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Item type:Publication, Access status: without files , Skeletal assessment with finite element analysis: Relevance, pitfalls and interpretation(2017-07-01); Purpose of review Finite element models simulate the mechanical response of bone under load, enabling noninvasive assessment of strength. Models generated from quantitative computed tomography (QCT) incorporate the geometry and spatial distribution of bone mineral density (BMD) to simulate physiological and traumatic loads as well as orthopaedic implant behaviour. The present review discusses the current strengths and weakness of finite element models for application to skeletal biomechanics. Recent findings In cadaver studies, finite element models provide better estimations of strength compared to BMD. Data from clinical studies are encouraging; however, the superiority of finite element models over BMD measures for fracture prediction has not been shown conclusively, and may be sex and site dependent. Therapeutic effects on bone strength are larger than for BMD; however, model validation has only been performed on untreated bone. High-resolution modalities and novel image processing methods may enhance the structural representation and predictive ability. Despite extensive use of finite element models to study orthopaedic implant stability, accurate simulation of the bone-implant interface and fracture progression remains a significant challenge. Summary Skeletal finite element models provide noninvasive assessments of strength and implant stability. Improved structural representation and implant surface interaction may enable more accurate models of fragility in the future.Publicationtype: Review Article89 - Some of the metrics are blocked by yourconsent settings
Item type:Publication, Access status: without files , Tracking the progression of osteolytic and osteosclerotic lesions in mice using serial in vivo μCT: applications to the assessment of bisphosphonate treatment efficacy(Wiley, 2017-03); ; ; ; The metastasis of tumor cells to bone can lead to osteolytic and osteosclerotic lesions, which cause severe, highly-localized bone destruction and abnormal bone apposition, respectively. Accurate quantification of lesion progression is critical to understand underlying mechanisms and assess treatment efficacy; however, standard structural parameters may be insensitive to local changes. We developed methods to quantify osteolytic and osteosclerotic lesions using micro–computed tomography (μCT) within in vivo mouse datasets. Two Balb/c nude datasets were used: (i) bone-homing MDA-MB-231 (osteolytic) cells injected into the left ventricle, treatment with alendronate or vehicle, and weekly μCT (proximal tibia) for 4 weeks, and (ii) MCF7 (osteosclerotic) cells injected into the right tibia and weekly μCT over 12 weeks. After registering images to baseline, osteolytic lesion volume was determined by summing all baseline bone voxels at distances greater than a threshold (150 μm) from the nearest follow-up. Osteosclerotic lesions were determined by measuring the distance from each follow-up surface voxel to the nearest baseline surface and calculating the standard deviation of distance values (SDDT) of the surrounding voxels. Bone mineral density (BMD), bone volume density (BV/TV), and separation (Sp) were determined for comparison. Osteolytic lesions were observed 1 week after tumor cell injection; however, no corresponding BV/TV losses or Sp increases were observed, indicating that standard parameters were unable to detect early metastatic changes. Lesion volume was smaller in the alendronate versus control group (15.0%, p = 0.004 and 18.6%, p = 0.002 of control lesion volume at weeks 3 and 4, respectively). In the osteosclerotic dataset, increased SDDT was observed following injection, providing a potential new measure of osteosclerotic bone apposition. These data show that quantification of local structural change with serial μCT may overcome the limitations of standard mineral and microstructural parameters, and successfully separates metastatic and normal bone turnover. © 2017 American Society for Bone and Mineral Research.Publicationtype: Journal Article225 - Some of the metrics are blocked by yourconsent settings
