The purpose of this research study is to see whether receiving a bisphosphonate medication called risedronate can reduce bone and muscle loss following bariatric surgery. Participation will involve up to 6 study visits and last about 1 year. Risedronate is a medication that prevents bone breakdown and has been approved by the US Food and Drug Administration (FDA) for the prevention and treatment of osteoporosis in older men and women. However, risedronate has not been approved for the prevention of bone and muscle loss following vertical sleeve gastrectomy.

Participation in this study will involve completing two visits before beginning the intervention. Participants who qualify will be scheduled to begin the intervention program which will involve taking 6 monthly doses of a risedronate or placebo pill. Participants will then receive monthly contacts by study staff during this time to remind participants to take the intervention pill and ask about any adverse events. After the completion of intervention period, participants will complete up to 4 follow up study visits at 6 months (2 visits) and at 12 months (2 visits).

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 musculoskeletal 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, and high-resolution peripheral quantitative computed tomography (HR-pQCT) derived changes in bone microarchitecture, density, and strength at the tibia and radius - allowing for novel assessment of intervention effectiveness on several state-of-the-art bioimaging metrics. Select measures of muscle function (fast 400-m walk, stair climb, knee extensor strength) are also included as proxies of fall risk. Finally, biomarkers of bone turnover (CTX, P1NP), bone-muscle crosstalk (TGF-β, RANKL, myostatin), and gut hormones (ghrelin, PYY, GLP-1) will be assessed in a tertiary aim, providing mechanistic insight into intervention-related changes to the bone-muscle unit. Thus, we aim to:

Aim 1: Determine the effect of risedronate compared to placebo on 12-month change from baseline in total hip aBMD following SG. We hypothesize that participants assigned to risedronate will better preserve total hip aBMD than participants assigned to placebo.

Aim 2: Determine the effects of risedronate compared to placebo on 12-month change from baseline in DXA-acquired aBMD at additional skeletal sites (femoral neck, lumbar spine, distal radius) and appendicular lean mass; QCT-derived measures of bone (volumetric BMD, cortical thickness, and strength) and muscle (cross sectional area, density, fat infiltration) at the hip and spine; HR-pQCT derived measures of bone microarchitecture, density, and strength at the tibia and radius; and muscle function (fast 400-m walk, stair climb, knee extensor strength) following SG. We hypothesize that participants assigned to risedronate will yield greater preservation/improvement in all secondary metrics than participants assigned to placebo.

Aim 3: Investigate the impact of treatment group assignment on biomarkers of bone turnover, bone-muscle crosstalk, and gut hormones to elucidate mechanisms underlying change in bone and muscle quantity and quality.

Inclusion Criteria:

• Subjects who have had sleeve gastrectomy
• Willing to provide informed consent
• Agree to all study procedures and assessments.

Exclusion Criteria:

• Weight greater than 450 lbs
• Regular use of growth hormones, oral steroids, or prescription osteoporosis medications;
• Known allergies to bisphosphonates
• Unstable gastric reflux requiring two or more additional doses per month of anti-reflux medication.
• Current participation in other research study
• Unable to provide own transportation to study visits
• Unable to position on scanner independently.

Both participants and study staff will be blinded to treatment allocation.