The National Institute for Health and Clinical Excellence (NICE) invited the manufacturer of denosumab (Amgen Inc., UK) to submit evidence for the clinical and cost effectiveness of denosumab for the prevention of fragility fractures in post-menopausal women, as part of the Institute's single technology appraisal (STA) process. The University of Aberdeen Health Technology Assessment Group were commissioned to act as the Evidence Review Group (ERG); the role of the ERG being to appraise the manufacturer's submission and to produce an independent report. This article provides a description of the company submission, the ERG review and NICE's subsequent decisions. The manufacturer considered that denosumab would be appropriate for patients unable to take, comply with or tolerate oral bisphosphonates. Comparator treatments selected for the submission were, therefore, 'no treatment', raloxifene, strontium ranelate, intravenous zoledronic acid, intravenous ibandronate and teriparatide. The main effectiveness evidence for denosumab was derived from a large randomized controlled trial comparing denosumab with placebo. Given by subcutaneous injection at 6-monthly intervals for 3 years, denosumab reduced the incidence of hip fracture by 40%, and reduced the incidence of clinical vertebral fracture by 69%. An indirect treatment comparison was used to derive adjusted relative risk (RR) estimates for different types of fracture for each comparator versus placebo. The RRs (95%CI) applied for denosumab were 0.316 (0.208, 0.478) for clinical vertebral fracture, 0.605 (0.373, 0.983) for hip fracture and 0.842 (0.638, 1.110) for wrist fracture. Despite a number of concerns surrounding the methodology of the indirect comparison, the ERG was satisfied with the robustness of the effect estimates The RR estimates were applied in a good-quality Markov model that took account of drug costs, administration and monitoring costs, costs associated with fractures, and long-term nursing home costs. Utility weights were used to adjust time spent in fracture states, allowing QALYs to be estimated. The base-case analysis was conducted for women aged 70 years with a T-score of -2.5 or less and no prior fracture, and women aged 70 years with a T-score of -2.5 or less with a prior fragility fracture. Subgroup analyses based on T-score and independent clinical risk factors were also undertaken. Applying a willingness-to-pay (WTP) threshold of d30 000 per QALY, the manufacturer's results suggested that denosumab would offer a cost-effective alternative to all treatment comparators for the primary and secondary prevention of fractures. The ERG was concerned about an assumption that denosumab would be administered in general practice at the average cost of two standard GP visits a year. As a result, the ERG requested some further sensitivity analysis and undertook some further modelling, applying an assumption that denosumab would be provided primarily in secondary care. This modification altered the cost effectiveness of denosumab versus 'no treatment' (in women with no prior fragility fracture) and zoledronic acid. The NICE Appraisal Committee concluded that, as a treatment option for the prevention of osteoporotic fractures, denosumab should be recommended only in post-menopausal women at increased risk of fracture who cannot comply with the special instructions for administering oral bisphosphonates, or have an intolerance of, or contraindication to, those treatments. For primary prevention, the Appraisal Committee also stipulated specific levels of fracture risk at which denosumab is recommended.