Pharmacology Update

Zoledronic Acid Injection (Reclast®)

By William T. Elliott, MD, FACP, and James Chan, PharmD, PhD, Dr. Elliott is Chair, Formulary Committee, Northern California Kaiser Permanente; Assistant Clinical Professor of Medicine, University of California, San Francisco; Dr. Chan is Pharmacy Quality and Outcomes Manager, Kaiser Permanente, Oakland, CA. Drs. Chan and Elliott report no financial relationship to this field of study.

A once yearly biophosphonate has been approved for the treatment of osteoporosis in postmenopausal women. Zoledronic acid was previously approved as Zometa for treating hypercalcemia due to malignancy, multiple myeloma and patients with documented bone metastases from solid tumors. Zoledronic acid injection is marketed by Novartis as Reclast for this new indication.

Indications

Zoledronic acid injection is indicated for the treatment of osteoporosis in postmenopausal women and Paget's disease in men and women.1

Dosage

The dosage for osteoporosis is 5 mg given by intravenous infusion (administered 15 minutes) once yearly. Patients should have adequate intake of calcium (1200 mg daily) and vitamin D (400 IU to 800 IU daily). For the treatment of Paget's disease the dose is a single infusion of 5 mg (administered 15 minutes). Calcium supplementation (1500 mg daily in divided doses) and vitamin D (800 IU daily) is recommended, particularly in the 2 weeks following zoledronic acid injection. Data on retreatment of Paget's disease is not available. However, retreatment may be considered in patients who have relapsed or have not achieved normalization of serum alkaline phosphatase.1

Zoledronic acid is available as a 5 mg/100 ml ready to infuse solution.

Potential Advantages

Zoledronic acid offers the convenience of a once yearly injection, eliminating weekly or monthly dosing of an oral bisphosphonate. It has been shown to be more effective and have a more rapid response than risedronate (30 mg daily for 2 months) for treatment of Paget's disease.1

Potential Disadvantages

Zoledronic acid requires an intravenous infusion. Infusion related adverse events include fever (18%), myalgia (9%), flu-like symptoms (8%), headache (7%), and arthralgia (7%). Atrial fibrillation has been reported (1.3% vs 0.4% for placebo).1,2 Renal impairment has been associated with parenteral bisphosphonates.1 Zoledronic acid may be less effective than weekly alendronate in maintaining or increasing bone mineral density over a 12-month interval.5

Comments

Zoledronic acid is a long-acting bisphosphonate that decreases bone turnover and improves bone density for at least 12 months.3 It is now approved for postmenopausal osteoporosis and Paget's disease.

Efficacy in postmenopausal osteoporosis was established in a randomized placebo-controlled study of women with a femoral neck BMD T-score of -1.5 or less with existing fracture(s) or -2.5 or less with no existing fractures (n = 7736). Annual doses of zoledronic acid significantly reduced morphometric vertebral fractures (3.3% vs 10.9%, p <0.001), and hip fractures (1.4% vs 2.5%, p = 0.02) over a 3-year followup.1,2 Nonvertebral fractures, clinical fractures, and clinical vertebral fractures were also significantly reduced. Bone mineral density was significantly increased. In a recent study in women who were post-op after a low trauma hip fracture (n = 2127), zoledronic acid significantly reduced any new clinical fractures (8.6% vs 13.9%, p = 0.001), new vertebral fractures (1.7% vs 3.8%, p = 0.02), new nonvertebral fractures (7.6% vs 10.7%, p = 0.03) and any cause mortality (9.6% vs 13.3%, p = 0.01).4 Zoledronic acid was compared to continuation of alendronate in patients who were previously treated with alendronate (70 mg weekly (n = 225) in a noninferiority study.5 While not as effective as alendronate in terms of increase in spine bone mineral density (0.120% vs 0.828%) zoledronic acid did narrowly meet the predetermined lower bound of the 95% confidence interval of noninferiority. However, patient preference was strongly for zoledronic acid with 78% preferring the once yearly infusion compared to 9% who preferred the weekly oral alendronate. In Paget's disease, zoledronic acid (5 mg) has been reported to be more effective than risedronate (30 mg orally for 2 months) in two 6-month studies (n = 347).1 Therapeutic response (normalization of serum alkaline phosphatase [SAP] or at least a 75% reduction in total SAP) at 6 months was achieved in 96% of zoledronic acid treated subjects compared to 74% for risedronate. About 90% achieved response by day 63 after zoledronic acid administration compared to less than 50% with risedronate. Adverse events were generally infusion-related (myalgia, pyrexia, influenza-like symptoms, headache, arthralgia), occurring the first 3 days after infusion. Renal impairment and atrial fibrillation may be potentially serious events. The wholesale cost for a 5 mg infusion of zoledronic acid is $1,041.54. This translates to $2.85 per day compared to $2.08 for alendronate (70 mg weekly).

Clinical Implications

Zoledronic acid injection is an effective bisphosphonate that inhibits osteoclast mediated bone resorption. It provides a once-yearly administration that may improve medication adherence over weekly or monthly oral administration and may be preferred by some patients.

References

1. Reclast Product Information. Novartis Pharmaceuticals Corporation. August 2007.

2. Black DM, et al. N Engl J Med. 2007:356:1809-1822.

3. Reid IR, et al. N Engl J Med. 2002;356:653-661.

4. Lyles KW, et al. N Engl J Med. 2007;357: epub.

5. McClung M, et al. Bone. 2007;41:122-128.