Bone Metabolism
Conditions
Keywords
Glucose Metabolism Disorder, Dysmetabolic Syndrome, Type II Diabetes, Diabetes Mellitus, Lipoatrophic, Postmenopausal
Brief summary
The purpose of this study is to evaluate the effect of pioglitazone on bone metabolism in postmenopausal women with impaired fasting glucose.
Detailed description
The World Health Organization has estimated that 30% of all women aged over 50 years (postmenopausal) have osteoporosis according to a definition of Bone Mineral Density at any site being more than 2.5 standard deviations below the mean for young healthy adult women. A known risk factor for development of osteoporosis and fracture is diabetes mellitus, with correlations to duration of disease and poor glycemic control. Pioglitazone is a thiazolidinedione developed by Takeda Pharmaceuticals for the treatment of type 2 diabetes. Preclinical studies to date on the bone effects of thiazolidinediones have not clearly identified a mechanism of bone loss. While there is evidence of increased bone fractures in postmenopausal diabetic females treated with a thiazolidinedione, the mechanism is not known. Initial studies with thiazolidinediones in humans have focused on short term exposure (12 to 14 weeks) and non-diabetic females. These studies have shown acute changes in circulating bone markers and bone density, but have been questioned because they may not represent bone metabolism in states of abnormal glucose metabolism. Impaired glucose tolerance has been identified not only as a risk factor for developing type 2 diabetes, but also at higher risk for known complications of diabetes. Examination of the effect of thiazolidinediones on bone metabolism in IGT patients will provide data in patients with abnormal glucose tolerance, but without the potential confounding effects of oral hypoglycemic medications to treat type 2 diabetes. The primary objective of this study is to evaluate the effect of pioglitazone on bone mass and metabolism in postmenopausal women with impaired fasting glucose or impaired glucose tolerance. Total participation time in this study is approximately 1 year and six months.
Interventions
DRUGPioglitazone
Pioglitazone 30 mg, tablets, orally, once daily for 4 weeks, then increased to Pioglitazone 45 mg, tablets, orally, once daily for up to 48 weeks.
DRUGPlacebo
Pioglitazone placebo-matching tablets, orally, once daily for up to 52 weeks.
Sponsors
Takeda
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
FEMALE
Age
No minimum to 70 Years
Healthy volunteers
No
Inclusion criteria
* Is female and has not experienced menses for at least 5 years. * Has a Fasting Plasma Glucose level greater than or equal to 100 and less than 126 mg/dL or a 2-hour post-oral glucose tolerance test greater than or equal to 140 and less than or equal to 199 mg/dL at Screening. * Has a body mass index greater than or equal to 16 and less than or equal to 40 kg/m2 and weighs less than 300 pounds (approximately 136 kilograms). * Agrees to take daily supplements of Vitamin D (a minimum of 800 IU daily) and calcium (a minimum of 1000 mg daily) during the treatment and wash-out periods. * Has clinical laboratory evaluations (including clinical chemistry, hematology, and complete urinalysis \[fasted for at least 8 hours\]) within the reference range for the testing laboratory unless the results are deemed not clinically significant by the investigator or sponsor. * Is in good health as determined by the physician (ie, via medical history and physical examination) at Screening.
