Aim: The trial was focused on assessing the effect of Denosumab in preventing anchorage loss during en-masse anterior retraction and evaluating its effect on the retraction. Materials and methods: This was a split-mouth randomized controlled trial. Ten subjects were randomly allocated with equal probability for Denosumab and control interventions in the contralateral quadrants using computer-generated randomization sequence. During the start of retraction, Denosumab (5 mg/0.2 mL) and injectable sterile water were administered locally on the intervention and control sides, respectively. Lateral cephalograms taken during the start of retraction and later in the 3rd and 6th months into retraction were used to evaluate anchorage loss and retraction. Independent sample t-test and Mann-Whitney U test compared anchorage loss and retraction between the two groups in the maxilla and mandible. Paired t-test and Wilcoxon signed-rank test assessed the anchorage loss and retraction during the first and the second 3 months of retraction. Results: In the maxilla, Denosumab was effective in preventing anchorage loss with a p-value of 0.001 whereas it was not effective in the mandible (p-value—0.172). A significant reduction in anchorage loss was observed with Denosumab in the second 3 months of retraction compared to the first 3 months. There was no significant difference in the retraction among both groups. Conclusion: Denosumab was effective in minimizing the anchorage loss in the maxilla without affecting the anterior retraction. Clinical significance: Denosumab can be effectively used for reinforcing anchorage in the maxilla during en-masse anterior retraction.