Preliminary evidence for a structural benefit of the new bisphosphonate zoledronic acid in early rheumatoid arthritis

Authors


Abstract

Objective

Bisphosphonates inhibit osteoclast activity, which is central to the development of bone damage in rheumatoid arthritis (RA). The aim of this study was to assess whether treatment with zoledronic acid, compared with placebo, could achieve a ≥50% reduction in the development of new erosions on magnetic resonance imaging (MRI) in patients with early RA.

Methods

In this proof-of-concept study, 39 patients with early RA and clinical synovitis of the hand/wrist were randomized to receive infusions with either zoledronic acid (5 mg) or placebo, administered at baseline and week 13. Patients in both groups received methotrexate (MTX) at a dosage of 7.5–20 mg/week. MRI and plain radiography were performed at baseline and week 26.

Results

At week 26, the mean ± SD change in MRI hand and wrist erosions was 61% lower in the zoledronic acid group compared with the placebo group (0.9 ± 1.63 versus 2.3 ± 3.09; P = 0.176). The mean ± SD increase in the number of hand and wrist bones with erosions was 0.3 ± 0.75 for zoledronic acid compared with 1.4 ± 1.77 for placebo (P = 0.029). The proportion of patients in whom new MRI-visualized bone edema developed was smaller in the zoledronic acid group compared with the placebo group (33% versus 58%; P = 0.121). The zoledronic acid group had a mean change in the number of radiographic erosions of 0.1 compared with 0.5 for the placebo group (P = 0.677). The safety profile of zoledronic acid was similar to that of placebo.

Conclusion

The results of this study suggest a structural benefit associated with zoledronic acid therapy in patients with RA, as demonstrated by consistent results in structural end points in favor of zoledronic acid plus MTX compared with MTX alone.

Several lines of evidence implicate the osteoclast as the effector cell in the pathogenesis of all forms of bone damage in rheumatoid arthritis (RA) (1, 2). Bisphosphonates are the most potent inhibitors of osteoclastic activity and are widely used in the treatment of osteoporosis. Although bisphosphonates are successful in preventing erosions in animal models of inflammatory arthritis, support from studies in humans is lacking (3–5). Zoledronic acid is a potent third-generation aminobisphosphonate that is thought to act by inhibiting the osteoclast lifespan (6–8). In this proof-of-concept study, we examined the hypothesis that zoledronic acid would prevent the development of new magnetic resonance imaging (MRI)–detected bone erosions in patients with early RA.

PATIENTS AND METHODS

Role of the study sponsor.

Novartis Pharma AG, in conjunction with the Leeds investigators, assisted in designing the study protocol and performing data analysis. Novartis Pharma AG had no role in the conduct of the study or in the collection of data.

Patients.

The study group comprised 39 patients fulfilling the 1987 American College of Rheumatology (formerly, the American Rheumatism Association) criteria for a diagnosis of RA (9). Inclusion criteria included age 20–75 years, RA symptoms for <2 years, and clinical synovitis in at least the wrist or hand joints. Doses of nonsteroidal antiinflammatory drugs had to have been stable for ≥2 weeks prior to randomization. Previous use of bisphosphonates was restricted; washout periods varied from 3 months for an oral agent taken for 1 week, to 2 years for an intravenous (IV) preparation. Patients in whom baseline creatinine clearance was <30 ml/minute were excluded. Other exclusion criteria were use of anabolic steroids, growth hormone, raloxifene, or calcitonin within the previous 6 months; current use of disease-modifying antirheumatic drugs other than methotrexate (MTX); and intraarticular injection of corticosteroids within 4 weeks prior to randomization.

Study design.

This single-center, double-blind, randomized, placebo-controlled trial was conducted at the Leeds General Infirmary, with the approval of the Research Ethics Committee of the Leeds Teaching Hospitals Trust, and was carried out in accordance with the Declaration of Helsinki (10). All patients gave written informed consent prior to any study procedure.

At the time of screening, patients were stratified for rheumatoid factor positivity and within each stratum were randomized 1:1 to receive IV infusions of either 5 mg of zoledronic acid or placebo. All patients received MTX (range of 7.5–20 mg per week) and were allowed 2 dose escalations, in 5-mg increments, to a maximum dosage of 20 mg/week. Folic acid supplementation (5 mg/day) was provided twice weekly. The study treatment was packaged in a blinded manner. Both placebo and zoledronic acid infusions were prepared by an independent pharmacist and were identical in appearance. Solutions were infused over 15 minutes, at baseline and week 13.

