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Denosumab could be
used for the long-term management of postmenopausal
women with osteoporosis as it produced progressive
increases in BMD and a sustained decrease in risk of fractures, with a
favorable safety profile.
Osteoporosis is a condition characterised by decreased bone mass, impaired bone strength due to increased bone resorption relative to the formation. So this chronic condition requires long-term safety and efficacy in its treatment. The study was aimed to analyse the long-term safety and efficacy of widely used denosumab as the treatment of osteoporosis in postmenopausal women.
The multicenter, randomised, double-blind, placebo-controlled, phase 3 FREEDOM trial, enrolled postmenopausal women with osteoporosis(60–90 years) in 214 centres. The centres were based in North America, Europe, Latin America, and Australasia. The patients were randomly provided (1:1) with 60 mg subcutaneous denosumab or placebo every 6 months for 3 years.
The eligible participants in this open-label, 7-year extension were those who had completed the FREEDOM trial and did not discontinue the treatment or missed more than a single dose of investigational product. All study participants received denosumab.
The data collected was from up to 10 years of denosumab exposure for women who
received 3 years of denosumab in FREEDOM and continued in the extension
(long-term group). On other hands up to 7 years for women who received 3 years
of placebo and transitioned to denosumab in the extension (crossover group).
1) The primary outcome was to measure - safety monitoring, comprising
assessments of adverse events incidence and serious adverse event incidence,
changes in safety laboratory analytes (ie, serum chemistry and haematology),
and participant incidence of denosumab antibody formation.
2) Secondary outcomes included - new vertebral, hip, and non-vertebral
fractures as well as bone mineral density (BMD) at the lumbar spine, total hip,
femoral neck, and one-third radius.
Analyses were done on the basis of randomised FREEDOM treatment assignments.
Participants whoever got at least a single dose of investigational product in
FREEDOM or the extension were included in the combined safety analyses. All
those participants enrolled in the extension with observed data were included
in the efficacy analyses.
Women were enrolled (n-7808) in the FREEDOM study between Aug 3, 2004, and June
1, 2005.
The findings revealed that 2626 patients completed the extension study out of which 1283 were crossover patients and 1343 were long-term patients.
Over 10 years, the yearly exposure-adjusted participant incidence of adverse
events for patients receiving denosumab got reduced from165.3 to 95.9 per 100 participant-years.
The incidence of serious adverse events found to be stable during the study
(11.5 to 14.4 per 100 participant-years).
Only one case of atypical femoral fracture occurred in each group during
extension, the 7 cases of osteonecrosis of the jaw occurred in the long-term
group and 6 cases of osteonecrosis of the jaw occurred in the crossover group
The annual incidence of new vertebral fractures and non-vertebral fractures was
low and found to be similar in occurrence to FREEDOM study (0.90-1.86% and
0.84-2.55%, respectively).
Long-term group: BMD increased by 21.7% at the lumbar spine, 9.2% at the total
hip, 9.0% at the femoral neck, and 2.7% at the one-third radius from FREEDOM
baseline
Crossover group: BMD increased by 16.5% at the lumbar spine, 7.4% at the total
hip, 7.1% at the femoral neck, and 2.3% at the one-third radius from FREEDOM
baseline.
The study estimated that denosumab treatment for up to 10 years was associated
with low rates of adverse events, low fracture incidence compared with that
observed during the original trial, and continued increases in BMD without
plateau.
The Lancet Diabetes & Endocrinology
10 years of denosumab treatment in postmenopausal women with osteoporosis: results from the phase 3 randomised FREEDOM trial and open-label extension
Henry G Bone et. al.
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