U.S. patent application number 12/609445 was filed with the patent office on 2010-05-06 for rapid and accurate detection of bone quality using ultrasound critical angle reflectometry.
This patent application is currently assigned to BOARD OF REGENTS, THE UNIVERSITY OF TEXAS SYSTEM. Invention is credited to Pietro Antich, Matthew A. Lewis, Charles Y.C. Pak, Edmond Richer, Billy Smith.
Application Number | 20100113932 12/609445 |
Document ID | / |
Family ID | 34068304 |
Filed Date | 2010-05-06 |
United States Patent
Application |
20100113932 |
Kind Code |
A1 |
Antich; Pietro ; et
al. |
May 6, 2010 |
Rapid and Accurate Detection of Bone Quality Using Ultrasound
Critical Angle Reflectometry
Abstract
The present invention is an apparatus, method and system for
determining the coefficient of elasticity of a target by detecting
an ultracritical reflection of ultrasound waves directed at the
target using an ultrasound transducer at two or more angles
simultaneously and calculating the elasticity coefficient of the
target.
Inventors: |
Antich; Pietro; (Richardson,
TX) ; Pak; Charles Y.C.; (Dallas, TX) ; Smith;
Billy; (Duncanville, TX) ; Richer; Edmond;
(Dallas, TX) ; Lewis; Matthew A.; (Farmers Branch,
TX) |
Correspondence
Address: |
CHALKER FLORES, LLP
2711 LBJ FRWY, Suite 1036
DALLAS
TX
75234
US
|
Assignee: |
BOARD OF REGENTS, THE UNIVERSITY OF
TEXAS SYSTEM
Austin
TX
|
Family ID: |
34068304 |
Appl. No.: |
12/609445 |
Filed: |
October 30, 2009 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
|
10630330 |
Jul 30, 2003 |
7611465 |
|
|
12609445 |
|
|
|
|
60487334 |
Jul 15, 2003 |
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Current U.S.
Class: |
600/449 |
Current CPC
Class: |
A61B 5/0048 20130101;
A61B 8/485 20130101; A61B 8/0875 20130101 |
Class at
Publication: |
600/449 |
International
Class: |
A61B 8/00 20060101
A61B008/00 |
Claims
1. A method for determining an elasticity coefficient of a target,
comprising the steps of: determining simultaneously two or more
critical-angle reflections of an ultrasound wave from the target
using an ultrasound transducer comprising a transmitter and two or
more receivers; and calculating the elasticity coefficients of the
target.
2. The method of claim 1, wherein the target comprises bone.
3. The method of claim 1, wherein the target comprises human
bone.
4. The method of claim 1, wherein the target comprises a human bone
from a human being suffering from or suspected of having
osteoporosis.
5. The method of claim 1, wherein the target comprises bone from a
human being suffering from or suspected of having osteoporosis
under treatment with bisphosphonate.
6. The method of claim 1, wherein the detection step is
non-invasive.
7. The method of claim 1, wherein one or more elasticity
coefficients are determined from the square of ultrasound velocity
as determined from the identified critical angle.
8. The method of claim 1, further comprising the steps of:
determining a maximum elasticity coefficient and a minimum
elasticity coefficient to estimate a degree of target anisotropy;
and using the critical-angle reflection values detected at multiple
rotational orientations from the ultrasound transducer fixed at a
position normal to a bone surface.
9. The method of claim 2, further comprising the step of
determining a maximum elasticity coefficient and a minimum
elasticity coefficient to estimate a degree of bone anisotropy.
10. The method of claim 1, further comprising the step of
automating the determination of the normal of the transducer to the
target.
11. The method of claim 1, wherein the step of detecting
simultaneously is further defined as comprising the simultaneous
reception from 2, 4, 8, 16, 24, 36, 48, 64 or 128 receivers.
12. The method of claim 1, further comprising the step of storing
the critical-angle values detected in the reflection of an
ultrasound wave at two or more receivers that are concentric with a
transmitter.
13. The method of claim 1, further comprising the steps of: storing
the detected critical-angle reflections of ultrasound waves at
different points in time; and comparing the measurements to track
changes in the coefficient of elasticity of the target.
14. The method of claim 1, wherein the step of detecting at two or
more angles uses a transducer head comprising at least one
transmitter and two or more receivers that detect simultaneously
the reflected ultrasound energy from the target, wherein the
transmitter and the two or more transducers have a common focal
point.
15. The method of claim 1, wherein the transmitter is concave.
16. The method of claim 1, wherein the two or more receivers for
part of a concave array in at least two dimensions.
17. The method of claim 1, wherein the transmitter and the two or
more receivers are concave and concentric.
18. The method of claim 1, wherein the transmitter is concave and
the two or more receivers are concave and the transmitter and the
two or more receivers are concentric about a common focal
point.
19. The method of claim 1, wherein the receivers are further
defined as a receiving array and the array comprises 48 independent
receiving transducers that are concentric and concave and share a
focal point with the transmitter.
20. The method of claim 4, wherein the human has bone disease, a
bone-losing condition other than osteoporosis, or a condition
suspected of causing inferior bone strength.
21. The method of claim 5, wherein the treatment of osteoporosis
comprises drugs other than bisphosphonate, e.g., an estrogen, an
estrogen analog, a parathyroid hormone peptide, a fluoride, a
vitamin D, and a calcitonin.
22. The method of claim 5, wherein the treatment is suspected of
causing bone loss.
23. The method of claim 5, wherein the treatment is suspected of
causing bone loss caused by a steroid or anticonvulsant.
24. The method of claim 5, wherein the step of detecting
simultaneously two or more critical-angle reflections of an
ultrasound wave from the target is taken prior to initiation of
bisphosphonate treatment, in order to identify patients with
inferior bone quality in whom bisphosphonate should be used with
caution.
25. A method for determining the effect on a coefficient of
elasticity of bone from a patient undergoing treatment for
osteoporosis, comprising the steps of: detecting simultaneously at
two or more angles the critical-angle reflections of ultrasound
waves directed at a bone using an ultrasound transducer with one or
more transmitters and two or more receivers; and calculating the
anisotropy of the bone from the ratio of a maximum elasticity
coefficient and a minimum elasticity coefficient, wherein
elasticity coefficients are derived as the square of the velocities
of an ultrasound waves as determined from the critical angle.
26. The method of claim 25, further comprising the steps of:
storing a first detected critical-angle reflection of ultrasound
waves at two or more receivers prior to, or concurrent with,
treatment with a bisphosphonate or derivative thereof storing a
second detected critical-angle reflection of ultrasound waves at
two or more receivers after a period of time; and comparing the
first and second measurements to track changes in the elasticity
coefficient of the bone during treatment with the bisphosphonate or
derivative thereof.
27. The method of claim 25, wherein the step of detecting
simultaneously at two or more angles the critical-angle reflection
of ultrasound waves directed at a bone using an ultrasound
transducer further comprises measuring a maximum and a minimum
elasticity of a cortical and a trabecular region of the bone; and
estimating the anisotropy of the bone in vivo.
28. The method of claim 27, wherein determining the elasticity of
cortical bone, trabecular bone, and anisotropy of a patient's bone
is non-invasive.
29. The method of claim 28, wherein the measurement of elasticity
is at a heel.
30. The method of claim 28, wherein the step of calculating the
anisotropy of the bone further comprises determining the maximum
and the minimum elasticity coefficient of a cortical and a
trabecular bone region, wherein the measurements correspond to an
axis of a weight-bearing and a non-weight-bearing bone,
respectively.
31. The method of claim 25, wherein the patient has bone disease, a
bone-losing condition other than osteoporosis, or a condition
suspected of causing inferior bone strength.
32. The method of claim 26, wherein the treatment of osteoporosis
comprises an estrogen, an estrogen analog, a parathyroid hormone
peptide, a fluoride, a vitamin D, and a calcitonin.
33. The method of claim 26, wherein the treatment is suspected of
causing bone loss caused by steroid or anticonvulsant.
34. The method of claim 26, wherein the step of detecting
simultaneously two or more critical-angle reflections of an
ultrasound wave from the target is prior to initiation of
bisphosphonate treatment, in order to identify patients with
inferior bone quality in whom bisphosphonate should be used with
caution.
35.-84. (canceled)
85. A method for simultaneously measuring maximum and minimum
elasticity coefficients and anisotropy of bone non-invasively in
vivo in accordance with the method of claim 1.
86. A method for taking simultaneous measurements of maximum and
minimum elasticity coefficients and anisotropy of cortical and
trabecular bone non-invasively in vivo in accordance with the
method of claim 25.
87-89. (canceled)
Description
CROSS-REFERENCE TO RELATED APPLICATION
[0001] This application claims priority to provisional patent
application Ser. No. 60/487,334, filed Jul. 15, 2003, and
co-pending U.S. patent application Ser. No. 10/630,330 filed Jul.
30, 2003, to issue as U.S. Pat. No. 7,611,465 on Nov. 3, 2009.
TECHNICAL FIELD OF THE INVENTION
[0002] The present invention relates in general to the field of
bone quality determination, and more particularly, to the rapid and
accurate measurement of elasticity coefficients, in vivo of
cortical and trabecular bone.
BACKGROUND OF THE INVENTION
[0003] Without limiting the scope of the invention, its background
is described in connection with bone density measurements, as an
example.
[0004] Need for Non-Invasive Measurement of Bone Quality.
Osteoporosis is a major medical problem, with a large percentage of
elderly persons being susceptible to sustain non-traumatic
fractures (bone fractures from minimum trauma). Bone strength is a
primary predictor of bone fractures. Bone strength is determined by
both bone density and bone quality.
[0005] Currently, bone density can be measured by several methods,
including: dual energy x-ray absorptiometry, computer-assisted
tomography and transmission ultrasound. From epidemiological
studies, bone density is inversely correlated with the rate of
skeletal fractures. Thus, bone density has been used to define
osteoporosis, with a value below 75% of normal peak value referred
to as osteoporosis even in the absence of fractures. Recent
discoveries, however, have presented situations in which severe
impairment of bone quality can occur. Introduced in 1996, a new
class of drugs called "bisphosphonate" has been widely used for the
treatment of osteoporosis (Liberman et al., N. Engl. J. Med.
333:1437-1443, 1995). With long-term use, new studies suggest that
these drugs can severely impair bone quality, leading to recurrent
fractures that do not heal properly (Ott, J. Clin. Endo. Metab.
