Aim. To evaluate the efficiency and safety of long-term Prolia therapy in patients with postmenopausal osteoporosis (OP). Subjects and methods. The open prospective study enrolled 98 women (mean age, 68±9 years; mean menopause duration, 17±4 years) with postmenopausal OP, who were followed up in an outpatient setting at the National Medical Research Center for Preventive Medicine and who had been treated with denosumab 60 mg subcutaneously every 6 months for 12 months or more. The maximum follow-up period was 4 years: 48, 29, 11, and 10 patients were treated for 12, 24, 36, and 48 months, respectively. The patients were allocated into 2 groups: those who received and those who had not previously received antiosteoporotic therapy. Bone mineral density (BMD) was measured using dual-energy X-ray densitometry of the lumbar spine (L—L) and proximal femur (PF). The ten-year probability of major osteoporotic fractures was estimated once in 72 patients not previously receiving antiosteoporotic therapy before the prescription of denosumab. Results. In the patients not previously receiving therapy, the median 10-year probability of major fractures using the FRAX algorithm was 14.9%; that of femoral neck (FN) fractures was 3.7%. During denosumab treatment, the BMD increase in the lumbar spine was 4.2% at 12 months, 7.5% at 24 months, was 8.8% at 36 months; that in FN was 3.1, 3.9, and 5.3%, that in PF was 2.8, 4.1, and 5%; and that in the 1/3 forearm was 0.9, 1.4, and 2.6%, respectively (p < 0.001). In the persons receiving and not previously receiving the therapy, the BMD increase was similar, i.e. there was an additional positive effect when switching to denosumab. The decrease in the serum concentration of C-terminal telopeptide of type I collagen (CTX-I) was 54% at 6 months after initiation of denosumab therapy (p < 0.001) and 72% at 12 months (p<0.001); and the achieved marker level remained unchanged at 48 months. Transition from the OP zone to osteopenia one was noted in 23 patients with low BMD (T-score -2.5 SD) in L—Land in 12 patients with that in FN at 12 months of denosumab therapy and this was in 25 patients at 24 months. Nine-eight patients receiving the first Prolia injection refused to continue treatment on their own; adverse events were not the reason for drug discontinuation. Conclusion. Therapy with denosumab was effective in increasing BMD in routine outpatient practice and in allowing 25% of patients to achieve target values of this indicator. The marked decrease in the level of the bone resorption marker STX suggested that the drug had antiresorptive potency. The frequency of adverse reactions was low, confirming the good tolerability and safety profile of the drug. The convenience of the scheme and route of drug administration contributed to strict compliance with the doctor’s recommendations. Denosumab was effective in increasing BMD not only in untreated patients, but also in those who had previously received antiosteoporotic therapy. The pharmacokinetic characteristics of denosumab, which contribute to its uniform distribution in trabecular and cortical bone tissue, regardless of active bone remodeling, and the fact that the clearance of the drug is independent of kidney function offer an advantage of administering the drug to patients with significant loss of FN and radius BMD and of reducing kidney function.