Denosumab does not raise atypical femur fracture risk

Study Design and Participant Demographics

The retrospective cohort study evaluated 272,834 adults diagnosed with osteoporosis. Participants with a documented history of atypical femur fractures or high-trauma fractures were rigorously excluded from the analysis. The cohort was predominantly female (81.5%) with a mean age of 73.7 years.

Participants were categorized into four distinct exposure groups: denosumab, bisphosphonates, alternative active therapies, and a supplement-only control group. The researchers employed multivariable models to adjust for critical covariates, including age, sex, race, body mass index (BMI), clinical comorbidity status, prior history of fracture, and historical bisphosphonate utilization (>5 years prior).

Table 1: Osteoporosis Treatment Exposure Cohorts

*Includes calcitonin, teriparatide, abaloparatide, and romosozumab.

Regarding baseline differences between the primary comparison groups, Dr. Qi noted, “Compared to bisphosphonate users, denosumab users were generally older and had a higher prevalence of renal insufficiency and flare fractures. We accounted for these differences in our adjusted models.”

Methodological Approach to Fracture Identification

The primary clinical outcome was the incidence of subtrochanteric and diaphyseal femur fractures. Because this was an analysis of administrative data, identifying true AFF events required a methodological proxy.

“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 explained. “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.”

Clinical Outcomes and Risk Assessment

Over a mean follow-up duration of 4.3 years, the study recorded a total of 662 subtrochanteric and diaphyseal femur fracture events across the entire cohort, yielding an overall incidence rate of 0.8 per 1,000 person-years.

When comparing the two primary antiresorptive therapies, the incidence rates were remarkably similar, and the adjusted hazard ratio indicated no statistically significant difference in fracture risk.

Table 2: Incidence and Relative Risk of Subtrochanteric/Diaphyseal Femur Fractures

The researchers emphasized that these findings remained consistent and did not vary significantly when stratified by patient age, sex, concomitant history of glucocorticoid use, or the total duration of the osteoporosis therapy.

The Impact of Sequential Therapy

A critical nuance in analyzing real-world pharmacological data in osteoporosis is the sequential nature of treatment. Dr. Qi highlighted the substantial crossover effect observed during the study period: at baseline, only 17% of denosumab users had prior exposure to bisphosphonates; however, by the 5-year mark, this figure had surged to 75%.

“This reflects the real-world sequence of osteoporotic management,” stated Dr. Qi. “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.”

To validate their primary findings against this confounding factor, the research team conducted a rigorous sensitivity analysis that explicitly excluded patients with prior bisphosphonate utilization. This secondary analysis confirmed the primary results: prolonged denosumab therapy did not independently elevate the risk of atypical femoral fractures when compared to bisphosphonate therapy.

Conclusion

The findings from this large administrative dataset provide substantial reassurance regarding the long-term safety profile of denosumab.

“We found a reassuring safety profile, with no evidence of an increased risk associated with denosumab use in a real-world setting,” Qi concluded. “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.”