Although Dr. Tanvetyanon states correctly that zoledronic acid—in common with all intravenous bisphosphonates—has the potential to affect renal function, I take issue with the assertion that “zoledronic acid is not as safe as [we] imply.” In our double-blind, placebo-controlled trial of 773 patients with lung carcinoma or other solid tumors, the incidence of adverse events was similar among patients who were randomized to receive either 4 mg zoledronic acid or placebo. In particular, the incidence of Grade 3 serum creatinine increase was 1.8% for both the 4-mg zoledronic acid group and the placebo groups over 21 months. Furthermore, in a 25-month study of 1648 patients with breast carcinoma or multiple myeloma, the incidence of Grade 3 or Grade 4 serum creatinine increase was 0.4% for 4 mg zoledronic acid versus 1.9μ for 90 mg pamidronate.1 Overall, the zoledronic acid Phase III clinical trial program evaluated > 3000 patients worldwide and found no evidence of a significantly increased risk of impaired renal function among patients with bone metastases from solid tumors who were treated with 4 mg zoledronic acid (as a 15-minute infusion) for up to 2 years. Dr. Tanvetyanon claims that “many patients require dialysis or die from this complication despite receiving the recommended dose and infusion time [of bisphosphonates]”; however, in his referenced citation (Chang et al., 20032), 72 cases of renal failure were reported among > 430,000 patients who were treated over a 2-year period, and there are many other compounding factors that may have caused renal failure in those patients with advanced malignancies (Tarassoff et al. NEJM, 2003). Dr. Tanvetyanon also cites infrequent case reports of uveitis, hypocalcemia, and avascular necrosis of the jaw as further proof of zoledronic acid's “questionable” safety profile. However, reports of symptomatic hypocalcemia and uveitis are infrequent, and a direct causal relation between zoledronic acid and osteonecrosis of the jaw has not been established.

Zoledronic acid is indicated for the prevention of skeletal complications from bone metastases secondary to any solid tumor in > 70 countries. It is the only bisphosphonate that has such broad regulatory approval. The skeletal complications that zoledronic acid prevents can cause significant morbidity in large numbers of patients and have been linked to significant declines in health-related quality of life and decreased survival.3, 4 Moreover, zoledronic acid significantly reduces bone pain compared with placebo in patients with breast or prostate carcinoma. Therefore, I disagree that zoledronic acid is “burdensome to our society.”

Finally, Dr. Tanvetyanon suggests that a better risk-benefit ratio might be achieved by delaying treatment with zoledronic acid until after a patient has experienced a skeletal complication. There is no evidence that this would improve the risk-benefit ratio. Patients with no prior events still are at substantial risk of debilitating skeletal complications. The American Society of Clinical Oncology has published consensus treatment guidelines—regarding the use of bisphosphonates for the treatment of patients with osteolytic lesions from multiple myeloma5 or bone metastases from breast carcinoma6—that specifically recommend initiation of either intravenous zoledronic acid or pamidronate at the first sign of bone destruction on plain radiographs. Therefore, early intervention with zoledronic acid seems a more rational approach than delaying treatment until skeletal integrity is compromised severely.


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  • 1
    Rosen LS, Gordon D, Kaminski M, et al. Long-term efficacy and safety of zoledronic acid compared with pamidronate disodium in the treatment of skeletal complications in patients with advanced multiple myeloma or breast carcinoma. A randomized, double-blind, multicenter, comparative trial. Cancer. 2003; 98: 17351744.
  • 2
    Weinfurt KP, Li Y, Castel LD, Timbie JW, Glendenning A, Schulman KA. The impact of skeletal-related events on health-related quality of life of patients with metastatic prostate cancer [abstract 662P]. Ann Oncol. 2002; 13( Suppl 5): 180.
  • 3
    Chang JT, Green L, Beitz J. Renal failure with the use of zoledronic acid. N Engl J Med. 2003; 349: 16761679; discussion, 1676–1679.
  • 4
    Oefelein MG, Ricchiuti V, Conrad W, Resnick MI. Skeletal fractures negatively correlate with overall survival in men with prostate cancer. J Urol. 2002; 168: 10051007.
  • 5
    Berenson JR, Hillner BE, Kyle RA, et al. American Society of Clinical Oncology clinical practice guidelines: the role of bisphosphonates in multiple myeloma. J Clin Oncol. 2002; 20: 37193736.
  • 6
    Hillner BE, Ingle JN, Chlebowski RT, et al. American Society of Clinical Oncology 2003 update on the role of bisphosphonates and bone health issues in women with breast cancer [published erratum appears in J Clin Oncol. 2004;22:1351]. J Clin Oncol. 2003; 21: 40424057.

Lee S. Rosen M.D.*, * John Wayne Cancer Institute and St. John's Health Center, Santa Monica, California.