Fractures, Bone, Type II Diabetes
Conditions
Keywords
thiazolidinediones, rosiglitazone, amiloride, pioglitazone, fracture, Spironolactone
Brief summary
Treatment with thiazolidinediones (TZD) has recently been reported to possibly increase the risk of fractures in a randomized trial exploring the efficacy of rosiglitazone (RSG), metformin, or glyburide encompassing 4360 patients with type 2 diabetes. It is hypothesized that spironolactone, a diuretic that is broadly used for the treatment of fluid retention and edema associated with TZD, has a potential protective effect against bone fractures. However, to our knowledge, this has not been tested in diabetic patients treated with TZD. Amiloride is another diuretic that shares with spironolactone the anti mineralocorticoid ion gated channels activity and will be analysed in this study with regard to possible protective effect against bone fracture in combination with TZD. This study is a nested case-control study conducted among type 2 diabetes subjects exposed to TZD. The study aims to explore if the risk of fracture is reduced among type 2 diabetic subjects exposed to spironolactone and TZD. The study will compare the odds of any low impact fracture, and hand, foot, upper arm, wrist, and hip fracture incidence in subjects treated with TZD+spironolactone and TZD+amiloride compared to subjects treated with TZD only. The study population will consist of type 2 diabetes patients aged 18 -65 years old exposed to TZD. To be eligible for the study, a subject must have had at least one International Classification of Disease (ICD)-9 code for type 2 diabetes and have at least 6 months or at least 12 months of exposure to TZD (rosiglitazone \[RSG\], pioglitazone \[PIO\] or troglitazone) during their follow-up time available in the database.
Detailed description
Patients were not recruited for nor enrolled in this study. This study is a retrospective observational study. Data from medical records or insurance claims databases are anonymised and used to develop a patient cohort. All diagnoses and treatment are recorded in the course of routine medical practice.
Interventions
DRUGTZD only (RSG or PIO or troglitazone)
Drug exposure will be inferred from prescription claims. Subjects who have been exposed to TZD for at least 6 months or at least 12 months will be considered for inclusion.
DRUGTZD + spironolactone
Subjects who have been exposed to TZD for at least 6 months or at least 12 months will be considered for inclusion. In order to be eligible for inclusion in this category, the prescription days supply for TZD and spirinolactone must overlap by at least 30 days.
DRUGTZD + amiloride
Subjects who have been exposed to TZD for at least 6 months or at least 12 months will be considered for inclusion. In order to be eligible for inclusion in this category, the prescription days supply for TZD and Amiloride must overlap by at least 30 days.
Sponsors
GlaxoSmithKline
Study design
Observational model
CASE_CONTROL
Time perspective
RETROSPECTIVE
Eligibility
Sex/Gender
ALL
Age
18 Years to 65 Years
Healthy volunteers
No
Inclusion criteria
* At least one ICD-9 code for type 2 diabetes * At least 6 months or at least 12 months of exposure to TZD (RSG, PIO or troglitazone) during their follow-up time available in the database (The subject's study period begin date will be defined as the earliest date of their first TZD prescription. Subjects included in the study are required to have at least six months of follow-up time in the database prior to their first TZD prescription)
Exclusion criteria
* Subjects with a diagnosis of Paget's disease and osteomalacia * A history of fracture, osteoporosis or cancer prior to the first prescription of TZD (study begin date)
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Low Impact Fractures in Males and Females After 6 Months of Exposure to TZD | From the earliest date of first TZD prescription to the fracture diagnosis date (Cases) or the end of follow-up in the database (Controls) between January 1, 1997 and December 31, 2008 | ICD-9 codes (805-807.4x, 808-810.xx, 812-829.xx) were captured from Uniform Billing-92 records and Health Care Finance Administration records. Case is defined as incident cases of fracture with an ICD-9 diagnostic code for any low impact fracture occurring after the study period begin date (earliest date of the first TZD prescription). For each subject defined as case, up to four controls were randomly selected from patients with type 2 diabetes exposed to TZD without a fracture diagnosis during follow-up and matched to cases on age (+ 5 years), gender, and year of fracture diagnosis. |