86:1835, 2001; Odvina, et al., J. Bone Miner. Res., September,
2003; Richer et al., J. Bone Miner. Res., September, 2003; Li et
al., Calc. Tissue Intern. 69:281-286, 2001). Moreover, with
improvement in surgical techniques and in medical treatments to
prevent rejection, more patients are living longer after kidney
(renal) transplantation. These patients are known to have increased
susceptibility to fractures, since they probably have defective
bone from taking steroids and suffer from other factors that are
harmful to bone. These clinical conditions presented situations
wherein a much more prominent reduction in ultrasound elasticity
might be expected by the UCR device, than previously disclosed in
untreated postmenopausal osteoporosis.
[0006] Another recent development that emphasizes the need for an
improved UCR device is the recognition that bone quality, aside
from bone density, is a critical determinant of fractures in
osteoporosis. In 1994, the World Health Organization defined
osteoporosis based on bone density alone. In 2000, the NIH
Consensus Conference on Osteoporosis defined osteoporosis as "a
skeletal disorder characterized by compromised bone strength
predisposing to an increased risk of fracture".
[0007] What is needed is a device that can measure reliably,
quickly and non-invasively the quality of bone in vivo. The device
should permit for the rapid, accurate, consistent detection of
critical bone density, elasticity and strength data. A need also
exists for the development of a system that may be automated and
which has a design, engineering and software for data acquisition
that is user-friendly. Also needed are a new system, method and
apparatus that minimizes the need for water or other media-baths
that are needed with current technology. Finally, a need has arisen
for a reliable, inexpensive method for monitoring the status of a
patient's bone density information during treatment of, e.g.,
osteoporosis.
SUMMARY OF THE INVENTION
[0008] The apparatus, method and system of the present invention
use ultrasound critical angle reflectometry to improve patient
care. The present invention is used to make the measurement of
critical bone density information practical and faster than in
previous devices, and expands the method to take explicitly into
account the anisotropy of bone, assumed to be hexagonally
symmetric. The device is designed to make measurements at multiple
sites of bone. An integral part of the device is a robotic gantry
of specific design, constructed to permit the rapid determination
of the "normal" to bone and to automate the measurement of spectra
at different orientations. The normal to bone must be determined
with considerable accuracy, as it represents the initial angle
(degrees) in the angular system, and thus dominates the accuracy of
the measurement. Using this gantry, once the normal has been
determined, the head can be rotated using the normal as the axis of
rotation to obtain the spectra at different orientations. This
activity is now rapid and automated. When made for a specific site,
the size of the device can be made smaller, while encompassing the
same basic features.
[0009] In one embodiment, the present invention is a transducer
that includes at least one ultrasound transmitter and two or more
receivers separated by an angle that form a receiver array that is
concentric and shares a focal point with the transmitter and,
wherein the receiver array detects simultaneously the reflected
ultrasound energy from a target. The transducer may include a
transmitter that is concave in at least two dimensions and/or two
or more receivers that form a concave array in at least two
dimensions; and/or a transmitter and two or more receivers that are
concave and concentric, e.g., about a common focal point. The
transducer may have an odd or even number of receiver elements or
receivers greater than one, e.g., 2, 4, 8, 16, 24, 36, 48, 64, 128
or more independent receivers. In one embodiment, the two or more
receivers form a receiving array system that includes at least one
transmitter and a 48-element receiver array located in a housing,
wherein the receiver array measures simultaneous the velocity of an
ultrasound wave across 120 degrees from a point of examination that
is at or about the focal point of the transmitter. The housing for
the transmitter and the at least two receivers, the housing having
at least one opening at or about the focal point of the transmitter
and receivers.
[0010] In one particular embodiment, the transducer includes a
housing for the transmitter and the at least two receivers, the
housing having at least one opening, a latex membrane at or about
the opening of the housing and an ultrasound conductive material
within the housing. In one example, the ultrasound conductive
material may include water, saline and the like. The transducer may
be part of a ultrasound system that further includes a
computer-controlled positioning arm connected to the transducer,
wherein the movement of the transducer permits accurate positioning
of device on a point of examination. The transducer may also
include a pressure detector in communication with the ultrasound
conductive material that detects when pressure within the housing
increases that may break the latex membrane. The at least one
computer may be connected to transmitter and receivers of the
transducer, the computer including at least one code segment that
gathers one or more reflected spectra from each receiver at each
angle, and calculates from the spectra the critical angles for a
cortical and a trabecular bone. From the data acquired, the
computer may also include at least one code segment that determines
critical angle velocities, and fits them to a linear-quadratic
equation for the determination of at least two principal
coefficients of elasticity.
[0011] Yet another embodiment of the present invention is a
transducer that includes at least one ultrasound transmitter and a
receiver array that is concentric and shares a focal point with the
transmitter, wherein the receiver array detects simultaneously the
reflected ultrasound energy from a target at multiple angles. The
transducer detects pressure waves that may be used to determine
reflected spectra from a bone that is undergoing bone treatment
therapy, e.g., for osteoporosis, that determined critical cortical
and a trabecular bone data, which may be used to calculate bone
anisotropy. The critical angle velocities may be used to
determination at least two principal coefficients of elasticity,
which correlate with bone density and strength data that may be
used to track improvements or degeneration of bone during treatment
with, e.g., bisphosphonate treatment versus other forms of bone
therapy.
[0012] The present invention also includes a method for determining
the coefficient of elasticity of a target, comprising the steps of,
detecting simultaneously two or more ultracritical reflections of
an ultrasound wave from the target using an ultrasound transducer
comprising a transmitter and two or more receivers separated by an
angle and calculating the elasticity coefficient of the target. The
target may be bone, e.g., a human bone, that may be suspected of
having osteoporosis. The method may further include the
determination of disease progression of a human bone suspected of
having osteoporosis that is treated with bisphosphonate, its salts
or mixtures thereof. The present invention includes the use of a
transducer that is non-invasive and that does not require the use
of water baths to obtain UCR data. The present invention may be
used to determine the elasticity coefficient by comparing the
square of the velocity of an ultrasound wave with the intrinsic
orientation of bone at a fixed position using values detected at
multiple orientations from the ultrasound transducer. Using the
maximum elasticity coefficient and a minimum elasticity coefficient
the degree of target anisotropy (e.g., bone anisotropy) may be
estimated in a rapid and automated manner. To achieve more reliable
results, the apparatus, method and system disclosed herein also
includes the use of an automated arm to rapidly and consistently
determine the normal of the transducer to the target. Data
processing and calculations are also may more efficient by the
concurrent or simultaneous detection from, e.g., 2, 4, 8, 16, 24,
36, 48, 64 or 128 receivers.
[0013] Ultracritical reflection value of a ultrasound wave at two
or more receivers that are concentric with a transmitter may also
be detected and stored, displayed and/or printed for further
analysis. As such, the present method may also include storing the
detected ultracritical reflection of ultrasound waves at different
points in time and comparing the measurements to track changes in
the coefficient of elasticity of the target over time.
[0014] The present invention may also be used to determine the
effect on a coefficient of elasticity of a bone undergoing therapy
for osteoporosis, comprising the steps of detecting simultaneously
at two or more angles the ultracritical reflection of ultrasound
waves directed at a bone using an ultrasound transducer with one or
more transmitters and two or multiple receivers and calculating the
anisotropy of the bone by calculating an elasticity coefficient for
the bone by comparing the square of the velocity of an ultrasound
wave with the intrinsic orientation of bone at a fixed position
using values detected at each of the two or more receivers. The
apparatus, method and system disclosed herein may also include the
steps of storing a first detected ultracritical reflection of
ultrasound waves at two or more receivers prior to, or concurrent
with, treatment with a bisphosphonate or derivative thereof,
storing a second detected ultracritical reflection of ultrasound
waves at two or more receivers after a period of time and comparing
the first and second measurements to track changes in the
coefficient of elasticity of the bone during treatment with the
bisphosphonate or derivative thereof. The detection and calculation
of the maximum and a minimum elasticity of a cortical and a
trabecular region of the bone may be used to estimate the
anisotropy of the bone in vivo, before and during the treatment of
a patient with bisphosphonate, and for those patients that do not
respond positively to treatment, or that respond negatively to
treatment, to identify those patients and change the treatment
prior to further damage. The present invention allows the
determination of the elasticity of cortical bone, trabecular bone,
and anisotropy of a patient's bone in a manner that is
non-invasive, e.g., at a patient's heel. Using the data acquired,
stored and/or processed, the user may calculate the anisotropy of
the bone (determining a maximum and a minimum elasticity of a
cortical and a trabecular bone region), wherein the measurements
correspond to an axis of a weight-bearing and a non-weight-bearing
bone, respectively.
[0015] The present invention also includes a system for measuring
bone anisotropy that includes a computer-controlled ultrasound
ultracritical reflectometry transducer that detects ultrasound
velocities at multiple angles simultaneously and automatically, an
articulated arm that permits motion in three-dimensions that
supports the ultrasound transducer and a computer connected to and
capable of receiving a signal from the ultrasound transducer to
calculate ultracritical reflectometry data from the ultrasound
transducer. The computer is connected to one or more controllers of
the articulated arm that direct the position of the transducer in
three dimensions. The transducer may be used to measure the
elasticity coefficient of a human bone suspected of having
osteoporosis, e.g, the elasticity coefficient of a human bone
suspected of having osteoporosis treated with bisphosphonate. The
computer can determine an elasticity coefficient by comparing the
square of the velocity of an ultrasound wave with the intrinsic
orientation of bone at a fixed position using values detected at
multiple orientations using the ultrasound transducer and/or
calculate a maximum elasticity coefficient and a minimum elasticity
coefficient to estimate a degree of target anisotropy. Using the
data, the computer of the present system may also calculate a
maximum elasticity coefficient and a minimum elasticity coefficient
to estimate a degree of bone anisotropy. To automate the
determination of bone anisotropy with results that are rapid and
consistent, the computer of the present invention automates the
determination of the normal of the transducer to the target. The
computer may stores a value for an ultracritical reflection of
ultrasound waves at different points in time, and even compare and
provide the user with a user-friendly output that shows the effect
on a coefficient of elasticity of a bone undergoing therapy for
osteoporosis by storing a first and a second value for the
coefficient of elasticity of a patient at a first and a second
point in time, and calculates a bone anisotropy value by
calculating an elasticity coefficient for the bone by comparing the
square of the velocity of an ultrasound wave with the intrinsic
orientation of bone at a fixed position using the first and second
values to determine the effect of treatment on bone quality.
