Osteoporosis in Rheumatoid Arthritis: Dangerous Liaisons

Abstract

Osteoporosis has been classically considered a comorbidity of rheumatoid arthritis (RA). However, recent advances in the pathogenesis of osteoporosis in RA have shown a close interplay between cells of the immune system and those involved in bone remodeling, introducing new actors into the classic route in which osteoclast activation is related to the RANK/RANKL/OPG pathway. In fact, the inflammatory state in early stages of RA, mediated by interleukin (IL)-1, IL-6, IL-8 and tumor necrosis factor (TNF)-α has the ability to activate and differentiate osteoclasts not only through their relationship with RANKL, but also through the Wnt/DKK1/sclerostin pathway, leading to bone loss. The role of synovial fibroblasts and activated T lymphocytes in the expression of the RANKL system and its connection to bone destruction is also depicted. In addition, autoantibodies such as rheumatoid factor and anti-citrullinated protein antibodies are other pathogenic mechanisms for the development of bone erosions and systemic osteoporosis in RA, even before the onset of arthritis. The aim of this review is to unravel the relationship between different factors involved in the development of osteoporosis in RA patients, both the classic factors and the most novel, based on the relationship of autoantibodies with bone remodeling. Furthermore, we propose that bone mineral density measured by different techniques may be helpful as a biomarker of severity in early arthritis patients.

Keywords: RANKL/RANK/OPG; Wnt signaling; bone erosions; inflammation; osteoimmunology; osteoporosis; rheumatoid arthritis.

Figure 1

Yearly variation of BMD in mid-radius, but no in other regions of forearm, correlates with cumulative disease activity (assessed by HUPI) after 2 years of follow-up in early arthritis patients. BMD, bone mineral density; UD, ultradistal radius; MID, middle distal radius; 1/3, third distal radius; HUPI, Hospital Universitario de la Princesa index [composite rheumatoid arthritis disease activity index, ref: (12)]; r, Pearson's correlation coefficient.

Figure 2

Schematic illustration of osteoblastogenesis and osteoclastogenesis regulation in RA patients. ACPA, anti-citrullinated protein antibodies; ACarPA, anti-carbamylated protein antibodies; DKK-1, dickkopf-1 protein; IL, interleukin family; IFN, interferon; OB, osteoblast; OC, osteoclast; OPG, osteoprotegerin; RA, rheumatoid arthritis; RANK/RANK-L, receptor activator of nuclear factor (NF)-kB (RANK) and its ligand; Runx2, transcription factor involved in the osteoblastogenesis; TNF-α, tumor necrosis factor alpha; Th, T helper lymphocytes; Treg, T regulators lymphocytes.