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Rodent models are commonly used in pre-clinical research of magnesium (Mg)-based and other types of biomaterials for fracture treatment. Most studies selected unstable fixation methods, and there is a lack of multimodal longitudinal in vivomonitoring of bone healing. The purpose of this study is to develop a rat femoral fracture model stabilized by external fixation with intra-medullary Mg implant, and to investigate the dynamic bone union process with several imaging techniques offering complementing insights into the process. Pure Mg pins were prepared, followed by an in vitrodegradation test. Male Sprague-Dawley rats in the experimental group underwent femoral osteotomy stabilized by external fixators with intra-medullary implantation of Mg pins, and the control group underwent external fixation without intra-medullary implants. Post-operative radiograph, micro-CT and B-mode ultrasonography were acquired directly after surgery, and re-examined at week 4, 8 and 12. Bone tissue volume, in vivoimplant degradation, histological staining and MRI images were analyzed using ex vivosamples. Both groups achieved fracture union at week 12, and the dynamic healing process was illustrated by in vivoradiograph, micro-CT and ultrasonography. Bilateral whole femur ex vivoanalysis further demonstrated increased ratio of bone tissue volume in the surgical femur with Mg implants, and in vivodegradation of Mg pins was slower than in vitroresults. Titanium screws rather than intra-medullary Mg pins were the source of artifact in MRI. This pilot study showed the rat fracture model with external fixation and intra-medullary Mg implantation to be an effective method for dynamic in vivomonitoring of the bone healing process. Future application of the animal model may facilitate pre-clinical translational research of biodegradable orthopaedic implant materials for fracture treatment.

X-ray-based analytics are routinely applied in many fields, including physics, chemistry, materials science, and engineering. The full potential of such techniques in the life sciences and medicine, however, has not yet been fully exploited. We highlight current and upcoming advances in this direction. We describe different X-ray-based methodologies (including those performed at synchrotron light sources and X-ray free-electron lasers) and their potentials for application to investigate the nano–bio interface. The discussion is predominantly guided by asking how such methods could better help to understand and to improve nanoparticle-based drug delivery, though the concepts also apply to nano–bio interactions in general. We discuss current limitations and how they might be overcome, particularly for future use in vivo.

Background: Nanoparticle imaging and tracking the release of the loaded material from the nanoparticle system have attracted significant attention in recent years. If the release of the loaded molecules could be monitored reliably in vivo, it would speed up the development of drug delivery systems remarkably. Methods: Here, we test a system that uses indocyanine green (ICG) as a fluorescent agent for studying release kinetics in vitro and in vivo from the lipid iron nanoparticle delivery system. The ICG spectral properties like its concentration dependence, sensitivity and the fluctuation of the absorption and emission wavelengths can be utilized for gathering information about the change of the ICG surrounding. Results: We have found that the absorption, fluorescence, and photoacoustic spectra of ICG in lipid iron nanoparticles differ from the spectra of ICG in pure water and plasma. We followed the ICG containing liposomal nanoparticle uptake into squamous carcinoma cells (SCC) by fluorescence microscopy and the in vivo uptake into SCC tumors in an orthotopic xenograft nude mouse model under a surgical microscope. Conclusion: Absorption and emission properties of ICG in the different solvent environment, like in plasma and human serum albumin, differ from those in aqueous solution. Photoacoustic spectral imaging confirmed a peak shift towards longer wavelengths and an intensity increase of ICG when bound to the lipids. The SCC cells showed that the ICG containing liposomes bind to the cell surface but are not internalized in the SCC-9 cells after 60 minutes of incubation. We also showed here that ICG containing liposomal nanoparticles can be traced under a surgical camera in vivo in orthotopic SCC xenografts in mice.

Osteoporotic fractures are a major health challenge in older adults. Despite the availability of safe and effective therapies for osteoporosis, these therapies are underused in individuals at high risk for fracture, calling for better case-finding and fracture risk assessment strategies. Artificial intelligence (AI) and machine learning (ML) hold promise for enhancing identification of individuals at high risk for fracture by distilling useful features from high-dimensional data derived from medical records, imaging, and wearable devices. AI–ML could enable automated opportunistic screening for vertebral fractures and osteoporosis, home-based monitoring and intervention targeting lifestyle factors, and integration of multimodal features to leverage fracture prediction, ultimately aiding improved fracture risk assessment and individualised treatment. Optimism must be balanced with consideration for the explainability of AI–ML models, biases (including information inequity in numerically under-represented populations), model limitations, and net clinical benefit and workload impact. Clinical integration of AI–ML algorithms has the potential to transform osteoporosis management, offering a more personalised approach to reduce the burden of osteoporotic fractures.

