麻豆传媒

Bisphosphonate treatment failed to prevent the development of bone erosions in patients with longstanding tophaceous gout, a 2-year randomized study found.

No differences in changes on computed tomography (CT) erosion scores of the feet were seen among patients treated with zoledronate (Zometa, Reclast) versus those given placebo at either year 1 or year 2 (P=0.49 for treatment, P=0.47 for time, P =0.23 for interaction of treatment by time), according to , and colleagues from the University of Auckland in New Zealand.

There also was no difference between zoledronate and placebo when the analysis was adjusted for mean serum urate (P=0.13 for treatment, P=0.49 for time, P=0.20 for interaction of treatment by time), the researchers reported in the June Annals of the Rheumatic Diseases.

Patients with chronic tophaceous gout often develop erosions in bone near sites of the tophi, which can result in articular damage. A role for osteoclasts in the development of these bone erosions in gout has been suggested because of the prevalence of preosteoclast cells in the synovium of patients with severe gout and the presence of osteoclast-like cells surrounding urate crystals.

"Osteoclast-like cells are also present at the tophus-bone interface within the joints of people with erosive gout. Taken together, these data provide a rationale for assessing anti-osteoclast therapies for bone erosion in this disease," Dalbeth and colleagues wrote.

To explore the possibility that targeting these osteoclasts with agents that impede osteoclast function (such as bisphosphonates) prevents bone erosion, Dalbeth and colleagues enrolled 100 patients with longstanding tophaceous gout.

Their mean age was 56, mean disease duration was 22 years, and more than 90% were men. The mean number of subcutaneous tophi was seven, and baseline CT erosion scores were 17.7 in the placebo group and 16.4 in the zoledronate group. More than 90% were on urate-lowering drugs.

The treatment consisted of 5 mg zoledronate administered intravenously once yearly or placebo.

CT images of both feet were obtained at baseline and at years 1 and 2. CT is the gold standard for measuring bone erosions, but plain radiographs of the hands and feet also were obtained at those time points.

Other assessments included measurements of bone mineral density (BMD) and markers of bone and cartilage turnover.

Findings on radiographs were similar to what was seen on CT, with no differences in damage or erosion scores between the zoledronate and placebo groups.

And while BMD was already "excellent" at baseline in these patients, 2 years of zoledronate treatment led to greater BMD at the spine, total hip, femur neck, and total body.

Significant decreases also were seen in the markers of bone turnover procollagen type 1 N-terminal propeptide and beta-C-terminal telopeptide of type I collagen.

In an additional exploratory analysis, the researchers found no changes in the number of tophi or in serum urate levels, or differences in the frequency of flares, pain, and disability over time in the active treatment versus placebo groups. A trend was seen for worsening in patient global assessment over time in patients receiving zoledronate, however.

A total of 48 serious adverse events occurred in 19 patients receiving zoledronate, and there were 35 events in 18 patients on placebo. In both groups, the serious events included arrhythmias, fractures, and disease flares. Two patients in the zoledronate group died of cardiac causes.

Acute phase responses, with symptoms such as muscle pain, were reported after the initial infusion in 50% of the zoledronate group compared with 36% of the placebo group.

"Our data do not support the use of anti-osteoclast therapy in the management of bone erosion in people with longstanding and tophaceous gout," Dalbeth and colleagues wrote.

In contrast, her group recently reported that, in a small exploratory study, in patients with tophaceous gout from a median of 69.25 to 57.25 by 12 months (P=0.02).

There also appeared to be repair of erosions in conjunction with shrinkage of tophi.

The findings of the current study raise important questions "about the processes of bone erosion in gout, particularly about the natural history of bone erosion" and "whether bone erosions can heal in those with long disease duration," the researchers observed.

They noted that laboratory studies have suggested that , and so in patients with persistent crystals, "the deleterious effects on osteoblasts may prevent erosion healing, even with potent anti-osteoclast therapy."

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