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National Library of Canada
Bibliothèque nationale du Canada
Acquisitions and Acquisitions et Bibliographic Services services bibliographiques
395 Wellington Street 395, rue Wellington Ottawa ON K I A ON4 Ottawa ON K 1 A O N 4 Canada Canada
The author bas pranted a non- L'auteur a accordé une Licence non exclusive licence allowing the exclusive permettant à la National Library of Canada to Bibliothèque nationale du Canada de reproduce, loan, distniute or sell reproduire, prêter, distribuer ou copies of ths thesis in microfom, vendre des copies de cette thèse sous paper or electronic formats. la forme de cnicrofiche/fihn, de
reproduction sur papier ou sur format électronique.
The author retains ownership of the L'auteur conserve la propriété du copyright in ths thesis. Neither the droit d'auteur qui protège cette thèse. thesis nor substantial extracts fiom it Ni la thèse ni des extraits substantiels may be printed or othewise de celle-ci ne doivent être imprimés reproduced without the author's ou autrement reproduits sans son permission. autorisation.
Misbah Gulam Department of Medical Biophysics
Submitted in partial fulfillrnent of the requirements o f the degree of
Masters of Science
Faculty of Graduate Studies The University of Western Ontario
London, Ontario December 2 1 . 1999
8 Copyright by Misbah Gulam 2000
An investigation was conducted to measure phalangeal bone mineral density
(BMD) using a conventional digital radiography system that was rnodified for area dual-
enegy x-ray absorptiometry (DEXA) and for quantitative computed tomography (QCT).
Two studies were performed: 1) DEXA precision and accuracy was assessed.
and the BMD measurements were compared with radiographic absorptiometry in two
groups ofwomen: and. 2) Phalangeai BMD measurements of cadavers by DEXA and
QCT were compared in order to establish an empirical relationship relating the two
techniques.
Phalangeal DEXA was precise (k 0.67%). accurate (* 4.1%). correlated with
radiographic absorptiometry (r2 = 0.8 1. p < 0.000 1 ) and also compared well with QCT.
An empirical relationship was established - relating areal and volumetnc measurements
( to 2 6%) - to obtain estimated volumetric BMD. which showed no significant
difference to tme volumeuic BMD. .4rnong these techniques. DEXA providing
estimated volumeuic BMD has the greatest potential for development in osteoporosis
diagnosis.
Keywords: digital radiography. bone densitometq. dual-energy x-ray absorptiomet~.
quantitative computed tomography. radiopphic absorptiometry. bone mineral density.
phalanges. osteoporosis. active-contour model.
CO-Auth orsh ip
The following thesis contains material From manuscnpts that are in press and in
preparation. Chapter 2 is an original manuscript entitled. "Bone Mineral Measurement of
the Phalanges: Cornparison of Radiographie Absorptiometry and Area Dual Energy X-
rap Absorptiometry" CO-authored by Misbah Gularn. Michael Thornton. Anthony B
Hodsman and David W Holdsworth. which was accepted to the journal Radiology (in
press: January 10.2000). Chapter 3 is an original manuscript entitled. "Volurnetric BMD
r\ssessment of the Phalanges by Dual-Energy X-ray Absorptiornetry and Quantitative
Computed Tomography" also CO-authored by Misbah Gularn. Michael Thornton.
Anrhony B Hodsman and David W Holdsworth. which is in preparation for publication.
Michaei Thornton. a representative from industry (Enhanced Vision Systems
Corp.. London. ON). was a consultant on this thesis. He developed the software for
DEXA and QCT image analysis. Anthony B Hodsman and David W Holdswonh
conceived the project. supervised with the acquisition of the images and assisted with the
preparation and revision of the manuscripts. As first author on both manuscripts 1 was
primarily responsible For data acquisition. data andysis. drafting and revising the
manuscript. 1 also contributed to snidy design and together with David W Holdsworth in
conceiving the empincal relationship descnbed in Chapter 3.
Acknowledgements
I'd like to th& the staff and students of the Department of Medical Biophysics and the
Imaging Research Labs of the John P. Robarts Reseach Institute for the help. support
and encouragement that I have received. The following people deserve speciai mention.
Dr. David Holdsrvorth. my supervisor. from taking me on as a 4" year student. and
giving me the exce2lent guidance. motivation and support throughout this work.
Dr. -4nrhoy Hodsman and Dr. Dick Drosr who were members of my advisory
cornmittee. for their support and helphl comments regarding this work. Furthemore.
thanks are due to Dr. Hodsman for an opporninity to be involved in a clinical study.
.Clike Thornion. for many helpful discussions and constantly upgrading software to enable
me to c m y on with my work in an efficient manner.
Dr. Parer Canham for providing interesting discussions relating to biomechanics.
The technical assistance from Dr. Hanif Ladak. Hristo Nikolov. Chris Norley and
Jonathon Thomas is also greatly appreciated. Thanks are also due to Dr. James A
Johnson for providing cadaver specimens that were used in this work. This work was
îùnded in part by Siemens Medical Systems. Erlangen. Gemany.
Lastly. thanks are due to my farnily: rny parents. my brothers and sister. Nausheen and
her family. for al1 their great support and for having the patience with me as 1 completed
this thesis.
1 .j. 1 Phaiangeal BMD by DEXA ................................................................... 19 1 3 2 QCT of the phalanges ............................................................................... 2 1
1.6.1 Outline of Chapter 2: Comparison of Radiographic Absorptiometry and Area Dual Energy X-ray Absorptiometry ........................................................... 23
1.6.1 Outline of Chapter 3: Volumetric BMD assessrnent of the phalanges ......... 24 1.6.3 Summary of Future Applications ............................................................... 25
Chapter 7: Bone Mineral Measurement of the Phalanges: Comparison of
Radiographic Absorptiometry and Area Dual-Energy X-ray Absorptiometry
4.1 . 1 Conclusions of Chapter 2: Cornparison of Radiographie Absorptiometry and Area Dud-Energy ;Y-ray Absorptiometry ................................................... 80
4 . 2 Conclusions ofchapter 3: Volurnetric BMD assessrnent of the phalanges . 8 1
4.21 QCT and DEXA cornparison in a clinical setting ....................................... 83 ............................................. 4 2 . 2 Phalangeai DEXA to assess skeletal maturity 83
4.2.3 Development of a compact DEXA system ................................................. 81 4.2.4 A three tissue component phalangeal DEXA technique .............................. 83
....... 4 . 2 Peripheral DEXA and QCT for the assessrnent of rheumatoid arthritis 85
.................................................................... 4.3 S~rrnmary of Friture Applications 87
List of Tables
Chapter 1:
1 - 1 The development and advancement of absorptiornttry techniques for non-invasive
.............................................................................................. bone m a s rneasurement 4
Chapter 7:
2- 1 Descriptive s tistics of DEXA and RA phalangeal bone density measurernents in the
............................ Young healthy women group and the postmenopausal wornen 43
7-2 The precision of DEXA measurements of the middle and proximal phalanges: studies
.............. perfamed with and without repositioning between image acquisition. 45
Chapter II:
3- l The precision and accuracy results for QCT volume segmentation: studies performed
using cylindrical phantorns of known volume and density ............................................. 68
3-2 The descriptive statistics for DEXA and QCT rneasurements of the middle and
measurements with RA in human volunteers: and. 4) adapt the sarne XRiI-based digital
radiography system to obtain QCT measurements of tme volumetric bone density for
cornparison with DEU-based areal BMD.
1.5 Approach
1.5.1 Phalangeal BMD by DEXA
Dual-energy imaging has been the focus of study in our lab for some time (56-58).
From investigations by Moreau et ai. (58). a technique for duai-energy im&g to
quanti@ calcium content in vitro of tissue samples has been developed. This dual-enerw
technique was extended to implement area DEXA on an XRII-based clinical digital
radiography system to quanti@ bone m a s in small rodent bones (59). The area DEXA
technique kvas compared to an existing clinical DEXA system. QDR 4500 (Hologic Inc.
Waltham. MA) to verify the accuracy of the BMD measurements. The primary
developrnent of area DEXA was done in order to overcome constraints imposed by the
physics of clinical bone densitometen when used in hi&-resolution mode to measure
BMD in rodent bones. The phalangeal DEXA technique development followed from this
work.
My project involved implementing DEXA using a clinical digital radiopphic
( XRI 1)- based sy stem for phaiangeai BMD measurements. This technique uses a digital
fluoroscopic system with an areal detector coupled to a charged coupled device (CCD)
camera. rather than pencil- and fan- beam scanners that are employed in conventional
DEXI\ scanners (as discussed above). Low- and hi&-enerw digital radiographs in the
posteroanterior (PA) view of the hand are obtained for analysis. Tne XRII has a
logarithmic amplifier so the output signal (log signai that is recorded in ADU) at the low-
and high-enera is proportionai to their respective logarithmic transmission factors.
lncluded in the field-of-view are the middle and proximal phalanges along with a
calibration crossed-step wedge that is composed of epoxy-based matends that mimic
cortical bone and soft-tissue. This 5 x 5 step calibration phantom - with h o w n
thickness and attenuation coefficients (at the two energies) - is used to detemine the
thickness of bone and soft-tissue (considered basis matenals) of every pixel in the image.
