Denosumab discontinuation in non-metastatic breast cancer treated with AI raises vertebral fracture risk

Aromatase inhibitors (AIs) are a cornerstone of adjuvant therapy for hormone receptor–positive breast cancer, significantly reducing recurrence and mortality. However, by suppressing estrogen production, AIs accelerate bone loss and increase fracture risk. To counter this, antiresorptive therapies such as denosumab or bisphosphonates are widely recommended.

Denosumab has strong evidence for fracture prevention during AI therapy. Yet, unlike bisphosphonates, its protective effects reverse rapidly once treatment is stopped. As a result, women with early-stage, estrogen receptor–positive breast cancer who discontinue denosumab after AI therapy may face a significant and under-recognized risk of spontaneous vertebral fractures, according to a new narrative review by the International Osteoporosis Foundation (IOF) Committee of Scientific Advisors Working Group on Cancer-Induced Bone Disease.

Published in Osteoporosis International, the review warns that discontinuing denosumab can trigger a “rebound phenomenon” marked by rapid bone turnover, bone loss, and potentially multiple vertebral fractures—even in women without prior osteoporosis or traditional fracture risk factors.

Key findings and clinical implications

“Denosumab is highly effective in preventing fractures during AI therapy, but its discontinuation represents a critical and often underestimated moment,” said Professor Maria Luisa Brandi, lead author and member of the IOF Working Group on Cancer-Induced Bone Disease. “Our review shows that stopping denosumab without a clear follow-on strategy can expose women to a real risk of spontaneous, sometimes multiple vertebral fractures—even in patients who were not considered at high fracture risk.”

The review highlights that:

• Bone turnover increases sharply after denosumab withdrawal, leading to rapid loss of bone mineral density
• Spontaneous vertebral fractures—often multiple and clustered at the thoracolumbar spine—have been reported after denosumab discontinuation in women treated with AIs
• Fracture risk may be underestimated because many affected women did not have osteoporosis at the start of cancer therapy
• Expert consensus supports initiating bisphosphonate therapy after denosumab discontinuation, although the optimal drug, dose, timing, and duration remain undefined

The authors emphasize that starting denosumab in women receiving AIs should never be viewed as a stand-alone decision, but rather as part of a planned therapeutic sequence that anticipates treatment discontinuation. They also highlight practical challenges, such as delayed denosumab dosing, limited access to bisphosphonates in some countries, and management difficulties in patients with contraindications to bisphosphonate therapy.

Research is needed to address major knowledge gaps

Despite growing recognition of the problem, the authors note that there are numerous open research questions which future prospective studies will have to answer in order to personalize the most appropriate antiresorptive therapy for each patient. The authors highlight the need for:

• Large prospective studies to define the true incidence, timing, and risk factors for rebound-associated vertebral fractures
• Randomized controlled trials comparing bisphosphonate regimens following denosumab discontinuation
• Studies investigating modified denosumab dosing or duration strategies to minimize rebound effects
• Biomarker- and bone density–guided approaches to personalize treatment decisions

By clearly defining the knowledge gaps and uncertainties, the review offers a valuable framework for further research priorities.

A clear message for clinicians

“This paper provides a timely and clinically important synthesis of evidence that directly affects the long-term care of bone health in breast cancer survivors. A key message is that clinicians should anticipate denosumab discontinuation from the moment therapy is initiated and ensure a structured transition to alternative antiresorptive treatment,” added Professor René Rizzoli, co-author and Chair of the IOF Working Group on Cancer-Induced Bone Disease.