Bisphosphonate Use to Mitigate Bone Loss Secondary to Bariatric Surgery

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PROJECT SUMMARY Despite well recognized improvements in obesity-related comorbidities, mounting evidence implicates sleeve gastrectomy (SG) in the onset of skeletal fragility. Bisphosphonate therapy reduces osteoporotic fracture risk and may also be effective in minimizing bone loss associated with SG. Once-monthly oral risedronate is a commonly prescribed bisphosphonate with a favorable gastrointestinal profile that acts by inhibiting the activity of osteoclast cells, thereby decreasing the rate of bone resorption. Because SG is associated with a significant increase in bone resorption, we hypothesize that risedronate use will counter bone loss in this clinical scenario, ultimately reducing long-term fracture risk. Indeed, pilot data from our group signal that six months of risedronate use is both feasible and likely effective at reducing bone resorption and bone mineral density (BMD) loss post- SG as compared to placebo. Intriguingly, we also observe a signal for appendicular lean mass preservation with risedronate use. This novel finding aligns with data from animal models of clinical pathology and limited observational data in humans, suggestive of a bisphosphonate-induced lean-mass sparing effect. If true, confirmatory data from a definitively designed trial is poised to influence clinical management of the SG patient, while also providing a platform upon which to interrogate mechanisms of bone-muscle crosstalk. To fill these knowledge gaps, the main objective of the proposed study is to definitively test whether risedronate use can effectively counter SG associated bone loss. To do this, we propose to randomize 120 middle-aged and older (≥40 years) SG patients to six months of risedronate or placebo treatment, with bone and muscle outcomes assessed at baseline, six, and 12 months. Due to its robust change following SG and clinical utility in predicting fracture, our primary outcome is change in total hip areal (a)BMD measured by dual energy x-ray absorptiometry (DXA). This will be complemented by DXA-acquired aBMD assessment at other skeletal sites and appendicular lean mass, as well as quantitative computed tomography (QCT) derived changes in bone (volumetric BMD, cortical thickness, and strength) and muscle (cross sectional area, fat infiltration) at the hip and spine — allowing for novel assessment of intervention effectiveness on several state of the art bioimaging metrics — as well as select physical function tasks. Biomarkers of bone turnover and bone-muscle crosstalk will also be assessed in a tertiary aim, providing mechanistic insight into intervention-related changes to the bone-muscle unit. Definitive data has the potential to shift current clinical practice while also offering insight into underlying biologic mechanisms.