Dr. Takahata and Mr. Maher contributed equally to this work.
Mechanisms of bone fragility in a mouse model of glucocorticoid-treated rheumatoid arthritis: Implications for insufficiency fracture risk
Version of Record online: 27 OCT 2012
Copyright © 2012 by the American College of Rheumatology
Arthritis & Rheumatism
Volume 64, Issue 11, pages 3649–3659, November 2012
How to Cite
Takahata, M., Maher, J. R., Juneja, S. C., Inzana, J., Xing, L., Schwarz, E. M., Berger, A. J. and Awad, H. A. (2012), Mechanisms of bone fragility in a mouse model of glucocorticoid-treated rheumatoid arthritis: Implications for insufficiency fracture risk. Arthritis & Rheumatism, 64: 3649–3659. doi: 10.1002/art.34639
- Issue online: 27 OCT 2012
- Version of Record online: 27 OCT 2012
- Accepted manuscript online: 25 JUL 2012 09:54AM EST
- Manuscript Accepted: 12 JUL 2012
- Manuscript Received: 24 OCT 2011
- University of Rochester Provost's Multidisciplinary Award
- NIH. Grant Numbers: R21-AR-061285, R01-AR-048697, R01-AR-053586, R01-AR-54041, P30-AR-061307
Glucocorticoid (GC) therapy is associated with increased risk of fracture in patients with rheumatoid arthritis (RA). To elucidate the cause of this increased risk, we examined the effects of chronic erosive inflammatory arthritis and GC treatment on bone quality, structure, and biomechanical properties in a murine model.
Mice with established arthritis and expressing human tumor necrosis factor α (TNFα) transgene (Tg) and their wild-type (WT) littermates were continually treated with GC (prednisolone 5 mg/kg/day via subcutaneous controlled-release pellet) or placebo for 14, 28, or 42 days. Microstructure, biomechanical properties, chemical composition, and morphology of the tibiae and lumbar vertebral bodies were assessed by micro–computed tomography, biomechanical testing, Raman spectroscopy, and histology, respectively. Serum markers of bone turnover were also determined.
TNF-Tg and GC treatment additively decreased mechanical strength and stiffness in both the tibiae and the vertebral bodies. GC treatment in the TNF-Tg mice increased the ductility of tibiae under torsional loading. These changes were associated with significant alterations in the biochemical and structural composition of the mineral and organic components of the bone matrix, a decrease in osteoblast activity and bone formation, and an increase in osteoclast activity.
Our findings indicate that the concomitant decrease in bone strength and increase in bone ductility associated with chronic inflammation and GC therapy, coupled with the significant changes in the bone quality and structure, may increase the susceptibility of the bone to failure under low-energy loading. This may explain the mechanism of symptomatic insufficiency fractures in patients with RA receiving GC therapy who do not have radiographic manifestations of fracture.