| Number of Low Impact Fractures in Males and Females After 12 Months of Exposure to TZD | From the earliest date of first TZD prescription to the fracture diagnosis date (Cases) or the end of follow-up in the database (Controls) between January 1, 1997 to December 31, 2008 | ICD-9 codes (805-807.4x, 808-810.xx, 812-829.xx) were captured from Uniform Billing-92 records and Health Care Finance Administration records. Case is defined as incident cases of fracture with an ICD-9 diagnostic code for any low impact fracture occurring after the study period begin date (earliest date of the first TZD prescription). For each subject defined as case, up to four controls were randomly selected from patients with type 2 diabetes exposed to TZD without a fracture diagnosis during follow-up and matched to cases on age (+ 5 years), gender, and year of fracture diagnosis. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Number of Fractures of the Hand, Foot, Upper Arm, and Wrist in Males and Females After 6 Months of Exposure to TZD | From the earliest date of first TZD prescription to the fracture diagnosis date (Cases) or the end of follow-up in the database (Controls) between January 1, 1997 to December 31, 2008 | ICD-9 codes (815.0x, 816.0x, 817.0x, 825.0x, 825.2x, 826.0x, 812.0x, 812.2x, 812.4x, 814.0x) were captured from UB-92 records and HCFA 1500 records. Case is defined as incident cases of fracture with an ICD-9 diagnostic code for hand, foot, upper arm, and wrist fracture after the study period begin date (earliest date of the first TZD prescription). For each case, up to four controls were randomly selected from patients with type 2 diabetes exposed to TZD without a fracture diagnosis during follow-up and matched on age (+ 5 yrs), gender, and year of fracture diagnosis. |
| Number of Fractures of the Hand, Foot, Upper Arm, and Wrist in Males and Females After 12 Months of Exposure to TZD | From the earliest date of first TZD prescription to the fracture diagnosis date (Cases) or the end of follow-up in the database (Controls) between January 1, 1997 to December 31, 2008 | ICD-9 codes (815.0x, 816.0x, 817.0x, 825.0x, 825.2x, 826.0x, 812.0x, 812.2x, 812.4x, 814.0x) were captured from UB-92 records and HCFA 1500 records. Case is defined as incident cases of fracture with an ICD-9 diagnostic code for hand, foot, upper arm, and wrist fracture after the study period begin date (earliest date of the first TZD prescription). For each case, up to four controls were randomly selected from patients with type 2 diabetes exposed to TZD without a fracture diagnosis during follow-up and matched on age (+ 5 yrs), gender, and year of fracture diagnosis. |
| Number of Hip Fractures Combined in Males and Females After 6 Months of Exposure to TZD | From the earliest date of first TZD prescription to the fracture diagnosis date (Cases) or the end of follow-up in the database (Controls) between January 1, 1997 to December 31, 2008 | ICD-9 codes (820.0x, 820.2x, 820.8x) were captured from UB-92 records and HCFA 1500 records. Case is defined as incident cases of fracture with an ICD-9 diagnostic code for hip fracture after the study period begin date (earliest date of the first TZD prescription). For each case, up to four controls were randomly selected from patients with type 2 diabetes exposed to TZD without a fracture diagnosis during follow-up and matched on age (+ 5 yrs), gender, and year of fracture diagnosis. |
| Number of Hip Fractures Combined in Males and Females After 12 Months of Exposure to TZD | From the earliest date of first TZD prescription to the fracture diagnosis date (Cases) or the end of follow-up in the database (Controls) between January 1, 1997 to December 31, 2008 | ICD-9 codes (820.0x, 820.2x, 820.8x) were captured from UB-92 records and HCFA 1500 records. Case is defined as incident cases of fracture with an ICD-9 diagnostic code for hip fracture after the study period begin date (earliest date of the first TZD prescription). For each case, up to four controls were randomly selected from patients with type 2 diabetes exposed to TZD without a fracture diagnosis during follow-up and matched on age (+ 5 yrs), gender, and year of fracture diagnosis. |
