Bone Remodeling in Postmenopausal Women Who Discontinued Denosumab Treatment: Off-Treatment Biopsy Study

Denosumab is a fully human monoclonal antibody that neutralizes the activity of RANKL, leading to the inhibition of osteoclast maturation, bone-resorbing activity, and survival. Evaluation of trans-iliac crest bone biopsy specimens in the phase 3 pivotal fracture study with denosumab in postmenopausal women with osteoporosis showed evidence of reduced bone turnover at the tissue level in subjects receiving denosumab, and up to one-third of subjects did not have evidence of tetracycline labeling in trabecular or cortical bone. Discontinuation of denosumab therapy has demonstrated that the effects of denosumab are reversible, as assessed by biochemical markers of bone turnover (BTM) and BMD. The precise nature of changes that occur at the tissue level with denosumab discontinuation have not been explored. Fifteen subjects were enrolled in a cohort study to evaluate the effects of denosumab discontinuation at the tissue level. Subjects had discontinued osteoporosis treatment for a mean time of 25.1 months (range 21 to 29 months). Bone histomorphometry results were compared with results from placebo-treated women with osteoporosis in the denosumab phase 3 pivotal fracture bone biopsy substudy, and BTMs were compared with subjects' pretreatment values. The results of this study showed normal histology and bone remodeling similar to those observed in untreated postmenopausal women with osteoporosis. With treatment cessation, 100% of biopsy specimens had evidence of tetracycline labels. Biochemical markers were comparable to and highly correlated with pretreatment levels. These data confirm that the effects of denosumab on bone turnover at the tissue level are fully reversible. (C) 2011 American Society for Bone and Mineral Research.