Given that many of the most common fracture sites, such as those of the distal radius and vertebrae, are predominantly trabecular, the prevailing view is that osteoporotic fractures primarily result from decreased density and impaired structural integrity of trabecular bone. However, 80% of the skeleton consists of cortical bone and some of the most devastating fractures, such as those of the femoral neck, occur at a location where the stresses are shared by the two types of bone. Hormonal loss following menopause causes enhanced cortical remodeling leading to increased pore volume fraction caused by expansion of Haversian and Volkman canals and formation of composite osteons. Paralleling these processes is a decrease in mineralization, referred to as degree of mineralization of bone (DMB), due to the bone's failure of undergoing secondary mineralization. Both effects have previously been shown to be modifiable and partially reversible by treatment with antiresorptive drugs as assessed with measurements in iliac bone biopsy specimens. In preliminary studies leading up to this project, we conceived new quantitative solid-state 1H and 31P MRI methods based on zero-echo-time (ZTE) PETRA encoding and new non-iterative reconstruction techniques for evaluating measures of cortical porosity and mineral density, thereby delineating a path toward noninvasive assessment of cortical bone ultrastructure and chemistry. The approach chosen makes use of T2-selective suppression pulses providing pore and collagen-bound water. The latter is shown to represent a surrogate for bone tissue matrix density yielding, along with 31P density, DMB. In this competing renewal application we propose to reduce to practice, validate, and translate these methods to patient studies. Our primary hypothesis is that postmenopausal women with osteoporosis (OP) have greater cortical porosity as assessed by 1H MRI surrogate markers than their healthy peers; and further that porosity in these patients decreases upon antiresorptive treatment. Our secondary hypothesis is that OP subjects have lower DMB as measured by 31P MRI surrogate markers, and that antiresorptive treatment increases DMB. We propose to evaluate these hypotheses with an integrated MRI protocol in a cohort of OP women in comparison to matched healthy controls, both at baseline and after 12 and 24 months of alendronate treatment. We expect the outcome to show that the proposed technology can quantify and distinguish inter-group differences of the parameters measured, both at baseline and in response to intervention. The proposed comprehensive quantitative MR imaging protocol, which can readily be implemented on standard clinical MRI equipment, should yield new insight into microstructure and mineral properties of cortical bone, and provide new ways to evaluate the response to antiresorptive treatment in patients.

Public Health Relevance

Postmenopausal osteoporosis is a major public health issue affecting millions of women in the United States. However, the microstructural implications of the disorder on cortical bone ? the dominant bone type of the skeleton ? are poorly understood and currently cannot be evaluated in vivo. The proposed research provides a path toward clinical assessment of cortical bone health as well as the effectiveness of drug intervention in patients with osteoporosis.

National Institute of Health (NIH)
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Research Project (R01)
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Medical Imaging Study Section (MEDI)
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Nicks, Kristy
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University of Pennsylvania
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Zhao, Xia; Song, Hee Kwon; Wehrli, Felix W (2018) In vivo bone 31 P relaxation times and their implications on mineral quantification. Magn Reson Med 80:2514-2524
Lee, Hyunyeol; Zhao, Xia; Song, Hee Kwon et al. (2018) Rapid dual-RF, dual-echo, 3D ultrashort echo time craniofacial imaging: A feasibility study. Magn Reson Med :
Li, Cheng; Magland, Jeremy F; Zhao, Xia et al. (2017) Selective in vivo bone imaging with long-T2 suppressed PETRA MRI. Magn Reson Med 77:989-997
Zhao, Xia; Song, Hee Kwon; Seifert, Alan C et al. (2017) Feasibility of assessing bone matrix and mineral properties in vivo by combined solid-state 1H and 31P MRI. PLoS One 12:e0173995
Seifert, Alan C; Wehrli, Felix W (2016) Solid-State Quantitative (1)H and (31)P MRI of Cortical Bone in Humans. Curr Osteoporos Rep 14:77-86
Rajapakse, Chamith S; Bashoor-Zadeh, Mahdieh; Li, Cheng et al. (2015) Volumetric Cortical Bone Porosity Assessment with MR Imaging: Validation and Clinical Feasibility. Radiology 276:526-35
Seifert, Alan C; Li, Cheng; Wehrli, Suzanne L et al. (2015) A Surrogate Measure of Cortical Bone Matrix Density by Long T2 -Suppressed MRI. J Bone Miner Res 30:2229-38
Seifert, Alan C; Wehrli, Suzanne L; Wehrli, Felix W (2015) Bi-component T2 * analysis of bound and pore bone water fractions fails at high field strengths. NMR Biomed 28:861-72
Rajapakse, Chamith S; Bashoor-Zadeh, Mahdieh; Li, Cheng et al. (2015) Volumetric Cortical Bone Porosity Assessment with MR Imaging: Validation and Clinical Feasibility. Radiology :141850
Li, Cheng; Magland, Jeremy F; Seifert, Alan C et al. (2014) Correction of excitation profile in Zero Echo Time (ZTE) imaging using quadratic phase-modulated RF pulse excitation and iterative reconstruction. IEEE Trans Med Imaging 33:961-9

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