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| TZD 6-month Cohort (Including TZD 12-month Cohort) The study population consisted of type 2 diabetes patients 18-65 years old exposed to thiazolidinedione (TZD). To be eligible for the study, a subject must have had at least one International Classification of Disease (ICD)-9 code for type 2 diabetes and have at least 6 months of exposure to TZD (rosiglitazone \[RSG\], pioglitazone \[PIO\], or troglitazone) during their follow-up time available in the database. A subset of patients were followed for at least 12 months (Outcome measure results for this subset also presented). Dose information was not collected. | 98,483 |
| Total | 98,483 |
Baseline characteristics
| Characteristic | TZD 6-month Cohort (Including TZD 12-month Cohort) |
|---|---|
| Age, Continuous | 52.2 Years STANDARD_DEVIATION 8.33 |
| Sex: Female, Male Female | 37738 Participants |
| Sex: Female, Male Male | 60745 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 0 / 0 | 0 / 0 |
| serious Total, serious adverse events | 0 / 0 | 0 / 0 |
Outcome results
Primary
Number of Low Impact Fractures in Males and Females After 12 Months of Exposure to TZD
ICD-9 codes (805-807.4x, 808-810.xx, 812-829.xx) were captured from Uniform Billing-92 records and Health Care Finance Administration records. Case is defined as incident cases of fracture with an ICD-9 diagnostic code for any low impact fracture occurring after the study period begin date (earliest date of the first TZD prescription). For each subject defined as case, up to four controls were randomly selected from patients with type 2 diabetes exposed to TZD without a fracture diagnosis during follow-up and matched to cases on age (+ 5 years), gender, and year of fracture diagnosis.
Time frame: From the earliest date of first TZD prescription to the fracture diagnosis date (Cases) or the end of follow-up in the database (Controls) between January 1, 1997 to December 31, 2008
Population: The study population consisted of type 2 diabetes patients aged 18 -65 years old exposed to TZD. To be eligible for the study, a subject must have had at least one ICD-9 code for type 2 diabetes and have at least 12 months of exposure to TZD (RSG, PIO or troglitazone) during their follow-up time available in the database.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| TZD Alone | Number of Low Impact Fractures in Males and Females After 12 Months of Exposure to TZD | Case | 2619 fractures |
| TZD Alone | Number of Low Impact Fractures in Males and Females After 12 Months of Exposure to TZD | Control | 10496 fractures |
| TZD+Spironolactone | Number of Low Impact Fractures in Males and Females After 12 Months of Exposure to TZD | Control | 181 fractures |
| TZD+Spironolactone | Number of Low Impact Fractures in Males and Females After 12 Months of Exposure to TZD | Case | 64 fractures |
| TZD+Amiloride | Number of Low Impact Fractures in Males and Females After 12 Months of Exposure to TZD | Case | 8 fractures |
| TZD+Amiloride | Number of Low Impact Fractures in Males and Females After 12 Months of Exposure to TZD | Control | 20 fractures |
| Other | Number of Low Impact Fractures in Males and Females After 12 Months of Exposure to TZD | Case | 0 fractures |
| Other | Number of Low Impact Fractures in Males and Females After 12 Months of Exposure to TZD | Control | 2 fractures |
95% CI: [1.05, 1.89]
95% CI: [0.88, 1.65]
95% CI: [0.69, 3.6]
95% CI: [0.7, 3.81]
95% CI: [0, 0]
95% CI: [0, 0]
Primary
Number of Low Impact Fractures in Males and Females After 6 Months of Exposure to TZD
ICD-9 codes (805-807.4x, 808-810.xx, 812-829.xx) were captured from Uniform Billing-92 records and Health Care Finance Administration records. Case is defined as incident cases of fracture with an ICD-9 diagnostic code for any low impact fracture occurring after the study period begin date (earliest date of the first TZD prescription). For each subject defined as case, up to four controls were randomly selected from patients with type 2 diabetes exposed to TZD without a fracture diagnosis during follow-up and matched to cases on age (+ 5 years), gender, and year of fracture diagnosis.