In an in vitro study, we found significant associations between QUS variables and properties and geometrical parameters of the compact bone of human finger phalanges. QUS variables were not only related to BMD but also to other skeletal properties, which explained 70% of the variability of speed of sound.Introduction:Transverse transmission quantitative ultrasound (QUS) measurements at the finger phalanges are known to be correlated with BMD and to predict osteoporotic fractures. To determine which other skeletal properties are affected by ultrasound, we investigated the impact of density, geometry, and porosity on QUS variables in vitro.Materials and Methods:Ultrasound variables were correlated with density, porosity, and geometrical characteristics of cortical bone. Additionally, we tested which combinations of geometry and bone properties best predicted the ultrasound results observed. Forty‐four proximal phalanges from the middle finger were investigated at their distal metaphysis, similar to the typical clinical measurement procedure. Donor age ranged from 52 to 98 years (15 males and 29 females; mean age, 80.9 ± 9.4 years). QUS variables were measured on the metaphysis of the phalanges using the DBMSonic 1200. Quantitative CT was used for the measurement of BMD, and high‐resolution MRI was used for the measurement of porosity and geometrical variables.Results:Speed of sound (SOS) and the clinically used variable AD‐SOS correlated significantly with area, relative area, density, and porosity of the compact bone (R2= 0.28‐0.58, p< 0.0001). Signal amplitude correlated significantly only with relative area of the compact bone and area of the medullary canal (R2= 0.18‐0.20, p< 0.01). The combination of cortical area, density, and porosity improved the determination of SOS to R2= 0.70, with a residual unexplained variability of 54 m/s (3.2%).Conclusions:These results clarify the impact of skeletal properties on QUS variables. SOS is affected by cortical area, cortical bone density, and cortical porosity, whereas attenuation only depends on geometry of the medulla. AD‐SOS, the variable routinely measured in clinical practice, is primarily affected by cortical area. QUS of the finger phalanges is not only related to BMD but also to other skeletal properties.

In an in vitro study, we found significant associations between QUS variables and properties and geometrical parameters of the compact bone of human finger phalanges. QUS variables were not only related to BMD but also to other skeletal properties, which explained 70% of the variability of speed of sound.

We compared the performance of five QUS devices with DXA in a population‐based sample of 2837 women. All QUS approaches discriminated women with and without osteoporotic vertebral fractures. QUS of the calcaneus performed as well as central DXA.

We compared the performance of five QUS devices with DXA in a population‐based sample of 2837 women. All QUS approaches discriminated women with and without osteoporotic vertebral fractures. QUS of the calcaneus performed as well as central DXA.Introduction:Quantitative ultrasound (QUS) methods have found widespread use for the assessment of bone status in osteoporosis, but their optimal use remains to be established. To determine QUS performance for current devices in direct comparison with central DXA, we initiated a large population‐based investigation, the Osteoporosis and Ultrasound Study (OPUS).Materials and Methods:A total of 463 women 20–39 years of age and 2374 women 55–79 years of age were measured on five different QUS devices along with DXA of the spine and the proximal femur. Their vertebral fracture status was evaluated radiographically. The association of QUS and DXA with vertebral fracture status was evaluated using logistic regression.Results:All QUS approaches tested discriminated women with and without osteoporotic vertebral fractures (20% height reduction), with age‐adjusted standardized odds ratios ranging 1.2–1.3 for amplitude‐dependent speed of sound (AD‐SOS) at the finger phalanges, 1.2–1.4 for broadband ultrasound attenuation (BUA) at the calcaneus, and 1.4–1.5 for speed of sound (SOS) at the calcaneus, 1.4–1.6 for DXA of the total femur, and 1.5–1.6 for DXA at the spine. For more severe fractures (40% height reduction), age‐adjusted standardized odds ratios increased to up to 1.9 for DXA of the spine and 2.3 for SOS of the calcaneus.Conclusions:In conclusion, all five QUS devices tested showed significant age‐adjusted differences between subjects with and without vertebral fracture. When selecting the strongest variable, QUS of the calcaneus worked as well as central DXA for identification of women at high risk for prevalent osteoporotic vertebral fractures. QUS‐based case‐finding strategies would allow halving the number of radiographs in high‐risk populations, and this strategy works increasingly well for women with more severe vertebral fractures. It is likely that the good performance of QUS was in part achieved by rigorous quality assurance measures that should also be used in clinical practice.

Bone densitometry is an established method for the assessment of osteoporosis as, according to the definition of osteoporosis, an accurate determination of the level of bone mass is central to the diagnostic assessment of osteoporosis. The diversity of different bone densitometry techniques, however, needs to be acknowledged. The World Health Organization criteria of osteoporosis should not be used for peripheral measurements, and their application to subject groups other than white women is still controversial. A large variety of bone densitometry and quantitative ultrasound techniques can be used for fracture risk assessment. Their results should be interpreted in the context of other clinical examinations and can then be used in making treatment decisions. For monitoring purposes, the ratio of response rate and long-term precision error determines longitudinal sensitivity. For all of these applications, careful quality assurance procedures need to be implemented. If applied in a responsible fashion, bone densitometry represents a powerful approach that is indispensable for the assessment of osteoporosis.

The longitudinal sensitivity of a technique, i.e., its ability to monitor skeletal changes, is affected by two parameters: the long‐term precision error (PElt) and the subject group‐specific response rate (i.e., annual rates of change). Both need to be considered to avoid misinterpretation of measured changes. A new concept to aid clinical decision making for longitudinal measurements is proposed which is based on three types of measures: criteria for detecting changes—the “least significant change” (LSC) is the smallest change to be considered statistically significant, but for certain clinical questions a smaller margin, the “trend assessment margin” (TAM), can be sufficient for decision making; follow‐up time intervals—for follow‐up exams the patient should be called in at about the time interval specified by the (population specific) “monitoring time interval” (MTI) or, about one‐third of the time earlier, after the “trend assessment interval” (TAI), depending on whether the decision can be based on the LSC or the TAM; and the standard precision error (stdPE)—the smaller stdPE, the more sensitive the technique to monitor skeletal changes. Together, these three measures yield a good characterization of a technique's ability to monitor skeletal changes. Compared with previous concepts, the proposed standardization by a response ratio instead of measures of spread or response rates makes the stdPE substantially less subject group dependent. It allows comparison of stdPE across different studies and could replace the misleading concept of expressing precision as a coefficient of variation. Application of this concept should facilitate the interpretation of measured skeletal changes.

