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Repair of local bone erosions and reversal of systemic bone loss upon therapy with anti-TNF in combination with OPG or PTH in TNF-mediated arthritis

Local bone erosion and systemic bone loss are hallmarks of rheumatoid arthritis and cause progressive disability. Tumour necrosis factor (TNF) is a key mediator of arthritis and acts catabolically on bone by stimulating bone resorption and inhibiting bone formation. We hypothesized that the concerted action of anti-TNF, which reduces inflammation, and of PTH, which stimulates bone formation, or of OPG, which blocks bone resorption, could lead to repair of local bone erosions and reversal of systemic bone loss. To test this, human TNF-transgenic (hTNFtg) mice with established erosive arthritis and systemic bone loss were treated with PTH, OPG and anti-TNF, alone or in combination. Local bone erosions almost fully regressed, upon combined treatment with anti-TNF and PTH and/or OPG, suggesting repair of inflammatory skeletal lesions. In contrast, OPG and anti-TNF alone led to arrest of bone erosions but did not achieve repair. Treatment with PTH alone had no influence on the progression of bone erosions. Local bone erosions showed all signs of new bone formation such as the presence of osteoblasts, osteoid formation and mineralization. Furthermore, systemic bone loss was completely reversed upon combined treatment and this effect was mediated by osteoblast stimulation and osteoclast blockade. In summary, we conclude that local joint destruction and systemic inflammatory bone loss due to TNF can regress, and that repair requires a combined approach by reducing inflammation, blocking bone resorption or stimulating bone formation.

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  • Rheumatoid Arthritis
  • Arthritis
  • Tumour Necrosis Factor
  • Bone Formation
  • Bone Erosion