Exclusion criteria
* Has a fasting triglyceride level greater than 500 mg/dL. * Has a hemoglobinopathy causing anemia or interfering with glycosylated hemoglobin assays. * Has an alanine transaminase level greater than or equal to 2.5 times the upper limit of normal, active liver disease or jaundice. * Has Vitamin D (25-OH-D) less than 20 ng/mL. * Has Baseline Bone Mineral Density defined as a T-score less than -2.0 at the total hip, spine, or femoral neck based on Caucasian reference values. * Has unexplained microscopic or macroscopic hematuria confirmed by repeat testing. * Has any of the following disorders: * Rheumatoid Arthritis * Thyroid (uncontrolled on thyroid replacement therapy), parathyroid, pituitary, nutritional, inflammatory, gastrointestinal, autoimmune, or renal or other disease known to affect bone metabolism. * A personal history of kidney stones. * Has a clinical history after age 45 of wrist, hip, or leg fractures. * Has a history of more than 1 asymptomatic vertebral deformity or any vertebral deformity attributed to osteoporosis. * Has a known history of drug abuse (defined as illicit drug use) or a known history of alcohol abuse within 2 years of Screening. * Has signs and/or symptoms of heart failure. * Is currently participating in another investigational study or has participated in an investigational study within the past 30 days or 5 half lives of the investigational product, whichever is longer. * Has any other serious disease or condition at screening or at randomization that might make it difficult to successfully manage and follow up with the subject according to the protocol. * Has a history of cancer, other than basal cell carcinoma or Stage 1 squamous cell carcinoma of the skin that has not been in remission for at least 5 years prior to the first dose of study drug. * Has a history of breast cancer. * Is taking or has ever taken pioglitazone or other Thiazolidinediones. * Has received or donated blood or blood products within 30 days preceding the Screening visit or plans to donate blood during the study.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Percent Change From Baseline to Month 12 in Bone Mineral Density in the Total Proximal Femur by Dual-Energy-Ray Absorptiometry (DXA) | Baseline and Month 12. | The change in bone mineral density in the total proximal femur at month 12 relative to baseline. DXA is a means of measuring BMD through x-ray. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Percent Change From Month 12 to Month 18 in Bone Mineral Density in the Total Proximal Femur by DXA | Month 12 and Month 18. | The change in bone mineral density in the total proximal femur at month 18 relative to month 12. DXA is a means of measuring BMD through x-ray. |
Other
| Measure | Time frame | Description |
|---|---|---|
| Change in Fasting Plasma Glucose (FPG) | Baseline and Month 12; Month 12 and Month 18. | The change between the fasting plasma glucose value collected at each time frame indicated. |
| Number of Participants Who Converted to Type 2 Diabetes Mellitus (T2DM) | Up to 18 months. | Participants were considered to have converted to T2DM if there were ≥2 consecutive post-Baseline FPG measurements ≥126 mg/dL. Participants meeting criteria were tabulated and summarized by Study Period (Treatment and Follow-up). Conversion to T2DM during Treatment Period occurred if either both of the consecutive post-Baseline high FPG values, or the first of the 2 consecutive high values occurred on or before the first day off study drug. Conversion to T2DM occurred during the Follow-up Period if both consecutive high values occurred after at least 1 day after the Treatment Period. |
| Number of Participants With Fracture | Up to 18 months. | Number of participants with confirmed (through an adjudication process) fractures during the study. Circumstances surrounding the fracture, available X-ray and other diagnostic results and healing status were collected for the adjudication process. |
Countries
United States
Participant flow
Recruitment details
Participants took part in the study at 25 investigative sites in the United States from 23 May 2008 to 02 February 2011.
Pre-assignment details
Postmenopausal participants enrolled in 1 of 2 treatment groups to examine the effect of pioglitazone on bone mineral density (BMD) by dual-energy-ray absorptiometry (DXA). Participants with \>7% decrease from baseline in BMD of the total proximal femur or spine based on DXA scan results (confirmed with a repeat scan) were to discontinue study drug.
