Clinical trial NCT04964388
Conditions: Osteoporosis, Postmenopausal Diabetes Mellitus, Type 2
Sponsor: University of Mississippi Medical Center
Start date: 2021-11-09; Completion date: 2023-07-01
Enrollment: 5 participants; Allocation: NON_RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This study will help determine the effect of Glucagon Like Peptide-1 (GLP-1)receptor agonists on bone strength in postmenopausal women with type 2 diabetes mellitus (T2DM)

Detailed description:
Postmenopausal women with diabetes mellitus have a higher risk of osteoporotic fractures, with significant associated mortality and morbidity. Osteoporosis is underdiagnosed in diabetes, as the bone mineral density (BMD) as currently measured is often normal despite underlying abnormalities. The trabecular bone score (TBS) is a novel modality to assess bone microarchitecture and accurately assess fracture risk in patients with diabetes. Due to increased co-prevalence of osteoporosis and diabetes mellitus, the potential effects of antidiabetic medications on fracture risk assume importance.

Based on findings in animal studies, we hypothesize that GLP-1 receptor agonists increase TBS in postmenopausal women with (T2DM). The investigators propose a prospective non-randomized study by enrolling 48 patients (24 in the GLP-1 group and 24 in the non-GLP group). Dual-energy X-ray Absorptiometry (DXA )scans, markers of bone formation, and resorption, and selected inflammatory markers will be assessed at baseline, six months, and one year.

Arms: arm 1: Participants on GLP-1 receptor agonists arm 2: Participants not on GLP-1 receptor agonists
Interventions: intervention 1: GLP-1 receptor agonist
Intervention descriptions: intervention 1: Diabetes medication

Protocol documents:
Prot_SAP_000.pdf: 
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RESEARCH PROTOCOL  
 
 
Title 
 
Effect of GLP-1 receptor agonists on trabecular bone score and visceral 
adiposity in postmenopausal women with type 2 diabetes mellitus. 
 
Principle 
Investigator/Co-
investigators 
PI: Vishnu Garla 
Co-Investigators: Licy Yanes Cardozo, Candace Howard-Claudio, Lillian 
Lien, Vikas Majithia, Damian Romero, Erika Wachs, David Gordy 
Shreena Dhawan, Abhishek Chhabra 
 
Abstract 
Postmenopausal women with diabetes mellitus have a higher risk of 
osteoporotic fractures, with significant associated mortality and 
morbidity. Osteoporosis is underdiagnosed in diabetes, as the bone 
mineral density (BMD) as currently measured is often normal despite 
underlying abnormalities. The trabecular bone score (TBS) is a novel 
modality to assess bone microarchitecture and accurately assess 
fracture risk in patients with diabetes. Due to increased co-prevalence 
of osteoporosis and diabetes mellitus, the potential effects of 
antidiabetic medications on fracture risk assume importance. 
  
Based on findings in animal studies, we hypothesize that GLP-1 
receptor agonists increase TBS in postmenopausal women with type 2 
diabetes mellitus (T2DM). We propose a prospective non-randomized 
case-control study by enrolling 48 patients (24 in the GLP group and 24 
in the non GLP group). DXA scans, markers of bone formation, and 
resorption, and selected inflammatory markers will be assessed at 
baseline, six months and one year. 
 
We expect to see a significant improvement in TBS in the GLP group as 
compared to the non GLP group. We also expect to see a decrease in 
bone resorption markers, inflammatory mediators, and visceral 
adiposity and an increase in bone formation markers in the GLP group 
as compared to the non GLP group. 
 


