Zoledronic Acid

Zoledronic acid (Aclasta®; Reclast®), a third-generation nitrogen-containing bisphosphonate, is the first once-yearly treatment to have been approved for use in patients with postmenopausal osteoporosis or at high risk of fracture. Intravenous zoledronic acid 5 mg once yearly is effective in reducing the risk of several types of fracture in patients with postmenopausal osteoporosis or recent low-trauma hip fracture. Moreover, improvements in bone mineral density (BMD) and reductions in markers of bone turnover are also generally observed. Zoledronic acid is generally well tolerated. Additional comparative data are required to definitively position zoledronic acid with respect to other agents. In the meantime, intravenous zoledronic acid 5 mg once yearly is a convenient and effective treatment option that may have an advantage over some other agents, for which adherence to treatment regimens is a recognized problem.

Zoledronic acid binds with high affinity to hydroxyapatite, localizing primarily at areas of high bone turnover. The drug becomes released during bone resorption and is subsequently internalized by osteoclasts. It acts primarily by inhibiting the mevalonate pathway in osteoclasts via farnesyl diphosphate synthase inhibition, resulting in the prevention of downstream protein prenylation, with subsequent inhibition of osteoclast-mediated bone resorption and osteoclast formation and the induction of osteoclast apoptosis.

In a large 3-year study in patients with postmenopausal osteoporosis, mean levels of biochemical markers of bone turnover were significantly lower in recipients of intravenous zoledronic acid 5 mg once yearly than in placebo recipients 1 year after initial infusion, although levels did not progressively decline with repeated administration. Moreover, in a 24-week study conducted in postmenopausal patients with osteoporosis or low BMD, intravenous zoledronic acid 5 mg (single dose) reduced biochemical markers of bone resorption more rapidly and to a significantly greater extent than oral alendronic acid. Furthermore, in a 1-year study, intravenous zoledronic acid 5 mg (single dose) produced significant reductions in biochemical markers of bone turnover at 3 months relative to oral alendronic acid once weekly in postmenopausal patients with low BMD or osteoporosis previously treated with alendronic acid, although maximal reductions were not maintained throughout the duration of the study.

As expected, maximum plasma concentrations (C_max) of zoledronic acid are reached at the end of intravenous infusion, with plasma concentrations of the drug rapidly declining to <10% and <1% of C_max 4 and 24 hours post-infusion. A large proportion of the administered dose is presumed to bind to bone; the drug is then released back into the circulation slowly, resulting in a prolonged post-infusion period of low plasma drug concentration. Zoledronic acid is not metabolized and is excreted via the kidneys as unchanged drug. The process of zoledronic acid elimination is triphasic, consisting of two rapid phases followed by a long terminal elimination phase (terminal elimination half-life of 146 hours). Zoledronic acid is not recommended for use in patients with severe renal impairment.

Intravenous zoledronic acid 5 mg once yearly, administered by infusion, was effective in the treatment of patients with postmenopausal osteoporosis in a large, well designed, long-term study. Zoledronic acid reduced the risk of a new morphometric vertebral fracture (primary endpoint) by 70% relative to placebo after 3 years of treatment in the group of patients not receiving concomitant osteoporosis medication. Moreover, during the 3-year treatment period, the risk of hip fracture (primary endpoint) was reduced by 41% with zoledronic acid compared with placebo in the overall patient population (patients who were or were not receiving concomitant treatment for osteoporosis). The drug was also effective in reducing the risk of other categories of fracture, including clinical vertebral fractures and nonvertebral fractures in the overall patient population, as well as multiple morphometric vertebral fractures in patients receiving no other osteoporosis treatments. Furthermore, zoledronic acid improved total hip, lumbar spine and femoral neck BMD relative to placebo after 3 years. Several histomorphometric measures of bone turnover were reduced with zoledronic acid relative to placebo, although bone remodelling remained evident after 3 years of treatment, with no evidence of qualitative bone abnormalities.

In a well designed 1-year study, intravenous zoledronic acid 5 mg (single dose) was no less effective than oral alendronic acid 70 mg once weekly in maintaining BMD at the lumbar spine in postmenopausal patients with osteoporosis or low BMD previously treated with oral alendronic acid. Zoledronic acid did not differ significantly from alendronic acid in terms of quantitative histomorphometric measures of bone turnover, with both treatments maintaining bone remodelling at a level generally similar to that seen in premenopausal women, without producing bone abnormalities.

Intravenous zoledronic acid once yearly was also effective in reducing the risk of clinical fractures in male and female patients with recent low-trauma hip fracture in a large well designed placebo-controlled 5-year study with a median duration of 1.9 years. The risk of any clinical fracture (primary endpoint) was reduced by 35% with zoledronic acid relative to placebo, with the drug also effective in reducing the risk of vertebral and nonvertebral fractures. Zoledronic acid also improved total hip and femoral neck BMD relative to placebo in this patient population.

Intravenous zoledronic acid 5 mg once yearly was generally well tolerated in patients with postmenopausal osteoporosis or low-trauma hip fracture in two large clinical trials of up to 5 years’ duration. Both pyrexia and myalgia were consistently reported in more zoledronic acid than placebo recipients within the first 3 days post-infusion, with the incidence of influenza-like symptoms, headache and arthralgia also greater with zoledronic acid than with placebo during this period in the 3-year study; such events generally resolved within 3 days. The drug was also associated with an increased incidence of arrhythmia and serious atrial fibrillation compared with placebo in one study, although these findings were not confirmed by the results of the 5-year trial. Intravenous zoledronic acid 5 mg once yearly was not associated with long-term renal toxicity, and there were no spontaneous reports of osteonecrosis of the jaw in these large randomized trials.

The tolerability profile of intravenous zoledronic acid 5 mg (single dose) was broadly similar to that of oral alendronic acid 70 mg once weekly in patients with postmenopausal osteoporosis or low BMD in a 1-year study, although more zoledronic acid than alendronic acid recipients appeared to experience adverse events (mainly influenza-like symptoms) within the first 3 days of administration.