Technical Principles of Dual Energy X-Ray Absorptiometry

Transcription

1 Technical Principles of Dual Energy X-Ray Absorptiometry Glen M. Blake and Ignac Fogelman Since its introduction nearly ten years ago, dualenergy x-ray absorptiometry (DXA) has become the single most widely used technique for performing bone densitometry studies. One reason for its popularity is the ability of DXA systems to measure bone mineral density (BMD) in the spine and proximal femur, the two most common sites for osteoporotic fractures. Other advantages of DXA include the exceptionally low radiation dose to patients, short scan times, high resolution images, good precision and inherent stability of calibration. For these reasons DXA scans are widely used to diagnose osteoporosis, assist making decisions in treatment, and as a follow-up response to therapy. Another important application has been the use of DXA in many clinical trials T HE PAST DECADE has seen the rapid evolution of new radiological techniques for quantifying skeletal integrity, l More than any other method, however, the introduction of dual-energy x-ray absorptiometry (DXA) 24 has been responsible for the recent rapid growth in the clinical applications of bone densitometry. 5 Compared with the earlier technique of dual photon absorptiometry (DPA) based on a gadolinium-153 (153Gd) radionuclide source, DXA has advantages of higher precision, shorter scanning times, low radiation dose, and improved calibration stability in the clinical environment. 6-8 One of the most important applications of DXA has been its widespread use in prospective clinical trials of new therapies for osteoporosis. 7,9-12 Because of the well established relationship between bone mineral density (BMD) and fracture risk 13,14 the demonstration of a statistically significant difference in the BMD changes of subjects on active drug and placebo is a primary objective of most trials of new treatments for osteoporosis. For such studies DXA provides a sensitive and specific method of measuring the BMD changes at selected sites in the skeleton. Usually the spine and hip are chosen for From the Department of Nuclear Medicine, Guy's Hospital, London, United Kingdom. Address reprint requests to G.M. Blake, PhD, Department of Nuclear Medicine, Guy's Hospital, St Thomas St, London SE1 9RT, United Kingdom. Copyright by W.B. Saunders Company /97/ /0 of new treatments for osteoporosis. Since the first generation pencil beam DXA systems became available, the most significant technical innovation has been the introduction of fan beam systems with shorter scan times, increased patient throughput, and improved image quality. New clinical applications include the measurement of lateral spine and total body BMD, body composition, and vertebral morphometry. Despite these advances, posteroanterior (PA) spine and proximal femur scans remain the most widely used application because of their utility in treatment decisions and monitoring response to therapy. Copyright9 1997by W.B. Saunders Company measurement because these are the most common sites for osteoporotic fractures. A second common use of DXA is for identifying perimenopausal and postmenopausal women with low bone density who can be advised to take estrogen or other preventive therapies. When interpreted in conjunction with the World Health Organization (WHO) criteria for the diagnosis of osteoporosis 15,16 DXA scans give a simple, safe, and precise method of identifying women at risk of fragility fracture. There is increasing evidence that such patients can benefit from preventive treatment that will reduce the risk of future fractures. 9,12,17,18 In many centers, women identified at risk of osteoporotic fractures on the basis of the WHO criteria have follow-up scans after one or two years to monitor their response to treatment. 19 Whether monitoring subjects in clinical trials or patients taking established therapies it is important that bone densitometry measurements are performed at sites where response can be reliably measured after a short interval. For many applications the lumbar spine has proved the ideal site because of the metabolically active trabecular bone in the vertebral bodies. 2~ A DXA scan measures BMD (units: grams per square centimeter), defined as the integral mass of bone mineral per unit projected area. In the conventional posteroanterior (PA) scan of the spine (Fig 1), however, this includes contributions from cortical bone and the spinous processes as well as the trabecular bone of the vertebral body. Further disadvantages of the PA scan include its susceptibility to spinal degenera- 210 Seminars in Nuclear Medicine, Vol XXVII, No 3 (July), 1997: pp

2 TECHNICAL PRINCIPLES OF DXA 211 ments of the spine and hip provide the most reliable indication of patients' skeletal status, there is continuing interest in new techniques for assessing the peripheral skeleton. Such instruments are cheaper, take up less space than a DXA scanner, and may give clinical data that are just as useful. X-ray absorptiometry of the forearm and ultrasound measurements of the calcaneus are the principal choices. The replacement of the iodine I) radionuclide source used in single photon absorptiometry (SPA) by a radiograph tube has given rise to a technique referred to as single x-ray absorptiometry (SXA). 2"I,25 Both SPA and SXA devices require the patient's forearm to be immersed in a water bath while the scan is acquired. In a recent development several manufacturers B Region Area BMC BMD (cm z) (grams) (g/cm 2) L L L tl L Total Fig 1. A posteroanterior (PA) projection DXA scan of the lumbar spine in a postmenopausal patient (A) with results of bone mineral density (BMD) measurements (B). Areal BMD expressed in units of grams of hydroxyapatite per square centimeter of projected area is measured for the individual vertebrae L1 to L4 and is then averaged over their total area. tive changes and aortic calcification (Fig 2). The alternative technique of quantitative computed tomography (QCT) permits direct measurement of the mineralization of trabecular bone in the lumbar spine (Fig 3). 21 QCT measures true physical density (units: grams per cubic centimeter) rather than the areal density measured by DXA. However, despite this, DXA remains the more widely used technique on the grounds of cost, precision, and radiation burden.22, 23 Despite the widespread belief that BMD measure- B Region Area BMC BMD (cm 2) (grams) (g/cm 2) LI L L3 i 3.37 i , Total Fig 2. Lumbar spine DXA scan of a patient with degenerative changes in 1.3 and L4 (A) showing the influence of such changes on the BMD results (B). BMD values are lower in L1 and L2 than for the patient in Figure 1, but higher in L3 and L4 due to the degenerative changes.

