Background Our laboratory has shown that bone destruction in the Lewis rat model of adjuvant arthritis (AdA) can be significantly reduced by daily administration of recombinant human osteoprotegerin (rhOPG) if treatment is initiated at the onset of clinical arthritis.1
Objectives The current study was performed to assess the ability of rhOPG to spare bone using an abbreviated dosing schedule.
Methods AdA was induced in male Lewis rats (8 weeks old, n = 6/group) on Day 0; clinical arthritis (indicated by hind paw swelling) developed on Day 9. Arthritic animals received rhOPG (daily s.c. bolus of 4 mg/kg) by one of four schedules: no rhOPG (Group 1, control for AdA induction); daily rHOPG, Days 9 to 15 (Group 2, control for rhOPG efficacy); early intervention, Days 9 to 11 (Group 3); or delayed intervention, Days 13 to 15 (Group 4). Rats were necropsied on Day 16, and bone mineral density [BMD] of bones in the tibiotarsal (ankle) joint was measured by DEXA (dual X-ray absorptiometry). Next, sections of formalin-fixed, decalcified, paraffin-embedded hind paws were stained by an indirect immunohistochemical method to detect cathepsin K, an osteoclast marker. Histopathologic scores to assess lesion severity (given below as group means ± standard deviation) were acquired for inflammation, bone erosion, and osteoclast numbers using tiered, semi-quantitative grading scales.
Results Joints of vehicle-treated arthritic animals (Group 1) exhibited measurable loss of BMD as well as extensive inflammation (4.0 ± 0), skeletal erosion (4.5 ± 0.5), and osteoclast production (4.0 ± 0). As noted previously,2 rhOPG therapy throughout the 7-day clinical course of AdA (Group 2) preserved BMD and almost completely inhibited erosions (1.2 ± 0.4) and osteoclastogenesis (0.8 ± 0.8) but did not modify the extent of inflammation (3.7 ± 0.5). Early initiation of rhOPG treatment (Group 3) yielded similar retention of BMD as well as reductions in erosion (1.2 ± 0.4) and osteoclast (1.7 ± 0.5) scores. However, in comparison to Groups 2 and 3, delayed rhOPG administration (Group 4) protected BMD and lowered the mean osteoclast score (2.0 ± 0.3) but was significantly less effective in preventing erosions (2.5 ± 1.4).
Conclusion Our data indicate that early intervention with a bone-sparing agent such as rhOPG is needed to obtain the greatest clinical benefit with respect to protecting skeletal integrity in arthritic joints but also show that delayed rhOPG therapy can reduce the loss of joint BMD even in the presence of severe inflammation.
Kong, et al. Nature 1999;402:304
Feige, et al. Ann Rheum Dis. 2000;59(Suppl I):148
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