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Purpose: To investigate the influence of hyperthermia up to 45 degrees C on fibrinolysis with recombinant tissue-type plasminogen activator (rt-PA).Methods: Standardized fibrin clots were incubated in a water bath for 5 hr with either rt-PA (test group) or 0.9% sodium chloride (control group) and blood plasma at temperatures of 30-45 degrees C. Concentrations of D-dimer and time to complete clot lysis were measured.Results: The activity of fibrinolysis with rt-PA rose with increasing temperature: time to lysis approximately halved from 30 degrees C to 40 degrees C and the concentration of D-dimer tripled. In the control group clot size did not change.Conclusions: Activity of rt-PA-induced fibrinolysis rises distinctly with higher temperatures. Since even healthy subjects show a physiologic decline in body temperature in the extremities, in patients with occlusive arterial disease decreased activity of fibrinolysis with rt-PA can be expected. Controlled hyperthermia may improve fibrinolysis with rt-PA and should be investigated in vivo. [ABSTRACT FROM AUTHOR]

In 100 patients (20 male, 80 female) radiographs of the lumbar spine were obtained in both planes, anteroposterior and lateral. Nine readers independently and without specific criteria or training assessed the radiographs for presence of osteopenia in the form of a binary decision. A posteranterior dual x-ray absorptiometry (PA DXA) measurement of the lumbar spine was performed in all patients using the Hologic QDR 1000 bone densitometer. A bone mineral density (BMD) of 0.83 g/cm2 (T-score about 2 SD and 2.5 SD lower than BMD in normal young female and male subjects respectively) was used as a threshold for the diagnosis of osteopenia. Complete agreement amongst the 9 readers was achieved in 43 patients. In 26 more patients at least 8 readers agreed. kappa-coefficients for interobserver variation ranged from 0.458 to 0.691 for reader pairs. For agreement between the observer ratings and the DXA results, kappa-coefficients ranging between 0.347 and 0.555 were found. The vast majority of readers agreed in the diagnosis of osteopenia in cases where the BMD was less than 0.73 g/cm2. Where the BMD was between 0.73 and 1.03 g/cm2 a substantial disagreement was found between reader evaluation and DXA measurement, and also amongst the readers. We conclude from our results that osteopenia can reliably be detected from lumbar spine radiographs by all readers only after a substantial amount of BMD is lost. On the other hand, a diagnosis based solely on PA DXA measurement of the spine may also lack accuracy, due to a substantial influence of degenerative changes of the lumbar spine and aortic calcification.(ABSTRACT TRUNCATED AT 250 WORDS) [ABSTRACT FROM AUTHOR]

We investigated whether quantitative ultrasound (QUS) parameters are associated with bone structure. In an in vitro study on 20 cubes of trabecular bone, we measured broadband ultrasound attenuation (BUA) and two newly defined parameters--ultrasound velocity through bone (UVB) and ultrasound attenuation in bone (UAB). Bone mineral density (BMD) was measured by dual X-ray absorptiometry (DXA) and bone structure was assessed by microcomputed tomography (microCT) with approximately 80 microns spatial resolution. We found all three QUS parameters to be significantly associated with bone structure independently of BMD. UVB was largely influenced by trabecular separation, UAB by connectivity, and BUA by a combination of both. For a one standard deviation (SD) increase in UVB, a decrease in trabecular separation of 1.2 SD was required compared with a 1.4 SD increase in BMD for the same effect. A 1.0 SD increase in UAB required a reduction in connectivity of 1.4 SD. Multivariate models of QUS versus BMD combined with bone structure parameters showed squared correlation coefficients of r2 = 0.70-0.85 for UVB, r2 = 0.27-0.56 for UAB, and r2 = 0.30-0.68 for BUA compared with r2 = 0.18-0.58 for UVB, r2 < 0.26 for UAB and r2 < 0.13 for BUA for models including BMD alone. QUS thus reflects bone structure, and a combined analysis of QUS and BMD will allow for a more comprehensive assessment of skeletal status than either method alone. [ABSTRACT FROM AUTHOR]