3 212 BLAKE AND FOGELMAN Fig 3. A QCT scan of a lumbar vertebra. Volumetric BMD expressed in units of grams of hydroxyapatite per cubic centimeter can be measured separately in the trabecular bone and cortical shell of the vertebral body. The phantom below the patient serves to calibrate BMD in terms of the Hounsfield units of the CT image. Courtesy of L.M. Banks. have produced dual x-ray absorptiometry devices for scanning the peripheral skeleton (p-dxa) that enable the forearm to be scanned in air. Like DXA, SXA and p-dxa instruments measure areal bone density. Thus a measurement of the ultradistal region of the wrist sums contributions from both cortical and trabecular bone. An alternative new technology for forearm studies has been the development of small, dedicated computed tomography (CT) scanners that image the wrist. This technique, referred to as peripheral QCT (pqct), measures the volumetric bone density of the trabecular and cortical bones separately. 26 Finally, improvements in technology have lead to a revival of the technique of radiographic absorptiometry in which the hand is radiographed with a small calibration wedge. 27 Such a technique is cheap and widely accessible, although it requires careful quality control if it is to give useful data. Another new peripheral technique, quantitative ultrasound (QUS) measurement of the calcaneus, has been widely evaluated in the past five years. Bone ultrasound systems use frequencies in the 200 to 600 khz range and measure broadband ultra- sonic attenuation (BUA) and the speed of sound (SOS) in the heel The calcaneus is chosen for measurement because it is an easily accessible trabecular bone site. Several prospective studies have confirmed that QUS measurements in elderly women patients are predictive of fracture risk. 32'33 However, comparisons of BUA and SOS measurements with spine and hip BMD in perimenopausal women show poor correlations. 34 This and the relatively poor precision of bone ultrasound devices mean that further technical improvements and clinical evaluation are required before QUS can be accepted as a reliable alternative to DXA. At the present time, DXA is the most widely used technique for bone densitometry studies. 1 In part this is because of its good precision and stable calibration. Another factor is the continuing importance of measurements of the lumbar spine. However, there are a wide variety of additional applications now available. These include BMD measurements of the proximal femur, distal forearm, and total body, together with specialist applications such as body composition and vertebral morphometry. As a result, the past five years have

4 TECHNICAL PRINCIPLES OF DXA 213 seen the rapid expansion of both research routine clinical studies based on DXA. 5 DXA TECHNOLOGY Physical Principles of DXA and The fundamental physical principle behind DXA is the measurement of the transmission through the body of x-rays with high- and low-photon energies. Because of the dependence of the x-ray attenuation coefficient on atomic number and photon energy, measurement of the transmission factors at two different energies enables the areal densities (ie, mass per unit projected area) of two different types of tissue to be inferred. In DXA scans these are taken to be bone mineral (hydroxyapatite) and soft tissue respectively. This basic principle can be simply explained using the DPA equation In the following equations primed variables denote the low-energy beam and unprimed variables the highenergy beam. The transmission of radiation through the body is given by: low energy: high energy: I' = I~exp - (/a~m s +/a~ma~ I = Io exp - (/asms + /asmb) (la) (lb) where la is the mass attenuation coefficient, M the areal density, and subscripts B and S respectively denote bone and soft tissue. Equations (1 a) and (lb) are simplified by writing J in place of the logarithmic transmission factor -ln(io), giving: J' =/a~m s +/a~m s J =/asms + ~tbm B Elimination of Ms gives the DPA equation: where: (2a) (2b) J' -kj Ms - - -, (3a) /a s -- k/a B k = i.t~//as (3b) In the earlier technology of DPA the radionuclide source 153Gd was used because its photon emissions at 44 and 103 kev were close to the ideal energies for in-vivo measurement of the lumbar spine. At photon energies above 100 kev there is little difference in the mass attenuation coefficients of bone and soft tissue and transmission measure- ments reflect essentially the total mass of tissue in the beam. Photon energies around 40 kev are ideal for the low energy beam because there is good contrast between bone and soft tissue without excessive attenuation to limit the signal reaching the detector. When a DXA scan is analysed the basic data processed create a pixel-by-pixel map of BMD over the entire scan field calculated from equation 3a. However, because of the effects of variable soft tissue composition and beam hardening the numerator in equation 3a may take non-zero values in the soft tissue regions adjacent to bone. The latter provide a reference area of comparable thickness and soft tissue composition from which a line-byline correction is applied to the BMD values in the bone region. An edge detection algorithm is first used to find the bone edges (Fig I A). The total projected area of bone is then derived by summing the pixels within the bone edges and the reported value of BMD calculated as the mean BMD over all the pixels identified as bone. Finally, bone mineral content (BMC) (Fig IB) is derived by multiplying mean BMD by projected area: BMC = BMD Area (4) Equations (2a) and (2b) also allow the areal density of soft tissue to be inferred. This information is usually not required, although a knowledge of the total tissue mass through which the x-ray beam passes may be useful for correcting for the effects of beam hardening) 5 The derivation of soft tissue mass is, however, an essential element in body composition studies which are a useful adjunct to total body DXA scanning. It is widely recognized that a significant limitation to the accuracy of DXA scanning is the variable lean and fat composition of soft tissue. Because of its higher hydrogen content, adipose tissue has a different x-ray attenuation coefficient to lean tissue, and differences in the composition of soft tissue in the path of the x-ray beam through bone compared to the adjacent soft tissue reference area will cause errors in the BMD measurements By extending basic principles, triple photon absorptiometry might allow for the measurement of three different types of tissue. However, because there are only two attenuation processes (Compton scattering and the photoelectric effect) in the passage of diagnostic x-rays through tissue, the equations of triple photon absorptiometry have

