OBJECTIVES: Depression is a common mental disorder, with more than 300 million people suffering from it. The presence of a relationship between depression and osteoporosis has been shown by a previous real world data study conducted in Italy. The objective of this analysis is to investigate whether the association observed could have been confused by antidepressants use or by time dependent confounders’ presence. METHODS: This was a retrospective analysis based on data extracted from Italian IMS Health Longitudinal Patient Database. Three cohorts have been defined: the cohort of incident depressed patients, consisting of individuals with a diagnosis of depression (index date) during the period January 2004 - December 2010. The cohort of non-depressed patients, containing subjects with a first contact with the general practitioner (Index date) during the period January 2004 - December 2010, and that were not included in the previous cohort (free from depression). The cohort of depressed patients using antidepressants, identified within the first cohort. Patients of all cohorts must not have an osteoporosis diagnosis or a depression diagnosis during the five years period preceding the Index Date. Extended multivariate Cox models were performed controlling for antidepressants use and for other time dependent confounders. RESULTS: No association was found between depression and osteoporosis during the follow-up period (HR 1.024, p=0.26), while a higher incidence of osteoporosis of about 7% (HR 1.07, p=0.0010) was observed among antidepressants users when compared to non-users. Focusing on patients with antidepressants, the risk of developing osteoporosis increased by 13% for each antidepressant prescribed and by 14% (HR 1.141, p=0.0012) at antidepressant switch. CONCLUSIONS: Results from this study suggest that patients receiving a higher number of antidepressants and those needing pharmacological treatment changes have an increased risk of osteoporosis. Thus, this study suggests an association between a severe status of depression and osteoporosis.