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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
2 . 1 Inrrodrtction ............................................................................................... 32
.................................................................................. . 2 . 2 -L(cllerials and Cferhods 33
2.2.1 Subjects ..................................................................................................... 33 .................................................................... 2.2.2 Radiographie Absorptiometry 34
....................................... 2.2.3 Dual-Energy X-ray Absorptiometry : Acquisition 35 ............................................ 2.2.4 Dual-Energy X-ray Absorptiometry : Analy sis 38 ... ............................................................................. 2 . 5 Precisiion and Accuracy 42
.......................................................................................... 2.2.6 Data Analysis 4 3
................................................................................................... 2 . j Conclusions 50
Chapter 3: Volumetric BMD Assessrnent of the Phalanges by Dual-Energy
X-ray Absorptiometry and Quantitative Computed Tomography
................................................................................................... 3.1 In&roclrtction j6
.................................................................................. 3.2 . t furerials und Methods 58
vii
3.2.1 Dual Energy X-ray Absorptiometry ....................................................... 5 8 3 2 . 2 Quantitative Computed Toinography: Acquisition ..................................... 61 3 .2.3 Quantitative Computed Tomography : Analy sis .......................................... 62 3.2.4 Patient Dose ............................................................................................... 65 3 2.5 Data Analysis .......................................................................................... 66
Chapter 4: Conclusions and Future Applications
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
4.7 Fz~fure .-l ppiications ....................................................................................... 8.3
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
proximal phalanges ................................................................................................. 6 9
List of Figures
Chapter 1:
1 . 1 Hand radiograph including aluminum calibration wedge that is used in RA ........... I O
Chapter 2:
2- 1 Numerical simulations of the X-ray spectra used for the DEXA acquisition ............ 36
3-1 Digital radiographs of a hand includingthe calibration crossed-step wedge ............. 38
....................................... 2-3 DEXA decomposition bone equivaleni (thickness) image 10
7-4 D E U semi-automatic segmentation using an active contour mode1 of the third
.............................................................................................................. phalanx 41
.................................... 2-5 Correlation between BMD as measured by RA and DEXA 45
7-6 Accuracy of BMD and BMC measurements as meaesured in tissue-mimicking
............................................................................................................ materials 46
Chapter 3:
...................... 3- 1 Cross-step wedge calibration phantom composed of Lucite and SB3 60
3-2 Saggital slice of the CT reconstnicted image of the hand ........................................ 63
.......... 3-3 Reconstructed CT slices of the cadaver hand in transverse and coronal view 64
............................... 3-4 QCT semi-automatic segmentation of the 2nd rniddle phalam 65
......................................... 3-5 Correlation in BMC rneasurements by DE= and QCT 70
........... 3 -6 Empirical relationship between projected area and volume of the phalanges 71
Ab breviations
BMD: bone mineral density BMC: bone mineral content DEXA: Dual-Energy X-ray Absorptiornetry RA: Radiographie Absorptiometry CT: Computed Tomography QCT: Quantitative Computed Tomography PQCT: peripheral Quantiative Computed Tomography HU: Hounsfield units CD.4: Computed Digital Absorptiometry 2 D: two-dimensional 3 D: ttiree-dimensional XRI I : x-ray image intensifier FOV: field of view CV: Coefficient of Variation GDM: geometncally deformable mode! SEE: standard error of the estimate RMS: root mean square BMDsiio: DEXA iniddle phalangeal BMD BMDPROx: DEXA proximal phalangeal BMD E3MDR,.!: RA BMD index aBb1 D: areal BMD cvBh/iD: votumetnc BMD eBh1D: estimated volumetric BMD dBMC: DEXA BMC qBMC: QCT BMC RLiA: Rheumatoid Arthritis
Chapter 1: Introduction
1.1 Motivation: Bone density meosurements as P screening tool for
Osteoporosis
1.1.1 Osteoporosis
The intemationally accepted definition of osteoporosis is 'a progressive systemic
skeletal Jisease c haracterized by low bone mass and microarc hitectural deterioration of
bone tissue. with a consequent increase in bone tiagility and susceptibility to hcture ' ( 1 ).
It is the increased fracture risk due ro osteoporosis that rnakes this disease a significant
clinical problem and a major public health concem. The most common fractures include
vertebral compression fractures (spine). and tiactures of the distal radius (forearm) and
proximal femur (hip fracture). In an osteoporotic skeleton. fractures also occur at the
pelvis. proximal humenis, distal femur and nbs (2). Associated with fractures are
considerable rnorbidity and mortality: for example. recent studies indicate 1544% excess
mortality within one year of suffering a hip fracture (2.3). Peak bone mass (on average) is
achirved at about the age of 30 and steadily declixs thereatier. However. in women the
loss of bone mass is accelerated d e r menopause and. hence. postmenopausai women are
at greatest risk for fractures. Underlying this menopausai bone loss is an alteration in the
manner in which bone is remodelled. whereby there is an increase in bone resorption (due
to osteoclast ce11 activity) that is not accompanied by bone formation (due to osteoblast
activity). It has been estimated that a 50 year old women has a 3040% chance of
experiencing a fracture related to decreased bone mass during her remairing lifetime (2).
1.1.2 Bone mass measurements: to identify individuals at risk
In Canada alone the cost to the health care system due to osteoporosis-related
illness is an estimated % 1.3 billion per year. In the United States this cost is above $13.8
billion per year (3). These costs are expected to rise during the coming years due to the
a.ging population. However. there are pharmaceuticai products available for treating
established osteoporosis. for preventing osteoporosis and reducing osteoporotic fracture
in individuals at highrisk. To ensure that these individuals receive the required treatrnent
they must tirst be identified. A nurnber of osteoporosis screening strategies have k e n
studied for clinicai usefulness (45) . but bone-mass assessrnent - also k n o m as bone
mineral density @MD) measurement - using any of severd methods is the best known
way to identi% asyrnptomatic individuals at risk of Fracture (6-8) . Not only does
measurement of bone m a s predict future fracture risk in women with osteoporosis. i t is
also a usefu1 tool to monitor the effectiveness of neatments designed to restore lost bone
mass and thereby reduce the risk of M e r fractures (9). The bone density measurement
is analogous to blood pressure and cholesterol rneasurements and is a better predictor of
fractures than is blood pressure of moke and cholesterol of ischemic heart disease ( 10).
