Focus on Zoledronic Acid

Gopal Garg, S.Saraf and Swarnlata Saraf*
Institute of Pharmacy, Pt. Ravishankar Shukla University
Raipur (C.G.) 492 010, INDIA

Summary

Zoledronate is also known as zometa. It is a treatment for hypercalcemia (high levels of calcium in the blood) caused by tumors. Tumor-induced hypercalcemia is also known as hyper-calcemia of malignancy (HCM). Tumor-induced hypercalcemia may be caused by a tumor spreading to and causing breakdown of bone, or by chemicals released from some tumors. The result is high levels of calcium in the blood. High levels of calcium may cause changes in mental status, constipation, and kidney damage.
Zoledronic acid is being investigated as a treatment for bone metastases. Bone metastases may develop if cells from breast, lung, or other cancers are transplanted to bone by the disease process. Bone metastasis may cause pain, compression of the nerves of the spine, and bone fractures. Other drugs in the same class as zoledronate are used to prevent pain or fractures in people with bone metastases. Zoledronate is being studied for this use as well.

Chemistry

Zoledronic acid is (1-hydroxy-2-imidazole-1-yl-phosphonoethyl) bisphosphonic acid monohydrate. Zoledronic acid is a bisphosphonic acid, a heterocyclic nitrogen-containing bisphosphonate that has an imidazole-ring side chain. The imidazole ring contains two critically positioned nitrogen atoms. Zoledronic acid is a white crystalline powder. Its molecular formula is C5H10N2O7P2• H2O and its molar mass is 290.1g/Mol. Zoledronic acid is highly soluble in 0.1N sodium hydroxide solution, sparingly soluble in water and 0.1N hydrochloric acid, and practically insoluble in organic solvents. The pH of a 0.7% solution of zoledronic acid in water is approximately 2.0.

Zoledronic acid is a highly potent, new-generation, nitrogen-containing bisphosphonate, with unique structure specifically, the presence of a second nitrogen atom may account for its substantially increased in vitro and in vivo potency compared with all other bisphosphonates. Structural changes in the nitrogen-containing side chain of bisphosphonates can affect their potency with respect to inhibition of osteoclast-mediated bone resorption. This is the first evidence that structural changes in bisphosphonates have a direct biochemical effect that is dependent on their ability to inhibit protein prenylation.
Zoledronic acid has superior potency and pharmacological properties compared with other bisphosphonates. Clinical trials have clearly shown its superiority to pamidronate disodium. Zoledronic acid has been shown to be highly effective in the treatment of osteolytic, mixed, and osteoblastic bone metastases/lesions in patients with a broad range of primary malignancies. Zoledronic acid an imidazole derivative that contains a second nitrogen atom in the ring structure, is the most potent intravenous bisphosphonate known to date (Green et al, 1994).

The mechanism of action

Bisphosphonates accumulate in the mineralized bone matrix making it more resistant to dissolution by osteoclasts. Their effects on bone resorption were initially thought to result primarily from this physicochemical effect on the stability of the mineralized bone matrix, but their molecular and cellular effects on osteoclasts have gradually been elucidated.
Bisphosphonates also indirectly inhibit the activity of osteoclasts by modulating signaling from osteoblasts to osteoclasts. Nitrogen-containing bisphosphonates have a unique mechanism of action that is related to their ability to inhibit the mevalonate biosynthetic pathway. (Russell et al, 1999. Luckman et al, 1998. Rogers et al, 1999. Russell et al, 1999. Rogers et al, 2000.)
Unlike their first-generation predecessors, which are metabolized into cytotoxic analogues of adenosine triphosphate, nitrogen-containing bisphosphonates inhibit the activity of farnesyl diphosphonate synthase, a key enzyme in the mevalonate pathway.
The mevalonate pathway is responsible for the biosynthesis of cholesterol, other sterols, and isoprenoid lipids. This latter group of compounds is required for the prenylation of small enzymes (GTPases) that are important intracellular signaling proteins. Prenylation of these enzymes activates them. These enzymes regulate a variety of intracellular processes that are required for osteoclast cell morphology, function, and survival. These processes include response to stimuli such as cytoskeletal arrangement, membrane ruffling, and apoptosis. Nitrogen-containing bisphosphonates inhibit prenylation of GTPases (Luckman et al, 1998. Oliff,1999. Zhange et al, 1996). Which disrupts osteoclast function, has cytostatic effects, and can induce apoptosis of osteoclasts (Benford et al, 1999).
Bisphosphonates have proven to be effective inhibitors of bone resorption, particularly when given intravenously. Nitrogen-containing bisphosphonates are potent inhibitors of bone resorption. They have a unique mechanism of action that is related to inhibition of protein prenylation, resulting in functional inhibition of osteoclasts and apoptosis. Zoledronic acid is a highly potent nitrogen-containing bisphosphonate. Zoledronic acid contains a second nitrogen atom in the imidazole ring and is the most potent bisphosphonate known to date. Zoledronic acid has superior potency and pharmacologic properties compared with other bisphosphonates.
The mechanism of action also includes:

