Aromatase inhibitors (AIs) have solidified their position as essential agents in the adjuvant treatment landscape for hormone receptor–positive breast cancer, offering substantial reductions in disease recurrence and mortality rates. However, their mechanism of action, specifically the suppression of estrogen synthesis, has a consequential downside: accelerated bone resorption resulting in rapid bone loss and increased susceptibility to fractures. This skeletal vulnerability necessitates the concurrent administration of antiresorptive therapies, predominantly denosumab or bisphosphonates, to preserve bone integrity during the extended course of AI therapy.
Denosumab’s role in fracture prevention during AI treatment has been well documented, with robust clinical evidence supporting its efficacy. Unlike bisphosphonates, which have prolonged skeletal retention, denosumab exerts its effects by inhibiting RANKL (Receptor Activator of Nuclear factor Kappa-Β Ligand), a critical mediator of osteoclastogenesis, leading to marked suppression of bone turnover. However, emerging data reveal a critical clinical challenge: the abrupt cessation of denosumab therapy induces a rapid rebound in bone turnover, precipitating a precipitous decline in bone mineral density (BMD). This phenomenon is associated with an increased risk of spontaneous vertebral fractures, often clustered in the thoracolumbar region, which can occur even in patients without pre-existing osteoporosis or traditional risk factors.
This alarming risk has been highlighted in a recent narrative review published in Osteoporosis International by the International Osteoporosis Foundation’s Committee of Scientific Advisors Working Group on Cancer-Induced Bone Disease. The review meticulously synthesizes current knowledge and raises awareness of the so-called “rebound phenomenon” that follows denosumab discontinuation in women receiving aromatase inhibitors for early-stage breast cancer. It underscores that while the therapeutic benefit of denosumab during AI administration is undeniable, the period following discontinuation represents a critical juncture requiring careful management to avert adverse skeletal events.
The pathophysiology underlying the rebound effect involves a surge in osteoclastic activity once the inhibitory influence of denosumab wanes. This sudden elevation in bone resorption leads to rapid loss of BMD and compromises bone microarchitecture, thereby significantly increasing fracture risk. Clinically, this translates to spontaneous vertebral fractures, which may manifest as acute back pain and height loss, often with multiple fractures occurring concurrently in the thoracic and lumbar vertebrae. Disturbingly, these fractures have been documented in women who were not initially considered at high fracture risk, challenging assumptions that osteoporosis status alone can predict vulnerability.
Clinicians are thus faced with a therapeutic conundrum: how to leverage the benefits of denosumab during AI therapy while mitigating post-discontinuation risks. The current expert consensus favors initiating bisphosphonate therapy as a follow-on treatment to blunt the rebound bone loss. Nonetheless, significant uncertainties remain regarding the optimal bisphosphonate choice, dosing regimen, timing of initiation, and duration necessary to ensure sustained skeletal protection. These gaps complicate clinical decision-making and underscore the need for individualized treatment plans based on patient-specific risk profiles and treatment responses.
Furthermore, the review emphasizes that starting denosumab should never be an isolated intervention but part of a comprehensive, anticipatory therapeutic strategy that explicitly plans for eventual transition off the drug. This strategic foresight is critical, as delays in denosumab administration or gaps in follow-on antiresorptive therapy can exacerbate rebound risks. The review also highlights practical challenges encountered in real-world settings, including disparities in bisphosphonate availability globally and the management complexities posed by contraindications to bisphosphonates, such as renal impairment or hypersensitivity reactions.
The clinical implications of these findings are profound. Oncologists, endocrinologists, and osteoporosis specialists must collaborate closely to monitor bone health dynamically throughout and after AI and denosumab treatment. This entails regular assessment of BMD, bone turnover markers, and vigilant clinical surveillance for signs of vertebral fractures. Importantly, patient education plays a pivotal role in ensuring adherence to treatment schedules and prompt reporting of symptoms suggestive of fracture during the post-denosumab phase.
Recognizing these challenges, the review calls for a concerted research effort to elucidate unresolved questions and refine management protocols. Large-scale prospective studies are urgently needed to accurately quantify the incidence and temporal pattern of rebound-associated vertebral fractures, delineate patient- and treatment-related risk factors, and inform risk stratification algorithms. Randomized controlled trials comparing various bisphosphonate regimens post-denosumab discontinuation will be instrumental in establishing evidence-based guidance on how best to prevent rebound bone loss and fractures.
Additionally, investigations into modified dosing schedules or extended durations of denosumab therapy may offer avenues to attenuate rebound effects, but these strategies require rigorous evaluation. The integration of biomarkers and advanced imaging techniques to guide personalized antiresorptive therapy represents a promising frontier, potentially enabling clinicians to tailor interventions precisely to an individual’s skeletal dynamics and fracture risk.
In conclusion, this comprehensive review from the International Osteoporosis Foundation serves as a clarity beacon amidst the complexities of managing AI-associated bone loss. It underscores the necessity of anticipating denosumab discontinuation from the outset and implementing structured transition plans to alternative antiresorptive therapies. By foregrounding the risks of the rebound phenomenon and identifying critical knowledge gaps, the review charts a path forward for improving long-term skeletal outcomes in breast cancer survivors. Ultimately, such insights are pivotal to safeguarding quality of life and functional mobility in this growing patient population.
Subject of Research: People
Article Title: Non-metastatic breast cancer patients discontinuing aromatase inhibitor on denosumab: what next?
News Publication Date: 12-Jan-2026
Web References:
https://link.springer.com/article/10.1007/s00198-025-07798-2
http://dx.doi.org/10.1007/s00198-025-07798-2
References:
Marcucci G, Biver E, Body JJ, Campusano C, Cannata-Andía J, Confavreux C, de Villiers TJ, Ebeling PR, Hadji P, Kendler D, El Maghraoui A, Napoli N, Veronesi P, Rizzoli R, Brandi ML. Non-metastatic breast cancer patients discontinuing aromatase inhibitor on denosumab: what next? Osteoporos Int. 2026.
Keywords: Breast cancer, Osteoporosis, Endocrinology, Gynecology, Rheumatology