Osteoporosis in women is now defmed by the World Health Organization entirely in
terms of bone density values ( 1 1 ). The measurement value is classified into 4 categories:
1 ) Normal: BMD or bone mineral content (BMC) not more than 1 standard deviation
(SD) below the young addt mean value, 2) Low bone mass (osteopenia). BMD or BMC
behveen 1 SD to 2.5 SDs below the young adult mean value. 3) Osteoporosis; BMD or
BMC of more than 2.5 SDs below the young adult mean value. and 4) Severe
osteoporosis: BMD or BMC of more than 2.5 SDs below the young aduit mean value in
the presence of one or more Fragility Fractures. This definition arose due to the fact that
the distribution of BMD or bone mineral content in young healthy women (age 30-35:
considered to be at their peak bone mass) approximately follows a normal distribution.
Hçnce. BMD values are often expressed in relation to a reference population in standard
deviation units (comrnonly referred to as the T-score) (2).
1.1.3 Bone mineral density testing
In November 1996. The Osteoporosis Society of Canada published its Clinical
Practice Guidelines for the diagnosis and management of osteoporosis in the Canadian
Medical Association Journal (12). These guidelines. as well as others (2). indicate that
bone density testing should be the primary basis for selecting patients for therapeutic
intervention.
Over the years a nurnber of non-invasive bone densitometry technologies have
been developed to estimate fracture nsk. The quantitative name of these measurements
has improved upon the diagnostic sensitivities achieved with standard x-rays. because x-
rays show bone loss (radiographie osteopenia) only when the loss exceeds 30% (13).
Many of the methods for the Ni vivo assessrnent of bone minera1 are listed by Blake et al.
( 14) and are also discussed in a comprehensive review by Genant et al.( 15). Included are
methods based on absorptiometry: such as single- and dual-photon absorptiometry.
single- and dual-energy X-ray absorptiometry (DEXA). quantitative evaluation of
radiographs by radiographie absorptiometry (RA): methods based on computed
tornography (including single- and dual-energy quantitative computed tomography (QCT)
and pcripheral QCT (pQCT)); and quantitative ultrasound assessrnent techniques. Table
1-1 lists the absorptiometry techniques and the approximate year in which they were
introduced. These radiopphic techniques have found clinicd application to rvaluate
bone status. e.xhibiting (or providing) accurate and reproducible rneasurements. stable
calibration and low radiation dose to the patient (14).
.4 bsorpt iometry Technique Year Introduced Advancemenc
Single-Photon 1963 Initial Absorptiomeu?, technique Requires placing f o r e m in a water bath
Dual-Photon early 1980's Dual-Photon technique replaces need for a water bath Measurement possible in the lumbar spine and femur
Dual-Energy X-ny 1985- 1987 X-ray source replaces radionucleide source resuking in faster scan times. bener precision and higher resolution
Single-Energy X-ray early 1990's Analogous to Single-Photon as it requires a water bath Peripheral ske letal measurement technique
Table 1-1. This table shows the year of introduction of the different absorptiometry
techniques and the resulting advancement to non-invasive diagnosis of osteoporosis.
1.2 Assessment of phalangeai bone minerai density
1.2.1 DEXA and the need for peripheral bone densitometry
Each absorptiometry technique marked an important transition - hiflighted in
Table 1-1 - in the ability of a bone densitometry measurement. in the past decade the
m o ~ ~ h g awareness of the impact of osteoporosis on the elderly population (and the C
consequent costs of hedthcare) has stimulated developrnent of new treatments to prevent
fractures. together with new imaging technologies to assist in diagnosis ( 16). The ability
of DEXA to obtain hi&-precision measurements of BMD in the axial or central skeletal
site. (Le. the spine and hip) makes it well suited to assess response to therapies in these
important sites of fracture (8.9.15-19). Therefore DEXA has become the most
thoroughly studied and most widely used technolog for BMD measurement (15).
However. in recent y e m there has been continuing interest in smaller. lower-cost
dwices dedicated to scanning the peripheral skeleton (20). A primary need for these
systems is to provide the primary care physician with direct access to mess a patient's
risk of fracture. Pivotal to these developments is the dernonstration in prospective
studies that penpheral measurement techniques cm identiQ patients at nsk of
osttioporotic fractures as reliably as a d DEXA (16). One of these techniques.
quantitative ultrasound assessment of bone mass in the calcaneus. (based on
measurements of the broad-band ultrasonic attenuation and speed of sound of bone). has
recently received approval as a diagnostic device by the US Federai Dmg Agency (2 1 ).
Although ultrasound technology is substantially cheaper than DEXA and has proven
ability to predict fracture nsk in the elderly. there are disadvantages: it is Iess precise.
there is a lack of appropriate phantoms for quality control. and there are doubts about
how to interpret resuits in younger women (16). Other penpheral or appendicular
skeletal sites of interest include the distal radius of the fore-. and the phalanges and
metacarpals of the hand. There is a growing consensus that alternative means of
measunng bone mass by RA or DEXA of the peripheral skeleton are just as effective as
central BMD measurernents for the diagnosis of fracture risk (1 5.22,23). With this in
mind. this thesis presents the development of a penpheral skeletal DEXA technique that
measures phalangeal bone density. Although perip heral D EXA technology has become
available. it appears that bone-density measuremenib in the phalanges may have the
ability to meet the current needs in bone densitometry as identified above.
1.2.2 Phalangeal BMD measurements
I t must be understood that the phalanges are not the pnmary site of fracture. One
ma) wonder: why perform a measurement of skeletal status in the phalanges and why not
perform a bone density measurement where the Fracture is expected? Since it is well
known that bone density assessment at the hip is a bener predictor of hip fracture than
measurement at any other skeletal site. then why not perform measurements at the hip?
These are valid questions that have resulted in much debate in the field and in
corresponding literature (7.9.10.1 5.2425). However. from a comrnunity health
perspective. bone density measurements - no matter how accurate. precise. and
mçaningful - have limited value if access to the technology is limited (24).
