Background/Purpose: Denosumab (DMAb)
is approved for the treatment of postmenopausal women with osteoporosis at
increased risk for fracture. In the pivotal 3-year FREEDOM trial comparing
placebo (Pbo) and DMAb, questions arose regarding imbalances of low-frequency adverse
events and some common adverse reactions. Here, we examined the incidences of
these events in women who originally received Pbo during FREEDOM and then
received DMAb for 3 years during the FREEDOM Extension (cross-over group). This
provided a unique opportunity for comparison with the original 3-year Pbo and DMAb
FREEDOM observations.

Methods: In FREEDOM, postmenopausal women
with osteoporosis received Pbo or DMAb for 3 years. Women were eligible for the
Extension if they completed the 3-year FREEDOM visit, missed no more than 1
dose of investigational product (IP) during FREEDOM, and agreed to enroll.
During the Extension, all women received DMAb. Three-year cumulative incidences
of selected adverse events of interest observed during FREEDOM for the Pbo and DMAb
groups were also determined for the first 3 years of DMAb exposure during the Extension
for the cross-over group. For each of these 3 groups, the safety analyses
included women who received ≥ 1 dose of IP during the respective 3-year
periods (FREEDOM Pbo, N=3883; FREEDOM DMAb, N=3879; Extension cross-over DMAb,
N=2206). Selected safety events of interest included malignancy, pancreatitis, endocarditis,
delayed fracture healing, serious infections, serious opportunistic infections,
and serious cellulitis or erysipelas, in addition to the top 5 most frequent adverse events in the US prescribing information
(USPI; back pain, pain in extremity, musculoskeletal pain,
hypercholesterolemia, and cystitis).

Results: The incidences of these adverse
events in the cross-over DMAb group during the first 3 years of the Extension were
similar to or lower than the incidences reported in FREEDOM and did not show a trend
for increasing risk of any of these events (Table). For example, the incidence
of serious adverse events of cellulitis or erysipelas observed in FREEDOM DMAb subjects
(0.31%) was not observed in the FREEDOM Pbo subjects who crossed over to DMAb
(0.05%) in the Extension.

Conclusion: Analyses of 3-year safety
data from FREEDOM (Pbo and DMAb groups) and 3-year safety data from the
Extension (cross-over DMAb group) did not show an increasing trend regarding
the imbalances of low-frequency events and some common adverse reactions observed
in FREEDOM.