The longitudinal sensitivity of a technique, i.e., its ability to monitor skeletal changes, is affected by two parameters: the long‐term precision error (PElt) and the subject group‐specific response rate (i.e., annual rates of change). Both need to be considered to avoid misinterpretation of measured changes. A new concept to aid clinical decision making for longitudinal measurements is proposed which is based on three types of measures: criteria for detecting changes—the “least significant change” (LSC) is the smallest change to be considered statistically significant, but for certain clinical questions a smaller margin, the “trend assessment margin” (TAM), can be sufficient for decision making; follow‐up time intervals—for follow‐up exams the patient should be called in at about the time interval specified by the (population specific) “monitoring time interval” (MTI) or, about one‐third of the time earlier, after the “trend assessment interval” (TAI), depending on whether the decision can be based on the LSC or the TAM; and the standard precision error (stdPE)—the smaller stdPE, the more sensitive the technique to monitor skeletal changes. Together, these three measures yield a good characterization of a technique's ability to monitor skeletal changes. Compared with previous concepts, the proposed standardization by a response ratio instead of measures of spread or response rates makes the stdPE substantially less subject group dependent. It allows comparison of stdPE across different studies and could replace the misleading concept of expressing precision as a coefficient of variation. Application of this concept should facilitate the interpretation of measured skeletal changes.

The authors determine flow characteristics and pressure gradients of different stents and stent grafts in an in vitro flow-model.

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. Regression slopes relating the BMD for the femoral regions were 1.00–1.04, with intercepts not significantly different from zero and small residual errors. As with the spine, the differences were small enough that they were not of clinical significance. However, in longitudinal drug trials requiring highly precise determination of spinal and femoral BMD changes, these differences may be important.

Jedes der Standardverfahren der Knochendensitometrie hat seine spezifischen Fehlergrenzen. Die Reproduzierbarkeit der Meßergebnisse der Ein-Energie-Röntgen-Absorptiometrie (SXA) bzw. deren Vorläuferin, der Ein-Photonen-Absorptiometrie (SPA), ist in erster Linie durch Beschränkung der Repositionierungs-genauigkeit begrenzt. Für die Zwei-Energien-Röntgen-Absorptiometrie (DXA) bzw. deren Vorläuferin, die Zwei-Photonen-Absorptiometrie (DPA), sind extraskeletale Kalzifikationen und degenerative Veränderungen der Wirbelsäule als Probleme zu nennen; aufgrund des relativ hohen Reproduzierbarkeitsfehlers ist die DPA als Meßverfahren nicht mehr zeitgemäß. Für die Quantitative Computertomographie (QCT) kommen in erster Linie der Fettfehler und Kalibrierprobleme infolge von Feldinhomogenität zum Tragen. Daneben können vermeidbare Fehler bei Aufnahme und Analyse der Meßdaten das Ergebnis verfälschen. Während die QCT eine selektive Messung des stoffwechselaktiveren trabekulären Knochens ermöglicht, bietet die DXA derzeit eine bessere Reproduzierbarkeit, was insbesondere bei Verlaufsuntersuchungen von Vorteil ist. Aufgrund der höheren Komplexität stellt die QCT generell höhere Anforderungen an den Anwender. Die Zukunft der SPA/SXA wird kontrovers eingeschätzt. Für alle Verfahren sind stringente Maßnahmen der Qualitätssicherung notwendig. Generell gilt, daß alle Verfahren bei konsequenter Qualitätssicherung verläßliche und aussagekräftige Ergebnisse bezüglich des Knochenmineralstatus des jeweils vermessenen Meßortes liefern.

Im zweiten Teil dieses Übersichtsartikels werden verschiedene Verfahren der Quantitativen Computertomographie (QCT) dargestellt. QCT ist neben den absorptiometrischen Verfahren das am weitesten verbreitete Standardverfahren der Knochendensitometrie und wird vorwiegend als Ein-Energie-QCT (SEQCT), teilweise aber auch als Zwei-Energien-QCT (DEQCT) eingesetzt. Ausgehend von einer Darstellung ihrer physikalischen und technischen Grundlagen werden Einsatzmöglichkeiten und Anwendungsgrenzen dargestellt. QCT ist als Routineuntersuchung gegenwärtig auf Messungen an der Wirbelsäule beschränkt, ermöglicht jedoch als einziges Verfahren die Bestimmung der echten Volumenknochenmineraldichte. Sie ist damit zur selektiven Analyse von trabekulärem und kortikalem Knochen geeignet. Für QCT werden neben dem gebräuchlichen SEQCT-Verfahren auch verschiedene DEQCT-Verfahren dargestellt und einer vergleichenden Analyse der zugrundeliegenden physikalischen Prinzipien unterzogen.