The fingen have m a t utility in the assessment of skeletal BMD status (26):
German researchers proposed single-energy scanning techniques over 3 0 y ears ago (27)
and recently. it has become practical to scan the kgers with dual-energy systerns (25).
The use of phalangeai measurements continues largely due to the ease and accessibility of
mesurement techniques (29.30), and secondly to improved knowledge of bone biology.
Osteoporosis is understood to be a systemic skeletal disease. The phalanges are made up
of both cortical (-40%) and the more metabolicaily active trabecular (-60%) bone (31);
the effects of osteoporosis are most clearly seen in trabecula. bone. Age-related bone loss
is clearly seen in the phalanges (32-34) and this includes accelerated bone loss due to the
onset of menopause in women aged 50-57 years. The magnitude of bone loss (in tems of
phalangeal BMD) is smail but measumble, estimated to be 0.9% per year in women aged
55 years and above (35).
The ability to measure phalangeai BMD has resulted in nvnerous long-term
prospective studies linking phalangeal bone minerai assessrnent to fracme nsk (23.2436-
3 8). AH these results (based on the rneasurement of phalangeai BMD by RA) indicate a
signi ticant. inverse relationship of bone density to fractures. The technical details of RA
are discussed below. The study by Huang er ai., found that hand RA (phalangeai and
metacarpal BMD) can predict fracture risk at any skeletal site and that phalangeal BMD
showed a strong and highly significant association with vertebral Fracture (36). Another
populatim-based prospective study by Mussolino er al. showed that phalangeai RA is a
signifiant predictor of funue hip fracture. with the strong predictive association k ing
comparable to that obtained with other foms of BMD measurement (37). Ross et ai.
have also shown that including spine or radius BMD dong with a hand BMD
measurement may not provide much additional information about risk of determination
(38) . One drawback of peripheral skeletal measurements is that they may remah largely
unresponsive to therapies. limiting their use for senal monitoring. However. a recent
study has s h o w an increase in bone density and bone strength at the distal radius due to
Alendronate therapy (39). Note that pQCT. which measures tme volumetric bone
density. was used in this study. The clear conclusion from al1 these recent studies is that
the assessrnent of phalangeai BMD provides long-term value in predicting both hip and
spine fracture (23).
1.3 Peripheral Bone Densitumetry Techniques
The intent of this discussion is not to give a comprehensive list and description of
available technologies but to highlight those technologies that will form the ba i s of study
in this thesis.
1.3.1 Radiographie Absorptiometry
The technique of radiographie absorptiometry (RA) is one of tne earlirst
quantitative methods of evaluating bone mineral (26). It uses a radi~~gaphic film image of
the hand or fingers to measure bone mass by comparing the optical density of the region
of interest (phalangeal and/or metacarpal bone) with a calibration or re ference material
( such as an aluminum wedge) that is included in the Unage (Figure 1 - I ) (3 1.35). The film
images are digitized and the absorption dong cross-sections of bone is analyzed. The
integral under the absorption curve represents the amount of bone mass: when summed
over a number of cross-sections and then divided by total bone area a measurement of
bone density is obtained. As the calibration is in duminum. the densi. has arbitrary
(alurninurn) units of mass per unit area. Further corrections to account for soFt-tissue and
x-rai exposure parameters have been implemented (29), but not until the past decade has
a standardized technique (which accounts for variation in kilovoltage (kVp). exposure.
film characteristics and soft tissue thickness) led to a revival in interest of RA (14).
The RA technique available commercially under the narne OsteoGram
(Cornpubled Inc.. Manhattan Beach. CA) has done precisely this. OsteoGrm consists
of a central evaluation facility. which implements a specific imag.ig and calibration
protocol with films that are submined for analysis (40). The technique. which requires a
simple hand radiograph (Figure 1-1). could be implemented on a standard x-ray system
obtainrd in any diagnostic x-ray department: thus there is no need to purchase any special
purpose rquipment except for the calibration wedge. The films are mailed to OsteoGram
for digitization by a high-resolution video camera or laser digitizer for analysis. The RA
technique measures the area and minerai content of the entire 2"- 4Lh middle phalanges.
Rrsults from the phalanges are averaged and volume density. (termed BMD index) is
reported as the final measurement result. The BMD measurement is obtained after
application of a volumetric correction factor that is based on the assumption that çach
cross-section of a phalanx is cylindncal in shape (37). For quality control. two films
(obtained at slightly different exposure settings) are analyzed separately: results are valid
if the two films agree to within 2% (JO).
OsteoGram has a large normdized population-based reference database becaw
EV, was used in the National Hedth and Nutritional Education Survey (1 97 1 to 19753.
which resulted in measurements on normal healthy women aged 43 - 74 years of age
(3 7.40). The success of this technique as discussed above is that the RA measurement is
equivalent to other bone densitometry methods for predicting fracture nsk, based on long-
term prospective data (23,35-37).
Figure 1-1. The film of a hand including an durninu. reference wedge for
radiographic absorptiometry measurement the BMD in the 2" - @' middle phalanges.
'4s the technique also has hi& precision (repeatable measurernents) and good accwacy
(measurements that cot~espond to the actual ashed weight of bones) (41). it is considered
an alternative technology to axial DEXA (1 5.22). However delays due to processing at a
central site as well as limitations of calibrating bone minera1 (hydroxyapatite) in aluminum
and failure to account for soft-tissue variation has resulted in Iimited success of this
technique clinicaily.
Due to RA'S performance and the utility of phaiangeal BMD measurements,
several portable techniques have been developed (35.42.43) (including digital RA and
variants called computed digital absorptiometry (CDA) and dual-energy CDA). Also,
uith the wide acceptance of DEXA, new peripheral DEXA techniques have emerged that
assess bone density in the distal radius and calcaneiis (20,44,45). In the following section
1 will describe the technical details of DEXA in some detail.
13.2 Dual Energy X-ray Absorptiometry @EXA)
This is a brief review of the technical principles of DEXA that is adapted from a
description by Blake et al. (14). As the terni indicates. Dual-Energy X-ray
.4bsorptiometry (DEXA) depends on recording the attenuation profiles of two different
x-ray eneqies through the body. The two-dimensional (2D) projection maps allow for
the determination of bone content in the projected area of the bone. thus obtaining the
principle measurement result. which is the areal bone mineral density (aBMD) with unit5
of p a m s per square centimetre (gcrn'?). With a dual-energy imaging algorithm it is
possible to account for the overlying soft tissue when determinhg the amount of cortical
bone and. subsequently. bone minerd (calcium hydroxyapatitie (Caio(P04)oOH2)).
