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1.
Bone ; 128: 115043, 2019 Aug 21.
Artigo em Inglês | MEDLINE | ID: mdl-31445224

RESUMO

Bone can become brittle when exposed to ionizing radiation across a wide range of clinically relevant doses that span from radiotherapy (accumulative 50 Gy) to sterilization (~35,000 Gy). While irradiation-induced embrittlement has been attributed to changes in the collagen molecular structure, the relative role of collagen fragmentation versus non-enzymatic collagen crosslinking remains unclear. To better understand the effects of radiation on the bone material without cellular activity, we conducted an ex vivo x-ray radiation experiment on excised mouse lumbar vertebrae. Spinal tissue from twenty-week old, female, C57BL/6J mice were randomly assigned to a single x-ray radiation dose of either 0 (control), 50, 1000, 17,000, or 35,000 Gy. Measurements were made for collagen fragmentation, non-enzymatic collagen crosslinking, and both monotonic and cyclic-loading compressive mechanical properties. We found that the group differences for mechanical properties were more consistent with those for collagen fragmentation than for non-enzymatic collagen crosslinking. Monotonic strength at 17,000 and 35,000 Gy was lower than that of the control by 50% and 73% respectively, (p < 0.001) but at 50 and 1000 Gy was not different than the control. Consistent with those trends, collagen fragmentation only occurred at 17,000 and 35,000 Gy. By contrast, non-enzymatic collagen crosslinking was greater than control for all radiation doses (p < 0.001). All results were consistent both for monotonic and cyclic loading conditions. We conclude that the reductions in bone compressive monotonic strength and fatigue life due to ex vivo ionizing radiation are more likely caused by fragmentation of the collagen backbone than any increases in non-enzymatic collagen crosslinks.

2.
J Biomech Eng ; 2019 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-31260520

RESUMO

High-resolution peripheral quantitative computed tomography (HRpQCT) is a promising imaging modality that provides in vivo three-dimensional assessment of bone microstructure by scanning fixed regions of the distal radius and tibia. However, how microstructural parameters and mechanical analysis based on these segment scans correlate to whole distal radius and tibia mechanics is not well-characterized. On 26 sets of cadaveric radius and tibia, HRpQCT scans were performed on the standard scan segment, a segment distal to the standard segment, and a segment proximal to the standard segment. Whole distal bone stiffness was determined through mechanical testing. Segment bone stiffness was estimated using linear finite element (FE) analysis based on segment scans. Standard morphological and Individual Trabecula Segmentation (ITS) analyses were used estimate microstructural properties. Significant variations in microstructural parameters were observed among segments at both sites. Correlation to whole distal bone stiffness was moderate for microstructural parameters at the standard segment, but correlation was significantly increased for FE-predicted segment bone stiffness based on standard segment scans. Similar correlation strengths were found between FE-predicted segment bone stiffness and whole distal bone stiffness. Additionally, microstructural parameters at the distal segment had higher correlation to whole distal bone stiffness than at standard or proximal segments. Our results suggest that FE-predicted segment stiffness is a better predictor of whole distal bone stiffness for clinical HRpQCT analysis, and that microstructural parameters at the distal segment is more highly correlated with whole distal bone stiffness than at the standard or proximal segments.

3.
Br J Radiol ; 92(1099): 20190115, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31170815
4.
J Biomech Eng ; 2019 Jan 31.
Artigo em Inglês | MEDLINE | ID: mdl-30703208

RESUMO

The high-resolution peripheral quantitative computed tomography (HRpQCT) provides unprecedented visualization of bone microstructure and the basis for constructing patient-specific micro-finite element (µFE) models. Based on HRpQCT images, we have developed a plate rod µFE (PRµFE) method for whole bone segments using individual trabecula segmentation (ITS) and an adaptive cortical meshing technique. In contrast to the conventional voxel approach, the complex microarchitecture of the trabecular compartment is simplified into shell and beam elements based on the trabecular plate-and-rod configuration. Compared to voxel-based µFE models of µCT and mechanical testing, nonlinear analyses of stiffness and yield strength using the HRpQCT-based PRµFE models demonstrated high correlation and accuracy, indicating that the combination of segmented trabecular plate-rod morphology and adjusted cortical mesh adequately captures mechanics of the whole bone segment. Meanwhile, the PRµFE approach reduced model size by nearly 300-fold and shortened computation time for nonlinear analysis from days to within hours, permitting broader clinical application of HRpQCT-based nonlinear µFE modeling. Furthermore, the presented approach was tested using a subset of radius and tibia HRpQCT scans of patients with prior vertebral fracture from a previous study. Results indicated that yield strength for radius and tibia predicted by the PRµFE model was effective in discriminating vertebral fracture subjects from non-fractured controls. In conclusion, the PR µFE model of HRpQCT images accurately predicted mechanics for whole bone segments and can serve as a valuable clinical tool to evaluate musculoskeletal diseases.

