The purpose of this study is to determine if a new test for osteoporosis can be useful in monitoring treatment. We are studying a new method for examining the quality of bone by an experimental method of computerized analysis of radiographic images (x-ray pictures) of the heel.

Condition	Intervention
Osteoporosis Osteopenia	Drug: Alendronate 70mg

Further Study Details: 

Primary Outcomes: -central BMD of the lumbar spine, proximal femur, total hip; -peripheral BMD of the heel; -results of texture analysis of the PIXI images; For assessment of bone turnover:; -Bone Formation Markers; **serum osteocalcin; **BSAP as a markers of bone formation; -Bone resorption Markers; **urinary NTx and serum CTx; Serum osteocalcin; -immunoradiometric assay
Expected Total Enrollment:  40

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 absorbtiometry (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.

Ages Eligible for Study:  59 Years and above,  Genders Eligible for Study:  Female

Criteria

Inclusion Criteria:

• The study will enroll 40 postmenopausal women with a T score < –2 either at the lumbar spine or the femoral neck: 20 who decide to begin anti-resorptive therapy (treated group), and 20 women who decline such therapy (control group). We will attempt to match the patients and the controls for T score (within 0.3) and age (within 5 years).

• All study participants will be:

  • at least 3 years past the last menstrual period,
  • not on HRT, Raloxifene or calcitonin for at least 6 months.

Exclusion Criteria:

• All study participants will not be on bisphosphonates during the previous 12 months.
• Women with secondary causes of osteoporosis will be excluded.

Please refer to this study by ClinicalTrials.gov identifier  NCT00145977

Tamara Vokes, MD      773-702-1465    tvokes@medicine.bsd.uchicago.edu
Ann Pham      773-702-1197    apham@medicine.bsd.uchicago.edu

Illinois
      The University of Chicago, Chicago,  Illinois,  60637,  United States; Recruiting

Study chairs or principal investigators

Tamara Vokes, MD,  Principal Investigator,  University of Chicago   

Study ID Numbers:  IRB# 11009B; NIH AR42739; NIH AR42739-S1; NIH K23
Last Updated:  September 2, 2005
Record first received:  September 1, 2005
ClinicalTrials.gov Identifier:  NCT00145977
Health Authority: United States: Institutional Review Board
ClinicalTrials.gov processed this record on 2005-09-06