[0016] In yet another embodiment, the system of the present
invention determines the effect on a coefficient of elasticity of a
bone undergoing bisphosphonate therapy for osteoporosis by storing
a first and a second value for the coefficient of elasticity of a
patient at a first and a second point in time, and calculates a
bone anisotropy value by calculating an elasticity coefficient for
the bone by comparing the square of the velocity of an ultrasound
wave with the intrinsic orientation of bone at a fixed position
using the first and second values to determine the effect of
bisphosphonate treatment on bone quality.
[0017] More particularly, the present invention includes a custom
designed transducer head, which permits a nearly instantaneous
measurement over a complete set of angle of reflection. The head
includes two ultrasound elements encased within a water-tight
enclosure with an elastic pliant interface (placed over the bone
tissue under examination). In one embodiment, the single-element
transmitter and the 48-element receiver array are separate. Both
are sections of right cylinders of different radii but with a
common axis, subtending 120 degrees. The midpoint of the axial
segment is the nominal center of the transducers. The two elements
are mounted in a fixed geometry within a water-tight solid
container, which is filled with water and terminates in a window
covered by a latex membrane, in a configuration such that the
common center of the transducers projects 1.5 cm beyond the window.
In operation, the liquid is under a slight pressure controlled by
gravity (by using a reservoir of water placed at a slight higher
elevation than the transducer head on the support base) and the
latex membrane bulges at least 0.5 cm beyond the rim of the window.
When the bulge is in contact with the patient's skin (overlying
bone being examined), the transducer center is a virtual point
projected under the skin at depth.
[0018] The positioning arm is a pantograph that includes two
segments shaped as parallelograms, one attached to the base and one
supporting the transducer head. The arm can be moved vertically and
horizontally (three degrees of freedom) by means of motors mounted
on the base. The arm is articulated so that the transducer head
pivots around a fixed point, coincident with the center of the
transducers. This geometric property makes it possible to determine
the normal by changing the tilt angles .phi. and .theta. at two
mutually orthogonal values of rotation angle .psi.. In this
fashion, the axis of the transducer head can be rotated with two
degrees of freedom to coincide with the normal to bone at the fixed
point and the transducer head can be rotated by an angle .psi.
around that axis to assume any orientation along the bone
surface.
[0019] During an examination, the operator places the transducer
head over the site of interest (bone tissue being examined), and
the transducer head is advanced by the operator using precise,
sub-millimeter steps of the arm using computer controls until the
transducer center is at the surface of the bone under study. This
advance, for the heel, is restricted to 0.5-1.0 cm, and the
patient's skin remains in contact with the flexible membrane and
does not come in contact with the rim or any other element of the
solid surface. Excessive pressure (which may occur, for example,
from a sudden movement of the foot that is being measured) causes
the advance to stop and the head to retract. A single (imploding
cylindrical) wave is emitted by the transmitter, and each receiving
element detects the reflected amplitude over a set of angles of
reflection, operationally determined as successive elements of the
receiving array. A critical angle .beta..sub.c, corresponds to a
maximum in this distribution. The velocity V is then given by
V=V.sub.c/Sin .beta..sub.c where V.sub.c is the velocity of sound
in the calibration medium (water). For each orientation .psi., a
different value of V is obtained, V(.psi.). As bone has an
intrinsic hexagonal symmetry, the distribution is determined a
priori to be V(.psi.)=ACos.sup.4.psi.+BCos.sup.2.psi.+C. In classic
textbook notations, these are expressed in terms of the elements of
the stiffness matrix {C} as A=C.sub.11+C.sub.33-k, B=k-2C.sub.11,
C=C.sub.11 and k=2(C.sub.13+2C.sub.44). The present invention
permits the determination of two principal coefficients:
E*.sub.min=C (=C.sub.11) and E*.sub.max=A+B+C (=C.sub.33). These
coefficients are intrinsic properties of bone reflective of its
mechanical properties.
[0020] Thus, key innovations of this UCR transducer and system are:
(a) "dual array" system of single transmitter and multiple receiver
elements, e.g., 48-receiver elements, which allow simultaneous
measurement of critical angle velocities across the whole spectrum
of angles of scattering; (b) a robotic arm engineered to
accommodate naturally the movements that permit accurate
positioning and alignment along the normal to bone of the
transducer head over the site of bone tissues being examined; (c)
the use of latex membrane containing water in the transducer head
avoiding immersion of bone tissue in a water bath; (d) special
engineering features that prevent excessive pressure to build on
the membrane or the patient; (e) data acquisition software to
obtain the reflected spectra from measurements of the reflected
wave train at each angle and to extract from the spectra the
critical angles for cortical and trabecular bone; and (f) special
post-processing software to determine the critical angle velocity V
at each angle .psi., and then fit the data onto a linear-quadratic
formula relating V.sup.2 on the Cos.sup.2 of the angle .psi., in
order to determine two principal coefficients of elasticity.
[0021] For example, the apparatus, method and system of the present
invention permits for a simple, fast determination of the vector
"normal" to the transducer for a more accurate and repeatable
measurement. The invention permits the simultaneous and automated
detection for the velocity of the sound signal with less dependence
on the orientation of the transducer. Furthermore, the system
allows for a rapid, automated and fast determination of elasticity
coefficients and hence permits, for the first time, a calculation
of anisotropy. Using the transducer, methods and system disclosed
herein, a more complex and hence more accurate determination and
measurement with full automation may be taken at, e.g., 3 points in
6 orientations with a reduction in the time for measurement time of
one-third or less than currently possible. The method is
non-invasive and does not require immersion of the patient or a
patient's body part in an immersion bath containing an ultrasound
carrier media. Furthermore, the present invention may be used to
determine and track the effect of patient therapy using, e.g., a
bisphosphonate, salt or derivatives thereof. Other patients, e.g.,
renal transplant and patients undergoing sodium fluoride treatments
will also benefit from the present invention.
[0022] The present inventors have recognized that bone density
alone is not predictive of the risk of fractures. Some patients
with normal bone density develop non-traumatic fractures, and some
with low bone density do not sustain fractures. One explanation for
this finding is that bone quality may be "out of line" from bone
density. Thus, some subjects with low bone density may be less
susceptible to fracture, if bone quality is superior. On the other
hand, some with high bone density may be susceptible to fractures
if bone quality is poor.
[0023] Measurement of bone quality is important, because there are
some conditions or treatments that are associated with, or may
cause, deterioration of bone quality. Examples where bone quality
is presumed to be impaired are: Paget's disease of bone (with
excessive formation of abnormal bone with fibrosis), osteomalacia
or rickets (with poorly mineralized bone), immobilization and
fluorosis (toxic fluoride exposure with abnormal mosaic bone).
Unfortunately, there is no commercial device that can measure bone
quality non-invasively (safely). The available ultrasound method is
based on transmission of ultrasound across bone tissue and thus
only yields a measure largely of bone density.
[0024] Clinical applications of the present invention permit the
determination of critical bone density, elasticity and strength
data. A device capable of measuring elasticity coefficients at
different sites of bone has been constructed by the new UCR method,
tested in the calcaneus (heel), and its important clinical
applications have been identified. With this new UCR device,
multiple measurements can be made rapidly and reliably, yielding
elasticity coefficients of cortical and trabecular bone
non-invasively in vivo (in living persons). The transducer
disclosed herein can determine peak and minimum elasticity
coefficients, where the peak elasticity coefficient is an intrinsic
property of bone that is critical in weight bearing, and minimum
elasticity coefficient is one that is less critical in weight
bearing. From the ratio of maximum and minimum elasticity
coefficients, anisotropy (asymmetry) of bone can be estimated. This
device has shown to be clinically useful in detecting inferior bone
quality during treatment with bisphosphonate (a widely used drug
for osteoporosis) and in renal transplantation (on steroid
treatment). As will be described below, the reductions in bone
quality shown in these conditions was much greater than disclosed
previously in postmenopausal osteoporosis.
BRIEF DESCRIPTION OF THE DRAWINGS
[0025] For a more complete understanding of the features and
advantages of the present invention, reference is now made to the
detailed description of the invention along with the accompanying
figures in which corresponding numerals in the different figures
refer to corresponding parts and in which:
[0026] FIGS. 1 and 2 are diagrammatic renderings that show the
general principles of UCR using two alternative embodiments of the
device and system of the present invention;
[0027] FIG. 3 is a diagrammatic rendering of another embodiment of
the present invention that shows a cross-section of the transducer
head placed over a bone tissue ready for UCR measurement in close
contact with a soft tissue overlying a bone by a latex membrane
filled with water;
[0028] FIG. 4 shows an isometric view of the transducer head, the
main body being on the left hand side and the cover on the right.
Water fills the volume between transducers and window. A single
coaxial cable transports the low current (xA), low voltage (xV) 1.5
MHz signals from the generator to transmitter element and a set of
coaxial cables transports the signal from the receiver to the data
acquisition system via a multi-element connector.
[0029] FIG. 5 shows the kinematics of the transducer support arm;
three motors mounted on the base and elevator support
three-dimensional translations, while three motors mounted on the
arm support two tilt rotations (.theta. and .phi., necessary to
identify and select the "normal" to bone) and the rotation of the
head around the normal (.psi.);
[0030] FIG. 6 shows the analog-to-digital acquisition board
designed to connect with and receive data from the transducer of
the present invention;
[0031] FIG. 7 is a basic flowchart that summarizes the basic data
acquisition model of the present invention;
[0032] FIG. 8 is a basic flowchart that shows the use of the
present invention in patient evaluation and treatment;
[0033] FIGS. 9A and 9B are photographs of polarized light
microscopy that shows the absence of tetracycline labeling in a
patient on long-term bisphosphonate treatment (9A), and normal
labeling in a normal subject (9B); and
[0034] FIG. 10 is a graph that shows independence of bone
elasticity from bone density during bisphosphonate treatment and in
renal transplantation.
DETAILED DESCRIPTION OF THE INVENTION
[0035] While the making and using of various embodiments of the
present invention are discussed in detail below, it should be
appreciated that the present invention provides many applicable
inventive concepts which can be embodied in a wide variety of
specific contexts. The specific embodiments discussed herein are
merely illustrative of specific ways to make and use the invention
and do not delimit the scope of the invention.
[0036] Ultrasound Critical Angle Reflectometry (UCR). In the early
1990s, the present inventors introduced a novel method, called
ultrasound critical angle reflectometry or UCR, for measuring bone
quality based on the "reflection" of ultrasound across small parts
of bone surfaces of about 0.2 mm (Antich, et al., J. Bone Min. Res.
