Reduction of Cortical Bone Turnover and Erosion Depth After 2 and 3 Years of Denosumab: Iliac Bone Histomorphometry in the FREEDOM Trial

Abstract

Denosumab, a RANKL inhibitor, reduced the risk of vertebral, hip, and nonvertebral fractures in the Fracture REduction Evaluation of Denosumab in Osteoporosis every 6 Months (FREEDOM) trial of postmenopausal women with osteoporosis compared with placebo. Previous bone histomorphometric analysis in FREEDOM showed decreased bone resorption and turnover in cancellous bone after 2 and 3 years. The purpose of the present study was to evaluate the effects of denosumab compared with placebo in the cortical compartment from transiliac bone biopsies obtained during FREEDOM. A total of 112 specimens were evaluable for cortical histomorphometry, including 67 obtained at month 24 (37 placebo, 30 denosumab) and 45 at month 36 (25 placebo, 20 denosumab). Eroded surface, osteoclast surface, erosion depth, and wall thickness were measured on the endocortical surface. Cortical thickness and cortical porosity were also measured. Dynamic parameters of bone formation were assessed for endocortical, periosteal, and intracortical envelopes. Endocortical osteoclast surface, eroded surface, and mean and maximum erosion depth were significantly lower in the denosumab group versus placebo at months 24 and 36 (p < 0.0001 to p = 0.04). Endocortical wall thickness and intracortical measures (cortical porosity and cortical thickness) were not different between the two groups. Dynamic parameters were low with tetracycline labels in cortical bone observed in 13 (43%) and 10 (50%) of denosumab biopsies at months 24 and 36, respectively, reflecting a marked decrease in bone turnover. In conclusion, our data reveal the mechanism of action of denosumab on cortical bone: inhibition of osteoclastic resorption and reduced activation of new remodeling sites. In addition, reduced endocortical erosion depth with no change of wall thickness may contribute to increased bone strength by reducing the bone loss and fragility associated with deep resorption cavities and may likely contribute to the greater BMD gain with denosumab than with other antiresorptive agents. © 2018 The Authors. Journal of Bone and Mineral Research Published by Wiley Periodicals Inc.

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“…Strongly inhibits bone resorption and increases bone mass and strength in cortical and trabecular bone. Bone formation rates are reduced in most patients after denosumab [77,78]. Administered subcutaneously every 6 months.…”

A single dose of zoledronate preserves bone mineral density for up to 2 years after a second course of romosozumab

“…Romosozumab is a monoclonal antibody that inhibits sclerostin and has a dual effect of increasing bone formation and decreasing bone resorption [ 15 – 17 ], and has also been shown to improve skeletal microarchitecture [ 18 , 19 ]. In the first 24 months of this dose-finding phase 2 study in postmenopausal women with low bone mass, we evaluated the efficacy and safety of different romosozumab doses (70 mg, 140 mg, and 210 mg) administered by subcutaneous (SC) injection at 1- or 3-month intervals to identify the optimal romosozumab regimen [ 17 , 20 ].…”

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“…The decreased bone turnover results in an elongation of the secondary mineralization and thus, an augmentation of the degree of mineralization ( 218 ). In addition, a reduction of the endocortical erosion depth with no change of the mean wall thickness also contributes to the greater gain of BMD with denosumab than with other antiresorptive agents ( 220 ). The persistence of a modeling-based formation process has also been suggested ( 221 ); when the remodeling is very low, modeling bone formation may sparsely occur to preserve the bone mass ( 222 ), especially in loaded regions ( 223 ).…”