From the low- and high-energy images. the low- and high-energy signals of each of the 25
basis material combinations are calculated resulting in a the-dimensional calibration
surface at each energy with log signal. bone thickness (cm) and tissue thickness (cm) on
the z.y. and x mis. respectively. A nonlinear transformation described by Johns and
Beauregard is used to fit this data (60). From the cdculated equivalent thickness of rach
of 75 combinations. the equivalent thickness of every pixel in the image is calculated and
hence a thickness value of soft-tissue and bone is obtained. resulting in material (bone and
so fi-tissue) specific images.
The use of a conventional XRII is problematic as it intrinsically suffers from a
number of problems that would influence its use in absorptiornetric applications.
Therefore the acquired digital images are exported to a workstation where a number of
knoun methods -descnbed by Moreau es al. (58) are used to correct the spatial
distortion and k ~ e d pattern noise of the intensifier. As the hand (and particularly the
phalanges) have linle thickness. non-linearities due to scatter and veiling glare are minimal.
With phalangeal DEXA in place. cornparison to the utility of plain hand x-rays b y
the OsteoGram RA technique was done. A correlation of phalangeal BMD measurements
between the two techniques was examined to predict the presence of clinically important
reductions in bone mas . Both young (healthy) and postrnenopausal women were studied
and DEXA analysis was also carried out on the middle and proximal phalanges in these
women. .4s the OsteoGram RA techniques reports one BMD value for the înd-4" rniddle
phalanges in arbitrary units, the DEXA technique averaged the BMD obtained in these
phalanges and reported a single measurement, but in terms of calcium hydroxyapatite.
1.5.2 QCT of the phalanges
Our [ab has been instrmiental in developing 3D CT that acquire images of an
entire volume (6 1 ) and for Computed Rotational Angiography (62). Furthemore.
dcvelopment of analysis software has allowed for the assessrnent of bone density in small
animals. Hence. with the rxisting techniques for 3D CT irnaging and available software. a
study to implement high-resolution 3D pQCT of intact phalanges was done. In QCT the
3D shape of the phalanges is used to determine vBMD. independent of bone size. Note
that areal BMD t y projection is dependent on bone size. This follows intuitively. given
that a larger bone would have greater minerai content. Normalizing the BMC by
projrcted area gives areal BMD that does not hlly account for the size dependence. as
the true physical density of the bone is volume specific (not area specific).
My project involved impiementhg a clinical digital subûaction angiography
system (Multistar. Siemens Medicd Systems. Germany) for an intekgai measurement of
trabecular and cortical BMD of entire phalanges by DEXA and QCT. The volume CT
data was acquired in 4.5 seconds while the C-am rotated around the hand. resulting in
approximately 130 projection images over the 200" required for the CT volume
reconstruction. Included in each image were cylindrical tissue-mimicking calibration
material used to quanti& the amount of bone in the image. As there is an exact linear
relationship in image intensity (measured in Hounsfield units (HU)) with respect to
object attenuation. only CT water-equivalent and CT cortical bone-cquivalent phantoms
were used for the calibration. Quantitative CT provides measurements of attenuaticn
constrained to material within a fixed voxel size. hence ailowing for single-energy QCT to
separate bonc from soft tissue in the image. Analysis was done in the 2nd - 4' middle and
proximal phalanges. but separate reports of BMD for each phalanv are used for
cornparison in this study.
The focus of this study was not only to establish a QCT technique to assess
BMD. but to develop (using 3D images of the hand) a method for estimating volumetnc
BMD from projected DEXA images. The study reports on comparison of measurement
w-iables (are& volume. BMC) obtained by DEXA and QCT of the phalanges and
rstablishes an empirical relationship that could be irnplemented to convert al1 DEXA areal
BMD rneasurements to an estimated volurnetric BMD.
1.6 Thesis Outfine
The body of work presented in this thesis consists of two papers: one accepted
for publication and the other recently submitted for publication. In Chapter 1. 1 describe
the phalangeal DEXA technique. determine its precision and accuracy. and compare
DE= with RA in a population of femaie volunteers. In Chapter 3. 1 descnbe how tme
volurnetric bone density measurements of the phalanges are accomplished using QCT and
how these measurements could be used to improve DEX4-based phalangeal
measurements.
1.6.1 Outline of Chapter2: Compatison of Radiographie Absorptiometry
and Area Dual Energy X-ray Absorptiometry
In Chapter 2. 1 evaluate an area DEXA technique to measure phalangeal BMD.
classi% its precision and accuracy. and compare DEXA with RA of the phalanges.
Ninetecn healthy premenopausal and 18 postmenopausal women underwent RA and
DEXA of the hand. Digital x-ray images (JO kVp without filtration and 125 kVp with 1.7
mm Cu filtration) for DEXA were obtained with a clinical digital radiography system.
Each image included a calibration wedge. (comprised of eposy-based materials that mimic
the radiognphic properties of soft tissue and compact bone) to quanti@ bone mineral
content. A linear regression analysis was used to compare RA with DEXA in aii
subjects. Reproducibility and accuracy of BMD measurements by DEXA were assessed
in cadaver hands and cylinders of bone-equivalent matenal. respectively.
There was a good correlation of DEXA of the middle phalanges with RA (6 =
0.81. p < 0.0001). The precision error of these DEXA rneasurements is * 0.67% and
accuracy is I 4.1%. These results suggest that digital DEXA of the phalanges with an
area detector provides rapid acquisition (<20 s) and immediate analysis. with hi&
precision and accuracy. Digital DEXA correlates well with RA. making it a potentialiy
viable tool for clinical diagnosis of oneoporosis.
1.6.2 Outline of Chapter 3: Volurnetrie BMD assessment of the
phalanges
Chapter 3 is a description of a high-resolution 3D peripheral QCT technique for
cvaluating vBMD of entire phalanges. The expenmental technique was assessed in the
phalanges of cadaver hands and the results were compared with DEXA-based areal B MD
measurements. Using a prototype CT scanner based on a rotating XRII. 3D CT images
of cadaver hands (including calibration material) were obtained. Two additional digital
radiographs of the hands were also acquired for DEXA analysis. A comparison of DEXA
aith QCT was done in order to develop an empirical relationship relating area and
volumetric measurements. Analysis was done in the entire 2"QLh middle and proximal
phalanges in each of the three cadavers. resulting in 1 8 separate measurernents of area
\.ohme. BMC. aBMD and vBMD.
The vBMD of the nine middle phalanges was not significantly different than that
of the proximal phalanges @ = 0.45). However. there is a significant difference @ < 0.01 )
between the aBMD of middle and proximal phalanges. A comparison of BMC
measurements for aii 18 phalanges shows no significant difference between QCT and
DEXA (p = 0.26). The QCT measurements may avoid artifacnial erron in BMD
merisurement (due to variations in bone site) that occur when using DEXA. The most
promising development, however is the fh~&qg of an empirical relationship that relates
phalangeal area and volume. This relatiûnship appears to improve estimates of phaiangeal
volumetric BMD obtained by DEXA techniques.
1.6.3 Summary and Future Applications
Chapter four summarizes the work described in this thesis. and presents some
future applications of DEXA and QCT phalangeal BMD measurements. The extension
of comparing DEXA and QCT phalangeal measurements in a clinicai study is discussed.
dong with approaches of ushg DEXA and QCT to assess skeletal growth and also
rheumatoid arthritis.
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60. Johns PC. Beauregard RM. Incorporation of scattered radiation into dual-energy ndiologic theory and application to rnammography. Med Phys 1994: 2 1 : 1455- 1462.
6 1. Holdsworth DW! Drangova M, Fenster A. A high-resolution XRH-based quantitative volume CT scanner. Med Phys 1993: 20:449462.
62. Fahng R. Moreau M. Holdsworth DW. Three-dimensional computed tomographic reconstmction using a C-arm mounted XRII: correction of image intensifier distortion. bled Phys 1997: 24: 1097- 1 106.
'chupter 2: Bone Mineral Measurement of the Phalanges: Cornparison of
Radiographic Absorptiomets, and Arecl Dual-Energy X-my Absorptiometry
2.1 Introduction
Clinical measurement of bone m a s in the assessment of osteoporosis is used to
diagnose low bone mas . predict fume skeletal fracture n s k and for serial rnonitonng ( 1 -
3). Although duai-enrrgy x-ray absorptiometry (DEXA) is widely available. alternative
means of rneasuring bone mass. particularly in the peripheral skeleton (calcaneus. forem.
and phalanges) may be just as etTective for the diagnosis of fracture risk (2.4.5).
Radiographic absorptiometry (RA) is a peripheral technique that uses a hand radiograph
to provide an image of the middle phalangeal bones by digitizing the optical absorption of
the radiographic image using a hi& resolution vidm canera. By including an alurninum
aedge in the onginai x-ray (used as a calibration device). a measure of phalangeal bone
mass is generated and an evaluation of the bone status is made (6.7).
