The vertebra is the most common fracture site in adults, making vertebral fractures (VF) a major public health problem. Because of the bone and mineral metabolism derangements associated with declining kidney function, people with chronic kidney disease (CKD) are particularly vulnerable to developing fractures, with elevated fracture rates compared to the general population. However, little is known about modifiable VF risk factors, both in the general population and in individuals with CKD. Also, current non-invasive clinical parameters to assess bone health fail to predict fracture risk in CKD patients accurately. This K23 proposal will investigate novel modifiable risk factors for VF and explore the potential role of non- invasive imaging modalities in VF risk assessment. Taking advantage of the unique strengths of the Nurses'Health Studies I and II including large sample sizes providing high statistical power, long follow-up period, rich, well-validated dietary and lifestyle information, and VF cases confirmed by medical record, we will prospectively study dietary and lifestyle factors and VF risk in women (Aim 1). Vertebral deformities are important predictors of VF, but there are no prospective longitudinal data on vertebral deformities in CKD patients. We will establish a cohort of CKD patients and controls and prospectively follow the development/ progression of vertebral deformities over time (Aim 2). Vertebral deformities will be assessed by vertebral fracture assessment, which images the lateral spine using x-ray absorptiometry, and is a reliable and accurate technique for identifying vertebral deformities and VF with the advantage of low radiation exposure. Amongst our study participants with CKD, we will examine the association between serum bicarbonate level and change in vertebral deformities over time. Current imaging techniques are unable to measure the bone matrix or mineralization, which may play important roles in fracture risk. We will study the bone mineral and matrix content using novel, innovative MR imaging techniques, solid-state (31P) and water- and fat-suppressed proton projection (1H WASPI) MRI in the wrists of patients with CKD and controls (Aim 3). A non-invasive measure of bone matrix and mineral content would provide important information on the intrinsic properties of a patient's bone quality and strength that no current imaging technique is able to provide. Results from this research proposal will have important clinical implications by improving our understanding of VF risk factors and their assessment, thus enabling the development of interventions to prevent fractures and their sequelae. This application is for a K23 award for Julie Paik, MD, MPH, MSc, a nephrologist at Brigham and Women's Hospital (BWH), who is establishing herself as a young investigator in patient-oriented clinical research in bone and mineral metabolism. Her long-term goal is to improve the spinal health of patients with CKD by studying modifiable risk factors and working to optimize their spinal health and prevent fractures. This K23 award will provide Dr. Paik with the support to develop the methodologic tools and research experience necessary to conduct epidemiologic (Aim 1) and patient-oriented (Aims 2 and 3) clinical research, and in the long-term to become an independent clinical investigator. This proposal takes advantage of the rich resources and infrastructure at Harvard Medical School, including the Channing Division of Network Medicine, BWH, the Harvard Catalyst Clinical Research Center at Beth Israel Deaconess Medical Center (BIDMC), and the Martinos Center for Biomedical Imaging at Massachusetts General Hospital (MGH). Dr. Paik's research efforts will be closely guided by her mentor at BWH, Gary Curhan, MD, ScD, Professor of Medicine at Harvard Medical School and Epidemiology at the Harvard School of Public Health, a renowned nephrologist and epidemiologist who has extensive experience conducting innovative research and mentoring investigators such as Dr. Paik. His commitment to mentorship is evidenced by a K24 award from the NIH. Dr. Curhan's expertise and experience will be complemented by an advisory committee comprised of accomplished investigators who are all committed to Dr. Paik's research efforts: Catherine Gordon, MD, MSc, a pediatric endocrinologist, senior clinical research investigator in metabolic bone disease, and Chief of the Division of Adolescent Medicine at Hasbro Children's Hospital;Harold Rosen, MD, an endocrinologist with clinical expertise in osteoporosis, bone health, and clinical densitometry and Director of the Osteoporosis Prevention and Treatment Center at BIDMC;and Jerome Ackerman, PhD, Director of the Biomaterials Laboratory at the MGH Martinos Center, who has been conducting research on solid state MR for over 40 years and has led the solid state MR program at MGH for 28 years. To expand her research skills, Dr. Paik will take advanced coursework in biostatistics and epidemiology at the Harvard School of Public Health. In addition, she will attend conferences and seminars within BWH's Channing Division of Network Medicine and Renal Division, and Harvard-wide seminars and conferences on metabolic bone disease. Through the different components of this K23 proposal, including the research proposal, direct mentorship by Dr. Curhan and the other Advisory Committee members, advanced coursework at the Harvard School of Public Health, and wealth of conferences and seminars within the different divisions of a major research and teaching institution, Dr. Paik will be able to successfully further develop and refine her research skills and work towards her goal of becoming an independent clinical investigator in the field of bone and mineral metabolism.

Public Health Relevance

Vertebral fractures are the most common type of fracture in adults, yet surprisingly little is known about modifiable risk factors, both in the general population and in individuals with chronic kidney disease. This proposal will investigate novel risk factors for vertebral fractures and explore the potential role of non-invasive imaging modalities in vertebral fracture risk assessment. Results from this study will have significant clinical implications by improving our understanding of vertebral fracture risk factors and their assessment, thus enabling the development of interventions to prevent fractures and their associated sequelae and morbidities.

National Institute of Health (NIH)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Mentored Patient-Oriented Research Career Development Award (K23)
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Digestive Diseases and Nutrition C Subcommittee (DDK)
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Rankin, Tracy L
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Brigham and Women's Hospital
United States
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Paik, Julie M; Rosen, Harold N; Gordon, Catherine M et al. (2018) Proton Pump Inhibitor Use, H2-Receptor Antagonist Use, and Risk of Incident Clinical Vertebral Fracture in Women. Calcif Tissue Int :
Paik, Julie M; Kim, Seoyoung C; Feskanich, Diane et al. (2017) Gout and Risk of Fracture in Women: A Prospective Cohort Study. Arthritis Rheumatol 69:422-428
Kim, Seoyoung C; Paik, Julie M; Liu, Jun et al. (2017) Gout and the Risk of Non-vertebral Fracture. J Bone Miner Res 32:230-236
Vaidya, Anand; Curhan, Gary C; Paik, Julie M et al. (2017) Body Size and the Risk of Primary Hyperparathyroidism in Women: A Cohort Study. J Bone Miner Res 32:1900-1906
Taylor, Eric N; Feskanich, Diane; Paik, Julie M et al. (2016) Nephrolithiasis and Risk of Incident Bone Fracture. J Urol 195:1482-1486
Vaidya, Anand; Curhan, Gary C; Paik, Julie M et al. (2016) Physical Activity and the Risk of Primary Hyperparathyroidism. J Clin Endocrinol Metab 101:1590-7
Paik, Julie M; Rosen, Harold N; Gordon, Catherine M et al. (2016) Diuretic Use and Risk of Vertebral Fracture in Women. Am J Med 129:1299-1306
Schaefer, Libby; Paik, Julie M; Rennke, Helmut et al. (2015) Clinical problem solving: Itching for a diagnosis. N Engl J Med 372:964-8
Vaidya, Anand; Curhan, Gary C; Paik, Julie M et al. (2015) Hypertension, Antihypertensive Medications, and Risk of Incident Primary Hyperparathyroidism. J Clin Endocrinol Metab 100:2396-404
Paik, J M; Curhan, G C; Sun, Q et al. (2014) Calcium supplement intake and risk of cardiovascular disease in women. Osteoporos Int 25:2047-56