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Long-term denosumab therapy safe, effective in postmenopausal osteoporosis
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Postmenopausal women with osteoporosis assigned denosumab therapy for up to 10 years saw sustained gains in bone mineral density and reductions in bone turnover with low fracture incidence vs. women assigned to placebo, according to an analysis of the FREEDOM extension trial.
“The year-by-year results show that the safety profile of denosumab remained consistent and favorable over 10 years of treatment,” Henry G. Bone, MD, Michigan Bone and Mineral Clinic in Detroit, and colleagues wrote. “In this aging population, the participant incidence of adverse events — such as serious infection, cellulitis, eczema and malignancy — remained low. ... Thus, many of the questions that were initially raised about long-term safety with denosumab’s unique mechanism of action have largely been addressed.”
Bone and colleagues analyzed data from 7,808 postmenopausal women with osteoporosis aged 60 to 90 years participating in the FREEDOM trial, conducted in 214 centers in North America, Europe, Latin America and Australia (mean age, 73 years). Women were enrolled between August 2004 and June 2005. Researchers randomly assigned women to 60 mg subcutaneous denosumab (Prolia, Amgen) or placebo every 6 months for 3 years; both groups were instructed to take daily calcium and vitamin D supplements. All participants who completed the FREEDOM trial without discontinuing treatment or missing more than one dose were eligible to enroll in the open-label, 7-year extension study in which all participants received denosumab. Data represent up to 10 years of denosumab exposure for women who received 3 years of denosumab and then continued in the extension (long-term group; n = 2,343) and up to 7 years for women who received 3 years of placebo and transitioned to denosumab in the extension (crossover group; n = 2,207). Primary outcome was safety monitoring, including adverse events, serious adverse events and denosumab antibody formation. Secondary outcomes included new vertebral, hip and nonvertebral fractures as well as BMD at the lumbar spine, total hip, femoral neck and one-third radius.
Within the cohort, 2,626 women (1,343 long-term group; 1,283 crossover group) completed the extension study. The yearly exposure-adjusted participant incidence of adverse events for all women receiving denosumab fell from 165.3 to 95.9 per 100 participant-years over 10 years. Serious adverse event rates remained stable during the study, ranging from 10.8 to 14.4 per 100 participant-years. One atypical femoral fracture was reported in each group during the extension. Seven cases of osteonecrosis of the jaw were reported in the long-term group vs. six in the crossover group.
The yearly incidence of new vertebral fractures (range, 0.9%-1.86%) and nonvertebral fractures (range, 0.84%-2.55%) remained low during the extension and similar to rates observed in the denosumab group during the first 3 years of the FREEDOM study, the researchers noted; rates were also lower than projected for a virtual long-term placebo cohort. During the extension period for the long-term group, the most common vertebral fracture sites were wrist (n = 72), rib (n = 23), hip (femoral neck or intertrochanteric; n = 22) ankle (n = 17) and humerus (n = 12). During extension for the crossover group, rates were slightly higher: The most common vertebral fracture sites were wrist (n = 93), hip (femoral neck or intertrochanteric; n = 26) ankle (n = 24) and humerus (n = 23) and rib (n = 20).
In the long-term group, BMD increased from FREEDOM baseline by 21.7% at the lumbar spine, 9.2% at total hip, 9% at femoral neck and 2.7% at the one-third radius, according to the researchers. In the crossover group, BMD increased from extension baseline by 16.5% at the lumbar spine, 7.4% at total hip, 7.1% at femoral neck and 2.3% at one-third radius.
“Our results support the skeletal safety of long-term treatment with denosumab,” the researchers wrote. “In this study, denosumab was employed as primary therapy in a population generally similar to those of other major clinical trials for postmenopausal osteoporosis. Over 10 years of treatment, we found that denosumab was efficacious, generally well tolerated, and had a favorable benefit–risk profile.” – by Regina Schaffer
Disclosure: Amgen funded this study. Bone reports receiving research support from Amgen, Merck and Shire; consultant fees from Alexion, Amgen, Grünenthal, Merck, Radius and Shire; and speakers’ honoraria from Amgen and Shire. Please see the full study for the other authors’ relevant financial disclosures.
Editor's Note: This article was updated on July 24 to reflect that one atypical femoral fracture was reported in each group during the extension.
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