Increased risk of serious vertebral fractures after stopping osteoporosis drug

A recent commentary in CMAJ highlights recent evidence of a serious risk of new vertebral compression fractures after discontinuation of the osteoporosis drug, denosumab. Denosumab use has become more common since 2009, when the large FREEDOM (Fracture Reduction Evaluation of Denosumab in Osteoporosis Every 6 Months) trial showed significant reductions in the incidence of vertebral fractures, as well as a reduction in nonvertebral and hip fractures, in postmenopausal women treated with denosumab versus placebo. Denosumab is administered subcutaneously at a dosage of 60 mg every six months.Reports of potential adverse effects on stopping denosumab arose in 2011, when the FREEDOM trial investigators noticed that patients who discontinued denosumab after taking it for two years had rapid drops in bone density and a marked rise in bone resorption markers that were well above baseline only 12 months after the last denosumab injection. This was followed by published case reports of new (often multiple) vertebral fractures developing within a few months of stopping denosumab. A systematic review of 24 cases of patients taking denosumab for an average of 2.9 years reported a mean of 4.7 vertebral fractures per patient only 5.2 months after the effects of the last injection of denosumab should have “worn off.”A follow-up of 1,001 participants who took denosumab in the FREEDOM trial showed that the vertebral fracture rate quickly rose almost six-fold from 1.2 per 100 participant-years while on the drug to 7.1 after stopping the drug. Also, patients who had stopped denosumab suffered multiple fractures at a rate of 4.2 per 100 participant-years, compared to 0.4 while on denosumab and 3.2 in the placebo group. No increase in nonvertebral fracture rate was apparent.Experts now warn that physicians and patients should be made aware of the potential risk of multiple rebound fractures when denosumab is stopped; they advise warning patients about this risk before starting the drug. They also emphasize that “drug holidays” cannot be safely taken in patients treated with denosumab.If a patient currently taking denosumab wants to stop treatment, physicians should discuss replacing denosumab with another antiresorptive osteoporosis medication (e.g., oral once-weekly bisphosphonate) for at least a year. Such replacement therapy should start no later than six to eight months after the last dose of denosumab. Another option is to continue denosumab therapy long-term or until evidence emerges for its safe “weaning.” Reasonable safety data exist for the continuous use of denosumab in osteoporosis over a period of 10 years, but evidence about outcomes is lacking beyond this period.ReferenceSymonds C, Kline G. Warning of an increased risk of vertebral fracture after stopping denosumab (commentary). CMAJ 2018;190:E485-6.

Increased risk of serious vertebral fractures after stopping osteoporosis drug

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