<p>Calcium and vitamin D supplementation is commonly recommended in conjunction with osteoporosis treatment. However, some patients are unable to tolerate or take these supplements due to various factors. This study aims to assess the impact of calcium and vitamin D supplementation on bone mineral density (BMD) changes over a two-year period in patients treated with denosumab, comparing those who received supplements with those who did not. This retrospective study included 344 patients who had received at least four doses of denosumab. Patients were divided into two groups: those who received calcium and vitamin D supplementation and those who did not. BMD was measured annually at the lumbar spine, total hip, and femoral neck, and denosumab efficacy was assessed by calculating the percentage change in BMD from baseline. We also evaluated BMD changes according to patients’ prior osteoporosis treatments and history of osteoporotic fractures. In addition, a subgroup analysis was conducted among treatment-naïve patients, comparing those who received denosumab alone with those who received denosumab combined with calcium and vitamin D supplementation. The study cohort consisted of 328 women, with a mean age of 70.50 ± 9.48&#xa0;years. Statistically significant differences were found between the two groups regarding prior osteoporosis treatment (<i>P</i> = 0.004) and baseline lumbar spine BMD (<i>P</i> = 0.027). However, no significant differences were observed in BMD changes at the lumbar spine, total hip, or femoral neck after one and two years of denosumab treatment, regardless of calcium and vitamin D supplementation. The type of prior osteoporosis medication and the presence of low-energy fragility fractures did not significantly affect BMD changes at either time point. In treatment-naïve patients (n = 209), BMD gains did not differ significantly between those with and without supplementation. Notably, none of the patients reported experiencing adverse events such as injection site infections, myalgia, or symptomatic hypocalcemia. The two-year treatment with denosumab resulted in improvements in BMD that were independent of calcium and vitamin D supplementation. These findings suggest that denosumab may increase BMD regardless of supplementation, though further studies are warranted to confirm this relationship.</p>