Efficacy assessments.

MRI of the second to fifth proximal interphalangeal (PIP) and metacarpophalangeal (MCP) joints and of the wrist of the signal hand was performed at baseline and week 26 using a Philips 1.5T scanner (Philips, Best, The Netherlands). T1-weighted and T2-weighted axial and coronal scans were performed using a dual-coil protocol. The parameters assessed were MRI-defined erosions (numeric count) and bone edema (number of bony sites involved), according to Outcome Measures in Rheumatology Clinical Trials definitions (11). The primary efficacy variable was the change from baseline in the number of MRI erosions, with the predefined primary outcome being a ≥50% reduction in the number of new erosions. In the current report, hands refer to the MCP and PIP joints (proximal and distal; i.e., 16 bony sites), and wrist refers to the 8 wrist bones, the bases of the 5 metacarpals, and the distal ulna and radius (15 bony sites). The 2 independent readers who performed the MRI evaluations were blinded to the clinical details and radiographic findings.

Radiographic assessment of both hands and dual x-ray absorptiometry of multiple sites were performed at baseline and week 26. Secondary efficacy variables included the change from baseline in the radiographic bone erosion count (scored on the second to fifth distal interphalangeal joints, the first to fifth PIP joints, the first to fifth MCP joints, the bases of the 5 metacarpals, the 8 wrist bones, the distal ulna, and the distal radius), the percent change in bone mineral density, the relative change in the levels of biochemical markers of bone resorption (serum C-telopeptide of type I collagen), bone formation (serum bone-specific alkaline phosphatase and osteocalcin), and changes from baseline in clinical outcomes, including patient's and physician's global assessments, tender and swollen joint count, and C-reactive protein levels.

Safety assessments.

The assessment of patient safety included the recording of all adverse events and serious adverse events; regular monitoring of hematologic parameters, serum chemistry, and urine parameters; and regular physical examinations and assessments of vital signs and body weight. All patients underwent a creatinine clearance assessment at baseline and within 2 weeks prior to receiving second infusion. Serum chemistry was assessed and urinalysis was performed at baseline, 9–11 days after each dose, 2 weeks prior to the second dose, and at the end of the study.

Statistical analysis.

The sample size was determined from the results of a previous MRI study in which MTX was administered to patients with early RA (12). The sample size was calculated based on the assumption that the probability of a zoledronic acid–treated patient having less progression of erosions than a placebo-treated patient was 0.75. Thus, a sample size of 18 evaluable patients per group was estimated to have 90% power to detect a treatment difference using Wilcoxon's rank sum test with a 1-sided significance level of 0.1 (calculated using nQuery Advisor version 2.0; Statistical Solutions, Saugus, MA).

Between–treatment group differences in secondary efficacy variables were evaluated using a 2-sided Wilcoxon's rank sum test, logistic regression, Fisher's exact test, analysis of variance, or analysis of covariance (ANCOVA), as appropriate. For biochemical marker variables, relative change was analyzed using an ANCOVA model with treatment and the loge baseline value as explanatory variables.

Statistical significance for secondary efficacy variables was evaluated at the 2-sided 0.05 significance level. All efficacy variables were analyzed using the intent-to-treat (ITT) population. The assessment of safety was based on the frequency of adverse events and the number of patients with laboratory values outside of the reference ranges. In accordance with standards for the clinical development program of zoledronic acid, additional renal safety evaluations were performed. The safety analysis population included all randomized patients who received at least 1 dose of study drug.

RESULTS

Patient population.

Forty-three patients were screened, and 39 were randomized: 18 patients were assigned to the zoledronic acid group, and 21 were assigned to the placebo group. All of the randomized patients completed the study and were included in the ITT analysis. The baseline characteristics of the 2 treatment groups were generally comparable (Table 1). However, patients in the zoledronic acid group had more severe disease at baseline. The mean dosage of MTX being taken at baseline was similar in the zoledronic acid group (11.8 mg/week) and the placebo group (10.1 mg/week). Concomitant intraarticular/intramuscular corticosteroid use was reported by 72% of patients in the zoledronic acid group and 43% of patients in the placebo group. All patients received 2 infusions as planned, and there was no significant difference in the mean weekly MTX dose between the groups at study completion (14 mg/week for the zoledronic acid group, 11.9 mg/week for the placebo group; P = 0.086).

