Correspondence to: Tawee Tanvetyanon, MD, Loyola University Stritch School of Medicine, Cardinal Bernardin Cancer Institute, 2160 S. First Ave., Maywood, IL 60153 (e-mail: ttanve{at}lumc.edu)
Serious concerns arose as I read the article by Saad et al. (1). First, the authors concluded that long-term treatment with zoledronic acid was safe. However, in my opinion, a 24-month follow-up for this potent bisphosphonate is not sufficiently long to make that conclusion. Longer use (i.e., >40 months) of another nitrogen-containing bisphosphonate, pamidronate, has been associated with renal failure from glomerular disease, an adverse effect that was not noticed during clinical trials (2). In addition, an epidemic of avascular necrosis of the jaws, often refractory to both medical and surgical interventions, has just recently been recognized, long after marketed use of pamidronate and zoledronic acid (3). Moreover, osteopetrosis, a disease characterized by pain, mandibular osteomyelitis, and recurrent fractures, has been reported during prolonged use (i.e., >24 months) of certain potent bisphosphonates (4,5).
Second, the authors emphasized that the benefit of this therapy was sustained as long as treatment continued (because patients who continued therapy beyond 15 months still derived benefits compared with patients who received placebo). Saad et al. also recommended that therapy continue for as long as it was tolerated. Their study, however, only provides follow-up information up to 24 months; thus, this treatment can be safely and scientifically recommended only up to a 24-month period. In fact, because the treatment is costly and associated with many complications, to make this recommendation valid, it is necessary to show that stopping treatment at 15 months is not an already adequate treatment. Indeed, short-term treatment may be long lasting because zoledronic acid accumulates in bone for months to years (6).
Third, the authors conclusion that zoledronic acid provided durable palliation of pain was based on an improvement in the brief pain inventory score (1). It is unclear, however, whether this score improvement is clinically meaningful. In fact, the authors previously reported that treatment with zoledronic acid did not improve the overall quality of life, as measured by Functional Assessment of Cancer Therapy (FACT) and EuroQoL (EQ-5D) questionnaires (7). Regardless, zoledronic acid is not a substitute for pain medication. The fact that pain continued to increase throughout this study raises a serious concern that the patients in this study were left without adequate pain medications so that the effect of zoledronic acid on pain could be more easily assessed.
Fourth, the authors wondered why the benefit of zoledronic acid diminished when a higher dose was used. One possible explanation is that patients who received high-dose zoledronic acid developed osteopetrosis, which accounted for the increase in skeletal complications. Although the effect of 8 mg of zoledronic acid on biochemical markers appears comparable to that of 4 mg of zoledronic acid, it is unknown if these markers, which are subject to confounding by fractures and many other conditions, still remain sensitive during the state of extremely suppressed bone resorption (8). Healthy bone is characterized by optimal bone strengthmade possible by adequate osteoclastic functionand bone density. Although patients with osteopetrosis have high bone density, they often develop fractures.
Finally, the authors attempted to perform an efficacy analysis by combining the 8-mg and 4-mg zoledronic acid arms. Unfortunately, this approach is useless because 8 mg of zoledronic acid is not approved for clinical use by the Food and Drug Administration. In my view, a more useful approach is one that helps us avoid giving too much zoledronic acid, and that at least improves our patients quality of life without imposing disproportionate risks.
REFERENCES
1 Saad F, Gleason DM, Murray R, Tchekmedyian S, Venner P, Lacombe L, et al. Zoledronic Acid Prostate Cancer Study Group. Long-term efficacy of zoledronic acid for the prevention of skeletal complications in patients with metastatic hormone-refractory prostate cancer. J Natl Cancer Inst 2004;96:87982.
2 Kunin M, Kopolovic J, Avigdor A, Holtzman EJ. Collapsing glomerulopathy induced by long-term treatment with standard-dose pamidronate in a myeloma patient. Nephrol Dial Transplant 2004;19:7236.
3 Ruggiero SL, Mehrotra B, Rosenberg TJ, Engroff SL. Osteonecrosis of the jaws associated with the use of bisphosphonates: a review of 63 cases. J Oral Maxillofac Surg 2004;62:52734.[CrossRef][ISI][Medline]
4 Whyte MP, Wenkert D, Clements KL, McAlister WH, Mumm S. Bisphosphonate-induced osteopetrosis. N Engl J Med 2003;349:45763.
5 Benichou OD, Laredo JD, de Vernejoul MC. Type II autosomal dominant osteopetrosis (Albers-Schonberg disease): clinical and radiological manifestations in 42 patients. Bone 2000;26:8793.[CrossRef][ISI][Medline]
6 Chen T, Berenson J, Vescio R, Swift R, Gilchick A, Goodin S, et al. Pharmacokinetics and pharmacodynamics of zoledronic acid in cancer patients with bone metastases. J Clin Pharmacol 2002;42:122836
7 Saad F, Gleason DM, Murray R, Tchekmedyian S, Venner P, Lacombe L, et al. A randomized, placebo-controlled trial of zoledronic acid in patients with hormone-refractory metastatic prostate carcinoma. J Natl Cancer Inst 2002;94:145868.
8 Watts NB. Clinical utility of biochemical markers of bone remodeling. Clin Chem 1999;45:135968.
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