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Background  
 
 
 
 
Osteoporosis is characterized by compromised bone strength and 
predisposition to fractures. It affects 200 million women worldwide; 
one in three women over age 50 will suffer an osteoporotic fracture. 
[1, 2]Osteoporotic hip fractures are expected to increase from 1.6 
million to 4.5 million worldwide by 2050. [3] T2DM affects 422 million 
people worldwide, including about 25% of adults in the United States. 
Several studies have reported a 20-30% increased risk of osteoporotic 
fracture with T2DM. Importantly, with increased life expectancy the co-
prevalence of T2DM and osteoporosis with resultant fractures, is 
expected to increase. [4, 5] 
 
Typically, osteoporosis is diagnosed by assessing BMD on a DXA scan.  
T2DM patients often have normal or increased BMD by DXA despite 
abnormalities of trabecular bone that can lead to increased fracture 
risk. A  TBS can be derived by analyzing pixel gray level variations in 
DXA image to assess the bone microarchitecture. Higher scores are 
seen in patients with dense trabecula and lower scores in those with 
sparse trabeculae. T2DM is known to be associated with low TBS even 
when BMD is normal. [6] 
 
Several T2DM medications can affect bone metabolism. 
Thiazolidinediones (TZD) are PPAR-γ agonists which are used in the 
treatment of T2DM. They inhibit osteocyte formation and are 
associated with decreased BMD and increased risk of fractures. [7] 
Sodium glucose co-transporter (SGLT2) canagliflozin has also been 
associated with increased fractures. [8] GLP-1 receptor agonists are 
FDA approved for the treatment of T2DM. In mice, GLP-1 receptor 
agonists have been shown to decrease visceral adiposity, reduce levels 
of inflammatory markers and improve trabecular bone 
microarchitecture but their effect on humans has not been assessed. 
[9] This is the objective of the current proposal. 
 
 
 
Purpose 
 
 
Hypothesis: 
 
“Administration of GLP-1 receptor agonists will increase TBS  in 
postmenopausal women (age > 55) with T2DM by reducing visceral fat 
mass and associated production of inflammatory mediators(IL-1, IL-6 
and TNF-alpha), leading to a decrease in bone resorption (assessed by 
measuring C-telopeptide). We further hypothesize that GLP-1 receptor 
agonists will decrease sclerostin levels, leading to increased bone 
formation (assessed by measuring osteocalcin and P1NP).” 


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Specific Aim(s) 
 
Aim 1: To test the hypothesis that administration of GLP-1 receptor 
agonists will increase trabecular bone score in postmenopausal women 
(age >55 years) with T2DM. 
 
Aim 2: To test the hypothesis that administration of GLP-1 receptor 
agonists will decrease visceral fat mass, and decrease production of 
inflammatory markers (IL-1, IL-6, TNF-alpha) in postmenopausal 
women (age>55 years) with T2DM, and that this will be associated with 
decreased bone resorption (assessed by measuring C-telopeptide). 
 
Aim 3: To test the hypothesis that administration of GLP-1 receptor 
agonists will decrease sclerostin, with an associated increase in bone 
formation (assessed by measuring osteocalcin and P1NP), in 
postmenopausal women (age >55 years) with T2DM. 
 
Study Period 
(inclusive years) 
Prospective (June 1, 2019- December 31, 2022)  
 


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Study Design 
This is a prospective non-randomized study of one year duration. A 
total of 48 (24 in the GLP group and 24 in the non GLP group) 
postmenopausal females will be enrolled in the study. This study 
design will allow us to study the effects of GLP-1 receptor agonists on 
bone metabolism (formation and resorption); and bone 
microarchitecture (TBS) and also provide evidence regarding the 
potential role of visceral adipose tissue in bone metabolism in 
postmenopausal women with T2DM.  
 
All UMMC providers in the division of endocrinology will be briefed 
about the study and all the participants will be drawn from the UMMC 
Endocrinee, Family Medicine, and Internal Medicine clinics. 
 
The treating providers will have sole discretion in the choice of 
medications to be used for the management of each patient’s type 2 
diabetes mellitus. 
 
Patients who are enrolled in the study will be placed in the GLP group if 
they are on GLP-1 receptor agonists (for the treatment of their 
diabetes mellitus as decided by their endocrine provider) or in the non 
GLP group if they are not on GLP-1 receptor agonists. 
 
Throughout the study, the management of the each patient’s T2DM 
will be according to standard of care as decided by the treating 
provider, for both the groups. 
 
