Bilezikian 2013.

Study characteristics
Methods	Study design: parallel RCT
Participants	Inclusion criteria: women, age between 55 to 80 years, 5 years postmenopausal, T2DM, BMD T‐score greater than 2.5 at the total hip, femoral neck, and lumbar spine, prior glucose‐lowering intervention with diet and exercise alone or monotherapy (non‐TZD) for 2 weeks within the past 12 weeks, HbA1c 9.0% if drug‐naive and 8.5% if on prior monotherapy Exclusion criteria: T1DM, history of diabetic ketoacidosis or uncontrolled hypertension, simultaneous treatment with 2 or more glucose‐lowering drugs within the past 12 weeks, previous intervention with estrogens and other bone‐active drugs Diagnostic criteria: not reported
Interventions	Intervention(s): metformin Comparator(s): rosiglitazone Duration of intervention: 52 weeks1 Duration of follow‐up: 52 weeks1 Run‐in period: 3 weeks Number of study centres: not reported
Outcomes	Reported outcome(s) in full text of publication: BMD, bone turnover markers, calcium and vitamin D status, safety, glycaemic variables, anthropometric measures
Study details	Trial identifier:NCT00679939 Trial terminated early: no
Publication details	Language of publication: English Funding: commercial funding (GSK) Publication status: peer‐reviewed journal / full article
Stated aim for study	Quote from publication: "The aims of this study are to evaluate the effects of RSG on BMD in postmenopausal women with T2DM and to evaluate the potential reversibility of changes in bone mass and turnover on cessation of RSG treatment, thereby providing insight into the clinical significance of the effect of RSG on fracture risk"
Notes	1After 52 weeks of metformin vs rosiglitazone all patients received open‐label metformin for an additional 24 weeks which was not of relevance to this review
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Quote from publication: "This study utilized a computer‐generated central randomisation within each geographical region stratified by prior therapy (drug‐naive and prior monotherapy) and randomised in a 1:1 ratio to one of two treatment arms..." Comment: method of random sequence generation adequately described
Allocation concealment (selection bias)	Low risk	Quote from publication: "This study utilized a computer‐generated central randomisation within each geographical region stratified by prior therapy (drug‐naive and prior monotherapy) and randomised in a 1:1 ratio to one of two treatment arms... Subjects were registered and medication was ordered using an interactive voice response system." Comment: method of allocation concealment adequately described
Blinding of participants and personnel (performance bias) all‐cause mortality	Low risk	Quote from publication: "Study medication taken during the double‐blind treatment period was blinded to the subjects and the investigator. Blinding was maintained during this phase by use of the double‐dummy technique. Blinded study medication was overencapsulated to appear the same." Comment: investigator‐assessed outcome measurement, adequate blinding
Blinding of participants and personnel (performance bias) cardiovascular mortality	Low risk	Quote from publication: "Study medication taken during the double‐blind treatment period was blinded to the subjects and the investigator. Blinding was maintained during this phase by use of the double‐dummy technique. Blinded study medication was overencapsulated to appear the same." Comment: investigator‐assessed outcome measurement, adequate blinding
Blinding of participants and personnel (performance bias) serious adverse events	Low risk	Quote from publication: "Study medication taken during the double‐blind treatment period was blinded to the subjects and the investigator. Blinding was maintained during this phase by use of the double‐dummy technique. Blinded study medication was overencapsulated to appear the same." Comment: investigator‐assessed outcome measurement, adequate blinding
Blinding of outcome assessment (detection bias) all‐cause mortality	Low risk	Quote from publication: "Study medication taken during the double‐blind treatment period was blinded to the subjects and the investigator. Blinding was maintained during this phase by use of the double‐dummy technique. Blinded study medication was overencapsulated to appear the same." Comment: investigator‐assessed outcome measurement, adequate blinding
Blinding of outcome assessment (detection bias) cardiovascular mortality	Low risk	Quote from publication: "Study medication taken during the double‐blind treatment period was blinded to the subjects and the investigator. Blinding was maintained during this phase by use of the double‐dummy technique. Blinded study medication was overencapsulated to appear the same." Comment: investigator‐assessed outcome measurement, adequate blinding
Blinding of outcome assessment (detection bias) serious adverse events	Low risk	Quote from publication: "Study medication taken during the double‐blind treatment period was blinded to the subjects and the investigator. Blinding was maintained during this phase by use of the double‐dummy technique. Blinded study medication was overencapsulated to appear the same." Comment: investigator‐assessed outcome measurement, adequate blinding
Incomplete outcome data (attrition bias) all‐cause mortality	Low risk	Quote from publication: "The safety population, comprising all subjects who had received at least one dose of drug, was used for analysis of all parameters" "The primary analysis was performed on the observed case dataset. In addition, supportive analyses were prespecified in the statistical analysis plan and performed based on last on‐therapy observation..." Comment: > 99% of participants included in the analysis, high dropout rate (67.5% to 75.9% of participants completed the study) and not balanced between arms, reasons for missing data similar between arms, inappropriate use of LOCF for handling missing data, it is assumed that mortality status has been investigated in death registers at the end of the study
Incomplete outcome data (attrition bias) cardiovascular mortality	Low risk	Quote from publication: "The safety population, comprising all subjects who had received at least one dose of drug, was used for analysis of all parameters" "The primary analysis was performed on the observed case dataset. In addition, supportive analyses were prespecified in the statistical analysis plan and performed based on last on‐therapy observation..." Comment: > 99% of participants included in the analysis, high dropout rate (67.5% to 75.9% of participants completed the study) and not balanced between arms, reasons for missing data similar between arms, inappropriate use of LOCF for handling missing data, it is assumed that mortality status has been investigated in death registers at the end of the study
Incomplete outcome data (attrition bias) serious adverse events	High risk	Quote from publication: "The safety population, comprising all subjects who had received at least one dose of drug, was used for analysis of all parameters" "The primary analysis was performed on the observed case dataset. In addition, supportive analyses were prespecified in the statistical analysis plan and performed based on last on‐therapy observation..." Comment: > 99% of participants included in the analysis, high dropout rate (67.5% to 75.9% of participants completed the study) and not balanced between intervention groups, reasons for missing data similar between intervention groups, inappropriate use of LOCF for handling missing data, the proportion of missing outcomes compared with observed event risk enough to induce clinically relevant bias in intervention effect estimate
Selective reporting (reporting bias)	High risk	Comment: the study protocol is available. It is clear that intervention failure was measured and analysed; trial report states that outcome was analysed but report no results. Clear that anthropometric variables were measured, since baseline values are reported, but was not necessarily analysed; judgement says likely to have been analysed but not reported because of non‐significant results.
Other bias	Unclear risk	Comment: received funding from a pharmaceutical company