a median age of 52 years (interquartile range, 29 to 67 years). HR-pQCT revealed a scaphoid fracture in 24 patients (26%), whereas CT revealed a scaphoid fracture in 15 patients (16%). Patients with a scaphoid fracture were younger and more often male. The correlation between CT and HR-pQCT was high for scaphoid fracture type according to the Herbert classification system (W = 0.793; 95% confidence interval [CI], 0.57 to 0.91; p < 0.001) and very high for scaphoid fracture location (W = 0.955; 95%, CI 0.90 to 0.98; p < 0.001).CONCLUSIONS: In the present study, the number of patients diagnosed with a scaphoid fracture was 60% higher when using HR-pQCT as compared with CT. These findings imply that a substantial proportion of fractures-in this study, more than one-third-will be missed by the current application of CT scanning in patients with a clinically suspected scaphoid fracture.LEVEL OF EVIDENCE: Diagnostic Level II. See Instructions for Authors for a complete description of levels of evidence.

INTRODUCTION: Diagnosing scaphoid fractures remains challenging. High-resolution peripheral quantitative computed tomography (HR-pQCT) might be a potential imaging technique, but no data are available on its feasibility to scan the scaphoid bone in vivo.METHODOLOGY: Patients (≥18 years) with a clinically suspected scaphoid fracture received an HR-pQCT scan of the scaphoid bone (three 10.2-mm stacks, 61-μm voxel size) with their wrist immobilized with a cast. Scan quality assessment and bone contouring were performed using methods originally developed for HR-pQCT scans of radius and tibia. The contouring algorithm was applied on coarse hand-drawn pre-contours of the scaphoid bone, and the resulting contours (AUTO) were manually corrected (sAUTO) when visually deviating from bone margins. Standard morphologic analyses were performed on the AUTO- and sAUTO-contoured bones.RESULTS: Ninety-one patients were scanned. Two out of the first five scans were repeated due to poor scan quality (40%) based on standard quality assessment during scanning, which decreased to three out of the next 86 scans (3.5%) when using an additional thumb cast. Nevertheless, after excluding one scan with an incompletely scanned scaphoid bone, post hoc grading revealed a poor quality in 14.9% of the stacks and 32.9% of the scans in the remaining 85 patients. After excluding two scans with contouring problems due to scan quality, bone indices obtained by AUTO- and sAUTO-contouring were compared in 83 scans. All AUTO-contours were manually corrected, resulting in significant but small differences in densitometric and trabecular indices (CONCLUSIONS: In vivo HR-pQCT scanning of the scaphoid bone is feasible in patients with a clinically suspected scaphoid fracture when using a cast with thumb part. The proportion of poor-quality stacks is similar to radius scans, and AUTO-contouring appears appropriate in good- and poor-quality scans . Thus, HR-pQCT may be promising for diagnosis of and microarchitectural evaluations in suspected scaphoid fractures.

Purpose As yet, there are no studies describing a relationship between radiographic subsidence after lumbar total disc replacement (TDR) and patient symptoms. To investigate if subsidence, in terms of penetrated bone volume or angular rotation over time (ΔPBV and ΔAR), is related to clinical outcome. To assess if subsidence can be predicted by position implant asymmetry (IA) or relative size of the TDR, areal undersizing index (AUI) on direct post-operative radiographs. Methods Retrospective cohort study consists of 209 consecutive patients with lumbar TDR for degenerative disc disease. A three-dimensional graphical representation of the implant in relation to the bony endplates was created on conventional radiographs. Consequently, the PBV, AR, IA and AUI were calculated, direct post-operative (DPO) and at last follow-up (LFU). For clinical evaluation, patients with substantial pain (VAS ≥ 50) and malfunction (ODI ≥ 40) were considered failures. Results At a mean follow-up of 16.7 years, 152 patients (73%) were available for analysis. In 32 patients, revision by spinal fusion had been performed. Both ΔAR (4.33° vs. 1.83°, p = 0.019) and ΔPBV (1448.4 mm3 vs. 747.3 mm3, p = 0.003) were significantly higher in the failure-compared to the success-group. Using ROC curves, thresholds for symptomatic subsidence were defined as ΔPBV ≥ 829 mm3 or PBV-LFU ≥ 1223 mm3 [area under the curve (AUC) 0.723, p = 0.003 and 0.724, p = 0.005, respectively]. Associations between symptomatic subsidence and AUI-DPO ≥ 0.50 (AUC 0.750, p = 0.002) and AR-DPO ≥ 3.95° (AUC 0.690, p = 0.022) were found. Conclusion Subsidence of a TDR is associated with a worse clinical outcome. The occurrence of subsidence is higher in case of incorrect placement or shape mismatch.

Improving the clinical outcome of scaphoid fractures may benefit from adequate monitoring of their healing in order to for example identify complications such as scaphoid nonunion at an early stage and to adjust the treatment strategy accordingly. However, quantitative assessment of the healing process is limited with current imaging modalities. In this study, high-resolution peripheral quantitative computed tomography (HR-pQCT) was used for the first time to assess the changes in bone density, microarchitecture, and strength during the healing of conservatively-treated scaphoid fractures. Thirteen patients with a scaphoid fracture (all confirmed on HR-pQCT and eleven on CT) received an HR-pQCT scan at baseline and three, six, twelve, and 26 weeks after first presentation at the emergency department. Bone mineral density (BMD) and trabecular microarchitecture of the scaphoid bone were quantified, and failure load (FL) was estimated using micro-finite element analysis. Longitudinal changes were evaluated with linear mixed-effects models. Data of two patients were excluded due to surgical intervention after the twelve-week follow-up visit. In the eleven fully evaluable patients, the fracture line became more apparent at 3 weeks. At 6 weeks, individual trabeculae at the fracture region became more difficult to identify and distinguish from neighboring trabeculae, and this phenomenon concerned a larger region around the fracture line at 12 weeks. Quantitative assessment showed that BMD and FL were significantly lower than baseline at all follow-up visits with the largest change from baseline at 6 weeks (-13.6% and -23.7%, respectively). BMD remained unchanged thereafter, while FL increased. Trabecular thickness decreased significantly from baseline at three (-3.9%), six (-6.7%), and twelve (-4.4%) weeks and trabecular number at six (-4.5%), twelve (-7.3%), and 26 (-7.9%) weeks. Trabecular separation was significantly higher than baseline at six (+13.3%), twelve (+19.7%), and 26 (+16.3%) weeks. To conclude, this explorative HR-pQCT study showed a substantial decrease in scaphoid BMD, Tb.Th, and FL during the first 6 weeks of healing of conservatively-treated scaphoid fractures, followed by stabilization or increase in these parameters. At 26 weeks, BMD, trabecular microarchitecture, and FL were not returned to baseline values. research foundation of VieCuri Medical Center Noord-Limburg, The Netherlands [NL62476.068.17]

In recent decades, an increasing number of tissue engineered bone grafts have been developed. However, expensive and laborious screenings in vivo are necessary to assess the safety and efficacy of their formulations. Rodents are the first choice for initial in vivo screens but their size limits the dimensions and number of the bone grafts that can be tested in orthotopic locations. Here, we report the development of a refined murine subcutaneous model for semi-orthotopic bone formation that allows the testing of up to four grafts per mouse one order of magnitude greater in volume than currently possible in mice. Crucially, these defects are also "critical size" and unable to heal within the timeframe of the study without intervention. The model is based on four bovine bone implants, ring-shaped, where the bone healing potential of distinct grafts can be evaluated in vivo. In this study we demonstrate that promotion and prevention of ossification can be assessed in our model. For this, we used a semi-automatic algorithm for longitudinal micro-CT image registration followed by histological analyses. Taken together, our data supports that this model is suitable as a platform for the real-time screening of bone formation, and provides the possibility to study bone resorption, osseointegration and vascularisation.