1.3.2.1 Absorptiometry: quantitative measurement of x-ray attenuation
Bone mineral measurement techniques - using x-ray radiation - are govemed b y
the processes of photon interaction with matter. predominantly the photoelectric effect
and Compton scattenng at diagnostic eneqies. The photoelectric ef3ect is characterized
by complete absorption of the incident photon by an atom, while in Compton scattering
the photon collides with an atomic electron and loses some of its energy proportional to
its deflection in this process. At the energies ilsed in bone densitome- (30440 keV).
the photoelectric effect is the predominant mode of interaction in bone and Compton
scattenng in soft tissue. As they pass through a material, photons are attenuated and the
fraction of the incident ray transmined depends on the mass attenuation coefficient of the
material. p (cm2/@, which depends solely on the energy of incident photons and the
atomic comp~sition of the attenuating medium. Hence. p depends on only the Fraction of
al1 atoms of a specific component in a material and not on the physical state. crystalline
state or mixture. With an initial intensity. 1,. the intensity. I(x). as photons pass through
a material of density. p. and of thickness. x. is descnbed by Eq 1.1
Equation 1.1 assumes that the
~ ( - ~ l = lOe-ppr .... . .. .... ...... -.... .... Eq 1.1
beam is traversing a homogeneous material. Soft
tissue and bone have different atomic composition. therefore their p are different. as is the
dependence of p on photon energy. At high photon energies there is little di fference in p
but this difference gets progressively larger at lower photon energies. At the lower
cnergies. the photoelectric effect is the dominant mode of interaction and because of the
direct relation of atomic number to the photoelectric effect. this results in a much higher p
for bone than for tissue. The challenge is to separate the attenuation due to bone and soH
tissue. which is accomplished by use of two incident photon intensities.
By using two energes and knowing the attenuation coefficients of bone and soft
tissue at these energies (14) the areai density M (where M = px) c m be obtained as
tollows:
Low energv:
High energy:
Where. the subscripts L,H,B,S represent low energy, high energy, bone and soft tissue.
respeciively. By taking the logarithm of both sides of Eq 1.2. 1.3. we have:
LE = ,uLBblB + p L S ~ S ....................... Eq 1.4
NOM.. rearranging and solving for the MO unknowns gives the areal densities:
These equations provide the mal densities of any pixel in terms of the tissue-specific
materials: in this case. bone and sofi tissue.
1.3.2.2 DEXA: Clinical Implementation
The above approach assumes that the attenuation coefficients of bone and soft
tissue are exactly known at both energies. which is not the case in reality. Therefore. in
the clinical implementation of DEXA calibration with known amounts (i.e.. know
attènuation coefficient and hence areal density ) of so ft tissue and bone-mimicking
materials is done. Transmission measurements through air. bone and soft tissue
calibration materials at the low- and hi&-energies are acquired resulting in each pkel
having six transmission measurements. By measuring the incrementai attenuation in bone
and soft tissue with the presence of these calibration rnaterials. the areal density of the
bone and soft tissue is exactly determined (14).
Following advancement fiom dual-photon absorptiometry. the x-ray generation
and detection initially implemented point or rectilinear scanning. In this method. a two-
dimensional raster scan is done to obtain projection images across the body site of interest
(bu moving a scanning m. which aligns and mechanically connects the source. pinhole
collimator and a single detector). Hence, this first generation of DEXA scanning uses a
pencil-bearn of x-rays. acquiring images in around 5-10 minutes (11). However.
acquisition times have been reduced to less than a minute in currenr - second generation
fan-beam - DEXA systems. This method uses a slit collimator to generate-fan beam of
x-rays that are coupled to a linear array of detectors. Therefore. images are acquired by
having the scanning am perform a single sweep across the patient instead of the two-
dimensional raster scan.
1.3.3 Quantitative Computed Tornography (QCT)
From its inception computed tomography (CT) has allowed for measurernent of
BMD (46.47). Unlike absorptiometry techniques. in which a measurement of x-ray
attenuation is made along a fixed line (thickness) through an object. in CT a series of
measurements is made at any point along that line by rotating the source and detector.
With the multiple projections or views obtained. each point can be separated fiom
another by the mathematicai reconstruction techniques (such as convolution back-
projection) to obtain a three-dimensional(3D). cross-sectionai CT image. This 3D image
represents the x-ray attenuation of a senes of volume elements (voxels), which have
defined size and position within the reconstnicted image. The caiculated attenuation
coetticients are expressed as "CT numbers" with use of an absolute Ihear scale
(Hounsfield scale! that is defined o d y by the attenuation of dry air (- 1 O00 HU) and O for
the attenuation of pure water (O HU) (48). Note that the Hounsfield scale is dependent
on the scanning ene ra used.
In quantitative CT (QCT) it is assumed that the materiai consists of two-
componrnts: tissue and bone marrow. By including (in the image) a calibration rnaterial
consisting of various concentrations of hydroxyapatite the BMD is determined. as there
is a linear correlation between BMD and CT number. Hence. the BMD obtained is the
true volumetnc BMD with units of grams per cubic centimetre (gacm''). To distinguish
from areal BMD - obtained by projection absorptiometry techniques and defined in the
litcrature as BMD - 1 will henceforih use vBMD to represent volumetric BMD.
1.3.3.1 A note on the "Gold Standard"
Only QCT provides a cross-sectionai or 3D image h m which the bone is
rneasured directly (independent of the surroundhg sofi tissue). whereas DEXA provides
a projection measurement or 2D image to obtain bone densip. Furthemore. QCT is the
only technoloa that provides separate measurements of the highly responsive trabecular
and less responsive cortical bone as a true volumetric minera1 densi5 (49). Hence. QCT
measurements of the trabecdae in the vertebra - likely the most sensitive technique to
measure changes in bone mass due to osteoporosis and response to therapy - are
accepted as the 'gold standard' for non-invasive rneasurement of bone s ta tu and
predicting Fracture risk (18.50). However. there is debate as to whether DEXA is the
practical 'gold standard' (18,46,19,50), as DEXA is the rnost widely available and tested
technolopy ( 15).
