Denosumab benefits short-lived following discontinuation
medwireNews: Discontinuing denosumab after 1 year of treatment quickly leads to reversal of its inhibitory effect on bone turnover markers and improvements in bone mineral density (BMD) among people using glucocorticoids for rheumatoid arthritis (RA), research shows.
Kenneth Saag (The University of Alabama at Birmingham, USA) and co-investigators say their findings “highlight the need for follow-on osteoporosis therapy to preserve BMD gains in patients who discontinue denosumab.”
Saag and team evaluated the impact of discontinuing denosumab among a subgroup of 82 people receiving glucocorticoid therapy for RA who were part of a larger phase 2 denosumab trial.
The participants were randomly assigned to receive placebo (n=26), denosumab 60 mg (n=27), or denosumab 180 mg (n=29) every 6 months for 12 months and then followed up for an additional 12 months after discontinuation, during which time no new bone loss prevention therapy was allowed.
As reported in Arthritis & Rheumatology, serum C-terminal telopeptide of type I collagen (CTX) levels decreased by a median 21.4% from baseline to 12 months in the placebo group, while levels fell by a median 41.6% and 56.6% during 12 months of treatment with denosumab 60 mg and 180 mg, respectively.
And the researchers note that the reductions in both denosumab groups were statistically significant relative to baseline and placebo.
A similar pattern of significant differences was observed for procollagen type I N-terminal propeptide (P1NP) levels. In this case, P1NP fell by a median 12.0% in the placebo group over 12 months, and by a respective 46.9% and 41.6% in the denosumab 60 mg and 180 mg groups.
During the subsequent 12-month off-treatment period, serum CTX levels returned to baseline within 6 months in both denosumab groups and remained stable and not significantly different from levels in the placebo group thereafter.
Serum P1NP levels also increased to baseline levels within 6 months of stopping denosumab then remained stable in the 60 mg group, but increased further in the 180 mg group to a significant 75.8% higher at 12 months after treatment cessation than at baseline. At both follow-up timepoints, serum P1NP levels were higher in the two denosumab groups relative to placebo.
Saag and co-authors also found that the decreases in both bone turnover markers during denosumab treatment corresponded to significant gains, versus placebo, in lumbar spine and total hip BMD at 12 months. The changes were apparent from as early as 1 month at the lumbar spine in the denosumab 60 mg group.
However, following denosumab discontinuation, BMD in both denosumab groups decreased to levels similar to those in the placebo group within 12 months.
Saag et al therefore conclude: “Postdiscontinuation bone loss in the present study was associated with a return of serum CTX to pretreatment baseline levels in both denosumab groups and an increase in serum P1NP to above baseline levels, particularly in the 180-mg group.”
They add: “These results provide further support for recommendations that patients discontinuing denosumab should transition to follow-on osteoporosis therapy to prevent or minimize remodeling-induced bone loss.”
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