| Study summary: |
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The study proposed in this application is a part of a larger project entitled “Clinical
utility of radiographic texture analysis in diagnosing and treating osteoporosis”. The
overall goal of the larger project is to determine whether computerized texture analysis of
digitized high-resolution images of trabecular bone (texture analysis) improves our ability
to diagnose bone fragility and follow natural history and/or response to pharmacological
therapy of osteoporosis. In the CRC study proposed here we plan to examine changes in the
results of texture analysis during two years of pharmacological therapy for osteoporosis.
Role of densitometry in osteoporosis:
Measurement of bone mineral density is the principal diagnostic method used in clinical
practice and in research studies, both to identify patients who have the disease and to
follow their response to therapeutic agents. The technique used most widely is dual-energy
X-ray absorptiometry (DXA), which has advantages of low cost and radiation exposure, and
high precision and accuracy of 1-2% and 4-8%, respectively [1, 2]. Based on the association
between the low BMD and increased risk of fracture [3], BMD-based treatment guidelines have
been developed [4]. There is, however, a considerable overlap between BMD of patients who
sustain fragility fractures and those who do not [5-9]. The problem arises because the
fragility is determined not only by the quantity of the bone (measured as bone density), but
also by its “quality” which is believed to be related to the preservation of the normal
trabecular pattern [10]. Bone quality is not specifically assessed using current diagnostic
methods. Information about bone quality, however, would be of substantial clinical and
scientific value, as it would complement the BMD measurement when selecting patients for
therapy and when studying bone loss or assessing effects of therapeutic agents.
Texture analysis:
A novel approach to noninvasive and practical assessment of bone structure is to analyze the
texture of high resolution radiographs of trabecular bone [11]. Dr. Giger, Professor of
Radiology and a co-investigator on this application, has developed a method for
characterizing bone structure by computerized texture analysis of digitized high-resolution
radiographs [12-16]. In this approach, the texture is analyzed in several ways, including
Fourier based analysis, which yields root mean square (RMS) as a measure of magnitude of
trabecular bone texture pattern, and the first moment of power spectrum (FMP) which
characterizes the texture pattern’s frequency [13, 15, 16]; and Minkowski dimension fractal
analysis [17-20]. Radiographic texture analysis has been studied in vivo, on lumbar spine
radiographs and found to predict presence of vertebral fractures elsewhere in the spine more
reliably than did the BMD of the spine [13, 14]. In addition, in an in vitro study texture
features as well as BMD were analyzed in femoral neck specimens obtained during surgical hip
replacement. Mechanical loading (crush test) was then performed on cubes of trabecular bone
machined from these specimens to determine their bone strength. It was found that the
combination of BMD and texture analysis predicted bone strength better than BMD alone [12,
15, 16].
Biochemical markers of bone turnover:
In studies of osteoporosis, the bone mass is assessed by measuring BMD while the metabolic
activity of the bone is assessed by measuring the biochemical markers of bone turnover [21].
These markers have limited utility in individual patients because they have high
within-person variability (low precision), and because it is not clear which markers are
useful in which clinical situation [21, 22]. In contrast, comparing biochemical markers
between groups of patients in clinical studies has been found to be useful in two settings.
Firstly, it has been found that high levels of biochemical markers of bone resorption
predict fractures independent of BMD [23, 24]. Secondly, early changes in bone markers (at
3-6 months) during anti-resorptive therapy predict later changes in BMD and fracture rates
[25-28]. The mechanisms underlying these observations have not been elucidated to date. It
is speculated that increased bone resorption, which is reflected in elevation of biochemical
markers of bone turnover, increases fragility by weakening trabecular structure prior to or
independent of measurable BMD changes. Similarly, decreased bone resorption during
pharmacological therapy is likely to improve the trabecular structure before or independent
of its effects on BMD. Since the aim of our research is to (indirectly) examine the
trabecular structure by performing the radiographic texture analysis, we plan to determine
whether the changes in biochemical markers of bone turnover during antiresorptive therapy
will correlate with changes in the results of texture analysis.