Time frame: From the earliest date of first TZD prescription to the fracture diagnosis date (Cases) or the end of follow-up in the database (Controls) between January 1, 1997 and December 31, 2008
Population: Type 2 diabetes patients 18-65 years old exposed to TZD. To be eligible for the study, a subject must have had at least one ICD-9 code for type 2 diabetes and have at least 6 months of exposure to TZD (RSG, PIO, or troglitazone) during their follow-up time available in the database.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| TZD Alone | Number of Low Impact Fractures in Males and Females After 6 Months of Exposure to TZD | Control | 17296 fractures |
| TZD Alone | Number of Low Impact Fractures in Males and Females After 6 Months of Exposure to TZD | Case | 4325 fractures |
| TZD+Spironolactone | Number of Low Impact Fractures in Males and Females After 6 Months of Exposure to TZD | Case | 105 fractures |
| TZD+Spironolactone | Number of Low Impact Fractures in Males and Females After 6 Months of Exposure to TZD | Control | 292 fractures |
| TZD+Amiloride | Number of Low Impact Fractures in Males and Females After 6 Months of Exposure to TZD | Case | 12 fractures |
| TZD+Amiloride | Number of Low Impact Fractures in Males and Females After 6 Months of Exposure to TZD | Control | 31 fractures |
| Other | Number of Low Impact Fractures in Males and Females After 6 Months of Exposure to TZD | Control | 2 fractures |
| Other | Number of Low Impact Fractures in Males and Females After 6 Months of Exposure to TZD | Case | 1 fractures |
95% CI: [1.13, 1.78]
95% CI: [0.93, 1.52]
95% CI: [0.78, 2.98]
95% CI: [0.74, 2.89]
95% CI: [0.18, 22.14]
95% CI: [0.12, 15.5]
Secondary
Number of Fractures of the Hand, Foot, Upper Arm, and Wrist in Males and Females After 12 Months of Exposure to TZD
ICD-9 codes (815.0x, 816.0x, 817.0x, 825.0x, 825.2x, 826.0x, 812.0x, 812.2x, 812.4x, 814.0x) were captured from UB-92 records and HCFA 1500 records. Case is defined as incident cases of fracture with an ICD-9 diagnostic code for hand, foot, upper arm, and wrist fracture after the study period begin date (earliest date of the first TZD prescription). For each case, up to four controls were randomly selected from patients with type 2 diabetes exposed to TZD without a fracture diagnosis during follow-up and matched on age (+ 5 yrs), gender, and year of fracture diagnosis.