Methodology: 
 
Eligible participants will be identified by designated Research 
Personnel, who are listed on the delegation log, by going through the 
UMMC Endocrine, Family Medicine, and Internal Medicine  clinic 
schedules using the inclusion and exclusion criteria. Once a potential 
participant is identified, the provider (Faculty, resident, nurse 
practitioner or fellow) scheduled to see the patient would be notified. 
Of note, Dr. Garla’s and Dr. Cardozo’s clinic patients will not be 
considered for the study. 
 
The treating provider will independently make the decision regarding 
the treatment of the patient’s diabetes mellitus (whether GLP-1 
receptor agonist or other medication needs to be started or not), then 
the treating provider will enquire if the patient is interested in 
participating in the study. 
 


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If the patient is interested, the treating provider will notify the research 
personnel who would see the patient promptly in the privacy of the 
examination room and  then explain to the patient about the study in 
detail (objectives, design, tests involved and follow up, etc.) and seek 
their consent. 
 
Once consent is obtained then the research personnel will enroll the 
participant to the appropriate group (GLP vs non GLP) based on the 
medications prescribed by the treating provider. The research 
personnel will coordinate with radiology to schedule the baseline, 6 
months and 1 year DXA scan. We will obtain research blood draws at 
baseline, 6 months and 1 year utilizing the same venipuncture done for 
routine clinical labs at these visits. 
 
A $10 gift card will be given to participants after completion of each of 
the three DXA scan amounting to a total of 30$ for the entire study.  
 
Please see the Schedule of events document for a detailed description 
of study procedures. 
 
Inclusion Criteria 
 
Criteria that will identify the study population  
 
-A diagnosis of Type 2 Diabetes Mellitus 
-Postmenopausal female 
-Age >55 years 
- Hemoglobin A1c between 7 and 10 within 6 months of the first visit. 
 
 
 
Exclusion Criteria 
 
 
List all exclusion criteria* 
 
-A diagnosis of Type 1 Diabetes mellitus 
-History of GLP-1 receptor agonist/DPP4 inhibitor use 
-eGFR <30 ml/min in the last 3 months 
-History of pancreatitis 
-Documented personal or family history of medullary thyroid cancer 
-Documented history of treatment with anti-osteoporosis agents 
- Documented secondary osteoporosis 
-Documented presence of prosthesis or devices in the spine 
-Unwilling or unable to consent 


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Number of 
Participants/ 
Records to be 
reviewed 
(anticipated) 
48 
 
Outcome Measures 
 
 
The primary outcome will be change in TBS from baseline to six months 
and one year after the initiation of a GLP-1 receptor agonist. TBS will be 
assessed by DXA scans done at baseline, six months and one year. 
 
The secondary outcomes are  
-  Change in visceral fat mass (measured by DXA) at 6 and 1 year after 
starting GLP-1 receptor agonists as compared to baseline. 
 
- Change in inflammatory markers and bone resorption markers (as 
measured by commercial assays) at 6 and 12 months after starting GLP-
1 receptor agonists as compared to baseline. 
 
-  Changes in levels of sclerostin, osteocalcin, and P1NP (as measured 
by commercial assays) from baseline to six months and one year after 
starting GLP-1 receptor agonist.  
 
Statistical methods to assess changes in individual measures and 
possible correlations among different measures (e.g. TBS, visceral fat 
mass, and biomarkers) are described below. 
 
 
Study Endpoints 
 
 
Outcomes will be assessed at six months and one year and will be 
compared to baseline values. 


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Protected Health 
Information (PHI) 
 
 
PHI to be accessed: Patient’s medical record 
 
PHI to be collected: 
Name, Address, phone number and email address 
Medical record number 
Date of birth 
Race (African American or Caucasian) 
Duration of menopause (Years and months) 
Duration of T2DM (Years and months) 
Smoker (Yes/No) and duration 
Alcohol use (Yes/No) (Years and months) 
Presence of diabetic retinopathy (Yes/No) 
Presence of diabetic neuropathy (Yes/No) 
History of falls and/or fractures (Yes/No) 
List of anti-hyperglycemic medications 
List of current medications 
Weight 
Height 
BMI 
Hip circumference 
Waist circumference 
Blood pressure  
Date of DXA scan 
Visceral adiposity index 
Subcutaneous adiposity 
Lumbar trabecular score 
Hemoglobin A1c (%) 
Low density lipoprotein (LDL)  
High density lipoprotein (HDL)  
Total cholesterol  
Triglycerides  
Microalbuminuria/Creatinine ratio 
Interleukin-1 (IL-1) 
Interleukin-6 (IL-6) 
Tumor necrosis factor-alpha 
C-telopeptide 
Sclerostin 
P1NP 
Osteocalcin. 
 