Item type:Publication, Access status: without files , Assessment of Bone Fragility in Patients With Multiple Myeloma Using QCT-Based Finite Element ModelingMultiple myeloma (MM) is a malignant plasma cell disease associated with severe bone destruction. Surgical intervention is often required to prevent vertebral body collapse and resulting neurological complications; however, its necessity is determined by measuring lesion size or number, without considering bone biomechanics. Finite element (FE) modeling, which simulates the physiological loading, may improve the prediction of fragility. To test this, we developed a quantitative computed tomography (QCT)-based FE model of the vertebra and applied it to a dataset of MM patients with and without prevalent fracture. FE models were generated from vertebral QCT scans of the T12 (T11 if T12 was fractured) of 104 MM patients, 45 with fracture and 59 without, using a low-dose scan protocol (1.5 mm slice thickness, 4.0 to 6.5 mSv effective dose). A calibration phantom enabled the conversion of the CT Hounsfield units to FE material properties. Compressive loading of the vertebral body was simulated and the stiffness, yield load, and work to yield determined. To compare the parameters between fracture and nonfracture groups, t tests were used, and standardized odds ratios (sOR, normalized to standard deviation) and 95% confidence intervals were calculated. FE parameters were compared to mineral and structural parameters using linear regression. Patients with fracture showed lower vertebral stiffness (–15.2%; p = 0.010; sOR = 1.73; 95% CI, 1.11 to 2.70), yield force (–21.5%; p = 0.002; sOR = 2.09; 95% CI, 1.27 to 3.43), and work to yield (–27.4%; p = 0.001; sOR = 2.28; 95% CI, 1.33 to 3.92) compared to nonfracture patients. All parameters correlated significantly with vBMD (stiffness: R2 = 0.57, yield force: R2 = 0.59, work to yield: R2 = 0.50, p < 0.001), BV/TV (stiffness: R2 = 0.56, yield force: R2 = 0.58, work to yield: R2 = 0.49, p < 0.001), and Tb.Sp (stiffness: R2 = 0.51, yield force: R2 = 0.53, work to yield: R2 = 0.45, p < 0.001). FE modeling identified MM patients with compromised mechanical integrity of the vertebra. Higher sOR values were obtained for the biomechanical compared to structural or mineral measures, suggesting that FE modeling improves fragility assessment in these patients. © 2016 American Society for Bone and Mineral Research.Publicationtype: Journal Article214 - Some of the metrics are blocked by yourconsent settings
Item type:Publication, Access status: without files , A new algorithm for estimating the rod volume fraction and the trabecular thickness from in vivo computed tomographyPurpose: Existing microstructure parameters are able to predict vertebral in vitro failure load, but for noisy in vivo data more complex algorithms are needed for a robust assessment. Methods: A new algorithm is proposed for the microstructural analysis of trabecular bone under in vivo quantitative computed tomography (QCT). Five fractal parameters are computed: (1) the average local fractal dimension FD, (2) its standard deviation FD.SD, (3) the fractal rod volume ratio fRV/BV, (4) the average fractal trabecular thickness fTb.Th, and (5) its coefcient of variation fTb.Th.CV. The algorithm requires neither an explicit skeletonization of the trabecular bone, nor a well-defned transition between bone and marrow phases. Two experiments were conducted to compare the fractal with established microstructural parameters. In the frst, 20 volumes-of-interest of embedded vertebrae phantoms were scanned fve times under QCT and high-resolution (HR-)QCT and once under peripheral HRQCT (HRpQCT), to derive accuracy and precision. In the second experiment, correlations between in vitro HRQCT structural parameters were obtained from 76 human T11, T12, or L1 vertebrae. In vitro fracture data were available for a subset of 17 human T12 vertebrae so that linear regression models between failure load and microstructural HRQCT parameters could be analyzed. Results: The results showed correlations of fTb.Th and fRV/BV with their nonfractal pendants trabecular thickness (Tb.Th) and respective structure model index (SMI) while higher precision and accuracy was observed on the fractal measures. Linear models of bone mineral density with two and three fractal microstructural HRQCT parameters explained 86% and 90% (adjusted R2) of the failure load and signifcantly improved the linear models based only on BMD and established standard microstructural parameters (68%-77% adjusted R2). Conclusions: The application of fractal methods may grant further insight into the study of bone quality in vivo when image resolution and quality are less than optimal for current standard methods.Publicationtype: Journal Article129 - Some of the metrics are blocked by yourconsent settings
