Postmenopausal women with osteoporosis who stop taking the monoclonal antibody denosumab risk a rapid loss of any bone mineral density gains and an increase in bone turnover markers, and should consider alternative therapies or avoiding a drug holiday, according to findings from a systematic review.
“Despite the fact that the concept of a treatment break does not apply to drugs without skeletal retention, we notice in clinical practice that after 5 years of denosumab treatment (Prolia, Amgen) many patients are now being taken off the drug,” Elena Tsourdi, MD, PhD, of the Center for Healthy Aging at Technical University Dresden, Germany, and colleagues wrote. “Also, patients are often advised by dentists that medication should be stopped temporarily before a dental procedure to avoid the risk of [osteonecrosis of the jaw]. Recently, there has been concern that discontinuation of denosumab will lead to an increased risk of multiple vertebral fractures associated with rapid bone loss when treatment is stopped.”
Tsourdi and colleagues analyzed data from 24 randomized controlled trials and observational studies investigating the effect of denosumab discontinuation on BMD, bone turnover markers and clinical or morphometric vertebral or nonvertebral fractures in postmenopausal women with osteopenia or osteoporosis. In studies related to BMD, bone turnover markers, bone biopsies and fractures after discontinuing denosumab, researchers observed a rapid reversal of BMD accrual gained over treatment periods.
“A small observational study involving 82 patients on long-term therapy with denosumab also showed reversal of the drug’s effect on BMD within 12 months after 8 years of treatment, and case-series of denosumab-treated patients presented in abstract form reported a similar effect after 10 years of treatment,” the researchers wrote. “In contrast, within 1 year of retreatment with denosumab, BMD increased again at all sites as shown by a phase 2 clinical trial.”
Researchers also noted a rapid increase in bone turnover marker concentrations to above pretreatment baseline levels after denosumab cessation. In one study evaluating changes in bone microarchitecture via high-resolution peripheral quantitative CT, researchers found that cessation of denosumab therapy for at least 12 months reversed any benefits achieved in bone microarchitecture.
Initial analysis from the phase 3 FREEDOM trial showed that fracture rates among those discontinuing denosumab or placebo were similar; 5.6% vs. 6.2%. However, among those who ceased therapy and sustained fractures, 60.7% of those who discontinued denosumab sustained multiple vertebral fractures, compared with 34.5% of those who discontinued placebo. In addition, researchers noted several case reports that showed multiple vertebral fractures occurring in patients within 2 to 10 months after stopping denosumab therapy.
“Especially in the case of patients with high fracture risk, treatment with drugs without skeletal retention, and in particular with denosumab, should not be terminated without considering substitution with an alternative agent, because gains in BMD will be lost rapidly,” the researchers wrote. “Based on the biological mechanism of action of denosumab it was stated early on that continued therapy is required to maintain treatment effects. Since denosumab treatment for 10 years is associated with a continuing gain in BMD, persistently low [bone turnover markers], a low fracture incidence and acceptable tolerance and safety, a case for a long-term treatment with denosumab up to 10 years can indeed be made in those patients that are still considered at high risk for fracture after 5 years.”
The researchers noted that more research is needed regarding whether it remains beneficial to continue denosumab beyond 10 years. – by Regina Schaffer
Disclosures: Tsourdi reports no relevant financial disclosures. Please see the study for all other authors’ relevant financial disclosures.