No Difference in Fracture Risk in Patients Taking Denosumab Versus Alendronate

A recent cohort study compared fracture outcomes in patients with osteoporosis being treated with denosumab (PROLIA from Amgen) versus alendronate and found both treatments carried the same risk for hip fracture and overall fracture.

“Head-to-head randomized clinical trials showed greater efficacy of denosumab vs alendronate in improving bone mineral density,” the study authors wrote. “Although there is an association of changes in bone mineral density with reductions in fracture risk, the magnitude of the association is not well established.”

To conduct their trial, the researchers collected Danish health registry data on patients aged ≥ 50 years initiating either denosumab or alendronate between May 2010 and December 2017. Patients were excluded if they had a recorded dispensing of any osteoporosis medication during the one-year period before the index date or if they had a history of cancer or Paget disease in the 10 years before the index date, because they are both “alternative indications for denosumab and alendronate,” the study authors noted. The primary outcome was hospitalization for hip fracture, and the secondary outcome was hospitalization for any fracture.

Similar Patient Populations and Outcomes

The analysis included 92,355 patients (mean age, 71 years; 81.3% female): 4,624 initiating denosumab and 87,731 initiating alendronate. There were more men in the alendronate group than the denosumab cohort (19% vs. 12.7%). Age breakdown was similar between the groups: in both the denosumab and alendronate cohorts, most patients were aged between 70 and 79 years (32.4% vs. 32.3%, respectively), followed by 60–69 years (29.9% vs. 30.7%, respectively). After three years of follow-up, cumulative hip fracture incidence was 3.7% in the denosumab group and 3.1% in the alendronate cohort. In both groups, the cumulative incidence for any fracture was 9.0%.

The overall adjusted hazard ratios (aHRs) for denosumab compared to alendronate were 1.08 (95% CI, 0.92-1.28) for hip fracture and 0.92 (95% CI, 0.83-1.02) for any fracture. The researchers also evaluated aHRs for hip fracture based on previous fracture history: comparing denosumab to alendronate, the aHR for hip fracture among patients with history of any fracture was 1.07 (95% CI, 0.85-1.34), and for patients with no fracture history, it was 1.05 (95% CI, 0.83-1.32); when evaluating for any fracture comparing denosumab to alendronate, aHRs were 0.84 (95% CI, 0.71-0.98) for those with previous fracture and 0.77 (95% CI, 0.64-0.93) for those without previous fracture.

“The results did not materially change after excluding patients with a recent fracture at the same site as a given outcome or after excluding atypical femoral fractures from the hip fracture outcome definition,” the study authors further observed. “Extending the required therapy-free period to 5 years to define new use yielded an aHR for hip fracture of 1.07 (95% CI, 0.88-1.30) and for any fracture of 0.93 (95% CI, 0.82-1.05) for denosumab compared with alendronate.”

One of the study’s limitations was potential residual confounding: “For example, renal impairment was more prevalent in the denosumab cohort than in the alendronate cohort but is incompletely measured by hospital diagnoses,” the researchers wrote. Data were also lacking on frailty, socioeconomic status, lifestyle, and bone mineral density. Finally, the researchers could not stratify patients into more than two age groups.