Item type:Publication, Access status: without files , Pharmacologically inactive bisphosphonates as an alternative strategy for targeting osteoclasts: in vivo assessment of 5-fluorodeoxyuridine-alendronate in a preclinical model of breast cancer bone metastases(Wiley, 2016-10-07); ; ; ; American Society for Bone and Mineral Research Bisphosphonates have effects that are antiresorptive, antitumor, and antiapoptotic to osteoblasts and osteocytes, but an effective means of eliciting these multiple activities in the treatment of bone metastases has not been identified. Antimetabolite-bisphosphonate conjugates have potential for improved performance as a class of bone-specific antineoplastic drugs. The primary objective of the study was to determine whether an antimetabolite-bisphosphonate conjugate will preserve bone formation concomitant with antiresorptive and antitumor activity. 5-FdU-ale, a highly stable conjugate between the antimetabolite 5-fluoro-2'-deoxyuridine and the bisphosphonate alendronate, was tested for its therapeutic efficacy in a mouse model of MDA-MB231 breast cancer bone metastases. In vitro testing revealed osteoclasts to be highly sensitive to 5-FdU-ale. In contrast, osteoblasts had significantly reduced sensitivity. Tumor cells were resistant in vitro but in vivo tumor burden was nevertheless significantly reduced compared with untreated mice. Sensitivity to 5-FdU-ale was not mediated through inhibition of farnesyl diphosphate synthase activity, but cell cycle arrest was observed. Although serum tartrate-resistant acid phosphatase (TRAP) levels were greatly reduced by both drugs, there was no significant decrease in the serum bone formation marker osteocalcin with 5-FdU-ale treatment. In contrast, there was more than a fivefold decrease in serum osteocalcin levels with alendronate treatment (p < 0.001). This finding is supported by time-lapse micro–computed tomography analyses, which revealed bone formation volume to be on average 1.6-fold higher with 5-FdU-ale treatment compared with alendronate (p < 0.001). We conclude that 5-FdU-ale, which is a poor prenylation inhibitor but maintains potent antiresorptive activity, does not reduce bone formation and has cytostatic antitumor efficacy. These results document that conjugation of an antimetabolite with bisphosphonates offers flexibility in creating potent bone-targeting drugs with cytostatic, bone protection properties that show limited nephrotoxicity. This unique class of drugs may offer distinct advantages in the setting of targeted adjuvant therapy and chemoprevention of bone diseases. © 2016 American Society for Bone and Mineral Research.Publicationtype: Journal Article65 - Some of the metrics are blocked by yourconsent settings
Item type:Publication, Access status: without files , Effects of insulin therapy on porosity, non-enzymatic glycation and mechanical competence in the bone of rats with type 2 diabetes mellitusType 2 diabetes mellitus increases skeletal fragility; however, the contributing mechanisms and optimal treatment strategies remain unclear. We studied the effects of diabetes and insulin therapy on non-enzymatic glycation (NEG), cortical porosity (Ct.Po) and biomechanics of the bone tissue in Zucker Diabetic Fatty (ZDF) rats. Eleven-week old ZDF diabetic and non-diabetic rats were given insulin to achieve glycaemic control or vehicle seven days per week over twelve weeks (insulin dose adapted individually 0.5 international units (IU) at week 1 to 13.0 IU at week 12). The right femora were excised, micro-CT scanned, and tested in 3-point bending to measure biomechanics. NEG of the midshaft was determined from bulk fluorescence. Diabetes led to increased NEG (+ 50.1%, p = 0.001) and Ct.Po (+ 22.9%, p = 0.004), as well as to reduced mechanical competence (max. stress: − 14.2%, p = 0.041, toughness: − 29.7%, p = 0.016) in the bone tissue. NEG and Ct.Po both correlated positively to serum glucose (NEG: R2 = 0.41, p < 0.001, Ct.Po: R2 = 0.34, p = 0.003) and HbA1c (NEG: R2 = 0.42, p < 0.001, Ct.Po: R2 = 0.28, p = 0.008) levels, while NEG correlated negatively with bone biomechanics (elastic modulus: R2 = 0.21, p = 0.023, yield stress: R2 = 0.17, p = 0.047). Twelve weeks of insulin therapy had no significant effect on NEG or Ct.Po, and was