Die Diagnostik und Verlaufskontrolle der Osteoporose eifordert eine genaue Kenntnis des Knochenmineralgehaltes. Zu dessen Bestimmung stehen mehrere nicht-invasive Verfahren der Knochendensitometrie zur Verfügung. Derzeit werden vor allem drei Standardverfahren eingesetzt: die Ein-Energie-Röntgen-Absorptiometrie (SXA) bzw. deren Vorläufer, die Ein-Photonen-Absorptiometrie (SPA), ferner die Zwei-Energien-Röntgen-Absorptiometrie (DXA) bzw. deren Vorläufer, die Zwei-Photonen-Absorptiometrie (DPA) und die Quantitative Computertomographie (QCT), vorwiegend als Ein-Energie-QCT (SEQCT), teilweise aber auch als Zwei-Energien-QCT (DEQCT). Basierend auf einer Darstellung ihrer physikalischen und technischen Grundlagen werden Einsatzmöglichkeiten und Grenzen dieser Verfahren dargestellt. Im ersten Teil dieses Übersichtsartikels werden die absorptiometrischen Methoden behandelt. SPA/SXA Verfahren sind auf periphere Meßorte beschränkt und liefern primär eine lineare Knochenmineraldichte. DXA hingegen erlaubt die Messung der wichtigsten Frakturorte, d.h. Wirbelsäule und proximaler Femur, und liefert eine Flächenknochenmineraldichte.

The comparison of patient data among different dual x‐ray absorptiometry (DXA) scanners is complicated because no universally accepted cross‐calibration procedure or standard currently exists. This study was performed under the auspices of the International DXA Standardization Committee to establish appropriate cross‐calibration parameters. Posteroanterior (PA) lumbar spine measurements of 100 women, ages 20–80 years (mean 52.6 + 16, range of BMD = 0.4–1.6 g/cm2) were obtained on a Norland XR26 Mark II, a Lunar DPX‐L, and a Hologic QDR 2000 densitometer using standard procedures (pencil beam mode for all three scanners). Area, BMC, and BMD results from the different scanners were compared for all patients. In addition, the European spine phantom (ESP) and the European spine phantom prototype (ESP prototype), as well as standard phantoms from all three manufacturers, were evaluated on the three systems. To achieve universal scanner calibration, we used the intercept and slope of the patient's correlations and the value of the middle vertebra of the ESP as a reference point in a series of standardization formulas, and we have expressed the results as sBMD (mg/cm2). The correlations of the patients' spinal BMD values were excellent for each of the three scanner pairs. The average absolute difference in patient spinal BMD values (L2–4) between Hologic and Norland was 0.012 g/cm2(1.3%); it was 0.113 g/cm2(11.7%) between Hologic and Lunar and 0.118 g/cm2(12.2%) between Norland and Lunar. The phantoms' regression lines approximated those of the patient regression lines, and the phantoms with only one measurement point were very close to the patients' regression lines. After applying the standardization formulas, the average absolute differences for the 100 patients were 28 mg/cm2(2.7%) for Hologic/Norland, 23 mg/cm2(2.2%) for Hologic/Lunar, and 29 mg/cm2(2.8%) for Norland/Lunar. Average BMD results for the patients before correction were 0.972 g/cm2for Hologic, 1.100 g/cm2for Lunar, and 0.969 g/cm2for Norland. After correction, sBMD results for patients were 1045 mg/cm2for Hologic, 1047 mg/cm2for Lunar, and 1043 mg/cm2for Norland. The standardization approach as performed in our study provided compatibility of DXA results obtained on different scanners.

Bone mass is the primary, although not the only, determinant of fracture. Over the past few years a number of noninvasive techniques have been developed to more sensitively quantitate bone mass. These include single and dual photon absorptiometry (SPA and DPA), single and dual X-ray absorptiometry (SXA and DXA) and quantitative computed tomography (QCT). While differing in anatomic sites measured and in their estimates of precision, accuracy, and fracture discrimination, all of these methods provide clinically useful measurements of skeletal status. It is the intent of this review to discuss the pros and cons of these techniques and to present the new applications of ultrasound (US) and magnetic resonance (MRI) in the detection and management of osteoporosis.

An assessment of the role of marrow fat as a source of error in single energy quantitative CT (SEQCT) measurements of the spine is presented. Fat-induced shifts and spreads in SEQCT findings are discriminated and quantified. Studies using chemical analysis have reported an average vertebral bone mineral (MIN) loss of ∼1.3 mg/ml (0.9) per year from a peak MIN of 150 mg/ml at age 30 years with a standard error of the estimate (SEE) of ∼23 mg/ml [coefficient of variation (CV) = 20]; intraosseous vertebral fat content increases by ∼2.4 mg/ml (1.4) per year from a fat density of 175 mg/ml at age 30 years with an SEE of ∼87.5 mg/ml (CV = 36). If one does not adjust for the average age-related fat change, SEQCT underestimates MIN and overestimates MIN loss by 10–30 (at a scanner setting of ∼80 kVp). Application of correction procedures reduces the average underestimation to 1–3. The impact of residual vertebral fat variability on the accuracy of MIN measurements accounts for only 12–24 of the total accuracy error of typically 10–15 mg/ml. The impact of fat changes between zero and twice the normal age-related rate on MIN loss measurements on individual patients and patient groups (treatment versus control) accounts for only 1–2 of the total precision error of typically 1.5–3 mg/ml. From 94 to 99 of the spread of SEQCT versus age data is caused by sources of variability other than fat. All fat-related errors are higher than the above estimates by a factor of approximately 1.5–2.5 when scanning at higher voltages of up to 130 kVp. Given the limited impact of fat variability, we conclude that for most clinical applications, MIN and bone loss measurements should use SEQCT. Adjustment for the average under/overestimation (by either explicitly correcting SEQCT findings or by comparing them with normative data obtained on a similar scanner), measuring at low voltages of −80 kVp, and strict compliance to quality assurance procedures are highly recommended to achieve optimum accuracy.