Table 1. Baseline characteristics of patients according to treatment group (ITT population)*
CharacteristicZoledronic acid (n = 18)Placebo (n = 21)
  • *

    Except where indicated otherwise, values are the number (%) of patients. Patient's and physician's assessments of pain and disease activity were scored on a 100-mm visual analog scale. ITT = intent-to-treat; RA = rheumatoid arthritis.

  • All reported erosions as visualized by magnetic resonance imaging (MRI) were included in the baseline count; this baseline count differs from the baseline count for the efficacy evaluations, for which only erosions for joints assessed at both baseline and post-baseline were included.

  • No data were available for 1 patient in the zoledronic acid group.

Age, mean (range) years50.2 (30–76)53.5 (33–72)
Male sex8 (44.4)9 (42.9)
Female sex10 (55.6)12 (57.1)
White race18 (100)21 (100)
Rheumatoid factor positivity15 (83.3)15 (71.4)
Treatment received during the 2 weeks prior to randomization
 Methotrexate, stable dosage18 (100)21 (100)
 Folic/folinic acid, stable dosage16 (89)18 (86)
 Nonsteroidal antiinflammatory drugs, none or stable dosage17 (94)21 (100)
MRI erosions, mean (range)14.2 (2–40)12.7 (4–29)
Joints with bone edema, mean (range)7.6 (0–16)7.3 (1–20)
Patient's assessment of RA pain, mean (range)55.2 (14–90)45.5 (2–90)
Patient's global assessment of disease activity, mean (range)57.8 (27–87)42.4 (2–87)
Physician's global assessment of disease activity, mean (range)35.7 (8–79)24.8 (6–52)
No. of tender joints (28 assessed), mean (range)2.3 (1–28)10.0 (2–26)
No. of swollen joints (28 assessed), mean (range)9.6 (0–25)6.3 (0–22)
C-reactive protein, mean (range) mg/liter22.2 (0.3–121.0)23.2 (1.0–179.0)
Disease duration, mean (range) months5.6 (0.4–20.6)5.5 (0.4–14.2)

Efficacy results.

At week 26, the mean ± SD change from baseline in the number of signal hand and wrist MRI erosions was 61% lower in the zoledronic acid group compared with the placebo group (0.9 ± 1.63 versus 2.3 ± 3.09) (Figure 1). However, the difference between the 2 treatment groups was not statistically significant at the 10% 1-sided level (P = 0.176). The median increase in the number of erosions from baseline to week 26 was 1.0 in both groups (range −2 to 4 for patients receiving zoledronic acid versus 0 to 10 for those receiving placebo) (Figure 2). The difference in the mean change in the number of erosions was mostly attributable to the reduction of erosion progression observed in the wrist (mean ± SD 0.7 ± 1.45 for zoledronic acid versus 2.0 ± 3.02 for placebo; P = 0.125). The mean ± SD increase in the number of hand and wrist joints and bones with erosions was 0.3 ± 0.75 for zoledronic acid versus 1.4 ± 1.77 for placebo (P = 0.029). The favorable difference was again attributable to the mean change in the number of bones with erosions in the wrist. The mean ± SD increase in the number of newly eroded joints/bones (i.e., erosion-free at baseline) in the hand and wrist was 0.5 ± 0.71 for zoledronic acid versus 1.4 ± 1.77 for placebo (P = 0.102).

Figure 1.

Change from baseline in the number of erosions on the signal hand and wrist. ZOL = zoledronic acid.

Figure 2.

Frequency of change in erosions on the signal hand and wrist, by magnetic resonance imaging. ZOL = zoledronic acid.

The proportion of patients in whom new bone edema developed in the signal hand and wrist was smaller in the zoledronic acid group (33%) than in the placebo group (58%), although the difference was not statistically significant (P = 0.121). In the zoledronic acid group, the mean change in the number of radiographic erosions was 0.1, compared with 0.5 in the placebo group (P = 0.677).

