Background Bone destruction in rheumatoid arthritis (RA) is the result of a combined effect of the osteoclast and the osteoblast. In the joints, this process is mainly driven by the inflammatory process, whereas the systemic bone loss is driven by an increase in various cytokines. At present, most therapies for RA target the inflammation, whereas no approved treatment directly targets the bone. Therefore, targeting bone formation and resorption may be a future treatment strategy for local and systemic bone loss in RA.
Objectives For the first time to investigate the combined local and systemic effects of simultaneous osteoclast inhibition with Zoledronate (Zln) and osteoblast stimulation with parathyroid hormone (PTH) in a mouse model of RA.
Methods Arthritis was induced with mannan in 36 female SKG mice. After 1.5 weeks mice were randomized to 3 treatment groups and a control group; placebo+placebo, placebo+Zln, PTH+placebo, and PTH+Zln. Arthritis score and ankle width were performed by an observer blinded for group distribution. Fluorochrome labels were injected 8 and 4 days before termination at the end of week 8. Sections were cut of the right hind paw and subsequently evaluated using design-based stereological estimators (1). Absolute osteoclast-covered bone surfaces (Oc.S), absolute mineralizing surfaces (MS), Mineral apposition rate (MAR), bone formation rate (BFR/BS), and absolute bone volume (BV) were estimated in the tarsus. The femora were DEXA and µCT scanned, and the bone strength was measured at the femoral neck and mid-diaphysis.
Results Locally, we found no differences in arthritis score or ankle width throughout the study. Similarly, we found no difference in BV, Oc.S, or MAR between the groups. However, MS was lower in the Zln+placebo and Zln+PTH groups, and BFR/BS was lower in the Zln group compared to controls (p<0.001).
Systemically, we found a higher BMD in the treatment groups than in the control group and a higher BMD with the combined Zln+PTH treatment than with the single treatments (p<0.05 for all comparisons). The mid-diaphyseal bone was stronger in the PTH and combination groups than in the control group (p<0.001). Finally, the femoral neck was stronger in all treatment groups than in the control group (p<0.01).
Cortical thickness and cross sectional area was larger in all treatment groups than in the control group (p<0.01). Trabecular parameters demonstrated a larger BV/TV, trabecular thickness, and trabecular number in all treatment groups than in the control group and the combination treatment resulted in higher BV/TV and trabecular thickness than the single treatments (p<0.001 for all comparisons). Likewise, we found a smaller structure model index and trabecular separation for all treatment groups than for the control group. Additionally, structure model index was lower for the combination treatment than for the single treatments (p<0.05 for all comparisons).
Conclusions The study demonstrated that no local effect was gained by inhibiting bone resorption and stimulating bone formation. In contrast, we demonstrated a clear systemic effect of the combination treatment. Thus, combination treatment with zoledronate and parathyroid hormone was effective on systemic but not local bone loss in a mouse model of RA.
Keller KK et al. Clin Exp Rheumatol 2011 May-Jun;29(3):536-543.
Acknowledgements This work was supported by grants from the Danish Rheumatism Association, The A.P. Møller Foundation for the Advancement of Medical Science, the Hørslev Foundation, Clinical Institute Aarhus University, Peter Ryholts Grant, the Hede Nielsens Family Foundation, and Aase and Ejnar Danielsens Foundation.
Disclosure of Interest None Declared
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