5.
J Bone Miner Res ; 34(7): 1229-1239, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-30779860

RESUMO

Osteoporosis screening rates by DXA are low (9.5% women, 1.7% men) in the US Medicare population aged 65 years and older. Addressing this care gap, we estimated the benefits of a validated osteoporosis diagnostic test suitable for patients age 65 years and older with an abdominal computed tomography (CT) scan taken for any indication but without a recent DXA. Our analysis assessed a hypothetical cohort of 1000 such patients in a given year, and followed them for 5 years. Separately for each sex, we used Markov modeling to compare two mutually exclusive scenarios: (i) utilizing the CT scans, perform one-time "biomechanical computed tomography" (BCT) analysis to identify high-risk patients on the basis of both femoral strength and hip BMD T-scores; (ii) ignore the CT scan, and rely instead on usual care, consisting of future annual DXA screening at typical Medicare rates. For patients with findings indicative of osteoporosis, 50% underwent 2 years of treatment with alendronate. We found that BCT provided greater clinical benefit at lower cost for both sexes than usual care. In our base case, compared to usual care, BCT prevented hip fractures over a 5-year window (3.1 per 1000 women; 1.9 per 1000 men) and increased quality-adjusted life years (2.95 per 1000 women; 1.48 per 1000 men). Efficacy and savings increased further for higher-risk patient pools, greater treatment adherence, and longer treatment duration. When the sensitivity and specificity of BCT were set to those for DXA, the prevented hip fractures versus usual care remained high (2.7 per 1000 women; 1.5 per 1000 men), indicating the importance of high screening rates on clinical efficacy. Therefore, for patients with a previously taken abdominal CT and without a recent DXA, osteoporosis screening using biomechanical computed tomography may be a cost-effective alternative to current usual care. © 2019 American Society for Bone and Mineral Research.

6.
Bone Rep ; 9: 165-172, 2018 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-30417036

RESUMO

One potentially important bone quality characteristic is the response of bone to cyclic (repetitive) mechanical loading. In small animals, such as in rats and mice, cyclic loading experiments are particularly challenging to perform in a precise manner due to the small size of the bones and difficult-to-eliminate machine compliance. Addressing this issue, we developed a precise method for ex vivo cyclic compressive loading of isolated mouse vertebral bodies. The method has three key characteristics: 3D-printed support jigs for machining plano-parallel surfaces of the tiny vertebrae; pivotable loading platens to ensure uniform contact and loading of specimen surfaces; and specimen-specific micro-CT-based finite element analysis to measure stiffness to prescribe force levels that produce the same specified level of strain for all test specimens. To demonstrate utility, we measured fatigue life for three groups (n = 5-6 per group) of L5 vertebrae of C57BL/6J male mice, comparing our new method against two methods commonly used in the literature. We found reduced scatter of the mechanical behavior for this new method compared to the literature methods. In particular, for a controlled level of strain, the standard deviation of the measured fatigue life was up to 5-fold lower for the new method (F-ratio = 4.9; p < 0.01). The improved precision for this new method for biomechanical testing of small-animal vertebrae may help elucidate aspects of bone quality.

7.
Inflamm Bowel Dis ; 2018 Nov 27.
Artigo em Inglês | MEDLINE | ID: mdl-30476314

RESUMO

Background: Inflammatory bowel disease (IBD) patients are at risk of developing complications from metabolic bone disease, but the exact prevalence is unknown. We evaluated fracture risk in IBD patients using (1) biomechanical CT analysis (BCT) using bone strength and bone mineral density (BMD), (2) Cornerstone guidelines, and (3) other clinical features predicting fracture risk. Methods: A retrospective review of consecutive IBD patients who underwent CT enterography (CTE) with BCT from March 2014 to March 2017 was performed. Measured outcomes were overall fracture risk classification (not increased, increased, or high) and femoral neck BMD World Health Organization classification (normal, osteopenia, or osteoporosis). Results: Two hundred fifty-seven patients with IBD underwent CTE and BCT. Fracture risk was classified as not increased in 45.5% (116/255) of patients, increased in 44.7% (114/255), and high in 9.8% (25/255). Femoral neck BMD was classified as normal in 56.8% (142/250), osteopenia in 37.6% (94/250), and osteoporosis in 5.6% (14/250). In multivariate analysis, only increasing age was associated with increased fracture risk (odds ratio, 1.06; 95% confidence interval, 1.04-1.08; P < 0.001). Cornerstone guidelines were met by 35.3% (41/116), 56.1% (64/114), and 76.0% (19/25) of patients in the not increased, increased, and high-risk groups, respectively (P = 0.0001). No Cornerstone criteria were met by 40% (56/139) of patients in the increased and high-risk groups. Conclusions: Using BCT, increased or high fracture risk was detected in more than half of this cohort, the prevalence being associated with increased age. A significant proportion of patients with increased or high fracture risk did not meet Cornerstone guidelines. Therefore, IBD patients who do not meet Cornerstone guidelines may benefit from BCT screening.

