Bone quality is partially recovered after the discontinuation of RANKL administration in rats by increased bone mass on existing trabeculae: an in vivo micro-CT study.
Bone loss and recovery in a receptor activator for nuclear factor κ B ligand (RANKL)-administered rat model was assessed. Microarchitecture, mineralization and strength deteriorated faster than ovariectomy (OVX). Recovery was dependent on the loss of trabecular elements and connections. Early recovery suggests a natural mechanism in rats to overcome excess RANKL, and may have implications for long-term bone loss.


OBJECTIVE
To compare a model for experimental osteoporosis that induces bone loss by injecting RANKL into rats to an OVX rat model, and measure subsequent recovery of bone architecture, mineralization, and mechanics after stopping injections.


METHODS
Mature, healthy, female Wistar rats were divided into high-dose RANKL, low-dose RANKL, OVX, and vehicle control groups. The right proximal tibiae were micro-computed tomography (micro-CT) scanned in vivo every 2 weeks from week 0 to week 12 and every 4 weeks from week 12 to week 20. Bone architectural, mineralization, and mechanical changes were determined. Serum calcium, RANKL, anti-RANKL, and osteoprotegerin were measured at weeks 0, 6, and 20.


RESULTS
High-dose RANKL administration resulted in severe deterioration of the trabecular architecture (39% of baseline BV/TV), and modest decreases in tissue mineralization, bone mass, and stiffness. Bone loss occurred more rapidly than in the OVX and low-dose RANKL group, and recovery occurred prior to stopping RANKL injections. Full recovery of trabecular thickness, tissue mineralization, and cortical bone mass, partial recovery of trabecular bone volume (55% of baseline), structural model index, bone mass (69% of baseline), and stiffness (90% of baseline) but no improvement in connectivity density or trabecular number was observed.


CONCLUSIONS
RANKL administration resulted in rapid and dose-dependent bone loss. The recovery of trabecular bone volume and stiffness appeared to be dependent on the number of remaining trabecular elements and their interconnections. Uncontrolled recovery suggests that further investigation into the RANKL-injected rat as a model of bone loss is required.
Campbell
Graeme M
GM
Department of Mechanical and Manufacturing Engineering, University of Calgary, 2500 University Drive, NW, Calgary, AB T2N1N4, Canada.
Ominsky
Michael S
MS
Boyd
Steven K
SK
D000818:Animals; D016723:Bone Remodeling / Q000187:drug effects*; D002118:Calcium / Q000097:blood; D016022:Case-Control Studies; D004195:Disease Models, Animal; D005260:Female; D007089:Image Enhancement; D021621:Imaging, Three-Dimensional; D010024:Osteoporosis / Q000139:chemically induced / Q000503:physiopathology*; D053244:Osteoprotegerin / Q000097:blood; D010052:Ovariectomy; D053245:RANK Ligand / Q000097:blood / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D013977:Tibia / Q000000981:diagnostic imaging / Q000187:drug effects* / Q000648:ultrastructure; D014057:Tomography, X-Ray Computed
D053244:Osteoprotegerin; D053245:RANK Ligand; D002118:Calcium