Effect of Pioglitazone Versus Metformin on Bone Health in Postmenopausal Women With Type 2 Diabetes

Study Overview
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Brief Summary
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The study tests whether pioglitazone (PIO)as compared to metformin (MET)affects bone health including bone mineral density, bone turnover markers, and osteocyte biomarker in patients with type 2 diabetes (T2DM).

Detailed Description
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Women with T2DM exhibit normal or higher bone mineral density (BMD) for their age, but with approximately twice the overall risk of bone fragility compared with nondiabetic subjects. Known the apparent association between T2DM and the risk of bone fragility, examining the effects of commonly used oral antidiabetic agents; such as MET and thiazolidinediones (TZDs; for example rosiglitazone [ROS] or PIO), on BMD and/or bone turnover is of great clinical relevance for both diabetic patients and their treating physicians. Recent clinical trials, showed that women treated with ROS had higher risk of bone fragility and self-reported adverse events. Similarly, women on long-term treatment with PIO for T2DM experienced higher incidence of distal extremity fractures. TZDs are agonists of the nuclear transcription factor peroxisome proliferator- activated receptor-γ (PPAR-γ) which increase insulin sensitivity and improve glycemic control in T2DM. PPAR (γ) acts also as a molecular factor that favours adipogenesis over osteoblastogenesis of mesenchymal stem cells. The latter was suggested as a potential mechanism for the effects of TZDs on bone among others. In humans, TZDs decrease BMD and increase bone fragility risk. This study tests whether pioglitazone as compared to MET (both are commonly used in the treatment of T2DM in Saudi Arabia and other countries) affects bone health including bone mineral density, bone turnover markers, and osteocyte biomarker in patients with T2DM.

Official Title
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Phase 1 Study of Pioglitazone Versus Metformin on Bone Health in Postmenopausal Women With Type 2 Diabetes

Conditions
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Diabetes Mellitus, Diabetes Mellitus, Type 2, Glucose Metabolism Disorders

Intervention / Treatment
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* Drug: Pioglitazone
* Drug: Metformin


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: BMD T-score greater than -2.5 at the total hip, femoral neck, and lumbar spine; No prior antidiabetic therapy; Drug-naïve with glycosylated hemoglobin A1c (HbA1c) ≥ 7.0 to ≤ 10.0%. 53.2 mmol/mol to 88.2 mmol/mol); Body-mass index of 40 Kg/m2 and less; Stable body weight for at least 4 months. Exclusion Criteria: Type 1 diabetes mellitus (presence of GAD auto antibodies); History of diabetes or uncontrolled hypertension; Treatment with antidiabetic agents including TZDs; Chronic diseases known to affect bone; Previous treatment with estrogens and other medications known to affect bone ; Creatinine clearance less than 60 ml/min

Ages Eligible for Study
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Minimum Age: 50 Years
Maximum Age: 65 Years

Sexes Eligible for Study
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Female

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Experimental: 1<br>Pioglitazone given 30mg/once daily for 12 months. | Drug: Pioglitazone<br>* 30 mg/daily for 12 months<br>* Other names: Actos;|
| Active Comparator: Active comparator: 2<br>Metformin given 850 mg/twice daily for 12 months. | Drug: Metformin<br>* 850 mg/daily for 12 months<br>* Other names: Glucophage;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in mean percentage change in BMD at various sites by Dual energy X-ray absorptiometry(DXA) from baseline and at 6, 12 months in PIO versus MET treatment group. | The primary endpoint was change in mean percentage change in BMD values at the lumbar spine (L1-L4), femoral neck and total hip by DXA from baseline and at 6 and 12 months in the PIO and the MET treatment groups. | 6-18 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Bone turnover Markers and other Biomarkers | Secondary end-points were changes in serum sclerostin, serum bone-specific alkaline phosphatase (BSAP), serum procollagen type1 N-terminal propeptide (P1NP) and serum C-terminal crosslinking telopeptide of type 1 collagen (CTX); and urinary N-terminal crosslinking telopeptide type 1 collagen (u-NTX); serum calcium, 25-hydroxyvitamin D (25-OHD), and serum Dickkopf-1( DKK-1) at various time intervals from baseline between PIO vs MET treatment. | 6-18 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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pioglitazone, metformin, hyperglycemic agents, physiological effects of drugs, bone health