OBJECTIVES: To evaluate the cost effectiveness of zoledronic acid 5 mg once yearly compared to the leading branded compounds in the UK, i.e. Fosamax once weekly, Actonel once weekly, Bonviva once monthly, and Protelos once daily in patients with postmenopausal osteoporosis. METHODS: The cost effectiveness model applied tracks the model NICE used in their appraisal document for the cost effectiveness of treatments of osteoporosis in postmenopausal women at increased risk of fracture. Lifetime costs and quality adjusted life years (QALYs) were calculated assuming five years of treatment. Relative risks of fracture protection were obtained from the HORIZON-PFT trial for zoledronic acid 5 mg, meta-analyses from NICE reviews for Fosamax, Actonel, and Protelos, and from the European label for Bonviva. Costs of fractures were taken from the NICE review of Protelos and costs of the medications were taken from the MIMS listing from February, 2007. Utilities were obtained from the literature (Kanis, OI 2004;15:20-6). RESULTS: For patients 50 and older, zoledronic acid 5 mg dominated (i.e., more effective at lower cost) branded Fosamax, Actonel, and Protelos. For patients 70 and older, zoledronic acid 5 mg dominated Bonviva while at lower ages, it was more cost effective (ICER £3,100/QALY gained). Incremental cost effectiveness ratios against calcium plus vitamin D for zoledronic acid 5 mg were around or below the usually referenced threshold of £20K/QALY, ranging from £20,582/QALY at age 50 to £7,418/QALY at age 80. For the other treatments, the ranges of ICER versus calcium plus vitamin D were £36,095/QALY to £12,542/QALY for Fosamax, £53,916/QALY to £22,261/QALY for Actonel, £50,840/QALY to £26,179/QALY for Protelos, and £158,479/QALY to £57,583/QALY for Bonviva. CONCLUSION: For patients aged 50 and above with a BMD T-score of -2.5, zoledronic acid 5 mg either dominates or is cost-effective compared with Fosamax, Actonel, Protelos, and Bonviva.