A noninvasive, quantitative technique to estimate joint fluid volume using three-dimensional (3D) processing of magnetic resonance (MR) imaging and CT data was evaluated. The mean accuracy error of this 3D approach with MR imaging, performed on five fresh cadaver knees, was −2.4 ± 5.1 SD when volume estimates were based on heavily T2-weighted transverse images. A considerably higher mean accuracy error of - 12.5 ± 16.9 SD was found when the 3D approach with CT was used (four fresh cadaver knees), probably because of the small attenuation differences between articular soft-tissue structures and joint fluid. A mean precision error of 4.9 ± 2.3 SD was found when two radiologists independently evaluated in vivo MR imaging studies of 12 knees with joint effusion. Because of the low CT accuracy, no in vivo studies were performed using CT. Thus, this preliminary study shows that quantification of joint fluid volume with 3D data processing offers more accuracy with MR imaging than with CT. The 3D approach with MR imaging provides a potential tool for clinical studies.

The purpose of this study was to examine the commonly available methods of noninvasively assessing bone mineral status across three defined female populations to examine their interrelationships, compare their respective abilities to reflect age‐ and menopause‐related bone loss, discriminate osteoporotic fractures, and classify patients diagnostically. A total of 47 healthy premenopausal (age 33 ± 7 years), 41 healthy postmenopausal (age 64 ± 9 years), and 36 osteoporotic postmenopausal (age 70 ± 6 years) women were examined with the following techniques: (1) quantitative computed tomography of the L1–L4 lumbar spine for trabecular (QCT TRAB BMD) and integral (QCT INTG BMD) bone mineral density (BMD); (2) dual X‐ray absorptiometry of the L1–L4 posterior‐anterior (DXA PA BMD) and L2–L4 lateral (DXA LAT BMD) lumbar spine, of the femoral neck (DXA NECK BMD) and trochanter (DXA TROC BMD), and of the ultradistal radius (DXA UD BMD) for integral BMD; (3) peripheral QCT of the distal radius for trabecular BMD (pQCT TRAB BMD) and cortical bone mineral content (BMC) (pQCT CORT BMC); (4) two radiographic absorptiometric techniques of the metacarpal (RA METC BMD) and phalanges (RA PHAL BMD) for integral BMD; and (5) two quantitative ultrasound devices (QUS) of the calcaneus for speed of sound (SOS CALC) and broadband ultrasound attenuation (BUA CALC). In general, correlations ranged from (r= 0.10−0.93) among different sites and techniques. We found that pQCT TRAB BMD correlated poorly (r≤ 0.46) with all other measurements except DXA UD BMD (r= 0.62, p≤ 0.0001) and RA PHAL BMD (r= 0.52, p≤ 0.0001). The strongest correlation across techniques was between QCT INT BMD and DXA LAT BMD (r= 0.87, p≤ 0.0001), and the weakest correlation within a technique was between pQCT TRAB BMD and pQCT CORT BMC (r= 0.25, p≤ 0.05). Techniques showing the highest correlations with age in the healthy groups also showed the greatest differences among groups. They also showed the best discrimination (as measured by the odds ratios) for the distinction between healthy postmenopausal and osteoporotic postmenopausal groups based on age‐adjusted logistic regression analysis. For each anatomic site, the techniques providing the best results were: (1) spine, QCT TRAB BMD (annual loss, −1.2% [healthy premenopausal and healthy postmenopausal]); Student's t‐value [not the T score], 5.4 [healthy postmenopausal vs. osteoporotic postmenopausal]; odds ratio, 4.3 [age‐adjusted logistic regression for healthy postmenopausal vs. osteoporotic postmenopausal]); (2) hip, DXA TROC BMD (−0.46; 3.5; 2.2); (3) radius, DXA UD BMD (−0.44; 3.3; 1.9) and pQCT, CORT BMC (−0.72; 2.9; 1.7); (4) hand, RA PHAL (−0.51; 3.6; 2.0); and (5) calcaneus, SOS (−0.09; 3.4; 2.1) and BUA (−0.52; 2.6; 1.7). Despite these performance trends, the differences among sites and techniques were statistically insignificant (p> 0.05) using age‐adjusted receiver operating characteristic (ROC) curve analysis. Nevertheless, kappa score analysis (using −2.0 T score as the cut‐off value for osteopenia and −2.5 T score for osteoporosis) showed that in general the diagnostic agreement among these measurements in classifying women as osteopenic or osteoporotic was poor, with kappa scores averaging about 0.4 (exceptions were QCT TRAB/INTG BMD, DXA LAT BMD, and RA PHAL BMD, with kappa scores ranging from 0.63 to 0.89). Often different patients were estimated at risk by using different measurement sites or techniques.

