Effect of clodronate on established collagen-induced arthritis in rats

Österman, T.; Kippo, K.; Laurén, L.; Hannuniemi, R.; Sellman, R.

doi:10.1007/bf01782979

Cited by 34 publications

(19 citation statements)

References 21 publications

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“…Bisphosphonates have been reported to reduce cartilage degradation in collagen-induced arthritis and adjuvant-induced arthritis (45)(46)(47). Recently, zoledronate was reported to be partially chondroprotective in carrageenan-induced inflammatory arthritis (48) and chymopapain-induced cartilage damage in rabbits (28).…”

Section: Discussionmentioning

confidence: 99%

The role of subchondral bone remodeling in osteoarthritis: Reduction of cartilage degeneration and prevention of osteophyte formation by alendronate in the rat anterior cruciate ligament transection model

Hayami

Pickarski

Wesolowski

et al. 2004

Arthritis & Rheumatism

511

466

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Objective. It has been suggested that subchondral bone remodeling plays a role in the progression of osteoarthritis (OA). To test this hypothesis, we characterized the changes in the rat anterior cruciate ligament transection (ACLT) model of OA and evaluated the effects of alendronate (ALN), a potent inhibitor of bone resorption, on cartilage degradation and on osteophyte formation.Methods. Male Sprague-Dawley rats underwent ACLT or sham operation of the right knee. Animals were then treated with ALN (0.03 and 0.24 g/kg/week subcutaneously) and necropsied at 2 or 10 weeks postsurgery. OA changes were evaluated. Subchondral bone volume and osteophyte area were measured by histomorphometric analysis. Coimmunostaining for transforming growth factor ␤ (TGF␤), matrix metalloproteinase 9 (MMP-9), and MMP-13 was performed to investigate the effect of ALN on local activation of TGF␤.Results. ALN was chondroprotective at both dosages, as determined by histologic criteria and collagen degradation markers. ALN suppressed subchondral bone resorption, which was markedly increased 2 weeks postsurgery, and prevented the subsequent increase in bone formation 10 weeks postsurgery, in the untreated tibial plateau of ACLT joints. Furthermore, ALN reduced the incidence and area of osteophytes in a dosedependent manner. ALN also inhibited vascular invasion into the calcified cartilage in rats with OA and blocked osteoclast recruitment to subchondral bone and osteophytes. ALN treatment reduced the local release of active TGF␤, possibly via inhibition of MMP-13 expression in articular cartilage and MMP-9 expression in subchondral bone. Conclusion. Subchondral bone remodeling plays an important role in the pathogenesis of OA. ALN or other inhibitors of bone resorption could potentially be used as disease-modifying agents in the treatment of OA.Osteoarthritis (OA) is a degenerative joint disease characterized by pain, cartilage loss, and joint stiffness. Although OA has long been considered to be primarily a cartilage disorder associated with focal articular cartilage degradation, this disease is accompanied by well-defined changes in the subchondral and periarticular bone, including sclerosis and cyst and osteophyte formation (1). The importance of the bone changes in the initiation and progression of OA is still being debated. It has been suggested that increased subchondral bone stiffness reduces the ability to dissipate the load and distribute the strain generated within the joint. This increases peak dynamic forces in the overlying articular cartilage and can accelerate its damage over time (2). The functional integrity of the articular cartilage can therefore depend on the mechanical properties of the underlying bone. Accordingly, cartilage damage leads to full-thickness cartilage loss only upon repetitive loading over an already stiffened subchondral bone plate (3).Recent studies have demonstrated increased subchondral bone turnover accompanied by specific architectural changes in the subchondral trabecular bone in OA joints (4,5...

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Section: Discussionmentioning

confidence: 99%

The role of subchondral bone remodeling in osteoarthritis: Reduction of cartilage degeneration and prevention of osteophyte formation by alendronate in the rat anterior cruciate ligament transection model

Hayami

Pickarski

Wesolowski

et al. 2004

Arthritis & Rheumatism

511

466

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“…In the context of bisphosphonate studies in experimental arthritis, the suppressive effect of single doses of ZA on focal bone destruction is noteworthy. The earlier-generation bisphosphonates usually reduced markers of increased bone resorption and physiologic bone resorption at the growth plate, although evidence of inhibition of focal bone erosions was not compelling (37)(38)(39)(40)(41)(42). A notable exception was pamidronate, which reduced the size of radiographic bone erosions in spontaneously arthritic TNF␣-transgenic mice to an extent similar to that observed with the TNF inhibitor infliximab (12).…”

Section: Discussionmentioning

confidence: 99%

Targeting osteoclasts with zoledronic acid prevents bone destruction in collagen‐induced arthritis

Sims¹,

Green²,

Glatt³

et al. 2004

Arthritis & Rheumatism

126

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Objective. To study the effect of zoledronic acid (ZA) on synovial inflammation, structural joint damage, and bone metabolism in rats during the effector phase of collagen-induced arthritis (CIA).Methods. CIA was induced in female dark agouti rats. At the clinical onset of CIA, rats were assigned to treatment with vehicle or single subcutaneous doses of ZA (1.0, 10, 50, or 100 g/kg). Clinical signs in all 4 paws were scored on a daily basis. After 2 weeks, the joints in the hind paws were assessed using plain radiographs, microfocal computed tomography (micro-CT), histologic scoring, and histomorphometry, and the serum levels of type I collagen crosslinks were measured by enzyme-linked immunosorbent assay.Results. Although ZA mildly exacerbated synovitis, it effectively suppressed structural joint damage. At doses of >10 g/kg, ZA significantly reduced radiographic bone erosions, Larsen scores, and juxtaarticular trabecular bone loss as quantified by micro-CT. ZA prevented increased type I collagen (bone) breakdown in CIA and diminished histologic scores of focal bone erosion by up to 80%. Increases in the percentage of eroded surface, osteoclast surface, and osteoclast numbers associated with CIA were prevented by ZA, even though synovitis scores were unchanged.Conclusion. Single doses (>10 g/kg) of ZA strikingly reduced focal bone erosions and juxtaarticular trabecular bone loss, although synovitis was mildly exacerbated. Targeting osteoclasts with ZA may therefore be an effective strategy for preventing structural joint damage in rheumatoid arthritis.

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“…Despite their success in preventing systemic bone loss, however, trials with bisphosphonates in patients with RA have not demonstrated efficacy with respect to attenuating the progression of focal bone erosions (6)(7)(8)(9)(10). In contrast, results of studies in several different animal models of inflammatory arthritis indicate that bisphosphonate treatment can produce beneficial effects in both systemic bone loss and progression of focal bone erosions (3,(11)(12)(13)(14)(15)(16)(17)(18)(19).…”

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confidence: 99%