Abstract Background and Aims Osteoporosis is a chronic progressive disease characterized by low bone mass and deterioration of bone tissue which results in a rapid increase in fracture risk. Osteoporosis in hemodialysed patients with Chronic Kidney Disease – Mineral and Bone Disorder (CKD-MBD) is a debilitating clinical condition with complex therapeutic management. In fact, most of the drugs commonly used to counteract osteoporosis are generally contraindicated when Glomerular Filtration Rate (GFR) is lower than 35 ml/min. Denosumab is approved for the treatment of osteoporosis and does not require dose adjustment in case of impaired renal function. For this reason, since 2014 this drug has been used by nephrologists for the treatment of osteoporotic patients also in hemodialysis. Although the interest and diffusion in this specialized clinical field are growing, only few data are still available in literature. The aim of the study was to evaluate the efficacy and safety of Denosumab in long-term therapies (up to 68 months of therapy) in hemodialysed patients. Method Since December 2013, a total of 22 hemodialysed patients have been treated with Denosumab annually (4) or semi-annually (18) for up to 68 consecutive months. During the treatment, we monitored the blood levels of calcium, phosphorus, PTH, beta-CrossLaps and bone alkaline phosphatase (BALP), T-SCORE and fracture risk (FR) using Qualitative UltraSonography (QUS) or Computerized Bone Mineralometry (CBM) every 30 months and every 2 years, respectively. Results 4/22 patients completed at least 48 months of follow-up, observing a substantial stability of the mean values of blood calcium (from 9.09 mg/dl to 8.63 mg/dl) and phosphorus (from 5.2 mg/dl to 4.1 mg/dl), against a reduction in the mean values of B-CrossLaps and bone alkaline phosphatase (BALP) (respectively from 2975.32 to 1452.75 pg/ml and from 32.09 to 14.58 mcg/L). Comparison of QUS exams demonstrated improved T-score (mean values from −4.71 to −4.17) and reduced fracture risk (mean value from 13% to 8%). The results of the CBMs confirmed the improvement of the bone disease at the lumbar spine (T-score from −3.8 to 2.8 after 2 years of treatment) and the substantial stability of the T-score at the femoral level (from −3.5 to −3.2 after 2 years of treatment). It should be noted that in our samples two patients achieved the longest observation period (68-month follow-up in continuous therapy), in which we observed improvement of the bone disease also at the femoral level compared to the start of treatment (T-score from −3.9 to −2.8 after 48 months of treatment). Only one fracture has been recorded. Conclusion The results obtained confirm efficacy and safety of Denosumab in reducing the risk of fractures, with the improvement of BMD and T-score at the lumbar spine using Computerized Bone Mineralometry (CBM). We underline that close biochemistry monitoring and careful evaluation of the therapeutic procedures before and after Denosumab administration helped us to minimise and promptly correct adverse effects due to hypocalcemia. In addition we are particularly satisfied to report in most patients a significant reduction of pain and an improvement of mobility. The results collected are consistent with acceptable safety and demonstrated efficacy of Denosumab in hemodialysis patients.