However. there are limitations to RA. including: the time delay resulting from
ccntralized analysis of the film. the use of a single x-ray energy. and the general limitation
of calibration in arbitrary (aluminum) units. This has resulted in proposals that RA (using
s-ray film) be replaced with di@ techniques ushg semi-automated analysis (8). Hence
new techniques have k e n developed. such as digital image processing (DiP) of the
metacarpal bones (9), computed digital absorptiometry (CDA) (10) and dual-enerw CDA
(accuDEXAM)(l 1) of the middie phalanx of the middle finger. Despite cdibrating bone
X version of this chapter has k e n accepted for publication in Rudiolo~. It is in press.
mineral in arbitrary units, these techniques continue to demonstrate the utility of
phalangeal BMD as they are precise and accurate. compare well with RA and provide for
widespread screening of osteoporosis patients (1 0,11).
We believe that DEXA of the phalanges, using a two-dimensional (area) x-ray
detector and calibrated in hydroxyapatite, is an ided technique for peripheral bone mass
mrasurements. Although DEXA is available to assess BMD at the distal radius and the
calcaneus ( 12-14). there have also been attempts using DEXA scanners (with point and
fan-barn geometry) to measure total hand. phalangeai and metacarpal BMD for the
assessment of rheumatoid arthritis (1 5- 18) and more recently, skeletal maturity (1 9). But
these DEXA scanners are designed for central sites (spine. hip and total body) with
sipni ticant surroundhg tissue and may not provide the spatial resoiution needed for small
bones (phalanges) with little soft-tissue covering. Hence. with the widespread availability
of digital radiography equipment, digital imqing techniques and simpie techniques for
duabenerg decomposition we undertook a study to implement DEXA of the phalanges.
assessed its precision and accuracy. and made direct cornparison of DEXA phalangeal
BbID measurements with M.
2.2 Muterials and Methods
2.2.1 Subjects
Two groups of subjects mere studied: Group 1 included 19 healthy pre-
menopausal volunteers, aged 3141 yean (mean of 36 +. 3 yrs.). with no k n o w risk
factors for metabolic bone disease and normal menstrual function: Group 2 included 18
post-menopausal women, aged 63-8 1 years (mean age 71 + 5 yrs.). Group 2 subjects
were healthy elderly women referred to an outpatient clinic either f ~ r assessrnent of
osteoporosis nsk factors or management of established osteoporosis. Of the post-
menopausal women, seven (mean age 70 * 4 yrs.) had no evidence for osteoporosis as
assessed by spinal x-rays and quantitative calcaneal ultrasound, while 1 1 (mean age 72 k 5
yrs.) were receiving on-going therapy for previously established diagnosis of
osteoporosis. The individuals in the 2 groups were chosen to cnsure a broad range of bone
mass. Routine blood screening was done to exclude individuals with other signiticant
rnetabolic bone diseases and dso those with impaired m a l Function (serum creatinine 2
1 IOpmoK). Subjects with significant radiological evidence for degenerative changes in the
interphalangeal joints of the hand were also excluded. Each subject had screen/film and
digital .u-raps of the hand for RA and DEXA acquisition and analysis. The hag@
procedures were fully eqlained and written infbrmed consent was obtained from al1
participating subjects. Our University's review board for research involving hurnan
subjec ts granted ethics approval (Appendix 1 ).
2.2.2 Radiographie Absorptiometry
The RA measurement of BMD of the phalanges was done as implernented by
OsteoGram (OsteoGram Analysis Center. El Segundo. CA). a central reading laboratory.
which had exclusively licensed the OsteoGram technolog h m CompuMed. Inc.
(Manhattan Beach. CA). The RA acquisition procedure has been descnbed previously in
the literature (20). Bnefly. the RA measurement required acquisition of standard.
unscreened radiographs of the lefl hand, including an aluminum reference wedge for
calibration. Two radiographs were obtained: the first at 50 kVp. and a subsequent one at
60 kVp. The radiographs were sent to OsteoGram for optical processing. where the
images are digitized by a high-resolution video camera. Anafysis is done on the entire
rniddle phalanges of 2nd to 4th digits to determine an index of BMD (BMDrn). The index
is the average BMD for these phalanges with dimensions of mass per unit volume, but in
arbitras units (6). Note that the OsteoGrarn RA technique provides only an estimate of
truc volumetric BMD of the phalanges. A simple post-processing algorithm is applied to
the projected x-ray data to obtain an apparent volumetnc BMD. assuming a circula cross
section for each phalam in each transverse slice of the RA analpsis (20).
Descriptive statistics for the precision analysis (repositioning and without
repositioning studies) were generated for each cadaver specimen. Table 2-2 lists the CV
for measurements of BMC and BMD. made with and without repositioning. For al1 the
measurements. the CV is lower for the BMC without repositioning than with
repositioning between DEXA acquisitions. The largest difference occun for proximal
phalangeal BMD measurement. Also the CV is slightly lower in proximal versus rniddle
phalangeal rneasurements for the cases of acquisitions without repositioning.
Linear regression analysis for the accuracy study in tissue mimicking material
(CIRS) is depicted in Figure 2-6. The DEXA BMC = 0.953-true BMC + 0.01 1 1 g, with
= 0.9994. SEE = 0.00727 g, p < 0.0001. n = 8. The accuracy error represented by the SEE
l i . . . l a . . . l . , , ,
0.20 0.25 0.30 0.35
BMDM~D (gmcm'*) Figure 2-5. Correlation between BMDRA and BMDkIID (middle phalangeal
BMD measured by DEXA). The highly significant correlation of ? = 0.8 1 1
( p < 0.0001) over a wide range of BMD in the 37 individuds shows that there
is a linear trend ailowing for conversion of RA measurements (in arbitrary
units) into DEXA BMD (an areal density in g*cm'2 of calcium hydroxyapatite).
Coefficient of Variation (%)
A(w/or) B(w1r)
Middle phalanges
BMD 0.67 0.77
BMC 0.75 0.9 1
Proximal ha langes
BMD
BMC
Table 2-2. Precision of DEXA on repeated measurements
with n repeated meaSuTements in each of the 3 cadaver hands; A) without repositioning (w/o r), n = 1 5,
B) with repositioning (w/r), n = 10.
divided by the mean BMC was 4.1 %. Similady, the DEXA BMD = 0.936.tnie BMD +
0.03 12 g*crn-2. with 9 = 0.9991. SEE = 0.00758 g ~ r n - ~ , p < 0.0001, n = 8. The accuracy
error for BMD was 3.2%.
Figure 2-6. Accuracy of DEXA
measurements as measured in
tissue mimicking materials. The
DEXA technique is linear over a
wide range of trabecular and
cortical BMD. Accuracy was not
only evaluated for BMC (a). but
also for BMD (b). using
knowledge of the true projected
BMD.
b ) true BMD (gmcm")
2.4 Discussion
In this study. we used a standard. image intensifier based. digital radiography
system to acquire high-resolution images of the hand. mcludhg a calibration wedge for
DEXA analysis of phalangeal BMD. Acquired images were post-processed for semi-
automatic analysis of the 2nd to 4th middle and proximal phalanges. An epoxy-based
calibration wedge allowed for BMD to be expressed as g ~ r n ' ~ of bone minera1 (calcium
hydroxy apatite). This study also focused on comparing phalangeal BMD measurements
using DEXA and RA. in a representative group of subjects and an analysis was done of
the precision and accuracy of DEXA BMC and BMD measurernents.
Radiographic absorptiometry has strong correlations with other bone
densi tome try techniques. including bone minerai density (BMD) measurements at the
radius. hip and spine (6.12.13.28-30). Our results also demonstrate a strong correlation of
R4 with DEXA over a wide range of BMD: thus the two phalangeal measurement
techniques are comparable. The results show that both RA and DEXA are able to
separate Young women from postmenopausal women in terms of their phalangeal BMD
mesurement. The accuracy and precision of these bone mineral measurements indicate
that the phalanges may be as clinically useful as any other body site for assessing BMD
( 5 ) . Our study shows that the precision error of our DEXA technique is very small. with
CVs less than 1% for BMC and BMD measurements. For e m p l e . the precision of
DEXA of the middle phalanges had a CV of 0.67%. which is comparable to the precision
for RA of 0.6% (3 1 ) and lower than the 1.8% reported for dual-energy CDA ( 1 1 ).
Likewise. the accuracy of DEXA BMC of 4.1 % compares well with the 1.8% for RA
olso reported by Yang et al43 1).
Recently. prospective studies on the fracture predictive ability of phalangeal
BMD measurements have become available. Huang et al., found that hand RA c m predict
fracture risk at either spine or non-spine sites. with phal=geal BMD showing a highly
significant association with non-spine fractures (32). In another population-based
prospective study, Mussolino er al. shcwed that RA is a significant predictor of future
hip tiacture (20). Hence, the measurement of phalangeal BMDRA is clinically useful. as it
is a strong nsk factor for osteoporotic fracture (5): our study indicates that measurement
of phalangeal BMD by penpheral DEXA should therefore have comparable utility.
Ofien the accuracy of bone densitornetry rneasurements is assessed in cadaver
specimens by ashing bories. In this study. the choice of test materiai used provided an
appropriate test of al1 aspects of the DEXA procedure including edge detection and
calibration in tme bone mineral units. We chose cylindrical bone-mirnicking phantoms.
which may be an appropnate mode1 for the phalanges. The advantage of using these
phantoms is that both tme BMC and BMD were known. whereas, only BMC is obtained
by ashing cadavers. Steel er al. have described a phantom for BMD of the hand by DEXA
that is made of aluminurn in the shape of cylindrical tubes embedded in Perspex (33).
