Reduced osteoprotegerin expression by osteocytes may contribute to rebound resorption after denosumab discontinuation
Qiang Fu, … , Elena Ambrogini, Charles A. O’Brien
Qiang Fu, … , Elena Ambrogini, Charles A. O’Brien
Published August 15, 2023
Citation Information: JCI Insight. 2023;8(18):e167790. https://doi.org/10.1172/jci.insight.167790.
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Research Article Bone biology

Reduced osteoprotegerin expression by osteocytes may contribute to rebound resorption after denosumab discontinuation

Abstract

Denosumab is an anti-RANKL Ab that potently suppresses bone resorption, increases bone mass, and reduces fracture risk. Discontinuation of denosumab causes rapid rebound bone resorption and bone loss, but the molecular mechanisms are unclear. We generated humanized RANKL mice and treated them with denosumab to examine the cellular and molecular conditions associated with rebound resorption. Denosumab potently suppressed both osteoclast and osteoblast numbers in cancellous bone in humanized RANKL mice. The decrease in osteoclast number was not associated with changes in osteoclast progenitors in bone marrow. Long-term, but not short-term, denosumab administration reduced osteoprotegerin (OPG) mRNA in bone. Localization of OPG expression revealed that OPG mRNA is produced by a subpopulation of osteocytes. Long-term denosumab administration reduced osteocyte OPG mRNA, suggesting that OPG expression declines as osteocytes age. Consistent with this, osteocyte expression of OPG was more prevalent near the surface of cortical bone in humans and mice. These results suggest that new osteocytes are an important source of OPG in remodeling bone and that suppression of remodeling reduces OPG abundance by reducing new osteocyte formation. The lack of new osteocytes and the OPG they produce may contribute to rebound resorption after denosumab discontinuation.

Authors

Qiang Fu, Nancy C. Bustamante-Gomez, Humberto Reyes-Pardo, Igor Gubrij, Diana Escalona-Vargas, Jeff D. Thostenson, Michela Palmieri, Joseph J. Goellner, Intawat Nookaew, C. Lowry Barnes, Jeffrey B. Stambough, Elena Ambrogini, Charles A. O’Brien

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Figure 3

Denosumab potently suppresses remodeling in hRANKL mice.

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Denosumab potently suppresses remodeling in hRANKL mice. Ten-month-old, ...
Ten-month-old, male hRANKL mice were injected with vehicle or denosumab (10 mg/kg) once every 2 weeks for a total of 4 doses. Bones were harvested 2 weeks after the last dose. (A) TRAPase stain of vertebral bone sections from vehicle- or denosumab-treated mice. The osteoclast surface per bone surface is shown below the images. *P < 0.01 by 2-tailed, unpaired t test. n = 3 per group. (B) ISH with probes for Acp5 or Bglap using vertebral bone sections from vehicle- or denosumab-treated mice. (C) Gene expression of the indicated genes using TaqMan assays of RNA from cortical bone. Data are shown as mean ± SD and P values are from 2-tailed, unpaired t tests. Vehicle-treated mice, n = 4; denosumab-treated mice, n = 5. (D) Three-month-old male mice were treated with a single dose of vehicle or denosumab (10 mg/kg) and tissues harvested 48 hours after injection. Serum levels of TRAP5b were measured by ELISA and gene expression of the indicated transcripts was measured in RNA from femoral cortical bone by TaqMan assays. Data are shown as mean ± SD and P values are from 2-tailed, unpaired t tests. n = 5 per group. Scale bars: 100 µm.