Fractures After Denosumab Discontinuation: A Retrospective Study of 797 Cases

Abstract

A rebound of osteoclast activity during the 2 years after a treatment or prevention of osteoporosis with denosumab (Dmab) leads to an increased risk of vertebral fractures (VFs). We attempted to identify the risk factors for these VF and to examine the protective role of bisphosphonates. For that, 22 specialists in Switzerland provided data of unselected patients, treated with denosumab for osteoporosis or breast cancer without metastases under aromatase inhibitors, who have received at least two injections of Dmab, with at least 1 year of follow-up after discontinuation. The questionnaire covered separately the periods before, during, and after Dmab treatment, and registered clinical, radiological, and lab data. For the analysis of the risk factors, the main outcomes were the time to the first VF after the treatment, the presence of multiple VFs (MVFs), and the number of VFs. The incidence of VF was 16.4% before, 2.2% during, and 10.3% after the treatment with Dmab. The risk of VF after Dmab discontinuation was associated with an increased risk of non-vertebral fractures. The pretreatment predictors of the post-treatment fracture risk were a parental hip fracture and previous VFs. Further risk factors appeared later, such as low total hip bone mineral density (BMD) during and after denosumab, increased bone resorption markers, and the loss of total hip BMD after the denosumab. Treatment with bisphosphonates, especially after Dmab, had a protective effect. Bisphosphonates given before Dmab did not further decrease the risk of VF in cases who got bisphosphonates after Dmab. This study shows that the risk of VF is poorly predictable before the prescription of denosumab. But during and after the treatment, bone resorption markers and BMD have a significant predictive value. Bisphosphonates after the treatment with denosumab are protective against VFs.

Management of patients at very high risk of osteoporotic fractures through sequential treatments

“…In the case of denosumab, there is some evidence that an infusion of 5 mg zoledronate helps to reduce the rebound loss in BMD on stopping denosumab, and helps prevent vertebral fractures [ 109 , 110 ]. Studies suggest that a longer duration of denosumab treatment, of more than 6 years, puts an individual at greater risk of fracture on stopping [ 111 , 112 ], as does the presence of prevalent fractures [ 113 ], so supporting the need for a careful clinical approach in denosumab cessation [ 113 , 114 ].…”

Breast Cancer with Bone Metastasis: Molecular Insights and Clinical Management

“…Unbalances in this mechanism lead to an increased risk of fractures, particularly at the distal femur and proximal tibia levels [28]. This complex process is regulated by resident bone cells and other cell types of the bone microenvironment, including lymphocytes, macrophages, hematopoietic cells, and endocrine signaling molecules [29][30][31][32][33][34]. In particular, the discovery of endocrine mediators produced by the skeleton has radically changed our understanding not only of the bone biology but also of the endocrinology in general [34].…”

COVID-19 lockdown negatively impacted on adherence to denosumab therapy: incidence of non-traumatic fractures and role of telemedicine

“…Similarly, BMD gains at all skeletal sites are lost with a return to pre-treatment baseline values after 1-2 years off-treatment [5,6]. As a consequence, denosumab withdrawal is associated with a 3-to fivefold higher risk for vertebral, major osteoporotic, and hip fractures [7][8][9]. The risk of rebound fractures is reported as early as 4-8 weeks after interruption in injection schedule, and therefore, it is recommended that injections of denosumab should not be delayed by more than 7 months after the previous dose [1,10].…”