Summary This study developed a well-standardized and reproducible approach for micro-finite element (mFE) and homogenized-FE (hFE) analyses that can accurately predict the distal radius failure load using either mFE or hFE models when using the approaches and parameters developed in this study. Introduction Micro-FE analyses based on high-resolution peripheral quantitative CT (HR-pQCT) images are frequently used to predict distal radius failure load. With the introduction of a second-generation HR-pQCT device, however, the default modelling approach no longer provides accurate results. The aim of this study was to develop a well-standardized and reproducible approach for mFE and hFE analyses that can provide precise and accurate results for distal radius failure load predictions based on second-generation HR-pQCT images. Methods Second-generation HR-pQCT was used to scan the distal 20-mm section of 22 cadaver radii. The sections were excised and mechanically tested afterwards. For these sections, mFE and hFE models were made that were used to identify required material parameters by comparing predicted and measured results. Using these parameters, the models were cropped to represent the 10-mm region recommended for clinical studies to test their performance for failure load prediction. Results After identification of material parameters, the measured failure load of the 20-mm segments was in good agreement with the results of mFE models (R2 = 0.969, slope = 1.035) and hFE models (R2 = 0.966, slope = 0.890). When the models were restricted to the clinical region, mFE still accurately predicted the measured failure load (R2 = 0.955, slope = 1.021), while hFE predictions were precise but tended to overpredict the failure load (R2 = 0.952, slope = 0.780). Conclusions It was concluded that it is possible to accurately predict the distal radius failure load using either mFE or hFE models when using the approaches and parameters developed in this study. Electronic supplementary material The online version of this article (10.1007/s00198-019-04935-6) contains supplementary material, which is available to authorized users.

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

Introduction The aim of this study was to investigate the associations of patient characteristics, bone mineral density (BMD), bone microarchitecture and calculated bone strength with secondary displacement of a DRF based on radiographic alignment parameters. Materials and methods Dorsal angulation, radial inclination and ulnar variance were assessed on conventional radiographs of a cohort of 251 patients, 38 men and 213 women, to determine the anatomic position of the DRF at presentation (primary position) and during follow-up. Secondary fracture displacement was assessed in the non-operatively treated patients (N = 154) with an acceptable position, preceded (N = 97) or not preceded (N = 57) by primary reduction (baseline position). Additionally, bone microarchitecture and calculated bone strength at the contralateral distal radius and tibia were assessed by HR-pQCT in a subset of, respectively, 63 and 71 patients. Outcome Characteristics of patients with and without secondary fracture displacement did not differ. In the model with adjustment for primary reduction [OR 22.00 (2.27–212.86), p = 0.008], total [OR 0.16 (95% CI 0.04–0.68), p = 0.013] and cortical [OR 0.19 (95% CI 0.05–0.80], p = 0.024] volumetric BMD (vBMD) and cortical thickness [OR 0.13 (95% CI 0.02–0.74), p = 0.021] at the distal radius were associated with secondary DRF displacement. No associations were found for other patient characteristics, such as age gender, BMD or prevalent vertebral fractures. Conclusions In conclusion, our study indicates that besides primary reduction, cortical bone quality may be important for the risk of secondary displacement of DRFs.

Spinner flask bioreactors have often been employed for bone tissue engineering. However, the reasons for their success in facilitating bone growth remain inconclusive. It was hypothesised that engineered bone tissue formation can be attributed to mechanical stimuli, which can be predicted in the tissue engineered construct. To test the hypothesis and draw conclusions as to how mechanical stimulation affects cell behaviour, a multi- disciplinary approach using cell culture experiments and computational fluid dynamics (CFD) to simulate the complex flow within the spinner flask and scaffold was employed. Micro-computed tomography and histology showed that statically cultured human bone marrow derived stromal cells on silk fibroin scaffolds did not form extracellular matrix (ECM) or deposit minerals. However, constructs cultured at 60 rpm resulted in ECM formation and mineralisation, mainly at the bottom of the scaffold (bottom: 78 ± 7 %, middle: 17 ± 5 %, top: 5 ± 2 % of total mineralised volume). Culturing at 300 rpm led to a more homogeneously distributed ECM (bottom: 40 ± 14 %, middle: 33 ± 1 %, top: 27 ± 14 % of total mineralised volume). These observations were in agreement (Pearson correlation coefficient: 97 %) with the computational simulations that predicted maximal scaffold mineralisation, based on wall shear stress stimulation, in the bottom at 60 rpm and in the main body at 300 rpm. Such combinations of CFD modelling and experimentation could advance our knowledge of the mechanical stimuli that cells experience in vitro and link them to biological responses.

Identifying determinants of long-term functional outcome after a distal radius fracture is challenging. Previously, we reported on the association between early HR-pQCT measurements and clinical outcome 12 weeks after a conservatively treated distal radius fracture. We extended the follow-up and assessed functional outcome after two years in relation to early HR-pQCT derived bone parameters.HR-pQCT scans of the fracture region were performed in 15 postmenopausal women with a distal radius fracture at 1-2 (baseline), 3-4 weeks and 26 months post-fracture. Additionally, the contralateral distal radius was scanned at baseline. Bone density, micro-architecture parameters and bone stiffness using micro-finite element analysis (FEA) were evaluated. During all visits, wrist pain and function were assessed using the patient-rated wrist evaluation questionnaire (PRWE), quantifying functional outcome with a score between 0 and 100.Two-year PRWE was associated with torsional and bending stiffness 3-4 weeks post-fracture (R-2: 0.49, p = 0.006 and R-2: 0.54, p = 0.003, respectively). In contrast, early micro-architecture parameters of the fracture region or contralateral bone parameters did not show any association with long-term outcome.This exploratory study indicates that HR-pQCT with mu FEA performed within four weeks after a distal radius fracture captures biomechanical fracture characteristics that are associated with long-term functional outcome and therefore could be a valuable early outcome measure in clinical trials and clinical practice.

We evaluated the association between prevalent vertebral fractures and bone micro-architecture and strength measured using HR-pQCT in postmenopausal women with a recent non-vertebral fracture visiting the Fracture Liaison Service. The presence and severity of prevalent vertebral fracture reflect generalized bone deterioration. Introduction We evaluated the association between prevalent vertebral fractures (VFs) and bone micro-architecture and strength measured using HR-pQCT in postmenopausal women visiting the Fracture Liaison Service. Methods In this cross-sectional study in women aged 50-90 with a recent non-vertebral fracture (NVF), VFs were identified on lateral spine images by dual-energy X-ray absorptiometry. Bone micro-architecture and strength were measured at the non-dominant distal radius and distal tibia using HR-pQCT. Linear regression analyses were used to estimate the association between prevalent VFs and HR-pQCT parameters. Results We included 338 women of whom 74 (21.9%) women had at least one prevalent VF. After adjustment for femoral neck aBMD (FN aBMD) and other parameters, women with at least one prevalent vertebral fracture had significantly lower total and trabecular vBMD and trabecular number (beta - 16.7, - 11.8, and - 7.8 in the radius and - 21.4, - 16.6, and - 7.2 in the tibia, respectively), higher trabecular separation at the radius and tibia (beta 9.0 and 9.3, respectively), and lower cortical thickness and calculated ultimate failure load and compressive bone strength at the tibia (beta - 5.9, - 0.6, and - 10.9, respectively) as compared with those without prevalent VFs. Furthermore, more severe prevalent VFs were associated with even lower total and trabecular vBMD and lower ultimate failure load and compressive stiffness at the radius and tibia, and lower trabecular number and higher trabecular separation at the radius. Conclusion This study indicates that the presence and severity of prevalent VFs reflect generalized bone deterioration in women with a recent NVF, independently of FN aBMD. This study was supported by funding of the Weijerhorst Foundation.

