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Osteoporosis (OP) can complicate the course of rheumatic musculoskeletal diseases (RMDs) and connective tissue diseases (CTDs). Denosumab, a monoclonal antibody against RANK-L, showed beneficial effect in rheumatoid arthritis in inhibiting radiographic progression and erosive burden. We tested the efficacy, safety, and persistence on the treatment of the combination of biologic disease-modifying antirheumatic drugs (bDMARDs)/denosumab versus bDMARD in patients with RMD and CTD.This is a retrospective evaluation of a single center, including patients with RMD/CTD (including rheumatoid arthritis, ankylosing spondylitis, psoriatic arthritis, systemic sclerosis, and overlap syndromes) treatment with bDMARD/denosumab, compared to age, gender, disease, bDMARD, and conventional synthetic disease-modifying antirheumatic drugs-matched controls.Twenty-eight bDMARD/denosumab patients and 49 bDMARD patients were eligible. Despite a statistically significant difference during the first-year efficacy (due to the different baseline timepoint), there was no difference in the efficacy profile in the second year of treatment and in the safety profile (including local, systemic, and serious adverse events). Moreover, no statistically significant difference in the persistence of bDMARD treatment over 2 years of evaluation was found. The combination of bDMARD and denosumab was not an independent predictor of disease flare or bDMARD treatment withdrawal.The combination of bDMARD and denosumab does not alter the efficacy and the safety profile of the bDMARD in patients with RMD/CTD. Future studies verifying the radiological disease inhibition could support denosumab use in RMD/CTD other than rheumatoid arthritis, when complicated by OP.