unable to improve the mechanical competence of the bone tissue. A reduction of mechanical competence was observed in the bone tissue of the diabetic rats, which was explained in part by increased collagen NEG. Twelve weeks of insulin therapy did not alter NEG, Ct.Po or bone biomechanics. However, significant correlations between NEG and serum glucose and HbA1c were observed, both of which were reduced with insulin therapy. This suggests that a longer duration of insulin therapy may be required to reduce the NEG of the bone collagen and restore the mechanical competence of diabetic bone.Publicationtype: Journal Article133 - Some of the metrics are blocked by yourconsent settings
Item type:Publication, Access status: without files , Bone-marrow densitometry: Assessment of marrow space of human vertebrae by single energy high resolution-quantitative computed tomographyPurpose: Accurate noninvasive assessment of vertebral bone marrow fat fraction is important for diagnostic assessment of a variety of disorders and therapies known to affect marrow composition. Moreover, it provides a means to correct fat-induced bias of single energy quantitative computed tomography (QCT) based bone mineral density (BMD) measurements. The authors developed new segmentation and calibration methods to obtain quantitative surrogate measures of marrow-fat density in the axial skeleton. Methods: The authors developed and tested two high resolution-QCT (HR-QCT) based methods which permit segmentation of bone voids in between trabeculae hypothesizing that they are representative of bone marrow space. The methods permit calculation of marrow content in units of mineral equivalent marrow density (MeMD). The first method is based on global thresholding and peeling (GTP) to define a volume of interest away from the transition between trabecular bone and marrow. The second method, morphological filtering (MF), uses spherical elements of different radii (0.11.2 mm) and automatically places them in between trabeculae to identify regions with large trabecular interspace, the bone-void space. To determine their performance, data were compared ex vivo to high-resolution peripheral CT (HR-pQCT) images as the gold-standard. The performance of the methods was tested on a set of excised human vertebrae with intact bone marrow tissue representative of an elderly population with low BMD. Results: 86% (GTP) and 87% (MF) of the voxels identified as true marrow space on HR-pQCT images were correctly identified on HR-QCT images and thus these volumes of interest can be considered to be representative of true marrow space. Within this volume, MeMD was estimated with residual errors of 4.8 mg/cm3 corresponding to accuracy errors in fat fraction on the order of 5% both for GTP and MF methods. Conclusions: The GTP and MF methods on HR-QCT images permit noninvasive localization and densitometric assessment of marrow fat with residual accuracy errors sufficient to study disorders and therapies known to affect bone marrow composition. Additionally, the methods can be used to correct BMD for fat induced bias. Application and testing in vivo and in longitudinal studies are warranted to determine the clinical performance and value of these methods.Publicationtype: Journal Article71 - Some of the metrics are blocked by yourconsent settings
Item type:Publication, Access status: without files , Effects of parathyroid hormone on cortical porosity, non-enzymatic glycation and bone tissue mechanics in rats with type 2 diabetes mellitusType 2 diabetes mellitus increases skeletal fragility; however, the contributing mechanisms and the efficacy of bone-forming agents are unclear. We studied diabetes and parathyroid hormone (PTH) treatment effects on cortical porosity (Ct.Po), non-enzymatic glycation (NEG) and bone mechanics in Zucker diabetic fatty (ZDF) rats.Eleven-week old ZDF diabetic (DB) and non-diabetic (ND) rats were given 75. μg/kg PTH (1-84) or vehicle 5. days per week over 12. weeks. The right femora and L4 vertebrae were excised, micro-CT scanned, and tested in 3-point bending and uniaxial compression, respectively. NEG of the samples was determined using fluorescence.Diabetes increased Ct.Po (vertebra (vert): + 40.6%, femur (fem): + 15.5% vs. ND group, p < 0.05) but had no effect on NEG. PTH therapy reduced vertebral NEG in the ND animals only (- 73% vs untreated group, p < 0.05), and increased femoral NEG in the DB vs. ND groups (+ 63%, p < 0.05). PTH therapy had no effect on Ct.Po. Diabetes negatively affected bone tissue mechanics where reductions in vertebral maximum strain (- 22%) and toughness (- 42%) were observed in the DB vs. ND group (p < 0.05). PTH improved maximum strain in the vertebra of the ND animals (+ 21%, p < 0.05) but did not have an effect in the DB group. PTH increased femoral maximum strain (+ 21%) and toughness (+ 28%) in ND and decreased femoral maximum stress (- 13%) and toughness (- 27%) in the DB animals (treated vs. untreated, p < 0.05). Ct.Po correlated negatively with maximum stress (fem: R = - 0.35, p < 0.05, vert: R = - 0.57, p. < 0.01), maximum strain (fem: R = - 0.35, p. <. 