Background: Osteoprotective therapy (OT), including denosumab and bisphosphonates, is approved as supportive treatment for patients with solid tumors to prevent skeletal-related events from bone metastases. Preclinical studies and clinical studies/series suggested a synergistic effect of OT and immune checkpoint inhibitor (ICI) therapy in metastatic melanoma patients with bone metastases. Therefore, we investigated this issue in a registry study. Methods: Melanoma patients with bone metastases undergoing first-line therapy with ICI were retrospectively identified from the prospective skin cancer registry ADOReg. Information on OT was additionally requested from the participating centers. The primary study endpoints were disease control rate (DCR), progression-free survival (PFS), overall survival (OS) and time to next treatment (TTNT). Results: 180 patients were identified and analysed. Of those, 107 patients (59.4 %) received PD-1 monotherapy and 73 (40.6 %) dual ICI therapy (PD-1 + CTLA-4). 64 patients received additional an OT therapy (36 %) (OT_pos). The median follow-up was 22.6 months (95 % CI = 18.2–27.1). There were no significant differences in demographics or clinical parameters between OT_pos and OT_neg patients. The DCR was comparable between groups (p = 0.758; OT_pos = 23.3 % (95 % CI = 12.7–35.1), OT_neg = 25.5 % (95 % CI = 17.0–35.2)). There was no significant difference observed between groups in PFS (p = 0.489; OT_pos = 6.7 months (95 % CI = 1.3–12.1), OT_neg = 6.4 months (95 % CI = 1.9–11.0)), in OS (p = 0.065; OT_pos = 26.1 months (95 % CI = 14.6–37.5), OT_neg = 16.9 months (95 % CI = 6.2–27.6)) and in TTNT (p = 0.891; OT_pos = 18.4 months (95 % CI = 10.9–25.9), OT_neg = 21.5 months (95 % CI = 7.8–35.1)). The majority of melanoma patients with bone metastasis did not receive an OT. No significant effects of OT were observed on efficacy outcomes, including response, PFS, OS, and TTNT.