8.
J Bone Miner Res ; 33(7): 1291-1301, 2018 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-29665068

RESUMO

Methods now exist for analyzing previously taken clinical computed tomography (CT) scans to measure a dual-energy X-ray absorptiometry (DXA)-equivalent bone mineral density (BMD) at the hip and a finite element analysis-derived femoral strength. We assessed the efficacy of this "biomechanical CT" (BCT) approach for identifying patients at high risk of incident hip fracture in a large clinical setting. Using a case-cohort design sampled from 111,694 women and men aged 65 or older who had a prior hip CT scan, a DXA within 3 years of the CT, and no prior hip fracture, we compared those with subsequent hip fracture (n = 1959) with randomly selected sex-stratified controls (n = 1979) and analyzed their CT scans blinded to all other data. We found that the age-, race-, and body mass index (BMI)-adjusted hazard ratio (HR; per standard deviation) for femoral strength was significant before (women: HR = 2.8, 95% confidence interval [CI] 2.2-3.5; men: 2.8, 2.1-3.7) and after adjusting also for the (lowest) hip BMD T-score by BCT (women: 2.1, 1.4-3.2; men: 2.7, 1.6-4.6). The hazard ratio for the hip BMD T-score was similar between BCT and DXA for both sexes (women: 2.1, 1.8-2.5 BCT versus 2.1, 1.7-2.5 DXA; men: 2.8, 2.1-3.8 BCT versus 2.5, 2.0-3.2 DXA) and was higher than for the (lowest) spine/hip BMD T-score by DXA (women: 1.6, 1.4-1.9; men: 2.1, 1.6-2.7). Compared with the latter as a clinical-practice reference and using both femoral strength and the hip BMD T-score from BCT, sensitivity for predicting hip fracture was higher for BCT (women: 0.66 versus 0.59; men: 0.56 versus 0.48), with comparable respective specificity (women: 0.66 versus 0.67; men: 0.76 versus 0.78). We conclude that BCT analysis of previously acquired routine abdominal or pelvic CT scans is at least as effective as DXA testing for identifying patients at high risk of hip fracture. © 2018 American Society for Bone and Mineral Research.

9.
Endocr Rev ; 39(3): 369-386, 2018 06 01.
Artigo em Inglês | MEDLINE | ID: mdl-29522088

RESUMO

The Testosterone Trials (TTrials) were a coordinated set of seven placebo-controlled, double-blind trials in 788 men with a mean age of 72 years to determine the efficacy of increasing the testosterone levels of older men with low testosterone. Testosterone treatment increased the median testosterone level from unequivocally low at baseline to midnormal for young men after 3 months and maintained that level until month 12. In the Sexual Function Trial, testosterone increased sexual activity, sexual desire, and erectile function. In the Physical Function Trial, testosterone did not increase the distance walked in 6 minutes in men whose walk speed was slow; however, in all TTrial participants, testosterone did increase the distance walked. In the Vitality Trial, testosterone did not increase energy but slightly improved mood and depressive symptoms. In the Cognitive Function Trial, testosterone did not improve cognitive function. In the Anemia Trial, testosterone increased hemoglobin in both men who had anemia of a known cause and in men with unexplained anemia. In the Bone Trial, testosterone increased volumetric bone mineral density and the estimated strength of the spine and hip. In the Cardiovascular Trial, testosterone increased the coronary artery noncalcified plaque volume as assessed using computed tomographic angiography. Although testosterone was not associated with more cardiovascular or prostate adverse events than placebo, a trial of a much larger number of men for a much longer period would be necessary to determine whether testosterone increases cardiovascular or prostate risk.

10.
Bone ; 103: 325-333, 2017 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-28778598

RESUMO

Patient-specific phantomless calibration of computed tomography (CT) scans has the potential to simplify and expand the use of pre-existing clinical CT for quantitative bone densitometry and bone strength analysis for diagnostic and monitoring purposes. In this study, we quantified the inter-operator reanalysis precision errors for a novel implementation of patient-specific phantomless calibration, using air and either aortic blood or hip adipose tissue as internal calibrating reference materials, and sought to confirm the equivalence between phantomless and (traditional) phantom-based measurements. CT scans of the spine and hip for 25 women and 15 men (mean±SD age of 67±9years, range 41-86years), one scan per anatomic site per patient, were analyzed independently by two analysts using the VirtuOst software (O.N. Diagnostics, Berkeley, CA). The scans were acquired at 120kVp, with a slice thickness/increment of 3mm or less, on nine different CT scanner models across 24 different scanners. The main parameters assessed were areal bone mineral density (BMD) at the hip (total hip and femoral neck), trabecular volumetric BMD at the spine, and vertebral and femoral strength by finite element analysis; other volumetric BMD measures were also assessed. We found that the reanalysis precision errors for all phantomless measurements were ≤0.5%, which was as good as for phantom calibration. Regression analysis indicated equivalence of the phantom- versus phantomless-calibrated measurements (slope not different than unity, R2≥0.98). Of the main parameters assessed, non-significant paired mean differences (n=40) between the two measurements ranged from 0.6% for hip areal BMD to 1.1% for mid-vertebral trabecular BMD. These results indicate that phantom-equivalent measurements of both BMD and finite element-derived bone strength can be reliably obtained from CT scans using patient-specific phantomless calibration.


