Background: Adjuvant androgen suppression and bisphosphonates with escalating doses of radiotherapy might improve efficacy outcomes in men with locally advanced prostate cancer. In this study, we investigated whether these treatments had a detrimental effect on patient-reported-outcome (PRO) scores. Methods: We undertook a phase 3 trial with a 2×2 factorial design in 23 centres in Australia and New Zealand in men with non-metastatic adenocarcinoma of the prostate (stage T2b-4 or T2a, Gleason score ≥7, and baseline prostate-specific antigen concentration [PSA] ≥10 μg/L), and without previous lymph node or systemic metastases or comorbidities that could reduce life expectancy to less than 5 years. The men were randomly assigned in a 1:1:1:1 ratio to 6 months of neoadjuvant (short-term) androgen suppression (STAS) with leuprorelin (22·5 mg every 3 months, intramuscularly) or an additional 12 months (intermediate-term androgen suppression [ITAS]) of leuprorelin with or without 18 months of zoledronic acid (4 mg every 3 months, intravenously). Study drug administration commenced at randomisation after which radiotherapy started within the fifth month in all groups. Treatment allocation was open-label, and computer-generated randomisation, stratified by centre, baseline concentrations of PSA, clinical stage of the tumour, Gleason score, and use of a brachytherapy boost, was done by use of the minimisation technique. PRO scores were calculated from European Organization for Research and Treatment of Cancer quality-of-life and prostate-specific quality-of-life module questionnaires and compared with multiple regression models at baseline, and end of radiotherapy, and 18 months and 36 months according to group and radiation dose. The trial is ongoing and the primary endpoint, prostate-cancer-specific mortality, will be reported in 2014. This study is the final report of PRO scores (a secondary endpoint). Analysis was by intention to treat. This trial is registered with ClinicalTrials.gov, number NCT00193856. Findings: 1071 men were randomly assigned to STAS (n=268), STAS plus zoledronic acid (n=268), ITAS (n=268), and ITAS plus zoledronic acid (n=267). At the end of radiotherapy, significant detrimental changes in PRO scores (p<0·01) occurred in all groups. There were no significant differences in global health status between groups at any timepoint. At 18 months, PROs that were significantly worse in the ITAS groups when compared with STAS were hormone-treatment-related symptoms (HTRS; STAS, 10·20 [95% CI 8·66-11·75]; ITAS, 17·36 [13·63-21·08], p<0·01; and ITAS plus zoledronic acid, 19·14 [15·43-22·85], p<0·01), sexual activity (STAS, 26·38 [23·50-29·27]; ITAS, 14·40 [7·44-21·36], p<0·01; and ITAS plus zoledronic acid, 16·34 [9·39-23·28], p<0·01), social function (STAS, 90·31 [87·89-92·73]; ITAS, 87·35 [81·52-93·18], p=0·09; and ITAS plus zoledronic acid, 83·66 [77·85-89·48], p<0·01), fatigue (STAS, 17·05 [14·58-19·51]; ITAS 24·52 [18·58-30·46], p<0·01; and ITAS plus zoledronic acid, 24·26 [18·33-30·18], p<0·01), and financial problems (STAS, 3·39 [1·29-5·48]; ITAS, 8·97 [3·92-14·02], p<0·01; and ITAS plus zoledronic acid, 8·92 [3·89-13·96], p<0·01). With the exception of HTRS, in which marginal differences remained, persisting significant differences disappeared by 36 months. Other factors associated with significant detrimental changes in PRO scores were a brachytherapy boost, incomplete testosterone and haemoglobin recoveries, age, and smoking. Interpretation: Compared with 6 months of androgen suppression, 18 months of androgen suppression causes additional detrimental changes at the 18 month follow-up in some PRO scores but not in global quality-of-life scores. However, with the exception of HTRS, these differences resolved by 36 months. The use of zoledronic acid every 3 months over 18 months does not result in additional detrimental changes, but the use of a brachytherapy boost to achieve radiation dose escalation in the prostate can adversely affect emotional function and financial problems. Funding: National Health and Medical Research Council of Australia, Novartis Pharmaceuticals Australia, Abbott Pharmaceuticals Australia, New Zealand Health Research Council, New Zealand Cancer Society, University of Newcastle (Australia), Hunter Medical Research Institute, Calvary Mater Radiation Oncology Fund, and Maitland Cancer Appeal.