6:417-426, 1991). Bone quality may be derived or inferred from
ultrasound velocity. The original UCR device determined velocity in
cortical bone ("hard bone" on outer parts of bone tissue) as well
as in trabecular bone ("spongy bone" in the inner core of bone
tissue).
[0037] The present invention describes an improvement of methods
for ultrasound critical angle reflectometry (UCR), which allows a
rapid and reliable measurement of elasticity coefficients (quality)
of cortical (hard) and trabecular (spongy) bone non-invasively in
vivo in human beings. The refinement permits simultaneous detection
of reflected ultrasound amplitudes at multiple angles, e.g., on an
array that includes 48 receivers separated by 47 angles, and the
measurement of ultrasound velocity at critical angle over a range
of orientations using a special "array system" and novel
engineering and software designs. The software implements from
these data the calculation of the principal elasticity coefficients
from the square of velocity. Both the maximum elasticity
coefficient C.sub.33 (approximately along the vertical axis,
critical in weight-bearing) and minimum elasticity coefficient
C.sub.11 (approximately along the horizontal axis, less critical in
weight-bearing) are separately calculated in cortical and
trabecular bone. This measurement is more precise than that
obtained at a fixed anatomical direction because the intrinsic
orientation of bone changes with position, causing the velocity
along a given anatomical direction to vary by more than the
measurement error, while the velocity along a given intrinsic
direction is affected only by measurement uncertainties. As
deterministic relationship exists between the square of velocity
and the intrinsic orientation, a fit to the values at multiple
orientations minimizes the measurement errors. Moreover, the
measurement is more accurate because acoustic waves that do not
propagate along a principal axis have a mixed nature (they are
quasi-pressure waves), obscuring correlations with mechanical
properties such as elasticity and strength. From the ratio of
maximum and minimum elasticity coefficients, the degree of
"anisotropy" (asymmetry) can be accurately estimated. The UCR
apparatus and method disclosed herein has been applied to detect
impaired bone quality that contributes to osteoporotic
fractures.
[0038] In patients with kidney transplantations taking steroids, a
condition known to be associated with impaired bone quality and
increased susceptibility to fractures, cortical and trabecular
elasticity coefficients were decreased by 15-30% from the normal
premenopausal state. Treatment with bisphosphonate, a widely used
drug to treat osteoporosis, can cause "adynamic bone disease"
(severe depression of bone turnover) after long-term use, resulting
in fractures of long bones that heal poorly. By the new UCR method,
the elasticity coefficients of cortical and trabecular bone were
also reduced by 15-30% during long-term bisphosphonate treatment,
indicative of impaired bone strength. Thus, this invention claims a
reliable and rapid method for measuring non-invasively in human
beings, the intrinsic (material) quality of cortical and trabecular
bone, that is useful in detecting conditions with inferior bone
strength, and in alerting to the development of defective bone
among patients taking bisphosphonate or steroid.
[0039] Three patents have been issued to the present inventors to
methods and applications of the original UCR device (U.S. Pat. No.
5,038,787, No. 5,197,475, and No. 5,228,445, relevant teachings of
UCR are incorporated herein by reference). In this approach,
ultrasound signal in bone was measured while varying the angle of
incidence and analyzing the amplitude of the ultrasound wave
reflected by bone. An apparatus that can measure ultrasound
velocity at the critical angle was described (Antich, et al., J.
Bone Miner. Res. 6:417-426, 1991; Antich, et al., J. Bone Miner.
Res. 8:301-311, 1993). Using this apparatus, ultrasound velocity in
trabecular bone was shown to be reduced by 7% in normal
postmenopausal women and by 13% in patients with untreated
postmenopausal osteoporosis, compared with normal premenopausal
women. Treatment with sustained-release sodium fluoride, that
increases bone density and inhibit fractures of the spine by
delivering therapeutic subtoxic amounts of fluoride (Pak, et al.,
Arch. Intern. Med. 123:401-408, 1995), was found to increase
ultrasound velocity of trabecular bone to the level of normal
postmenopausal women (Antich, et al., J. Bone Miner. Res.
8:301-311, 1993; Zerwekh et al., J. Bone Miner. Res. 6:239-244,
1991).
[0040] The original UCR device was mounted on a simple gantry that
allowed linear motions and rotations; its transducer head may
include two transducers moving in unison. While the design was
simple, it requires considerable manual adjustments and complex
movements in order to measure critical angle velocity at different
orientations at a given site of bone (Antich, et al., J. Bone
Miner. Res., 6:417-426, 1991). Thus, only a single measurement of
velocity could be obtained in vivo in cortical bone and trabecular
bone. The maximum and minimum velocities could not be reliably
determined, and thus an accurate estimation of anisotropy
("asymmetry" of bone material) was not possible. Moreover, the
original device was cumbersome and time-consuming to use. Lastly,
the degree of change in ultrasound velocity with disease shown by
the original UCR device was modest as previously mentioned, with
the value in postmenopausal osteoporosis being about 13% below that
of normal premenopausal state (Antich, et al., J. Bone Miner. Res.
8:301-311, 1993).
[0041] As used the term "emitting" is used to describe the
transmission of an ultrasound wave or pulse by an ultrasound wave
transmitter. As used herein the term "receiving" is used to
describe the reception by an ultrasound wave receiver of an
ultrasound pressure pulse or wave reflected by a material. Together
the transmitter and the receiver are described as forming a
"transducer" that is able to emit and receive an ultrasound wave
reflected from a target material, whether the wave hits the target
directly and/or if the wave traverses an ultrasound conductive or
transmissive material prior to striking the target, which may be a
target point or plane.
[0042] As used herein, the term "ultracritical reflection" is used
to describe the reflection an ultrasound wave emitted from an
ultrasound transmitter after striking a target, where the reflected
ultrasound wave travels back toward the ultrasound transmitter. In
order to receive or detect an ultrasound wave reflected from a
target as an ultracritical reflection, the receivers of the
ultrasound wave are at, behind or about the ultrasound transmitter,
e.g., in the direction of the ultracritical reflection, which is
generally the normal of the transmitter and the receivers.
[0043] The receiver array is connected to one or more signal
analyzers that operable to determine at least one characteristic of
the received ultrasound wave, e.g., amplitude and phase of the
received ultrasound wave. The receivers transmit data to an
analyzer, e.g., a computer that includes a code segment that
acquires, processes and/or stores data from the two or more
receivers with respect to, e.g., the amplitude of the received
ultrasound wave; parameters such as maxima, minima (collectively
referred to as "extrema"); and edges used to determine various
velocities; and/or estimates of the mechanical properties of the
target material. With respect to phase, parameters such as the
angle of incidence at which phase first appreciably deviates from
zero can also be acquired, processed and/or stored and used to
calculate and/or estimate the mechanical properties of the target
material.
[0044] Using data acquired from the receiving array the present
invention also includes a system and method for determining,
acquiring and automating the detection of the normal using, e.g., a
computer from data acquired by the receiving array. Automated
determination of the "normal" increases the accuracy of present,
past and future measurements to the target, e.g., the surface of
the bone that is undergoing bone therapy, which permits the use of
a rational set of measurements to align the detectors and the bone
in a present and future measurements. Consistent, automated
determination of the normal is important because the normal defines
the zero angle as well as the emitting plane (or plane of
scattering), which must contain the normal and the incident wave
(I). When the plane and zero are chosen incorrectly, the
measurements obtained would be of little value as the angles are
not well measured. The method and system of the present invention
increase both the accuracy and speed of the determination of the
normal, and hence the rapid, precise and repeatable measurement and
calculation of critical target data, e.g., a patient's critical
bone density, with a great reduction in patient waiting time. By
reducing patient processing time, more patients may be served and
cost per determination is reduced. Furthermore, by acquiring and
processing data more accurately, a reduced number of visits is
required to improve patient data, patient compliance and improve
patient treatment.
[0045] General Description and Mode of Operation of the New UCR
Device. The transducer disclosed herein was designed to implement
the methodology of ultrasound critical angle reflectometry (Antich,
et al., J. Bone Min. Res. 6:417-426, 1991; Antich, et al., J. Bone
Min. Res. 8:301-311, 1993) by making the measurement practical and
faster than in previous devices and expands the method to take
explicitly into account the anisotropy of bone, assumed to be
hexagonally symmetric. The apparatus disclosed herein is designed
to make measurements at multiple sites of bone. When made for a
specific site, the size of the device should be much smaller,
though encompassing the same basic features.
[0046] FIGS. 1 and 2 illustrate the general critical angle of
reflection apparatus and method of the present invention. FIG. 1
illustrates an ultrasound transducer 10 functioning as a
transmitter 12 and a receiver array 14 that includes two or more
receivers (16a, 16b). An ultrasound wave (I) having an angle
.theta..sub.1 strikes a solid target 22 (e.g., a bone tissue). For
convenience, the plane defined by the direction of propagation of
the transmitted wave is defined from the Normal (N) to the surface
of the target 24, which includes a focal point 32 for the
transmitter 12 and the receiving array 14. The reflected (R)
ultrasound waves arrive at the receivers 16a, 16b with a
pre-defined targeting angle .theta..sub.2, which are separated be
pre-defined angle .theta..sub.3.
[0047] FIG. 2 shows another embodiment of the present invention in
which the transmitted wave (I) contacts the target 24 after
crossing a soft layer 22 (e.g., a soft tissue like skin) and which
shows an alternative receiver array 14 that includes an odd number
of receivers 16a through 16i after striking the focal point 32 that
is about the focal point 32 of the transmitter 12 and the receiving
array 14. The receiving array 14 detects simultaneously the
reflections R from the target 24 after the pressure waves cross the
soft layer 22.
[0048] FIG. 3 is a diagrammatic rendering of another embodiment of
the present invention that shows a cross-section of the transducer
head 10 ready for UCR measurement in close contact with a target
24. The central elements of the transducer head 10 are a
transmitter 12 and a receiver array 14 (together ultrasound
elements 12, 14) that includes two or more receivers 16a, 16b in
the receiver array 14. The transducer 12 includes two ultrasound
elements (12, 14) encased in a housing 18 or container with patient
interface 20 depicted here in contact with a soft tissue 22 (e.g.,
skin) at or about a bone tissue 24 under examination), as shown in
FIGS. 2-4. In one example, a single-element transmitter 12 and the
48-element receiver array 14 are separate. Both are sections of a
right cylinder with a common axis, subtending 120 degrees. The
midpoint of the axial segment is the nominal center of the
transducer elements 12, 14. The two ultrasound elements 12, 14 may
be mounted with a fixed geometry within, e.g., a water-tight solid
housing 18, which is filled with an ultrasound conductive material
26 (e.g., water) and terminates in a window 28 covered by, e.g., a
latex membrane 30, in a configuration such that the common center
or focal point 32 of the ultrasound elements 12, 14 projects, e.g.,
about 1.5 cm beyond the window 28.