Assuntos
Densidade Óssea , Osso e Ossos/diagnóstico por imagem , Tomografia Computadorizada por Raios X/métodos , Tomografia Computadorizada por Raios X/normas , Adulto , Idoso , Idoso de 80 Anos ou mais , Calibragem , Feminino , Análise de Elementos Finitos , Humanos , Masculino , Pessoa de Meia-Idade , Variações Dependentes do Observador , Imagens de Fantasmas
11.
Lancet ; 390(10102): 1585-1594, 2017 Sep 30.
Artigo em Inglês | MEDLINE | ID: mdl-28755782

RESUMO

BACKGROUND: Previous bisphosphonate treatment attenuates the bone-forming effect of teriparatide. We compared the effects of 12 months of romosozumab (AMG 785), a sclerostin monoclonal antibody, versus teriparatide on bone mineral density (BMD) in women with postmenopausal osteoporosis transitioning from bisphosphonate therapy. METHODS: This randomised, phase 3, open-label, active-controlled study was done at 46 sites in North America, Latin America, and Europe. We enrolled women (aged ≥55 to ≤90 years) with postmenopausal osteoporosis who had taken an oral bisphosphonate for at least 3 years before screening and alendronate the year before screening; an areal BMD T score of -2·5 or lower at the total hip, femoral neck, or lumbar spine; and a history of fracture. Patients were randomly assigned (1:1) via an interactive voice response system to receive subcutaneous romosozumab (210 mg once monthly) or subcutaneous teriparatide (20 µg once daily). The primary endpoint was percentage change from baseline in areal BMD by dual-energy x-ray absorptiometry at the total hip through month 12 (mean of months 6 and 12), which used a linear mixed effects model for repeated measures and represented the mean treatment effect at months 6 and 12. All randomised patients with a baseline measurement and at least one post-baseline measurement were included in the efficacy analysis. This trial is registered with ClinicalTrials.gov, number NCT01796301. FINDINGS: Between Jan 31, 2013, and April 29, 2014, 436 patients were randomly assigned to romosozumab (n=218) or teriparatide (n=218). 206 patients in the romosozumab group and 209 in the teriparatide group were included in the primary efficacy analysis. Through 12 months, the mean percentage change from baseline in total hip areal BMD was 2·6% (95% CI 2·2 to 3·0) in the romosozumab group and -0·6% (-1·0 to -0·2) in the teriparatide group; difference 3·2% (95% CI 2·7 to 3·8; p<0·0001). The frequency of adverse events was generally balanced between treatment groups. The most frequently reported adverse events were nasopharyngitis (28 [13%] of 218 in the romosozumab group vs 22 [10%] of 214 in the teriparatide group), hypercalcaemia (two [<1%] vs 22 [10%]), and arthralgia (22 [10%] vs 13 [6%]). Serious adverse events were reported in 17 (8%) patients on romosozumab and in 23 (11%) on teriparatide; none were judged treatment related. There were six (3%) patients in the romosozumab group compared with 12 (6%) in the teriparatide group with adverse events leading to investigational product withdrawal. INTERPRETATION: Transition to a bone-forming agent is common practice in patients treated with bisphosphonates, such as those who fracture while on therapy. In such patients, romosozumab led to gains in hip BMD that were not observed with teriparatide. These data could inform clinical decisions for patients at high risk of fracture. FUNDING: Amgen, Astellas, and UCB Pharma.

12.
Bone ; 103: 93-101, 2017 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-28666970

RESUMO

Clinical bone sonometers applied at the calcaneus measure broadband ultrasound attenuation and speed of sound. However, the relation of ultrasound measurements to bone strength is not well-characterized. Addressing this issue, we assessed the extent to which ultrasonic measurements convey in vitro mechanical properties in 25 human calcaneal cancellous bone specimens (approximately 2×4×2cm). Normalized broadband ultrasound attenuation, speed of sound, and broadband ultrasound backscatter were measured with 500kHz transducers. To assess mechanical properties, non-linear finite element analysis, based on micro-computed tomography images (34-micron cubic voxel), was used to estimate apparent elastic modulus, overall specimen stiffness, and apparent yield stress, with models typically having approximately 25-30 million elements. We found that ultrasound parameters were correlated with mechanical properties with R=0.70-0.82 (p<0.001). Multiple regression analysis indicated that ultrasound measurements provide additional information regarding mechanical properties beyond that provided by bone quantity alone (p≤0.05). Adding ultrasound variables to linear regression models based on bone quantity improved adjusted squared correlation coefficients from 0.65 to 0.77 (stiffness), 0.76 to 0.81 (apparent modulus), and 0.67 to 0.73 (yield stress). These results indicate that ultrasound can provide complementary (to bone quantity) information regarding mechanical behavior of cancellous bone.


