| Abstract | 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. |
| Authors | Georg Schett, Scot Middleton, Brad Bolon, Marina Stolina, Heather Brown, Li Zhu, Jim Pretorius, Debra J Zack, Paul Kostenuik, Ulrich Feige
(Affiliation: Amgen Inc., Thousand Oaks, California, and Medical University of Vienna, Vienna, Austria.)
|
| Journal | Arthritis and rheumatism
(Arthritis Rheum)
Vol. 52
Issue 5
Pg. 1604-11
(May 2005)
ISSN: 0004-3591 United States |
| PMID | 15880601
(Publication Type: Journal Article)
|
| Chemical References |
- Carrier Proteins
- Glycoproteins
- Membrane Glycoproteins
- Osteoprotegerin
- PEGylated tumor necrosis factor alpha receptor 1
- Parathyroid Hormone
- Polyethylene Glycols
- RANK Ligand
- Receptors, Cytoplasmic and Nuclear
- Receptors, Tumor Necrosis Factor
- Receptors, Tumor Necrosis Factor, Type I
- Tnfrsf11b protein, rat
- Tumor Necrosis Factor-alpha
|
| Topics |
- Animals
- Arthritis
(drug therapy)
- Bone Development
(drug effects)
- Bone Diseases
(prevention & control)
- Bone Resorption
(prevention & control)
- Carrier Proteins
(antagonists & inhibitors)
- Cell Count
- Disease Models, Animal
- Drug Synergism
- Female
- Glycoproteins
(pharmacology)
- Male
- Membrane Glycoproteins
(antagonists & inhibitors)
- Osteoblasts
- Osteoprotegerin
- Parathyroid Hormone
(pharmacology, therapeutic use)
- Polyethylene Glycols
(pharmacology, therapeutic use)
- RANK Ligand
- Rats
- Rats, Inbred Lew
- Receptors, Cytoplasmic and Nuclear
- Receptors, Tumor Necrosis Factor
- Receptors, Tumor Necrosis Factor, Type I
(therapeutic use)
- Tumor Necrosis Factor-alpha
(antagonists & inhibitors)
|
