Risk for osteonecrosis of the jaw (ONJ) remains very low with the standard doses of antiresorptive agents, with little to no significant differences between bisphosphonates (BPs), denosumab, and selective estrogen receptor modulators (SERMs), according to a study presented at the American Society for Bone and Mineral Research (ASBMR) 2026 Annual Meeting in Boston.

The findings offer “reassurance for starting therapy in patients at high fracture risk,” Kyoung Jin Kim, MD, PhD, an associate professor of endocrinology and metabolism at the Korea University College of Medicine in Seoul, told attendees. “For osteoporosis treatment, ONJ is rare and should not be overestimated when balancing fracture prevention against potential harm.”

ONJ occurs among the general population at an incidence less than 0.001% but is slightly higher, at 0.02%-0.05%, in those with osteoporosis taking a low-dose antiresorptive.

However, few studies offer head-to-head comparisons of the risk of the three main drug classes. BPs remain the most commonly used antiresorptive class, but the use of denosumab has rapidly increased since 2018, and SERMs have seen a steady but less dramatic rise since around 2012.

Target Trial Emulation Designed to Remove Bias

Prior observational evidence attempting to compare risk for ONJ from these drugs has been inconsistent, Kim noted, with results also varying based on how the studies are designed. To remove the immortal-time bias seen in observational studies that define groups only by treatment received, without regard to start date, the researchers designed an observational “target trial emulation” study that defined groups by initiation of the medication.

They used data from the Korean National Health Insurance Service database to compare the risk for ONJ among 177,693 adults aged 50 years or older with osteoporosis who started taking an antiresorptive therapy from July 2016 to December 2021.

After excluding those with end-stage renal disease, prior cancer, prior ONJ, or history of prior anabolic agents, the population included 156,448 taking BPs, 7996 taking denosumab, and 13,249 taking a SERM.

The mostly female (94%) patients were an average 68 years old. Those taking SERMs were slightly younger (average, 64 years), and those taking denosumab had more kidney disease and previous fractures.

The primary outcome, tracked through December 2023, was incident ONJ after starting the medication, defined as exposed bone in the maxillofacial region that does not heal within 8 weeks in patients treated with an antiresorptive agent.

The 63 incident cases that occurred in the per-protocol analysis showed lower risks for ONJ with denosumab and SERMs than with BPs, but the differences were not significant (hazard ratio [HR], 0.89; 95% CI, 0.28-2.89 with denosumab and HR, 0.21; 95% CI, 0.03-1.51 with SERMs). The 70 incident cases in the intent-to-treat analysis yielded similar findings with denosumab (HR, 0.80; 95% CI, 0.25-2.58) and SERMs (HR, 0.56; 95% CI, 0.18-1.81).

The comparative difference in ONJ rate seen in a third time-varying analysis of 163 incident cases, which captured switches between medications and restarts, was also not significant for denosumab (HR, 1.48; 95% CI, 0.97-2.26) but was significant for SERMs (HR, 0.45; 95% CI, 0.21-0.94), though that finding should be “interpreted with caution” given the small number of events, Kim said.

The absolute risk for incident ONJ was 0.38 cases per 1000 person-years for BPs and 0.36 cases per 1000 person-years for denosumab. There was a higher absolute rate of 0.71 cases per 1000 person-years seen with denosumab in the time-varying analysis, but this “likely reflects switching from [BPs] and longer cumulative antiresorptive exposure,” Kim said.

Reassuring Findings

Lauren E. Crocco, MD, an attending orthopedic trauma surgeon and assistant professor of medicine at Montefiore Einstein in New York City, who was not involved in the trial, agreed that these findings are reassuring, “again highlighting the fact that [ONJ] is a very rare event for patients regardless of medication choice,” she told Medscape Medical News. “The risk of fragility fracture from osteoporosis is a much more frequent event, and as such providers should feel comfortable to continue to prescribe appropriate osteoporosis prevention medications, as indicated.”

Crocco noted that about half of all women will experience an osteoporotic fracture at some point in their lifetimes. “Fragility fractures from osteoporosis can be life-altering, and prevention is always top of mind for people at risk for fracture,” she said. “Antiresorptive osteoporotic medications can significantly decrease the risk of fracture by up to 40% with routine use in appropriate populations,” she said, and “treatment and prevention of fragility fractures is important to keep patients mobile and healthy into their later years.”

Crocco acknowledged that ONJ is a devastating complication that providers seek to avoid at all costs. “Everything in medicine is a balance between risks and benefits,” she said. “For the majority of patients, the benefit of osteoporosis treatment continues to outweigh the risk of [ONJ].”

That said, providers need to know whether any dental surgery may be planned in the near future before a patient starts an osteoporosis medication because it may alter the timing or choice of medications.

“What is absolutely critical to remember is that communication between the patient and the provider prescribing the medication is essential,” Crocco said. “Additionally, facts about the patient’s current dental health and prior dental issues are important for the provider to know how to make a well-informed decision when writing these medications.”

She found this study’s approach to analyzing the data to be novel, designed to mimic a randomized controlled trial to help better understand the existing data. “True randomized control trials for rare occurrences, like ONJ, are challenging because the numbers are so few it can take a long time to get enough patients for a prospective study,” she said.

“This type of study is a step towards helping us establish protocols to determine who is most at risk for [ONJ] prior to initiating osteoporosis treatment,” Crocco said. She hopes to see additional studies that further define the scope of patients who may potentially be affected by ONJ after starting treatment for osteoporosis.

The research did not use external funding, and the authors reported no disclosures. Crocco had no disclosures.

Tara Haelle has been an independent science/health journalist for over 15 years, with work appearing in over two dozen trade and consumer publications. She is the author of Vaccination Investigation: The History and Science of Vaccines and The Informed Parent: A Science-Based Resource for Your Child’s First Four Years. She is the Public Health Beat Leader for the Association of Health Care Journalists, where she develops resources to help other journalists report on medical studies and public health. She is based in Dallas.