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Bone loss in inflammatory arthritis: mechanisms and therapeutic approaches with bisphosphonates

https://doi.org/10.1016/j.berh.2005.06.008Get rights and content

The inflammatory process in rheumatoid arthritis provokes intense bone resorption, evidenced as bone erosions, juxta-articular osteopenia and generalized osteoporosis. These types of bone loss share a common pathogenesis, and the role of osteoclasts in focal bone erosion was verified in elegant animal studies. The tumour necrosis factor (TNF) family of cytokines and receptors—specifically TNF-α, RANKL, RANK and OPG—are dominant regulators of osteoclastic bone resorption in rheumatoid arthritis. The confirmation of the osteoclast mechanism provides new insight into the structural joint protection afforded by disease—modifying drugs and suggests innovative approaches to limit bone destruction. Emerging treatment strategies for bone disease in rheumatoid arthritis are the use of monoclonal antibodies to neutralize RANKL, and powerful bisphosphonates that target pathogenic osteoclasts.

Section snippets

What is the effect of synovial inflammation on bone?

Rheumatoid arthritis is accompanied by three types of bone loss: (1) focal articular bone erosion; (2) juxta-articular osteopenia adjacent to inflamed joints; and (3) systemic osteoporosis.1 This bone loss is attributed to fundamental alterations in bone remodelling that result in disturbed bone homeostasis to favour bone resorption over bone formation.2 It is clear that radiographic joint destruction is strongly associated with systemic osteoporosis.3, 4 Therefore, these types of bone loss are

What is the molecular basis of bone loss in RA?

Over 20 years ago, Bromley and Woolly described a ‘bi-directional attack’ on the joint, whereby pannus drives ‘outside-in’ erosions and osteoclast cutting cones arising in the bone marrow erupt through the subchondral bone to cause ‘inside-out’ erosions.29, 30 The MRI morphology of bone lesions in RA, which are always associated with synovitis, yet not always characterized by ‘outside-in’ breaches of cortical bone, apparently supports this hypothesis.10, 11, 12, 31 Until very recently, the

Targeting osteoclasts in inflammatory arthritis

The most obvious drugs to invoke for bone protection in arthritis are bisphosphonates (BPs). Chemically, the BPs are analogues of inorganic pyrophosphate in which an oxygen atom has been replaced with a carbon atom. The resulting phosphate-carbon-phosphate moiety confers a unique high-affinity binding property of BPs to hydroxyapatite mineral, generating high local concentrations of drug on bone surfaces where these agents can preferentially interfere with osteoclast-mediated bone resorption.55

Summary

Bone erosion is a prognostic turning point for patients with RA. The link between the inflammatory disease process and all types of bone loss in RA is indisputable. Tumour necrosis factor is a pivotal cytokine for inflammatory synovitis and promotes bone loss in many ways. In the presence of permissive amounts of RANKL, TNF-α drives massive osteoclast recruitment which results in local and systemic bone resorption. Targeting osteoclasts directly is a logical approach. The investigation of

Acknowledgements

This work was funded by The National Health and Medical Research Council (Project Grant: 247909).

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