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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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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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FEED FAX THIS END

I Dept.:

F U N O b b 3 , - 3 4 0 0 1

Company:

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Cornmen ts:

' ~ h a ~ t e r 3: Volumetric BMD Assessrnent of the Phalanges by Dual-

Energy X-ray Absorptiometry and Quantitative Computed Tomography

3.1 Introduction

The most common method of measuring bone mass is dual-energy X-ray

absorptiometry (DEXA) and this technique, ofien used in clinical practice and research.

has also been the most thoroughly studied (1 ) . The resulting values are usually

represented as bone minera1 density (BMD). which is an areal density representing the

~ m s of bone mineral in a projected area of bone (p?uns*cm''). Since DEXA

measurements are by areal projection. a volumeaic density (gams*crn4) is not obtained

and the true geometric assessment of a bone is impossible. Furthemore. the areal BMD

measurement may have a dependence on bone size.

In order to reduce this effect of bone size on BMD measurements. several

attempts have been made to provide estimates of volurnetric BMD From planar

projections. These techniques have k e n applied on clinical DEXA systems assessing

bone mass in the avial skeleton (vertebrae) ( 2 - 3 . Estimated volumetric BMD

mrasurements have also been applied to penpheral skeletal sites. particularly to the

phalanges of the hand. where it may be more appropnate. A radiographie absorpti~metry

method developed by Trouerbach eî al. involves measurement of the optical density on

both the posteromterior and laterai views of the index fmger. followed by

volurnetric density values (6.7). Another radiographie absorptiometry

calculation of

technique -

! A version of this chapter has k e n prepared for publication.

initially described by Bachtell and Colbert and later developed as the CompuMed method

- obtains an apparent volumetnc BMD, which assumes a circular cross section for each

phalmv in each transverse slice of the analysis (8-10). Volumetric corrections have also

been used for DEXA-based phaiangeai BMD measurements. A technique by Bnillon et

ut. assumes that the projected area of a phalam obtained fiom the DEXA scan is that of a

cylinder and a calculation is done to obtain volumetric BMD ( 1 1 j.

An x-ray image intensifier (XRl1)-based digital radiography system has recently

been adapted for DEXA assessrnent of phalangeal BMD ( 12). Although the technique is

precise. accurate and compares well with radiographie absorptiometry of the phalanges.

there is interest in examining techniques to correct for the dependence of bone size. i.e. to

find an empirical determination of the shape factor relating the area and volume of the

phalanges. To this end a study was undertaken to adapt the sarne XRII-based digital

rad iograp hy sy stem to provide high-resolution quantitative conputed tomography

(QCT') of the phalanges. Quantitative CT is the only densitometry technology that

provides information about the three-dimensional (3D) shape of the phalanges:

information that is required to determine the true volumetric BMD (expressed as grams

per cubic centimeter) (1 3).

In this study. we compare two-dimensional(2D) areal bone density measurements

fiom human cadaves (middle and proximal phalanges) with the QCT volumehic density.

The DEXA and QCT rneasurements are used to determine an empirical relaiionship

between the projected area and volume of the phalanges, making it possible to estimate

volumetric BMD fiom DEXA-based measurements. As an interna1 test of accuracy the

bone minera1 content (BMC) of the DEXA and QCT measurements are also compared.

Three human cadaver forearms were obtained frozen fiom a local orthopedic

depanment. The cadavers were thawed to room temperature pnor to DEXA and QCT

Unaging. Al1 three cadavers were male but information regarding age at death was

unavailable. The cadaven were kept in their original storage plastic bags during the

imqing procedures and no surgically invasive procedures were performed. Correct

placement of the hands on the scanning table. such that the middle and proximal phalanges

were included in the field of view was done with the assistance of x-ray tluoroscopy.

Furthemore. for the purposes of planar radiography (DEXA) and the following

comparison with QCT. hand positioning was done so that there was no obliquity or

rotation of the hand. This was conti~rmed with a simple observation that the concavities

of both sides of the shafis of phalanges are symmetric. Also the phalanges wew

separated with no overlapping of the bones or sot? tissues of the fingers.

3.2.1 Dual-Energy X-ray Absorptiometry

The DEXA procedure has been described in detail previously (1 2). Briefly. areal

DEXA measurements of the cadaver hands were performed with a digital radiography

sy stem (Multistar, Siemens Medical Syaems. Germany). The digital x-ray images were

acquired at the 20 cm field-of-view and each output image was digitized into an 880 x 880

image matrix, with pixel size of 1 84 pm x 1 84 Pm. Al1 DEXA images were acquired with

a 95 cm source-to-detector distance with a geometric magnification of 1.19. The x-ray

source was a water cooled, rotating tungsten anode tube with a 0.6 mm focal spot. The X-

ray exposures wcre acquired at 40 kVp. 3 18 mA and 166 rns for the low-energy image,

and 125 kVp. 28 mA and 166 ms with 1.7 mm of additional copper filtration for the high-

rnergy image. Image acquisition was performed sequentially: i.e. three image h e s over

n 3 second penod were acquired at the low energy. after which the copper filter was

introduced. Then three image hunes over a 3 second period were acquired at the hi&

energy.