RedCap will be utilized to record all study date. Access to study data 
will be restricted to members of the study team. 
 
 


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Statistical 
Methodology  
 
 
 
 
Statistical analyses were designed in collaboration with Dr. 
Wondwosen Yimer, PhD (Statistics). 
 
 
Means and standard deviations of baseline, six month and one year 
TBS values will be reported. Changes in TBS will be analyzed using a 
linear mixed model contrasting the GLP and non GLP groups. 
 
Means and standard deviations of baseline, and 6 and 12-month values 
of visceral fat mass, IL-1, IL-6 , TNF-α and C-telopeptide levels will be 
reported. Changes in TBS will be analyzed for any correlation the 
changes in visceral fat mass, levels of inflammatory mediators and C-
telopeptide in the GLP and non GLP groups using linear or logistic 
regression as appropriate. 
 
Means and standard deviations of baseline, six month and one-year 
values of sclerostin, P1NP and osteocalcin will be reported and 
analyzed for any correlation to the changes in TBS in the GLP and non 
GLP groups linear or logistic regression as appropriate. 
 
 
Power analysis: The primary endpoint is the change in TBS at 6 and 12 
months compared to baseline. From prior studies we expect a 10% 
increase in TBS (corresponding to 0.117 for human TBS) for the GLP 
group only. With a difference of 0.117 between 24 cases and 24 
controls we have power of >0.8 and < 5% probability of type 1 error. 
The primary motivation for this pilot study is to assess effect sizes to 
support more accurate power calculations, to be used in an application 
for extramural funding to conduct a larger, definitive study. 
 
 


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References  
 
 
 
 
1) Kanis JA (2007) WHO Technical Report, University of Sheffield, UK: 
66. 
 
2) https://www.iofbonehealth.org/facts-statistics#category-14 as 
accessed on 4/1/2019. 
 
3) Gullberg B, Johnell O, Kanis JA (1997) World-wide projections for hip 
fracture. Osteoporos Int 7:407. 
 
4) Paschou SA, Dede AD, Anagnostis PG, Vryonidou A, Morganstein D, 
Goulis DG. Type 2 Diabetes and Osteoporosis: A Guide to Optimal 
Management. J Clin Endocrinol Metab. 2017 1; 02(10):3621-3634. 
 
5) Schacter GI, Leslie WD. Diabetes and Bone Disease. Endocrinol 
Metab Clin North Am. 2017; 46(1):63-85. 
 
6) Jiang N, Xia W. Assessment of bone quality in patients with diabetes 
mellitus. Osteoporos Int. 018; 29(8):1721-1736. 
 
7) Zhu ZN, Jiang YF, Ding T. Risk of fracture with thiazolidinediones: an 
updated meta-analysis of randomized clinical trials. Bone. 2014; 68: 
115-23. 
 
8) Watts NB, Bilezikian JP, Usiskin K, Edwards R, Desai M, Law G, 
Meininger G.Effects of Canagliflozin on Fracture Risk in Patients With 
Type 2 Diabetes Mellitus. J Clin Endocrinol Metab. 2016; 101(1):157-66 
 
9) Mabilleau G, Pereira M, Chenu C. Novel skeletal effects of glucagon-
like peptide-1 (GLP-1) receptor agonists. J Endocrinol. 2018; 236(1):R29-
R42. 
 
Data Collection 
Sheet 
 
See Case report form attached to the proposal 
 
 
Funding Source 
 
 
 
We have been successful in obtaining an MCCTR pilot grant for this 
study.