Delays between denosumab injections may worsen BMD response
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A longer interval between denosumab injections is associated with suboptimal bone mineral density response at the spine and total hip, and strategies to improve the timely administration of denosumab in real-world settings are needed, according to findings published in The Journal of Clinical Endocrinology & Metabolism.
“In a study led by Daniel H. Solomon, MD, MPH, from Brigham and Women’s Hospital, the researchers found long-term adherence of denosumab was suboptimal,” Houchen Lyu, MD, PhD, a research fellow in the section of clinical sciences, division of rheumatology at Brigham and Women’s Hospital, told Healio. “Patients with good adherence had an average BMD increase of 3.9% at the lumbar spine, higher than patients with moderate (3%) or poor adherence (1.4%). Similar association was found for BMD at the total hip.”
Lyu and colleagues analyzed electronic medical records data from 151 adults aged at least 45 years identified as new users of denosumab (Prolia, Amgen) who received at least two 60 mg doses between October 2010 and December 2017 (938 injections; mean age, 69 years; 95% women). Denosumab adherence was evaluated by the medication coverage ratio (MCR), which measures the percentage of days a person was covered therapeutically during a given time interval after receiving denosumab.
“The MCR was calculated based on the assumption that each injection of denosumab provides 180 days of therapeutic coverage and the effect of denosumab wanes after this period,” the researchers wrote.
Researchers defined good adherence as a dosing interval of 7 months or shorter (defined by MCR 93%); moderate adherence as a dosing interval of 7 to 10 months (MCR 75%-93%); and poor adherence was defined as a dosing interval at least 10 months (MCR 74%). Primary outcomes were annualized percent BMD changes from baseline at the lumbar spine, total hip and femoral neck.
Within the cohort, adults received an average of six doses of denosumab, with 15% receiving two to three doses, 62% receiving four to eight doses, and 23% receiving more than eight doses. Mean follow-up time was 37 months.
Overall, 21% of administered denosumab injections were delayed by more than 1 month. Nearly all adults received their second injection within 10 months of the first dose; however, only 40% of patients received a dose within the same time frame after their 10th injection, suggesting that 60% of adults would have at least one injection delayed for more than 4 months at year 5, according to the researchers.
Researchers found that adults with good adherence experienced an annualized BMD increase of 3.9% at the lumbar spine compared with those with moderate (3%) or poor adherence (1.4%; P = .002), with results persisting after adjustment for age, sex, BMI, fracture history, bisphosphonate history and duration and number of previous denosumab injections. Similarly, adults with good adherence experienced an annualized BMD increase of 2.1% at the total hip compared with those with moderate (1.3%) or poor adherence (0.6%; P = .002).
“These results highlight the importance of timely denosumab administration when using this drug for long-term osteoporosis management,” Lyu said. “Strategies to improve timely administration of denosumab in the real-world setting are needed.”
Lyu said the findings suggest that a delay in denosumab administration of more than 4 months may be “unacceptable”; however, future studies are needed to determine the exact threshold.
“Also, future studies with fracture as an endpoint are needed to provide a conclusive answer as to whether this difference in BMD response among different groups predicts an increase in fracture risk,” Lyu said. – by Regina Schaffer
For more information:
Houchen Lyu, MD, PhD, can be reached at the Division of Rheumatology, Brigham and Women’s Hospital, 60 Fernwood Road, Boston, MA 02115; email: hlyu1@bwh.harvard.edu.
Disclosure: One of the study authors reports he receives salary support from research grants unrelated to osteoporosis from Amgen.
Perspective
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Rachel Pessah-Pollack, MD
Osteoporotic fractures are associated with a reduced quality of life and increased mortality. Numerous studies have shown the benefit of bone treatments on fracture reduction; however, these medications require adherence with recommended dosing intervals for maximum efficacy.
Denosumab is an anti-RANK ligand antibody that rapidly inhibits bone remodeling with effects that are quickly reversible upon stopping treatment. When given at 6-month intervals, denosumab results in significant increases in BMD and a reduction in vertebral, nonvertebral, and hip fractures. Continued treatment with denosumab for up to 10 years has showed a sustained BMD increase. If denosumab is discontinued without transitioning to an alternate bone treatment agent, there is a rapid reversal of treatment effects and potential increased risk for vertebral fractures, which can occur within a short time frame.
The authors in this study retrospectively looked at electronical medical records to examine the off-treatment effects on BMD of delaying/missing a dose of denosumab in patients with osteoporosis. They found that delaying denosumab dosing to an interval of up to 10 months resulted in significantly reduced BMD gains in the lumbar spine compared with interrupted dosing of 7 to 10 months or less than 7 months (1.4% versus 3.0% versus 3.9%, respectively). A similar trend was seen at the total hip; however, this was not noted at the femoral neck. At least one out of five people had a dose delayed by more than 1 month in this study.
Some reasons for interrupting therapy may be perceived issues tolerating, concerns about rare side effects and anticipation of an invasive dental procedure. Rare cases of atypical femoral fractures have been reported in patients treated with denosumab and these patients often were previous recipients of bisphosphonates. Other potential reasons for postponements in dosing include issues with insurance authorizations, scheduling dilemmas and other health care system delays.
There are very few reasons for discontinuing denosumab; however, the study illustrates delays are not infrequent. Implementing system-wide mechanisms to ensure patients receive the recommended dosing intervals of denosumab is vital to avoid interrupted therapy, even for a short time, and maximize the potential benefits of treatment.
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