Kinetics of bone protection by recombinant osteoprotegerin therapy in Lewis rats with adjuvant arthritis.
OBJECTIVE
To assess the effect of different dosages and treatment schedules of osteoprotegerin (OPG) on joint preservation in an experimental model of adjuvant-induced arthritis (AIA).


METHODS
Male Lewis rats with AIA (6-8 per group) were treated with a subcutaneous bolus of recombinant human OPG according to one of the following schedules: daily OPG (an efficacious regimen) starting at disease onset (days 9-15), early intervention (days 9-11), delayed intervention (days 13-15), and extended therapy (days 9-22). Inflammation (hind paw swelling) was quantified throughout the clinical course; osteoporosis (bone mineral density [BMD], by quantitative dual x-ray absorptiometry) and morphologic appraisals of inflammation, bone damage, intralesional osteoclasts (by semiquantitative histopathologic scoring), and integrity of the articular cartilage matrix (by retention of toluidine blue stain) were determined in histology sections of arthritic hind paws.


RESULTS
OPG provided dose- and schedule-dependent preservation of BMD and periarticular bone while essentially eliminating intralesional osteoclasts. Dosages > or = 2.5 mg/kg/day preserved or enhanced BMD and prevented essentially all erosions. A dosage of 4 mg/kg/day protected joint integrity to a comparable degree when given for 7 (days 9-15) or 14 (days 9-22) consecutive days. At this dosage, early intervention (days 9-11) was twice as effective as delayed intervention (days 13-15) at preventing joint dissolution. Erosions and osteoclast scores were greatly decreased for 26 days (measured from the first treatment) after 7 or 14 daily doses of OPG (4 mg/kg/day). OPG treatment also prevented loss of cartilage matrix proteoglycans, an indirect consequence of protecting the subchondral bone. No OPG dosage or regimen alleviated weight loss, inflammation, or periosteal osteophyte production.


CONCLUSIONS
These data indicate that OPG preserves articular bone and (indirectly) articular cartilage in arthritic joints in a dose- and schedule-dependent manner, halts bone erosion when given at any point during the course of arthritis, produces sustained antierosive activity after a short course, and is most effective when initiated early in the disease.
Amgen, Inc., Thousand Oaks, California 91320-1789, USA.
Giuseppe
G
Campagnuolo
Brad
B
Bolon
Ulrich
U
Feige
D015502:Absorptiometry, Photon; D000818:Animals; D001169:Arthritis, Experimental / Q000188:drug therapy* / Q000473:pathology; D015519:Bone Density; D002358:Cartilage, Articular / Q000473:pathology; D004195:Disease Models, Animal; D004334:Drug Administration Schedule; D006023:Glycoproteins / Q000008:administration & dosage*; D008297:Male; D010010:Osteoclasts / Q000166:cytology; D053244:Osteoprotegerin; D051381:Rats; D011917:Rats, Inbred Lew; D018160:Receptors, Cytoplasmic and Nuclear / Q000008:administration & dosage*; D018124:Receptors, Tumor Necrosis Factor; D011994:Recombinant Proteins / Q000008:administration & dosage
D006023:Glycoproteins; D053244:Osteoprotegerin; D018160:Receptors, Cytoplasmic and Nuclear; D018124:Receptors, Tumor Necrosis Factor; D011994:Recombinant Proteins; C506030:TNFRSF11B protein, human; C506032:Tnfrsf11b protein, rat