544 - Blockade of Osteoclast-mediated Bone Resorption with a RANKL Inhibitor...

Oral Posters: Innovative Technologies

Presented by: V.V. Patel - View Audio/Video Presentation (Members Only)

Author(s):

V.V. Patel(1), K.A. Payne(1), M. Sauque(1), C. Erickson(1), P. Yarger(1), N. Shaw(1), T. Baldini(1), C.J. Kleck(1), E. Burger(1)

(1) University of Colorado Denver Anschutz Medical Campus, Orthopedics, Aurora, CO, United States

Abstract

Osteoprotegerin (OPG) is a RANKL inhibitor that blocks osteoclast differentiation and activation. It does not incorporate into bone matrix and has a quick and reversible effect, thus making it a potential candidate to control the remodeling process and enhance bone formation. Interestingly, the administration of OPG as an enhancer of spinal fusion has not been studied previously. This study aimed to determine whether administration of an antiresorptive agent such as OPG will increase the amount of bone formed in a rat model of spinal fusion, and whether a timing-dependent dosing regimen of OPG would allow for a more targeted control.
Forty-eight, 12-week old, male Sprague-Dawley (SD) rats received a one-level posterolateral intertransverse fusion of L4-L5 with 0.4 g of bone allograft from age- and sex-matched SD rats. Rats received weekly subcutaneous injections of rat OPG-Fc (10 mg/kg, Amgen) and were divided into 4 groups according to initiation of administration: saline at day 0, or OPG initiated at day 0, 10, or 21 post-surgery. Rats were euthanized at 6 weeks post-surgery and quantitative microCT performed to determine bone volume/total volume and mean trabecular thickness. Spines were excised, decalcified, and processed for histology. Sections along the sagittal plane were stained using Masson's Trichrome and Hematoxylin and Eosin. Histological analysis was performed using ImageJ to determine the percentage of the trabecular bone surface lined with osteoclasts. Statistics were performed using a one-way ANOVA using SigmaStat Software.
MicroCT analysis revealed a greater bone volume fraction in the groups that received OPG injections starting at day 0 and day 10 after surgery when compared to the group receiving saline (p< 0.05). Administration of OPG at 21 days after surgery did not significantly affect bone volume compared to the saline group. Mean trabecular thickness was significantly increased in the groups receiving OPG at day 0 and day 10 after surgery, but not at day 21 (p< 0.05). Quantitative histological analysis supported microCT results, revealing a smaller percentage of trabecular bone surface lined with osteoclasts in the groups that received OPG injections at post-surgical day 0 and day 10 when compared to the group that received saline. Injection of OPG at post-surgical day 21 did not yield a significant decrease in osteoclasts when compared to the control group.
This study demonstrated that administration of OPG after spinal fusion has a dramatic impact on bone metabolism. Both increased bone volume and mean trabecular thickness indicate additional bone formation with OPG injections initiated on the surgical day or at post-surgical day 10 when compared to saline control. Demonstration of reduced trabecular bone surface occupied by osteoclasts suggests success of OPG in inhibiting osteoclast bone resorption and allowing additional bone formation to promote a more mature spinal fusion when initiated either on the day of surgery or at post surgical day 10. Initiating antiresorptive therapy 21 days after surgery did not have an effect on bone formation. The results of this pre-clinical study show that timed-administration of OPG could potentially have a dramatic impact on bone healing and bone fusion, not only in spine fusion surgery, but also in the general area of bone healing from fractures or around implants.