ObjectivesThe purpose of the study was to prospectively investigate change (repair or progression) in the number, surface area and volume of cortical interruptions, bone density (vBMD) and micro-structural parameters assessed by high-resolution peripheral quantitative computed tomography (HR-pQCT) in finger joints of patients with rheumatoid arthritis (RA) treated with synthetic disease modifying anti-rheumatic drugs (sDMARDs) and/or biologic DMARDs (bDMARDs) over a 1-year follow-up period, and in comparison with healthy subjects (HS).MethodsThirty-two patients with RA (221 joints, 53% on bDMARDs) and 32 HS (117 joints) were assessed at baseline and after 1year using semi-automatic analysis of HR-pQCT images. Mean changes (group level) and the proportion of joints (joint level) with changes beyond the least significant change were calculated.ResultsAt baseline, 530 interruptions were identified in patients, and 136 in HS. The mean of the interruption parameters did not significantly change in either group Mean vBMD decreased more in patients than in HS (-4.4 versus -1.1 mgHA/cm(3), respectively). In patients versus HS, proportionally more joints showed repair in interruption volume (6.6% versus 1.7%, respectively) and loss of vBMD (26.7% versus 12.9%, respectively). In patients on sDMARDs versus patients on bDMARDs, proportionally more joints showed progression in the number of interruptions and loss of vBMD (6.1% versus 1.8% and 31.3% versus 17.2%, respectively).ConclusionsHR-pQCT is able to quantify bone repair and progression. Cortical interruption-, vBMD-, and micro-structure were impaired in RA, of which vBMD and micro-structure further deteriorated, particularly in patients on sDMARDs. The study is supported by unrestricted grants from the Weijerhorst foundation (WH-2) and Pfizer (WS2056904).

Objectives: To study the relationship between structural damage and inflammatory features on magnetic resonance imaging (MRI) or radiography and other risk factors [anti-citrullinated protein antibody (ACPA) and/or rheumatoid factor (RF) seropositivity, hand dominance, disease duration] and the presence or number of cortical interruptions in finger joints on high-resolution peripheral quantitative computed tomography (HR-pQCT). Method: Finger joints of 38 healthy subjects and 39 patients with rheumatoid arthritis (RA) were examined through radiographs, MRI, and HR-pQCT. Radiographs were scored according to the Sharp/van der Heijde (SvH) method; MRI for the presence of cortical interruptions, bone marrow oedema (BMO), and synovitis; and HR-pQCT images for cortical interruptions. Descriptive statistics were calculated and associations examined using generalized estimating equations. Results: Cortical interruptions were found in healthy subjects and patients with RA on HR-pQCT (mean +/- sd 0.33 +/- 0.63 vs 0.38 +/- 0.64 per joint quadrant, respectively, p < 0.01). Structural damage on MRI (cortical interruptions) or radiographs (SvH >= 1) was associated with the presence of cortical interruptions on HR-pQCT [odds ratio (OR) 12.4, 95% confidence interval (CI) 7.5-21.4, p < 0.01 and OR 4.8, 95% CI 1.9-11.7, respectively, p < 0.01]. The presence of BMO or synovitis was associated with more cortical interruptions on HR-pQCT (beta 0.47, 95% CI 0.4-0.6, p < 0.01 and beta 1.9, 95% CI 0.6-3.1, p < 0.01). In patients with RA, ACPA, and/or RF seropositivity, hand dominance and disease duration were not associated with more cortical interruptions on HR-pQCT. Conclusion: Structural damage and inflammatory features on MRI and radiographs are associated with cortical interruptions on HR-pQCT. No association between other risk factors and cortical interruptions was demonstrated. This study was funded by an unrestricted grant from Pfizer and the Weijerhorst Foundation.

A longitudinal analysis of bone microstructure in postmenopausal women of the Geneva Retirees Cohort indicates that age-related cortical bone loss is attenuated at non-bearing bone sites in fermented dairy products consumers, not in milk or ripened cheese consumers, independently of total energy, calcium, or protein intakes.INTRODUCTION: Fermented dairy products (FDP), including yogurts, provide calcium, phosphorus, and proteins together with prebiotics and probiotics, all being potentially beneficial for bone. In this prospective cohort study, we investigated whether FDP, milk, or ripened cheese consumptions influence age-related changes of bone mineral density (BMD) and microstructure.METHODS: Dietary intakes were assessed at baseline and after 3.0 ± 0.5 years with a food frequency questionnaire in 482 postmenopausal women enrolled in the Geneva Retirees Cohort. Cortical (Ct) and trabecular (Tb) volumetric (v) BMD and microstructure at the distal radius and tibia were assessed by high-resolution peripheral quantitative computerized tomography, in addition to areal (a) BMD and body composition by dual-energy X-ray absorptiometry, at the same time points.RESULTS: At baseline, FDP consumers had lower abdominal fat mass and larger bone size at the radius and tibia. Parathyroid hormone and β-carboxyterminal cross-linked telopeptide of type I collagen levels were inversely correlated with FDP consumption. In the longitudinal analysis, FDP consumption (mean of the two assessments) was associated with attenuated loss of radius total vBMD and of Ct vBMD, area, and thickness. There was no difference in aBMD and at the tibia. These associations were independent of total energy, calcium, or protein intakes. For other dairy products categories, only milk consumption was associated with lower decrease of aBMD and of failure load at the radius.CONCLUSION: In this prospective cohort of healthy postmenopausal women, age-related Ct bone loss was attenuated at non-bearing bone sites in FDP consumers, not in milk or ripened cheese consumers, independently of total energy, calcium, or protein intakes.STUDY REGISTRATION: ISRCTN11865958 ( http://www.isrctn.com ).