However. they conclude that the phantom c m o t be used to m e s s the accuracy of BMD
measurements. as it has not been calibrated against standards of known bone density (33).
Our phantom addressed this limitation as it incorporated cortical bone-rnimicking
material.
Dual-energy x-ray absorptiometry has become the most widely used technology
to measure BMD and has been the most thoroughly studied (34). However. due to the
relativeiy high cost and dedicated space required for this equipment. there continues to be
interest for developing compact densitometry applications for the peripheral skeleton.
particularly since DEXA at the peripheral sites may have the same ability to predict
fracture as axial DEXA technologies (34). Our DEXA technique measures BMD of mal1
bones. with linle soft-tissue covering, at high resolution (< 200 pm) with rapid
acquisition tirne ( 4 0 seconds), equal to or better than operating charactenstics of
conventional clinicai DEXA scanners. With direct digital acquisition and immediate
analysis the entire DEXA procedure could be less than 1 minute thus providing m
advantage over RA. where interpretation of measurement resuits is delayed by analysis of
hand films at a central reading facility. DEXA also has a distinct advantage over RA and
CDA as it allows for soft-tissue correction using the dual-energy algorithm while also
reporting true bone mineral density, rather than arbitrary (aluminum) units.
This D E L U technique was implemented on a clinical digitai radiography sy stem
using large area (XNI) detectors. cornrnonly used for digital subtraction angiography.
Although this system is highly specialized - and hence rnay not be available at smaller
centres - this is not a sipificant limitation. since the technique could easily be
implemented on a smaller. dedicated portable digital DEXA system with a reduced range
of s-ray rnrrgies and analysis area. Wiîh large area detectors. the high spatial resolution
ensures reliable semi-autornated bone drtection, which is particularly important near the
joints. Funhermore. the excellent performance of the active contour sekgmenration
technique allows for separate analysis on entire phalanges. Implementation of a hlly
automated segmentation technique may be feasible with a priori knowledge of hand and
calibration matenal placement (35). Note that DEXA systems with a fixed region of
interest may introduce additional variability, as the andysis rnay include portions of
adjacent bone (11). Clearly. development of a dedicated portable digital DE4U
incorporating fuily automatic BMD detection would be an invaluable tool for quick and
easy diagnosis of bone mûrs.
2.5 Conclusion
These data indicate that high-resolution area DEXA accurately and precisely
predicts the BMD and BMC in the middle and proximal phalanges. The strong correlation
between RA and DEXA indicates that it tvill be possible to convert between BMDRa4
values and areal DEXA phalangeal BMD in funire studies. High-resolution. digital DEXA
BMD measurements of entire phalanges with an area detector results in rapid acquisition
and immediate analysis. making it a potentially viable tool for dinical diagnosis of
ostsoporosis. Using a conventional digital radiography system. phalangeal D E X 4 may be
performed with iittie extra cost: this method requires only the reference phantom and
analysis software as was donç in this study. However. this technique has the greatest
potentiai for development as a dedicated and compact. penpheral DEXA unit.
2.6 References
1. Kanis JA. Delmas P, Burckhardt P, Cooper C. Torgerson D. Guidelines for diagnosis and management of osteoporosis. ïhe European Foundation for Osteoporosis and Bone Disease. Osteoporos Int 1997: 7:390-406.
2. Baran DT. Faulkner KG. Genant HK. Miller PD, Pacifici R. Diagnosis and management of osteoporosis: guidelines for the utilization of bone densitometry. Calcif Tissue Int 1997: 6 1 :433440.
3. Marshall D. Johnell O, Wedel H. Meta-analysis of how well measures of bone mineral density predict occurrence of osteoporotic fractures. BMJ 1996: 3 12: 1254- 1259.
1. Gluer CC. Jergas M. Ham D. Peripheral measurement techniques ror the assessment of osteoporosis. Semin Nucl Med 1997: 27229-247.
5 . Wasnich RD. Perspective on fracture risk and phalangeal bone mineral density. Journal of Clinical Densitometry 1 998: 1 259-268.
6. Cosman F. Hemngton B, Himmelstein S. Lindsay R. Radiographic absorptiomeuy: a simple method for determination of bone mass. Osteoporos Int 1 99 1 : 3 : 3 W 8.
7. Yates AJ. Ross PD. Lydick E. Epstein RS. Radiogaphic absorptiometry in the diagnosis of osteoporosis. Am J Med 1995: 98:j l S47S.
S. van Kuijk C. Genant HK. Radiogrammetry and Radiographic Absorptiometry. In: Genant HK. Guglielmi G Jergas M. ed. Bone densirornetry and osteoporosis. Berlin Heidelberg. Springer-Verlag, 1998: 29 1 -3OJ.
9. Hagiwara S. Engeke K. Takada M. et al. Accuracy and diagnostic sensitivity of radiographic absorptiometry of the second metacarpal. Calci f Tissue Int 1 998: 6î:95-98.
10. Bousein ML. Michaeli DA. Plass DB. Schick DA. Melton ME. Precision and accuracy of computed digital absorptiometry for assessment of bone density of the hand. Osteoporos Int 1 997: 7:444-449.
11. Michaeli DA, Mirshahi A, Singer J, Rapa FG, Plass DB. Bowsein ML. .4 new x-ray based osteoporosis screening tool provides accurate and precise assessment of phalanv bone mineral content. Journal of Clinical Densitometry 1999: 23 -30 .
12. Grampp S. Genant HK? Mathur A. et al. Cornparisons of noninvasive bone mineral measurements in assessing age- related loss. fracture discrimination and diagnostic c~assification. J Bone Miner Res 1997; 12:697-7 2 1.
13. Ravn P' Overgaard K, Huang CI Ross PD, Green D, McClung M. Cornparison of bone densitometry of the phalanges, distal forearrn and axial skeleton in early postmenopausal women participating in the EPIC Study. Osteoporos Int 1996; 6:308-3 13.
14. Heilmann P. Wuster C. Prolingheuer C. Gotz M. Ziegler R. Measurement of forearm bone minerai density: cornparison of precision of five different instruments. Calcif Tissue [nt 1998: 62:383-387.
15. Deodhar .4A. Brabyn J, Jones PW. Davis MJ, Woolf AD. Longitudinal study of hand bone densitometry in rheumatoid arthritis. Arthntis Rheum 1995; 38: 1-04- 12 10.
16. Deodhar AA. Brabyn J, Jones PW. Davis MJ. Woolf AD. Measurement of hand bone mineral content by duai energy x-ray absorptiometry: development of the method. and its application in normal volunteers and in patients with rheumatoid anhntis. Ann Rheum Dis 1994: 53:685-690.
17. Peel NF. Spittlehouse AJ. Bax DE. Eastell R. Bone mineral density of the hand in rheumatoid arthritis. M r i t i s Rheum 1994: 37:983-99 1.
18. Florescu A. Podenphant J. Thamsborg G. Hansen M. Leffers AM. Andersen V. Distal metacarpal bone minenl density by dual energy X-ray absorptiometry (DEXA) scan. Melhodologicd investigation and application in rheurnatoid arthntis. Clin Exp Rheumatol 1993: 1 1 :635-638.
19. BraiIIon PM. Guibal AL. Pracros-Deffrenne P. Serban A. Pracros P. ChateIain P. Dual energy X-ray absorptiometry of the hand and wrist-a possible technique to assess skeletal maturation: methodology and data in normal youths. Acta Paediatr 1998: 87:924- 929.
70. Mussolino ME. Looker AC. Madans M. et al. Phalangeai bone density and hip fracture risk. Arch Intern Med 1997; 157:433-43 8.
I l . Moreau M. Holdsworth DW. Fenster A. Dual-energy x-ray ima@ng technique for in vitro tissue composition measurement. Med Phys 1994: 2 1 : 1807- 18 15.
23. Huda W. Gkanatsios NA. Radiation dosimetry for extremity radiographs. Health Phys 1998: 75:492-499.
24. Johns radioiogic
PC. Beauregard KM. Incorporation of scattered radiation into dualtnergy theory and application to mamrnography. Med Phys 1 994: 2 1 : 1455- 1462.
25. Lobregt S, Viergever MA. Discrete dynarnic contour model. IEEE Transactions on Medical Imaging 1 995; 14: 17-24.
26. Mueller KHI Trias A, Ray D. Bone density and composition: age-related changes in water and mineral content. J Bone Jt Surg 1966; 48: 140- 148.
27. Gluer CC, Blake G. Lu Y. Blunt BA. Jergas M. Genant HK. Accurate assessment of precision errors: how to measure the reproducibility of bone densitometry techniques. Osteoporos Int 1995: 5:262-270.
28. Kleerekoper M, Nelson DA. Flynn MJ. Pawluszka AS. Jacobsen G. Pcterson EL. Cornparison of radiographic absorptiometry with dual-energy x-ray absorptiometry and quantitative computed tomography in normal older white and black wornen. J Bone miner Res 1994: 9: 1 745- 1749.
79. Ross P. Huang C. Davis J. et al. Predicting vertebral deformity using bone - densitometry at various skeletal sites and calcaneus ultrasound. Bone 1995: 16:325-332.