1 A3.2 QCT: Clinical Im plementation
Quantitative CT can be implemented on most commercial CT scanners with the
use of calibration reference phantoms and analysis sofi\vare. The technique involves a
patient Iying on the calibration standard. thus providing a specific calibration for each
image. In these spinal QCT techniques. typically (5 or 1 O mm thick) axial slices scans are
obtainrd through the mid-plane of 4 consecutive vertebral bodies for ZD analysis of the
trabecular bone cornpartment (46). From each of these slices. the CT density is
determined in a selected region of interest (e.g. anterior portion of trabecular bone) and
conversion to vBMD is done by the calibration technique described above. -2mong the
âdvantages of spinal QCT for noninvasive bone minerai measurement are the hi@
precision of the technique. the high sensitivity of the vertebral trabecular measurement
site. and the potential for widespread application (5 1 ).
Recently. volumetric CT images of the spine and hip obtained by stacked slice or
spiral CT scans have been used to reformat the CT data into anatornically relevant
projections for quantitative analysis (46). This 3D approach allows for encompassing the
rntire object of interest: and. when done in hi&-resolution, for assessment of trabecular
bone microarchitecture. To make QCT more affordable, development of dedicated QCT
sy stems have been irnplemented for quantitative analysis of the peripheral skeleton. in
particular the distal radius (52-55).
1.4 Research Goal
1.4.1 Goal and Hypothesis
A review of the ciinid problem may be surnrnarized as follows: 1 ) there is
continuing interest in quantitative, non-invasive techniques to diagnose osteoporosis and
monitor treatment in the peripheral skeleton, as the measurements in these sites are not
only predictive of fracture but are also cost effective: and. 2) the results GL recent
investigations have shown that accurate measurements of bone density at peripheral
skeletal sites (phalanges. calcaneus) may provide the sarne diagnostic accuracy as more
di ffïcult measurements of the spine and pelvis.
The overafï goal of this project. therefore. was to develop and evaluate a novel
DEXA technique to measure phalangeal BMD that could be implemented on a standard.
s-ray image intensifier (XRiI) based digital radiography system. This project proceeded
in two stages: the f rst was to compare ZD DEXA areal bone density measurernents
(calibrated in hydroxyapatite) of the second. third and fourth middle phalanges in the left
hand with the RA BMD index (calibrated in arbitrary durninum units). The resulting
development and cornparison study leads to discussion and consideration of the
impiernentation of a commercial DEXA system for clinical use in the management of
osteoporosis. Afier development of a phalangeal DEXA technique the second stage of
this study was to implement QCT for phalangeai vBMD measurements and therefore
compare phalangeal BMD measurements fiom DEXA with QCT. This cornparison
study was done to evaluate the relationship of phalangeai projected area (as obtained by
DEXA) and volume (as obtained by QCT) to determine whether there exists an empirical
relationship between these quantities, allowing an improved estimate of volmettic BMD
from DEXA measurements.
The tec!iniczl hypotheses of this thesis are as follows: 1) ZD DEXA will provide
BMD measurements that are precise (to within 1%), accurate (to within 5%) and
correlate (significant correlation with > 0.8) directly with M. when assessed in the
same patient: 2) True volumetric bone density of the phalanges (as obtained by 3D QCT)
will account for the phalangeal size dependence in ZD DEXA areai BMD measurements:
md 3) an empirical relationship exists wliich relates area and volume of the phalanges.
ailowing the accurate determination of an estimated volumetric BMD tiom DEXA-based
measurements.
1.4.2 Research Plan
My research plan included the following stages:
1 ) Develop a novel. XRII-based digitai radiography system including a calibration cross-
step wedge for DEXA phaiangeal BMD measurements: 2) characterize the DEXA
technique by assessing precision. accuracy md dose: 3) compare phalangeal BMD
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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'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).
2.2.3 Dual-Energy X-ray Absorptiornetry : Acquisition
Areal DEXA measurements of the lefi hand were performed with a clinical digital
radiography unit (hiiiltistar. Siemens Medical Systems. Germany) in dl women. We
implemented the dual-energy x-ray imaghg technique for in vitro tissue composition
measurement described by Moreau et ai. (21) on our x-ray image intensifier (XRi1)-based
scanner. The digital .u-ray sy'tem has a 20 cm field-of-view XRII coupled to a logaridunic
10-bit digitizinp video camera as its detector system. The output image was digitized into
an 880 x 880 image ma& with pixel size of 184 pm x 184 Pm. Ail images were acquired
with a 95 cm source-to-detector distance with a geometric mafification of 1.19. The x-
a source is a water cooled. rotating tungsten anode tube with a 0.6 mm focal spot. The
x-ray exposures for the dual-energy radiographs were 40 kVp, 3 18 mA and 166 ms for the
low-energy image, and 125 kVp, 28 mA and 166 ms with 1.7 mm of additional copper
Photon Energy (keV) a)
Photon Energy ( k W )
b) Figure 2-1. The numerical simulations of the X-ray spectra used for
the dual-energy x-ray acquisition. (a) Low-eneqy [40 kVp. 3 18 rnA]
spectrum. (b) High-energy [125 kVp. 28 mA. 1.7 mm Copper
filtration] spectrum.
filtration for the hi&-energy image. These tube voltages were the lowest and highest x-ray
exposures available on the dinical digital radiography system and were chosen to
optimize the differential attenuation of two assurned components (bone and soft-tissue)
k i n g measured. Numerical simulations of the polyenergetic spectra, ushg the Tucker-
Barnes algorithm (22) are s h o w in Figure 2-1. Note that although we recommend using
the lowest and highest availahle exposure senings (in order to provide the largest
separation in low- and hdgh-energy x-ray spectra) the DEXA technique works well with a
spectral separation less than used here. Three image frames over a 3 second period were
acquired at the low energy? afier which the copper filter was introduced. Then three image
frames over a 5 second penod were acquired at the high enere. resulting in a total
acquisition time of approximately 25 seconds. The participants were required to keep
their hand tlat and maintain hand position for the entire scan sequence.
