7. Abstract Metabolic bone diseases including osteoporosis (OP), osteopenia, osteomalacia and renal osteodystrophy (ROD) affect more than 55 million Americans with an annual cost of more than $17B. The gold standard, dual energy X-ray absorptiometry (DEXA) measures bone mineral density (BMD). However, the majority of bone, the organic matrix and water which together occupy ~60% of bone by volume, is inaccessible. A recent study of over 14,613 participants found that ~80% of all non-vertebral fractures occurred among individuals with BMD above the WHO definition of OP. Furthermore, the etiologies and treatments for OP/osteopenia (reduced bone content) and osteomalacia/ROD (reduced mineralization) are different, but DEXA cannot differentiate between these diseases. More comprehensive techniques are needed for the evaluation of cortical and trabecular bone quantity/quality with information not only about mineral, but about organic matrix and water. Bone is ?invisible? with clinical MRI sequences due to its short T2*. Ultrashort echo time (UTE) sequences with minimal TEs of 8 s make it possible to detect signal from bone. In the first four years of this award (1R01 AR068987, 09/2015 ? 08/2019), we investigated 3D UTE Cones imaging of bound and pore water content as well as T1, T2* and magnetization transfer (MT) ratio. However, those biomarkers showed only low to moderate correlation with biomechanics, likely due to inaccurate measure of bound and pore water as well as incomplete assessment of organic matrix and mineral in bone. UTE with a soft-hard composite pulse suppresses chemical shift artifact, thus allowing more accurate measure of total water. Double adiabatic inversion recovery UTE (DIR-UTE) provides more complete suppression of pore water, thus allowing more accurate measure of bound water. UTE with MT (UTE-MT) modeling measures collagen proton fraction, exchange and relaxation. UTE with quantitative susceptibility mapping (UTE-QSM) maps bone susceptibility, providing information about BMD. Our goal is to develop a package for fast and accurate mapping of total, bound and pore water, collagen proton fraction, exchange, relaxation, and mineral, and to apply it to OP, osteopenia and ROD patients.
Aim 1 targets UTE techniques for fast and accurate mapping of water, collagen and mineral in femur (midshaft, head and neck), using CT, histomorphometry, Raman and gravimetry as reference standard.
Aim 2 will evaluate UTE techniques for water, collagen and mineral in femur from donors with OP (n=20), osteopenia (n=20) and ROD (n=20), with UTE biomarkers correlated with CT, histomorphometry, Raman and biomechanical testing.
Aim 3 targets translational UTE sequences to measure water, collagen and mineral in femur of young (<40y, n=30) and older women (>70y) with (n=30) and without (n=30) OP, with osteopenia (n=30) and with ROD (n=30). UTE biomarkers in different groups will be compared, and correlated with BMD, biochemical markers and fracture history. This work will provide panels of 3D UTE biomarkers for more accurate assessment of bone quantity and quality, and may have a major impact on the diagnosis of various metabolic bone diseases.

Public Health Relevance

The goal of this project is to develop and combine novel 3D UTE MRI techniques to evaluate cortical and trabecular bone offering full insight into bone characterization and correlation with function. In the cadaveric human bone studies the 3D UTE MRI techniques will be compared with reference techniques including CT, histomorphometry, Raman spectroscopy, and biomechanical testing as reference standard. In the human studies the 3D UTE MRI techniques will be applied to elderly women (age > 70y) with (n = 30) and without (n=30) osteoporosis, with osteopenia (n = 30) and with ROD (n = 30), as well as a group of young healthy women (age < 40y, n = 30), to compare the 3D UTE biomarkers in the different groups and correlate the results with BMD, biochemical markers and fracture history.

Agency
National Institute of Health (NIH)
Institute
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Type
Research Project (R01)
Project #
2R01AR068987-05A1
Application #
9981928
Study Section
Clinical Translational Imaging Science Study Section (CTIS)
Program Officer
Nicks, Kristy
Project Start
2015-09-17
Project End
2025-03-31
Budget Start
2020-04-01
Budget End
2021-03-31
Support Year
5
Fiscal Year
2020
Total Cost
Indirect Cost
Name
University of California, San Diego
Department
Radiation-Diagnostic/Oncology
Type
Schools of Medicine
DUNS #
804355790
City
La Jolla
State
CA
Country
United States
Zip Code
92093
Ma, Ya-Jun; Chang, Eric Y; Carl, Michael et al. (2018) Quantitative magnetization transfer ultrashort echo time imaging using a time-efficient 3D multispoke Cones sequence. Magn Reson Med 79:692-700
Ma, Ya-Jun; Lu, Xing; Carl, Michael et al. (2018) Accurate T1 mapping of short T2 tissues using a three-dimensional ultrashort echo time cones actual flip angle imaging-variable repetition time (3D UTE-Cones AFI-VTR) method. Magn Reson Med 80:598-608
Ma, Ya-Jun; Tadros, Anthony; Du, Jiang et al. (2018) Quantitative two-dimensional ultrashort echo time magnetization transfer (2D UTE-MT) imaging of cortical bone. Magn Reson Med 79:1941-1949
Jang, Hyungseok; Lu, Xing; Carl, Michael et al. (2018) True phase quantitative susceptibility mapping using continuous single-point imaging: a feasibility study. Magn Reson Med :
Ma, Ya-Jun; Carl, Michael; Searleman, Adam et al. (2018) 3D adiabatic T1? prepared ultrashort echo time cones sequence for whole knee imaging. Magn Reson Med 80:1429-1439
Nguyen, S; Lu, X; Ma, Y et al. (2018) Musculoskeletal ultrasound for intra-articular bleed detection: a highly sensitive imaging modality compared with conventional magnetic resonance imaging. J Thromb Haemost 16:490-499
Zhu, Yanchun; Cheng, Xin; Ma, Yajun et al. (2018) Rotator cuff tendon assessment using magic-angle insensitive 3D ultrashort echo time cones magnetization transfer (UTE-Cones-MT) imaging and modeling with histological correlation. J Magn Reson Imaging 48:160-168
Ma, Ya-Jun; Zhao, Wei; Wan, Lidi et al. (2018) Whole knee joint T1 values measured in vivo at 3T by combined 3D ultrashort echo time cones actual flip angle and variable flip angle methods. Magn Reson Med :
Carl, Michael; Ma, Yajun; Du, Jiang (2018) Theoretical analysis and optimization of ultrashort echo time (UTE) imaging contrast with off-resonance saturation. Magn Reson Imaging 50:12-16
Park, C Kevin; Zlomislic, Vinko; Du, Jiang et al. (2018) Nonoperative Management of a Severe Proximal Rectus Femoris Musculotendinous Injury in a Recreational Athlete: A Case Report. PM R 10:1417-1421

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