Feasibility of Bisphosphonate Use on Sleeve Gastrectomy Associated Bone Loss: Healthy Body, Healthy Bones Trial
Phase: PHASE1
Conditions: Bariatric Surgery Candidate, Bone Loss, Bone Resorption
Sponsor: University of Nebraska

Feasibility of Bisphosphonate Use on Sleeve Gastrectomy Associated Bone Loss: 
Healthy Body, Healthy Bones Trial 
 
NCT04279392 
 
21 Apr 2021 
 
 
 
 

Protocol 
 
Summary 
 
One in three adults in the Unites States suffers from obesity. Bariatric surgery is an 
increasingly utilized and effective treatment for obesity and obesity-related comorbidities, however, the 
massive weight loss associated with bariatric surgery adversely affects bone metabolism. Significant 
decreases in bone mineral density lead to an increased risk of fracture and subsequent reduction in 
physical function among bariatric surgery patients. Bisphosphonate medications, such as zoledronic 
acid, have been evaluated for safety and efficacy in combating bone loss in patients with osteoporosis, 
but their use in bariatric surgery induced bone loss has not been explored. The study’s primary goal is to 
investigate whether bisphosphonate therapies are able to combat bone loss associated with surgical 
weight loss procedures. This research proposal is a 1-year, pilot randomized controlled trial involving 20 
adult sleeve gastrectomy participants randomized to receive either a onetime zoledronic acid infusion or 
placebo. The hypothesis is that zoledronic acid, a standard treatment for low bone density, will be an 
effective intervention to reduce sleeve gastrectomy-induced bone loss. Bone loss is an unintended 
consequence of an otherwise life-saving procedure, with declining bone health potentially contributing 
to major morbidity in those undergoing a bariatric procedure. Identifying effective interventions to 
minimize bone loss is crucial for comprehensive treatment of patients who undergo bariatric surgery. 
Specific Aim 1: To determine the efficacy of zoledronic acid in preventing bone loss associated with 
sleeve gastrectomy. We will measure bone mineral density and bone turnover markers at baseline and 9 
months. The primary outcome is change in bone mineral density as measured by Dual-energy x-ray 
absorptiometry. Secondary outcomes are change in bone mineral density as measured by Quantitative 
Computed Tomography and change in the serum bone turnover markers, urinary collagen type 1 cross-
linked N-telopeptide (a bone formation marker), serum type 1 procollagen N-terminal (bone resorption 
marker), sclerostin, and osteocalcin. Specific Aim 2: To evaluate the feasibility of this trial in those who 
have undergone sleeve gastrectomy surgery. We will assess the feasibility of the intervention by 
documenting adverse events and compliance rates at each study time point. 
 
 
Purpose 
 
The purpose of this study is to evaluate the effect of zoledronic acid, a bisphosphonate medicine used 
for osteoporosis, in preventing bone loss after bariatric surgery. 
Specific Aim 1: determine the efficacy of zoledronic acid in preventing bone loss associated with 
sleeve gastrectomy (SG). 
Specific Aim 2: evaluate the safety and tolerance of zoledronic acid in populations who have 
undergone SG surgery. 
 
 
Background 
 
Bone loss is accelerated after sleeve gastrectomy (SG) procedures, which can lead to an increased 
incidence of fragility fractures. This problem is becoming increasingly more important as bariatric 
surgery rates continue to rise. Fragility fractures due to poor bone health, are a leading cause of 
morbidity in older adults. Observational studies link weight loss with a reduction in bone mineral density 
(BMD) and an increased fracture risk, regardless of initial body weight.  Dietary-induced weight loss 

interventions have also been associated with decreases in total hip BMD. Greater weight loss 
exacerbates this decline in BMD and subsequent risk of fracture. (Tirosh, 2015) Data collected in the year 
following bariatric surgery shows a rapid decline in BMD and a significant association between bariatric 
surgery and fracture risk. Emerging long-term data suggest that bone loss continues in these patients 
even after weight stabilizes, with elevated bone turnover markers seen up to five years post-surgical 
treatment and fracture risk remaining high in long-term follow up. While cardiovascular and metabolic 
health improve after bariatric surgery, patients are increasingly vulnerable to fracture and the associated 
disability and morbidity. Bariatric surgery irreversibly increases skeletal fragility and future fracture risk. 
Identifying effective interventions to minimize bone loss is crucial for comprehensive treatment of 
patients who undergo bariatric surgery. There are many available pharmacotherapeutic options to 
effectively treat low bone density and decrease fracture risk. These treatments include anti-resorptive 
agents, such as the bisphosphonate zoledronic acid, which inhibit osteoclast-mediated bone loss. 
Bisphosphonates have been well studied for safety and efficacy in the treatment of low bone density in 
non-surgical populations, but the question of whether these pharmacotherapies may benefit patients 
after surgical weight loss procedures still remains. Guidelines put forth by The American Association of 
Clinical Endocrinologists sparsely address bisphosphonate use after surgical weight loss, and further 
evidence is needed to provide robust recommendations for prevention of bone loss after bariatric 
procedures.  Weight loss is associated with a significant increase in bone resorption which is mediated by 
osteoclasts. This makes bisphosphonates an appropriate treatment choice. Thus, bisphosphonate use 
may prove to be an effective intervention for countering bone loss during active weight loss, which is 
critical in reducing long-term fracture risk in the bariatric surgery population. 
 