Included in each image was a crossed-wedge calibration phantom composed of
material that is radiograp hicaily equivalent to so fi-tissue (LuciteT 3 and compact bone
(SB3. Garnex RMI. Middleton. WI). These step wedges were supenmposed in an
orthogonal marner to produce the phantom and obtain 35 different material combinations
for the calibration of the system. The crossed-wedge calibration phantom encompasses an
a r a of 50 x 50 mm' with maximum step thickness of 1 1.2 mm and 18.1 mm for the SB3
and LuciteTM. respectively. Figure 2-2 shows representative images of a hand obtained at
the low- and high-energy exposure senings. Exposure measurements (obtained with an ion
chamber dosimeter) were obtained for low- and high-energy acquisitions and converted to
effective dose (23). The complete DEXA scan procedure resdted in an effective dose of
1.1 ysv.
2.2.4 Dual-Energy X-ray Absorptiometry: Analysis
The image data set was transfened from the digital radiography system to an
image-processing workstation (Silicon Graphics, Mountainview, CA) for analysis. To
improve the signal-to-noise ratio, each image was obtained as an average of the three
acquired frames. Image correction and normalization was done to account for pixel-to-
pixel nonuniformity (fixed pattern mottle) which occun when using r-ray image
intensifiers (2 1 ). For each low- and high-energy image pair. the low- and high-energy log-
sigals of ba rn attenuation (corresponding to each of the 25 thickness combinations of
the crossed-wedge calibration phantom) determined the bais-material thickness.
Figure 2-2. Digital Radiopphs of hand including the calibration step wedge
(sw). (a) Low-energy [4O kVp] image. (b) High-energy [125 kVp] image. The
photon energies provide large separation of bone minerai and soft-tissue
components in the region of interest. Note that the RA aiuminum reference
wedge (aw) is not used in DEXA analysis.
Conversion fiom radiographic images to quantitative matend thickness was
performed in a manner simila. to that described by Moreau et al. (21 j. Logsignal values
from both low- and high-energy images were measured in a 4 mm' region of interest
within each of the 25 thickness combinations available within the crossed-wedge
calibration phantom. The nonlinear transformation behveen radiographic signal and
marenal thickness for polyenergetic x-ray beams has been drscribed by Johns and
Beauregard (24). Pararneterization of the image data in this manner allows for the
calculation of basis materiai thickness (bone or sofi tissue) at any pixel location in the
image.
This DEXA decomposition of low- and high-energy image was performed for each
hand to obtain tissue-equivalent (LuciteTM) and bone-equivalent (SB3) thickness images.
However. subsequent analysis was performed on the bone-equivalent image (Figure 2-3).
The high spatial resolution of these thickness maps allowed for accurate serni-automated
edge determination of individuai phalanges. The edge detection aigorithm for segmentation
is an implementation of an active contour rhat deforms an initial estimate contour. which
is represented as a senes of weights c o ~ e c t e d by a thin narrow plate of adjustable
stiffness. The contour is deformed by two forces: an extemal force (analogous to gravity).
which is calculated as the negative inverse of the gradient of image intensity values and
intemal force that is modeied as a bending stiffhess (23). This process involved two
steps: manuai selection of the boundary with a mal1 number of control points. followed
by automated refinement of the boundary area determination (Figure 24) .
Standard algorithms were then used to caiculate the BMC (g) and determine areal
BMD (g-crn'2) of each phalanx. Analysis was done for the 2nd-4th middle phalanges
(chosen as analogous to RA analysis), and for the 2nd-4th proximal phalanges.
Figure 2-3. DEXA decomposition bone equivalent (thickness) image. The bnghtness
of a pixel indicates greater thickness of material. Segmentation of regions of interest
(middle and proximal phalangeal bones) is done using this digital image.
The middle phalangeal BMD measurements were then averaged - represented as
BMDsfID - as were pro.xima1 phalangeal rneasurements (BMDPROx). The BMC of the
middle and proximal phalanges is also taken as the average BMC of the individuai
phalanges. The area DEXA technique estimates the BMD of the phalanges in cortical
bone equivalent units. However. calculation of the bone rnineral (hydroxyapatite)
cornponent is obtained by correcthg for the known fraction of bone rnineral in compact
bone (0.58) (26). This approach results in areal BMD measurernent (g hydroxyapatite
cm-') that is consistent with other clinical DEXA measurements.
Figure 2-1. DEXA semi-automatic segmentation showing a close-up
of the 3rd middle phalanx of the subject. (a) Software ailows for user
selection of boundary. (b) Edge detection with active contour mode1
allows for automated refmement of bone boundary .
2.2.5 Precision and Accuracy
To evaluate the precision of this DEXA technique, 3 frozen cadaver specimens
were malyzed. The cadaver hands were thawed ovemight and DEXA was perfomed the
next day. Each specimen was imaged 15 times without repositioning and 10 times with
repositioning between acquisitions to evaluate machine precision and operator
repositioning precision, respectively. The DEXA analysis was canied out on the
specimens to determine the BMC and BMD of the middle and proximal phalanges. The
mean and standard deviation for these measurements were obtained and the coefficient of
variation (CV. %) was calculated. using the method of Gluer et ai. (27).
The accuracy of BMC and BMD measurements was determined by scanning eight
cy lindrical tissue-mimicking solids of known dimensions and BMD (C IRS. Norfolk. VA).
The test samples included a range of trabecular BMD fiom O to 400 rngcm" and cortical
BMD of 1 100 mgcm" (SB3). The nue bone mineral mass of each sample was determined
from measured volume and known density. These samples were placed in a plastic
container and immersed in 15 mm of water and DEXA kvas performed to obtain the
projected area. BMC and BMD. Linear regression analysis of paired results of BMC
versus known bone mineral mass was then performed, yielding the equation of the line.
correlation coefficient r, a standard error of the estimate (SEE) about the regression line
and a P value. This study also aüowed for determhing the accuracy of BMD
rneasurements by linear regression analysis of BMD versus a i e areai density (g*m-2),
where tme BMD is obtained by dividing the tme bone minerai mass by the caiculated
projected area of the cylinder.
