Renal osteodystrophy (ROD) is a multifactorial and pervasive disorder of bone remodeling in chronic kidney disease (CKD). The prevalence CKD in the United States is estimated at 15.1% in 2011. With the aging population, the number of patients affected by ROD, therefore, is expected to increase. Despite the widespread use of therapies, such as phosphate binders, calcium, and vitamin D, bone-fracture rates and mortality risk following fractures are markedly greater in patients on dialysis, compared with the general population. Furthermore, the effectiveness of treating dialysis patients with conventional osteoporosis drugs is not established. The high cost and numerous side effects of drug therapies have spurred the search for alternative treatment options for ROD. It has recently been shown that low-magnitude mechanical stimulation (LMMS) is osteogenic. Although many theories exist, the mechanism of action of LMMS is not well established. A more precise understanding of how vibrations work is needed to optimize the efficacy of LMMS treatment and increase its appeal as a viable non-pharmacological solution to the problem of weak bone. One major hurdle in monitoring efficacy of treatment to LMMS in particular and other interventions in general is the lack of non-invasive tools to study the anabolic response at micro-structural levels in humans. All LMMS trials conducted to date use BMD as the outcome variable, an approach which has many limitations. In high-turnover ROD, for example, increased trabecular bone volume may offset cortical bone loss, resulting in normal or increased areal-BMD despite poor bone strength. The proposed project focuses on overcoming a critical barrier towards understanding the mechanism of action of LMMS therapy in humans by developing a non-invasive high-resolution imaging based biomechanics technique to study the dependence of local-strain on bone formation at the microstructural level in response to LMMS intervention in dialysis patients. If the aims of this project are achieved, scientific knowledge of LMMS treatment in humans and technical capabilities to monitor bone's anabolic response to treatment will be improved. Most importantly, the successful completion of the aims has the potential to change the current paradigm of managing ROD by adapting LMMS as an attractive and preventive intervention.

Public Health Relevance

Current drug treatments for renal osteodystrophy (ROD)-the bone disorder associated with renal disease-is expensive, has significant side effects, and indicated only at a late stage of the disease at which point the bone disease is no longer reversible. Low-magnitude mechanical stimulation is a new, noninvasive, and FDA- approved nonpharmacologic intervention, but the manner in which LMMS stimulates bone growth in humans is not known. This project focuses on prevention and treatment of ROD by evaluating changes in bone's microstructure associated with local mechanical stimulation using image-based biomechanics in a cohort of patients with end-stage renal disease.

National Institute of Health (NIH)
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Small Research Grants (R03)
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Special Emphasis Panel (ZAR1)
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Sharrock, William J
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University of Pennsylvania
Schools of Medicine
United States
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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
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