In this study, the cross-calibration of a fan beam DXA system (Hologic QDR-2000) to a pencil beam scanner from the same manufacturer (Hologic QDR-1000/W) is described. The scanners were calibrated by the manufacturer using the same anthropomorphic spine phantom at installation. To verify consistent machine calibration, a group of 69 female subjects, aged 46-75, had anteroposterior (AP) spine and proximal femur scans on the QDR-1000/W followed by pencil and array scans of the same sites on the QDR-2000 during the same visit. Many of the subjects had bilateral examinations of the proximal femur for a total of 123 hip scans. Pencil and array area, bone mineral content (BMC), and bone mineral density (BMD) from the QDR-2000 were compared with the values obtained on the QDR-1000/W, and linear regression equations were derived for relating the two instruments. At the spine, no differences were found between the QDR-1000/W BMD values and the QDR-2000 array BMD values. A slight difference between pencil beam modes was detected but was not deemed clinically significant. Linear regression models relating the QDR-2000 and QDR-1000/W AP spine BMD measurements showed correlation coefficients greater than 0.99, with slopes of 1.00, intercepts equivalent to zero, and small root mean square errors. Comparisons at the proximal femur showed equivalency at the femoral neck and trochanter regions for the two machines in pencil mode, but slight increases in BMC and BMD at the other femoral sites on the QDR-2000 in both pencil and array mode. Correlation coefficients were 0.97-0.99 for all measurement regions except for Ward's.(ABSTRACT TRUNCATED AT 250 WORDS) [ABSTRACT FROM AUTHOR]

Summary: We reviewed the experimental and clinical evidence that hip bone strength estimated by BMD and/or finite element analysis (FEA) reflects the actual strength of the proximal femur and is associated with hip fracture risk and its changes upon treatment. Introduction: The risk of hip fractures increases exponentially with age due to a progressive loss of bone mass, deterioration of bone structure, and increased incidence of falls. Areal bone mineral density (aBMD), measured by dual-energy X-ray absorptiometry (DXA), is the most used surrogate marker of bone strength. However, age-related declines in bone strength exceed those of aBMD, and the majority of fractures occur in those who are not identified as osteoporotic by BMD testing. With hip fracture incidence increasing worldwide, the development of accurate methods to estimate bone strength in vivo would be very useful to predict the risk of hip fracture and to monitor the effects of osteoporosis therapies. Methods: We reviewed experimental and clinical evidence regarding the association between aBMD and/orCT-finite element analysis (FEA) estimated femoral strength and hip fracture risk as well as their changes with treatment. Results: Femoral aBMD and bone strength estimates by CT-FEA explain a large proportion of femoral strength ex vivo and predict hip fracture risk in vivo. Changes in femoral aBMD are strongly associated with anti-fracture efficacy of osteoporosis treatments, though comparable data for FEA are currently not available. Conclusions: Hip aBMD and estimated femoral strength are good predictors of fracture risk and could potentially be used as surrogate endpoints for fracture in clinical trials. Further improvements of FEA may be achieved by incorporating trabecular orientations, enhanced cortical modeling, effects of aging on bone tissue ductility, and multiple sideway fall loading conditions. [ABSTRACT FROM AUTHOR]

Introduction Established scores estimate 10-year fracture risk in osteoporosis to assist with treatment recommendations. This study compared the risk probabilities of major osteoporotic and hip fractures calculated by the FRAX tool with those of the DVO score, established in German-speaking countries. Material and Methods This seven-year retrospective study analyzed data of 125 male patients (mean age: 59.2±10.7 years) evaluated for osteoporosis. For the DVO score, the therapy threshold of>30% for vertebral and hip fractures suggested by DVO guidelines was implemented. We calculated fracture risks based on FRAX scores with aBMD and applied a common therapy threshold of≥3% for hip fracture and subsequently determined the "DVO-equivalent risk level" for FRAX-based assessment that would identify as many male patients as identified by the DVO score. Results Based on DVO score, 60.0% of patients had a 10-year risk of hip and vertebral fractures>30%. The recommendations for individuals based on FRAX scores for hip fracture with aBMD with risk≥3% overlapped with those based on DVO score in 36% of patients. Patients identified for treatment only by DVO score presented a higher percentage of spine fractures (65 vs. 41%). The thresholds for this "DVO-equivalent risk level" for 'FRAX with aBMD' was estimated to be≥6.7% for major osteoporotic fracture and≥2.1% for hip fracture. This study demonstrates that the DVO score was more sensitive than the FRAX score for patients with prevalent spinal fractures. We suggest considering the appropriate score and therapy threshold carefully in the daily care of male patients. [ABSTRACT FROM AUTHOR]