5 214 BLAKE AND FOGELMAN built in redundancy and in practice it is possible to discriminate only two types of tissue. A number of studies have examined the magnitude of the BMD measurement errors caused by adipose tissue in either DXA or DPA. These include theoretical studies based on the mass attenuation coefficients of hydroxyapatite, lean tissue, and fat, 36 and studies using phantoms 2,3 and cadavers. 38 Tothill and Pye 37 used computed tomography (CT) images to delineate the distribution of lean and fat tissue in transaxial Scans through the lumbar vertebrae and hence estimate the effect on PA and lateral projection BMD measurements of the spine. In a small group of subjects it was possible to use CT studies to estimate the effect of weight change on longitudinal BMD measurements. 39 The Radiation Source The replacement of the J53Gd radionuclide source used in DPA with a x-ray tube improved the performance of dual photon absorptiometry by combining higher photon flux with a smaller diameter source. The availability of an intense, narrow beam of radiation shortened scan times, enhanced image definition, and improved precision. These advantages were first highlighted by Rutt and coworkers in an unpublished study presented at the 1985 Annual Meeting of the American Society for Bone and Mineral Research. 4~ On the basis of theoretical calculations. Rutt et al showed that replacement of the DPA radionuclide source with a x-ray tube could simultaneously improve image resolution from 2 mm to 1 ram, improve prectsion of the BMD measurements from 2% to 1%. and shorten scan times from 20 minutes to 2 minutes. It is therefore not surprising that when the first commercial DXA scanner was introduced in 1987 DPA technology was immediately superseded. The use of a x-ray tube rather than a radionuclide source for photon absorptiometry requires the solution of several significant technical problems. A highly stable source is essential. Image noise must be limited by photon statistics and not by instabilities in the x-ray generator. Because x-ray tubes produce polyenergetic spectra rather than the discrete line emissions of a radionuclide, the effects of beam hardening are a potential source of error. 6,35 In beam hardening, lower energy photons are preferentially removed from the radiation beam compared to higher energy photons, leading to a progressive shift in spectral distribution to higher effective photon energies with increasing body thickness. As a result the attenuation Coefficients for bone and soft tissue in the DPA equation (equation 3a) change with body thickness, and so vary from patient to patient and from site to site within the body. In their original description of the DXA technique in 1985, Rutt et al 4~ suggested two methods of generating the dual energy x-ray spectrum: (1) The use of a K-absorption edge filter to split the polyenergetic x-ray beam into high- and low-energy components that mimic the emissions from 153Gd: Because the two Components have inherently narrow spectral distributions the problems associated with beam hardening are minimized(fig 4A). Manufacturers selling DXA systems that use the K-edge filter technique include Lunar (Madison, WI), Norland (Fort Atkinson, WI) and Osteometer (Roedovre, Denmark). The Lunar DPX systems 4,5 have a cerium filter and use pulse height analysis at the detector to discriminate between high- and low-energy photons. Norland systems use a samarium filter and separate detectors for high and low energy x,rays.5 Dynamic range is extended by a system for switching filters with different thicknesses of samarium into the beam; (2) The second way of producing a dual energy x-ray beam is to switch the high voltage generator between high and low kvp during alternate half cycles of the mains supply. This method is used by H01ogic (Waltham, MA) in the QDR series of DXA systems. s The spectral distribution is wider than with the K-edge filter method and the consequent effects of beam hardening are corrected by a rotating calibration wheel (Fig 4B) containing bone and soft tissue equivalent filters that measure the attenuation coefficients in the DPA equation and calibrate the scan image pixel by pixel. 35 Pulse height analysis is not required, giving the instrument an inherently wide dynamic range. Fan Beam DXA The first generation of DXA scanners such as the Hologic QDR-10002,3 and Lunar DPX 4 used a pinhole collimator producing a pencil beam Coupled to a singl e detector in the scanning arm. Since then the most significant development in DXA technol, ogy has been the introduction of a new generation of systems such as the Hologic QDR-45004~ and Lunar Expert-XL 41 that use a slit collimator to generate a fan beam coupled to a linear array of detectors (Fig 5A,B). Fan beam studies are acquired by the scanning arm performing a single sweep across the patient instead of the two dimensional raster scan required by pencil beam geometry (Fig 5C). As a result scan times have been shortened from around 5 to 10 minutes for the early pencil beam scanners to 10 to 30 seconds for the

6 TECHNICAL PRINCIPLES OF DXA 215 A Fig 4. (A) The K-edge filtration technique produces a dual energy x-ray beam by filtering the continuous spectrum x-rays produced by an 80 kv generator (top) with a filter made from a rare earth metal (bottom), In Lunar DPX scanners a cerium filter with a K-absorption edge of 42 kev is used. (B) The calibration wheel used as the internal reference standard in Hologic scanners, The segments in the wheel include bone and soft tissue equivalent filters together with an empty air sector. Each of these 3 segments has separate high and low energy x-ray sectors with and without an additional brass filter, In the wheel shown here the BMD of the bone filter is g/cml latest fan beam systems. Shorter scan times and higher patient throughput, around twice that for first generation scanners, are the major advantages of fan beam DXA systems. Another advantage of fan beam systems is higher image resolution. This allows easier identification of vertebral structure together with the artifacts because of degenerative disease that are a significant limitation in DXA studies of the lumbar spine. A major motivation behind the development of both the Lunar Expert-XL and the Hologic QDR is a system with a resolution sufficient for

