PROJECT SUMMARY Night shift work is known to increase risk for cardiovascular disease, cancer, and metabolic syndrome, but an adverse effect that has received little attention is the disruption of bone metabolism. Animal and human data suggest sleep restriction and circadian disruption, which are inherent in night shift work, are novel, potentially modifiable risk factors for low bone mineral density (BMD) and increased fracture risk. Humans exposed to several weeks of cumulative sleep restriction and concurrent circadian disruption induced by a recurring 28 hour/day protocol had significantly decreased bone formation, with no change or an increase in bone resorption. These changes in bone metabolism, if persistent, would be predicted to increase fracture risk by limiting the development of peak BMD in young adults and/or accelerating bone loss later in life. In fact, the Nurses’ Health Study identified an increased risk of fracture in postmenopausal women who reported 20+ years of night shift work compared to those who never worked the night shift. The acute and chronic skeletal effects of typical night shift schedules in humans, underlying mechanisms, and bone’s ability to recover or adapt are unknown. This application will fill these knowledge gaps by using simulated acute and real-world chronic night shift work to evaluate its effects on bone. The scientific objectives are to determine the effects of night shift work on bone metabolism, density, microarchitecture and strength, and investigate a plausible underlying mechanism (e.g., increased sympathetic tone) by which night shift work impairs bone metabolism to promote optimal bone strength and healthy aging. The specific aims are to: 1. Expose healthy adults to normal sleep or simulated night shift work to (a) Determine if a typical night shift work schedule acutely uncouples bone turnover markers; (b) Investigate increased sympathetic tone as a mechanism for the disruption in bone metabolism; and (c) Evaluate whether resumption of a normal sleep/wake pattern reverses bone turnover marker uncoupling. 2. Characterize changes in bone turnover markers, BMD, bone microarchitecture and strength by evaluating a cohort of hospital nurses in their first year of night compared to day shift work. This interdisciplinary, collaborative research will enhance the health of individuals. It will generate human data to establish night shift work as a novel, potentially modifiable risk factor for impaired bone health and inform mechanisms by which it alters bone metabolism in women and men. This knowledge will provide an opportunity to intervene to prevent low bone mass, osteoporosis and fractures, including the loss of functional independence and mortality they cause. Furthermore, this line of research offers new treatment options for bone health. This research will ultimately inform clinical recommendations for night shift workers and introduce a paradigm shift in the prevention, evaluation and treatment of osteoporosis.

PROJECT NARRATIVE Our work has shown that humans exposed to several weeks of recurring 28-hour days to induce sleep restriction and circadian disruption (e.g., shift work, jet lag) had significantly decreased bone formation, with no change or an increase in bone resorption - an imbalance that could lead to bone loss, osteoporosis, and increased fracture risk. This R01 proposal will investigate the acute and chronic effects of real-world night shift work schedules on bone metabolism, density, quality and strength, and evaluate system-level mechanisms, including increased sympathetic tone. Results will inform screening recommendations for night shift workers, and introduce a paradigm shift in the prevention, evaluation, and treatment of osteoporosis.