Early effects of IL-6 receptor inhibition on bone homeostasis: a pilot study in women with rheumatoid arthritis.
OBJECTIVE
A critical role of interleukin-6 (IL-6) in bone homeostasis has been suggested in experimental studies. We examined whether inhibition of IL-6 receptor in patients with rheumatoid arthritis (RA) results in early alterations of circulating markers of bone remodelling.


METHODS
Circulating levels of osteoprotegerin, receptor activator of nuclear factor-kappaB ligand (RANKL), Wnt signalling pathway inhibitors Dickkopf-1 (Dkk-1) and sclerostin, markers of bone resorption (C-terminal cross-linking telopeptide of collagen type-I (CTX), tartrate-resistant acid phosphatase isoform-5b) and bone formation (bone-specific alkaline-phosphatase, osteocalcin) were examined in 22 women with active RA before and after two monthly infusions of tocilizumab (8mg/kg each); 'healthy', non-osteopenic, 1:1 age-matched women served as controls.


RESULTS
At baseline, osteoprotegerin/RANKL ratio in patients was lower than controls by 5-fold; circulating osteoprotegerin correlated negatively with corresponding 28-joint-count disease activity scores and circulating RANKL correlated positively with C-reactive protein. Also, Dkk-1, sclerostin, CTX and osteocalcin levels were higher in RA than controls. After two months, osteoprotegerin/RANKL ratio increased, Dkk-1 decreased and sclerostin increased comparing to baseline; other markers did not change significantly. Increases of osteoprotegerin/RANKL ratio were more prominent in 10 patients who achieved remission or low disease activity after tocilizumab than in 12 patients who did not. In contrast, the significant alterations of both Wnt inhibitors were comparable between these patient subgroups.


CONCLUSIONS
Anti-IL-6 therapy induced suppression of the inflammatory response affects rapidly the disrupted bone homeostasis in active RA. An additional, possibly specific, effect of IL-6 receptor inhibition on bone remodelling in humans should be further examined.
First Department of Propedeutic and Internal Medicine, Athens University Medical School, Athens, Greece. eterpos@hotmail.com
Evangelos
E
Terpos
Kalliopi
K
Fragiadaki
Maria
M
Konsta
Cornelia
C
Bratengeier
Athanasios
A
Papatheodorou
Petros P
PP
Sfikakis
D048868:Adaptor Proteins, Signal Transducing; D000328:Adult; D000469:Alkaline Phosphatase / Q000097:blood; D061067:Antibodies, Monoclonal, Humanized / Q000627:therapeutic use; D018501:Antirheumatic Agents / Q000627:therapeutic use; D001172:Arthritis, Rheumatoid / Q000188:drug therapy / Q000378:metabolism* / Q000503:physiopathology; D015415:Biomarkers / Q000097:blood; D019485:Bone Morphogenetic Proteins / Q000097:blood; D001842:Bone and Bones / Q000187:drug effects / Q000502:physiology*; D024042:Collagen Type I / Q000097:blood; D004359:Drug Therapy, Combination; D005260:Female; D005819:Genetic Markers; D006706:Homeostasis / Q000187:drug effects / Q000502:physiology*; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000097:blood; D008727:Methotrexate / Q000627:therapeutic use; D015675:Osteocalcin / Q000097:blood; D010012:Osteogenesis / Q000187:drug effects / Q000502:physiology; D053244:Osteoprotegerin / Q000097:blood; D010455:Peptides / Q000097:blood; D010865:Pilot Projects; D011239:Prednisolone / Q000627:therapeutic use; D053245:RANK Ligand / Q000097:blood; D019947:Receptors, Interleukin-6 / Q000037:antagonists & inhibitors / Q000378:metabolism*
D048868:Adaptor Proteins, Signal Transducing; D061067:Antibodies, Monoclonal, Humanized; D018501:Antirheumatic Agents; D015415:Biomarkers; D019485:Bone Morphogenetic Proteins; D024042:Collagen Type I; C501126:DKK1 protein, human; D005819:Genetic Markers; D036341:Intercellular Signaling Peptides and Proteins; D053244:Osteoprotegerin; D010455:Peptides; D053245:RANK Ligand; D019947:Receptors, Interleukin-6; C422903:SOST protein, human; C505688:TNFSF11 protein, human; C052929:collagen type I trimeric cross-linked peptide; D015675:Osteocalcin; D011239:Prednisolone; D000469:Alkaline Phosphatase; C502936:tocilizumab; D008727:Methotrexate