Background In elderly subjects, renal insufficiency and osteoporosis often coexist with high risk of fracture and elevated socio-economic burden. Today a large number of effective anti-osteoporotic drugs are available but generally they are contraindicated in patients with chronic kidney disease (CKD) because of their progressive accumulation. Denosumab, instead, does not require dose adjustments for different degrees of renal impairment so it can be a valid treatment in osteoporotic patients with CKD. Limited data are available in the literature concerning the use of denosumab in hemodialysis (HD). The aim of our study was, therefore, to study the efficacy and tolerability of this drug in this particular subset of patients. Methods We retrospectively reviewed the charts of 12 osteoporotic HD patients who received a single 60-mg subcutaneous dose of denosumab every 6 months for an observation period of 24 months. Serum electrolyte, markers of bone turnover and quantitative ultrasound (QUS) were evaluated. Results Over 24 months, we observed a gradual improvement of bone metabolism: beta-CrossLaps from 2567.08 +/- 1264 to 1492.5 +/- 1182.5 pg/ml; bone alkaline phosphatase (BALP) from 33.5 +/- 28.8 to 11.8 +/- 3.7 mcg/l, and of QUS index (T-score from -5.33 +/- 1.58 to -4.84 +/- 1.2; risk of fracture from 13.9 +/- 4.7 to 11.07 +/- 5.3 %). Few cases of hypocalcemia were detected, more significant after the first and second injection, but with careful monitoring of serum calcium and rapid therapy adjustment we could easily manage serum Ca levels. Conclusions Our pilot experience highlights the safety and efficacy of denosumab in the treatment of osteoporosis in HD patients, potentially supporting its use to reduce the burden of fractures in this patient population.