OBJECTIVE: To investigate whether the bone-preserving effects of a RANKL antagonist or a tumor necrosis factor (TNF) antagonist could be further improved by the addition of a bone anabolic agent in inflammatory arthritis. METHODS: Lewis rats with either adjuvant-induced arthritis (AIA) or collagen-induced arthritis (CIA) were treated for 10 days with PEGylated soluble tumor necrosis factor receptor type I (PEG sTNFRI), interleukin-1 receptor antagonist (IL-1Ra), osteoprotegerin (OPG), parathyroid hormone (PTH), or combinations of these agents starting on day 4 after disease onset. Treatment effects were assessed clinically, radiologically, and histologically, and by morphometry for the extent of paw swelling, bone erosive changes, and synovial inflammation. RESULTS: Paw swelling and synovial inflammation were significantly inhibited by PEG sTNFRI in AIA and CIA, and by IL-1Ra in CIA. OPG and PTH had no significant effect on these parameters. Analysis of bone erosion revealed a significant bone-sparing effect of monotherapy with PEG sTNFRI or OPG in both models, whereas IL-1Ra was only effective in CIA. PTH treatment alone did not show a bone-protective effect in either model. With the combination of PEG sTNFRI and PTH, erosion scores (-74% in AIA and -61% in CIA versus controls) were significantly lower than those elicited by PEG sTNFRI alone (-41% and -29%, respectively, versus controls). Similar results were also obtained with the combination of OPG and PTH (-88% in AIA and -73% in CIA, compared with -70% and -55%, respectively, with OPG monotherapy). Coadministration of IL-1Ra and PTH had no synergistic bone-sparing effect. Morphometric analysis revealed that the addition of PTH to PEG sTNFRI or OPG resulted in higher bone volume and higher osteoblast numbers in both AIA and CIA. CONCLUSION: The bone-protective effects resulting from RANKL or TNF antagonism can be further improved by the addition of a bone anabolic agent.
OBJECTIVE: To investigate whether the bone-preserving effects of a RANKL antagonist or a tumor necrosis factor (TNF) antagonist could be further improved by the addition of a bone anabolic agent in inflammatory arthritis. METHODS: Lewis rats with either adjuvant-induced arthritis (AIA) or collagen-induced arthritis (CIA) were treated for 10 days with PEGylated soluble tumor necrosis factor receptor type I (PEG sTNFRI), interleukin-1 receptor antagonist (IL-1Ra), osteoprotegerin (OPG), parathyroid hormone (PTH), or combinations of these agents starting on day 4 after disease onset. Treatment effects were assessed clinically, radiologically, and histologically, and by morphometry for the extent of paw swelling, bone erosive changes, and synovial inflammation. RESULTS: Paw swelling and synovial inflammation were significantly inhibited by PEG sTNFRI in AIA and CIA, and by IL-1Ra in CIA. OPG and PTH had no significant effect on these parameters. Analysis of bone erosion revealed a significant bone-sparing effect of monotherapy with PEG sTNFRI or OPG in both models, whereas IL-1Ra was only effective in CIA. PTH treatment alone did not show a bone-protective effect in either model. With the combination of PEG sTNFRI and PTH, erosion scores (-74% in AIA and -61% in CIA versus controls) were significantly lower than those elicited by PEG sTNFRI alone (-41% and -29%, respectively, versus controls). Similar results were also obtained with the combination of OPG and PTH (-88% in AIA and -73% in CIA, compared with -70% and -55%, respectively, with OPG monotherapy). Coadministration of IL-1Ra and PTH had no synergistic bone-sparing effect. Morphometric analysis revealed that the addition of PTH to PEG sTNFRI or OPG resulted in higher bone volume and higher osteoblast numbers in both AIA and CIA. CONCLUSION: The bone-protective effects resulting from RANKL or TNF antagonism can be further improved by the addition of a bone anabolic agent.