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Bone breaking work:
New scan for earlier diagnosis of osteoporosis
By Jenn Shreve
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“We’re
in the business of trying to predict who’s going to
get this disease before they actually get it,” Keaveny
says to graduate student Jenni Buckley, who is creating finite
element models of the spine—complex mathematical formulations—for
computer simulations.
MARTIN SUNDBERG PHOTO |
You'll be going about your daily life for years, unaware that
the bones inside your body are slowly, steadily deteriorating,
then one day—snap! You’re bending to pick up your
grandchild or the car door swings shut and thwacks you on the
hip and you end up with not a bruise but a fractured bone that
may take months or years to heal.
Osteoporosis, called a “silent disease” because of
the way it creeps up on you, affects as many as 10 million Americans;
34 million more are considered at risk due to factors like low
bone mass, family history, hyperparathyroidism, and vertebral
abnormalities. “As our population lives longer,” says
Berkeley bioengineering and mechanical engineering professor Tony
Keaveny, “this disease is becoming more common and much
more of a problem. More than just a bone break, fractures caused
by osteoporosis often signal the end of life.”
As director of the UC Berkeley Orthopaedic Biomechanics Laboratory
and working closely with the Department of Radiology at the University
of California San Francisco (UCSF) School of Medicine, Keaveny
has spent much of his 20-year career studying the factors affecting
bone strength—from the cellular and molecular structure
of bone to the mechanics of an actual break. Now, he and a multidisciplinary
team of software experts, Berkeley mechanical engineering and
bioengineering professors and students, and physicians from UCSF’s
Departments of Neurological Surgery and Radiology hope to prevent
the trauma of sudden, low-impact bone breaks for millions of at-risk
people with a new diagnostic bone scan, expected to enter clinical
trials as early as July.
“Our goal is to create a better gold standard, a more accurate
predictor, for diagnosing osteoporosis much earlier so that doctors
can predict who is going to get this disease before it actually
strikes,” says Keaveny, who hopes the research will also
enable pharmaceutical companies to greatly reduce costs in the
clinical evaluation of new osteoporosis drugs in the pipeline.
The breakthrough technology Keaveny’s team has been working
on for almost 10 years is what they term a biomechanical computed
tomography, or BCT scan. “If we’re successful,”
says Keaveny; “it could be the next big thing in diagnosing
osteoporosis, with applications in surgical planning and assessment
of the effect of drug treatments.”
Osteoporosis—literally porous bone from the Greek—is
a condition in which low bone mass and structural deterioration
of the bone can lead to increased risk for fractures, most often
in the hip, spine, and wrist. Bone loss is an unfortunate but
natural part of aging, beginning at the unexpectedly youthful
age of 30, the time bone begins to break down at a faster rate
than new bone replaces it. For women, this process accelerates
significantly during menopause. One of the universal levelers
of aging is that everyone experiences this decrease in bone mass
over the years, but only some of us will develop osteoporosis.
“The definitive clinical marker of osteoporosis is a fracture,”
explains Keaveny. “Unless you’ve broken a bone, you
don’t feel the effects of osteoporosis. But because clinically
one doesn’t want to wait until a fracture before starting
treatment, osteoporosis is often defined in terms of only bone
density.”
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One
in six osteoporosis cases, or some 200,000 men, suffer from
osteoporosis fractures each year. “There’s a 50
percent morbidity rate after a hip fracture,” Keaveny
tells former ME grad student, now ME staff member, Atul Gupta.
MARTIN SUNDBERG PHOTO |
The current diagnostic protocol for the disease is a dual energy
X-ray absorptiometry, or DXA scan, routinely offered to women
65 and older and other high-risk patients. More refined than a
chest X-ray, DXA produces a 2-dimensional digital X-ray that measures
“areal” bone density, or the amount of bone mineral
per unit area of a predefined region. From this, a statistical
measure or “T-score” is calculated, the difference
between the subject’s bone density and that of an average
30-year-old of the same sex, expressed in standard deviations.
According to World Health Organization guidelines, a T-score of
—2.5 deviations below the norm signals the presence of osteoporosis,
and a medication regimen is often initiated. Values between —1
and —2.5 signal osteopenia, or low bone density, a risk
factor for developing osteoporosis.
But the problem with DXA, says Keaveny, is that it’s an
extremely limiting and crude test. “DXA flattens the image,
distorting the information about what’s happening inside
the bone. Because bone is three-dimensional, assessing bone strength
depends on a 3-D picture. Our process starts with a clinical CT
scan. To produce the BCT scan from that, we take the entire 3-D
geometry of the bone from the CT scan and add in the relevant
biomechanics and finite element modeling. This gives us the full
picture of bone strength. It’s crucial because osteoporosis
is a condition related to the shape and structural integrity of
the bone, not just to how much bone is present, as measured rather
crudely by DXA.”