Bariatric surgery has resulted in remarkable cardiovascular and metabolic health improvements, but 
often this occurs at the expense of bone health. The full extent of the lifelong consequences of bone loss 
on quality of life and mobility are not known. This study is significant because it could provide evidence 
for use of an existing therapy to counteract bone loss seen in post-bariatric surgery patients. 
 
 
Methods 
 
Enrolled participants will have blood drawn from the to evaluate menopausal status in those < 60 years 
old. Study personnel will also collect and store serum at 80 degrees Celsius, for assay of bone turnover 
markers and metabolic regulator proteins at a later date. Analysis of bone formation markers including 
procollagen Type 1 N-TerminalPropeptide (P1NP) and bone resorption marker N-Terminal Telopeptide of 
Type 1 Collagen (CTX) will be performed via commercially available ELISA by our laboratory. Participants 
will complete three surveys at baseline. The first, the Human Activity Profile (HAP), is a 94-question 
physical activity survey used to assess routine physical activity. The second, the Knee Injury and 
Osteoarthritis Outcome Score (KOOS), will assess overall knee pain, function, and knee-associated 
problems. Participants will also complete a modified National Osteoporosis Foundation Calcium Intake 
Estimate to collect dietary calcium habits. Participants will then be asked to perform three tasks relating 
to muscle function and gait speed: hand grip test, repeated chair stands, and a four-meter gait speed 
test. Participants will be measured on a standard scale for weight and have their waist circumference 
measured by study personnel. 
 
Participants will obtain dual energy x-ray absorptiometry (DXA) scan or bone densitometry scan and a 
computed tomography (CT) scan at baseline. Bone density measurement (BDM) of the bilateral hips, 
spine, radius, proximal tibia as well as body composition will be measured by DXA. A CT scan of the spine 
and hip will be completed using the Mindway Phantom to assess bone density and bone structure, as 

well as abdominal composition. CT scans will be de-identified and transferred to Wake Forest University 
to complete analyses of the CT scans. 
 
All participants will receive calcium citrate and vitamin D supplements, with instructions for taking. 
Calcium, Vitamin D, and Bariatric ProCare multivitamins will be processed and dispensed by the research 
pharmacist. A total intake of 1200 mg of calcium will be prescribed throughout the entirely of the study. 
Participants with normal serum 25(OH)D will be prescribed 1000 IU Vitamin D. Participants with serum 
25(OH)D between 20-29mg/mL will be prescribed 2000 IU Vitamin D. Vitamin D will be prescribed for 
the pre-operative period. Following non-study surgery, participants will be instructed to take the 
Bariatric ProCare vitamins and calcium citrate, and to discontinue any remaining Vitamin D supplements. 
 
Participants will be contacted via email and phone as a reminder prior to their infusion date. They will be 
provided with an appointment reminder text and directions to the Clinical Research Center with 
instructions on what to expect at their study visit. Based on prior randomization, participants will receive 
either non-active saline (placebo) or active-medication (zoledronic acid) infusion. To minimize the risk of 
adverse effects of Zoledronic acid, all participants will have a baseline glomerular filtration rate (GFR) 
measured prior to infusion to ensure they have adequate kidney function. A stat blood draw with 
comprehensive metabolic panel will be ordered prior to the infusion. Those participants with glomerular 
filtration rate (GFR) less than 35mL/min or those with evidence of acute kidney impairment will not 
receive the treatment. A single dose of Zoledronic acid should not exceed 5mg, and the duration of 
infusion should be no less than 15 minutes. Therefore, infusion of both the active and non-active  
intervention will take place over 15 minutes. To minimize risk of adverse events such as anaphylaxis, a 
Clinical Research Center nurse will be present during the infusion and will monitor the patient for 15 
minutes after the infusion. Adverse events including potential infusion reaction and other side effects 
will be recorded by study personnel at the time of infusion. Participants will be provided with a take-
home sheet detailing common and/or expected reactions to the medication intervention, with 
instructions as to how to manage them. This sheet will be reviewed with the participant by study 
personnel, with ample time for questions. 
 
