Dilemma of denosumab therapy: rebound fractures with denosumab cessation or dose delay

Abstract

Denosumab, a human monoclonal antibody against RANK ligand, has gained popularity for the treatment of osteoporosis over the last decade. However, case reports of spontaneous vertebral fractures and bone loss following denosumab discontinuation or delay have emerged in recent years. Although randomised controlled trials assessing fracture risk following denosumab cessation are unavailable, these case reports raise concerns regarding optimal transition from denosumab therapy. In post-menopausal women, denosumab reduces bone resorption through its inhibitory action on osteoclast formation, action and survival, and can reduce risk of vertebral and hip fractures by 68% and 40% respectively. It is administered 6 monthly as a subcutaneous injection, providing an attractive alternative to more frequent oral anti-resorptive preparations. We identified three post-menopausal women at our tertiary referral centre who sustained spontaneous vertebral fractures between 31 June 2018 and 1 June 2019 following a delay in denosumab dosing. All had established osteoporosis and while causality of fracture could not be established, all women were fracture free during their treatment with denosumab. Patient #1 had a history of liver cirrhosis, surgical menopause at 35 years and cigarette smoking. Patient #3 had received glucocorticoids for rheumatoid arthritis and prior bisphosphonates. All identified risk factors for osteoporosis are documented in Table 1. Patient #1 received zoledronic acid to consolidate treatment while the others did not receive further anti-resorptives following denosumab. The duration of exposure to denosumab, T-scores prior to denosumab cessation and time from last dose to fracture were variable. Bone Mineral Density (BMD) can decrease to baseline 12 months after discontinuation of denosumab. Bone turnover markers increase beyond pre-treatment levels within 3–6 months of denosumab discontinuation; their utility in predicting spontaneous vertebral fractures is not yet established. It is hypothesised that the sudden loss of osteoclast inhibition leads to increased bone turnover and the phenomenon of rebound vertebral fractures. The timely transition to a bisphosphonate may prevent the rapid loss of BMD after denosumab cessation. Alendronate commenced 6 months from the last dose of denosumab and zoledronic acid administered 26 weeks after the last dose of denosumab may both maintain bone density.