Time frame: From the earliest date of first TZD prescription to the fracture diagnosis date (Cases) or the end of follow-up in the database (Controls) between January 1, 1997 to December 31, 2008
Population: The study population consisted of type 2 diabetes patients aged 18 -65 years old exposed to TZD. To be eligible for the study, a subject must have had at least one ICD-9 code for type 2 diabetes and have at least 12 months of exposure to TZD (RSG, PIO or troglitazone) during their follow-up time available in the database.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| TZD Alone | Number of Fractures of the Hand, Foot, Upper Arm, and Wrist in Males and Females After 12 Months of Exposure to TZD | Case | 1285 fractures |
| TZD Alone | Number of Fractures of the Hand, Foot, Upper Arm, and Wrist in Males and Females After 12 Months of Exposure to TZD | Control | 5115 fractures |
| TZD+Spironolactone | Number of Fractures of the Hand, Foot, Upper Arm, and Wrist in Males and Females After 12 Months of Exposure to TZD | Control | 94 fractures |
| TZD+Spironolactone | Number of Fractures of the Hand, Foot, Upper Arm, and Wrist in Males and Females After 12 Months of Exposure to TZD | Case | 29 fractures |
| TZD+Amiloride | Number of Fractures of the Hand, Foot, Upper Arm, and Wrist in Males and Females After 12 Months of Exposure to TZD | Case | 0 fractures |
| TZD+Amiloride | Number of Fractures of the Hand, Foot, Upper Arm, and Wrist in Males and Females After 12 Months of Exposure to TZD | Control | 12 fractures |
| Other | Number of Fractures of the Hand, Foot, Upper Arm, and Wrist in Males and Females After 12 Months of Exposure to TZD | Case | 0 fractures |
| Other | Number of Fractures of the Hand, Foot, Upper Arm, and Wrist in Males and Females After 12 Months of Exposure to TZD | Control | 2 fractures |
95% CI: [0.8, 1.88]
95% CI: [0.62, 1.57]
95% CI: [0, 0]
95% CI: [0, 0]
95% CI: [0, 0]
95% CI: [0, 0]
Secondary
Number of Fractures of the Hand, Foot, Upper Arm, and Wrist in Males and Females After 6 Months of Exposure to TZD
ICD-9 codes (815.0x, 816.0x, 817.0x, 825.0x, 825.2x, 826.0x, 812.0x, 812.2x, 812.4x, 814.0x) were captured from UB-92 records and HCFA 1500 records. Case is defined as incident cases of fracture with an ICD-9 diagnostic code for hand, foot, upper arm, and wrist fracture after the study period begin date (earliest date of the first TZD prescription). For each case, up to four controls were randomly selected from patients with type 2 diabetes exposed to TZD without a fracture diagnosis during follow-up and matched on age (+ 5 yrs), gender, and year of fracture diagnosis.
Time frame: From the earliest date of first TZD prescription to the fracture diagnosis date (Cases) or the end of follow-up in the database (Controls) between January 1, 1997 to December 31, 2008
Population: The study population consisted of type 2 diabetes patients aged 18 -65 years old exposed to TZD. To be eligible for the study, a subject must have had at least one ICD-9 code for type 2 diabetes and have at least 6 months of exposure to TZD (RSG, PIO or troglitazone) during their follow-up time available in the database.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| TZD Alone | Number of Fractures of the Hand, Foot, Upper Arm, and Wrist in Males and Females After 6 Months of Exposure to TZD | Case | 2163 fractures |
| TZD Alone | Number of Fractures of the Hand, Foot, Upper Arm, and Wrist in Males and Females After 6 Months of Exposure to TZD | Control | 8615 fractures |
| TZD+Spironolactone | Number of Fractures of the Hand, Foot, Upper Arm, and Wrist in Males and Females After 6 Months of Exposure to TZD | Control | 148 fractures |
| TZD+Spironolactone | Number of Fractures of the Hand, Foot, Upper Arm, and Wrist in Males and Females After 6 Months of Exposure to TZD | Case | 48 fractures |
| TZD+Amiloride | Number of Fractures of the Hand, Foot, Upper Arm, and Wrist in Males and Females After 6 Months of Exposure to TZD | Case | 2 fractures |
| TZD+Amiloride | Number of Fractures of the Hand, Foot, Upper Arm, and Wrist in Males and Females After 6 Months of Exposure to TZD | Control | 18 fractures |
| Other | Number of Fractures of the Hand, Foot, Upper Arm, and Wrist in Males and Females After 6 Months of Exposure to TZD | Case | 1 fractures |
| Other | Number of Fractures of the Hand, Foot, Upper Arm, and Wrist in Males and Females After 6 Months of Exposure to TZD | Control | 2 fractures |
95% CI: [0.92, 1.79]
95% CI: [0.71, 1.45]
95% CI: [0.1, 1.9]
95% CI: [0.08, 1.54]
95% CI: [0.18, 21.93]
95% CI: [0.09, 12.36]
Secondary
Number of Hip Fractures Combined in Males and Females After 12 Months of Exposure to TZD
ICD-9 codes (820.0x, 820.2x, 820.8x) were captured from UB-92 records and HCFA 1500 records. Case is defined as incident cases of fracture with an ICD-9 diagnostic code for hip fracture after the study period begin date (earliest date of the first TZD prescription). For each case, up to four controls were randomly selected from patients with type 2 diabetes exposed to TZD without a fracture diagnosis during follow-up and matched on age (+ 5 yrs), gender, and year of fracture diagnosis.
