Changes in Bone Turnover With Increased Incretin Hormone Exposure

Type 2 Diabetes Mellitus Clinical Trial

— DRTC  

Official title:

Changes in Bone Turnover With Increased Incretin Hormone Exposure (UAB Diabetes Research and Training Center Pilot and Feasibility Study)

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT01374568
• Other study ID #: UAB F100317002
• Status: Recruiting
• Phase: Phase 4
• First received: June 10, 2011
• Last updated: May 31, 2016
• Start date: July 2010
• Est. completion date: December 2017

Study information

• Verified date: May 2016
• Source: University of Alabama at Birmingham
• Contact: Tammy Perkins, RN
• Phone: 205-934-4112
• Is FDA regulated: No
• Health authority: United States: Institutional Review Board
• Study type: Interventional

Clinical Trial Summary

The purpose of this study is to determine if the use of sitagliptin increases bone formation and reduces bone turnover in postmenopausal women with type 2 diabetes.

Description:

Patients with Type 2 Diabetes Mellitus (T2DM) are at an increased risk of fracture, despite having bone mineral density (BMD) similar to age and sex matched cohorts. Recent studies have indicated that changes in incretin (INtestinal seCRETion of INsulin) hormones in the setting of T2DM may play a role in bone metabolism. Two of these incretin hormones, gastric inhibitory polypeptide (GIP) and glucagon-like peptide-1 (GLP-1), have been shown to be involved in bone turnover regulation, in addition to their effect in increasing insulin secretion and decreasing glucagon secretion in a glucose-dependent manner. In addition, the rise in glucagon-like peptide-2 (GLP-2) in the postprandial state has been found to have a direct effect on reduced bone resorption in a non-fasting state and treatment with GLP-2 improved BMD in postmenopausal women. Due to their glucose lowering effects, incretins have been a therapeutic target for the treatment of T2DM through GLP-1 receptor analogs or inhibition of incretin metabolism via dipeptidyl peptidase 4 (DPP-4) inhibitors (i.e. sitagliptin). Inhibition of DPP-4 leads to an approximate doubling of GLP-1 and GIP levels but also leads to reduced breakdown of GLP-2.

Less is known about the effect of incretin-directed therapies, specifically sitagliptin, and bone metabolism. To our knowledge, two studies have looked at the direct effects of currently available incretin-directed therapies on bone metabolism. Exenatide (a GLP-1 analog) treatment of insulin resistant and type 2 diabetic rats resulted in osteogenic effects with increased osteocalcin levels following treatment. In a study of female non-diabetic Sprague-Dawley rats treated with pioglitazone, rosiglitazone, sitagliptin, vs. placebo, no significant change in bone mineral density was seen in the sitagliptin or placebo treated rats (compared to significant loss of bone mineral density in the TZD groups). Even fewer published studies are available evaluating changes in bone metabolism with the use of incretin hormones in humans. The majority of the human studies have been completed with GLP-2. These studies show a dose-dependent effect of GLP-2 on bone resorption and, preliminarily, show improved bone mineral density in postmenopausal women treated with GLP-2. However, the changes in incretin activity vary in persons with glucose intolerance and T2DM. Therefore, it is important to understand the potential effects of these medications on bone metabolism in persons prescribed these medications for treatment of their T2DM.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 40
• Est. completion date: December 2017
• Est. primary completion date: April 2017
• Accepts healthy volunteers: Accepts Healthy Volunteers
• Gender: Female
• Age group: 45 Years and older

Eligibility

Inclusion Criteria:

• Postmenopausal women (as defined by age >55 years old or amenorrhea for >1years)

• Type 2 DM currently not on diabetes-specific medication(s) or treated with monotherapy of metformin or a sulfonylurea. Patients treated with insulin monotherapy will also be eligible if the total daily dose of insulin is <10units.

• Hemoglobin A1c (HbA1c) of 6.5-9.0%

Exclusion Criteria:

• Use of an incretin mimetic (i.e. exenatide), a DPP-4 inhibitor (i.e. sitagliptin, saxagliptin), a thiazolidinedione, or oral glucocorticoids in the 6 months prior to the study will not be eligible

• Known osteoporosis or patients treated with an osteoporosis-specific medication (bisphosphonate, teriparatide) or estrogen (including Selective Estrogen Receptor Modulators (SERMs)) or those who anticipate imminent treatment with one of these medications will be excluded from the study

• Chronic kidney disease (calculated GFR <30 ml/min) or a disease known to affect bone turnover (i.e. Paget Disease, Osteogenesis Imperfecta, HIV) will be excluded from the study.

• History of pancreatitis

Study Design

Allocation: Randomized, Intervention Model: Single Group Assignment, Masking: Double Blind (Subject, Investigator), Primary Purpose: Health Services Research

Related Conditions & MeSH terms

• Diabetes Mellitus, Type 2
• Type 2 Diabetes Mellitus

Intervention

Drug:
• sitagliptin
sitagliptin 100mg daily

Other:
• Placebo
1 pill daily

Locations

Country	Name	City	State
United States	University of Alabama at Birmingham	Birmingham	Alabama

Sponsors (1)

Lead Sponsor	Collaborator
University of Alabama at Birmingham

Country where clinical trial is conducted

United States, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Bone turnover, measured by osteocalcin, type I collagen cross-linked aminoterminal peptide in urine (Urine NTX), and bone-specific alkaline phosphatase will be lower in subjects treated with sitagliptin when compared to those treated with placebo.	Further information regarding the effect of incretin hormones on bone is important for safety reasons (recent information linking thiazolidinediones with increased risk of fracture), but more importantly,to better understand the mechanism of bone changes seen in persons with T2DM. Further information is needed to help guide clinicians in charge of caring for the growing population of persons with T2DM at risk of many complications, including an increased risk of fracture.	8 weeks	Yes