Background Preservation, repair and progression of cortical interruptions in finger joints has been observed in RA using conventional radiography, MRI, ultrasound and high-resolution peripheral quantitative computed tomography (HR-pQCT). Accurate and quantitative information about such changes over time, however, is still lacking. Objectives To evaluate changes over one year in cortical interruptions (number, surface area and volume), bone density (vBMD) and micro-structural parameters from HR-pQCT scans of finger joints in RA and healthy subjects (HS) using a recently developed semi-automatic algorithm for cortical interruptions detection.1 Methods Baseline and 1 year follow up HR-pQCT scans of finger joints of 32 patients with RA (221 joints, 53% on biologic DMARDSs (bDMARDs)) and 32 HS (117 joints) were analysed for changes in cortical interruption, density and morphological parameters. Mean changes (at the group level) and proportions of joints (at the joint level) with changes beyond least significant changes were calculated after correction for baseline damage. Results At baseline, 530 interruptions (3.25/joint) were identified in RA, and 136 (1.45/joint) in HS. The mean of the interruption parameters did not change in either group, except for a significant increase in number of interruptions in PIP joints in RA. However, the proportion of joints showing repair in interruption volume was higher in RA than in HS (6.6% versus 1.7%, p=0.041). Changes in cortical interruption parameters were negatively correlated with changes in cortical BMD and thickness (p Conclusions Using HR-pQCT based semi-automatic cortical interruption analysis a large number of interruptions was identified in RA and HS. Cortical interruptions, vBMD and micro-structural parameters were more impaired in RA, of which vBMD and micro-structural parameters further deteriorated. Patients on sDMARDs had more joints with progression in number of interruptions and more loss of vBMD compared to bDMARDs. Reference [1] Peters M, Scharmga A, de Jong J, van Tubergen A, Geusens P, Arts JJ, Loeffen D, Weijers R, van Rietbergen B, van den Bergh J. An automated algorithm for the detection of cortical interruptions on high resolution peripheral quantitative computed tomography images of finger joints. PLoS One2017Apr 20;12(4):e0175829. Disclosure of Interest None declared

Background: We developed a semi-automated algorithm that detects cortical interruptions in finger joints using high-resolution peripheral quantitative computed tomography (HR-pQCT), and extended it with trabecular void volume measurement In this study we tested the reproducibility of the algorithm using scan/re-scan data. Methods: Second and third metacarpophalangeal joints of 21 subjects (mean age 49 (SD 11) years, 17 early rheumatoid arthritis and 4 undifferentiated arthritis, all diagnosed < 1 year ago) were imaged twice by HR-pQCT on the same day with repositioning between scans. The images were analyzed twice by one operator (OP1) and once by an additional operator (OP2), who independently corrected the bone contours when necessary. The number, surface and volume of interruptions per joint were obtained. Intra- and inter-operator reliability and intra-operator reproducibility were determined by intra-class correlation coefficients (ICC). Intra-operator reproducibility errors were determined as the least significant change (LSCSD). Results: Per joint, the mean number of interruptions was 3.1 (SD 3.6), mean interruption surface 4.2 (SD 7.2) mm(2), and mean interruption volume 3.5 (SD 10.6) mm(3) for OP1. Intra- and inter-operator reliability was excellent for the cortical interruption parameters (ICC >= 0.91), except good for the inter-operator reliability of the interruption surface (ICC >= 0.70). The LSCSD per joint was 4.2 for the number of interruptions, 5.8 mm(2) for interruption surface, and 3. 2 mm(3) for interruption volume. Conclusions: The algorithm was highly reproducible in the detection of cortical interruptions and their volume. Based on the LSC findings, the potential value of this algorithm for monitoring structural damage in the joints in early arthritis patients needs to be tested in clinical studies. The study is supported by unrestricted grants from the Weijerhorst foundation (WH-2) and Pfizer (WS2056904). The funders had no role in the design of the study, the collection, analysis and interpretation of the data, and in writing the manuscript.

Intra- and inter-operator reliability of the cortical interruption parameters. Table with the intra- and inter-operator reliability of the cortical interruption parameters. Values are as value (95% Confidence Interval) ICC, intra-class correlation coefficient; SDRMS, root mean square of the standard deviation; LSCSD, absolute least significant change (DOCX 20Â kb)

Background In clinical practice, clubfeet feel stiffer compared to healthy feet. Furthermore, the clinical impression is that stiffer clubfeet have a higher tendency to relapse. Until now, no objective measure has been available to determine the stiffness of clubfeet. The goal of the current project was to objectively quantify ankle and subtalar joint stiffness in clubfeet patients and to compare this stiffness between clubfeet patients and healthy controls using a newly developed measurement device. Methods The newly developed Torque-Displacement-Handpiece in combination with an adjusted Abduction Dorsiflexion Mechanism clubfoot-brace, made it possible to move a foot over two rotational axis, while continuously capturing the applied torque and the achieved angulation. Based on this information, stiffness of the ankle and subtalar joint were assessed for 11 clubfoot patients with 17 clubfeet and 11 healthy subjects with 22 healthy feet. Findings With the Torque-Displacement-Handpiece measuring device it was possible to measure torque, angulation and stiffness in a reliable and precise manner. Clubfoot patients showed less angulation and a higher stiffness for measurements over the ADM subtalar axis compared to controls. After adjusting for shoe size, the stiffness for measurements over the ADM tibiotalar axis was also significantly higher in clubfeet than controls. Interpretation Overall, these results indicate that clubfoot patients have a higher ankle and subtalar joint stiffness in the affected joint compared to healthy controls. In the future, the Torque-Displacement-Handpiece could be used to monitor stiffness of clubfeet during treatment, and as such, play a potential role in the early detection of relapsing clubfeet.

To improve the handling properties of S53P4 bioactive glass granules for clinical applications, bioactive glass putty formulations were developed. These formulations contain both granules and a synthetic binder to form an injectable material that is easy to shape. To explore its applicability in load-bearing bone defect grafting, the relation between the putty composition and its mechanical behaviour was assessed in this study. Five putty formulations with variations in synthetic binder and granule content were mechanically tested in confined compression. The results showed that the impaction strains significantly decreased and the residual strains significantly increased with an increasing binder content. The stiffness of all tested formulations was found to be in the same range as the reported stiffness of cancellous bone. The measured creep strains were low and no significant differences between formulations were observed. The stiffness significantly increased when the samples were subjected to a second loading stage. The residual strains calculated from this second loading stage were also significantly different from the first loading stage, showing an increasing difference with an increasing binder content. Since residual strains are detrimental for graft layer stability in load-bearing defects, putty compositions with a low binder content would be most beneficial for confined, load-bearing bone defect grafting.

Objectives To introduce a fully-automated algorithm for the detection of small cortical interruptions (>= 0.246mm in diameter) on high resolution peripheral quantitative computed tomography (HR-pQCT) images, and to investigate the additional value of manual correction of the automatically obtained contours (semi-automated procedure). Methods Ten metacarpophalangeal joints from seven patients with rheumatoid arthritis (RA) and three healthy controls were imaged with HR-pQCT. The images were evaluated by an algorithm according to the fully-and semi-automated procedure for the number and surface of interruptions per joint. Reliability between the fully-and semi-automated procedure and between two independent operators was tested using intra-class correlation coefficient (ICC) and the proportion of matching interruptions. Validity of single interruptions detected was tested by comparing it to visual scoring, as gold standard. The positive predictive value (PPV) and sensitivity were calculated. Results The median number of interruptions per joint was 14 (range 2 to 59) and did not significantly differ between the fully-and semi-automated procedure (p = 0.37). The median interruption surface per joint was significantly higher with the fully-vs. semi-automated procedure (respectively, 8.6mm(2) vs. 5.8mm(2) and 6.1mm(2), p = 0.01). Reliability was almost perfect between the fully-and semi-automated procedure for both the number and surface of interruptions (ICC >= 0.95) and the proportion of matching interruptions was high (>= 76%). Also the inter-operator reliability was almost perfect (ICC >= 0.97, proportion of matching interruptions 92%). The PPV ranged from 27.6% to 29.9%, and sensitivity from 69.7% to 76.3%. Most interruptions detected with the algorithm, did show an interruption on a 2D grayscale image. However, this interruption did not meet the criteria of an interruption with visual scoring. Conclusion The algorithm for HR-pQCT images detects cortical interruptions, and its interruption surface. Reliability and validity was comparable for the fully- and semi-automated procedures. However, we advise the use of the semi-automated procedure to assure quality. The algorithm is a promising tool for a sensitive and objective assessment of cortical interruptions in finger joints assessed by HR-pQCT. This work was supported by: Weijerhorst Foundation (JvdB), http//www.deweijerhorst.nl/ weijerhorst/home. funding that was used to purchase the HR-pQCT scanner and pay half of the PhD student salaries of MP and AS. It was also supported by Pfizer (PG), grant number: WS2056904, http//www.pfizer.nl/. This funding was used to perform our study (NL42300.068.12 / METC 12-2-037) of HR-pQCT imaging in patients with RA compared to conventional imaging techniques.

