Due to the rising prevalence of morbid obesity and type 2 diabetes mellitus, the number of patients undergoing Roux-en-Y gastric bypass (RYGB) surgery for weight loss has increased from 75,000 in 2002 to almost 300,000 patients in 2012. Despite its popularity and successes, RYGB is associated with a state of increased bone resorption which can ultimately decrease bone mass. This is thought to be due primarily to compromised gut calcium and vitamin D absorption leading to secondary hyperparathyroidism. Clinical efforts to improve this resorption have focused on increased calcium and vitamin D supplementation with little research to understand the responsible mechanisms and prevent them. With funding from an NIH K08 award in 2010, our group established a diet-induced obese (DIO) male rat model of RYGB that mimics the human RYGB procedure, with similar post-operative weight loss and fat malabsorption. Our preliminary investigations of bone markers and mass in this male RYGB model have demonstrated that obese rats after RYGB have markedly reduced trabecular bone volume, less cortical bone, and higher markers of bone resorption (evidenced by higher serum CTX levels) than age-matched sham controls. In addition, our RYGB animals have lower levels of P1NP, a biomarker of bone formation, than sham controls-an unexpected finding in the setting of secondary hyperparathyroidism. High PTH levels should stimulate both formation and resorption, since the two processes are coupled in vivo. We hypothesize that bone turnover in our model of RYGB is negatively influenced by altered gut and reproductive hormone activity in addition to the known skeletal effects of secondary hyperparathyroidism and weight loss. These abnormalities may represent targets for bone loss prevention strategies in humans undergoing RYGB. Laboratory research into the effects of RYGB on bone and mineral metabolism, to date, has relied solely on male rodent models. This is despite the fact that 80% of human RYGB procedures are done in women. The objective of this application is to identify the cause of this high resorptive and low formative state in a femae model of RYGB surgery replete post- operatively with vitamin D. Dr. Thomas Carpenter (Yale), Dr. Anne Schafer (UCSF), Dr. Sylvia Christakos (UMDNJ), clinical and basic science experts in bone and mineral metabolism, and Dr. Benjamin Canales, urologic surgeon with an interest in RYGB effects, have designed an interventional study to accomplish this goal. After 18 weeks of DIO, female rats will be assigned into one of three groups: sham controls - vitamin D sufficient diet (1000 IU/kg);RYGB - vitamin D sufficient diet (1000 IU/kg);and RYGB - vitamin D supplementation (5000 IU/kg). Focusing uniquely on female-specific outcomes in bone and mineral metabolism and vitamin D, we expect our working model will overcome many of the limitations of human nutritional and skeletal research studies, such as radiological equipment weight limitations, invasiveness and cost of iliac crest bone biopsies, patient reliability or lossof follow up, and patient compliance with standardized diets or supplements. This work will form the basis for future RYGB studies that will evaluate more detailed histomorphometry, gut calcium absorption studies, and the impact of senescence and female reproductive axis function on bone health.

Public Health Relevance

Roux-en-Y gastric bypass (RYGB) surgery may cause long-term bone problems, like osteoporosis and bone fractures. Although this has been studied to a limited extent in humans, animal models allow for better controlled, mechanistic studies that cannot be done readily in humans. Exploring RYGB in this model should positively impact the care delivered to human RYGB patients through better understanding of the effects of rapid weight loss and gut hormones, vitamin D deficiency, and calcium malabsorption on bone and mineral metabolism.

National Institute of Health (NIH)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Small Research Grants (R03)
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Special Emphasis Panel (ZDK1)
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Rankin, Tracy L
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University of Florida
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United States
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Canales, Benjamin K; Smith, Jennifer A; Weiner, I David et al. (2017) Polymorphisms in Renal Ammonia Metabolism Genes Correlate With 24-Hour Urine pH. Kidney Int Rep 2:1111-1121
Canales, Benjamin K (2014) Urologists fix the plumbing, but can they reinforce the walls? Curr Opin Urol 24:593-4
Canales, Benjamin K; Schafer, Anne L; Shoback, Dolores M et al. (2014) Gastric bypass in obese rats causes bone loss, vitamin D deficiency, metabolic acidosis, and elevated peptide YY. Surg Obes Relat Dis 10:878-84