Zoledronate infusion preserves BMD gains after denosumab discontinuation for women with osteoporosis
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Postmenopausal women with osteoporosis who received a single infusion of zoledronate after 2 to 5 years of denosumab therapy retained more than half of bone mineral density gained before stopping treatment with no increase in vertebral fractures, according to findings published in the Journal of Bone and Mineral Research.
Discontinuation of denosumab is associated with a rapid return to pretreatment BMD levels and an increased risk for multiple vertebral fractures, Judith Everts-Graber, MD, senior rheumatologist with OsteoRheuma Bern AG, Switzerland, and colleagues wrote. No subsequent treatment regimen has been established for preventing BMD loss or multiple vertebral fractures after denosumab (Prolia, Amgen) discontinuation.
“We demonstrated that a single infusion of 5 mg zoledronate after 2 to 5 years of denosumab treatment retained more than half of gained BMD and was not associated with multiple vertebral fractures, as reported in patients who discontinued denosumab without subsequent bisphosphonate treatment,” Everts-Graber told Healio. “After discontinuation of denosumab treatment, a single infusion of zoledronate 6 months post-injection seems to be a safe method to prevent complete bone loss and rebound-associated vertebral fractures. This pragmatic, therapeutic regime may be a promising step in identifying sequential long-term treatment strategies for osteoporosis.”
In an 8-year, observational study, Everts-Graber and colleagues analyzed data from 120 white, postmenopausal women with osteoporosis who were treated with 60 mg denosumab every 6 months for 2 to 5 years (mean duration, 3 years), followed by 5 mg zoledronate 6 months after the last denosumab injection. Researchers assessed vertebral fractures via DXA before the first and after the final denosumab injections and at a median of 2.5 years after denosumab discontinuation.
Within the cohort, 97 women received four to six denosumab injections (81%), 11 received between seven and nine injections (9%) and 12 women received 10 denosumab injections (10%).
After stopping denosumab therapy, three women sustained a single, symptomatic vertebral fracture between 1 and 3 years after the last injection, for a rate of 1.1 per 100 patient-years. No women developed multiple vertebral fractures. Four women sustained peripheral fractures, for a rate of 1.4 per 100 patient-years.
After denosumab discontinuation, researchers observed decreases in BMD at all sites for the cohort (P < .0001 at the lumbar spine; P < .005 at the femoral neck). All bone loss occurred within the first 18 months after zoledronate infusion. Researchers found that 66% of BMD gain was retained at the lumbar spine (95% CI, 57-75), 49% was retained at the total hip (95% CI, 31-67) and 57% was retained at the femoral neck (95% CI, 25-89).
There was no significant difference in the decrease of BMD between patients with BMD gains of > 9% vs. < 9% during denosumab treatment.
Women with or without prior bisphosphonate treatment and women with or without a drug holiday experienced a similar percentage decrease of lumbar spine BMD after stopping denosumab treatment.
“Further prospective studies are needed to confirm our observations,” Everts-Graber said. “Also, other therapeutic strategies (eg, other bisphosphonates than zoledronate) should be tested as post-denosumab treatment options.” – by Regina Schaffer
For more information:
Judith Everts-Graber, MD, can be reached at OsteoRheuma Bern AG, Bahnhofplatz 1, CH-3011 Bern, Switzerland; email: judith.everts@hih.ch.
Disclosures: The authors report no relevant financial disclosures.
Perspective
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David L. Kendler, MD
This observational study investigates the important question of how to manage patients after discontinuation of denosumab therapy for postmenopausal osteoporosis. The concern that has been raised is the reversibility of bone suppression on denosumab leading to an overshoot of bone resorption and the potential for fractures, especially multiple vertebral fractures, to ensue. Theoretically, zoledronic acid infusion given 6 months or more after denosumab discontinuation should have the capability of maintaining suppression of bone turnover and preventing resultant bone loss and fractures. Prior studies have investigated limited numbers of patients, often with nonstandardized protocols utilizing oral or intravenous bisphosphonate. There are reports of 1 year alendronate therapy and 1 year zoledronic acid infusion after 1 year of denosumab leading to stable bone density.
It is possible that patients with longer durations of denosumab exposure may lose bone despite switching to zoledronic acid. The present study seems to confirm this.
As well, there is no apparent protection from bone loss in patients with bisphosphonate exposure prior to denosumab. Certainly, the partial protection of bone density and absence of fracture by a single zoledronic acid infusion is encouraging. Perhaps this should lead us to continuing annual zoledronic acid infusions in patients switching from denosumab or treating longer with denosumab to achieve a higher BMD prior to switching to zoledronic acid infusion.
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