7 216 BLAKE AND FOGELMAN clinically useful vertebral morphometry studies. 42 It is important, however, to recognize that the inevitable consequence of improved spatial resolution is higher radiation dose to patients and to staff operating equipmenc 43 Many centers providing a DXA-based bone densitometry service have either recently replaced or are considering replacing an older pencil beam scanner with a fan beam system. A major issue is the degree of concordance between the measurements obtained on the old system and its replacement. 4~ Equivalence of pencil beam and fan beam measurements is important both for the interpretation of follow-up scans and the continuing applicability of normative data. One consequence of the change to fan beam geometry is that measurements of projected area and BMC (equation 4) are sensitive to the height of the measured object above the scanning table and therefore can only be regarded as approximate estimates. 4s-47 BMD. however, is the important diagnostic measure 15,16 and is more robust than BMC and projected area to the change in system geometry and variation in height above the scanning table. 45 In general the difference in BMD scale between a pencil beam and a fan beam system can be expressed in a scaling factor (always close to unity) that allows for the change in beam geometry. 44 This factor is specific to each measurement site. 4~ Centers replacing a DXA system should perform an in vivo cross-calibration study since cross-calibration based purely on phantom measurements may be misleading. 48 Linear regression analysis is used to establish the relationship between the two systems for the BMD results at each scan site. 44 The statistical significance of the intercept of each regression line is assessed and, if not statistically significantly different from zero, linear regression analysis is repeated with the intercept forced through the origin. The slope of the regression line through the origin is then tested to determine whether it is statistically significantly different from unity. Provided statistical significance is demonstrated, the slope can be used as a correction factor between scans on the two systems. Radiation Dose to Patients and Staff Studies of radiation dose to patients from DXA scans confirm that patient dose is small compared to that given by many other investigations involv- ing ionising radiation. ~,22 The radiation hazard to the patient is best expressed in terms of the effective dose, which is defined as the uniform whole body dose that would put the patient at equivalent risk from the carcinogenic and genetic effects of radiation; 49 As noted earlier, one consequence of the introduction of fan beam systems with improved image resolution is higher patient dose. Table 1 compares the effective dose received from first generation pencil beam and the latest fan beam systems for a spine and hip DXA investigation on a postmenopausal woman. Despite the increase associated with the development s in technology, patient dose from DXA remains very low when compared with natural background radiation or other common radiological procedures (Fig 6A), Associated with the increase in patient dose and higher patient throughput with fan beam DXA is a greater occupational hazard to staff from scattered radiation. 43 For pencil beam systems, such as the Lunar DPX and Hologic QDR-1000, the time averaged dose to staff from scatter is very low even with the operator sat as close as 1 meter from the patient during scanning. However, the scatter dose from fan beam systems such as the QDR-4500 and Lunar ExpertzXL is potentially considerably higher and approaches limits set by the regulatory authorities for occupational exposure (Fig 6B). When installing fan beam systems active precautions to reduce dose to staff should be considered such as use Of a radiation barrier or scanning room large enough to place the operator at least 3 meters from the patient. DXA APPLICATIONS PA Lumbar Spine and Hip The scanning software developed for first generation DXA systems provided for clinical studies Tabie i. Patient Dose for a DXA Spine and Hip Examination Beam Effective DXA System Geometry Dose Scan Speed Lunar DPX Pencil beam 0.06 psv 750 pa medium scan (5 min) Hol0gic Pencil beam 0.3 psv Quick scan QDR-1000 (3 rain) Hologic Fan beam 2.6 psv Fast scan QDR-4500 (30 sec) Lunar Expert-XL Fan beam 34 psv 5 ma fast scan (15sec) NOTE. The effective dose results are for a postmenopausal woman and ignore the genetic risk from dose to the ovaries. Data from Blake et al. 82

8 TECHNICAL PRINCIPLES OF DXA 217 Fig 5. Illustrations of two fan beam DXA systems. (A) The Hologic QDR~IS00A; (B) The Lunar Expert-XL. {Reprinted with permission of the manufacturers.) (C) Comparison of x-ray beam and detector geometry for a pencil beam configuration with a single detector {right) and a fan beam configuration with a multidetector array (left). C FAN BEAM Fig. 5 Continued, PENCIL BEAM using PA projection scans of the lumbar spine (Fig 1) and proximal femur. It is usual to examine BMD in the hip in up to four regions: the femoral neck, trochanter, Ward's triangle, and total hip (Fig 7). The Ward's triangle area measures the earliest site of postmenopausal bone loss in the hip and is of interest because in theory it gives the best measure of trabecular bone in the proximal femur. In practice, use of the Ward's region is limited by the poor precision of measurements at this site, and femoral neck BMD has been the hip parameter most frequently used for making the diagnosis of osteopenia or osteoporosis. Clinical trial studies show, however, that the trochanter shows a larger

