Denosumab in Osteoporosis: Predicting Long-Term Efficacy beyond 10 Years

Abstract

Osteoporosis, characterized by diminished bone density and microarchitectural deterioration, has become a global health concern and can lead to increased fracture susceptibility and subsequent morbidity and mortality.[1] The goal of treating postmenopausal osteoporosis is to increase bone density and prevent fractures, and various medications have been developed to achieve these goals.[2,3] Denosumab, a fully human monoclonal antibody targeting receptor activator of nuclear factor-κB ligand (RANKL), has emerged as a key therapeutic tool for osteoporosis management.[4] Denosumab is a RANKL-mediated osteoclast differentiation inhibitor that strongly inhibits bone resorption, thereby reducing bone loss and lowering fracture incidence, making it a potent treatment for patients at high risk of fractures.[4,5] Many clinical trials and real-world studies have demonstrated denosumab’s efficacy in improving bone mineral density (BMD) and mitigating fracture risk.[5,6] Therefore, denosumab is widely accepted by clinicians as an important treatment for osteoporosis management, as reflected in clinical guidelines.[2,7-11] Long-term studies of up to 10 years have demonstrated the continued effectiveness of denosumab in increasing bone density and preventing fractures.[5,12] Moreover, continuing treatment beyond the initial years confers further fracture risk mitigation, highlighting denosumab's sustained efficacy over prolonged durations.[5] Notably, a 10-year denosumab treatment yielded a substantial increase in spine (21.7%) and hip BMD (9.2%).[5] Denosumab’s potent inhibitory effect on bone resorption effectively reduces fracture risk and increases the likelihood of reaching target BMD compared to bisphosphonates.[13] Therefore, once fracture risk has been reduced to moderate after a period of denosumab treatment, the drug can be discontinued in favor of sequential treatment with bisphosphonates.[2] However, in some clinical situations, once denosumab treatment has been initiated, it may need to be continued. Some patients who have reached their goals wish to continue denosumab treatment because of high adherence, dosing convenience, and fewer side effects. [14] In patients who remain at high risk of fracture after 10 years of treatment, continued treatment should be considered.[7] Denosumab discontinuation results in a rebound phenomenon and should be followed by an agent such as bisphosphonate. [15,16] However, in patients with advanced renal dysfunction, sequential therapy with bisphosphonates is not feasible, and there are difficult clinical situations where, once denosumab is administered, long-term therapy should be considered. Denosumab was first administered to patients in South Korea in November 2016. Some patients will require longterm denosumab treatment (>10 years). However, there are currently no reports on the effect of denosumab treatment on BMD after a 10-year administration. Therefore, we used a statistical approach to predict the changes in BMD after 10 years of denosumab treatment. In this study, we analyzed the results of the original Fracture Reduction Evaluation of Denosumab in Osteoporosis Every 6 Months (FREEDOM) extension study and clinical studies to make statistical projections of the effects of denosumab treatment after 10 years. Utilizing multiscale indirect response models based on pharmacological studies is an appropriate approach to understanding the integrated dynamic impact of denosumab on longitudinal changes in BMD. [17-19] We utilized the following two methods as predictive models.