The treatment of osteoporotic patients with teriparatide is associated with a significant increase in bone formation and gain of bone mass. The purpose of this post hoc analysis was to determine if the cross-sectional area (CSA) of the spinal canal and the vertebral body is affected by teriparatide treatment. Narrowing of the spinal canal might represent a safety problem, while widening of the vertebral CSA might improve mechanical stability. High-resolution computed tomography (HRCT) scans of vertebra T12 were obtained at baseline and after 6, 12, and 24 months of teriparatide treatment (20 microg/day) from 44 postmenopausal women with established osteoporosis participating in the prospective, randomized EUROFORS study. The CSA of the spinal canal did not decrease but increased marginally by 0.9% (2.6 mm(2)) over 24 months (P < 0.001), with a range from -0.5% (-2 mm(2)) to 3.1% (+8 mm(2)). Even when analyzing the spinal CSA on a slice-by-slice basis, no clinically relevant narrowing of the spinal canal was observed. For vertebral bodies, the CSA increased by 0.7% (5.7 mm(2)) over 24 months (P < 0.001), with a range from -0.4% (-3 mm(2)) to 1.6% (+14 mm(2)). Our data do not provide evidence for safety concerns regarding spinal canal narrowing. On the other hand, the increases observed for vertebral CSA apparently also only minimally contribute to the mechanical strengthening of the vertebral body under teriparatide treatment. [ABSTRACT FROM AUTHOR]

Bone mineral density (BMD) measured with dual energy X-ray absorptiometry (DXA) techniques is the current gold standard for osteoporotic fracture risk prediction. Quantitative ultrasound (QUS) techniques in transmission measurements are, however, increasingly recognized as an alternative approach. It is feasible to select different QUS methods, one type being optimized to assess microarchitectural properties of bone structure and another to assess BMD. Broadband ultrasonic attenuation (BUA) and ultrasonic velocity (UV) measured on the proximal human femur have been shown to be both significantly correlated with BMD. However, a great diversity of algorithms has been reported to measure the time-of-flight used to derive UV values. The purpose of this study was to determine which procedure results in the optimal BMD prediction at the proximal femur from ultrasound measurements. Thirty-eight excised human femurs were measured in transmission with a pair of focused 0.5-MHz central frequency transducers. Two-dimensional scans were performed and radiofrequency (RF) signals were recorded digitally at each scan position. BUA was estimated and eight different signal processing techniques were performed to estimate UV. For each signal-processing technique UV was compared to BMD. We show that the best prediction of BMD was obtained with signal-processing techniques taking into account only the first part of the transmitted signal (r2BMD-SOS = 0.86). Moreover, we show that a linear multiple regression using both BUA and speed of sound (SOS) and applied to site-matched regions of interest improved the accuracy of BMD predictions (r2BMD-SOS/BUA = 0.95). Our results demonstrate that selecting specific signal-processing methods for QUS variables allows optimal assessment of BMD. Correlation is sufficiently high that this specific QUS method can be considered as a good surrogate of BMD. [ABSTRACT FROM AUTHOR]

Abstract: Quantitative ultrasound has been recognized as a useful tool for fracture risk prediction. Current measurement techniques are limited to peripheral skeletal sites. Our objective was to demonstrate the in vitro feasibility of ultrasonic velocity measurements on human proximal femur and to investigate the relationship between velocity and bone mineral density (BMD). Sound velocity images were computed from 2-D scans performed on 38 excised human femurs in transmission at 0.5 MHz. Different regions-of-interest were investigated. Dual x-ray absorptiometry scans have been achieved for BMD measurements in site-matched regions. Our study demonstrates the feasibility of ultrasonic velocity measurements at the hip with reasonable precision (coefficient of variation of 0.3%). The best prediction of BMD was reached in the intertrochanter region (r2 = 0.91, p &#60; 10−4), with a residual error of 0.06 g/cm2 (10%). Because BMD measured at the femur is the best predictor of hip fracture risk, the highly significant correlation and small residual error found in this study suggest that speed of sound measurement at the femur might be a good candidate for hip fracture risk prediction. (E-mail: Frederic.padilla@lip.bhdc.jussieu.fr) [Copyright &y& Elsevier]