Participants by arm
| Arm | Count |
|---|---|
| Pioglitazone Pioglitazone 30 mg, tablets, orally, once daily for 4 weeks, then increased to Pioglitazone 45 mg, tablets, orally, once daily for up to 48 weeks. | 78 |
| Placebo Pioglitazone placebo-matching tablets, orally, once daily for up to 52 weeks. | 78 |
| Total | 156 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 4 | 5 |
| Overall Study | BMD loss >7% | 2 | 3 |
| Overall Study | Lost to Follow-up | 5 | 3 |
| Overall Study | Protocol Violation | 2 | 3 |
| Overall Study | Withdrawal by Subject | 5 | 7 |
Baseline characteristics
| Characteristic | Total | Pioglitazone | Placebo |
|---|---|---|---|
| Age Continuous | 59.6 years STANDARD_DEVIATION 5.65 | 59.0 years STANDARD_DEVIATION 5.04 | 60.2 years STANDARD_DEVIATION 6.17 |
| Age, Customized <45 years | 1 participants | 0 participants | 1 participants |
| Age, Customized ≥65 years | 35 participants | 12 participants | 23 participants |
| Age, Customized Between 45 and 64 years | 120 participants | 66 participants | 54 participants |
| Body Mass Index (BMI) | 29.95 kg/m2 STANDARD_DEVIATION 4.96 | 29.61 kg/m2 STANDARD_DEVIATION 5.055 | 30.29 kg/m2 STANDARD_DEVIATION 4.872 |
| Ethnicity Hispanic or Latino | 72 participants | 38 participants | 34 participants |
| Ethnicity Non Hispanic or Latino | 84 participants | 40 participants | 44 participants |
| Height | 160.7 cm STANDARD_DEVIATION 7.28 | 160.3 cm STANDARD_DEVIATION 6.85 | 161.1 cm STANDARD_DEVIATION 7.7 |
| History of hip fracture? No | 148 participants | 73 participants | 75 participants |
| History of hip fracture? Yes | 8 participants | 5 participants | 3 participants |
| Race (NIH/OMB) American Indian or Alaska Native | 1 participants | 1 participants | 0 participants |
| Race (NIH/OMB) Asian | 6 participants | 2 participants | 4 participants |
| Race (NIH/OMB) Black or African American | 12 participants | 6 participants | 6 participants |
| Race (NIH/OMB) More than one race | 1 participants | 1 participants | 0 participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 participants | 0 participants | 0 participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 participants | 0 participants | 0 participants |
| Race (NIH/OMB) White | 138 participants | 70 participants | 68 participants |
| Region of Enrollment United States | 156 participants | 78 participants | 78 participants |
| Sex: Female, Male Female | 156 Participants | 78 Participants | 78 Participants |
| Sex: Female, Male Male | 0 Participants | 0 Participants | 0 Participants |
| Smoking Classification Current smoker | 16 participants | 7 participants | 9 participants |
| Smoking Classification Ex-smoker | 33 participants | 19 participants | 14 participants |
| Smoking Classification Never smoked | 107 participants | 52 participants | 55 participants |
| Weight | 77.53 kg STANDARD_DEVIATION 14.964 | 76.03 kg STANDARD_DEVIATION 13.406 | 79.02 kg STANDARD_DEVIATION 16.326 |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 32 / 78 | 34 / 78 |
| serious Total, serious adverse events | 3 / 78 | 1 / 78 |
Outcome results
Primary
Percent Change From Baseline to Month 12 in Bone Mineral Density in the Total Proximal Femur by Dual-Energy-Ray Absorptiometry (DXA)
The change in bone mineral density in the total proximal femur at month 12 relative to baseline. DXA is a means of measuring BMD through x-ray.
Time frame: Baseline and Month 12.
Population: All randomized participants who received at least 1 dose of study medication (Full Analysis Set). This was an observed case analysis with no imputation for missing data. If a valid pre-treatment scan was not available, the earliest (within 30 days) post-dosing scan was used as Baseline. There was one such participant for this endpoint.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Pioglitazone | Percent Change From Baseline to Month 12 in Bone Mineral Density in the Total Proximal Femur by Dual-Energy-Ray Absorptiometry (DXA) | -0.69 percent | Standard Error 0.284 |
| Placebo | Percent Change From Baseline to Month 12 in Bone Mineral Density in the Total Proximal Femur by Dual-Energy-Ray Absorptiometry (DXA) | -0.14 percent | Standard Error 0.277 |
Comparison: The sample size was calculated using a precision approach to estimate the difference between the pioglitazone and placebo treatment groups in the percent change from baseline in BMD.p-value: 0.1795% CI: [-1.33, 0.24]ANCOVA
Secondary
Percent Change From Month 12 to Month 18 in Bone Mineral Density in the Total Proximal Femur by DXA
The change in bone mineral density in the total proximal femur at month 18 relative to month 12. DXA is a means of measuring BMD through x-ray.
