April 23, 2026
3 min read
Key takeaways:
- A large population-based study showed denosumab does not increase atypical femur fracture risk compared with bisphosphonate therapy.
- The data suggest denosumab is a safe option for osteoporosis treatment.
LAS VEGAS — Adults with osteoporosis prescribed the antiresorptive denosumab were no more likely to sustain an atypical femur fracture compared with bisphosphonate users over 4 years, according to data from a large, real-world study.
Long-term use of bisphosphonates, the first-line therapy for osteoporosis, is associated with rare but serious atypical femur fractures, which come with a high clinical burden that include delayed healing and significant morbidity, Haolan Qi, MD, MSc, a masters student in epidemiology at McGill University in Montreal, said during a presentation at the American Association of Clinical Endocrinology Annual Scientific and Clinical Conference.
Adults with osteoporosis receiving denosumab do not have long-term increased risk for atypical femur fracture compared with those using bisphosphonates. Image: Adobe Stock
“To mitigate this risk, a drug holiday was introduced for bisphosphonate treatment,” Qi said during the presentation. “Denosumab is another potent antiresorptive agent, but unlike bisphosphonates, denosumab is not retained in the bone matrix and does not exert residual activity after discontinuation. Its effects are highly reversible, and treatment cessation leads to a rebound phenomenon, where bone density rapidly drops and vertebral fracture risk spikes. Therefore, denosumab is technically administered without a drug holiday. Since it is also antiresorptive, there are concerns that it might also increase atypical femur fracture risk.”
An active comparator study
The researchers analyzed data from 272,834 adults with osteoporosis without a history of atypical femur fractures or high-trauma fractures, using the U.K. Clinical Practice Research Datalink linked to Hospital Episode Statistics (mean age, 73.7 years; 81.5% women). The exposure groups included adults prescribed denosumab (Prolia, Amgen; n = 2,310); bisphosphonates (n = 161,839); other osteoporosis treatments such as calcitonin, teriparatide, abaloparatide (Tymlos, Radius Health) and romosozumab (Evenity, Amgen; n = 277); and adults taking supplements only (calcium and/or vitamin D; n = 108,408). Researchers adjusted for demographics, age, sex, race, BMI, clinical status, history of bisphosphonate use (> 5 years ago) and prior fracture history.
“Compared to bisphosphonate users, denosumab users were generally older and had a higher prevalence of renal insufficiency and flare fractures,” Qi said. “We accounted for these differences in our adjusted models.”
The primary outcome was incidence of subtrochanteric and diaphyseal femur fractures, identified using ICD-10 codes.
“To diagnose atypical femur fractures, according to the gold standard established by the American Society of Bone and Mineral Research, a blind review of X-ray images with radiographic features such as transverse fracture line, cortical thickening, etc, is required,” Qi said. “To extract and review individual X-ray images is not feasible within an administrative dataset. So, we used ICD-10 codes for subtrochanteric and diaphyseal femur fractures as proxies for atypical femur fractures.”
During mean follow-up of 4.3 years, researchers observed 662 subtrochanteric and diaphyseal femur fracture events, for an overall incidence rate of 0.8 per 1,000 person-years.
Twenty-four events occurred in the denosumab group, for an incidence rate of 0.89 per 1,000 person-years, and 397 occurred among current bisphosphonate users, for a rate of 0.82 per 1,000 person-years, Qi said.
The adjusted HR was 0.94 (95% CI, 0.62-1.43), indicating no statistically significant difference in atypical femur fracture risk.
The results did not vary by age, sex, history of glucocorticoid use or duration of therapy.
Treatment sequence considerations
At baseline, 17% of denosumab users had prior bisphosphonate exposures, Qi said; however, by year 5, 75% did.
“This reflects the real-world sequence of osteoporotic management,” Qi said. “Denosumab is often prescribed as a second-line therapy. Many patients who fail or who are intolerant of bisphosphonates transition to denosumab. Therefore, adjusting for prior bisphosphonate use was very crucial to estimate the true effect of denosumab.”
A sensitivity analysis excluding prior bisphosphonate use further confirmed the primary results, Qi said. A longer duration of denosumab use did not significantly increase atypical femoral fracture risk compared with bisphosphonates, Qi said.
“We found a reassuring safety profile, with no evidence of an increased risk associated with denosumab use in a real-world setting,” Qi said. “Clinically, these results should be reassuring and support the use of denosumab as a vital therapy option for osteoporosis, with a risk profile similar to the standard of care.”
Sources/Disclosures
Source:
Qi H, et al. The association between denosumab use and the risk of subtrochanteric and diaphyseal fractures. Presented at: American Association of Clinical Endocrinology Annual Scientific and Clinical Conference; April 22-24, 2026; Las Vegas.
Disclosures:
Qi reports no relevant financial disclosures.
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