In the zoledronic acid group, there was a significant increase from baseline in the mean percent change in bone mineral density at all sites, while the placebo group demonstrated a decrease at all sites except the lumbar spine (data not shown). The mean levels of bone biomarkers remained largely unchanged in the placebo group but decreased markedly in the zoledronic acid group. At week 26, the differences in the percent decrease from baseline between the zoledronic acid group and the placebo group for serum C-telopeptide of type I collagen, serum bone-specific alkaline phosphatase, and osteocalcin were 69.9%, 33.4%, and 48.1%, respectively (P < 0.05 for all 3 markers).

The mean improvement in patient's global assessment of disease activity (on a 100-mm visual analog scale [VAS]) was greater for the zoledronic acid group compared with the placebo group at week 13 and week 26 (−13.1 mm versus 0.9 mm [P= 0.051] and −13.4 mm versus 0.0 mm [P = 0.035], respectively). The mean change in physician's global assessment of disease activity (on a 100-mm VAS) also favored patients in the zoledronic acid group at week 13 (−2.6 mm versus 14.3 mm; P = 0.029); at week 26 the treatment difference was not significant (+1.2 mm versus +6.8 mm; P = 0.568). The mean changes in pain on the VAS were −11.1 mm for zoledronic acid and 0.2 mm for placebo (P = 0.143) at week 13, and −9.1 mm for zoledronic acid and −3.0 mm for placebo (P = 0.114) at week 26. No statistically significant differences between treatment groups were observed for the number of tender and swollen joints or the C-reactive protein level.

Safety results.

The safety population included all 39 patients. None of these patients discontinued their participation in the trial. Overall, the proportion of patients experiencing at least 1 adverse event was lower in the zoledronic acid group (50%) than in the placebo group (76%). Renal abnormalities did not develop in any patient. Of the 3 patients in the zoledronic acid group (versus 0 in the placebo arm) who experienced influenza-like symptoms within 24 hours of infusion, 1 was hospitalized for 2 days, with complete resolution of symptoms 5 days after admission. (It should be noted that the patient was hospitalized overnight because meningitis had to be excluded).

DISCUSSION

In this study, the administration of zoledronic acid to a small group of patients with early RA reduced the number of bone erosions by 61% compared with the placebo group, in which patients received standard doses of MTX early in the disease course. The prespecified level of clinical difference was therefore achieved but was not statistically significant, probably due to the use of Wilcoxon's test, which loses sensitivity when many ties in the outcome variable occur. This is reflected by the fact that in this trial 54% of the change scores in bone erosions were 0 or 1 (i.e., minimal change). In support of the validity of the findings are the significant reduction in the mean change in the number of eroded sites in favor of zoledronic acid and the trend in favor of zoledronic acid in terms of reducing new bone edema, which is regarded as the precursor lesion to erosion (12, 13).

At week 26, improvement in the patient's global assessment of disease activity was significantly greater among patients in the zoledronic acid group compared with those in the placebo group, and a similar trend in the physician's global assessment of disease activity was observed. There are reports of analgesia associated with the administration of intravenous bisphosphonates, but the clinical relevance of any such effect remains unproven (14). Zoledronic acid was well tolerated and displayed an overall safety profile similar to that of placebo. An influenza-like illness postinfusion has been described previously (15).

Limitations of this study include the small number of subjects, which led to differences in baseline disease activity measures, and the fact that it was not controlled for the degree of MRI synovitis in the target joints. However, these data confirm the concept of the osteoclast being central to the pathogenesis of RA and suggest that zoledronic acid may be a useful addition to current therapy for RA. This is especially applicable when inflammation is incompletely suppressed or there is a contraindication (e.g., infection) to use of a tumor necrosis factor antagonist.

Acknowledgements

We would like to acknowledge the following individuals for their assistance in the conduct of this study: Claire Brown, RGN, BSc Hon, Belinda Rees-Evans, RGN, Sheena P. Stewart, BSc (University of Leeds); Alexander Chesi, PhD, Andrea Fabel (Novartis Pharma AG); Gemma Dobson, BSc, Nick Hodges, BSc Hon, Peter Mesenbrink, PhD, Alison Park, BSc Hon (Novartis UK); Peter Richardson, MRCP (Novartis Pharma KK); Karen Nicholson, PhD (Roche Products Limited UK).

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