9 218 BLAKE AND FOGELMAN A 09 t- D.. o O a t~ #= I,LI B ~E 0 a~ Lateral spinal X-rays Skull X-ray 9 -- QCT ~ Cheat X-ray Expert-XL DPX 9 -- QDR-4500 QDR-IO00 Expert-XL QDR QDR-IO00 1 year natural background 1 month natural background 1 week natural background 1 day natural background 7.5 psv/hr = 15 msv/yr Controlled Area limit 2.5 psv/hr = 5 msv/yr Supervised Area limit 0.5 ~Sv/hr = 1 msv/yr ICRP (1990) limit for Member of Public Distal Forearm Studies of the radius are performed by placing the nondominant forearm on the scanning table and scanning the distal half from the mid-radius to the wrist (Fig 8). 24,5o Bone density measurements are made at two principal sites. The first of these, the ultradistal region, is a rectangular strip 1.5-cmwide immediately adjacent to the endplates of the radius and ulna. This site is chosen because it is the area in the forearm with the highest percentage of trabecular bone. The second measurement site is the one third region, a 2-cm-wide strip centered over cortical bone at a point one third the distance between the ulna styloid and the olecranon. BMD results at these sites are given for radius and ulnar either separately or combined. DXA forearm scans provide BMD data equivalent to SPA and SXA scans. 24,5~ Although forearm scans may be used to assess fracture risk or response to treatment, it is usually preferred to perform such measurements at the spine and hip since these are the most common sites for osteoporotic fractures DPX Fig 6. (A) Comparison of the effective dose to the patient from a PA spine and hip DXA examination on two pencil beam (Lunar DPX and Hologic QDR-1000) and two fan beam (Lunar Expert-XL and Hologic QDR-4500) systems. Also shown is the effective dose from some common radiological procedures and from natural background radiation. Data from references 22, 81 and 82. (B) Comparison of the time averaged scatter dose to an operator positioned 1 meter from the scanning table for four DXA systems. Results show the mean ambient dose equivalent per hour assuming that 2 patients per hour are scanned on the pencil beam systems (Lunar DPX and Hologic QDR-1000) and 4 patients per hour on the fan beam systems (Lunar Expert-XL and Hologic QDR-4500). (Data from references 43 and 82; regulatory limits were taken from the United Kingdom Ionising Radiation Regulations 83 and recommendations of the ICRR 4s) response to therapy than the femoral neck 12 and recently there has been considerable interest in the use of total hip BMD because this site shows both favorable precision and good response to treatment. For the majority of bone densitometry studies DXA scans of the PA spine and hip provide sufficient information. Developments in DXA, however, have made available new scanning modes and specialized applications that supplement the conventional spine and hip studies. Total Body Studies Total body DXA is of interest because of the comprehensive view it affords of changes across the whole skeleton (Fig 9). Whole body scans measure BMC and average BMD in the total skeleton together with subregions that include the skull, arms, ribs, thoracic and lumbar spine, pelvis and legs. 51 An interesting new application made possible by total body DXA is body composition studies. 52 In those areas of a whole body scan where the x-ray beam does not intersect bone, it is possible to use the attenuation at the two photon energies to measure separately the masses of fat and lean tissue. Over bone, however, only BMD and total (fat and lean) soft tissue mass can be measured. Extrapolation of measurements of percentage body fat in soft tissue over adjacent bone means that a whole body DXA scan can provide estimates of total body fat and lean mass as well as BMC. A wide variety of methods have been developed to measure body fat including hydrodensitometry, neutron activation analysis, total body potassium, total body water and skinfold measurements. Each of these has individual limitations in its assumptions, calibration and accuracy, and this has compli-

10 TECHNICAL PRINCIPLES OF DXA 219 C Global Region of Interest Symmetry Axis Ward's Triangle Search Region ] Femoral Neck [] Ward's Triangle ] Trochanteric Region [] Inter-Trochanteric Region g Region Neck Troch Ward's Total Area BMC BMD (cm z) (grams) (g/cm 2) Fig 7. A DXA scan of the proximal femur (A). The hip analysis software generates BMD results (B) for the femoral neck, trochanter, Ward's triangle and the total hip regions. The placement of the regions is shown in the line diagram (C). The total hip region includes the femoral neck, trochantaric and inter-trochantaric regions. cated the assessment of the place of DXA in body composition studies. Body composition by DXA has evolved rapidly with a succession of software revisions that have refined accuracy. 53-s5 With its high precision, low radiation dose, and general accuracy, DXA is likely to become a widely used method for assessing body fat. Prosthetic Implants Another specialized application under evaluation is the integrity of hip prostheses. In such patients, scanning of the hip is complicated by the high x-ray attenuation of the metal implant. Software can now identify and reject the prothesis and automatically place ROI's around the periprosthetic bone. Studies are underway to determine whether serial DXA scanning after hip replacement can identify mechanical loosening and the durability of implants to aid improvements in the design of future implants. 56 Lateral Lumbar Spine The rapid turnover of the metabolically active trabecular bone in the vertebral bodies makes the spine the optimum site for monitoring changes in bone mineralization. 2~ DXA scans of the lumbar spine using the lateral instead of the PA projection isolate the vertebral bodies from the posterior elements and better approximate the objective of measuring trabecular bone free of artifacts (Fig 10). The first lateral DXA studies were performed using the decubitus technique in which subjects lie on their side However, the difficulty in reproducing subjects' positions on follow-up scans gives poor precision. 59 The latest generation of fan beam DXA systems have a rotating C-arm that enables the lateral scan to be performed with the patient in the supine position. The precision of supine lateral DXA is much improved compared to the decubitus scan, 59 but it has yet to be shown that lateral scans are superior to PA spine scans for following patients' response to treatment. 6~ As well as the evaluation of lateral DXA for monitoring longitudinal changes, several recent studies have compared the ability of PA and lateral spine scans for identifying patients with osteopenia and osteoporosis. The diagnostic potential of lateral DXA remains controversial. Although some studies