30. Takada M. Engelke K. Hagiwara S. et al. Assessrnent of osteoporosis: compa.rison of radioçraphic absorptiometry of the phalanges and duai X-ray absorptiometry of the radius and lumbar spine. Radiology 1997: 202:7)9-763.
3 1. Yang SO. Hagiwara S, Engelke K. et al. Radiographie absorptiometry for bone mineral measurement of the phalanges: precision and a~curacy study . Radiology 1 994: 1 97:857- 859.
33. Huang C. Ross PD. Yates AJ. et ai. Prediction of fracture risk by radiopphic absorptiometry and quantitative ultrasound: a prospective study. Calcif Tissue Int 1998: 633380-384.
33. Steel SA. Swann P. Langley G. Langton CM. A phantom for evaluating bone mineral dsnsity of the hand by dual- energy x-ray absorptiometry. Physiol Meas 1997: l8:233- Ml.
31. Genant HK. Engeke K. Fuerst T. et al. Noninvasive assessment of bone mineral and structure: state of the art. J Bone Miner Res 1996; 1 1 :707-730.
35. Duryea J. Jiang Y. Countryman P. Genant HK. Automated algorithm for the identification of joint space and phaianv rnargin locations on digitized hand radiopphs. Med Phys 1999: 26:453461.
The University of Western Ontario Review Board for EIevlth Sciences Research
Involving Human Subjects Ethics Approvnl.
nie UNIVERSITYqf WESTERN ONTARIO
Dr. AB. Hodsman, Departmant of Medi cinq St. Joseph's Hal& Csotrc, Londoe Ontaria.
Dear Dr. Hodsman;
This i ~ e r wiU & that the above pmtocol was wxuidered at the September 10, 1997, mee- of the Review Board for Healrh Scie- Rucarch hvolving H u m Çubjects; md was appmved on Novpnbcr 12, 1997.
Thcm were no dvmse events repartcd, and the ~tudy wos noted as completcd in Septcrnber 1998.
Wevi Board for Heeith Scimces R a d Involving Human Subjects.
FEED FAX THIS END
I Dept.:
F U N O b b 3 , - 3 4 0 0 1
Company:
Fax No.:
Cornmen ts:
' ~ h a ~ t e r 3: Volumetric BMD Assessrnent of the Phalanges by Dual-
Energy X-ray Absorptiometry and Quantitative Computed Tomography
3.1 Introduction
The most common method of measuring bone mass is dual-energy X-ray
absorptiometry (DEXA) and this technique, ofien used in clinical practice and research.
has also been the most thoroughly studied (1 ) . The resulting values are usually
represented as bone minera1 density (BMD). which is an areal density representing the
~ m s of bone mineral in a projected area of bone (p?uns*cm''). Since DEXA
measurements are by areal projection. a volumeaic density (gams*crn4) is not obtained
and the true geometric assessment of a bone is impossible. Furthemore. the areal BMD
measurement may have a dependence on bone size.
In order to reduce this effect of bone size on BMD measurements. several
attempts have been made to provide estimates of volurnetric BMD From planar
projections. These techniques have k e n applied on clinical DEXA systems assessing
bone mass in the avial skeleton (vertebrae) ( 2 - 3 . Estimated volumetric BMD
mrasurements have also been applied to penpheral skeletal sites. particularly to the
phalanges of the hand. where it may be more appropnate. A radiographie absorpti~metry
method developed by Trouerbach eî al. involves measurement of the optical density on
both the posteromterior and laterai views of the index fmger. followed by
volurnetric density values (6.7). Another radiographie absorptiometry
calculation of
technique -
! A version of this chapter has k e n prepared for publication.
initially described by Bachtell and Colbert and later developed as the CompuMed method
- obtains an apparent volumetnc BMD, which assumes a circular cross section for each
phalmv in each transverse slice of the analysis (8-10). Volumetric corrections have also
been used for DEXA-based phaiangeai BMD measurements. A technique by Bnillon et
ut. assumes that the projected area of a phalam obtained fiom the DEXA scan is that of a
cylinder and a calculation is done to obtain volumetric BMD ( 1 1 j.
An x-ray image intensifier (XRl1)-based digital radiography system has recently
been adapted for DEXA assessrnent of phalangeal BMD ( 12). Although the technique is
precise. accurate and compares well with radiographie absorptiometry of the phalanges.
there is interest in examining techniques to correct for the dependence of bone size. i.e. to
find an empirical determination of the shape factor relating the area and volume of the
phalanges. To this end a study was undertaken to adapt the sarne XRII-based digital
rad iograp hy sy stem to provide high-resolution quantitative conputed tomography
(QCT') of the phalanges. Quantitative CT is the only densitometry technology that
provides information about the three-dimensional (3D) shape of the phalanges:
information that is required to determine the true volumetric BMD (expressed as grams
per cubic centimeter) (1 3).
In this study. we compare two-dimensional(2D) areal bone density measurements
fiom human cadaves (middle and proximal phalanges) with the QCT volumehic density.
The DEXA and QCT rneasurements are used to determine an empirical relaiionship
between the projected area and volume of the phalanges, making it possible to estimate
volumetric BMD fiom DEXA-based measurements. As an interna1 test of accuracy the
bone minera1 content (BMC) of the DEXA and QCT measurements are also compared.
Three human cadaver forearms were obtained frozen fiom a local orthopedic
depanment. The cadavers were thawed to room temperature pnor to DEXA and QCT
Unaging. Al1 three cadavers were male but information regarding age at death was
unavailable. The cadaven were kept in their original storage plastic bags during the
imqing procedures and no surgically invasive procedures were performed. Correct
placement of the hands on the scanning table. such that the middle and proximal phalanges
were included in the field of view was done with the assistance of x-ray tluoroscopy.
Furthemore. for the purposes of planar radiography (DEXA) and the following
comparison with QCT. hand positioning was done so that there was no obliquity or
rotation of the hand. This was conti~rmed with a simple observation that the concavities
of both sides of the shafis of phalanges are symmetric. Also the phalanges wew
separated with no overlapping of the bones or sot? tissues of the fingers.
3.2.1 Dual-Energy X-ray Absorptiometry
The DEXA procedure has been described in detail previously (1 2). Briefly. areal
DEXA measurements of the cadaver hands were performed with a digital radiography
sy stem (Multistar, Siemens Medical Syaems. Germany). The digital x-ray images were
acquired at the 20 cm field-of-view and each output image was digitized into an 880 x 880
image matrix, with pixel size of 1 84 pm x 1 84 Pm. Al1 DEXA images were acquired with
a 95 cm source-to-detector distance with a geometric magnification of 1.19. The x-ray
source was a water cooled, rotating tungsten anode tube with a 0.6 mm focal spot. The X-
ray exposures wcre acquired at 40 kVp. 3 18 mA and 166 rns for the low-energy image,
and 125 kVp. 28 mA and 166 ms with 1.7 mm of additional copper filtration for the high-
rnergy image. Image acquisition was performed sequentially: i.e. three image h e s over
n 3 second penod were acquired at the low energy. after which the copper filter was
introduced. Then three image hunes over a 3 second period were acquired at the hi&
energy.
Included in each image was a crossed-step wedge calibration phantom (Figure 3- 1 )
composed of material that is radiographically equivalent to soft-tissue iLuciteTM) and
compact bone (SB3. Gamex MI. Middleton. WI). These step wedges were
superimposed in an orthogonal manner to obtain 25 different materiai combinations for
the calibntion of the system. h in-depth description of the dual-energy calibration.
decomposition to material specific images and analysis has been provided previously
( 12).
Anaiysis was performed on an image-processing workstation (Silicon Graphics.
blountainview, CA). Using the bone-equivalent image. semi-automated segmentation of
each phalam was perfbmed to determine the area. BMC (g) and areal BMD (g*cm*2) of
each phalan.-. Analysis was done for the 2nd3th rniddle phalanges and for the 2nd-4th
proximal phalanges. Note that in this snidy the area BMC and BMD were determined
separately for each pha lm.
Figure 3- 1. 25-step cali bration phantom composed of Lucite and SB3 is scanned simul taneously with the hand as part of the crossed-wedge cali brated DEXA system.
Table 3-2. Descriptive statistics for DEXA and QCT measurements of the
middle (n=9) and proximal (n=9) phalanges presented as mean (standard deviation).
* p < 0.0001 for comparison of middle vs. proximal BMD.
Figure 3-6 plots projected area (fiorn DEXA) versus the volume ( fiom QCT) of the 1 8
phalanges. The non-linear regression analysis shows a strong correlation between area
and volume in al1 phalanges with area = 2.13 (95% C.I. 1.94 O 2.3 1) volume 0.603 (95?/0 C.I
O ï39 ro O 667) (i = 0.965 with standard error of 0.242 about the regression line that
corresponds to a 5.94% error in the area measurements).
The area - volume relation was used to calculate an estimated volume from the
projected area and hence. estimated BMD (eBMD) obtained. A paired t-test cornparison
of eBMD - obtained fiom dBMC divided by estimated volume - (mean * SD: 0.476 *
0.087 ycm") with vBMD (0.456 * 0.091 g.cm") showed no significant difference
between these two rneasurements @ = 0.24). Futthemore, the root mean square (RMS)
difference in these measurements was determined to be 15.4% of the mean vBMD.
