Denosumab is a fully human monoclonal antibody that inhibits receptor activator of
nuclear factor-kappa B ligand (RANKL), an essential mediator of osteoclast formation,
function, and survival that has been shown to decrease bone turnover and increase
bone mineral density (BMD) in treated patients. We assessed the long-term efficacy
and safety of denosumab, and the effects of discontinuing and restarting denosumab
treatment in postmenopausal women with low bone mass.
Postmenopausal women with a lumbar spine T-score of -1.8 to -4.0 or proximal femur
T-score of -1.8 to -3.5 were randomized to denosumab every 3 months (Q3M; 6, 14, or
30 mg) or every 6 months (Q6M; 14, 60, 100, or 210 mg); placebo; or open-label oral
alendronate weekly. After 24 months, patients receiving denosumab either continued
treatment at 60 mg Q6M for an additional 24 months, discontinued therapy, or discontinued
treatment for 12 months then re-initiated denosumab (60 mg Q6M) for 12 months. The
placebo cohort was maintained. Alendronate-treated patients discontinued alendronate
and were followed. Changes in BMD and bone turnover markers (BTM) as well as safety
outcomes were evaluated.
Overall, 262/412 (64%) patients completed 48 months of study. Continuous, long-term
denosumab treatment increased BMD at the lumbar spine (9.4% to 11.8%) and total hip
(4.0% to 6.1%). BTM were consistently suppressed over 48 months. Discontinuation of
denosumab was associated with a BMD decrease of 6.6% at the lumbar spine and 5.3%
at the total hip within the first 12 months of treatment discontinuation. Retreatment
with denosumab increased lumbar spine BMD by 9.0% from original baseline values. Levels
of BTM increased upon discontinuation and decreased with retreatment. Adverse event
rates were similar among treatment groups.
In postmenopausal women with low BMD, long-term denosumab treatment led to gains in
BMD and reduction of BTM throughout the course of the study. The effects on bone turnover
were fully reversible with discontinuation and restored with subsequent retreatment.