Assuntos
Calcâneo/diagnóstico por imagem , Calcâneo/fisiologia , Osso Esponjoso/diagnóstico por imagem , Osso Esponjoso/fisiologia , Ultrassonografia/métodos , Análise de Elementos Finitos , Humanos , Estresse Mecânico , Microtomografia por Raio-X
13.
Bone ; 105: 93-102, 2017 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-28739416

RESUMO

It is not clear which non-invasive method is most effective for predicting strength of the proximal femur in those at highest risk of fracture. The primary aim of this study was to compare the abilities of dual energy X-ray absorptiometry (DXA)-derived aBMD, quantitative computed tomography (QCT)-derived density and volume measures, and finite element analysis (FEA)-estimated strength to predict femoral failure load. We also evaluated the contribution of cortical and trabecular bone measurements to proximal femur strength. We obtained 76 human cadaveric proximal femurs (50 women and 26 men; age 74±8.8years), performed imaging with DXA and QCT, and mechanically tested the femurs to failure in a sideways fall configuration at a high loading rate. Linear regression analysis was used to construct the predictive model between imaging outcomes and experimentally-measured femoral strength for each method. To compare the performance of each method we used 3-fold cross validation repeated 10 times. The bone strength estimated by QCT-based FEA predicted femoral failure load (R2adj=0.78, 95%CI 0.76-0.80; RMSE=896N, 95%CI 830-961) significantly better than femoral neck aBMD by DXA (R2adj=0.69, 95%CI 0.66-0.72; RMSE=1011N, 95%CI 952-1069) and the QCT-based model (R2adj=0.73, 95%CI 0.71-0.75; RMSE=932N, 95%CI 879-985). Both cortical and trabecular bone contribute to femoral strength, the contribution of cortical bone being higher in femurs with lower trabecular bone density. These findings have implications for optimizing clinical approaches to assess hip fracture risk. In addition, our findings provide new insights that will assist in interpretation of the effects of osteoporosis treatments that preferentially impact cortical versus trabecular bone.


Assuntos
Fêmur/fisiologia , Absorciometria de Fóton , Fenômenos Biomecânicos , Cadáver , Osso Esponjoso , Osso Cortical , Demografia , Feminino , Análise de Elementos Finitos , Humanos , Imagem Tridimensional , Modelos Lineares , Masculino , Pessoa de Meia-Idade , Análise Multivariada , Reprodutibilidade dos Testes , Tomografia Computadorizada por Raios X , Suporte de Carga
14.
J Bone Miner Res ; 32(9): 1956-1962, 2017 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-28543940

RESUMO

Romosozumab is a monoclonal antibody that inhibits sclerostin and has been shown to reduce the risk of fractures within 12 months. In a phase II, randomized, placebo-controlled clinical trial of treatment-naïve postmenopausal women with low bone mass, romosozumab increased bone mineral density (BMD) at the hip and spine by the dual effect of increasing bone formation and decreasing bone resorption. In a substudy of that trial, which included placebo and teriparatide arms, here we investigated whether those observed increases in BMD also resulted in improvements in estimated strength, as assessed by finite element analysis. Participants received blinded romosozumab s.c. (210 mg monthly) or placebo, or open-label teriparatide (20 µg daily) for 12 months. CT scans, obtained at the lumbar spine (n = 82) and proximal femur (n = 46) at baseline and month 12, were analyzed with finite element software (VirtuOst, O.N. Diagnostics) to estimate strength for a simulated compression overload for the spine (L1 vertebral body) and a sideways fall for the proximal femur, all blinded to treatment assignment. We found that, at month 12, vertebral strength increased more for romosozumab compared with both teriparatide (27.3% versus 18.5%; p = 0.005) and placebo (27.3% versus -3.9%; p < 0.0001); changes in femoral strength for romosozumab showed similar but smaller changes, increasing more with romosozumab versus teriparatide (3.6% versus -0.7%; p = 0.027), and trending higher versus placebo (3.6% versus -0.1%; p = 0.059). Compartmental analysis revealed that the bone-strengthening effects for romosozumab were associated with positive contributions from both the cortical and trabecular bone compartments at both the lumbar spine and hip. Taken together, these findings suggest that romosozumab may offer patients with osteoporosis a new bone-forming therapeutic option that increases both vertebral and femoral strength within 12 months. © 2017 American Society for Bone and Mineral Research.


Assuntos
Anticorpos Monoclonais/administração & dosagem , Densidade Óssea/efeitos dos fármacos , Quadril/diagnóstico por imagem , Vértebras Lombares , Osteoporose Pós-Menopausa , Teriparatida/administração & dosagem , Idoso , Idoso de 80 Anos ou mais , Feminino , Humanos , Vértebras Lombares/diagnóstico por imagem , Vértebras Lombares/metabolismo , Pessoa de Meia-Idade , Osteoporose Pós-Menopausa/diagnóstico por imagem , Osteoporose Pós-Menopausa/tratamento farmacológico , Osteoporose Pós-Menopausa/metabolismo
15.
Bone ; 101: 62-69, 2017 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-28442297

