LAS VEGAS — Denosumab (Prolia, Amgen) use in patients with osteoporosis was not associated with increased risks for subtrochanteric and diaphyseal femur fractures compared with bisphosphonate use, according to results of a real-world observational study.

The findings from a study population of nearly 300,000 adults who were prescribed osteoporosis medications “support the use of denosumab as a vital therapeutic option for osteoporosis, with a risk profile similar to bisphosphonates,” Haolan Qi, MD, research assistant in the Department of Epidemiology at McGill University, Montreal, Canada, said at the American Association of Clinical Endocrinology (AACE) Annual Meeting 2026.

Long-term use of bisphosphonates for treating osteoporosis has been associated with atypical femoral fractures (AFFs), defined as stress or insufficiency fractures located in the subtrochanteric or diaphyseal femur. These fractures, which can occur with minimal trauma, lead to significant morbidity, delayed healing, high risk of nonunion, and potential bilaterality, said Qi.

Denosumab differs from bisphosphonates in that it is not retained in the bone matrix, so its effect is noncumulative and reversible. Therefore, it does not require “drug holidays,” she explained. However, cessation of use leads to a “rebound phenomenon,” in which rapid bone loss occurs within about a year of discontinuation, resulting in a high risk for multiple vertebral fractures 7-18 months after the last dose.

Real-World Data, Active Comparator

There have been case reports of AFFs in patients treated with denosumab. Some clinical trials, including the FREEDOM trial, have shown a low AFF risk but have lacked active comparators and excluded patients with comorbidities. 

In 2012, Osteoporosis Canada issued a statement saying that for those with osteoporosis at high risk for fracture, “the benefits of taking a bone drug far outweigh the risks of experiencing a rare fracture of the thigh bone.”

This new study is believed to be the first observational study using real-world data to investigate the association between subtrochanteric and diaphyseal fractures among patients with osteoporosis, using data from the UK Clinical Practice Research Datalink Aurum linked to the Hospital Episode Statistics database. 

The study population was 272,834 patients with osteoporosis aged 40 years or older who were new users of an osteoporosis medication between 2011 and 2023. Of those, 2310 initiated denosumab, 161,839 took a bisphosphonate, 277 used other osteoporosis treatments, and 108,408 used supplementation (calcium/vitamin D) only. The study population was 81.5% women and had a mean age of 73.7 years. 

At baseline, denosumab users were older (78.7 years vs 73.5 years), were more likely to have renal insufficiency (13.77% vs 9.38%), and were more likely to have had prior fractures (66.5% vs 50.9%).

A total of 662 AFFs occurred over a mean follow-up of 4.3 years. 

In the primary analysis, there were 24 AFFs among the current denosumab users (incidence rate, 0.89/1000 person-years) and 397 AFFs (incidence rate, 0.82/1000 person-years) with bisphosphonates, giving a nonsignificant adjusted hazard ratio of 0.94. 

Qi noted that because denosumab is typically prescribed as a second-line therapy, many of these individuals had prior exposure to bisphosphonates, rising from just 17.1% at baseline to 74.8% by the fifth year of follow-up. But a sensitivity analysis excluding the prior bisphosphonate users still showed no increase in AFF risk. 

“Further studies with a larger population that were treated with denosumab only are needed to further address whether denosumab use is associated with subtrochanteric and diaphyseal fractures,” study lead author Hoi Yun Oriana Yu, MD, associate professor in the Department of Epidemiology, Biostatistics, and Occupational Health and the Division of Endocrinology and Metabolism at McGill University, told Medscape Medical News. 

No significant differences in AFF rates were seen in secondary analyses by age (younger than 70 years vs 70 years or older), men vs women, glucocorticoid history, or cumulative duration (< 3 years vs 3 years or greater) of use. “These results were remarkably consistent,” Qi commented. 

No dose-response relationship was seen.

Prior Use of Biphosphonates ‘Muddies the Water’

Asked to comment, session moderator Lance A. Sloan, MD, president of the Texas Institute for Kidney and Endocrine Disorders, Lufkin, Texas, told Medscape Medical News, “I think it was reassuring that they weren’t finding any increased risk for atypical fractures compared with bisphosphonates.” 

He noted, however, that the high prior use of bisphosphonates was “a pretty major limitation, because bisphosphonates stay in the bone and in the system for very long time…I think that really kind of muddies the water.”

The researchers are still completing sensitivity analyses to confirm the primary findings, said Yu.

Sloan added, “There’s some question as to whether any of these medications are really increasing any of these fractures to begin with. And if not, then maybe when we do see them, they could be due to some other secondary cause like kidney disease or vitamin D deficiency that has nothing to do with the medicine.” 

The study authors had no disclosures. Sloan reported serving as a clinical investigator, consultant, and/or speaker for Abbott, Amgen, AstraZeneca, Bayer, Boehringer Ingelheim, Corcept, Eli Lilly, GlaxoSmithKline, Janssen, Merck, Novo Nordisk, Pfizer, and Sanofi Aventis.

Miriam E. Tucker is a freelance journalist based in the Washington, DC area. She is a regular contributor to Medscape, with other work appearing in the Washington Post, NPR’s Shots blog, and Diatribe. She is on X @MiriamETucker and BlueSky @miriametucker.bsky.social.