Included in each image was a crossed-step wedge calibration phantom (Figure 3- 1 )

composed of material that is radiographically equivalent to soft-tissue iLuciteTM) and

compact bone (SB3. Gamex MI. Middleton. WI). These step wedges were

superimposed in an orthogonal manner to obtain 25 different materiai combinations for

the calibntion of the system. h in-depth description of the dual-energy calibration.

decomposition to material specific images and analysis has been provided previously

( 12).

Anaiysis was performed on an image-processing workstation (Silicon Graphics.

blountainview, CA). Using the bone-equivalent image. semi-automated segmentation of

each phalam was perfbmed to determine the area. BMC (g) and areal BMD (g*cm*2) of

each phalan.-. Analysis was done for the 2nd3th rniddle phalanges and for the 2nd-4th

proximal phalanges. Note that in this snidy the area BMC and BMD were determined

separately for each pha lm.

Figure 3- 1. 25-step cali bration phantom composed of Lucite and SB3 is scanned simul taneously with the hand as part of the crossed-wedge cali brated DEXA system.

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

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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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9. Cosrnan F. Herrington B. Himrnelstein S, Lindsay R. Radiographic absorptiometry: a simple method for determination of bone mass. Osteoporos Int 199 1 : 234-38.

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1 1. Braillon PM. Guibal AL. Pracros-Defienne P. Serban A. Pracros JP. Chatelain P. Dual energy X-ray absorptiometry of the hand and wrist--a possible technique to assess skeletal maturation: methodology and data in normal youths. Acta Paediatr 1998: 87:924- 929.

12. Gulam M. Thomton M, Hodsman AB. Holdsworth DW. Bone mineral measurement of the phalanges: cornparison of radiographie absorptiometry and area dual energy x-ray absorptiometry . Radiology (in press).

13. Kleerekoper M. Nelson DA. Which bone density measurernent? J Bone Miner Res 1997: 12:712-714.

1 4 Fahrig R Fox AJ, Lownie S? Holdsworth DW. Use o fa C-arm system to generate tnie three-d imensional computed rotational angiograms: preliminary in vitro and in vivo results. M N R Am J Neuroradiol 1997; 18: 1507- 15 14.

15. Fahrig R, Moreau M. Holdsworth DW. Three-dimensional computed tomographic reconstruction using a C-arm mounted XRII: correction of image intensifier distortion. Ved Phys 1997: 24: 1097-1 106.

16. Huda W. Gkanatsios NA. Radiation dosimetry for extremity radiographs. Health Phys 1998: 75A92-199.

17. Lobregt S. Viergever MA. Discrete dynamic contour model. IEEE Transactions on Medical Imaging 1995: 14: 1 2-24.

18. Mueller KH. Trias A. Ray D. Bone density and composition: age-related changes in water and mineral content. J Bone Jt Surg 1966: 48: M O - 148.

19. Guglielmi G. Lang TF. Cammisa M. Genant HK. Quantitative computed tomography at the axial skeleton. In: Genant HK. Gug1ieirn.i G Jergas M. ed. Bone densitometry and osteoporosis. Berlin Heidelberg. Springer-Verlag, 1998: 335-347.

10. Huda W. Morin FU. Patient doses in bone minerai densitometry. Br J Radio1 1996: 69:422425.

2 1 . Grarnpp S. Genant HK. Mathur A. et al. Cornparisons of noninvasive bone minera1 measurements in assessing age- related loss. fracture discrimination. and diagnostic classification. J Bone Miner Res 1997: 12697-71 1.

23. Schneider P. Reiners C. Peripheral quantitative computed tomography. In: Genant HK. Guglielmi G lergas M. ed. Bone densitometry in osteoporosis. Berlin Heidelberg, Springer-Verlag. 1998: M+-363.

23. Gluer CC. Jergas M, Hans D. Penpheral measurement techniques for the assessrnent of osteoporosis. Semin Nucl Med 1997: 27229-247.

24. Michaeli DA, Mirshahi A, Singer J, Rapa FG, Plass DB, Bouxsein ML. A new x-ray based osteoporosis screening tool provides accurate and precise assessrnent of phalanx bone mineral content. Journal of Clinical Densitometry 1 999; 2:23-30.

25. Bolotin HH. A new perspective on the causal influence of soft tissue composition on DXA-measured in vivo bone mineral density. J Bone Miner Res 1998; 13: 1739- 1746.

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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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