Quantifying the Impact of Frailty on Osteoporosis and Fractures in Veterans with Rheumatoid Arthritis

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Background. Two million osteoporotic fractures occur each year in the United States, resulting in more than 400,000 hospital admissions and over $20 billion spent annually on osteoporosis care. Osteoporotic fractures cause loss of independence and excess mortality, and persons with rheumatoid arthritis (RA) are twice as likely to sustain an osteoporotic fracture than the general population. Frailty occurs prematurely in RA and the underlying pathophysiologic mechanisms are not well studied. Furthermore, Veterans are three times as likely to be frail and have excess mortality after osteoporotic hip fracture compared to the general population, underscoring the importance of studying the relationship between frailty, bone mineral density (BMD) and osteoporotic fractures in Veterans Affairs (VA)-based RA cohorts. Inflammation plays an important role in the pathogenesis of both frailty and osteoporosis, making RA, a disease of chronic inflammation, an ideal disease state in which to study these processes. While associations between inflammatory biomarkers, frailty and osteoporosis have been identified in the general population (most notably interleukin-6 (IL-6), Interleukin-1 (IL- 1β) and tumor necrosis factor alpha (TNFa)), the association between these inflammatory markers and frailty in RA has not been comprehensively studied. With the aging US population and >10 million Veterans over the age of 60, it is imperative to improve the management of frailty and osteoporosis especially in high-risk groups, such as those with RA. Scientific Gap. This proposal addresses two scientific gaps in the high-risk Veteran RA population: 1) the impact of frailty on BMD loss and osteoporotic fractures and 2) the impact of inflammatory biomarkers on frailty. Specific Aims. Aim 1 will use a local clinical Veteran RA Cohort to determine if frailty is independently associated with BMD and longitudinal BMD loss. Frailty will be measured by three unique frailty indices: (1) a well-established frailty index (Fried Physical Frailty Phenotype), (2) a quick patient-reported scale (FRAIL scale), and (3) a VA electronic health record-based frailty index (VA-FI). Hypotheses: 1a. Pre-frail and frail Veterans will have lower baseline total hip BMD than robust Veterans when controlling for traditional osteoporosis risk factors. 1b. Veterans with worsening frailty will have larger declines in total hip BMD at follow- up compared to those whose frailty status improves or is unchanged. Aim 2 will use a national RA registry (VARA) of over 3,000 Veteran enrollees to determine if frailty is a predictor of declines in BMD and incident osteoporotic fractures. Frailty will be assed using the VA-FI which will be calculated at baseline and at two-year intervals. Hypotheses: 2a. Worsening frailty is an independent predictor of total hip BMD loss. 2b. Worsening frailty is an independent predictor of incident osteoporotic fractures. Aim 3 will utilize both cohorts to determine if IL-6, IL-1β and TNFa associate with baseline frailty status as well as predict the onset of frailty. Hypothesis: Of the three inflammatory biomarkers measured, IL-6 will have the strongest association with prevalent and incident frailty in both the local RA cohort and the national VARA registry. Impact. This study will be the first to quantify the association between frailty, BMD loss and osteoporotic fractures in Veterans with RA, and will do so using three unique measures of frailty. This study will also determine the extent to which specific inflammatory pathways underlie the frailty phenotype, observations that may provide insight to novel strategies to prevent its development. Future Directions. The results of this study will inform future clinical trials aimed at improving frailty to prevent BMD loss and fractures while also improving the quality of life and independence of high-risk Veterans with RA. Candidate. Dr. Katherine Wysham is a physician scientist and rheumatologist at the VA Puget Sound Health Care System. Through this award Dr. Wysham will gain training and research experience to support her long-term goal of becoming an independent VA researcher focused on the prevention and treatment of frailty, osteoporosis and fractures in Veterans with rheumatic diseases.