The International Dual‐Photon X‐Ray Absorptiometry (DXA) Standardization Committee (IDSC) conducted a cross‐calibration study among three models of DXA machines from three different manufacturers. In that study, 100 subjects were scanned on all three machines. A set of equations were derived to convert bone mineral density (BMD) on each machine to a “standardized BMD” (sBMD) such that sBMD from the same subject derived from different machines would be approximately the same. In a reanalysis of the cross‐calibration data, we showed that the conversion method used in the IDSC study did not achieve several optimal properties desirable in such conversions. We derived new conversion equations to sBMD based on minimizing differences among sBMD from the three machines. More important is that the new conversions have no residual bias that was present in the IDSC conversions. The performance of the methods were compared on the cross‐calibration data as well as an external data set. We conclude that the IDSC conversions are adequate for clinical use on other machines worldwide, but that researchers should standardize their own machines in a laboratory using the new method.

The purpose of this study was to examine the commonly available methods of noninvasively assessing bone mineral status across three defined female populations to examine their interrelationships, compare their respective abilities to reflect age‐ and menopause‐related bone loss, discriminate osteoporotic fractures, and classify patients diagnostically. A total of 47 healthy premenopausal (age 33 ± 7 years), 41 healthy postmenopausal (age 64 ± 9 years), and 36 osteoporotic postmenopausal (age 70 ± 6 years) women were examined with the following techniques: (1) quantitative computed tomography of the L1–L4 lumbar spine for trabecular (QCT TRAB BMD) and integral (QCT INTG BMD) bone mineral density (BMD); (2) dual X‐ray absorptiometry of the L1–L4 posterior‐anterior (DXA PA BMD) and L2–L4 lateral (DXA LAT BMD) lumbar spine, of the femoral neck (DXA NECK BMD) and trochanter (DXA TROC BMD), and of the ultradistal radius (DXA UD BMD) for integral BMD; (3) peripheral QCT of the distal radius for trabecular BMD (pQCT TRAB BMD) and cortical bone mineral content (BMC) (pQCT CORT BMC); (4) two radiographic absorptiometric techniques of the metacarpal (RA METC BMD) and phalanges (RA PHAL BMD) for integral BMD; and (5) two quantitative ultrasound devices (QUS) of the calcaneus for speed of sound (SOS CALC) and broadband ultrasound attenuation (BUA CALC). In general, correlations ranged from (r= 0.10−0.93) among different sites and techniques. We found that pQCT TRAB BMD correlated poorly (r≤ 0.46) with all other measurements except DXA UD BMD (r= 0.62, p≤ 0.0001) and RA PHAL BMD (r= 0.52, p≤ 0.0001). The strongest correlation across techniques was between QCT INT BMD and DXA LAT BMD (r= 0.87, p≤ 0.0001), and the weakest correlation within a technique was between pQCT TRAB BMD and pQCT CORT BMC (r= 0.25, p≤ 0.05). Techniques showing the highest correlations with age in the healthy groups also showed the greatest differences among groups. They also showed the best discrimination (as measured by the odds ratios) for the distinction between healthy postmenopausal and osteoporotic postmenopausal groups based on age‐adjusted logistic regression analysis. For each anatomic site, the techniques providing the best results were: (1) spine, QCT TRAB BMD (annual loss, −1.2% [healthy premenopausal and healthy postmenopausal]); Student's t‐value [not the T score], 5.4 [healthy postmenopausal vs. osteoporotic postmenopausal]; odds ratio, 4.3 [age‐adjusted logistic regression for healthy postmenopausal vs. osteoporotic postmenopausal]); (2) hip, DXA TROC BMD (−0.46; 3.5; 2.2); (3) radius, DXA UD BMD (−0.44; 3.3; 1.9) and pQCT, CORT BMC (−0.72; 2.9; 1.7); (4) hand, RA PHAL (−0.51; 3.6; 2.0); and (5) calcaneus, SOS (−0.09; 3.4; 2.1) and BUA (−0.52; 2.6; 1.7). Despite these performance trends, the differences among sites and techniques were statistically insignificant (p> 0.05) using age‐adjusted receiver operating characteristic (ROC) curve analysis. Nevertheless, kappa score analysis (using −2.0 T score as the cut‐off value for osteopenia and −2.5 T score for osteoporosis) showed that in general the diagnostic agreement among these measurements in classifying women as osteopenic or osteoporotic was poor, with kappa scores averaging about 0.4 (exceptions were QCT TRAB/INTG BMD, DXA LAT BMD, and RA PHAL BMD, with kappa scores ranging from 0.63 to 0.89). Often different patients were estimated at risk by using different measurement sites or techniques.

