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Modeling-Based Bone Formation in the Human Femoral Neck in Subjects Treated With Denosumab

Dempster DW, Frms1,2, Chines A3, Bostrom MP4, Nieves JW1,2, Zhou H2, Chen L3, Pannacciulli N3, Wagman RB3, Cosman F1.

J Bone Miner Res. 2020 Mar 12. doi: 10.1002/jbmr.4006. [Epub ahead of print]

Denosumab is associated with continued gains in hip and spine BMD with up to 10 years of treatment in postmenopausal women with osteoporosis. Despite potent inhibition of bone remodeling, findings in non-human primates suggest modeling-based bone formation (MBBF) may persist during denosumab treatment. This study assessed whether MBBF in the femoral neck (FN) is preserved in the context of inhibited remodeling in subjects receiving denosumab. This open-label study enrolled postmenopausal women with osteoporosis who had received ≥2 doses of denosumab (60 mg subcutaneously Q6M) per standard of care and were planning elective total hip replacement (THR) owing to osteoarthritis of the hip. Transverse sections of the FN were obtained after THR and analyzed histomorphometrically. MBBF, based on fluorochrome labeling and presence of smooth cement lines, was evaluated in cancellous, endocortical, and periosteal envelopes of the FN. Histomorphometric parameters were used to assess MBBF and remodeling-based bone formation (RBBF) in denosumab-treated subjects (n=4; mean [range] age=73.5 [70-78] years) and historical female controls (n=11; mean [range] age=67.8 [62-80] years) obtained from the placebo group of a prior study and not treated with denosumab. All analyses were descriptive. All subjects in both groups exhibited MBBF in the periosteal envelope; in cancellous and endocortical envelopes, all denosumab-treated subjects and 81.8% of controls showed evidence of MBBF. Compared with controls, denosumab-treated subjects showed 9.4- and 2.0-fold higher mean values of MBBF in cancellous and endocortical envelopes, respectively, while RBBF mean values were 5.0- and 5.3-fold lower. In the periosteal envelope, MBBF and RBBF rates were similar between subjects and controls. These results demonstrate the occurrence of MBBF in the human FN and suggest that denosumab preserves MBBF while inhibiting remodeling, which may contribute to the observed continued gains in BMD over time after remodeling is maximally inhibited.