2.2.6 Data Analysis
The primary analysis was to compare RA and DEXA rniddle phalangeal
measurements of ail patients and perform a linear regression analysis of the two
measurement techniques. For both groups of subjects, descriptive statistics were
generated for B MDRfl, B MDHID, B MDPROx. and DEU-based measurements of middle
and proximal phalangeal BMC. The statistical significance of differences between the
aroups for these measurements were calculated with unpaired Student r test @ < .Oj). s
2.3 Results
Descriptive statistics for BMDRa4, BMC and BMD variables for each group are
given in Table 2- 1.
Group 1 Group 2 (YoUW) ( post-menopausal)
HanJ R-l
BMD index (arbitrary units)
BMC (le) 1-56 0.226 1-39 0.226 Table 2-1. Descriptive statistics of bone density measurements in group 1 (n = 19) and
* t group 2 (n = 18). Data are mean * SD. p < 0.0001 compared with Group 1. p <
0.0001 for ail proximal BMD vs. middle BMD.
Statisticd anaiysis (unpaired t-test) of the DEXA results showed that the mean
BMDLllD of Group 1 (0.289 i 0.025 gcrn-*, mean * SD) was significantly different @ <
0.000 1) than that of Group 2 (0.745 * 0.032 gcm").
The RA analysis also showed a significant difference @ < 0.0001) in the mean
B M D R , of the two groups. Pro'cimal phalangeai BMD measurements were also
significantly higher than rniddle phalangeal BMD measurements in both age groups (p <
0.0001 ). Although BMC tended to be lower in Group 2. differences were not as
significant as was observed with BMD. in any case. it is inappropriate to make
conclusions about group differences based on BMC alone as these measurements are
confounded by differences in bone size. Linear regression analysis showed a strong
correlation betwcen BMDU and BMDhlID in al! 37 individuals (Figure 2-5) with BMDRA
= (119 r 34) BMDbIlD - 15 (2 = 0.81 1.p < 0.0001).
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.
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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.
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' ~ 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.
3.2.2 Quantitative Cornputed Tomography: Acquisition
Using the sarne Siemens Multistar digital x-ray system (conventionally used for
digital subtraction angiography). CT images of the human hand were obtained. Using 3 D
CT i m i e C zcquisition protocols developed in our laboratory (14.1 5). a 3D volume data set
was acquired fiom projected data at the 20 cm field of view while the C-arm rotated
around the hand. resulting in approximately 130 images over the 200" required for the
volume reconstruction. The focal spot to detector distance was set to 120 cm with a
geometric magnification of 1 .S. Hence. the volurneaic images were acquired over a 1 3 cm
tield-of-view with 0.3 mm isotropie voxel spacing. The exposure parameters were 8 1
kVp. 34.3 mA and 3 ms during a 4.5 second acquisition sequence for a total of 19 mAs.
resulting in an etrective dose of 5.4 pSv (16). After each acquisition. 40 bright-tield
images were acquired with nothing in the field of view. to provide a correction for detector
non-uni forniin;.
Included in each image were cy linders of tissue-mimicking calibration matenal of
known trabecular BMD (CIRS. Norfblk, VA) and cortical BMD (SB3 Gamex RMZ.
Middleton. WI). The cylindrical calibration phantoms were placed over the metacarpals
of the hand. insuring that the phantoms remained in the field of view at al1 view angles.
The system was calibrated ushg the water-equivalent and cortical-bone-equivalent
phantoms. while the remahhg trabecular BMD phantoms (50.100.200.300.350.400
rngwn") were used ro verify the linear relationship between image intensity (CT Number
in Hounsfield (HU) units) and BMC (gvmJ).
3.2.3 Quantitative Computed Tomography: Analysis
The image data set was transferred from the CT system to an image-processing
workstation (Silicon Graphics. Mountainview. CA). Correction of images for XRII
distorti on and reconstruction b y convolut ion backprojection was performed as described
by Fahrig el al. (14.15). In brief. each projected image is corrected for signal non-
l inearities. distort ion. tixed-pattern noise and shi fi. With the reconstmcted CT image.
semi-automated segmentation was performed using a geometrically deformable model
(GDM) ( 17). The CT volume was re-formatted into sagittal cross-sections prior to
segmentation as these slices had the best identification of phalangeal boundary
(independent of an adjacent bone) in almost al1 image slices (Figure 3-7). The other
reformatted views (transverse and coronal) are aiso available for analysis (Figure 3-3a and
3 - b . These images also show the distribution of cortical and trabecuiar bone and give
some indication of the complex 3D shape of the phalanges.
The GDM segmentation involves a 2D implementation of an active contour that
deforms an initial estimate contour. The contour is represented as a series of weights
connected by a thin narrow plate of adjustable stiffness. [t is deformed by two forces: an
eaemal force (analogous to gravitv). which is calculated as the negative inverse of the
gradient of image intensity values. and an intemal force that is modeled as a bending C
stiffness (17). The segmentation process involved two steps: manual selection of the
boundary with a small number of control points, followed by automated refinement of the
bound-;. An example of semi-automated edge determination of a phaianv tiom QCT
data is shown in Figure 3 4 .
Figure
middle
3-2. Sagittal slice of the CT reconstnicted image showing the
and proximal phalanges of the 2nd finger. ïhe sagittal siices
provided the best view for segmentation procedure. Included in this image
slice is a calibration cylinder used for QCT analysis.
Figure 3-3. a) Transverse slice of CT reconstnicted image of the cadaver hand
showing the three middle phalanges of interest. This view shows that the phalanges
have cornplex shape. which indicates dificulty in assuming a single geometric
approximation. b) Coronal slice (O.3mm) of the cadaver hand. This slice shows
separate regions of cortical and trabecular bone in the die middle phalanges.
Standard algonths were then used to calculate the phalangeal BMC (g) and
volume (cm3). The volume is simply the m a of segmented boundary of the phaianx
scaled by the known slice thickness. The QCT analysis was performed on contiguous
image slices c o v e ~ g an entire bone to obtain true volurnetric BMD (vBMD. g*cm-3).
