Denosumab Doses Must Be Delivered On Time for Patients With Osteoporosis

Houchen Lyu, MD, PhD

Delayed administration of subsequent denosumab doses by more than 16 weeks is associated with increased risk of vertebral fracture compared with on-time administration in patients with osteoporosis, according to recent study findings.

Still, the evidence was insufficient to conclude risk for fracture was increased at other anatomical sites with long delay.

Houchen Lyu, MD, PhD, and colleagues estimated the risk for fracture among denosumab users who delayed subsequent doses compared with those who received doses on time. The team used an electronic database of medical records from primary care physicians in the UK. The database contained health information on nearly 17 million patients from 790 general practices. The investigators extracted data on demographic characteristics, diagnosis, and medications from 2010-2019.

Lyu and the team compared 3 dosing intervals for subsequent denosumab injections: on time, short delay, and long delay.

The investigators included injection data from patients at least 45 years old who initiated denosumab therapy for the management of osteoporosis. They identified denosumab dosages of 60 mg subcutaneously every 6 months. Patients were excluded if they had only 1 denosumab prescription record, received the subsequent injection within 150 days after the prior dose, or used any other antiosteoporosis drugs.

The recommended date of a subsequent dose of denosumab was set at 6 months after a prior dose. The team compared the effect of various delays of the subsequent dose on time (within 4 weeks after the recommended date), short delay (between 4 and 16 weeks after the recommended date), and long delay (more than 16 weeks after the recommended date but not beyond 6 months.

Lyu and the investigative team compared fracture risk among the 3 groups during the six-month follow-up. The main outcome was composite fracture, while additional outcomes included major osteoporotic fracture, vertebral fracture, hip fracture, and nonvertebral fracture.

Overall, 3964 patients who initiated denosumab treatment for osteoporosis were included in the study. The team excluded 1370 patients who did not complete the run-in period, resulting in the final cohort of 2594 patients. Patients included contributed a total of 6144 qualified denosumab injections.

Participants had a low burden of comorbid conditions but had a very high risk for fracture, with a mean 10-year risk for major osteoporotic fracture of 22%. More than half of the patients (53%) had a history of major osteoporotic fracture, while 19% had a history of hip fracture and 15% had a vertebral fracture.

Over 6 months, the risk for composite fracture was 27.3 in 1000 for on-time dosing, 32.2 in 1000 for short delay, and 42.4 in 1000 for long delay. In a comparison with on-time injections, short delay had a hazard ratio (HR) for composite fracture of 1.03 (95% CI, .63-1.69) and long delay had an HR of 1.44 (95% CI, .96-2.17) both with P=.093). The team noted for vertebral fractures, short delay had an HR of 1.48 (95% CI, .58-3.79) and long delay had an HR of 3.91 (95% CI, 1.62-9.45).

“…Findings are consistent with known denosumab pharmacokinetics and prior studies of fracture incidence after denosumab treatment discontinuation,” Kristine Ensrud, MD, MPH, and John Schousboe, MD, PhD, both of University of Minnesota, wrote in an accompanying editorial. “Therefore, it is of utmost importance that clinicians considering denosumab treatment carefully counsel patients before its initiation on the importance of not delaying or abruptly discontinuing injections.”

The study, “Delayed Denosumab Injections and Fracture Risk Among Patients With Osteoporosis,” was published online in the journal Annals of Internal Medicine.