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

• Published in: Journal of bone and mineral research Vol. 35; no. 7; pp. 1282 - 1288
• Main Authors: Dempster, David W, Chines, Arkadi, Bostrom, Mathias P, Nieves, Jeri W, Zhou, Hua, Chen, Li, Pannacciulli, Nico, Wagman, Rachel B, Cosman, Felicia
• Format: Journal Article
• Language: English
• Published: Hoboken, USA John Wiley & Sons, Inc 01.07.2020; Oxford University Press
• Subjects: ANTIRESORPTIVES; Bone Density; Bone Density Conservation Agents - therapeutic use; Bone growth; BONE HISTOMORPHOMETRY; BONE MODELING AND REMODELING; Bone Remodeling; Clinical Trial; Clinical Trials; Denosumab - therapeutic use; Envelopes; Female; Femur; Femur Neck - diagnostic imaging; Femur Neck - drug effects; Femur Neck - physiology; Hip; Humans; Immunotherapy; Monoclonal antibodies; Neck; Osteoarthritis; Osteogenesis; OSTEOPOROSIS; Osteoporosis, Postmenopausal - drug therapy; Post-menopause; Total hip arthroplasty; BONE HISTOMORPHOMETRY; BONE MODELING AND REMODELING; ANTIRESORPTIVES; OSTEOPOROSIS
• ISSN: 0884-0431; 1523-4681; 1523-4681
• DOI: 10.1002/jbmr.4006

ABSTRACT 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 nonhuman 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 two or more doses of denosumab (60 mg subcutaneously every 6 months [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 age = 73.5 years; range, 70 to 78 years) and historical female controls (n = 11; mean age = 67.8 years; range, 62 to 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‐fold and 2.0‐fold higher mean values of MBBF in cancellous and endocortical envelopes, respectively, whereas RBBF mean values were 5.0‐fold 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. © 2020 The Authors. Journal of Bone and Mineral Research published by American Society for Bone and Mineral Research Femoral neck histomorphometry was assessed in adult subjects (n = 4) with osteoporosis who received at least two doses of denosumab and were scheduled for total hip replacement. Compared with historical controls (n = 11), denosumab‐treated subjects showed 9.4‐fold and 2.0‐fold higher values of MBBF in cancellous and endocortical envelopes, respectively. RBBF values were 5.0‐fold and 5.3‐fold lower. Thus, denosumab may preserve MBBF while inhibiting RBBF, resulting in the continued increases in BMD observed with long‐term treatment. MBBF = modeling‐based bone formation; RBBF = remodeling‐based bone formation.