Therefore, the sum of BMC and volume from al1 slices of a phalanx were obtained and the
\-olumetric density detemiined by dividing the BMC by the volume. Analysis was done
for the 2nd- 4' middle and proximal phalanges to obtain six separate measurements of
phaiangeal BMC, volume and BMD in each hand. As was the case with the DEXA
analysis. the QCT technique estimates the BMD of the phalanges in cortical-bone
equivalent units. Hence. to obtain bone mineral (hydroxyapatite). the BMD is scaled by
estimating the known Fraction of bone minerd in compact bone as (0.58) (18).
Figure 3-4. a) The two-dimensionai active contour
segmentation procedure allows for user selection of
boundary. b) with automatic refinement to obtain the
required region of interest.
3.2.4 Patient Dose
Entrance dose for the CT acquisition was measured using a calibrated Keithley ion
chamber. The entrance exposure of 0.379 Roentgens was converted to air k e m using a
conversion of 8.77 mGy/R. Following the technique described by Huda and Gkanatsios
(19), the effective dose for a 3D CT acquisition of a hand was caiculated to be 5.4 pSv.
which is at the lower end of the exposure range encountered in diagnostic radiology (20).
3.2.5 Data Analysis
The active contour segmentation technique allows for boundary selection of an
entire phalanx. For DEXA dus resulted in the projected area, and for QCT we obtain the
total volume of each phalam. Hence al1 data is obtained with respect to the entire size of
each phalam and allows for direct cornparison of projected area to volume. by DEXA and
QCT. respectively.
The precision and accuracy of the QCT volume estimation was determined by
performing volume segmentation on the 300. 350 and 400 mgcm'-' cylindical phantoms
that were included in the image acquisition of the three hands. The three repeat
measurements of each phantom allowed for assessing the precision as assessed by
coefficient of variation in the volume measurements. The average volume rneasurement
for each of the cy lindrical phantoms was also compared to the me physical volume - as
assessed by caliper measurements - to determine the percentage difference and therefore
accuracy.
Descriptive statistics were generated for the middle and proximal phalangeal
measurements. The parameten obtained from DEXA were area. BMC (dBMC) and areal
BMD (aBMD) and that fiom QCT were volume. BMC (qBMC) and volumetric BMD
(vBMD). The primary anaiysis was to compare the BMD measurements of the middle
and proximal phalanges. A Student's t-test was used to examine whether a siCdcant
difference in aBMD exists in the middle and proximal phalanges. Sirnilarly, a Student's r-
test was used to compare vBMD in the middle and proximal phalanges. As a test of
intemal consistency, we also compared (using a paired t-test and !inear regression) the
BMC rneasurements fiom both QCT and DEXA techniques.
An additional goal of this analysis was to determine if there is a relationship
between area (determined by DEXA) and volume (detemined by QCT) for the
phalanges. If such an empirical relationship is observed. it may be possible to provide a
correction to DEXA-based BMD measurements that better accounts for bone size. To
this end. non-linear regression analysis \vas performed on the area and volume data.
assuming a relationship with the t o m of a power law. To test the validity of the
resultinç correlation. the empirical power-law relationship was used to estimate bone
volume from each DEXA area measurement, and these bone volumes were used to
calculate an estimated volurnetric BMD (eBMD). Lastly. eBMD was compared to
known vBMD by a paired t-test. Note that it is expected that the entire bone mineral
content of a complete phalam will be reported equivalently by either technique.
3.3 Results
4 linear regression analysis was performed to determine the linearity of the QCT
rneasurements. The line of best fit obtained was CT Number = 2.5 1 vBMD (g.cmJ) +
65.6 HU. with 2 = 0.9998. p < 0.0001 and SEE = 19.4 HU. The error in this
measurement represented by the SEE divided by the mean CT Number was 2.3% and a
m s test confirmed that the rneasurement was not significantly nonlinear @ = 0.714).
nea
Descriptive statistics for both DEXA and QCT middle and proximal phalangeal
surements are provided in Table 3-2 below. Statistical analysis (unpaired t-test) of the
QCT results showed that the vBMD of the nine middle phaimges (mean * SEM) was
0.439 + 0.025 gmcm=', which was not significantly different @ = 0.45) than that of the
proximal phalanges (0.473 0.036 g.cm"). However, there was a significant difference @
< 0.000 1 ) between the DEXA measured aBMD of middle (0.308 = 0.0 18 g*cm-2) and
proximal phalanges (0.389 k 0.01 7 g*cmd).
Table 3-1 shows the results of the precision and accuracy studies of volume
segmrntat ion in the three calibration cy linden. Average precision was 4.1 % and average
accuracy was 62%. The precision and accuracy of QCT volume estimation was 4.1%
and 6.2?6. respectively.
Sample True Average measured Percentage Coefficient of Deosity volume volume 2 s.d. error Variation
(mg*cm") (cm3) (cm3) CW (%)
300 0.375 0.3986 k 0.02464 6.2 1 6.18 350 0.3 77 0.4059 ft 0.00671 7.66 1.65 400 0.370 0.3863 * 0.0 12 1 1 4.75 3.13
Table 3-1. Precision and accuracy results obtained using cylindrical phantoms of L~own
density. Three volume measurernents of each sample were made and the mean and
standard deviation (s.d.) obtained was used to determine precision and accuracy.
Paired t-test showed no sipifkant difference @ = 0.29) in cornparison of average
phalangeal BMC by DEXA (1.406 g) and QCT (1.370 g). Figure 3-5 illustrates the
significant linear relationship between these two measurements (? = 0.948, p < 0.0001 ),
with the equation of the line given by dBMC = 0.968 qBMC + 0.0799 g.
DEXA - -- - -
Phalangeal Site Area (cm') BMC (g) BMD (gwn*2) iMiddle 2.94 (0.390) 0.870 (0.2 14) 0.308 (0.054)*
Proximal 5.22 (0.527) 1.94 (0.307) 0.389 (0.050)
OCT Phalangeal Site Volume (cm3) BMC (g) BMD (gaci-3)
Middle 1.80 (0.328) 0.850 (0.255) 0.373 (0.107) Pro'ùmai 4.37 (1.013) 1.90 (0.35 1 ) 0.439 (0.074)
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.
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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).
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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.
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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.
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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
QCT are: 1) high-resolution (0.3 mm voxel spacing) volurnetnc QCT: 2) cornpiete
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.
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