Machak GN, Bruland ØS, Kovalev AV, Rodionova SS. Rethinking the role of bisphosphonates after denosumab treatment in locally advanced or unresectable aneurysmal bone cysts: A meta-analysis. World J Orthop 2025; 16(8): 107083 [DOI: 10.5312/wjo.v16.i8.107083]
Corresponding Author of This Article
Gennady N Machak, MD, PhD, Clinical and Diagnostic Center, FSBI “National Medical Research Center for Traumatology and Orthopedics named after N.N. Priorov” of the Ministry of Health of the Russian Federation, 10 Priorova Street, Moscow 127299, Russia. machak.gennady@mail.ru
Research Domain of This Article
Oncology
Article-Type of This Article
Meta-Analysis
Open-Access Policy of This Article
This article is an open-access article which was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/
World J Orthop. Aug 18, 2025; 16(8): 107083 Published online Aug 18, 2025. doi: 10.5312/wjo.v16.i8.107083
Rethinking the role of bisphosphonates after denosumab treatment in locally advanced or unresectable aneurysmal bone cysts: A meta-analysis
Gennady N Machak, Øyvind S Bruland, Alexey V Kovalev, Svetlana S Rodionova
Gennady N Machak, Clinical and Diagnostic Center, FSBI “National Medical Research Center for Traumatology and Orthopedics named after N.N. Priorov” of the Ministry of Health of the Russian Federation, Moscow 127299, Russia
Øyvind S Bruland, Department of Oncology, Norwegian Radium Hospital, Oslo University Hospital, Oslo N-0310, Norway
Alexey V Kovalev, Laboratory of Cell Technologies and Medical Genetics, FSBI “National Medical Research Center for Traumatology and Orthopedics named after N.N. Priorov” of the Ministry of Health of the Russian Federation, Moscow 127299, Russia
Svetlana S Rodionova, Center of Osteoporosis, National Medical Research Center of Traumatology and Orthopedics named after N.N. Priorov, Moscow 127299, Russia
Co-first authors: Gennady N Machak and Øyvind S Bruland.
Author contributions: All authors contributed to the study conception and design. Machak GN designed the research study; material preparation, data collection, and analysis were performed by Machak GN, Bruland ØS, Kovalev AV, and Rodionova SS; the first draft of the manuscript was written by Machak GN and all authors commented on previous versions of the manuscript; all authors have read and approved the final manuscript.
Conflict-of-interest statement: The authors declare that they have no known competing financial, political, intellectual and religious interests or personal relationships that could have appeared to influence the work reported in this paper.
PRISMA 2009 Checklist statement: The authors have read the PRISMA 2009 Checklist, and the manuscript was prepared and revised according to the PRISMA 2009 Checklist.
Open Access: This article is an open-access article that was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution NonCommercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: https://creativecommons.org/Licenses/by-nc/4.0/
Corresponding author: Gennady N Machak, MD, PhD, Clinical and Diagnostic Center, FSBI “National Medical Research Center for Traumatology and Orthopedics named after N.N. Priorov” of the Ministry of Health of the Russian Federation, 10 Priorova Street, Moscow 127299, Russia. machak.gennady@mail.ru
Received: March 16, 2025 Revised: May 5, 2025 Accepted: July 23, 2025 Published online: August 18, 2025 Processing time: 146 Days and 15.5 Hours
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.
Core Tip: Benign bone tumors containing giant cells undergo significant ossification after denosumab treatment. In these conditions, sequentially administered bisphosphonates (BPs) accumulate better in newly formed bone, which may lead to long-term local control, presumably due to a pro-apoptotic effect on residual tumor cells. In this context, we studied a group of patients with inoperable aneurysmal bone cysts (ABCs) who were treated with denosumab and found that among those patients who received BPs for post-denosumab rebound hypercalcemia, there were no local relapses. We assume that BPs could have the same irreversible effect on residual tumor cells in ABCs and propose to continue experimental and prospective clinical studies to confirm this hypothesis.
