Abstract
BACKGROUND: Aneurysmal bone cysts (ABCs) are usually treated with curettage or various minimally invasive percutaneous procedures. Patient refractory to these treatments, as well as those with locally advanced or unresectable tumors, present a challenge for orthopedic surgeons and require new treatment approaches. Anti-resorptive drugs inhibit osteoclastic resorption and increase intralesional osteogenesis. Denosumab induces tumor ossification, but this effect may disappear after drug withdrawal due to limited impact on neoplastic cells. Bisphosphonates (BPs) may induce apoptosis of tumor cells and allow for long-term local control. We hypothesized that after denosumab treatment, BPs would better accumulate in the tumor and exert an irreversible antitumor effect. AIM: To test the hypothesis that the sequential use of BPs after denosumab induction improves treatment outcomes in surgically unsalvageable ABCs. METHODS: Using data from five electronic databases (Scopus, MEDLINE, EMBASE, PubMed, Web of Science), we aimed to identify all patients who received denosumab therapy (DT) for unresectable ABCs. Among published case reports and case series, we identified patients who discontinued denosumab for various reasons and divided them into two groups: Group 1 included 31 patients without further anti-resorptive therapy and Group 2 included 12 patients who received BPs in the context of rebound hypercalcemia. Local control rates in both groups were analyzed. RESULTS: As of December 2024, 43 patients have been reported in the literature who received DT for locally advanced/unresectable ABCs. There were 27 males and 16 females with a mean age of 15.8 years. At a median follow-up time of 15.5 months, there were 10 confirmed and two pathologically unconfirmed relapses after denosumab discontinuation. All 10 relapses occurred in patients in Group 1 at a median time of 13.5 months. Among patients in Group 2, with a median follow-up time of 12.5 months after completion of therapy, no local relapses were observed. The difference between local recurrence rates (32% vs 0%) is statistically significant (P value = 0.02). Kaplan-Meier estimates show the same trend with marginal statistical significance (P value = 0.085). Here we put forward a novel treatment algorithm. CONCLUSION: BPs used in post-denosumab ossifying ABCs appear to improve treatment outcomes, presumably by targeting residual tumor cells. Prospective clinical studies are warranted to validate this promising two-stage conceptual strategy in difficult-to-treat ABC.