Figure 35. Linear regession between dBMC and
qBMC. The equation of the line of best fit is dBMC =
0.968 qBMC + 0.080 with ? = 0.948. p < 0.000 1.
3.4 Discussion
In this study we eaended the application of a prototype volumetric CT system
to acquire hi&-resolution images of cadaver hands for QCT analysis of phalangeal BMD.
The CT images included calibration cylinden that were used to obtain mie phalangeai
VB MD measurements in the proximal and middle phalanges. Standard digital radiographs
were also acquired, including a caiibrahon crossed-step wedgee, for DEXA-based areal
BMD measurements. Al1 acquired images were post-processed by semi-automatic
analysis to detemine the areal and volumetric BMD of each of the 2"*, 3rd and 4" middle
and proximal phalanges.
Volume (cm3)
Figure 3-6. Nonlinear regession between projected area and volume
of 18 entire phalanges as obtained by DEXA and QCT. respectively.
The power-law line of best fit was found to be Area = 7.13
~ o l u r n e ' . ~ ~ ~ with 6 = 0.965 and SEE = 0.242.
Quantitative computed tomography is the only technique that determines B M D
based on the true 3D shape of the bone and is the only technology that has the capability
to analyze the bone minerd in its two components of trabecdar and cortical bone (21).
The continual interest in peripheral-skeletai densitometry technologies (due to their
perceived lower costs and ease of access) has rnotivated much of the development of
stand-alone peripheral QCT (pQCT) systems (22,23). The capabilities of the novel 3 D
QCT technique that made this study possible are that the 3D volume of interest is
acquired in 4.5 seconds. analysis is done on entire bones (phalanges in this case), -es
are acquired at high-resolution (0.3mm isotropie voxel spacing). and the technique has
precise calibration (k 9% within each voxel). These factors are likely to make volumetric
QCT the gold standard for phalangeal BMD measurement in research protocols.
However. the primary intent of this study was not to introduce a new routine
clinical tool - due to the limited availability of CT equipment - but rather to compare
DEXA and QCT BMD values and establish an empincal relationship bctwecn the ared
and volumetric measurements. Although it may be possible to further develop the QCT
technique as the "gold standard" for penpheral bone densitornetry. a biggr impact is
possible by improving existing phalangeal DEXA techniques (12.24). The empincal
relation between projected area and volume couid be applied to these existing techniques
as a correction factor in order to obtain an estimated volumetric BMD (eBMD).
As an indication of the potential for enors in aBMD. our findings show no
signiticant difference in vBMD of the middle versus proximal phalanges. but show that
aBMD was significantly different in these same phalanges. Hence. QCT c o n h s the
existence of a bone-size dependence in the DEXA areal BMD rneasurement. Clinically.
this size dependence may underestimate the overail Fracture nsk of an individual. To
overcome this problem. it rnay be appropriate to apply correction facton to convert
aBMD to estimated vBMD.
The idea of applying correction factors to correct DEXA projected measurements
is not new as various techniques have been applied previously in the phalanges (6-
8.10.1 1,25). Volumetric corrections have also been applied to the DEXA measurements h
the wtebrae (2-5.26.27). In the case of vertebral BMD. these volume estimates resulted
in signiticant improvements in discriminatory power (4.5). However. dl these
approac hes (including the phalangeal measurements) made assumptions regarding the
shape of the bones (6.10.1 1.26.27). Although it is possible to incorporate similar
algonthms to correct for bone shape in the phalangeai areal BMD measurements. we took
an alternative approach in this study.
Our study proposes an entirely empirical determination of the relation between
are3 and volume: made possible because of availability of high resolution QCT. This
npproac h involves fewer a priori assumptions regarding the speci tic shape of the phalam.
i.e.. only the form of the equation. Therefore. we chose a function with the form of a
power-law relation and nonlicear regession resulted in the equation area = 2.13
volume0 'O3. allowing For conversion tiom projected area to volume to an accuracy of
better than 6%. For a cylinder. the projected area is directly proportion to volumeo ' However. the 95% confidence interval of 0.539 to 0.667 shows that the shape of the
phalanges is not that of a cylinder. By applying this area - volume 'correction' to DEXA
measurements the phalangeal eBMD was determined and proved to be not significantly
different than the vBMD obtained From QCT.
The implications of these fhdings are that given a DEXA projected m a
measurement and an empincal cdibration to obtain eBMD. it may be possible to obtain
voiumetric BMD of the phalanges without ha- tc implement QCT. However. a
limitation of the present study is that this calibration was performed on a small number of
bones. Furthemore, d l cadavers obtained were male and age information was unavailable.
The next step in this investigation requires that we obtain phalangeal area - volume
calibration data in a clinical population of women incorporating two groups: young
(healthy) and postmenopausal (osteoporotic) women. This ensemble of women should
have a large variation in bone size that will cover the entire clinical range. If the empirical
relationship we observed in this study holds in a larger population of wornen. it may be
possible to obtain clinical measurements of estimated volumetric BMD in the phalanges.
One immediate advantage of this approach would be the possibility of averaging eBMD
results over al1 middle and proximal phalanges. potentially improving the precision of
clinical peripheral BMD measurements.
3.5 Conclusions
These data indicate that hi&-resolution 3-D QCT provides measurements of
volumetric BMD. regardless of bone sire. Phalangeal BMC measurements obtained by
DEXA and QCT are highly correlated. providing an intemal verification of accuracy. An
empirical power-law relationship of area to volume was applied to obtain eBMD tiom
DEXX-based measurements. A direct cornparison of eBMD to vBMD showed that
there was no signifiant difference between these two measurements. although a
substantial RMS difference in these measurements remained. Hence. hi&-resolution
phalangeai QCT and DEXA have both been implemented on a standard clinical digital
radiography system and both techniques could be developed as stand-alone peripheral
bone densitometry techniques. However. digital DEXA of the phalanges can be modified
to provide estimated volumetric BMD, which may increase the diagnostic sensitivity of
the BMD mrasurement. Given recent interest in low-cost. portable systems. a phalangeal
DEXA technique - with the inclusion of estimated volumetxic BMD - may have the
highest clinical impact.
3.6 References
1. Genant HK. Engelke K, Fuerst T, et al. Noninvasive assessment of bone mineral and structure: state of the art. J Bone Miner Res 1996; 11:707-730.
2 . On SM. O'Hanlan M. Lipkin EW. Newell-Moms L. Evaluation of vertebnl volurnetric vs. areal bone minerai density during growth. Bone 1997: 20:533-556.
3. Sabin MA. Blake GM. MacLaughlin-Black SM, Fogelman I. The accuracy of volurnetric bone density measurements in duai x-ray absorptiometry. Caicif Tissue [nt 1 995: 56:2 10-2 14.
4. Jergas M. Breitenseher M. Gluer CC. Yu W, Genant HK. Estimates of volurnetric bone density frorn projectionai measurements improve the discnminato~ capabi lity of dual X-ray absorptiometry. J Bone Miner Res 1995: 10: 1 10 1 - 1 1 10.
5 . Duboeuf F. Pommet R. Meunier P.J. Delmas PD. Dual-energy X-ray absorptiometry of the spine in anteroposterior and lateral projections. Osteoporos [nt 1994: 4: 1 10- 1 16.
6. Trouerbach WT. Hoomstra K. Birkenhager JC. Zwamborn AW. Rorntgendensitornetnc study of the phalanu. Diagn Imaging Clin Med 1985: 546477.
7. van Kuijk C. Genant HK. Radiogrammetry and Radiographic Absorptiometry. In: Grnmt HK. Guglielmi G Jergas M. ed. Bone densitometry and osteoporosis. Berlin Heidelberg. Sprhger-Verlag. 1998: 29 1-301.
8. Colbert C. Bachtell RS. Radiopphic absorptiometry. In: Cohn SH. ed. Noninvasive meesurements of bone mass and their clinical application. Boca Raton. FL. CRC Press. 1981:
9. Cosrnan F. Herrington B. Himrnelstein S, Lindsay R. Radiographic absorptiometry: a simple method for determination of bone mass. Osteoporos Int 199 1 : 234-38.
10. Mussolino ME, Looker AC. Madans .JH. et al. Phaiangeal bone density and hip Iiacnire rîsk. Arch Intern Med 1997: 1573433438.
1 1. Braillon PM. Guibal AL. Pracros-Defienne P. Serban A. Pracros JP. Chatelain P. Dual energy X-ray absorptiometry of the hand and wrist--a possible technique to assess skeletal maturation: methodology and data in normal youths. Acta Paediatr 1998: 87:924- 929.
12. Gulam M. Thomton M, Hodsman AB. Holdsworth DW. Bone mineral measurement of the phalanges: cornparison of radiographie absorptiometry and area dual energy x-ray absorptiometry . Radiology (in press).
13. Kleerekoper M. Nelson DA. Which bone density measurernent? J Bone Miner Res 1997: 12:712-714.
1 4 Fahrig R Fox AJ, Lownie S? Holdsworth DW. Use o fa C-arm system to generate tnie three-d imensional computed rotational angiograms: preliminary in vitro and in vivo results. M N R Am J Neuroradiol 1997; 18: 1507- 15 14.