Quantitative ultrasound (QUS) methods have been introduced in recent years for the assessment of skeletal status in osteoporosis. The performance of QUS techniques has been evaluated in a large number of studies. Reviewing existing knowledge, an international expert panel formulated the following consensus regarding the current status of this technology. To date, evidence supports the use of QUS techniques for the assessment of fracture risk in elderly women. This has been best established for water‐based calcaneal QUS systems. Future studies should include the predictive validity of other QUS systems. Additional clinical applications of QUS, specifically the assessment of rates of change for monitoring disease progression or response to treatment, require further investigation. Its low cost and portability make QUS an attractive technology for assessing risk of fractures in larger populations than may be suitable or feasible for bone densitometry. Additional investigations that assess innovative QUS techniques in well defined research settings are important to determine and utilize the full potential of this technology for the benefit of early detection and monitoring of osteoporosis.

The International Dual‐Photon X‐Ray Absorptiometry (DXA) Standardization Committee (IDSC) conducted a cross‐calibration study among three models of DXA machines from three different manufacturers. In that study, 100 subjects were scanned on all three machines. A set of equations were derived to convert bone mineral density (BMD) on each machine to a “standardized BMD” (sBMD) such that sBMD from the same subject derived from different machines would be approximately the same. In a reanalysis of the cross‐calibration data, we showed that the conversion method used in the IDSC study did not achieve several optimal properties desirable in such conversions. We derived new conversion equations to sBMD based on minimizing differences among sBMD from the three machines. More important is that the new conversions have no residual bias that was present in the IDSC conversions. The performance of the methods were compared on the cross‐calibration data as well as an external data set. We conclude that the IDSC conversions are adequate for clinical use on other machines worldwide, but that researchers should standardize their own machines in a laboratory using the new method.

Quantitative CT (QCT) studies of trabecular vertebral bone tissue have been carried out in vitro on a GE CT/T 9800 scanner. Results of both single energy (SE) 80 kVp and dual energy (DE) 80/140 kVp QCT data are compared with chemical mineral analysis to determine accuracy. We examined 62 vertebral specimens, from 28 cadavers (19 male and 9 female with an age range of 19–93 years, mean = 60.4). Averaging the results of all vertebral bodies of the same individual for SEQCT versus ashweight, we found a correlation coefficient (r) of 0.94 (p < 0.0001), a standard error of the estimate (SEE) of 12.2 mg/cm3(calibrated to K2HPO4), with a coefficient of variation (CV) of 13.2 and an average underestimation of bone mineral content of 18.7 mg/cm3. The corresponding DEQCT results were r = 0.98 (p < 0.0001), SEE = 7.4 mg/cm3, CV = 7.0, and an average underestimation of 4.9 mg/cm3. The SE and DE results are, and CV = 8.7. From our SEQCT data and the results of the chemical analysis of bone mineral and fat content we calculated a fat sensitivity of 7.7 mg/cm3 K2HPO4per 100 mg/cm3fat change for our scanner. Using an average fat variability of 87.5 mg/cm3, this leads to a fat-related uncertainty for the normative SEQCT data of 6.7 mg/cm3, which is far lower than the normal biological variation of 29.4 mg/cm3. Using tabulated normative data on fat content versus age and versus mineral content of 188 vertebral specimens from five collaborating centers, we derived a correction algorithm for QCT measurement that reduces our average underestimation to 0.88 mg/cm3with an SEE of 12.1 mg/cm3. Hence, this correction procedure can be used to estimate the fat corrected absolute mineral density for research purposes or for scanners with high fat sensitivity. For the GE CT/T 9800 scanner, with a relatively low fat to mineral sensitivity at 80 kVp, the correction procedure is generally not recommended for clinical studies since it minimizes the average fat induced error but does not reduce the residual, partially fat related uncertainty. Finally, since the fat related uncertainty is small compared to biological variation, the correlation is high between SEQCT and DEQCT, and the radiation dose is lower and the precision higher for SEQCT, we suggest that most clinical diagnostic studies using the GE CT/T 9800 scanner for bone mineral determination employ SEQCT at 80 kVp.

Quantitative ultrasound (QUS) methods have been introduced in recent years for the assessment of skeletal status in osteoporosis. The performance of QUS techniques has been evaluated in a large number of studies. Reviewing existing knowledge, an international expert panel formulated the following consensus regarding the current status of this technology. To date, evidence supports the use of QUS techniques for the assessment of fracture risk in elderly women. This has been best established for water‐based calcaneal QUS systems. Future studies should include the predictive validity of other QUS systems. Additional clinical applications of QUS, specifically the assessment of rates of change for monitoring disease progression or response to treatment, require further investigation. Its low cost and portability make QUS an attractive technology for assessing risk of fractures in larger populations than may be suitable or feasible for bone densitometry. Additional investigations that assess innovative QUS techniques in well defined research settings are important to determine and utilize the full potential of this technology for the benefit of early detection and monitoring of osteoporosis.

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 posteroanterior 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, ?-coefficients for interobserver variation ranged from 0.458 to 0.691 for reader pairs. For agreement between the observer ratings and the DXA results, ?-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. Therefore, spine radiographs remain an important cornerstone in the detection and differential diagnosis of osteopenia.

