Vertebral Fractures Following Denosumab Discontinuation in Patients with Prolonged Exposure to Bisphosphonates

Abstract

Denosumab (DMAB) efficacy for treatment of osteoporosis was demonstrated in a pivotal trial with a reduction in vertebral and hip fractures during 3 years, and fracture risk reduction was sustained up to 10 years in an extension study. DMAB causes potent yet reversible inhibition of bone resorption. Bone density declines rapidly upon discontinuation and bone turnover markers increase above baseline in a rebound fashion. Spontaneous multiple vertebral fractures after DMAB discontinuation were recently reported. Prior treatment with bisphosphonates (BP) was postulated to decrease the risk for this alarming phenomenon. We aimed to describe our experience of fractures following DMAB withdrawal with special attention to past history of osteoporosis treatment. A phone survey of physicians engaged in bone metabolism from nine hospitals in Israel was performed. Clinical data of the patients presenting with vertebral fractures upon DMAB discontinuation were summarized and compared to the previously published cases. Nine elderly (74.2 ± 5.3 years) female patients were identified. Most patients had a prolonged prior exposure to BP (7.4 ± 3.2 years). All but one sustained osteoporotic fractures prior to DMAB initiation and their FRAX scores were high. Thirty-six vertebral fractures were identified in nine patients. Eight patients presented with multiple fractures, and most fractures were spontaneous. In line with the previous reports, the timing and severity of the fractures raise concern of DMAB discontinuation effect. Prolonged BP exposure in most of our patients challenges the protective effect hypothesis. Care providers, patients, and regulatory authorities should be aware of the possible risk of DMAB treatment interruption.

Hip fractures following denosumab discontinuation: three clinical cases reports

“…1 However, it has recently been described that, when denosumab is suspended, a damaging rebound effect is observed with a sharp decrease in previously gained bone mineral density, and spontaneous vertebral fractures occurring in up to 25% of these patients, which tend to be multiple. [2][3][4][5][6][7] To date, only vertebral fractures have been described. In this paper, we present the cases of three patients who suffered hip fractures after denosumab treatment was discontinued.…”

Rebound vertebral and non‐vertebral fractures during denosumab interruption in a postmenopausal woman

“…4 However, denosumab poses a unique risk of withdrawal fractures upon treatment cessation/interruption, owing to rebound increases in osteoclastogenesis and bone turnover. 1,3 This contrasts with bisphosphonates, which have prolonged antiresorptive activity due to incorporation into bone. 2 We report a 70-year-old woman with postmenopausal osteoporosis and no prior fractures.…”

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Herein we report a postmenopausal woman who developed nine denosumab withdrawal fractures, including non-vertebral sites, with a rise in bone turnover markers within four weeks and commencement of rebound fractures within five weeks of her missed denosumab dose.Denosumab is a monoclonal antibody against the receptor activator of nuclear factor kappa-B ligand (RANKL) with potent antiresorptive activity. [1][2][3] In Australia, it is available alongside bisphosphonates as a first-line osteoporosis therapy on the Pharmaceutical Benefits Scheme (PBS). Denosumab is often preferred because of ease of administration, tolerability and safety/efficacy in patients with restricted renal function.

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“…Denosumab is a monoclonal antibody against the receptor activator of nuclear factor kappa-B ligand (RANKL) with potent antiresorptive activity. [1][2][3] In Australia, it is available alongside bisphosphonates as a first-line osteoporosis therapy on the Pharmaceutical Benefits Scheme (PBS). Denosumab is often preferred because of ease of administration, tolerability and safety/efficacy in patients with restricted renal function.…”

“…Investigations showed no evidence of secondary causes of osteoporosis or fracture, including normal intact parathyroid hormone level at 2.2 pmol/L (reference interval 1.6-6.9 pmol/L) and adequate vitamin D level at 89 nmol/L (reference interval 50-160 nmol/L). Due to the timing and multiplicity of her spontaneous fractures together with raised bone turnover markers, these fractures were attributed to the 14-week interruption in denosumab therapy.Denosumab withdrawal fractures are typically multiple, 1,2 spontaneous,3 and, until now, limited to the vertebrae. 1 The literature to date has focussed on the risk of withdrawal fractures following treatment cessation.…”