Clinical trial NCT01374568: Changes in Bone Turnover With Increased Incretin Hormone Exposure
Official title: Changes in Bone Turnover With Increased Incretin Hormone Exposure (UAB Diabetes Research and Training Center Pilot and Feasibility Study)
Study type: INTERVENTIONAL
Overall status: TERMINATED
Phase: PHASE4
Conditions: Type 2 Diabetes Mellitus
Keywords: Type 2 diabetes
sitagliptin
Januvia
Lead sponsor: University of Alabama at Birmingham
Sponsor class: OTHER
First posted: 2011-06-16
Enrollment: 6
Sex: FEMALE
Minimum age (years): 45
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: yes
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: HEALTH_SERVICES_RESEARCH

Brief 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.

Detailed 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.

Eligibility criteria: 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

Primary outcomes:
measure: Bone Turnover in Subjects Treated With Sitagliptin When Compared to Those Treated With Placebo.
timeFrame: 8 weeks
measure: Bone Turnover in Subjects Treated With Sitagliptin When Compared to Those Treated With Placebo
timeFrame: 8 WEEKS
Secondary outcomes:
Other outcomes:
Locations:
city: Birmingham
country: United States
facility: University of Alabama at Birmingham
state: Alabama
Study officials:
affiliation: University of Alabama at Birmingham
name: Amy Warriner, MD
role: PRINCIPAL_INVESTIGATOR
References: