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On-time osteoporosis treatments are vital for reaping their full prevention benefits, according to a new study.

In a study of 2,594 adults initiating denosumab for non-cancer indications (Prolia), on-time injections -- defined as administering the subsequent injection within 4 weeks after the recommended date -- had a significantly lower cumulative risk for all fractures compared with a delayed dosing schedule, Houchen Lyu, MD, PhD, of the General Hospital of Chinese PLA in Beijing, and colleagues reported in .

Those who received "on time" dosing saw a cumulative composite fracture risk of 27.3 in 1,000 over a 6-month period. On the other hand, those who had a "short delay" in dosing -- a delay by 4-16 weeks -- or a "long delay" by more than 16 weeks saw a composite fracture risk of 32.2 in 1,000 and 42.4 in 1,000, respectively.

However, a short delay or long delay in dosing did not actually equate to a significantly higher risk difference for a composite of all fracture types when compared with on-time dosing (HR 1.03, 95% CI 0.63-1.69; HR 1.44, 95% CI 0.96-2.17, P for trend=0.093, respectively).

But when categorized by specific fracture types, those on a long-delay dosing schedule did have a nearly four-fold increased risk for vertebral fractures versus on-time dosers (HR 3.91, 95% CI 1.62-9.45). This increased risk for vertebral fractures was not apparent for those on a short-delay schedule, though (HR 1.48, 95% CI 0.58-3.79).

Not so surprisingly, long-dosing delayers who were over age 75 had an even higher risk for a vertebral fracture (HR 4.09, 95% CI 1.17-14.3). Those who also were on a prior oral bisphosphonate for only 3 years or less also had one of the highest risks for vertebral fracture (HR 4.83, 95% CI 1.68-13.9).

Delayed dosing didn't significantly increase the risk for hip fractures (HR 1.75, 95% CI 0.81-3.79) or nonvertebral fractures (HR 1.25, 95% CI 0.80-1.94).

"Delayed dosing of denosumab is very common in routine clinical practice," the researchers pointed out. "Among patients who had been using denosumab for several years, almost 50% had at least one injection delay of more than 4 months."

Writing in an , Kristine Ensrud, MD, MPH, and John Schousboe, MD, PhD, both of the University of Minnesota in Minneapolis, noted that discontinuation of denosumab can yield a "rapid reversal" of its benefits, sometimes resulting in rebound increases in bone turnover within 3 to 6 months after discontinuation paired with accelerated bone loss.

"In the absence of initiation of an alternative osteoporosis drug treatment, measurements of bone mineral density return to pretreatment levels by 24 months after discontinuation," wrote Ensrud and Schousboe, who also noted that delayed denosumab dosing is likely even more common now during the COVID-19 pandemic.

For the analysis, Lyu and co-authors included injection data on patients age 45 or older from the Health Improvement Network U.K. primary care database who were initiators of denosumab therapy for osteoporosis management. Those who received only one dosage or those who were also on other anti-osteoporosis drugs such as estrogen, alendronate, risedronate, ibandronate, zoledronic acid, other bisphosphonates, or teriparatide, were excluded from the analysis.

The researchers then utilized a target trial emulation design that included observational data to mimic a hypothetical trial to assess the three type of dosing schedules.

Study limitations, the team said, included that the dosing schedules were not randomly assigned, and that there was a lack of data on immobility and falls, which are both tied to increased fracture risk and lower persistence with on-time dosing. Also, the study may have been underpowered for some outcomes.

"Whether the long-delay group is more representative of long delay (that is, temporary discontinuation) or permanent discontinuation is uncertain, because if a subsequent dose was not administered by the end of the 6-month follow-up, it was classified as a long-delay injection," the editorialists wrote.

Nonetheless, they said, the findings are largely in line with those of prior studies, and healthcare providers should therefore be sure to counsel patients on the dangers of delaying or abruptly discontinuing treatment prior to initiating denosumab. In addition, patients who do discontinue denosumab should subsequently be transitioned to an alternative antiresorptive medication.

In response to the COVID-19 pandemic, the issued new recommendations for providers to temporarily transition denosumab patients to an oral bisphosphonate if it is not possible to have a subsequent injection within 7-8 months of their most recent injection.

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