Big Gains With Denosumab in Osteoporosis a Risk for Later Decline

Nancy A. Melville

September 23, 2019

ORLANDO, Florida — — A new analysis has identified a predictor for rebound bone loss when osteoporosis patients take sequential bisphosphonate therapy following cessation of treatment with the antiresorptive therapy denosumab.

"We found that patients with the greatest increase in BMD on denosumab in the first year were at risk for the greatest declines in BMD on alendronate in the second year," author David Kendler, MD, of the University of British Columbia, Vancouver, told Medscape Medical News.

"The lack of other predictors means that (monitoring) bone density for a year after switching to alendronate would be prudent," he added.

Kendler presented the findings here at the American Society for Bone and Mineral Research (ASBMR) 2019 Annual Meeting.

"The key take-home message here is that doctors should use denosumab for appropriate patients, but patients should be warned that when and if they are to discontinue denosumab, subsequent treatment strategies need to be carefully planned," Felicia Cosman, MD, a professor of clinical medicine at Columbia University College of Physicians and Surgeons in New York City, told Medscape Medical News.

And "Patients must notify doctors if they need to miss or delay their next denosumab administration," said Cosman, who moderated the ASBMR session.

Data Limited on Ideal Follow-Up Therapy for Denosumab

Denosumab, administered as an injection every 6 months, provides a reduction in bone turnover markers and increase in BMD in patients with osteoporosis.

But after discontinuation a rebound effect causes some bone turnover markers to increase to levels even higher than they were at baseline, increasing the risk of fragility fracture, hence the need for sequential therapy.

However, data are limited on the ideal follow-up therapy.

In the 24-month DAPS (Denosumab Adherence Preference Satisfaction) study in postmenopausal women, the bisphosphonate alendronate (70 mg once weekly) was found to maintain gains in BMD achieved with 1 year of treatment with denosumab (60 mg given once every 6 months).

Of the 126 women treated with denosumab, 115 (91%) transitioned to alendronate at month 12. The mean increases in BMD reported after the 12 months on denosumab were 5.6% in the lumbar spine, 3.2% in total hip, and 3.1% in the femoral neck. Mean changes in measures in the subsequent 12 months of alendronate treatment were 0.6%, 0.4%, and –0.1%, respectively.

Importantly, although most participants maintained or further increased BMD over the year of alendronate treatment, some lost BMD, with 15.9% showing losses in the lumbar spine, 7.6% in total hip BMD, and 21.7% in the femoral neck. Just one participant lost BMD in all three sites.

However, few patients who lost BMD while on alendronate dropped to levels below their pre-study baseline BMD value.

Which Patient Characteristics Are Associated With BMD Loss?

To investigate which patient characteristics were associated with BMD loss, Kendler and colleagues conducted a post-hoc analysis of DAPS, dividing participants into those who lost BMD (a change of ≤ 3%), maintained BMD (a gain or loss of ≤ 3%), or gained BMD (an increase of ≥ 3%).

The analysis revealed only one marker — having the greatest increase in BMD in the first year — was associated with the greatest declines in the second year.

Kendler speculated that the effect may in fact be a "regression to the mean."

"This is an artefact of imprecision of BMD measurements," he explained. "It may also relate to patients whose bone turnover is highest having the greatest BMD response to denosumab's antiresorptive effect."

"When denosumab is discontinued, this higher endogenous bone turnover may be incompletely suppressed by alendronate resulting in bone loss."

Kendler noted an important unanswered question is what happens after that first year of maintenance on alendronate.

"Our study did not follow patients after 1 year on alendronate, but it is possible that BMD in patients experiencing declines stabilizes or increases in the following year," he said.

Longer Use of Denosumab Could Present an Even Bigger Challenge

In commenting further on the findings, Cosman noted that the concerns of rapid losses of benefits after denosumab have been shown to be real — and potentially consequential.

"Without sequential antiresorptive therapy, BMD loss is dramatic after denosumab discontinuation," she said.  

"This is associated with an increased risk of multiple vertebral fractures, which can also be very dramatic. Obviously, this is a clinical scenario which must be avoided."

Cosman agreed that an important caveat is that the study only evaluated the effectiveness of alendronate after 1 year of denosumab exposure.

"It is possible that longer use of denosumab could present a bigger challenge regarding maintaining benefits after discontinuation," she explained.

Weekly Bisphosphonate First After Denosumab

Another study presented at the ASBMR meeting looked at therapy with another bisphosphonate, zoledronic acid, to extend the effects of denosumab; however, the results showed a failure to fully prevent BMD loss in patients with osteopenia, regardless of whether the zoledronic acid infusion was provided at 6 or 9 months after an average of 4.6 years of denosumab.

Kendler speculated that reasons for the failure to maintain benefits could be that denosumab therapy was longer than in his DAPS study or that patient variability could play a role.

"The offset of action of denosumab varies between patients and bisphosphonate must be available when resorption begins to increase," he explained, noting that weekly alendronate offers more flexibility in that regard.

"With the weekly bisphosphonate [alendronate], drug is available whenever the offset of denosumab action occurs. [However], with an annual infusion [with zoledronic acid], precise individual timing is likely not possible."

"Therefore, a clinical approach using weekly oral bisphosphonate for 6 to 12 months followed by intravenous bisphosphonate, if desired, may be optimal," Kendler concluded.

Kendler has reported consulting or other relationships with Amgen, Eli Lilly, and Pfizer. Cosman has reported being a consultant, advisor, grant recipient, and speaker for Amgen and an advisor and speaker for Radius Health. She is a consultant for Tarsa/R-Pharma. In the recent past (within the last 3 years), Cosman was an advisor, consultant, and speaker for Eli Lilly and consultant/advisor for Merck. 

ASBMR 2019 Annual Meeting. Presented September 21, 2019. Abstract 1047, LB-1169.

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