Rationale for the study:
Anti-resorptive therapy reduces bone fragility and increases bone density. It is likely that
the trabecular structure of the bone also changes during treatment. Peripheral densitometry
has not been used so far to monitor response to therapy. If the combination of texture
analysis and peripheral BMD change reproducibly during treatment it may be possible to
employ this combination to monitor therapeutic response. In so doing, one could avoid the
need to use the central densitometry and biochemical markers of bone turnover since the
former is cumbersome while the latter suffers from low precision.
Potential advantages of using a portable peripheral densitometer: The texture analyses
described above were developed for high-resolution radiographs, which were digitized and
subjected to computer analysis. The new DXA imaging systems such as GE/Lunar PIXI which will
be used in our research, provide digital images with resolution sufficient for computerized
texture analysis (200 micron pixels). Furthermore, PIXI can generate the image in a shorter
time (seconds vs. minutes) and at a fraction of radiation dose of conventional radiographs.
Finally, since this is a portable densitometer, the methodology developed in this proposal
has the potential to be widely applicable to large segments of the population, including
frail elderly who have limited mobility and high prevalence of osteoporosis.
Future Directions:
If we find in this preliminary study that texture features change during antiresorptive
therapy, future studies will be designed to examine these changes more precisely. With the
results of the present study we will know what magnitude of change in texture analysis to
expect during therapy and will be able to accurately calculate the sample size to further
study these changes. Most interestingly, however, we will be to compare texture analysis
during therapies with different pharmacological agents. Specifically, comparing an anabolic
agent such as PTH to antiresorptive therapies such as biphosphonates and estrogen may
provide important information about the mechanism of action and timing of effects on the
bone structure for different agents.
Another direction for further research will be to test whether the combination of BMD and
texture analysis both from a portable instrument could be used to monitor therapy,
particularly in a primary care setting or in long-term care institutions. To test this, we
will conduct studies which will compare the outcomes and cost-effectiveness of approach
where decisions regarding treatment changes are based on BMD and texture analysis from a
portable instrument and the conventional approach based on periodic monitoring by central
densitometry with or without use of the biochemical markers of bone turnover.
STUDY PROCEDURES
The studies will be performed in the outpatient facility of the University of Chicago GCRC.
Every 3 months for the first 6 months and every 6 months for the reminder of 2 years, the
subjects will come in the morning in the fasting state, provide a urine sample (second
morning void) and blood sample for measurement of biochemical markers of bone turnover.
Height and weight will be recorded at each visit, and any change in health status, including
fractures ascertained. We will also assess other factors known to influence bone turnover,
such as diet and physical activity. Every 12 months, the subjects will fill out Block food
frequency questionnaire from Berkley Nutrition Services [29]. In addition, every 6 months
they will fill out a calcium intake questionnaire (included in Appendix), which will be
analyzed by the CRC nutritionist and a short physical activity questionnaire, which was used
in PEPI trial [30] for assessment of physical activity. Medication compliance will be
assessed by questioning the patients and counting the number of calcium and alendronate
tablets remaining from the previous visit.
After these tests are completed, the subjects will go to the densitometry suite of the
Endocrinology clinic where BMD will be measured and heel images obtained for texture
analysis. The left heel will be scanned twice using the PIXI densitometer (GE/Lunar
corporation) for measurement of BMD of the heel and texture analysis. (If there is a
deformity of the left heel, right heel will be used for all examinations.) In addition,
every 6 months, BMD of the lumbar spine and proximal femur will be measured using the
central densitometer Prodigy (GE/Lunar corporation). The same instrument will be used for
lateral vertebral assessment (a method used for detecting vertebral deformities on images of
the lateral spine from the densitometer), which will be performed every 12 months. |