15. Fahrig R, Moreau M. Holdsworth DW. Three-dimensional computed tomographic reconstruction using a C-arm mounted XRII: correction of image intensifier distortion. Ved Phys 1997: 24: 1097-1 106.
16. Huda W. Gkanatsios NA. Radiation dosimetry for extremity radiographs. Health Phys 1998: 75A92-199.
17. Lobregt S. Viergever MA. Discrete dynamic contour model. IEEE Transactions on Medical Imaging 1995: 14: 1 2-24.
18. Mueller KH. Trias A. Ray D. Bone density and composition: age-related changes in water and mineral content. J Bone Jt Surg 1966: 48: M O - 148.
19. Guglielmi G. Lang TF. Cammisa M. Genant HK. Quantitative computed tomography at the axial skeleton. In: Genant HK. Gug1ieirn.i G Jergas M. ed. Bone densitometry and osteoporosis. Berlin Heidelberg. Springer-Verlag, 1998: 335-347.
10. Huda W. Morin FU. Patient doses in bone minerai densitometry. Br J Radio1 1996: 69:422425.
2 1 . Grarnpp S. Genant HK. Mathur A. et al. Cornparisons of noninvasive bone minera1 measurements in assessing age- related loss. fracture discrimination. and diagnostic classification. J Bone Miner Res 1997: 12697-71 1.
23. Schneider P. Reiners C. Peripheral quantitative computed tomography. In: Genant HK. Guglielmi G lergas M. ed. Bone densitometry in osteoporosis. Berlin Heidelberg, Springer-Verlag. 1998: M+-363.
23. Gluer CC. Jergas M, Hans D. Penpheral measurement techniques for the assessrnent of osteoporosis. Semin Nucl Med 1997: 27229-247.
24. Michaeli DA, Mirshahi A, Singer J, Rapa FG, Plass DB, Bouxsein ML. A new x-ray based osteoporosis screening tool provides accurate and precise assessrnent of phalanx bone mineral content. Journal of Clinical Densitometry 1 999; 2:23-30.
25. Bolotin HH. A new perspective on the causal influence of soft tissue composition on DXA-measured in vivo bone mineral density. J Bone Miner Res 1998; 13: 1739- 1746.
76. Katzman DK, Bachrach LK. Carter DR Marcus R. Clinical and anthropometric correlates of bone mineral acquisition in healthy adolescent girls. J Clin Endocnnol Metab 1991: 73: 1332-1339.
17. Blake GM. Wahner HW. Fogelman 1. Measurement of bone density in the lumbar spine: the lateral spine scan. In: Blake GM. Wahner HW Fogehan 1. ed. The rvaluation of osteoporosis: dual energy x-ray absorptiometry and ultrasound in clinical practice. 2nd ed. London. Martin Dunitz Ltd. 1999: 236-358.
Ch apter 4: Conclusions and Future Applications
This chapter surnmarizes the major results presented in this thesis. Both Chapters
2 and 3 are addressed in turn. Also. some future applications of DEXA and QCT
phalangeal BMD measurements are presented. Future studies to implement a cornparison
of DEXA and QCT in a clinical population are discussed. dong with approac hes of ushg
DEX.4 and QCT to assess skeletal grorth. and also rheumatoid arthritis.
4.1 Summary of Results
As outlined in the introduction, peripheral bone density measurements are
predictive of fracture risk and have the capability to meet the need for compact. portable.
lower-cost. hi&-resolution quantitative techniques in the clinical diagnosis of
osrroporosis. By developing novel techniques for assessrnent of bone rnass in the
phalanges 1 attempted to provide solutions that could be implemented as alternative
approaches to the universal measurements of bone density. Modifications to a clinical
digital radiographic system resulted in the development of two phalangeal BMD
techniques: 1) Area Dual-Energy X-ray Absorptiometry (DEXA): and. 2) 3D Volurnetric
Quantitative Computed Tomography (QCT).
In Chapter 2. 1 addressed the development of DEXA. which was a significant
undertaking in that the performance of BMD measurements was charactenzed and a
clinical study was performed to compare DEXA with radiographic absorptiometry in two
groups of women. In Chapter 3. I presented a method to adapt CT for the development C
of QCT in order to obtain volumetric BMD and hence account for possible artifacnial
errors in DEXA areai BMD measurements. A cornparison study between DEXA and
QCT was performed in cadaves to fùrther explore this size dependence in the areal and
vo Iumetric measurements.
In this thesis 1 presented a progression of phalangeal bone mass measurement
techniques from plain-film. to digital radiographie, to quantitative computed tomography:
and also the calibraiion of bone mineral in arbitrary alurninurn units to areal bone mineral
(grams of calcium hydroxyapatite per unit area), and tinally to volumetric bone minerai
( g m s of calcium hydroxyapatite per unit volume). The conclusions from each chapter
are ciescribed below.
4.1.1 Conclusions of Chapter 2: Comparison of Radiographic Absorptiometry and Area Dual-Energy X-ray Absorptiometry
A phalangeal DEXA technique was developed where digital images in hi&-
resolution ( 1 80 pm resolution) were acquired for semi-automatic analysis of BMD. The
precision of the phalangeal BMD measurements by DEXA were * 0.67%. which is lower
than the expected decrease (0.9%) in a postmenopausal woman's phalangeal BMD per
year. Le.. ( i ). The accuracy of DEXA (as assessed in tissue-rnimicking material) was also
quite good. Results were obtained for both BMC and BMD measurements with accuracy
error of bener than 4.1%. which is equivalent to or better than accuracy of other
techniques (2-1).
The cornparison of DEXA to RA midde phdangeai measurements yielded a hi&
correlation ($ = 0.81? p < 0.0001) indicating that the phalangeai BMD measurements are
comparable. Furthemore. the linear regression anaiysis allowed for conversion from RA
measurements to D E m . This is significant as digital techniques with image analysis
tools that provide immediare (semi-) automated analysis will eventually replace
traditional film-based RA (5). The other prominent advantage of DEXA over RA is that
calibration of bone mineral is made in real calcium hydroxyapatite units rather than in
arbitrary ûluminurn units, which facilitates beaer cornparison to other (DEXA)
techniques that also calibrate bone minerai in calcium hydroxyapatite (6-9).
In summary. the novel approaches tu the field of bone densitometry with this
DEXA technique are: 1 ) high-resolution (180 pm pixel spacing) DEXA with an area
detrctor: 2) BMD measurements of entire phalanges cdibrated in calcium hydroxyapatite
(real bone minerai units); 3) digital DEXA technique with rapid acquisition (c 20 seconds)
and immediate analysis: and. 4) potential for commercial use as is (requiring calibration
phantom and software) or for development as a compact system.
4.1.2 Conclusions of Chapter 3: Volumetric BMD assessment of the phalanges
The techniques for CT image acquisition. reconstmction and corrections that have
been described by Fahrig et al. for computed rotational angiography (10.1 1 ) have been
used hue to acquire images of human hands with 0.3 mm isotropic voxel spacing. The
effective dose fiorn these rotational k g e s of a hand was calculated to be 5.4 pSv. The
linearity of the QCT measuremenis showed that the CT nurnbers (HU) had a highly linear
association with vBMD (gmcm") over the full range of BMD values.
The volumetric BMD was not significantly different between the middle and
proximal phalanges, whereas the areal B MD measurements c learly showed a significant
difference (p < 0.000 1) in these same phalanges. ïherefore. these data indicate that hi&
resolution 3D QCT provides vol?imetric BMD. regardless of bone size. The most
promising result - the empirical relationship found between projected area and volume
- allowed for obtaining an estimated volume. and hence an estimated volumetric B M D
(eBMD). frorn areal DEXA measurements. The calculated eBMD was not significantly
different than vBMD although a higher than rxpected RMS error was observed between
these rneasurements.
In summary. the novel approaches to the field of bone densitometry with this 3D
volurnetric acquisition in 4.5 seconds and the ability to have the images viewed at multiple
angles: 3) 3D volumetric BMD measurements of entire phalanges calibrated in +grarn.s
(calcium hydroxyapatite) per unit volume: 4) the denved empirical relationship of
projected area to volume of the phalanges: and. 5 ) the potential for further clinical
validation (highly accurate and precise measurements) of phalangeai BMD by 3D
volumeuic measurements.
Although the 3D QCT technique developed here has salient features that could be
esploited to make it the gold standard for penpheral BMD measurements. the limited
availability of such a synem would not h d widespread clinical use. Hence, the greatest
impact fiom the observations in this study was the finding of the empincal relationship
that could be implemented as a post-processing correction factor in digital DEXA. This
eBMD measurement may increase the diagnostic sensitivity of the DEXA measurements,
particularly when assessing skeletal status of groups of individuals with large di fferences
in bone size.
4.2 Future Applications
42.1 QCT and DEXA comparison in a clinical setting
The imrnediate objective fiom the QCT and DEXA comparison study would be to
perfonn a comparison study in a clinical population of women incorporating both young
healthy and postmenopausal osteoporotic women. The access to a large range of bone
loss and bone size in the middle and proximal phalanges in these women should result in a
more accurate determination of the empirical relationship between phalangeal projected
area and volume. It would also be possible to develop separate equations specific to each
phalam. Furthemore. the rneasured eBMD of al1 the phalanges (or just the rniddle
phalanges) in a hand could be averaged improving the precision of clinicd BMD values.
