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Annual Zoledronic Acid: Is Less More?

Departments of Medicine and Urology, University of Washington, Seattle, WA

The concept of using the lowest possible dose of a drug while maintaining activity is not a new one. In this issue of the Journal of Clinical Oncology, Michaelson et al¹ report on the beneficial effect of a single annual dose of zoledronic acid on bone mineral density (BMD) in prostate cancer patients without metastases treated with androgen deprivation therapy (ADT). Previously, zoledronic acid administered every 3 months to the same population of men resulted in an increase in BMD compared with a loss of BMD in those treated with placebo.² Why, then, are the expected findings seen with annual dosing of interest?

By now, it is common knowledge that androgen deprivation causes significant loss of BMD and that BMD is a surrogate for fracture risk. This is why it has been suggested that men who are about to start ADT for any length of time undergo a baseline dual-energy x-ray absorptiometry scan with follow-up scans at appropriate intervals based on risk factors.³ Although there are no prospective reports of fracture risk in ADT-treated men, Shahinian et al have shown in a large retrospective study that men treated with ADT are at greater risk for fracture,⁴ leading to the question as to whether interventions to prevent osteoporosis might lower this risk.

The report by Michaelson et al is a well-conducted, randomized trial comparing a single annual dose of zoledronic acid with placebo in men with prostate cancer who did not have bone metastases or osteoporosis and are treated with ADT. At 12 months, BMD (measured by dual-energy x-ray absorptiometry) increased and bone turnover was suppressed (as measured by serial serum N-telopepetide and bone-specific alkaline phosphatase levels) in men treated with zoledronic acid compared with placebo. The improvement in BMD after a single annual dose of zoledronic acid was similar to that previously reported with quarterly dosing and this finding is complementary to the findings that a single annual dose improves BMD in women with osteoporosis.⁵

This trial did not, however, evaluate the ability of zoledronic acid to prevent ADT-related osteoporosis or fracture or its ability to treat ADT-induced osteoporosis (patients with a T score of –2.5 were excluded). In fact, at this time, there is no long-term fracture prevention data for zoledronic acid in the setting of osteoporosis, and zoledronic acid is not yet U.S. Food and Drug Administration approved for the prevention or treatment of osteoporosis.

Zoledronic acid given every 3 weeks to patients with androgen-independent prostate cancer and bone metastases has been shown to decrease the risk of skeletal complications⁶ while the current report evaluates BMD as the primary end point in men without bone metastases. While the authors of the current study make this distinction in the discussion, this point cannot be overemphasized: annual dosing of zoledronic acid should not be used to treat men with bone metastases if the intention is to decrease risk of skeletal complications.

Returning to the concept of the lowest possible effective dose, the data from this study now allow us to ask the following questions in relevant areas in prostate and other cancers. If annual dosing of zoledronic acid is proven effective in the prevention of osteoporosis and fracture, should all men receiving ADT be treated prophylactically with zoledronic acid? Can less frequent dosing be used in the setting of metastatic disease to delay or prevent skeletal morbidity? Will annual dosing with zoledronic acid be less likely to cause osteonecrosis of the jaw or renal impairment associated with more frequent dosing schedules? Will annual administration of zoledronic acid prevent or delay the onset of bone metastases by interfering with bone turnover?

In addition to the ability to use the lowest possible effective dose that will potentially result in less toxicity and treatment time for patients, annual dosing of zoledronic acid could have a significant economic impact on the use of health care dollars. In 2005, the global sales of zoledronic acid totaled over $1.2 billion. ⁷ The data from the report by Michaelson et al now permits the design of future trials that might have more far-reaching consequences.

AUTHOR'S DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST

The author or immediate family members indicated a financial interest. No conflict exists for drugs or devices used in a study if they are not being evaluated as part of the investigation. For a detailed description of the disclosure categories, or for more information about ASCO's conflict of interest policy, please refer to the Author Disclosure Declaration and the Disclosures of Potential Conflicts of Interest section in Information for Contributors.

Employment: N/A Leadership: N/A Consultant: N/A Stock: N/A Honoraria: N/A Research Funds: N/A Testimony: N/A Other: N/A

REFERENCES

1. Michaelson MD, Kaufman DS, Lee H, et al: Randomized controlled trial of annual zoledronic acid to prevent gonadotropin-releasing hormone agonist-induced bone loss in men with prostate cancer. J Clin Oncol 25:1038-1042, 2007[Abstract/Free Full Text]

2. Smith MR, Eastham J, Gleason DM, et al: Randomized controlled trial of zoledronic acid to prevent bone loss in men receiving androgen deprivation therapy for nonmetastatic prostate cancer. J Urol 169:2008-2012, 2003[CrossRef][Medline]

3. Diamond TH, Higano CS, Smith MR, et al: Osteoporosis in men with prostate carcinoma receiving androgen-deprivation therapy: Recommendations for diagnosis and therapies. Cancer 100:892-899, 2004[CrossRef][Medline]

4. Shahinian VB, Kuo YF, Freeman JL, et al: Risk of fracture after androgen deprivation for prostate cancer. N Engl J Med 325:154-164, 2005

5. Reid IR, Brown JP, Burckhardt P, et al: Intravenous zoledronic acid in postmenopausal women with low bone mineral density. N Engl J Med 346:653-661, 2002[Abstract/Free Full Text]

6. Saad F, Gleason DM, Murray R, et al: A randomized, placebo-controlled trial of zoledronic acid in patients with hormone-refractory metastatic prostate carcinoma. J Natl Cancer Inst 94:1458-1468, 2002[Abstract/Free Full Text]

7. Novartis. www.novartis.com

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