Many studies have reported on the effects of cyclooxygenase-2 (COX-2) inhibition on osteogenesis. However, far less is known about the effects of COX-2 inhibition on chondrogenic differentiation. Previous studies conducted by our group show that COX-2 inhibition influences in vitro chondrogenic differentiation. Importantly, this might have consequences on endochondral ossification processes occurring in vivo, such as bone fracture healing, growth plate development and ectopic generation of cartilage. The goal of our study was to investigate, in vivo, the effect of COX-2 inhibition by celecoxib on the cartilaginous phase of three different endochondral ossification scenarios.10 mg/kg/d celecoxib or placebo were orally administered for 25 d to skeletally-immature New Zealand White rabbits (n = 6 per group). Endochondral ossification during fracture healing of a non-critical size defect in the ulna, femoral growth plate and ectopically-induced cartilaginous tissue were examined by radiography, micro-computed tomography (mu-CT), histology and gene expression analysis.Celecoxib treatment resulted in delayed bone fracture healing, alterations in growth plate development and progression of mineralisation. In addition, chondrogenic differentiation of ectopically-induced cartilaginous tissue was severely impaired by celecoxib. In conclusion, we found that celecoxib impaired the chondrogenic phase of endochondral ossification.

Objectives The objective of this study is to determine in healthy premenopausal women with a history of fracture which bone structural components of the distal radius are the most closely associated with a risk of fracture. Methods and participants The method was as follows: measurement of radial areal bone mineral density (aBMD) by DXA, microstructural components by high-resolution quantitative peripheral computerized tomography (HR-pQCT) and strength variables by micro Finite Element Analysis (µFEA) in 196 healthy premenopausal women aged 45.9 ± 3.7 (± SD) years with (FX, n = 96) and without (NO-FX, n = 100) a history of fracture. We evaluated differences in T-scores between FX and NO-FX and risk of fracture by Odds ratios (OR with 95% confidence intervals, CI) per one SD decrease, using logistic regression analysis after adjustment for age, height, weight, menarcheal age, calcium and protein intakes, and physical activity. Results In the whole group the mean radial metaphysis aBMD T-score was not significantly different from zero. In the FX as compared to the NO-FX group, the differences in T-scores were as follows: for radial metaphysis: aBMD, - 0.24 (P = 0.005); for distal radius microstructure components: cortical volumetric BMD, - 0.38 (P = 0.0009); cortical thickness, - 0.37 (P = 0.0001); cross-sectional area (CSA), + 0.24 (P = 0.034); and endosteal perimeter, + 0.28 (P = 0.032); and for strength estimates: stiffness, - 0.15 (P = 0.030); failure load, - 0.14 (P = 0.044); and apparent modulus, - 0.28 (P = 0.006). T-scores of trabecular volumetric BMD and thickness did not significantly differ between the FX and the NO-FX group. Accordingly, the risk of fracture (OR, 95% CI) for 1 SD decrease in radius bone parameters was as follows: radial metaphysis aBMD: 1.70 (1.18–2.44), P = 0.004; cortical volumetric BMD: 1.86 (1.28–2.71), P = 0.001; and cortical thickness: 2.36 (1.53–3.63), P = 0.0001. The corresponding fracture risk for the strength estimates was as follows: stiffness: 1.66 (1.06–2.61), P = 0.028; failure load: 1.59 (1.02–2.47), P = 0.041; and apparent modulus: 1.76 (1.17–2.64), P = 0.006. Conclusions In healthy premenopausal women, a history of fracture is associated with reduced T-scores in the distal radius, with the cortical components showing the greatest deficit. A reduction of one SD in cortical thickness is associated with a nearly three-fold increased risk of fracture. This finding strengthens the notion that, in healthy women, a certain degree of bone structural fragility contributes to fractures before the menopause and therefore should be taken into consideration in the individual prevention strategy of postmenopausal osteoporosis. Keywords : Healthy premenopausal women; Fracture risk; Areal and volumetric BMD; Microstructure; HR-pQCT; Bone strength

The two main load bearing tissues of the intervertebral disc are the nucleus pulposus and the annulus fibrosus. Both tissues are composed of the same basic components, but differ in their organization and relative amounts. With degeneration, the clear distinction between the two tissues disappears. The changes in biochemical content lead to changes in mechanical behaviour of the intervertebral disc. The aim of the current study was to investigate if well-documented moderate degeneration at the biochemical and fibre structure level leads to instability of the lumbar spine. By taking into account biochemical and ultrastructural changes to the extracellular matrix of degenerating discs, a set of constitutive material parameters were determined that described the individual tissue behaviour. These tissue biomechanical models were then used to simulate dynamic behaviour of the degenerated spinal motion segment, which showed instability in axial rotation, while a stabilizing effect in the other two principle bending directions. When a shear load was applied to the degenerated spinal motion segment, no sign of instability was found. This study found that reported changes to the nucleus pulposus and annulus fibrosus matrix during moderate degeneration lead to a more stable spinal motion segment and that such biomechanical considerations should be incorporated into the general pathophysiological understanding of disc degeneration and how its progress could affect low back pain and its treatments thereof.

Introduction: Bioactive glass (BAG) has been studied widely and seems to be a very promising biomaterial in regeneration of large bone defects and osteomyelitis treatment, because of its bone bonding and antibacterial properties[1]-[5]. Its high stiffness could potentially also enable mechanical reinforcement of large defects. The loose-granular nature of this material, however, makes it difficult to handle by the surgeon. Moreover, in previous research we found only sub-optimal mechanical properties for pure BAG fillings[6]. Recently a BAG putty was developed that is easier to handle. The aim of the current study is to determine the mechanical properties of this putty and its dependence on composition. Materials and Methods: Five different compositions of S53P4 putty were tested in mechanical confined compression tests, after impaction of the samples (n=5 per group). The putty materials all consist of a synthetic binder (matrix: 20 wt% PEG 400, 40 wt% PEG 1500, 15 wt% PEG 3000 and 25 wt% glycerol), BAG granules (2.0-3.15 mm) and BAG powder (300-500 µm). Impaction was performed with the use of a custom-made impaction device (providing clinical relevant strains)[7]. After the samples were equally confined in PMMA chambers, they were subjected to 900 cycles of loading (40 – 850 N) followed by 300 s of rest. From the recorded displacement – time curves, the Young’s Modulus (elastic behaviour), plastic strains (permanent deformations) and creep strains (viscous behaviour) were determined and compared for the five compositions[7],[8]. Results and discussion: The results for impactability (measure for the height difference before and after impaction), Young’s Moduli, creep and plastic strain are shown in Figure 2. Significant differences between the putty compositions were found only for impactability and plastic strain. With an increasing amount of matrix the impactability decreases significantly. It has to be noted that the overall impactability is low, compared to graft materials such as morsellized cancellous bone or porous titanium[6],[7]. However, these materials are much less mouldable than the putty materials. The Young’s moduli of all putty compositions were found to be in range of the modulus of cancellous bone (100-500 MPa), which is the desired range[9]. Furthermore, creep strains were low, which indicate that viscous behaviour will not likely affect the graft layer stability. The plastic strain increases with larger matrix content. Such plastic strain can threaten the graft stability in load-bearing applications and thus should be kept low. Conclusion: For load bearing sites where the putty can be well confined in the defect, putty compositions with the low amount of matrix could be beneficial since their plastic strains are lowest. In other situations, the compositions with more matrix would be preferred because they are easier to handle.