Participants will be contacted via text message, email or phone call 24-hours and 2-months following 
their infusion to collect and address any adverse events/reactions/concerns they may have. The contact 
will include a link to a RedCap survey to self-report adverse events. If contacted via phone, study 
personnel will complete the adverse events form with the participant. Participants will be contacted up 
to 3 times, with at least 24 hours between contact in the case of non- responders.  
 
Nine months post-bariatric surgery, participants will have a follow-up visit. Participants will be measured 
on a standard scale for weight and have their waist circumference measured. Participants will have blood 
drawn and serum will be stored at 80 degrees Celsius, for assay of bone turnover markers and metabolic 
regulator proteins at a later date. Analysis of bone formation markers including procollagen Type 1 N-
TerminalPropeptide(P1NP) and bone resorption marker N-Terminal Telopeptide of Type 1 Collagen (CTX) 
will be performed via commercially available ELISA by our laboratory. Participants will complete three 
surveys: the Human Activity Profile (HAP), is a 94-question physical activity survey used to assess routine 
physical activity; the Knee Injury and Osteoarthritis Outcome Score (KOOS), will assess overall knee pain, 
function, and knee-associated problems; and a modified National Osteoporosis Foundation Calcium 
Intake Estimate to collect dietary calcium habits. Participants will complete a hand grip test, repeated 
chair stands, and a 4-meter gait speed test. The National Osteoporosis Foundation Calcium Intake 
Estimate will be used post-operatively to gather data about calcium intake from diet. 
 

A whole body DXA scan will be obtained one month after follow-up visit to assess body composition and 
bone mineral density (BMD) of the hip, lumbar vertebrae (L1-L4), knee and radius. To minimize variability 
between baseline and follow-up scans, each participant  will be scanned on the exact same DXA scanner 
with identical scan parameters for each anatomic location. A real BMD (a BMD, g/cm2) will be  
determined from each scan. For the femoral scan, a BMD will  be calculated from the proximal femur 
using the scanners standard procedures. For the vertebral scan, a BMD will be calculated for each 
vertebral body and for all four combined using the scanners standard procedures. For the distal radius 
scan, a BMD will be calculated for the distal one-third of the radius using the scanners standard 
procedures. The DXA technologist will be blinded to treatment group for each subject. The whole body 
DXA also provides data on lean and fat mass, as well as distribution of these tissues. A CT scan of the 
lumbar vertebrae, hips and associated soft tissue will be obtained from one month after follow-up visit. 
To minimize variability between the baseline and follow-up scans, each participant will be scanned on 
the exact same CT scanner with identical scan parameters. 
 
 
Statistical Analysis 
 
In this pilot study, thirty participants will be enrolled: 15 randomized to the intervention group, and 15 
randomized to the control group with a goal of 10 participants completing the study in each group. Data 
gathered from this study will be used to complete sample size and power calculations for a larger 
randomized controlled trial. A sample size of 10 per group achieves 80% power to detect a difference of -
0.02 (correlation coefficient) between the null hypothesis correlation of 0.0 and the alternative 
hypothesis correlation of 0.02 using a two-sided hypothesis test with an estimated standard deviation of 
0.02 and with a significance level of 0.05 using a two-sided Wilcoxon test, assuming that the actual 
distribution is normal.  
 
Collection of study data is focused on feasibility and gathering evidence to inform future studies, thus, all 
analyses are considered exploratory rather than confirmatory. Baseline characteristics will be 
summarized using descriptive measures, both overall, by gender, and by group, at baseline. The primary 
outcome of feasibility will be based on retention of participants at follow-up visits and description of 
tolerance of the active and inactive group in response to infusion. Follow-up treatment effect estimates 
at 9 months will be used in power calculations for future clinical trials. Secondary analyses will examine 
change in bone metrics between groups assessed by a Students t-test. The effect of changes in relevant 
co-variates such as lean mass, muscle function and nutrition status on study outcomes will be assessed. 
Regression models will used to control for appropriate co-variates and further explore the 
effect of zoledronic acid on bone after bariatric surgery.