0.05, vert: R. = - 0.43, p. < 0.05) and toughness (fem: R = - 0.34, p < 0.05, vert: R = - 0.55, p < 0.01), and NEG correlated negatively with toughness at the femur (R = - 0.34, p < 0.05) and maximum strain at the vertebra (R = - 0.49, p < 0.05).Diabetes increased cortical porosity and reduced bone mechanics, which were not improved with PTH treatment. PTH therapy alone may worsen diabetic bone mechanics through formation of new bone with high AGEs cross-linking. Optimal treatment regimens must address both improvements of bone mass and glycemic control in order to successfully reduce diabetic bone fragility.This article is part of a Special Issue entitled "Bone and diabetes".Publicationtype: Journal Article155 - Some of the metrics are blocked by yourconsent settings
Item type:Publication, Access status: without files , Administration of romosozumab improves vertebral trabecular and cortical bone as assessed with quantitative computed tomography and finite element analysis(Elsevier, 2015-07-29); ; ; ; Romosozumab inhibits sclerostin, thereby increasing bone formation and decreasing bone resorption. This dual effect of romosozumab leads to rapid and substantial increases in areal bone mineral density (aBMD) as measured by dual-energy X-ray absorptiometry (DXA). In a phase 1b, randomized, double-blind, placebo-controlled study, romosozumab or placebo was administered to 32 women and 16 men with low aBMD for 3. months, with a further 3-month follow-up: women received six doses of 1 or 2. mg/kg every 2. weeks (Q2W) or three doses of 2 or 3. mg/kg every 4. weeks (Q4W); men received 1. mg/kg Q2W or 3. mg/kg Q4W. Quantitative computed tomography (QCT) scans at lumbar (L1-2) vertebrae and high-resolution QCT (HR-QCT) scans at thoracic vertebra (T12) were analyzed in a subset of subjects at baseline, month 3, and month 6. The QCT subset included 24 romosozumab and 9 placebo subjects and the HR-QCT subset included 11 romosozumab and 3 placebo subjects. The analyses pooled the romosozumab doses. Linear finite element modeling of bone stiffness was performed. Compared with placebo, the romosozumab group showed improvements at month 3 for trabecular BMD by QCT and HR-QCT, HR-QCT trabecular bone volume fraction (BV/TV) and separation, density-weighted cortical thickness, and QCT stiffness (all p<. 0.05). At month 6, improvements from baseline were observed in QCT trabecular BMD and stiffness, and in HR-QCT BMD, trabecular BV/TV and separation, density-weighted cortical thickness, and stiffness in the romosozumab group (all p<. 0.05 compared with placebo). The mean (SE) increase in HR-QCT stiffness with romosozumab from baseline was 26.9%. ±. 6.8% and 35.0%. ±. 6.8% at months 3 and 6, respectively; subjects administered placebo had changes of -. 2.7%. ±. 13.4% and -. 6.4%. ±. 13.4%, respectively. In conclusion, romosozumab administered for 3. months resulted in rapid and large improvements in trabecular and cortical bone mass and structure as well as whole bone stiffness, which continued 3. months after the last romosozumab dose.Publicationtype: Journal ArticleScopus© Citations 54 27 - Some of the metrics are blocked by yourconsent settings
Item type:Publication, Access status: without files , The role of patient-mode high-resolution peripheral quantitative computed tomography indices in the prediction of failure strength of the elderly women’s thoracic vertebral bodyResults: For the prediction of vertebral failure load, the inclusion of BV/TV into L1 aBMD was the best model (R2 = 0.52), Tb.N and Tb.Sp added significant information to the L1 aBMD and to the cortical BMD, but none of the vertebral microarchitectural parameters yielded additional significant information to the trabecular BMD (or BV/TV) and to the vertebral BMD.Publicationtype: Journal ArticleScopus© Citations 14 30