Zoledronic Acid: Better Than Pamidronate?

ABSTRACT & COMMENTARY

Synopsis: Zoledronic acid, a newly developed bisphosphonate, was used in patients with neoplastic bone disease at 3 different doses (0.4 mg, 2 mg, 4 mg) and each administered intravenously over 5 minutes. For comparative purposes, a fourth group received pamidronate at the standard dose of 90 mg over 2 hours. Patients were treated monthly for a total of 10 months. The results indicate that the 2-mg and 4-mg dose of zoledronic acid was at least as effective and safe as pamidronate in treatment of osteolytic metastases.

Source: Berenson JR, et al. Cancer. 2001;91: 191-200.

Zoledronic acid is a new generation bisphosphonate that has demonstrated greater potency and a higher therapeutic ratio than other bisphosphonates in preclinical and early clinical trials.1 For example, in recent phase III trials, a single infusion of 4.0 mg was significantly more effective than a single 90 mg pamidronate infusion in treatment of hypercalcemia associated with malignancy (HCM).2 In the current study, Berenson and colleagues report the results of a double-blind, randomized dose-response study in which myeloma or breast cancer patients with known osteolytic skeletal metastases were treated with 1 of 3 doses of zoledronic acid or 90 mg of pamidronate.

This research project, supported by Novartis (the manufacturer of both pamidronate and zoledronic acid), was carried out at several institutions and involved the investigation of 280 patients who were treated with 0.4, 2.0, or 4.0 mg of zoledronic acid or 90 mg of pamidronate. For most, this was in addition to their tumor-directed chemotherapy. The primary end point was the proportion of patients with skeletal disease progression to the point where radiation therapy was required during the 10-month study duration. The study was without a "no treatment" arm. Thus, an assumption was made that approximately 30% of untreated patients would require radiation during this period, as was the case in similarly designed prior clinical trials in which there were nonbisphosphonate-treated patients.3 The study was powered in such a way that if any of the 4 selected treatments resulted in a reduction to approximately 15% requiring radiation, there would be enough enrolled patients to detect this difference.

Other outcome variables were also examined. These included the number and type of skeletal-related events (SREs) (eg, fracture, spinal cord compression, hypercalcemia), bone mineral density (BMD), ECOG performance status, pain score, and analgesic score.

Analysis of the trial outcomes revealed that zoledronic acid (at 2-mg and 4-mg doses, but not at the lowest dose of 0.4 mg) reduced the need for radiation similar to that of pamidronate. Furthermore, SREs including hypercalcemia and pathological fractures were reduced similarly in these groups. Bone resorption, as measured by the urinary excretion of N-telopeptides (NTX) were observed in all treatment groups (including the lowest dose of zoledronic acid), and this correlated with increased BMD in all groups. The decrease in NTX and the increase in BMD were observed to be dose-related for the zoledronic acid-treated patients (greater effects in those treated at 4 mg).

Although infusion-related skeletal pain was common in all groups (40-60%), significant adverse events were uncommon and there was no difference among the treatment groups. There was a notable rise in serum creatinine in some patients. Thirty-seven patients had an increase in serum creatinine of at least 0.5 mg/dL, and this seemed to be dose-related for the zoledronic acid treatment groups. However, only 5 patients had grade 3 creatinine elevations, and this occurred in 1 patient in each of the zoledronic acid groups and in 2 patients in the pamidronate group.

Thus, this study established that a 5-minute infusion of 2 mg or 4 mg of zoledronic acid was at least as effective and safe as a 2-hour 90-mg pamidronate infusion in treatment of osteolytic disease in breast cancer and myeloma.

COMMENT by William B. Ershler, MD

Zoledronic acid is being developed as a third-generation bisphosphonate for the treatment of cancer-related bone disease. Early studies have indicated that it is more potent and probably more effective than earlier drugs in this general class, including etidronate, alendronate, and pamidronate. Furthermore, because of the lower dose required, it can be safely administered over a much shorter period of time. This would offer significant practical advantages in the outpatient setting.

The current study was not designed to compare zoledronic acid with pamidronate, but to establish an effective dose range for its use in this setting. A larger, multi-institutional study is currently underway to determine if zoledronic acid is indeed more effective.

The rise in serum creatinine is of some concern, inasmuch as it occurred in a dose-related manner. In other trials, an 8 mg dose of zoledronic acid has been used and it is possible that significant renal toxicity may be observed. Slowing the rate of infusion may be sufficient to reduce renal toxicity, but this remains to be established.

Patients with myeloma and with breast cancer are at risk for developing generalized osteoporosis in addition to lytic metastases. Thus, it was encouraging to see a fairly pronounced rise in BMD (6.2-9.6% for the 3 zoledronic acid groups) over the relatively short 10-month treatment period. This compares favorably to all forms of osteoporosis treatment, including the daily oral administration of alendronate, which over 3 years was shown to result in an increase in BMD by 8.8%.4 It is possible that zoledronic acid, administered by periodic brief infusions, will offer therapeutic advantages over alendronate in the management of nonmalignancy-associated osteoporosis. This, no doubt, is under consideration by the developers of this exciting new agent.

References

1. Green JR, et al. J Bone Miner Res. 1994;9:745-750.

2. Major P, et al. J Clin Oncol. 2001;19:558-567.

3. Berenson JR, et al. N Engl J Med. 1996;334:488-493.

4. Liberman UA, et al. N Engl J Med. 1995;333: 1437-1443.