Sieber 2004.

Methods	Start date, end date of recruitment: not reported Follow‐up period: Subsequent assessments were obtained within 7 days of weeks 24, 48, 72 and 96 Design: randomised controlled trial
Participants	Population/Inclusion criteria: Study population consisted of men with histologically confirmed prostate cancer with no distant metastases (T1–T4, Nx, M0) for whom immediate androgen deprivation was indicated Inclusion criteria were an Eastern Cooperative Oncology Group performance status of 0 or 1; life expectancy greater than 6 months; no history or presence of metabolic bone disease, renal failure, malabsorption, rheumatoid arthritis, recent fracture or any other condition known to affect bone metabolism; no hormone therapy within the previous 6 months, no concomitant treatment with any drugs known to affect calcium or vitamin D metabolism and no treatment with systemic steroids. Participants were also required to have a baseline testosterone level greater than the lower limit of normal (194 ng/dL or greater), a calcium level less than the upper limit of normal (10.6 mg/dL or less), a thyroid‐stimulating hormone level within normal limits (0.4 to 10 mg/mL) and a bone mineral density (BMD) within 2 standard deviations of age‐matched controls Setting: multi‐centre (11 locations) Geographical location: United States Exclusion criteria: not reported Total number randomly assigned: 103 Baseline imbalances: balanced Number of participants with non‐metastatic disease: 103 Number of participants with metastatic disease: 0 Age: intervention: mean 74.6 years (range 53 to 87 years); control: mean 75.2 years (range 61 to 90 years) PSA: not reported Subgroup measured: no
Interventions	Intervention Description/Timing: bicalutamide 150 mg once daily for 96 weeks Number randomly assigned to this group: 51 Control Description/Timing: medical castration with an LHRH agonist for 96 weeks (drug not specified) Number randomly assigned to this group: 52
Outcomes	Overall survival Outcome not measured/reported Cancer‐specific mortality Outcome not measured/reported Treatment discontinuation due to adverse events Comparison: non‐steroidal antiandrogen versus castration Subgroup: no Time points measured: at 96 weeks Time points reported: at 96 weeks Number of participants randomly assigned: intervention: 51; control: 52 Number of participants in evaluation for ITT: intervention: 50; control: 51 Clinical progression Outcome not measured/reported Biochemical progression Outcome not measured/reported Treatment failure Outcome not measured/reported Adverse events Comparison: non‐steroidal antiandrogen versus castration Subgroup: no Time points measured: at 96 weeks Time points reported: at 96 weeks Number of participants randomly assigned: intervention: 51; control: 52 Number of participants in evaluation for ITT: intervention: 50; control: 51 Other outcomes reported Primary efficacy end points were mean percentage change in lumbar spine BMD, hip BMD and fat‐free mass (FFM) from baseline to 96 weeks. Secondary efficacy end points included mean percentage change in lumbar spine (L2 to L4) BMD, hip BMD and FFM from baseline to 24, 48 and 72 weeks; and mean change from baseline in serum lipid levels of HDL, LDL, total and very low‐density lipoprotein (VLDL) cholesterol and triglycerides. Lumbar spine BMD, hip BMD and FFM were assessed by dual‐energy x‐ray absorptiometry within 6 weeks before random assignment
Notes	Study funding source: supported by a research grant from AstraZeneca Possible conflict of interest: financial interest and/or other relationship with AstraZeneca. Two authors had financial interest and/or another relationship with AstraZeneca
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Insufficient information to permit judgement (eligible participants were randomly assigned in a 1:1 ratio to receive bicalutamide 150 mg once daily or medical castration with an LHRH analogue for 96 weeks)
Allocation concealment (selection bias)	Unclear risk	Not reported
Blinding of participants and personnel (performance bias) overall survival, cancer‐specific mortality, biochemical progression	Unclear risk	Not measured/reported
Blinding of participants and personnel (performance bias) treatment discontinuation due to adverse events, clinical progression, treatment failure, adverse events	High risk	No blinding for treatment discontinuation due to adverse events and adverse events. Blinding was not possible because of different interventions provided. We judge that outcomes such as treatment discontinuation due to adverse events and adverse events are likely to be influenced by lack of blinding
Blinding of outcome assessment (detection bias) overall survival, cancer‐specific mortality, biochemical progression	Unclear risk	Not measured/reported
Blinding of outcome assessment (detection bias) treatment discontinuation due to adverse events, clinical progression, treatment failure, adverse events	High risk	No blinding for treatment discontinuation due to adverse events and adverse events. Blinding was not possible because of different interventions provided, and study authors reported insufficient information only. We judge that it is likely that outcome assessment for treatment discontinuation due to adverse events and adverse events are influenced by lack of blinding
Incomplete outcome data (attrition bias) overall survival, cancer‐specific mortality	Unclear risk	Not measured/reported
Incomplete outcome data (attrition bias) treatment discontinuation due to adverse events, adverse events	Low risk	Missing outcome data balanced in numbers across intervention groups, with similar reasons for missing data across groups. The proportion of missing outcomes compared with observed event risk not enough to have a clinically relevant impact on the intervention effect estimate (2 participants, 1 in each treatment group, who did not receive randomly assigned therapy and were excluded from the analysis of adverse events). For analyses of all efficacy variables, a modified per‐protocol data set was used. Participants were included according to the treatment received but, unlike in a true per‐protocol data set, participants with major protocol violations were not excluded
Incomplete outcome data (attrition bias) clinical progression, biochemical progression	Unclear risk	Not measured/reported
Incomplete outcome data (attrition bias) treatment failure	Unclear risk	Not measured/reported
Selective reporting (reporting bias)	Low risk	Study protocol is not available, but it is clear that the published reports include all expected outcomes
Other bias	Unclear risk	Unclear risk for conflict of interest