Time frame: Month 12 and Month 18.
Population: All randomized participants who received at least 1 dose of study medication (Full Analysis Set). This was an observed case analysis with no imputation for missing data.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Pioglitazone | Percent Change From Month 12 to Month 18 in Bone Mineral Density in the Total Proximal Femur by DXA | -0.14 percent | Standard Error 0.265 |
| Placebo | Percent Change From Month 12 to Month 18 in Bone Mineral Density in the Total Proximal Femur by DXA | 0.04 percent | Standard Error 0.258 |
p-value: 0.6495% CI: [-0.91, 0.56]ANCOVA
Other Pre-specified
Change in Fasting Plasma Glucose (FPG)
The change between the fasting plasma glucose value collected at each time frame indicated.
Time frame: Baseline and Month 12; Month 12 and Month 18.
Population: All randomized participants who received at least 1 dose of study medication (Full Analysis Set).
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|---|
| Pioglitazone | Change in Fasting Plasma Glucose (FPG) | Baseline to Month 12 (n=57; n=61) | -2.8 mg/dL | Standard Error 1.66 |
| Pioglitazone | Change in Fasting Plasma Glucose (FPG) | Month 12 to Month 18 (n=54; n=57) | 0.4 mg/dL | Standard Error 2 |
| Placebo | Change in Fasting Plasma Glucose (FPG) | Baseline to Month 12 (n=57; n=61) | 6.0 mg/dL | Standard Error 1.61 |
| Placebo | Change in Fasting Plasma Glucose (FPG) | Month 12 to Month 18 (n=54; n=57) | -1.0 mg/dL | Standard Error 1.94 |
Other Pre-specified
Number of Participants Who Converted to Type 2 Diabetes Mellitus (T2DM)
Participants were considered to have converted to T2DM if there were ≥2 consecutive post-Baseline FPG measurements ≥126 mg/dL. Participants meeting criteria were tabulated and summarized by Study Period (Treatment and Follow-up). Conversion to T2DM during Treatment Period occurred if either both of the consecutive post-Baseline high FPG values, or the first of the 2 consecutive high values occurred on or before the first day off study drug. Conversion to T2DM occurred during the Follow-up Period if both consecutive high values occurred after at least 1 day after the Treatment Period.
Time frame: Up to 18 months.
Population: All randomized participants who received at least 1 dose of study medication (Full Analysis Set).
| Arm | Measure | Group | Value (NUMBER) | Dispersion |
|---|---|---|---|---|
| Pioglitazone | Number of Participants Who Converted to Type 2 Diabetes Mellitus (T2DM) | Double-Blind Period (n=76; n=75) | 1 participants | 1.3 |
| Pioglitazone | Number of Participants Who Converted to Type 2 Diabetes Mellitus (T2DM) | Follow-up Period (n=63; n=59) | 0 participants | 0 |
| Placebo | Number of Participants Who Converted to Type 2 Diabetes Mellitus (T2DM) | Double-Blind Period (n=76; n=75) | 7 participants | 9.3 |
| Placebo | Number of Participants Who Converted to Type 2 Diabetes Mellitus (T2DM) | Follow-up Period (n=63; n=59) | 1 participants | 1.7 |
Other Pre-specified
Number of Participants With Fracture
Number of participants with confirmed (through an adjudication process) fractures during the study. Circumstances surrounding the fracture, available X-ray and other diagnostic results and healing status were collected for the adjudication process.
Time frame: Up to 18 months.
Population: All randomized participants who received at least 1 dose of study medication (Full Analysis Set).
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Pioglitazone | Number of Participants With Fracture | 1 participants |
| Placebo | Number of Participants With Fracture | 3 participants |