[0049] In operation, the ultrasound conductive material 26 is under
a slight pressure controlled by gravity (e.g., by a reservoir of
water placed at a slight higher elevation than the transducer head
10 on a support base (not depicted in FIG. 3)) and the latex
membrane 30 bulges to, e.g., 0.5 cm beyond the rim of the window
28. When the latex membrane 30 bulge is in contact with the
patient's soft tissue 22 (overlying bone 24 being examined), the
transducer common center 32 is a virtual point projected under the
soft tissue 22 at depth.
[0050] A positioning arm 50 for the transducer head 10 is shown in
FIG. 5, which is a pantograph that includes two segments shaped as
parallelograms, one attached to the base 52 and one supporting the
transducer head 10. The arm 54 can be moved vertically and
horizontally (three degrees of freedom) by, e.g., motors mounted on
the base 52. The arm 54 is articulated so that the transducer head
10 pivots around a fixed point, coincident with the center of the
ultrasound elements. In this fashion, the axis of the transducer
head 10 can be rotated with two degrees of freedom to assume any
orientation around the fixed point.
[0051] During an examination, the operator places the transducer
head 10 over the site of interest (bone tissue being examined), and
the transducer head 10 is advanced by the operator using precise,
submillimeter steps of the arm 54 using computer controls until the
transducer center is at the surface of the bone under study. This
advance, for the heel, is restricted to 0.5-1 cm and the patient's
skin remains in contact with the flexible membrane, and does not
come in contact with the rim or any other element of the solid
surface. Excessive pressure, which occurs, for example, from a
sudden movement of the foot that is being measured, causes the
advance to stop and the head to retract.
[0052] Transducer Head. The ultrasound transducer head includes two
elements built on, e.g., PVDF (poly-vinyl-di-fluorene) substrates.
The element used as transmitter is single and spans a large
interval of degrees from the center, terminating in a latex-covered
window. A single coaxial cable transports the low current (xA), low
voltage (xV) 1.5-MHz signals from the generator to the transmitter
and a set of coaxial cables transports the signal from the receiver
to the data acquisition system. A diagram of the head is shown in
FIG. 3 and an expanded close-up of the view is shown in FIG. 4,
which further includes the leads or connections that transfer a
signal acquired by the individual receivers to, e.g., a
computer.
[0053] While ultrasound has traditionally used ceramics and
crystals such as PZT (lead zirconate titanate) and quartz to
translate acoustical energy to electrical and visa versa, PVDF is
ideally suited in its properties for use in medical ultrasound as
it is matched to tissue and pliable. In addition, it is generally
cheaper and easier to integrate than traditional ceramics and
crystals. The present invention is not limited to the actual
materials described herein, as those skilled in the art will know
how to match materials to specific target to maximize, e.g, data
accuracy, signal strength and/or optimize the signal-to-noise
ratio. Compared to PZT, PVDF has two significant advantages as a
receiving element. It has a wide frequency response (0.001 to 1
GHz), easily spanning the standard range of biomedical ultrasound.
In addition, it has a low acoustic impedance, approaching that of
water and human tissue. In contrast, PZT is in general a high Q
material that requires multiple matching layers to couple to
liquids and soft tissues.
[0054] In the UCR transducer head disclosed herein, PVDF may also
be used to as the receiving element, because of the ease of working
with it and integrating it into receiver arrays. As a film, PVDF
can be obtained in a variety of thicknesses, and therefore a
variety of sensitivities. With the use of a commercial adhesive
(micro-measurements AE-10 thin glue-line epoxy), PVDF films were
glued to support structures of non-traditional design and shape. In
addition, developed unique methods for gluing PVDF films together
were developed to create novel detector elements. Also developed
were techniques for coupling these multi-layer films to 1D and 2D
electric arrays to create novel ultrasound detectors capable of
both full waveform reception and excellent beam shape sampling. The
receiver array pattern is etched on, e.g., 0.005''-thick fiberglass
copper-clad board. The integrated PVDF receiver arrays are
integrated with specially designed, multi-channel amplifier and
digitization systems that are well-matched to the intrinsic
electrical properties of PVDF, which is well matched to human soft
tissues.
[0055] In order to improve and automate the accurate of UCR
measurements, the system of the present invention was developed. It
has been found that patient compliance and reproducible measurement
are best achieved when the ultrasound head is oriented
perpendicular to the bone surface at each measurement site. The
system of the present invention achieves the goals of patient
compliance and reproducibility by using two orthogonal rotating
(pivoting) motions around the center of the transmitter, one
longitudinal and the other transversal. These motions were found to
provide minimal requirements for normal alignment. The longitudinal
rotation is implemented using a pantograph mechanism that may
include two parallelograms, the first one linked to a base shaft
and the second to the transducer head. The mechanism is actuated
by, e.g., one or more A-max 12V-DC gear motors (Maxon Precision
Motors, Inc., Burlingame, Calif.). The actual angular position of
the arm is read using a 24,000 steps/revolution optical encoder
(model 755A--high precision, Encoder Products Co., Sagle, Id.) for
an effective angular resolution of 0.9 minutes of angle (MOA). The
range of motion is .+-.45.degree. from the vertical central
position.
[0056] The transversal rotation is performed by the base shaft and
includes both the transducer head and the pantograph mechanism. The
actuating mechanism may include a precision rotary table (model
200RT, Parker Hannifin Corporation, Daedal Division, Irwin, Pa.),
and a motor/optical encoder assembly. The angular resolution for
the transversal rotation is 0.12 MOA, and the range of motion is
180.degree..
[0057] In addition to these two pivoting motions, a third rotation
around the surface normal is required for the measurement of the
anisotropy. The motion may be implemented using the same Maxon 12V
DC motor and a 10,000 steps/revolution optical encoder (model 260
accu-coder, Encoder Products Co., Sagle, Id.), for an angular
resolution of 2.16 MOA and a range of motion off 180.degree..
[0058] Precision ball bearings (ABEC 3) may be used for all the
rotating parts in order to insure the mechanical precision of the
mechanisms. The scanning on the measured surface requires three
linear motions oriented along the axis of an orthogonal coordinates
system. Each motion is implemented using precision linear ball
bearings and shafts, actuated by Maxon 12 V DC motors and precision
ball screw and nut mechanisms. The position of each moving element
is read by 4,000 steps/rev optical encoders providing a linear
resolution of 1.25 .mu.m.
[0059] Thus, a total of six degrees of freedom (DOF), three
translations and three rotations, are implemented for the precise
positioning of the ultrasound transducer head. The motion of each
of the six DOF is controlled using a PCI-Flexmotion motion control
card (National Instruments, Austin, Tex.). This card uses PID
closed loop feedback control algorithm for each axis and allows the
implementation of complex 3D trajectories.
[0060] The control algorithm monitors the "error" (the difference
between the actual position at a certain time and the desired
position on the requested trajectory); it will stop the motion of
the device if the error becomes larger then a threshold value set
at 1 mm for the linear motions and 1.degree. for rotations. Thus,
the correct execution of the programmed trajectory of the
transducer head is permanently monitored.
[0061] In addition, a pressure sensor monitors the contact force
between the patient and the elastic membrane of the transducer
head. If the contact force becomes larger than 10 N, for example,
from a sudden movement of the patient or error in programming of
the trajectory of the transducer head, the transducer head is
retracted along the direction of the normal to the measured
surface, thus preventing potential injury to a subject being
examined. Also, the motion control card limits the torque generated
by the electrical motors such that the maximum force exerted by the
mechanism cannot be larger than 20 N.
[0062] UCR Data Acquisition System and Motor Control Electronics.
All of the electronic equipment required to operate the UCR system
is contained in one 32 inch tall, 19 inch wide, relay rack, with
wheels to make it mobile. The tabletop height allows the monitor
and computer keyboard to be mounted on top of the rack, and all
equipment is connected to a 120-volt, surge protected, rack-mount
power strip. There are five rack-mounted modules in the system,
containing the following six devices:
[0063] (1) Computer. The computer has a 1.3 GHz AMD Athlon
motherboard with four PCI slots, and one ISA slot. It has 512 MB of
PC100 memory, and a 10 GB hard drive. It contains a PCI bus,
48-bit, digital I/O card used to communicate with a delay module
(described later) and a proprietary ISA bus interface card, which
essentially buffers the address and data lines to transfer data to
and from the Data Acquisition Module. A PCI GPIB card is used to
program the transmitter, and a PCI card is installed that controls
the six DC motors and reads the encoders used to provide the motion
in the UCR system. The computer is in a seven-inch high industrial
rack-mount case. One or more computers for use with the present
invention will generally include code segments that permit data
acquisition, normal acquisition and arm positioning, data storage,
data processing and a user-interface that permits the user to start
a measurement cycle, conduct the data acquisition and capture,
interpret the data and graph and/or output the data in a format for
immediate analysis, analysis over time, integration with other data
and/or data export.
[0064] (2) Data Acquisition Module. Also mounted in a seven inch
high case (FIG. 7) data acquisition module, which as depicted is a
12-slot ISA passive back plane that has had the connector pin
numbers redefined to match signals on a set of proprietary cards
developed to digitize the signals from the UCR receiver.
[0065] The A/D cards mounted in this rack may include four dual
eight-bit analog-to-digital converters (Analog Devices AD9059) for
a total of eight channels per board. In one example, there are six
boards per system, giving forty-eight channels of digitized data,
which are sent to the computer for analysis via the ISA bus
interface card in the computer. All six A/D cards operate from a
40-MHz, crystal controlled, master clock to assure that all A/D
converters start digitizing at the same point on the signal. This
gives 25 nanoseconds per point resolution. Sixty-four 8-bit points
are collected per acquisition cycle. The digitized data from all
A/D converters is read simultaneously into dual-port static ram
chips, which is 16 bits wide, organized into two bytes. One-half of
the dual A/D converter writes into the upper byte, and the other
half writes into the lower byte. This arrangement allows use of the
16-bit ISA to transfer data from two channels at once for faster
throughput. The data is stored in the primary port of the ram chip,
and read out from the secondary port by the 12-MHz ISA computer
bus. It is simply read as external memory at location C000h, which
is a space reserved for add-on cards in the IBM computer
architecture. A DIP-switch can change this address if there are
conflicts with another board in the computer.