11 220 BLAKE AND FOGELMAN with lateral radiographs arising from the x-ray cone beam to cause errors because of variable projection and magnification. 67 A further significant advantage is the much lower radiation dose to the patient from DXA compared with radiographs. 68 Initial studies of DXA vertebral morphometry have shown good agreement with radiographic studies after allowing for elimination of the magnification error. 67 If DXA can be shown to give adequate image quality for reliably identifying vertebral deformities, morphometry would be a major rationale for its use in future clinical trials and for monitoring patients with established spinal osteoporosis. 42 B Region Area BMC BMD (cm 2) (grams) (g/cm 2) Ultradistal Mid One-Third Total Fig 8. A DXA scan of the distal forearm (A). BMD measurements (B) are made in the radius and ulna in the ultradistal (UD) and one-third radius {1/3) regions as well as a mid region between these two. suggest it may be superior to conventional PA spine DXA, 61,62 other studies have reached the opposite conclusion.63, 64 Vertebral Morphometry Recent trials of new treatments for osteoporosis have given increased emphasis to demonstrating that therapies are successful in reducing the incidence of fragility fractures. Spinal crush fractures are an important sequelae of osteoporosis and the incidence of new vertebral deformities may be monitored by performing serial morphometric measurements on lateral radiographs of the lumbar and thoracic spine. 65,66 The latest fan beam DXA systems are designed to perform fast, high resolution lateral scans of the lumbar and thoracic spine (L4-T-4) acquired with the patient in the supine position (Fig 11). A major advantage of DXA vertebral morphometry is the elimination of the geometrical distortion associated ACCURACY AND PRECISION The accuracy errors of a test reflect the degree to which the measul"ed results deviate from true values. In the case of bone mineral measurements it is generally accepted that true BMC is obtained by defatting bone and then ashing under standard conditions in a muffle furnace. To find true BMD it is necessary to radiograph specimens to measure the projected area. Despite the obvious importance of validating the accuracy of bone densitometry techniques, only a few studies of DPA or DXA have addressed this issue. 38,6974 Comparison of in situ BMD measurements in cadavers with results of ashing show differences between 0 and 15 percent. The differences may be explained by factors such as errors caused by soft tissue composition, the fat content of bone and bone marrow, and errors in the measurement of the projected area inherent in different edge detection algorithms. In general, small accuracy errors are of little clinical significance provided they remain constant. Precision errors reflect the reproducibility of a diagnostic technique and in practice often have greater clinical relevance than accuracy errors. An understanding of the precision error is useful for two reasons. First, results are usually interpreted in the context of the relevant normal range and a technique with poor precision may lead to misinterpretation of results. Second, it is frequently necessary to decide whether a follow-up scan provides evidence of a significant change and this can only be decided with knowledge of the precision errors of the technique. Short-Term Precision Most studies of new instrumentation or new applications include a measurement of short-term

12 TECHNICAL PRINCIPLES OF DXA 221 precision. This entails performing a number of repeated measurements on a representative set of individuals to characterise the reproducibility of the technique. Generally, short-term precision errors are evaluated from repeated measurements performed either on the same day or extending over a period of time of no more than two weeks. Over short time periods no true change in BMD is expected and the precision error is expressed by the standard deviation (SD) of repeated measurements (Fig 12A). It is often necessary to combine precision data obtained from a group of subjects. In this circumstance short-term precision is evaluated by first taking the mean and variance of two or more repeated measurements on each subject. The means and variances for all the individual subjects are then averaged and the root mean square standard deviation (RMS SD) calculated For many purposes the absolute error expressed by the RMS standard deviation is the most satisfactory definition of short-term precision. It is, however, a popular convention to express precision data as the coefficient of variation (CV) by dividing the standard deviation by the mean for all subjects and expressing the result as a percentage: RMS SD (x) CV = 100% (5) B Region Area BMC BMD (cm 2) (grams) (g/cm z) L Arm R Arm L Ribs R Ribs T Spine L Spine Pelvis L Leg a.da..4!.233 R Leg i.250 Head Total !.228 A fact not widely appreciated is the large statistical error inherent in many precision studies. If m repeated measurements are made on each of n subjects there will be a total of n x m measurements. However, since it was necessary to calculate the mean BMD of each subject there were only n x (m - 1) independent measurements from which to evaluate precision. This number is the degrees of freedom (df) and determines the statistical weight of the study. The error in the precision measurement cannot be smaller than the component arising from the finite data set available which can be estimated from the x-squared distribution. 59'75 In practice real differences in precision between subjects will make the statistical errors in precision studies even larger. Fig 9. A DXA scan of the total skeleton (A). As well as measuring bone mineral content (BMC) and bone mineral density (BMD) over the whole body, results are given separately for 10 subregions in the skeleton (B). From the same scan the body composition software will also estimate total body and subregional fat and lean tissue masses.

13 222 BLAKE AND FOGELMAN Fig 10. Paired PA/!ateral DXA scans of the lumbar spine showing the analysis for L2-L4. The PA scan is acquired first (A) and then the scanning arm rotated through 90 degrees to acquire the lateral scan (B). Vertebral body BMD is measured on the lateral scan anterior to the vertical line intersecting the neural arches while mid-vertebral BMD is measured inside the black regions of interest within each vertebral body, Long-Term Precision It is important to recognise that precision errors may depend on the time interval between repeated measurements. 75 When a new application is developed. often only the short-term precision error is evaluated from repeated measurements made on a single day or. at most. over a period of a few weeks. Frequently such studies reflect optimal conditions unlikely to be realised in routine practice. 76 Although the short-term precision error is readily evaluated it is often more relevant to the interpretation Of clinical data to know the long-term precision error defined by the random variations of repeated measurements over time periods of a few months or years. Generally, long-term precision errors are expected to be larger than short-term errors because they reflect additional sources of random variation attributable to small drifts in instrumental calibration, changes in patients' weight and soft tissue composition, variations in patient positioning, and other differences in technique for performing and analysing scans between different personnel performing a test. Because long-term precision errors are measured over time periods in which true changes in BMD can be expected, the calculation of long-term precision requires a different mathematical approach than that for short-term precision. Because of these changes, use of the standard deviation would result in overestimation of the true precision errors. It is reasonable to assume that many subjects will experience a long-term secular bone mass decrease with aging (Fig 12B). A parameter that correctly quantifies variability for reasons other than a true linear change is available from regression analysis. 75 When repeated measurements are taken from the same patient over time the variability about the regression line is quantified by the standard error of the estimate (SEE); and SEE rather than SD should be taken as the estimate of the long-term precision error. As with short term precision, results from different individuals are combined to find the RMS average SEE. In a manner analogous to short-term precision, the long-term precision may be expressed as the coefficient of variation by dividing the RMS SEE by the mean for all subjects and expressing the result as a percentage: RMS SEE (x) CV- 100% (6) It is important to be aware that this definition of long-term precision might still include variability because of nonlinear changes in bone density. It may not be appropriate therefore in patients who have recently commenced or discontinued treatment for osteoporosis.