Summary The Risk-stratified Osteoporosis Strategy Evaluation (ROSE) study investigated the effectiveness of a two-step screening program for osteoporosis in women. We found no overall reduction in fractures from systematic screening compared to the current case-finding strategy. The group of moderate- to high-risk women, who accepted the invitation to DXA, seemed to benefit from the program. Introduction The purpose of the ROSE study was to investigate the effectiveness of a two-step population-based osteoporosis screening program using the Fracture Risk Assessment Tool (FRAX) derived from a self-administered questionnaire to select women for DXA scan. After the scanning, standard osteoporosis management according to Danish national guidelines was followed. Methods Participants were randomized to either screening or control group, and randomization was stratified according to age and area of residence. Inclusion took place from February 2010 to November 2011. Participants received a self-administered questionnaire, and women in the screening group with a FRAX score ≥ 15% (major osteoporotic fractures) were invited to a DXA scan. Primary outcome was incident clinical fractures. Intention-to-treat analysis and two per-protocol analyses were performed. Results A total of 3416 fractures were observed during a median follow-up of 5 years. No significant differences were found in the intention-to-treat analyses with 34,229 women included aged 65–80 years. The per-protocol analyses showed a risk reduction in the group that underwent DXA scanning compared to women in the control group with a FRAX ≥ 15%, in regard to major osteoporotic fractures, hip fractures, and all fractures. The risk reduction was most pronounced for hip fractures (adjusted SHR 0.741, p = 0.007). Conclusions Compared to an office-based case-finding strategy, the two-step systematic screening strategy had no overall effect on fracture incidence. The two-step strategy seemed, however, to be beneficial in the group of women who were identified by FRAX as moderate- or high-risk patients and complied with DXA. [ABSTRACT FROM AUTHOR]

Summary: Population-based screening for osteoporosis is still controversial and has not been implemented. Non-participation in systematic screening was evaluated in 34,229 women age 65-81 years. Although participation rate was high, non-participation was associated with comorbidity, aging other risk factors for fractures, and markers of low social status, e.g., low income, pension, and living alone. A range of strategies is needed to increase participation, including development of targeted information and further research to better understand the barriers and enablers in screening for osteoporosis. Introduction: Participation is crucial to the success of a screening program. The objective of this study was to analyze non-participation in Risk-stratified Osteoporosis Strategy Evaluation, a two-step population-based screening program for osteoporosis. Methods: Thirty-four thousand two hundred twenty-nine women aged 65 to 81 years were randomly selected from the background population and randomized to either a screening group (intervention) or a control group. All women received a self-administered questionnaire designed to allow calculation of future risk of fracture based on FRAX. In the intervention group, women with an estimated high risk of future fracture were invited to DXA scanning. Information on individual socioeconomic status and comorbidity was obtained from national registers. Results: A completed questionnaire was returned by 20,905 (61%) women. Non-completion was associated with older age, living alone, lower education, lower income, and higher comorbidity. In the intervention group, ticking 'not interested in DXA' in the questionnaire was associated with older age, living alone, and low self-perceived fracture risk. Women with previous fracture or history of parental hip fracture were more likely to accept screening by DXA. Dropping out when offered DXA, was associated with older age, current smoking, higher alcohol consumption, and physical impairment. Conclusions: Barriers to population-based screening for osteoporosis appear to be both psychosocial and physical in nature. Women who decline are older, have lower self-perceived fracture risk, and more often live alone compared to women who accept the program. Dropping out after primary acceptance is associated not only with aging and physical impairment but also with current smoking and alcohol consumption. Measures to increase program participation could include targeted information and reducing physical barriers for attending screening procedures. [ABSTRACT FROM AUTHOR]

Type 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: R 2 = 0.41, p < 0.001, Ct.Po: R 2 = 0.34, p = 0.003) and HbA1c (NEG: R 2 = 0.42, p < 0.001, Ct.Po: R 2 = 0.28, p = 0.008) levels, while NEG correlated negatively with bone biomechanics (elastic modulus: R 2 = 0.21, p = 0.023, yield stress: R 2 = 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. [ABSTRACT FROM AUTHOR]