INTRODUCTION: Denosumab is a monoclonal antibody that received approval by the FDA for the treatment of osteoporosis in 2010. Available higher level research evidence concerns the treatment of patients that have not received any anti-osteoporotic medication in the past. Further investigation is warranted, since clinicians often face the challenge of administering the most efficacious drug in patients, pretreated with other medications.AREAS COVERED: We conducted a systematic review and meta-analysis to evaluate the efficacy and safety of denosumab compared to other active anti-osteoporotic agents in patients formerly receiving other treatments. We searched MEDLINE, EMBASE, CENTRAL, the metaRegister of Controlled Trials (mRCT) and clinicaltrials.gov up to April 2017 to identify eligible trials in patients with primary osteoporosis.EXPERT OPINION: Our meta-analysis included 6 Randomised Controlled Trials encompassing 2968 patients formerly treated with anti-osteoporotic medications. Quantitative data synthesis demonstrated superiority of denosumab in augmenting Bone Mineral Density in all skeletal sites studied compared to controls [treatment difference in total hip: 1.59% (95% CI 1.01, 2.17)], whereas the overall incidence of serious adverse events was not increased (OR 1.12, 95% CI 0.85 to 1.47, p = 0.42). Future research geared towards the fracture incidence, quality of life and patient reported outcomes is warranted.