14 TECHNICAL PRINCIPLES OF DXA 223 A B C Fig 11. High resolution lateral scans of the lumbar and thoracic spine(l4-t-4) can be used for vertebral morphometry studies of spinal crush fractures, These images were produced on a Hologic QDR-4500A system. An initial PA scan of the spine {C) generates a enter ine in the middle of the spine which is tracked during the lateral scan to eliminate magnification errors Both dual energy(a) and single energy (B) lateral images are available for analysis. (Reprinted with permission of the manufacturer). Stcmdaiztized Coeffk:ient qf ~%/iclticm Short-term precision studies expressed b\ the coefficient of variation are frequently used as a measure of the clinical performance of instrumentation. As pointed out earlier, in practice long-term precision studies are likely to be more useful for this purpose than short-term studies. However. a further significant limitation of using CV to express the clinical performance of equipment is the normalization of the SD or SEE error by the bone density parameter (equations 5 and 6). This practice overlooks the significance of the size of the expected changes in bone density in limiting the sensitivity of equipment for measuring response to treatment or rate of loss of bone. To avoid this problem, Miller et a177 proposed that the clinical utility of different equipment and applications would be better compared using the standardised coefficient of variation (SCV) defined as the RMS SD divided be a ll]c~.t~kll'e Ol" the clinical l-an~c of the parameter: R.klS SD (x) SCV Ran.ge ( x ) x 100~ (7) A convenient definition of the range is the population standard deviation obtained from studies to obtain normati\e data. SCV is particularly useful when comparing the performance of BMD measurements at different skeletal sites or comparing DXA parameters with bone ultrasound measurements such as speed of sound (SOS) which, while having excellent precision, has a relatively narrow clinical range (Table 2). QUALITY CONTROL FOR DXA STUDIES Phantoms Daily scanning of a suitable phantom is an essential quality assurance procedure for all DXA

15 224 BLAKE AND FOGELMAN A 1.10 B "'''''-~..~ ~-" 1,00. E O 9 O ~" E ~o ca o SD CVshort-term = ~ x 100 % Mean r m SEE CVl~ - M~n x 100 % Time (minutes) Time (years) Fig 12. (A) Definition of short-term precision, Over short time Periods no real change in BMD is expected. Precision is expressed =is the coefficieilt Of variation by giving the standard deviation (SD) as a percentage of the mean. Often sh0rt-term precision is derived from repeated scans performed within a period of one hour. (B) Definition of long-term precision. Over long time periods real changes in BM0 are likely. If the Secular change is linear with time anappropriate parameter to express the random measurement errors is the standard error of the estimate (SEE) derived from linear regression analysis. Precision is expressed as the coefficient of variation by giving the SEE as a percentage of the mean. equipment (Fig 13). Not only does this provide a daily check of system calibration, but the large numbei~ of phantom stiidies acquired Over a period of time allow even small drifts to be detected (Fig 13 C). It is especially important that users of bone densitometry equipment follow the manufacturer's recommendations on daily quality control (QC) procedures because in the event of equipment failure this is the best guarantee of ensuring the integrity of clinical data. In general; phantoms should be constructed of hydroxyapatite and a water equivalent epoxy resin so attenuation cisefficients resemble as closely as possible those of bone mineral and soft tissue in the body. Ideally, suitable phantoms should enable BMD to be monitored over a range of values so that the linearity of the BMD scale can be regularly Verified. The European spine phantom has three simulated vertebrae constructed to give BMD values of 0.5, 1.0 and 1.5 g/c m2 respectively, making it particularly suitable for this purpose (Fig 13 B). 78 Staff Training As well as the regular scanning of phantoms to check SYstem calibration, the other major quality assurance issue is the training of staff performing bone densitometry investigations to ensure consistency in patient positioning and scan analysis. This i s especially important for clinical trial studies, the special requirements of which are discussed below. In follow-up studies particular care is needed both in the performance of Scans and their analysis if Optimu m precision is to be achieved, 79 Attention to the training Of radiographers and consistency in their approach to scanning and analysis are esseiitial. Care is needed in patient positioning so that the spine is straight and central in the area imaged. Vigilance is needed to ensure that items of clothing Table 2. Comparative Precision Data for Dual Energy X-ray Absorptiometry (DXA) Scans of the Spine and Hip and Quantitative Ultrasound (QUS) Scans Of the Caicaneus PA Spine BMD., DXA* QUSt Femoral Neck BMD BUA SOS Young Adult mean (and poi~ulation SD) i.00 (0.12) g/cm (0.11) g/cm 2 75 i15) db/mhz Short-Term Precision (SD) g/cm g/cm db/mhz Short-Term Precision (CV) 1.0% 1.5% 4.0% L0ng-Term Precision (CV) 1.5% 2.5% -- Standardized Precision (scv) 8% 11% 20% 1600 (25) m/s 5.0 m/s 0.30% *DXA normative data for Hologic QDR-1000 system courtesy of Dr. H. Ahmed; DXA long-term precision data for Hologic QDR-1000 SyStem courtesy O f Mr. R. PateL tqus normative and short-term precision data for Hologic Sahara clinical bone sonometer courtesy of Ms. M. Frostl 20%