2 × 2 contingency tables. 2 × 2 contingency tables for Reader 1 (all joints and MCP and PIP separately) and Reader 2 (all joints and MCP and PIP joints separately). (DOCX 17 kb)

Introduction: Bioactive glass (BAG) has been studied widely and seems to be a very promising biomaterial in regeneration of large bone defects and osteomyelitis treatment, because of its bone bonding and antibacterial properties[1]-[5]. Potentially, it could also mechanically reinforce large defects, thus making it suitable for load-bearing applications. However, the mechanical properties of the reconstructive layer and its dependence on BAG:bone allograft mixture composition are unknown. In this study, we measured the mechanical properties of different impacted BAG/bone graft mixtures. Then these properties were used in micro-Finite Element (FE) patient-specific models to investigate whether these mixtures could restore mechanical properties of large bone defects.Materials and Methods: Five different S53P4 BAG/bone graft mixtures were impacted in a cylindrical holder, mechanically tested in confined compression and scanned with micro-CT. From these images, the mixture was identified by its three phases: bone, glass or interface region. Micro-Finite-Element (FE) models of the composites were made using a Young’s modulus of 2.5 GPa for bone and 35 GPa for BAG. The Young’s modulus for the interface region was determined by fitting experimental and micro-FE results for the same specimens.High-Resolution peripheral quantitative CT scans of a 9 mm region of the distal tibia of seven subjects were used for studying the reinforcement potential. Micro-FE models of this region were made to determine its stiffness in the original state, with a simulated cortical defect, and after that a mixture of BAG/bone or BAG alone was simulated in the defect.Results: The confined compression tests showed a strong dependence of the Young’s modulus of the BAG/bone composite on the amount of BAG, ranging from 116.7±18.2 to 654.2±35.2 MPa. The micro-FE results could fairly reproduce these measured moduli, when using a stiffness of 25 MPa for the interface layer (R2=0.678, see Figure 1).

Summary: End-stage renal disease (ESRD) patients have a high risk of fractures. We evaluated bone microstructure and finite-element analysis-estimated strength and stiffness in patients with ESRD by high-resolution peripheral computed tomography. We observed an alteration of cortical and trabecular bone microstructure and of bone strength and stiffness in ESRD patients. Introduction: Fragility fractures are common in ESRD patients on dialysis. Alterations of bone microstructure contribute to skeletal fragility, independently of areal bone mineral density. Methods: We compared microstructure and finite-element analysis estimates of strength and stiffness by high-resolution peripheral quantitative computed tomography (HR-pQCT) in 33 ESRD patients on dialysis (17 females and 16 males; mean age, 47.0 ± 12.6years) and 33 age-matched healthy controls. Results: Dialyzed women had lower radius and tibia cortical density with higher radius cortical porosity and lower tibia cortical thickness, compared to controls. Radius trabecular number was lower with higher heterogeneity of the trabecular network. Male patients displayed only a lower radius cortical density. Radius and tibia cortical thickness correlated negatively with bone-specific alkaline phosphatase (BALP). Microstructure did not correlate with parathyroid hormone (PTH) levels. Cortical porosity correlated positively with "Kidney Disease: Improving Global Outcomes” working group PTH level categories (r = 0.36, p

Summary: Using in vivo microcomputed tomography (micro-CT), we found in parathyroid hormone (PTH)-treated osteopenic rats linear increases in cortical and trabecular, due to increased trabecular thickness and number, bone mass. Bone was formed in cavities, leading to restoral of nearly cleaved trabeculae. For the first time, effects in PTH-treated rats were analyzed longitudinally. Introduction: Our aims were to over time (1) determine changes in trabecular thickness and number after PTH, (2) compare responses to PTH between the meta- and epiphysis, (3) determine effects of PTH on mineralization and mechanical properties, (4) determine locations of new bone formation due to PTH on a microlevel, and (5) determine the predictive value of bone structural properties for gain in bone mass after PTH. Methods: Adult rats were divided into ovariectomy (OVX; n = 8), SHAM-OVX (n = 8), and OVX and PTH treatment (n = 9). Between weeks 8 and 14, PTH rats received daily subcutaneous PTH injections (60 µg/kg/day). At weeks 0, 8, 10, 12, and 14, in vivo micro-CT scans were made of the proximal and diaphyseal tibia. After sacrifice, all tibiae were tested in three-point bending. Results: PTH increased bone volume fraction linearly over time in meta- and epiphysis, accompanied by increased trabecular thickness in both and increased trabecular number only in the latter one. CT-estimated mineralization increased in trabecular and remained constant in cortical bone. Ultimate load and energy were increased and ultimate displacement and stiffness unaltered compared to SHAM rats. For those trabeculae analyzed, bone was formed initially on places where it was most beneficial for increasing their strength and later on to all surfaces. © 2009 The Author(s).

Micro-finite element (micro-FE) analysis became a standard tool for the evaluation of trabecular bone mechanical properties. The accuracy of micro-FE models for linear analyses is well established. However, the accuracy of recently developed nonlinear micro-FE models for simulations of trabecular bone failure is not known. In this study, a trabecular bone specimen was compressed beyond the apparent yield point. The experiment was simulated using different micro-FE meshes with different element sizes and types, and material models based on cortical bone. The results from the simulations were compared with experimental results to study the effects of the different element and material models. It was found that a decrease in element size from 80 to 40 mum had little effect on predicted post-yield behaviour. Element type and material model had significant effects. Nevertheless, none of the established material models for cortical bone were able to predict the typical descent in the load-displacement curve seen during compression of trabecular bone.

Trabecular bone strength is marked not only by the onset of local yielding, but also by post-yield behavior. To study and predict trabecular bone elastic and yield properties, micro-finite element (micro-FE) models were successfully applied. However, trabecular bone strength predictions require micro-FE models incorporating post-yield behavior of trabecular bone tissue. Due to experimental difficulties, such data is currently not available. Here we used micro-FE modeling to determine failure behavior of trabecular bone tissue indirectly, by iteratively fitting FE simulation to experimental results. Failure parameters were fitted to an isotropic plasticity model based on Hill's yield function, using materially and geometrically nonlinear micro-FE models of seven bovine trabecular bone specimens. The predictive value of the averaged effective tissue properties was subsequently tested. The results showed that compression softening had to be included on the tissue level in order to accurately describe the apparent-level behavior of the bone specimens. A sensitivity study revealed that the simulated response was less sensitive to variations in the post-yield properties of the bone tissue than variations in the elastic and yield properties. Due to fitting of the tissue properties, apparent-level behavior could be accurately reproduced for each specimen separately. Predictions based on the averaged and fixed tissue properties were less accurate, due to inter-specimen variations in the tissue properties.