The proposed study would have QCT performed twice in the group of women
volunteers. providing data for the analysis of the short-term precision error. Furthemore.
in a future clinicai study. the inclusion of standard BMDs of lumbar spine and hip could
allow for verification of sensiUvity of the peripheral BMD techniques to the sarne
changes in disease and treatment observations.
1.2.2 Phalangeal DEXA to assess skeletal maturity
During (childhood) growth there is a large increase in the size of bones that leads
to an increased areal density, even without changes in volumetric density ( 12). As DEXA
c a ~ o t account for these changes in body and skeletal size that occur during growth. its
use in longitudinal studies in children is lirnited (1 3). Therefore. QCT of the vertebrae has
ofien been used to assess skeletal growth as it rneasures both the volume and the density
of bone without influence fiom body or skeletal size (13.14). However. plain radiographs
of the hand and wist are the most frequently studied to assess bone age. therefore DEXA
of the hand and wrist - providing estimated volurnetric BMD - has k e n atternpted to
assess skeletal maturity (1 5). A previous technique implemented by Braillon el a/.
obtained estimated volumerric BMD assuming that the DEXA projected m a
rneasurement of the phalanges is that of cy lindrical projected surface area ( 15). There fore.
with the deïelopment of a more accurate method of determining eBMD from projection
images (i.e. our empincai relationship) another potential application the phalangeal
DEXA would be to assess skeletal rnaturity during adolescent growth.
4.2.3 Development of a compact DEXA system
.4 development of a compact DEXA system is warranted if the technique is to be
a low-cost and portable alternative to current bone densitometry techniques. With the
recent introduction of novel phalangeai bone mineral assessment technologies. namely
accuDEXA (6). computed digital absorptiomrtry (3) and new phalangeal uitrasound
techniques (16) there is indication for c h c a l utility and acceptance of phalangeal BMD
technologies.
However. several technical challenges must be met before deploying a system for
cliniccil use and detennining the capability in fracture risk assessment and m o n i t o ~ g
treatment. As regards to the developrnent of phalangeal DEXA using a large-area XNI-
based system. scaling down to a portable system would require a smailer x-ray source and
detector. One solution could be to replace the XRII with an advanced, compact-solid
state deiector. Some possibilities are a seleniurn-based Bat panel or an morphous silicon-
based device ( 17). Another solution would be to employ large CCD cameras in the
dedicated system. However. this decision will have to be made by industry by
determining the feasibility (in ternis of cost and clinical utility) of the approach.
Furthemore. due ro cost constraints. evaluation of bone status may have to be
made on a single phalanx. Lastly. full- automatic bone segmentation may be required to
al low For as little operator involvernent as possible.
4.2.4 A three-tissue component Phalangeal DEXA technique
One limitation of dual-energy imaging is the lack of separation of soft tissue and
adipose tissue. These materials do have different attenuation properties at the effective
eneqies used in Our study resulting in less accurate measurements of BMD ( 18). Hence.
one strategy of dual-energy quantitative imqing would be the use of a water bath along
wi th an adipose tissue-equivalent ( 1 9.20) and bone-equivalent cross-wedge caiibration
phantom to improve the accuracy of the DEXA measurements. Complete submersion of
the hand in a water bath would result in a homogenous amount of sofi-tissue along ail
scan paths. Hence. the dual-energy basis matenal decomposition couid be used to
separate adipose tissue fiom bone to quanti@ the BMD.
1.2.5 Peripheral DEXA and QCT for the assessrnent of rheumatoid arthrîtis
Rheumatoid arthritis (RhA) is an a u t o h u n e disorder of unknown etiology
c haracterized by symmetric. erosive synovitis and sometimes mu1 ti-system involvement
(2 1 ). I t affects 1% of adults and exhibits a chronic fluctuating course that may result in
progressive joint destruction, deformity. disability and premature death (2 1). Rheumatoid
anhritis can affect any joint. but it is usually found in metacarpophalangeal. proximal
interphalangeal and metatanophalangeaf joints. as well as in the wrists and knee (22).
Plain film radiography is the standard investigation to assess the extent of anatornic
changes in RhA patients where the radiographie features of the hand joints in early
disease are characterized by soft tissue swelling and mild juxtaarticular osteoporosis (22).
However. the potential for penpheral bone mass rneasurements in RhA as an assessrnent
of long-term disease activity has recently been studied (23).
Some studies have been performed that have adapted axial DEXA to rneasure both
BMC and BMD of the hand (21-37) in the assessment of EUA. As BMD is conhunded
by bone size. investigators have used the outcome parameter of BMC frorn DEXA
measurements in longitudinal studies to monitor bone loss in individuals with RhA (28).
The de~elopmerit of a dedicated phalangeal DEXA technique can therefore offer several
advantages in clinical assessment of RhA. These are: 1) BMD and BMC measurement at
high-resoiution; 2) high precision of these measurements. therefore allowing for
monitoring reductions of bone mass: and. 3) user defmed regions of interest (using active
contour segmentation tools) t~ examine more closely the bone mineral at the different
phalangeal joints. Hence a study to investigate phaiangeal DEXA for the clinical utility in
assessing RA is warranted.
Phalangeal DEXA is aiso highly dependent on hand position because of the nature
of projected areal BMD measurements. However, in RhA there is often limited
movement or deforrnity that results in inaccurate or imprecise measurements of BMD
( 2 5 ) . Therefore. the use of 3D volumetric acquisitions by QCT could be irnplemented to
determine BMD independent of hand positioning. Furthemore. the volumetric BMD
measurement would require no corrections for height. weight or other factors in DEXA
assessrnent of RhA (25).
4.3 Summary of Fuîwe Applications
1 have s h o w that modifications to a clinical digital radiography system result in a
technique to obtain quantitative measurement of bone mass in the phalanges using DEXA
and QCT. and that there is significant potential for iùrther developrnrnt of both
phalangeal DEXA and QCT as well as clinical applications for these techniques.
4.4 References
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2. Yang SO. Hagiwara S, Engeike K, et al. Radiographic absorptiometry for bone mineral measurement of the phalanges: precision and accuracy study . Radiology 1994: 192857- 859.
3. Bowsein ML, Michaeli DA, Plass DB, Schick DAI Melton ME. Precision and accuracy of computed digital absorptiornetry for assessment of bone density of the hand. Osteoporos Int 1997: 7:444-449.
4. Genant HK. Engeike K. Fuerst T. et al. Noninvasive assessment of bone mineral and structure: state of the art. J Bone Miner Res 1996: 1 1 :707-730.
5 . van Kuijk C. Genant HK. Radiogrammeiry and Radiographic Absorptiometry. In: Genant HK. Guglieimi G Jergas M. ed. Bone densitometry and osteoporosis. Berlin Heidelberg, Springer-Verlag, 1998: 29 1 -3M.
6. Michaeli DA. Mirshahi A, Singer S. Rapa FG. Plass DB. Bouxsein ML. A new x-ray based osteoporosis screening tool provides accurate and precise assessment of phalanv bone mineral content. Journal of Clinical Densitometry 1999: 223-30.
7. Klrerekoper M. Nelson DA. Flynn MJ, Pawluszka .4S. Jacobsen G. Peterson EL. Comparison of radiopphic absorptiometry with dual-enerm x-ray absorptiometry and quantitative computed tomography in normal older white and black women. J Bone .Miner Res 1994: 9: 1745- 1749.
8. Ravn PI Overgaard K. Huang C. Ross PD. Green D. McClung M. Comparison of bone densitometry of the phalanges. distal forearm and âxid skeleton in early postmenopausal women participating in the EPIC Study. Osteoporos Int 1996: 6:308-3 13.
9. Grampp S. Genant HK. Mathur A. et al. Cornparisons of noninvasive bone mineral measurements in assessing age- related loss. Cracnue discrimination. and diagnostic classitïcation. J Bone Miner Res 1997: l2:697-7 1 1.
1 0. Fahrig R Fox AJ, Lownie S. Holdsworth D W. Use of a C-arm system to generate true three-dimensional computed rotational angiogams: preliminary in vitro and in vivo results. A N R Am J Neuroradiol 1997; 1 8: 1507- 1 5 14.
1 1. Fahrig R. Moreau M, Holdsworth DW. Three-dimensional computed tomographie reconstruction using a C-arm mounted XNI: correction of image intensifier distortion. Med Phys 1997; 24: 1097- 1 106.
13. Ott SM. O'Hanlan M. Lipkin EW. Newell-Morris L. Evaluation of vertebral volumetric vs. areal bone mineral density during growth. Bone 1997: 20:553-556.
13. Gilsanz V. Bone density in children: a review of the available techniques and indications. Eur J Radiol 1998: 26: 177- 182.
14. Gilsanz V. Gibbens DT. Roe TF. et al. Vertebral bone density in children: effect of p u b e q . Radiology 1988; l66:847-8jO.
15. Braillon PM, Guibal AL. Pracros-Defieme P. Serban A. Pracros JP. Chatelain P. Dual energy X-ray absorptiometry of the hand and wrist--a possible technique to assess skelrtal maturation: methodology and data in normal youths. Acta Paediatr 1998: 87:924- 929.
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