RESUMO

PURPOSE: Bone fracture risk assessed ancillary to positron emission tomography with computed tomography co-registration (PET/CT) could provide substantial clinical value to oncology patients with elevated fracture risk without introducing additional radiation dose. The purpose of our study was to investigate the feasibility of obtaining valid measurements of bone mineral density (BMD) and finite element analysis-derived bone strength of the hip and spine using PET/CT examinations of prostate cancer patients by comparing against values obtained using routine multidetector-row computed tomography (MDCT) scans-as validated in previous studies-as a reference standard. MATERIALS AND METHODS: Men with prostate cancer (n=82, 71.6±8.3 years) underwent Fluorine-18 NaF PET/CT and routine MDCT within three months. Femoral neck and total hip areal BMD, vertebral trabecular BMD and femur and vertebral strength based on finite element analysis were assessed in 63 paired PET/CT and MDCT examinations using phantomless calibration and Biomechanical-CT analysis. Men with osteoporosis or fragile bone strength identified at either the hip or spine (vertebral trabecular BMD ≤80mg/cm3, femoral neck or total hip T-score ≤-2.5, vertebral strength ≤6500N and femoral strength ≤3500N, respectively) were considered to be at high risk of fracture. PET/CT- versus MDCT-based BMD and strength measurements were compared using paired t-tests, linear regression and by generating Bland-Altman plots. Agreement in fracture-risk classification was assessed in a contingency table. RESULTS: All measurements from PET/CT versus MDCT were strongly correlated (R2=0.93-0.97; P<0.0001 for all). Mean differences for total hip areal BMD (0.001g/cm2, 1.1%), femoral strength (-60N, 1.3%), vertebral trabecular BMD (2mg/cm3, 2.6%) and vertebral strength (150N; 1.7%) measurements were not statistically significant (P>0.05 for all), whereas the mean difference in femoral neck areal BMD measurements was small but significant (-0.018g/cm2; -2.5%; P=0.007). The agreement between PET/CT and MDCT for fracture-risk classification was 97% (0.89 kappa for repeatability). CONCLUSION: Ancillary analyses of BMD, bone strength, and fracture risk agreed well between PET/CT and MDCT, suggesting that PET/CT can be used opportunistically to comprehensively assess bone integrity. In subjects with high fracture risk such as cancer patients this may serve as an additional clinical tool to guide therapy planning and prevention of fractures.


Assuntos
Densidade Óssea/fisiologia , Tomografia Computadorizada com Tomografia por Emissão de Pósitrons/métodos , Neoplasias da Próstata/patologia , Neoplasias da Próstata/fisiopatologia , Absorciometria de Fóton , Idoso , Idoso de 80 Anos ou mais , Fenômenos Biomecânicos , Colo do Fêmur/patologia , Colo do Fêmur/fisiopatologia , Análise de Elementos Finitos , Humanos , Masculino , Pessoa de Meia-Idade , Osteoporose/patologia , Osteoporose/fisiopatologia
16.
JAMA Intern Med ; 177(4): 471-479, 2017 04 01.
Artigo em Inglês | MEDLINE | ID: mdl-28241231

RESUMO

Importance: As men age, they experience decreased serum testosterone concentrations, decreased bone mineral density (BMD), and increased risk of fracture. Objective: To determine whether testosterone treatment of older men with low testosterone increases volumetric BMD (vBMD) and estimated bone strength. Design, Setting, and Participants: Placebo-controlled, double-blind trial with treatment allocation by minimization at 9 US academic medical centers of men 65 years or older with 2 testosterone concentrations averaging less than 275 ng/L participating in the Testosterone Trials from December 2011 to June 2014. The analysis was a modified intent-to-treat comparison of treatment groups by multivariable linear regression adjusted for balancing factors as required by minimization. Interventions: Testosterone gel, adjusted to maintain the testosterone level within the normal range for young men, or placebo gel for 1 year. Main Outcomes and Measures: Spine and hip vBMD was determined by quantitative computed tomography at baseline and 12 months. Bone strength was estimated by finite element analysis of quantitative computed tomography data. Areal BMD was assessed by dual energy x-ray absorptiometry at baseline and 12 months. Results: There were 211 participants (mean [SD] age, 72.3 [5.9] years; 86% white; mean [SD] body mass index, 31.2 [3.4]). Testosterone treatment was associated with significantly greater increases than placebo in mean spine trabecular vBMD (7.5%; 95% CI, 4.8% to 10.3% vs 0.8%; 95% CI, -1.9% to 3.4%; treatment effect, 6.8%; 95% CI, 4.8%-8.7%; P < .001), spine peripheral vBMD, hip trabecular and peripheral vBMD, and mean estimated strength of spine trabecular bone (10.8%; 95% CI, 7.4% to 14.3% vs 2.4%; 95% CI, -1.0% to 5.7%; treatment effect, 8.5%; 95% CI, 6.0%-10.9%; P < .001), spine peripheral bone, and hip trabecular and peripheral bone. The estimated strength increases were greater in trabecular than peripheral bone and greater in the spine than hip. Testosterone treatment increased spine areal BMD but less than vBMD. Conclusions and Relevance: Testosterone treatment for 1 year of older men with low testosterone significantly increased vBMD and estimated bone strength, more in trabecular than peripheral bone and more in the spine than hip. A larger, longer trial could determine whether this treatment also reduces fracture risk. Trial Registration: clinicaltrials.gov Identifier: NCT00799617.