Dual X‐ray absorptiometry (DXA) is widely used to monitor treatment efficacy in reducing the rate of bone mineral loss. In order to assure the validity of these measurements, instrument quality control of the DXA scanners becomes very important. This paper compares five quality control procedures (visual inspection, Shewhart chart with sensitizing rules, Shewhart chart with sensitizing rules and a filter for clinically insignificant mean changes, moving average chart and standard deviation, and cumulative sum chart [CUSUM]) in their ability to identify scanner malfunction by means of (1) an analysis of five longitudinal phantom data sets that had been collected during a clinical trial and (2) an analysis of simulated data sets. The visual inspection method is relatively subjective and depends on the operator's experience and attention. The regular Shewhart chart with sensitizing rules has a high false alarm rate. The Shewhart chart with sensitizing rules and an additional filter for clinically insignificant mean changes has the lowest false alarm rate but a relatively low sensitivity. The CUSUM method has good sensitivity and a low false alarm rate. In addition, this method provides an estimate of the date a change in the DXA scanner performance might have occurred. The method combining a moving average chart and a moving standard deviation chart came closest to the performance of the CUSUM method. Comparing the advantages and disadvantages of all methods, we propose the use of the CUSUM method as a quality control procedure for monitoring DXA scanner performance. For clinical trials use of the more intuitive Shewhart charts may be acceptable at the individual sites provided their scanner performance is followed up by CUSUM analysis at a central quality assurance center.

Previous research suggests that physical activity may have a beneficial effect on bone mineral density (BMD) in women. This relationship was explored in a 2‐year, randomized, intervention trial investigating the efficacy of exercise and calcium supplementation on increasing peak bone mass in young women. One hundred and twenty‐seven subjects (ages of 20–35 years) were randomly assigned either to an exercise program that contained both aerobics and weight training components or to a stretching program. Calcium supplementation (up to 1500 mg/day including dietary intake) or placebo was given in a double‐blinded design to all subjects. Spinal trabecular BMD was determined using quantitative computed tomography (QCT). Spinal integral, femoral neck, and trochanteric BMD were measured by dual X‐ray absorptiometry (DXA) and calcaneal BMD by single photon absorptiometry (SPA). Fitness variables included maximal aerobic capacity (VO2max), and isokinetic muscle performance of the trunk and thigh. Measurements were made at baseline, 1 year, and 2 years. Sixty‐three subjects (32 exercise, 31 stretching) completed the study, and all the measured bone parameters indicated a positive influence of the exercise intervention. There were significant positive differences in BMD between the exercise and stretching groups for spinal trabecular (2.5%), femoral neck (2.4%), femoral trochanteric (2.3%), and calcaneal (6.4%) measurements. The exercise group demonstrated a significant gain in BMD for spinal integral (1.3 ± 2.8%, p< 0.02), femoral trochanteric (2.6 ± 6.1%, p< 0.05), and calcaneal (5.6 ± 5.1, p> 0.01) measurements. In contrast to exercise, the calcium intervention had no positive effect on any of the bone parameters. In regard to fitness parameters, the exercise group completed the study with significant gains in VO2maxand isokinetic (peak torque) values for the knee flexion and extension and trunk extension. This study indicates that over a 2‐year period, a combined regimen of aerobics and weight training has beneficial effects on BMD and fitness parameters in young women. However, the addition of daily calcium supplementation does not add significant benefit to the intervention.

To determine whether estimates of volumetric bone density from projectional scans of the lumbar spine have weaker associations with height and weight and stronger associations with prevalent vertebral fractures than standard projectional bone mineral density (BMD) and bone mineral content (BMC), we obtained posteroanterior (PA) dual X‐ray absorptiometry (DXA), lateral supine DXA (Hologic QDR 2000), and quantitative computed tomography (QCT, GE 9800 scanner) in 260 postmenopausal women enrolled in two trials of treatment for osteoporosis. In 223 women, all vertebral levels, i.e., L2–L4 in the DXA scan and L1–L3 in the QCT scan, could be evaluated. Fifty‐five women were diagnosed as having at least one mild fracture (age 67.9 ± 6.5 years) and 168 women did not have any fractures (age 62.3 ± 6.9 years). We derived three estimates of “volumetric bone density” from PA DXA (BMAD, BMAD*, and BMD*) and three from paired PA and lateral DXA (WA BMD, WA BMDHol, and eVBMD). While PA BMC and PA BMD were significantly correlated with height (r= 0.49 and r= 0.28) or weight (r= 0.38 and r= 037), QCT and the volumetric bone density estimates from paired PA and lateral scans were not (r= −0.083 to r= 0.050). BMAD, BMAD*, and BMD* correlated with weight but not height. The associations with vertebral fracture were stronger for QCT (odds ratio [OR] = 3.17; 95% confidence interval [CI] = 1.90–5.27), eVBMD (OR = 2.87; CI 1.80–4.57), WA BMDHol(OR = 2.86; CI 1.80–4.55) and WA‐BMD (OR = 2.77; CI 1.75–4.39) than for BMAD*/BMD* (OR = 2.03; CI 132–3.12), BMAD (OR = 1.68; CI 1.14–2.48), lateral BMD (OR = 1.88; CI 1.28–2.77), standard PA BMD (OR = 1.47; CI 1.02–2.13) or PA BMC (OR = 1.22; CI 0.86–1.74). The areas under the receiver operating characteristic (ROC) curves for QCT and all estimates of volumetric BMD were significantly higher compared with standard PA BMD and PA BMC. We conclude that, like QCT, estimates of volumetric bone density from paired PA and lateral scans are unaffected by height and weight and are more strongly associated with vertebral fracture than standard PA BMD or BMC, or estimates of volumetric density that are solely based on PA DXA scans.