[0066] The read-and-write addressing function is performed by an
address decoder card on the passive back plane. The address decoder
card generates the master clock and the write address for the ram
chips, and also decodes the memory address for each board. The
decoder card in the Acquisition chassis is connected to the ISA bus
interface card in the computer chassis by a 50-pin ribbon cable.
Linear type power supplies are used to supply the 1 ampere, minus 5
volts and the 10 ampere, plus 5 volts required by all six A/D
cards, in order to eliminate the noise generated by the more
commonly used switching regulator power supplies.
[0067] (3) Transmitter. The transmitter, which is used to excite
the transmit section of the UCR transducer, includes two
components: a rack-mounted, synthesized function generator
(Stanford Research Systems model DS345), and a Mini-Circuits model
ZHL-32A RF power amplifier which is mounted in the back of the rack
with its 24-volt power supply. The transmitter configuration puts
out a 24-volt peak-to-peak, 3-cycle, 1 MHz, sine wave burst into a
50-ohm load. The transmitter has the capability of being programmed
by the computer via a GBIB interface mounted in one of the PCI
slots.
[0068] (4) Preamplifier Assembly. The function of the preamplifiers
is to amplify the low-level (millivolt range) signals from the
receiver section of the UCR transducer to match the 100-millivolt
peak-to-peak input sensitivity of the A/D cards. The A/D converters
have, e.g., a 1-volt sensitivity, with a X10 amplifier at each A/D
input. The preamplifiers have a gain of 100 (40 dB), which gives an
overall gain of 1000. There may be eight channels per board, with
six boards in the system, for a total of 48 channels. Each channel
contains a 50-ohm pulse transformer to match the input impedance of
the A/D cards and prevent ground loops by isolating the
preamplifier assembly. The input impedance of the preamplifiers
(Analog Devices AD844) is set at 10,000 ohms to match the high
impedance of the PVDF film used in the receiver construction. As
depicted, the preamplifier cards are mounted in a EIA-standard
sub-rack with a built-in linear, plus and minus 15-volt power
supply. The input connectors are standard DB37S, as are the
connectors on the A/D card inputs.
[0069] (5) Motor Controller Chassis. There are six, 12-volt DC
motors, each with their own position encoder, used to control the
motion of the platform, arm, and transducer assembly in the UCR
system. The motor controller chassis contains power supplies,
drivers for the motors, and an interface to the motor controller
board, in the computer. The motor drives are National Semiconductor
LM1875 power amplifiers used in a direct-coupled configuration.
This arrangement allows clockwise and counter-clockwise rotation at
any velocity, and the 4-phase position encoders provide precise
positioning.
[0070] (6) Programmable Delay Generator. It is programmed by three
of the 8-bit ports on the PIO card in the computer, and simply sets
a delay between the software instruction to fire the transmitter
and the signal to start the data acquisition. The velocity of sound
through the water the transducer is 1.5 Km per second, and only 64
points are captured. The above arrangement prevents the
digitization of all the dead time between the transmitted and
received signals. The counter is programmable up to 4096
microseconds, with 100-nanosecond resolution. It may include three
74F163 pre-settable binary counters, and a 10-MHz crystal clock. It
is housed in a small chassis, with power supply, in the back of the
rack.
[0071] Operational Description of Data Acquisition. The Scalable
Multichannel Data Acquisition System (SMDAS) is a high frequency
digital system for collecting data in the standard ultrasonic
frequency range (50 kHz to 10 MHz). The SMDAS hardware component
generally includes multiple channels with two stages:
pre-amplification and digitization. The system is scalable with a
granularity of, e.g., 8 channels.
[0072] The SMDAS is a triggerless, computer-controlled system,
based on a low-cost, 8-bit, 60-MHz analog-to-digital converter.
Because traditional UCR used three-cycle, 4-MHz pulses, a 40-MHz
solution was chosen so as to permit 10 times oversampling of these
signals. A sampling memory of 64 samples (1.6 .mu.s) provides
sufficient storage for each channel. A total of 48 channels were
chosen because each channel maps to a specific angle of incidence,
and all pressure critical angles and 2-gamma shear dynamics occur
for angles less than 40 degrees in solids of interest.
[0073] Digitization Subsystem. The heart of digitization is the
AD9059 (Analog Devices, Norwood, Mass.), a dual channel IC package
capable of sampling at 40 million samples per second. Although this
chip can be supplied a reference voltage, the AD9059 can
self-generate the required level to operate the internal pipeline
of comparators. With self-referencing enabled, the AD9059 accepts
two single-ended inputs with a voltage range between 1.5 and 2.5
Volts. Upon cycling with a TTL compatible clock, the 16 digital
output pins on the AD9059 will output 8-bit digital samples for the
two input channels. While digital crosstalk is negligible, the
AD9059 is rated with 1.5 bits of noise. For 8 channels, a two-layer
printed circuit board was designed, wire-wrap tested, and built
(Alpha Printed Circuits, Mesquite, Tex.) to accommodate four
independent subsystems of two channels. For each AD9059, a 16-bit
dual port static RAM (CY7C133, Cypress Semiconductor, San Jose,
Calif.) with .about.25 ns access time is used to record the 64
samples for two channels, although in principle only 128 bytes of
memory should suffice. The PCBs are equipped with DB37F connectors
(Amphenol, Wallingford, Conn.), and each channel is routed to a
pre-amplification stage with a coaxial wire to avoid the noise
associated with a trace on the PCB.
[0074] Before digitization, each channel passes through an
operational amplifier (CLC440, ComLinear/Nationional Semiconductor,
Santa Clara, Calif.) with a gain of 10. The amplification stage
expects all inputs to be 50 ohms in impedance. Each board has a
98-pin on-board edge connector designed to fit into a 14-slot ISA
standard backplane (JDR Microdevices, San Jose, Calif., part number
BP141) mounted in a separate computer chassis. For each board,
there is also a selectable board identification jumper needed for
reading from a given card. A special decoder board also in the bus
associates each digitizing board with a memory address relative to
some selectable base address, in steps of 128 bytes (0x080h). The
decoder board is in turn connected with a parallel ribbon cable to
a buffer board on the computer system's ISA bus. If the base
address is set to be in the x86 architecture's high memory area
(that is, 0xD0000h to 0xE0000h), this configuration allows direct
memory access to samples stored in the memories for each individual
channel. If a 2-byte read is utilized, data can be read for two
channels simultaneously. In the initial design, sampling was
initiated by a memory write to the base address. It should be noted
that memory reads are limited in time by clocking of the ISA bus,
which on recent motherboards was maximized at 12.5 MHz.
[0075] Pre-Amplification Subsystem. Although the digitization
subsystem includes some amplification, it is often necessary to
condition signals from transducers with additional amplification.
With certain transducers, there may also be issues involved with
impedance matching, especially for high impedance, polymer based
piezoelectric system. A high impedance input amplification system
was designed and built around a 44-pin EIA card subrack (Vector
Electronics, North Hollywood, Calif.). Each amplifier cards uses
high impedance operation amplifiers (Analog Devices, AD844) to
amplify signals ideally from PVDF transducers. With a nominal gain
of 100 for 10,000 ohm input impedance, these amplifiers also resist
oscillations that can occur with impedance mismatches. The AD844
has a bandwidth-gain product of over 300 MHz, so signal distortion
should be negligible at typical ultrasonic frequencies. Output of
each channel is transformer (Mini Circuits, Brooklyn, N.Y., part
number T1-1) coupled to prevent catastrophic ground loops. The EIA
rack is connected to the chassis containing the digitization
subsystem with shielded, coaxial cables.
[0076] Signal Generation and Timing. In order to have precise
timing between pulse generation and the start of the sampling, it
was necessary with the original SMDAS design to have a computer
system with little or no overhead. With a data acquisition window
of 1.6 .mu.s, precise timing could be guaranteed with a real time
operating system (RTOS). With a Windows (Microsoft, Redmond, Mass.)
or Linux brand operating system, the system timing granularity is
on the order of 1 millisecond. Rather than going with an expensive
embedded solution, the flexibility of an industry standard
operating system was retained, and the timing for signal generation
and sampling was moved to a custom-made external module. The timing
module is enclosed in a rack mountable case. It contains three
4-bit binary counters operating at 10 MHz, programmable with the
digital output from a PIO card (PCI-DIO48H, Measurement Computing,
Middleboro, Mass.). Twelve bits of programmability at 10 MHz
translates to a delay range of 409.6 .mu.s. For typical ultrasonic
velocities in water and soft tissues, this window accounts for
propagations up to 60 cm. After the pulse generator firing is
commenced, the counters complete their programmed delay, and then a
TTL level signal is transmitted via external co-axial cable to the
decoder board in the DAQ chassis to commence sampling.
[0077] Software for Data Acquisition. The SMDAS software component
includes, e.g., several layers of libraries for accessing the SMDAS
hardware component. It offers entry points at several layers of
system programming, providing maximum flexibility for application
development and future systems integration.
[0078] Memory Mapping. As designed, the data acquisition board
memory that contains sampled data is mapped to a physical memory
address in the upper memory area of the Intel x86 architecture. By
reading at this address and storing the information in a variable
array, the sampled data can be transferred from board memory to
system memory without need for complex communications or system
drivers. Because reading of sampled data is ultimately multiplexed
across the ISA bus, it is most efficient to read in two-byte words
to maximize the bus bandwidth. After transfer, the 8-bit samples
must be separated. On a modern microprocessor, such as a Pentium
(Intel Corporation, Santa Clara, Calif.) or Athlon (AMD, Sunnyvale,
Calif.) class chips, this separation should be accomplished in a
single clock cycle instruction. An arbitrary bit shift (also known
as a barrel shift) or a bit-wise AND operation can be used to
extract the upper or lower 8 bits from the 16-bit word.
[0079] To facilitate this memory mapped read, a dynamic linked
library (DLL) was created using Visual Studio Professional 6.0
(Microsoft Corporation, Redmond, Wash.) using the C programming
language. This low level library provides a function for reading a
2-byte word at an arbitrary address in the upper memory area
(unsigned short int 1v48chdaq(int addr)) and two functions for
extracting upper and lower samples (unsigned char
left/right(unsigned short int a)). This portable DLL can, e.g., be
linked into Windows applications developed in a variety of
programming languages, and by cycling through memory address all
sampled data can be transferred to system memory for analysis or
for saving to storage media.