Assuntos
Densidade Óssea/efeitos dos fármacos , Fraturas do Quadril/prevenção & controle , Vértebras Lombares , Fraturas da Coluna Vertebral/prevenção & controle , Testosterona , Absorciometria de Fóton/métodos , Idoso , Androgênios/administração & dosagem , Androgênios/sangue , Androgênios/deficiência , Método Duplo-Cego , Vias de Administração de Medicamentos , Monitoramento de Medicamentos , Fraturas do Quadril/sangue , Fraturas do Quadril/diagnóstico , Humanos , Vértebras Lombares/diagnóstico por imagem , Vértebras Lombares/efeitos dos fármacos , Masculino , Fraturas da Coluna Vertebral/sangue , Fraturas da Coluna Vertebral/diagnóstico , Testosterona/administração & dosagem , Testosterona/sangue , Testosterona/deficiência , Tomografia Computadorizada por Raios X/métodos , Resultado do Tratamento
17.
J Orthop Res ; 35(4): 805-811, 2017 04.
Artigo em Inglês | MEDLINE | ID: mdl-27302535

RESUMO

Virtual stress testing (VST) provides a non-invasive estimate of the strength of a healing bone through a biomechanical analysis of a patient's computed tomography (CT) scan. We asked whether VST could improve management of patients who had a tibia fracture treated with external fixation. In a retrospective case-control study of 65 soldier-patients who had tibia fractures treated with an external fixator, we performed VST utilizing CT scans acquired prior to fixator removal. The strength of the healing bone and the amount of tissue damage after application of an overload were computed for various virtual loading cases. Logistic regression identified computed outcomes with the strongest association to clinical events related to nonunion within 2 months after fixator removal. Clinical events (n = 9) were associated with a low tibial strength for compression loading (p < 0.05, AUC = 0.74) or a low proportion of failed cortical bone tissue for torsional loading (p < 0.005, AUC = 0.84). Using post-hoc thresholds of a compressive strength of four times body-weight and a proportional of failed cortical bone tissue of 5%, the test identified all nine patients who failed clinically (100% sensitivity; 40.9% positive predictive value) and over three fourths of those (43 of 56) who progressed to successful healing (76.8% specificity; 100% negative predictive value). In this study, VST identified all patients who progressed to full, uneventful union after fixator removal; thus, we conclude that this new test has the potential to provide a quantitative, objective means of identifying tibia-fracture patients who can safely resume weight bearing. © 2016 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 35:805-811, 2017.


Assuntos
Tíbia/fisiopatologia , Fraturas da Tíbia/fisiopatologia , Tomografia Computadorizada por Raios X , Adulto , Área Sob a Curva , Fenômenos Biomecânicos , Estudos de Casos e Controles , Força Compressiva , Fixadores Externos , Feminino , Fixação de Fratura , Humanos , Masculino , Pessoa de Meia-Idade , Militares , Valor Preditivo dos Testes , Estudos Retrospectivos , Sensibilidade e Especificidade , Fraturas da Tíbia/diagnóstico por imagem , Fraturas da Tíbia/cirurgia , Resultado do Tratamento , Adulto Jovem
18.
J Bone Miner Res ; 32(1): 188-195, 2017 01.
Artigo em Inglês | MEDLINE | ID: mdl-27449958

RESUMO

Skeletal fluorosis (SF) is endemic in many countries and millions of people are affected worldwide, whereas in the United States SF is rare with occasional descriptions of unique cases. We report a 28-year-old American man who was healthy until 2 years earlier when he gradually experienced difficulty walking and an abnormal gait, left hip pain, loss of mobility in his right wrist and forearm, and progressive deformities including enlargement of the digits of both hands. Dual-energy X-ray absorptiometry (DXA) of his lumbar spine, femoral neck, total hip, and the one-third forearm revealed bone mineral density (BMD) Z-scores of +6.2, +4.8, +3.0, and -0.2, respectively. Serum, urine, and bone fluoride levels were all elevated and ultimately explained by chronic sniffing abuse of a computer cleaner containing 1,1-difluoroethane. Our findings reflect SF due to the unusual cause of inhalation abuse of difluoroethane. Because this practice seems widespread, particularly in the young, there may be many more such cases. © 2016 American Society for Bone and Mineral Research.


