Increased bone mass with pamidronate treatment in rheumatoid arthritis. Results of a three‐year randomized, double‐blind trial

126

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.

Section: Discussionmentioning

confidence: 99%

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

Sims¹,

Green²,

Glatt³

et al. 2004

126

“…At least in animal models, a positive effect in slowing bone erosion was observed, although no full protection could be achieved (9). Moreover, data from human clinical trials that used bisphosphonates for preventing or slowing bone erosion in RA are contradictory (31)(32)(33)(34). However, it should be considered that these agents were added to the DMARD regimens, which modulate disease activity and joint destruction, and that the dose and potency of the agents used were comparably low.…”

Section: Discussionmentioning

confidence: 99%

Zoledronic acid protects against local and systemic bone loss in tumor necrosis factor–mediated arthritis

Herrak¹,

Görtz²,

Hayer³

et al. 2004

112

Objective. Increased osteoclast activity is a key factor in bone loss in rheumatoid arthritis (RA). This suggests that osteoclast-targeted therapies could effectively prevent skeletal damage in patients with RA. Zoledronic acid (ZA) is one of the most potent agents for blocking osteoclast function. We therefore investigated whether ZA can inhibit the bone loss associated with chronic inflammatory conditions. Methods. Human tumor necrosis factor (TNF)-transgenic (hTNFtg) mice, which develop severe destructive arthritis as well as osteoporosis, were treated with phosphate buffered saline, single or repeated doses of ZA, calcitonin, or anti-TNF, at the onset of arthritis.Results. Synovial inflammation was not affected by ZA. In contrast, bone erosion was retarded by a single dose of ZA (؊60%) and was almost completely blocked by repeated administration of ZA (؊95%). Cartilage damage was partly inhibited, and synovial osteoclast counts were significantly reduced with ZA treatment. Systemic bone mass dramatically increased in hTNFtg mice after administration of ZA, which was attributable to an increase in trabecular number and connectivity. In addition, bone resorption parameters were significantly lowered after administration of ZA. Calcitonin had no effect on synovial inflammation, bone erosion, cartilage damage, or systemic bone mass. Anti-TNF entirely blocked synovial inflammation, bone erosion, synovial osteoclast formation, and cartilage damage but had only minor effects on systemic bone mass.Conclusion. ZA appears to be an effective tool for protecting bone from arthritic damage. In addition to their role in antiinflammatory drug therapy, modern bisphosphonates are promising candidates for maintaining joint integrity and reversing systemic bone loss in patients with arthritis.

“…The target sample size was based on an estimated mean Ϯ SD loss of BMD in RA patients of 4.12 Ϯ 6.25% over 2 years (27). To demonstrate a complete inhibition of bone loss by the high-intensity exercise when compared with usual care, and based on 90% power to detect a significant difference (2-sided P ϭ 0.05), a sample size of 48 patients would be required in each study group.…”

Section: Methodsmentioning

confidence: 99%

Slowing of bone loss in patients with rheumatoid arthritis by long‐term high‐intensity exercise: Results of a randomized, controlled trial

Jong

Munneke

Lems

et al. 2004

Self Cite

Objective. Patients with rheumatoid arthritis (RA) are more at risk for the development of osteoporosis and osteoporotic fractures than are their healthy peers. In this randomized, controlled, multicenter trial, the effectiveness of a 2-year high-intensity weight-bearing exercise program (the RheumatoidArthritis-Patients-In-Training [RAPIT] program) on bone mineral density (BMD) was compared with usual care physical therapy, and the exercise modalities associated with changes in BMD were determined.Methods. Three hundred nine patients with RA were assigned to an intervention group, either the RAPIT program or usual care physical therapy. The primary end points were BMD of the hip and spine. The exercise modalities examined were aerobic fitness, muscle strength, and, as a surrogate for those effects not directly measured by the RAPIT program, attendance rate.Results. The data on the 136 RAPIT participants and 145 usual care participants who completed the study were analyzed. The mean rate of decrease in hip BMD, but not in lumbar spine BMD, was smaller in patients participating in the RAPIT program when compared with that in the usual care group, with a mean decrease of 1.6% (95% confidence interval [95% CI] 0.8-2.5) over the first year and 0.5% (95% CI 1.1-2.0) over the second year. The change in hip BMD was significantly and independently associated with changes in both muscle strength (multivariate odds ratio [OR] 1.75, 95% CI 1.07-2.86) and aerobic fitness (OR 1.79, 95% CI 1.10-2.90), but not with the attendance rate (OR 1.00, 95% CI 0.99-1.00).Conclusion. A long-term high-intensity weightbearing exercise program for RA patients is effective in slowing down the loss of BMD at the hip. The exercise modalities associated with this effect are muscle strength and aerobic fitness.