[0080] Noise Reduction. The visual programming environment LabVIEW
(National Instruments, Austin, Tex.) was chosen for development of
data acquisition software due to its rapid development scheme, its
ease of use, and its recognition as an industry standard. In order
to maximize flexibility for future applications, an intermediate
library of "virtual instruments" (VIs) was developed using a
bottom-up approach where a special global VI contains parameters
common to all components (that is, number of channels, base memory
address).
[0081] At the lowest level, the "download 2 channels" VI is
attached to the DLL described above and cycles through the
appropriate memory addresses to transfer 128 bytes to system
memory. Each channel possesses repeatable error that is measurable
with the pre-amplification stage disabled or the open inputs.
Fourier analysis of averages of this residual indicates
contributions at 40 MHz and its subharmonics. This is entirely
consistent with reference voltage noise due to a lack of shielding
on the address lines for the buffer memories. Because 6 address
lines are required, one would not be surprised to find noise at the
fundamental and at the 5 subharmonics (20, 10, 5, 2.5, and 1.25
MHz).
[0082] The "download 2 cleaner channels" VI subtracts this
repeatable signal from sampled data, and the resultant noise is
consistent with the manufacturer's specifications. An application
can either generate these average background waveforms itself, or
it can use the default ones produced by the "calibrate average
background waveforms" VI. The "download n cleaner channels" VI
packages multiple channels into an n by 64 matrix.
[0083] The pipeline architecture of the AD9059 requires a 1-MHz
minimum sampling rate. At slower rates, the internal registers are
degraded, and the sampling is extremely inaccurate. Because the
transfer of one block of 64 two-channel words occurs at ISA bus
speeds (in the order of 10 MHz), the effective rate for sequential
acquisitions is less than 200 kHz. Thus, the first 5 samples of
every acquisition of each channel may be suspect. Because the
granularity of the time delay subsystem is 0.1 .mu.s, it is
convenient to drop the first 8 samples (0.2 .mu.s).
[0084] Multiple Frame Acquisition. The real power of this
intermediate library is its ability to construct time windows
larger than the 1.6 .mu.s given by 64 samples. In one determination
using steady-state dynamics, it is possible to adjust the delay
time between sequential acquisitions so that they are properly
aligned in time. The "acquire" VI uses the "set delay time" VI to
form contiguous frames from "download n cleaner channels". The
process is repeated a number of times, with each sequential
acquisition appending to the previous set of data. The resulting
output of N channels and M 1.4 .mu.s frames gives a matrix of
dimensions N.times.(56.times.M). It should be noted that the
rate-limiting step in the data acquisition process is the transfer
of information across the ISA bus. Increasing the number of frames
and time window increase the scan time, which in general grows at a
linear rate.
[0085] Stochastic Frame Acquisition. In some imaging situations,
the alignment of contiguous time frames will lead to spurious
signals. This problem is especially evident with large blocks of
time (order of 100 .mu.s) in scenarios where secondary reflections
or reverberations from early pulses are captured in later frames.
These signals cannot be removed by taking an average. In order to
minimize these unwanted data, it is sometimes necessary to gather
multiple frames in a stochastic manner. For a given time window,
the 1.4 .mu.s frames are selected at random from a list until
exhausted and the window is filled. If this method is repeated and
averaged, the cross-correlated signals from separate frame pulses
may be eliminated.
[0086] In operation, the system of the present invention is
summarized in the flowchart 70 of FIG. 7. In step 72, an ultrasound
wave or pulse is transmitted toward a target, e.g., a bone, and the
reflected signals are captured by two or more receivers in step 74.
Based on the signals acquired from the receptors a determination is
made as to whether the normal was found is made at step 76, which
is made by a computer that directs, e.g., the articulated arm to
either move the transducer or begin data acquisition. If the normal
was found, then the final data from the target is acquired
simultaneously in final data acquisition step 78, and the results
stored as an analog signal or a digital equivalent. Based on the
data acquired from the final acquisition step 78, the Emax and Emin
are calculated at step 80 to determine the ultracritical
reflectometry data of the target, from which the anisotropy may be
calculated in step 82. Finally, the raw data, processed data and/or
the calculated results may be stored, processed, displayed, printed
and/or compared to earlier or later target data and calculations to
provide the user with useful results at step 84.
[0087] In FIG. 8, the ultracritical reflectometry data acquisition
transducer, method and system are used in flowchart 90 to make a
determination for treatment of a patient. In step 92, the normal is
determined for bone, in this example at the heel. Upon acquisition
of the normal, the transducer takes the critical UCR measurements.
If the patient is concurrently or about to begin a treatment
regimen, that occurs at step 96, with subsequent measurements taken
at time-intervals (e.g., weekly, bi-weekly, monthly, depending on
the physicians instructions and type of treatment) in step 98. Data
from before patient treatment (step 94) and subsequent treatments
(step 98) are acquired, processed and/or stored as patient data
(step 100). The measurements, data and processed patient
information is then compared at step 102 with normal patient data,
and with the UCR measurements from the same or other treatments
(step 104) from the same and/or other patients and a determination
is made to see if the patient is improving at step 106. If the
patient is improving then they may be returned to the bone scanning
regime. If the patient is not improving or getting worse, then the
physician can direct a change in treatment and the patient is
returned to the monitoring regime (step 84).
[0088] The collection of reflected signal begins when bone surface
is reached. This time is operationally defined by an abrupt
increase in the reflected signal over all angles. The operator then
initiates a series of automated steps to accurately identify the
normal. These steps control the acquisition of reflected angular
spectra from at least two orthogonal directions on the bone
surface. For each direction the plane of the normal is found by
tilting the transducer head until the integrated signal is maximum;
the intersection of the two orthogonal planes defines the normal.
The reflected spectra (signals at all receiver elements) are then
obtained by rotating the head around the normal in 15-degree
intervals over 120 degrees; the two orientations at which the first
critical angle is smallest and greatest identify the two principal
axes of bone.
[0089] Calculation of Key Indices of Bone Quality from UCR. In
general practice, measurements are made at three discrete areas of
bone tissue being examined. At each site, multiple critical angle
velocities (v) are obtained over 120 degrees. The data for v are
mathematically fitted to the formula: v.sup.2=a+bx.sup.2+cx.sup.4,
where x=cos (orientation), and v.sup.2 is elasticity normalized to
a density of 1 g/cc. From the resulting graph, the minimum
(E.sub.min) and maximum (E.sub.max) elasticities of trabecular and
cortical bone are calculated as a measure of bone material quality.
The term "elasticity" may be used interchangeably with the term
"elasticity coefficient". From the area-under the curve of v data,
"integrated" or "mean" elasticity (E.sub.int) is calculated.
E.sub.int is essentially the same as the square of average
velocity. Anisotropy (A) is calculated as the ratio of
corresponding maximum and minimum elasticities.
[0090] Clinical Application of New UCR Device. Development of
adynamic bone disease during bisphosphonate treatment of
osteoporosis. Bisphosphonates (such as Fosamax.RTM. and
Actonel.RTM.) are widely used for the treatment of postmenopausal
osteoporosis throughout the world. This treatment is known to
increase bone density and decrease fractures (Liberman, et al., N.
Engl. J. Med., 333:1437-1443, 1995). The primary action of this
drug is to inhibit bone resorption (destruction). There is
secondary reduction in bone formation that lags behind the fall in
bone resorption during the first 1-3 years of treatment. During
this period, a gain in bone mass occurs resulting in increased bone
density. The inhibition of fractures has been ascribed to this rise
in bone density. From studies in experimental animals, however, a
concern has been raised that bisphosphonate may produce a profound
suppression of bone turnover that could cause microdamage and
compromise bone quality (Li, et al., Calc. Tissue Intern.,
69:281-286). Moreover, in human beings, it has been suggested that
chronic bisphosphonate treatment may impair bone quality from
marked suppression of bone turnover, causing increased rate of
fracture after long-term bisphosphonate treatment (Ott, J. Clin.
Endo. Metab. 86:1835, 2001).
[0091] The study summarized below was undertaken in order to
determine if such complication can occur in human beings, using the
apparatus, method and system disclosed herein. Using the present
invention, it was discovered that long-term bisphosphonate
treatment causes "adynamic bone disease," a histologic appearance
of bone displaying a marked suppression of bone turnover with
virtual absence of cellular activity (Odvina, et al., J. Bone
Miner. Res., publication expected September 2003).
[0092] A transiliac crest bone biopsy was performed in 6
postmenopausal osteoporotic women (49-76 years), who developed
fractures after they had been on long-term bisphosphonate treatment
for 3-7 years. Besides bisphosphonate, 3 patients took hormone
replacement therapy, 2 prednisone (one for fibromyalgia, the other
for asthma), 4 vitamin D, and all 6 patients received calcium
supplements. Fractures occurred in finger in 1 patient, pelvis in
3, hip in 1, foot in 1, and femur in 2. In four patients, bone
biopsy was obtained because patients displayed delayed healing of
fractures (of ischium, femur, pelvis) for 3 months to 2 years while
maintained on bisphosphonate treatment. In two patients, the biopsy
was taken shortly after they developed fractures (sacrum, pubic
rami, rib), because the physician felt that the index of suspicion
for adynamic bone disease was high.
[0093] Histomorphometric findings in trabecular bone are summarized
in Table 1. As shown in FIGS. 9A and 9B, bone formation were
markedly diminished with low osteoblast surface (Ob.S/BS) and
absence of double tetracycline label (dLS) and absent or diminished
single label (sLS) in all specimens. Before a biopsy was obtained,
tetracycline was given in two coursed 10 days apart. Tetracycline
is picked up in area of active bone formation, imparting yellow
lines under polarized light microscopy. FIGS. 9A and 9B are
photographs of polarized light microscopy that shows the absence of
tetracycline labeling in a patient on long-term bisphosphonate
treatment (9A), and normal labeling in a normal subject (9B). Two
courses of tetracycline were given 10 days apart. Tetracycline is
picked up in area of active bone formation, imparting yellow lines
under polarized light microscopy. The distance between two labels
represent the amount of new bone formed over 10 days. Absence of
tetracycline labeling indicated markedly impaired bone formation.