Ultimately, the strength of a structure is controlled by its weakest
region, so the distribution of material in the bone plays an important
role, according to Paul Crawford, who received his doctorate at
Berkeley and is now a research engineer at UCSF’s Department
of Neurological Surgery. “By using complete information
on the three-dimensional distribution of material in the bone,
we believe we have developed a more sensitive and specific test
of bone strength.” Crawford, a colleague and visiting scholar
in Keaveny’s lab for the past three years, helped put together
the computational, experimental, and statistical details for this
project.
It’s conceivable that people with a T-score in the —1
to —2.5 range could pass the DXA scan, because they have
high bone density in all the wrong places. Their structure could
collapse, according to Jenni Buckley, third-year mechanical engineering
doctoral student and researcher in Keaveny’s lab. “These
are the people at risk of fracture who’d be missed in a
DXA scan,” she adds. “Then there are people who have
low bone density, but it might be distributed in such a way that
it doesn’t compromise bone structure. Clearly a test that
provides a more complete picture is needed for more accurate diagnosis
and more specific treatments.”
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Irish
native and former jazz saxophone player (known in music circles
and among his students as ‘T-Bone’ Keaveny) is
a world leader in finite element modeling as it applies to
the cancellous, or spongy, bone found in the center of the
vertebral body.
MARTIN SUNDBERG PHOTO |
To develop a scan that could leap into the third dimension took
some creative thinking and near hands-on bone cracking. “The
most accurate way to assess the load a spine could handle would
be to take the bone out of the body and break it,” says
Buckley. Ruling out animal tests frequently used in bone experiments
because they don’t apply to human scenarios, the team worked
with vertebrae removed from cadavers and scanned them using the
3-D CT scan.
Then, to get an accurate measure of the bone’s load strength,
they fractured the bone, using a standard mechanical testing machine.
The set of complex measurements gave them the tools necessary
to develop their CT-based finite element model, “a fancy
name for a 3-D computer model that behaves like a piece of bone,”
says Buckley. The resulting software generates a computer model
from the 3-D CT scan of a spine and applies virtual forces to
the bones to calculate the strength. “It allows us to pay
close attention to structure and how the bone density varies within
the bone itself,” says Buckley.
Keaveny began making 3-D computer finite element models from CT
scans of bone as a doctoral student almost 20 years ago. He has
been tightening the agreement between the cadaver experiments
and the computer models during his 10 years at Berkeley.
One remaining challenge is getting the model to account for the
action of muscles, which aid and support the spine, says Keaveny.
The team also wants to improve the existing hip modeling, bringing
it up to par with that what they’ve developed for the spine.
“But once the model is perfected, I believe it will be a
far more accurate measure of fracture risk, providing a higher
level of information than the DXA to doctors and drug manufacturers,”
all of which will soon be tested in clinical trials.
The National Institutes of Health (NIH) is currently reviewing
a $2,250,000 grant application that, if approved, will enable
Keaveny’s team to further refine their CT-based finite element
model and apply it to data from an ongoing NIH clinical study
of 6,000 men with osteoporosis.
Keaveny’s team plans to piggyback their research on the
ongoing trial, an ideal proving ground for their theories because
it includes both DXA and CT scans for all participants. While
it may seem at first glance an oversight for osteoporosis trials
to be limited to men, in fact it isn’t, says Keaveny.
“We were very lucky to find a suitable existing clinical
trial, saving millions of dollars, and at no cost to the results,”
he says. When it comes to the ability of the computer models to
predict bone strength, there should be no difference between men
and women, so that’s not a crucial factor at this juncture.”
If all goes as planned, the team will spend another two years
refining the biomechanics of the team’s computer model and
another two analyzing the data. “We’re very close,”
says Keaveny of the slow but steady process. “We hope to
have a definitive answer in about four years. Then the challenge
will be convincing clinical radiologists to use the test, which
could gobble up another few years,” he adds.
“Osteoporosis is a very serious bone and joint disease,
but it is preventable,” Keaveny adds. “We hope to
be able to drastically reduce the incidents of fracture and to
spur drug companies to use the test to better understand how the
drugs they currently produce are working.”
Oakland-based freelance writer Jenn
Shreve writes about technology and other subjects for
Wired, Photo District News, and Slate.com, and
is currently pursuing an M.F.A. in creative writing at San Francisco
State University.
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