Due to remodeling of bone architecture, an optimal structure is created that minimizes bone mass and maximizes strength. In the case of osteoporotic vertebral bodies, however, this process can create over-adaptation, making them vulnerable for non-habitual loads. In a recent study, micro-finite element models of a healthy and an osteoporotic human proximal femur were analyzed for the stance phase of gait. In the present study, tissue stresses and strains were calculated with the same proximal femur micro-finite element models for a simulated fall to the side onto the greater trochanter. Our specific objectives were to determine the contribution of trabecular bone to the strength of the proximal femurs for this non-habitual load. Further, we tested the hypothesis that the trabecular structure of osteoporotic bone is over-adapted to habitual loads. For that purpose, we calculated the load distributions and estimated the apparent yield and ultimate loads from linear analyses. Two different methods were used for this purpose, which resulted in very similar values, all in a realistic range. Distributions of maximal principal strain and effective strain in the entire model suggest that the contributions to bone strength of the trabecular and cortical structures are similar. However, a thick cortical shell is preferred over a dense trabecular core in the femoral neck. When the load applied to the osteoporotic femur was reduced to approximately 61% of the original value, strain distributions were created similar in value to those obtained for the healthy femur. Since a comparable reduction factor was found for habitual load cases, it was concluded that the osteoporotic femur was not ‘over-adapted’.

Nowadays, S53P4 bioactive glass is indicated as a bone graft substitute in various clinical applications. This review provides an overview of the current published clinical results on indications such as craniofacial procedures, grafting of benign bone tumour defects, instrumental spondylodesis, and the treatment of osteomyelitis. Given the reported results that are based on examinations, such as clinical examinations by the surgeons, radiographs, CT, and MRI images, S53P4 bioactive glass may be beneficial in the various reported applications. Especially in craniofacial reconstructions like mastoid obliteration and orbital floor reconstructions, in grafting bone tumour defects, and in the treatment of osteomyelitis very promising results are obtained. Randomized clinical trials need to be performed in order to determine whether bioactive glass would be able to replace the current golden standard of autologous bone usage or with the use of antibiotic containing PMMA beads (in the case of osteomyelitis)., BioMed Research International, 2015, ISSN:2314-6133, ISSN:2314-6141

It is widely believed that mechanical forces affect trabecular bone structure and orientation. The cellular mechanisms involved in this relationship, however, are poorly understood. In earlier work we developed a theoretical, computational framework, coupling bone-cell metabolic expressions to the local mechanical effects of external bone loading. This theory is based on the assumption that osteocytes within the bone tissue control the recruitment of bone-resorbing osteoclasts and bone-forming osteoblasts, by sending strain-energy-density (SED) related signals to trabecular surfaces through the osteocytic, canalicular network. The theory explains the known morphological effects of external bone-loading variations in magnitude and frequency. It also explains the development of osteoporosis, as an effect of increased osteoclast resorption due to estrogen deficiency in postmenopausal women, and to reduced physical activity levels in general. However, the theory uses lumped variables to represent the mechanisms of osteocyte mechano-sensing and signaling. The question is whether these mechanisms could not be specified in a more realistic way. On the one hand, anabolic osteocyte signals might be triggered by the local mechanical loading variables they experience directly, as we assumed in our original theory. On the other hand, osteocyte signals might be triggered by fluid flow in the osteocytic network at large, as was suggested by others. For that purpose we compared the effects of SED, maximal principal strain and volumetric strain as representing local loading variables, to their spatial gradients on the morphological predictions of our computational model. We found that, in concept, they all produced reasonable trabecular structures. However, the predicted trabecular morphologies based on SED as the triggering variable were more realistic in dimensions and relevant metabolic parameters.

A three-dimensional digital image correlation technique is presented for strain measurements in open-cell structures such as trabecular bone. The technique uses high-resolution computed tomography images for displacement measurements in the solid structure. In order to determine the local strain-state within single trabeculae, a tetrahedronization method is used to fill the solid structure with tetrahedrae. Displacements are calculated at the nodes of the tetrahedrae. The displacement data is subsequently converted to a deformation tensor in each of the tetrahedral element centers with a least-squares estimation method. Because the trabeculae are represented by a mesh, it is possible to deform this mesh according to the deformation tensor and, at the same time, visualize the calculated local strain in the deformed mesh with a finite element post-processing tool. In this way, the deformation of a single trabecula from an aluminum foam sample was determined and validated with rendered images of the three-dimensional sample. A precision analysis showed that a rigid translation or rotation does not affect the accuracy. Typical values for the standard deviation in the displacement and strain components are 2.0 microm and 0.01, respectively. Presently, the precision limits the technique to strain measurements beyond the yield strain.

Although osteoporosis is characterized by quantitative (mass) and qualitative (structural) changes, standard clinical techniques (dual-energy X-ray absorptiometry, DXA) only measure the former. Three-dimensional micro-finite-element (micro-FE) models based on high-resolution images can account for structural aspects as well, and it has recently been shown that an improved prediction of distal radius strength is possible with micro-FE analysis. A clinical application of this technique, however, is limited by its high imaging and computational demands. The objective of this study is to investigate if an improved prediction of bone strength can be obtained as well when only a small part of the radius is used for micro-FE modeling. Images of a 1-cm region of the metaphysis of the distal radius of 54 cadaver arms (mean age: 82 ± 9 SD) made with a three-dimensional peripheral quantitative computed tomography (pQCT) device at 165-μm resolution formed the basis for micro-FE models that were used to predict the bone failure load. Following imaging, specimens were experimentally compressed to failure to produce a Colles'-type fracture. Failure loads predicted from micro-FE analyses agreed well with those measured experimentally ( R 2 = 0.66, p R 2 = 0.48, p R 2 = 0.47, p

Osteoarthritis (OA) is a multifactorial disease, resulting in diarthrodial joint wear and eventually destruction. Swelling of cartilage, which is proportional to the amount of collagen damage, is an initial event of cartilage degeneration, so damage to the collagen fibril network is likely to be one of the earliest signs of OA cartilage degeneration. We propose that the local stresses and strains in the collagen fibrils, which cause the damage, cannot be determined dependably without taking the local arcade-like collagen-fibril structure into account. We investigate this using a poroviscoelastic fibril-reinforced FEA model. The constitutive fibril properties were determined by fitting numerical data to experimental results of unconfined compression and indentation tests on samples of bovine patellar articular cartilage. It was demonstrated that with this model the stresses and strains in the collagen fibrils can be calculated. It was also exhibited that fibrils with different orientations at the same location can be loaded differently, depending on the local architecture of the collagen network. To the best of our knowledge, the present model is the first that can account for these features. We conclude that the local stresses and strains in the articular cartilage are highly influenced by the local morphology of the collagen-fibril network.