Time frame: From the earliest date of first TZD prescription to the fracture diagnosis date (Cases) or the end of follow-up in the database (Controls) between January 1, 1997 to December 31, 2008
Population: The study population consisted of type 2 diabetes patients aged 18 -65 years old exposed to TZD. To be eligible for the study, a subject must have had at least one ICD-9 code for type 2 diabetes and have at least 12 months of exposure to TZD (RSG, PIO or troglitazone) during their follow-up time available in the database.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| TZD Alone | Number of Hip Fractures Combined in Males and Females After 12 Months of Exposure to TZD | Case | 44 fractures |
| TZD Alone | Number of Hip Fractures Combined in Males and Females After 12 Months of Exposure to TZD | Control | 182 fractures |
| TZD+Spironolactone | Number of Hip Fractures Combined in Males and Females After 12 Months of Exposure to TZD | Case | 2 fractures |
| TZD+Spironolactone | Number of Hip Fractures Combined in Males and Females After 12 Months of Exposure to TZD | Control | 1 fractures |
95% CI: [0.66, 80.35]
95% CI: [0.03, 96.47]
95% CI: [0, 0]
95% CI: [0, 0]
95% CI: [0, 0]
95% CI: [0, 0]
Secondary
Number of Hip Fractures Combined in Males and Females After 6 Months of Exposure to TZD
ICD-9 codes (820.0x, 820.2x, 820.8x) were captured from UB-92 records and HCFA 1500 records. Case is defined as incident cases of fracture with an ICD-9 diagnostic code for hip fracture after the study period begin date (earliest date of the first TZD prescription). For each case, up to four controls were randomly selected from patients with type 2 diabetes exposed to TZD without a fracture diagnosis during follow-up and matched on age (+ 5 yrs), gender, and year of fracture diagnosis.
Time frame: From the earliest date of first TZD prescription to the fracture diagnosis date (Cases) or the end of follow-up in the database (Controls) between January 1, 1997 to December 31, 2008
Population: The study population consisted of type 2 diabetes patients aged 18 -65 years old exposed to TZD. To be eligible for the study, a subject must have had at least one ICD-9 code for type 2 diabetes and have at least 6 months of exposure to TZD (RSG, PIO or troglitazone) during their follow-up time available in the database.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| TZD Alone | Number of Hip Fractures Combined in Males and Females After 6 Months of Exposure to TZD | Case | 92 fractures |
| TZD Alone | Number of Hip Fractures Combined in Males and Females After 6 Months of Exposure to TZD | Control | 387 fractures |
| TZD+Spironolactone | Number of Hip Fractures Combined in Males and Females After 6 Months of Exposure to TZD | Case | 6 fractures |
| TZD+Spironolactone | Number of Hip Fractures Combined in Males and Females After 6 Months of Exposure to TZD | Control | 4 fractures |
95% CI: [1.53, 19.45]
95% CI: [0.64, 15.86]
95% CI: [0, 0]
95% CI: [0, 0]
95% CI: [0, 0]
95% CI: [0, 0]