Bone resorption (destruction) parameters (ES/BS and Oc.S/BS) were
also decreased in 3 patients. A similar trend was observed in
cortical bone (data not shown).
TABLE-US-00001 TABLE 1 Histomorphometric Findings in 6 Patients
with Adynamic Bone Disease After Long-Term Bisphosphonate Treatment
Normal Parameters Patient 1 Patient 2 Patient 3 Patient 4 Patient 5
Patient 6 Mean .+-. SD BV/TV (%) 9.4 8.9 14.3 15.2 12.2 10.9 21.17
.+-. 4.9 OV/BV (%) 0 0.05 0.42 0.66 0 0.89 0.38 .+-. 0.25 Oc.S/BS 0
0.12 1.0 0.3 0.17 0.29 0.7 .+-. 0.7 ES/BS (%) 0.85 1.7 9.5 9.3 2.1
1.3 4.0 .+-. 2.0 Ob.S 0 0.19 1.7 0 0 3.6* 4.4 .+-. 3.2 dLS/BS (%) 0
0 0 0 0 0 4.3 .+-. 2.9 SLS/BS (%) 0 0.3 0.58 0 0 0 6.0 .+-. 4.1
Abbreviations: BV = bone volume; TV = total volume; OV = osteoid
volume; Os.S/BS = osteoclastic surface/bone surface; ES = eroded
surface; Ob.S = osteoblactic surface; dLs = double-label
tetracycline label; sLS = single tetracycline label. *= probably
falsely high, since osteoclasts appeared flat and inactive.
[0094] The results suggest that bisphosphonate may cause adynamic
bone disease with markedly reduced bone formation. "Bone turnover",
a process by which "old" or damaged parts of bone are removed and
replaced by new healthy bone, is markedly suppressed as well.
Following a chronic suppression of bone turnover, bone microdamage
may accumulate (Li, et al., Calc. Tissue Intern. 69:281-286, 2001).
This explanation can account for recurrent fractures that display
delayed healing.
[0095] UCR Reflectometry in vivo Among Patients with Adynamic Bone
Disease. Bone elasticity was measured in vivo by new UCR in two
patients from the preceding study with adynamic bone disease on
bisphosphonate treatment, 8 months and 12 months after withdrawal
of bisphosphonate treatment. At the beginning of this study the UCR
device was not available. In the former patient, the mean
(integrated) cortical and trabecular elasticities were depressed by
15.4% and 27.1%, respectively, from the mean of normal
premenopausal women. In the latter patient, the mean (integrated)
cortical and trabecular elasticities were within the range of
values in normal premenopausal women, indicative of eventual
correction of defective bone quality after stopping bisphosphonate
treatment.
[0096] In two patients, UCR analysis of the heel was performed in
vivo when they presented with fractures while still on
bisphosphonate treatment. Mean cortical elasticity was decreased by
25% and 26%, and mean trabecular velocity by 16% and 15%, compared
to mean values for normal premenopausal women. The remaining two
patients underwent bone biopsies elsewhere and were not available
for UCR measurements.
[0097] The finding of reduced elasticities of cortical and
trabecular bone in patients with adynamic bone disease from
bisphosphonate treatment strongly suggests that abnormal structural
derangement in bone (shown on histomorphometry) is correlated with
impaired bone quality, affirming the previously stated
hypothesis.
[0098] Detection of impaired bone quality by new UCR in vivo among
patients on long-term bisphosphonate treatment. Using the new UCR
device disclosed herein, the ultrasound elasticity of cortical and
trabecular bone was measured at multiple orientations in the
calcaneous in vivo. UCR analysis using the present invention was
performed in 14 normal postmenopausal women, 9 with postmenopausal
osteoporosis on conventional treatment (untreated PO), and 25 on
bisphosphonate treatment (mean duration 3.5 years). Values were
expressed as percentage of values in 14 normal premenopausal women
(Table 2). Mild or no decreases (<5%) were observed in normal
postmenopausal women. A mild-moderate reduction in elasticity
(.about.10%) was disclosed in untreated postmenopausal women. In
bisphosphonate treatment, trabecular elasticity (both maximum and
minimum) significantly declined by about 15%, and cortical
elasticity decreased by about 25%. Anisotropy of cortical and
trabecular bone decreased during bisphosphonate treatment, owing to
a more prominent decline in maximum elasticity. Thus, bone material
became less anisotropic after this treatment, signaling an abnormal
character of bone. Integrated cortical elasticity decreased
significantly by 25.9% in cortical bone and by 17.5% in trabecular
bone from normal premenopausal values following bisphosphonate
treatment.
[0099] Much of the decline in elasticity occurred during the first
3 years of bisphosphonate treatment. In bisphosphonate treatment,
elasticity was independent of heel bone mineral density obtained
simultaneously by dual photon x-ray absorptiometry.
[0100] FIG. 10 is a graph that shows the independence of bone
elasticity from bone density during bisphosphonate treatment and in
renal transplantation. The integrated (mean) elasticity coefficient
of cortical bone by new UCR and bone density by dual photon x-ray
absorptiometry were simultaneously measured in the calcaneus in
vivo. There were two "outliers" with elasticity coefficients that
were much higher than in the rest. One of them was a patient in
whom bisphosphonate treatment had been stopped for 1 year.
[0101] This finding confirms earlier conclusion (Antich, et al., J.
Bone Miner. Res., 8:301-311, 1993) that UCR measures material or
intrinsic bone quality, not bone density at the organ level. In
normal pre- and postmenopausal women and in postmenopausal
osteoporotic patients on conventional treatment, elasticity was
modestly correlated with bone density.
TABLE-US-00002 TABLE 2 Trabecular and Cortical Elasticities
Measured in vivo by UCR Normal Osteoporotic Elasticity
Postmenopausal Untreated PO BISPHOS Trabecular E.sub.min 100.1 .+-.
3.1 94.2 .+-. 5.7 85.1 .+-. 5.5.sup.+ E.sub.max 98.6 .+-. 4.3 89.9
.+-. 6.2* 82.3 .+-. 6.0.sup.+ E.sub.int 98.3 .+-. 3.6 91.8 .+-.
5.9* 82.5 .+-. 5.6.sup.+ A 98.5 .+-. 3.4 95.3 .+-. 1.4** 96.8 .+-.
3.4.sup.+ Cortical E.sub.min 97.4 .+-. 5.0 91.7 .+-. 1.8.sup.+ 75.4
.+-. 5.5.sup.+ E.sub.max 96.8 .+-. 5.9 87.4 .+-. 1.4.sup.+ 72.1
.+-. 6.9.sup.+ E.sub.int 97.4 .+-. 4.7 90.8 .+-. 2.0.sup.+ 74.1
.+-. 6.2.sup.+ A 99.4 .+-. 4.3 95.4 .+-. 2.7* 95.6 .+-. 6.8**
Elasticities are presented as percentage of normal premenopausal
women. *p < 0.05; **p < 0.01; .sup.+p < 0.001 vs. normal
premenopausal women. PO = postmenopausal osteoporosis; BISPHOS =
bisphosphonate; E.sub.max = maximum elasticity; E.sub.min = minimum
elasticity; E.sub.int = integrated elasticity; A = anisotropy; .+-.
= plus/minus standard deviation.
[0102] Inferior Bone Quality in Renal Transplantation Shown by New
UCR. Ultrasonic analysis was performed in vivo using the new UCR
device in 9 patients who underwent kidney transplantation and
taking steroids (Table 3). In renal transplantation, a condition
known to be associated with weakened bone and propensity to
fractures, maximum and minimum elasticities in trabecular bone were
significantly lower by 15-17% compared to normal premenopausal
women. Cortical elasticities were reduced by 25-29%. The decline in
maximum elasticities was more prominent than that of minimum
elasticities, resulting in significantly lower anisotropy, compared
with the normal premenopausal state. Findings were remarkably
similar to those of bisphosphonate treatment (Table 2 vs. Table
3).
TABLE-US-00003 TABLE 3 Trabecular and Cortical Elasticities in
Renal Transplantation and During Treatment with Sustained-Release
Sodium Fluoride Elasticity RT-St SR-NaF Trabecular E.sub.min 85.1
.+-. 1.8.sup.+ 96.3 .+-. 4.6 E.sub.max 83.2 .+-. 1.8.sup.+ 93.3
.+-. 2.5.sup.+ E.sub.int 83.4 .+-. 1.4.sup.+ 94.9 .+-. 2.1.sup.+ A
97.8 .+-. 2.0* 97.1 .+-. 3.7 Cortical E.sub.min 75.0 .+-. 2.4.sup.+
95.0 .+-. 6.2 E.sub.max 71.4 .+-. 2.6.sup.+ 95.4 .+-. 6.9 E.sub.int
73.2 .+-. 1.5.sup.+ 94.1 .+-. 4.8** A 95.2 .+-. 2.1.sup.+ 100.5
.+-. 5.1 Elasticities are presented as percent of normal
premenopausal women. *p < 0.05; **p < 0.01; .sup.+p <
0.001 vs. normal premenopausal women. RT-St = renal transplantation
on steroids; SR-NaF = sustained-release sodium fluoride; E.sub.max
= maximum elasticity; E.sub.min = minimum elasticity; E.sub.int =
integrated elasticity; A = anisotropy; .+-. = plus/minus standard
deviation.
[0103] Improved bone quality following treatment with
sustained-release sodium fluoride. The treatment of osteoporotic
patients with sustained-release sodium fluoride was shown to
increase trabecular bone velocity when measured by the original UCR
device (Zerwekh, et al., J. Bone Miner. Res. 6:239-244, 1991;
Antich, et al., J. Bone Miner. Res. 8:301-311, 1993, see also U.S.
Pat. No. 5,228,445, relevant portions incorporated herein by
reference). Ultrasonic analysis was performed in vivo using new UCR
device in 8 patients with osteoporosis after treatment with
sustained-release sodium fluoride. The elasticities of cortical and
trabecular bone from patients undertaking this treatment resided
between the values in normal postmenopausal women and
postmenopausal osteoporotic patients on conventional treatment
(Table 2 vs. Table 3). Anisotropy in patients undergoing
sustained-release sodium fluoride treatment was found to be
intact.
[0104] While this invention has been described in reference to
illustrative embodiments, this description is not intended to be
construed in a limiting sense. Various modifications and
combinations of the illustrative embodiments, as well as other
embodiments of the invention, will be apparent to persons skilled
in the art upon reference to the description. It is therefore
intended that the appended claims encompass any such modifications
or embodiments.
* * * * *