Quantitative information about bone tissue-level loading is essential for understanding bone mechanical behavior. We made microfinite element models of a healthy and osteoporotic human femur and found that tissue-level strains in the osteoporotic femoral head were 70% higher on average and less uniformly distributed than those in the healthy one. INTRODUCTION: Bone tissue stresses and strains in healthy load-adapted trabecular architectures should be distributed rather evenly, because no bone tissue is expected to be overloaded or unused. In this study, we evaluate this paradigm with the use of microfinite element (microFE) analyses to calculate tissue-level stresses and strains for the human femur. Our objectives were to quantify the strain distribution in the healthy femur, to investigate to what extent this distribution is affected by osteoporosis, to determine if osteoporotic bone is simply bone adapted to lower load levels, and to determine the "safety factor" for trabecular bone. MATERIALS AND METHODS: microFE models of a healthy and osteoporotic proximal femur were made from microcomputed tomography images. The models consisted of over 96 and 71 million elements for the healthy and osteoporotic femur, respectively, and represented their internal and external morphology in detail. Stresses and strains were calculated for each element and their distributions were calculated for a volume of interest (VOI) of trabecular bone in the femoral head. RESULTS: The average tissue-level principal strain magnitude in the healthy VOI was 304 +/- 185 microstrains and that in the osteoporotic VOI was 520 +/- 355 microstrains. Calculated safety factors were 8.6 for the healthy and 4.9 for the osteoporotic femurs. After reducing the force applied to the osteoporotic model to 59%, the average strain compared with that of the healthy femur, but the SD was larger (208 microstrains). CONCLUSIONS: Strain magnitudes in the osteoporotic bone were much higher and less uniformly distributed than those in the healthy one. After simulated joint-load reduction, strain magnitudes in the osteoporotic femur were very similar to those in the healthy one, but their distribution is still wider and thus less favorable.

Bone mineral density (BMD) and bone microarchitecture are important determinants for the mechanical properties of cancellous bone. Although BMD alone is a good predictor of average mechanical properties of cancellous bone, there remains unexplained variation in mechanical properties that might be due to missing information regarding bone microarchitecture. Recent developments in three-dimensional (3D) structural analysis have provided possibilities for measuring a variety of structural indices to characterize bone microarchitecture. The objectives of this study were to calculate structural indices and elastic constants of human cancellous bone from different skeletal sites and to investigate the predictive value of different 3D structural indices for the elastic properties of bone. A total of 237 cancellous bone samples taken from the iliac crest, lumbar spine, femoral head, and calcaneus were imaged with a 3D microcomputed tomography (microCT) system. The segmented 3D images were used to calculate BV/TV, BS/TV, Tb.Th, Tb.Sp, Tb.N, and MII ratio and for microstructural finite-element (microFE) analysis to calculate Young's moduli, shear moduli, and Poisson's ratios. A subgroup of "critical" specimens within each site was selected to represent specimens that could not be identified as osteoporotic or normal on the basis of BMD measurement alone. For these "critical" specimens, structural indices and elastic constants were correlated by means of linear multivariate regression analysis. It was found that the elastic constants clearly correlated better when one of the 3D structural indices was included as independent variable than when BV/TV was the only independent variable. Each of the examined structural indices could improve the correlation: the R2 values were maximally increased from 53% (BV/TV alone) to 82% (BV/TV and MIL ratio). The most effective indices, however, were not the same for the different skeletal sites. Even better correlations were found when more than one of the 3D structural indices were included as independent variables: the R2 values were maximally increased from 53% (BV/TV alone) to 92% (BV/TV, Tb.Sp, and MIL ratio). The prediction of elastic constants for cancellous bone samples is clearly improved when BV/TV is supplemented with 3D structural indices. These results suggest that the determination of mechanical properties of bone and the diagnosis of osteoporosis can be improved if, in addition to BMD, the 3D bone microarchitecture is assessed in vivo.

This study addresses the possible significance of trabecular connectivity for the mechanical quality of cancellous bone. A total of 141 cubic trabecular bone specimens collected from autopsy material from 56 individuals without any known bone or metastatic diseases were used. Age variation was in the range of 14-91 years and a wide range of trabecular architecture was found. Each specimen was three-dimensionally reconstructed with a voxel size of either 20 or 25 microm. Using the detailed three-dimensional reconstructions as input for microstructural finite-element models, the complete elastic properties of the trabecular architecture were obtained and maximum and mean stiffness could be calculated. Volume fraction and true three-dimensional architectural measurements of connectivity density and surface density were determined. Connectivity density was determined in an unbiased manner by the Euler number, which is a topological property. Using multiple regression analysis it was found that volume fraction explained by far the greatest part (84%-94%) of the variation in both mean and maximum stiffness. When connectivity density and surface density were included, the correlations increased marginally to 89%-95%. Noticeably negative regression coefficients were found for connectivity density. The results suggest that, in normal cancellous bone, the connectivity density has very limited value for assessment of elastic properties by morphological variables, but if a relation exists then stiffness decreases with increasing connectivity. [Journal Article; In English; United States]

A quantitative assessment of bone tissue stresses and strains is essential for the understanding of failure mechanisms associated with osteoporosis, osteoarthritis, loosening of implants and cell- mediated adaptive bone-remodeling processes. According to Wolff's trajectorial hypothesis, the trabecular architecture is such that minimal tissue stresses are paired with minimal weight. This paradigm at least suggests that, normally, stresses and strains should be distributed rather evenly over the trabecular architecture. Although bone stresses at the apparent level were determined with finite element analysis (FEA), by assuming it to be continuous, there is no data available on trabecular tissue stresses or strains of bones in situ under physiological loading conditions. The objectives of this project were to supply reasonable estimates of these quantities for the canine femur, to compare trabecular-tissue to apparent stresses, and to test Wolff's hypothesis in a quantitative sense. For that purpose, the newly developed method of large-scale micro-FEA was applied in conjunction with micro-CT structural measurements. A three-dimensional high-resolution computer reconstruction of a proximal canine femur was made using a micro-CT scanner. This was converted to a large-scale FE-model with 7.6 million elements, adequately refined to represent individual trabeculae. Using a special-purpose FE-solver, analyses were conducted for three different orthogonal hip-joint loading cases, one of which represented the stance-phase of walking. By superimposing the results, the tissue stress and strain distributions could also be calculated for other force directions. Further analyses of results were concentrated on a trabecular volume of interest (VOI) located in the center of the head. For the stance phase of walking an average tissue principal strain in the VOI of 279 strain was found, with a standard deviation of 212 microstrain. The standard deviation depended not only on the hip-force magnitude, but also on its direction. In more than 95% of the tissue volume the principal stresses and strains were in a range from zero to three times the averages, for all hip-force directions. This indicates that no single load creates even stress or strain distributions in the trabecular architecture. Nevertheless, excessive values occurred at few locations only, and the maximum tissue stress was approximately half the value reported for the tissue fatigue strength. These results thus indicate that trabecular bone tissue has a safety factor of approximately two for hip-joint loads that occur during normal activities.

The hypothesis that trabecular morphology can predict the elastic properties of cancellous bone has only partly been verified and no predictive analytical model is currently available. Such models are becoming increasingly relevant as the resolution levels of three-dimensional scanning techniques approach the size of trabeculae. This study took advantage of micro-finite-element methods and tested the aforementioned hypothesis in normal cancellous bone material collected at six anatomical locations from 56 individuals. Numerical analysis was based on high-resolution three-dimensional computer reconstructions of cancellous bone specimens from which the complete elastic characteristics and trabecular morphology, represented by three different fabric measures (the mean intercept length and two volume-based ones), were calculated. Each fabric measure was analyzed individually using the tensorial relationships derived by Cowin (Mech Mater 4:137-147; 1985). Models for both stiffness and compliance entries were developed. The models based on stiffness entries could explain 93.4%-95.6% of the variance, whereas those based on compliance entries could explain 89.2%-89.4%. When using the former model, the MIL (mean intercept length measure) performed slightly better than the two volume-based measures, VO (volume orientation) and SVD (star volume distribution), with 23% less remaining variance. The high correlations found strongly support the hypothesis and increase the hope that, on the basis of information on trabecular morphology, it will be possible to obtain considerably better estimates of bone quality in vivo compared with the rough two-dimensional density measurements used today. [Journal Article; In English; United States]