Significant bone loss after stopping long-term denosumab treatment: a post FREEDOM study.

We evaluate 38 elderly women who had received long-term denosumab treatment after stopping the drug. Taking into account the gain during treatment and the loss after stopping treatment, they lost 35.5% of the total gain in the spine, 44.6% of the total gain in the femoral neck, and 103.3% in the total hip. INTRODUCTION: Denosumab (DMAb) is a soluble inhibitor of the receptor activator of nuclear factor-kappaB ligand (RANKL) and, therefore, does not incorporate into the bone matrix. Consistently, DMAb discontinuation is associated with reversal of the effects attained with treatment. PURPOSE: The aim of this study is to assess changes in BMD after a year of discontinuation of DMAb in a group of postmenopausal women treated with DMAb for 7 or 10 years. Secondly, is to evaluate the occurrence of fragility fractures. METHODS: Women who had participated in the FREEDOM study and its extension were invited to participate in this follow-up study. BMD at LS and hip and spine X-rays were obtained. Results were compared to the last value obtained while in treatment to assess changes after discontinuation. RESULTS: Thirty-eight women, mean age: 81 ± 3.4 years completed study procedures; none had received bisphosphonates after stopping DMAb. Mean gap time between DMAb last dose and the follow-up visit was 17 months (range 16-20 months). Bone mineral density (BMD) decreased significantly in all regions: - 8.1% in LS, - 6% in FN, and - 8.4% in TH. Five (5/38, 13.15%) patients had a fragility fracture, one suffered a wrist fracture, and four experienced vertebral fractures. Three patients suffered one vertebral fracture and one of them had two vertebral fractures. Laboratory results showed the following mean values: CTX = 996 ± 307 pg/ml (normal values 550 ± 226 pg/ml); osteocalcin = 55.2 ± 18.6 ng/ml (normal value 42 ng/ml); and 25 OH vitamin D = 23.7 ± 6.9 ng/ml. CONCLUSION: Our results describe the rapid bone loss occurring after cessation of denosumab treatment. Further studies are needed to assess if patients have a higher risk of fracture after stopping DMAb and if so, which patients have the highest risk, and assess the role of transitioning to bisphosphonates in the long term.

Denosumab: an update.

Denosumab is a fully human monoclonal antibody that inhibits the formation, function and survival of osteoclasts, preventing the interaction of tumor necrosis factor ligand superfamily member 11 (receptor activator of nuclear factor kappa-B ligand, RANKL) with the tumor necrosis factor receptor superfamily member 11A (osteoclast differentiation factor receptor, ODFR, receptor activator of NF-KB, RANK). This results in a reduction in bone resorption and an increase in bone mineral density. In clinical studies, denosumab has been shown to decrease the risk for vertebral, hip and nonvertebral fractures in women with postmenopausal osteoporosis and the risk for new vertebral fractures in men with nonmetastatic prostate cancer receiving androgen deprivation therapy, with a rate of side effects similar to placebo. A number of clinical trials with denosumab are ongoing to demonstrate its value for other indications and to further characterize its effects on immunomodulation. Denosumab is a new alternative for the prevention and treatment of postmenopausal osteoporosis and a promising agent for the treatment of other bone diseases associated with bone loss.