16 TECHNICAL PRINCIPLES OF DXA 225 C I f I I I ] I I I I I I 1 I I I I I I I I ~J ~, ~ r,-.,m i.849,,m, m ~ E o o o ~0 o o,...o OQ**.O (~.'~..,;g~ o,.,,o o^ (~o o o,,0-' OOaD 0~000~m~176 ~ 0 0 ) I;iO0 o o oa o OaD o O0 0 O 0-- o o _^o o o o o o~ oo-~ _ O o _a I I I I D Fig 13. Daily scans of phantoms such as (A) the Hologic spine phantom and (B) the European spine phantom are an essential part of the quality control of bone densitometry equipment. (C) A plot of daily BMD measurements of a phantom is a sensitive indication of any long-term departure in instrument calibration. or jewelry do not introduce artifacts into the scan. For the hip the radiographer must ensure that the angles of internal rotation of the foot and abduction of the leg remain unchanged on follow-up scans, s~ Images from previous studies should be available at the time of scanning to ensure that the best match with past studies is obtained. During scan analysis comparisons ensure the employment of an analysis region identical in size and location to that previously used. To ensure optimum use of the compare function each follow-up scan is compared directly with the original baseline scan. The greatest care is needed in analyzing the proximal femur where small differences in the positioning of the femoral neck box and Ward's triangle can lead to significant changes in the BMD measurements. Where interactive hip analysis software is provided this can be used to

17 226 BLAKE AND FOGELMAN ensure that regions in the hip reproduce as closely as possible those on the baseline scan. Clinical Trials Because of the high precision and long-term stability of calibration DXA is widely used for prospective clinical trials of therapies to prevent bone loss in postmenopausal women. 7 High precision is an important factor for clinical trials because it determines the smallest change in bone density that can be detected and thus can influence the size and cost of studies. 10 In major clinical trials it is now usual for an experienced international center to coordinate quality assurance for bone densitometry studies. 1~ Initial training is given to radiographers and scans are analyzed at a central laboratory. This ensures a consistent approach to analysis and ensures that both patient and doctor remain blinded to whether the subject is taking the active drug or placebo. A set of master phantoms is passed between participating centers to cross-calibrate DXA systems. Results of daily phantom QC scans at individual sites are regularly reviewed to verify that systems are functioning within specifications and may be used to correct clinical scan data in the event of drifts in system calibration. Particular problems may arise if there is a need to replace a DXA scanner during the course of a study. Because studies may last for five years or longer it is inevitable that some centers will upgrade their scanner during the course of a study, whether because of aging of equipment or taking advantage of advances in technology. In this situation the new scanner should be cross-calibrated with the old using phantoms recommended by the manufacturer. However, phantoms are not perfect representations of the human body and it is particularly important that in vivo cross-calibration studies are performed to verify the phantom studies. Typically, studies including at least 20 patients are required to cross-calibrate in vivo with an accuracy of 1%.4s CONCLUSIONS Over the past decade growing awareness of the affect of osteoporosis on the elderly population and the consequent costs of health care has stimulated development of new treatments such as bisphosphonates and wider provision of imaging technology to assist in diagnosis. With its ability to perform high precision measurements of the spine and hip, DXA is well suited to meet this latter need. The provision of scanning equipment has expanded rapidly, and DXA studies are widely used in diagnosing osteopenia and osteoporosis and aiding decisions over treatment. DXA technology is also playing a major role in clinical research, especially in trials of the new treatment agents. Many large clinical trials are currently in progress, and reports over the next few years will clarify the role of preventive treatment in maintaining bone mass and reducing fracture incidence. Whether DXA technology can meet the anticipated need for more diagnostic equipment to properly target these treatments is presently unclear. The major alternative is bone ultrasound (QUS). Although QUS technology is cheaper than DXA and is proven in its ability to predict fracture risk in the elderly, its future role remains unclear because of poor precision (as measured by SCV), poor stability, lack of appropriate phantoms, and doubts about how to interpret low ultrasound results in perimenopausal women. The outcome of this debate will determine whether the expansion in DXA provision over the last five years will continue or whether the technology is regulated to a clinical research tool. 1. Genant HK, Engelke K, Fuerst T, et al: Noninvasive assessment of bone mineral and structure: State of the art. J Bone Min Res 11: , Wahner HW, Dunn WL, Brown ML, et al: Comparison of dual-energy X-ray absorptiometry and dual photon absorptiometry for bone mineral measurements of the lumbar spine. Mayo Clin Proc 63: , Cullum ID, Ell PJ, Ryder JP: X-ray dual photon absorptiometry: A new method for the measurement of bone density. Br J Radio162: , Mazess R, Collick B, Trempe J, et al: Performance evaluation of a dual-energy x-ray bone densitometer. Calcif Tissue Int 44: , Wahner HW, Fogelman I: The evaluation of osteoporosis: REFERENCES Dual energy x-ray absorptiometry in clinical practice. Martin Dunitz, London, Sorenson JA, Duke PR, Smith SW: Simulation studies of dual-energy X-ray absorptiometry. Med Phys 16:75-80, Orwell ES, Oviatt SK: Longitudinal precision of dualenergy x-ray absorptiometry in a multicenter study. J Bone Min Res 6: , Lewis MK, Blake GM, Fogelman I: Patient dose in dual x-ray absorptiometry. Osteoporos Int 4:11-15, Storm T, Thamsborg G, Steiniche T, et al: Effect of intermittent cyclical etidronate therapy on bone mass and fracture rate in women with postmenopausal osteoporosis. N Engl J Med 322: , Gltier C-C, Fanlkner KG, Estilo MJ, et al: Quality

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Br J Clin Res 4: , Wilson CR, Fogelman I, Blake GM, et ah The effect of positioning on dual energy x-ray densitometry of the proximal femur. Bone & Mineral 13:69-76, Shrimpton PC, Wall BF, Jones DG, et al: A national survey of doses to patients undergoing a selection of routine x-ray examinations in English hospitals, in National Radological Protection Board NRPB-R200. London, HMSO, Blake GM, Patel R, Lewis MK, et al: New generation dual x-ray absorptiometry scanners increase dose to patients and staff. J Bone Min Res 11:S157, 1996 (suppl 1) 83. The Ionising Radiation Regulations 1985, London, HMSO, 1985.