How Long Should Patients with Prostate Cancer That Has Spread to the Bones Receive Denosumab? [Health Check]

[Financial News] A study found that among patients with bone-metastatic castration-resistant prostate cancer who received the bone-protective drug denosumab for more than a year, one in eight developed osteonecrosis of the jaw within three years. However, the drug’s fracture-prevention effect was no different from that in patients treated for one year or less.
A research team at the Catholic University of Korea College of Medicine—Professor Choi Su-in of the Department of Clinical Pharmacology at The Catholic University of Korea, Seoul St. Mary's Hospital; Professor Kim Seo-ri of Hemato-Oncology at The Catholic University of Korea Bucheon St. Mary's Hospital; and researcher Jeong Seung-pil of the Data Science Department at Catholic University of Korea PIPET—said on the 10th that it had confirmed these findings by comparing the benefits and risks associated with different durations of denosumab treatment in patients with bone-metastatic castration-resistant prostate cancer (CRPC). The results were published in the October 21 issue of JAMA Network Open, an international journal published by the American Medical Association (AMA).
Denosumab is a standard treatment for reducing skeletal complications, such as fractures and spinal cord compression, in patients whose cancer has spread to the bones. Bone is maintained through a constant balance between “osteoclasts,” which break down old bone, and “osteoblasts,” which build new bone. When cancer cells metastasize to the bones, however, the signaling protein that activates osteoclasts (RANKL) increases excessively, causing too much bone to be broken down. As a result, bones can fracture more easily or press on the spinal cord. Denosumab binds to this signaling protein and blocks it from sending signals to osteoclasts, slowing the rate of bone breakdown.
The problem is that the normal process of bone remodeling is also suppressed. As a result, if an injury such as a tooth extraction occurs, the jawbone may not heal and can become necrotic—a side effect known as osteonecrosis of the jaw (ONJ). The risk of ONJ is known to accumulate as the duration of treatment increases.
However, there was little evidence on how long treatment should continue. Existing clinical trials were designed to establish the drug’s effectiveness, not to compare treatment durations, so in clinical practice treatment was often continued until a patient’s condition worsened.
The research team analyzed national claims data from the Health Insurance Review & Assessment Service (HIRA) for 2009–2024, covering 3,307 men (mean age, 72.6) who began receiving an oncology dose of denosumab for bone-metastatic castration-resistant prostate cancer. The team divided treatment duration into three groups—six months or less, 7–12 months, and 13 months or more—and compared the cumulative incidence over three years.
The analysis used a “target trial emulation” design, which uses observational data to simulate a randomized clinical trial. The bias that “patients who survive longer receive treatment for longer” was adjusted for using the clone-censor-weight method, and death was treated as a competing event.
The analysis found that the risk of ONJ continued to rise with longer treatment, while the preventive effect against skeletal complications did not increase after 7–12 months of treatment. The three-year incidence of ONJ rose nearly fourfold, from 3.3% in the 7–12-month treatment group to 12.2% in the group treated for 13 months or more. By contrast, the incidence of skeletal complications, such as fractures and spinal cord compression, was about 4% in both groups, with no difference between them. However, skeletal complications were less common in the 7–12-month group than among patients treated for six months or less.
Keeping the interval between doses at 12 weeks or less did not further improve the preventive effect against skeletal complications. The risks of both ONJ and skeletal complications depended on total treatment duration rather than the interval between doses. The unfavorable trend associated with treatment for more than a year was particularly pronounced in patients under 70, and patients with a history of tooth extraction had a higher risk of ONJ.
Professor Choi Su-in explained, “Clinical trials showed that denosumab delays skeletal complications, but they did not answer how long it should be used. When treatment durations are compared using real-world clinical data, a bias arises that makes long-term treatment appear more beneficial than it actually is, because patients who received treatment for longer were also those who had survived longer.” She continued, “This time, we minimized this bias by virtually assigning all patients to one of three treatment strategies and comparing them as in a randomized clinical trial. Using nationwide data, we were able to provide evidence that the balance of benefits and risks changes at the one-year mark of treatment.”
Professor Kim Seo-ri said, “ONJ is a complication that significantly affects eating and quality of life, so dental care is especially important for patients with a history of tooth extraction. However, because stopping treatment may cause a temporary rebound in which bone is rapidly broken down, decisions such as adjusting the dosing interval should be made carefully for each patient, taking both dental and bone risks into account.”
These findings are expected to serve as a reference for clinical decisions on when patients receiving long-term bone-protective treatment should undergo dental examinations and whether to continue treatment. 


[email protected] Jeong Myeong-jin, Medical Specialist Reporter