Assuntos
Doenças Ósseas/induzido quimicamente , Computadores , Exposição por Inalação/efeitos adversos , Adulto , Doenças Ósseas/diagnóstico por imagem , Doenças Ósseas/patologia , Cotovelo/diagnóstico por imagem , Colo do Fêmur/diagnóstico por imagem , Colo do Fêmur/patologia , Análise de Elementos Finitos , Humanos , Hidrocarbonetos Fluorados , Masculino , Pelve/diagnóstico por imagem , Tomografia Computadorizada por Raios X
19.
J Bone Miner Res ; 31(8): 1586-95, 2016 08.
Artigo em Inglês | MEDLINE | ID: mdl-27149403

RESUMO

Finite element analysis has not yet been validated for measuring changes in whole-bone strength at the hip or spine in people after treatment with an osteoporosis agent. Toward that end, we assessed the ability of a clinically approved implementation of finite element analysis to correctly quantify treatment effects on vertebral strength, comparing against direct mechanical testing, in cynomolgus monkeys randomly assigned to one of three 16-month-long treatments: sham surgery with vehicle (Sham-Vehicle), ovariectomy with vehicle (OVX-Vehicle), or ovariectomy with denosumab (OVX-DMAb). After treatment, T12 vertebrae were retrieved, scanned with micro-CT, and mechanically tested to measure compressive strength. Blinded to the strength data and treatment codes, the micro-CT images were coarsened and homogenized to create continuum-type finite element models, without explicit porosity. With clinical translation in mind, these models were then analyzed for strength using the U.S. Food and Drug Administration (FDA)-cleared VirtuOst software application (O.N. Diagnostics, Berkeley, CA, USA), developed for analysis of human bones. We found that vertebral strength by finite element analysis was highly correlated (R(2) = 0.97; n = 52) with mechanical testing, independent of treatment (p = 0.12). Further, the size of the treatment effect on strength (ratio of mean OVX-DMAb to mean OVX-Vehicle, as a percentage) was large and did not differ (p = 0.79) between mechanical testing (+57%; 95% CI [26%, 95%]) and finite element analysis (+51% [20%, 88%]). The micro-CT analysis revealed increases in cortical thickness (+45% [19%, 73%]) and trabecular bone volume fraction (+24% [8%, 42%]). These results show that a preestablished clinical finite element analysis implementation-developed for human bone and clinically validated in fracture-outcome studies-correctly quantified the observed treatment effects of denosumab on vertebral strength in cynomolgus monkeys. One implication is that the treatment effects in this study are well explained by the features contained within these finite element models, namely, the bone geometry and mass and the spatial distribution of bone mass. © 2016 American Society for Bone and Mineral Research.


Assuntos
Denosumab/farmacologia , Análise de Elementos Finitos , Ovariectomia , Coluna Vertebral/fisiologia , Animais , Fenômenos Biomecânicos , Osso Esponjoso/diagnóstico por imagem , Osso Esponjoso/efeitos dos fármacos , Osso Esponjoso/fisiologia , Osso Cortical/diagnóstico por imagem , Osso Cortical/efeitos dos fármacos , Osso Cortical/fisiologia , Feminino , Macaca fascicularis , Interpretação de Imagem Radiográfica Assistida por Computador , Coluna Vertebral/diagnóstico por imagem , Coluna Vertebral/efeitos dos fármacos , Microtomografia por Raio-X
20.
Bone ; 86: 58-67, 2016 May.
Artigo em Inglês | MEDLINE | ID: mdl-26924718

RESUMO

High-resolution peripheral quantitative computed tomography (HR-pQCT) provides in vivo three-dimensional (3D) imaging at the distal radius and tibia and has been increasingly used to characterize cortical and trabecular bone morphology in clinical studies. In this study, we comprehensively examined the accuracy of HR-pQCT and HR-pQCT based micro finite element (µFE) analysis predicted bone elastic stiffness and strength through comparisons with gold-standard micro computed tomography (µCT) based morphological/µFE measures and direct mechanical testing results. Twenty-six sets of human cadaveric distal radius and tibia segments were imaged by HR-pQCT and µCT. Microstructural analyses were performed for the registered HR-pQCT and µCT images. Bone stiffness and yield strength were determined by both HR-pQCT and µCT based linear and nonlinear µFE predictions and mechanical testing. Our results suggested that strong and significant correlations existed between the HR-pQCT standard, model-independent and corresponding µCT measurements. HR-pQCT based nonlinear µFE overestimated stiffness and yield strength while the linear µFE underestimated yield strength, but both were strongly correlated with those predicted by µCT µFE and measured by mechanical testing at both radius and tibia (R(2)>0.9). The microstructural differences between HR-pQCT and µCT were also examined by the Bland-Altman plots. Our results showed HR-pQCT morphological measurements of BV/TV(d), Tb.Th, and Tb.Sp, can be adjusted by correction values to approach true values measured by gold-standard µCT. In addition, we observed moderate correlations of HR-pQCT biomechanical and microstructural parameters between the distal radius and tibia. We concluded that morphological and mechanical properties of human radius and tibia bone can be assessed by HR-pQCT based measures.


Assuntos
Simulação por Computador , Rádio (Anatomia)/diagnóstico por imagem , Rádio (Anatomia)/fisiologia , Tíbia/diagnóstico por imagem , Tíbia/fisiologia , Tomografia Computadorizada por Raios X , Idoso , Fenômenos Biomecânicos , Feminino , Análise de Elementos Finitos , Humanos , Modelos Lineares , Masculino , Rádio (Anatomia)/anatomia & histologia , Reprodutibilidade dos Testes , Tíbia/anatomia & histologia , Microtomografia por Raio-X
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