Inhibition of osteoclast maturation (Evans et al, 1994 ).
Inhibition of osteoclast recruitment to the site of bone resorption .
Suppression of mature osteoclast function (Green et al, 1994 ).
Reduced production of cytokines (eg, interleukin [IL1]
Direct antitumor activity (cytostatic and cytolytic) (Aparicio et al, 1998. Fromigue et al, 2000. Senaratne et al, 2000. Jagdev et al, 2000).
Inhibition of tumor-cell dissemination, invasion, and adhesion to the bone matrix (Boissier et al, 2000, Marion et al, 1998 )

Recommended dosage

One preliminary suggestion is that 2-4 milligrams of zoledronic acid may be given by injection. Zoledronate may be given intravenously over a short time (five to fifteen minutes for example). This might represent an advantage over other drugs in the bisphosphonate class. The frequency of administration of zoledronate for hypercalcemia depends on the calcium blood level.

potency

Zoledronic acid has higher potency in preserving bone mass, architecture, and strength than other bisphosponates. In the TPTX rat model, zoledronic acid demonstrated 850-fold greater potency than pamidronate disodium and was the most potent bisphosphonate tested. In the mouse calvaria assay, zoledronic acid was 40 to 100-fold more potent than pamidronate disodium in inhibiting calcium release induced by parathyroid hormone, parathyroid hormone-related protein, and human IL-13. Comparison of various bisphosphonates with respect to their median effective dose for inhibition of vitamin D3 stimulated hypercalcemia in TPTX rats versus their 50% inhibitory concentration (IC 50) values for the inhibition of vitamin D3 stimulated calcium release from mouse calvaria demonstrated a close correlation between the in vitro and in vivo potencies of these drugs, with a correlation coefficient of 0.97 (Green et al, 1994).
Several in vivo experiments have also shown that zoledronic acid preserves bone mass, architecture, and strength in estrogen deficient animals. In ovariectomized rats, weekly subcutaneous injections of 1.5-µ/kg zoledronic acid preserved the density of lumbar vertebrae and maintained mechanical strength at 52 weeks post ovariectomy (Glatt, 2000).
Similarly, long-term treatment with zoledronic acid of ovariectomized adult rhesus monkeys was well tolerated and effectively suppressed increased bone turnover and bone loss in a dose-dependent fashion without adversely affecting bone mineralization (Binkley et al, 1998. Bare et al, 1997. Green et al, 1997).
The synergy
Recent in vitro findings indicate that the combination of zoledronic acid with standard anticancer drugs (paclitaxel, tamoxifen, or dexamethasone) results in a synergistic apoptotic effect greater than that produced by either single agent alone (Jagdev et al, 2000. Tassone et al,2000).

Pharmacokinetics

Metabolism
Zoledronic acid does not inhibit human P450 enzymes in vitro. Zoledronic acid does not undergo biotransformation in vivo. In animal studies, <3% of the administered intravenous dose was found in the feces, with the balance either recovered in the urine or taken up by bone, indicating that the drug is eliminated intact via the kidney.
Excretion
In 64 patients with cancer and bone metastases on average (± s.d.) 39 ± 16% of the administered zoledronic acid dose was recovered in the urine within 24 hours, with only trace amounts of drug found in urine post Day 2. The cumulative percent of drug excreted in the urine over 0-24 hours was independent of dose. The balance of drug not recovered in urine over 0-24 hours, representing drug presumably bound to bone, is slowly released back into the systemic circulation, giving rise to the observed prolonged low plasma concentrations. The 0-24 hour renal clearance of zoledronic acid was 3.7 ± 2.0 L/h.
Zoledronic acid clearance was independent of dose but dependent upon the patient’s creatinine clearance. In a study in patients with cancer and bone metastases, increasing the infusion time of a 4-mg dose of zoledronic acid from 5 minutes (n=5) to 15 minutes (n=7) resulted in a 34% decrease in the zoledronic acid concentration at the end of the infusion.

Pharmacodynamics

Clinical studies in patients with hypercalcemia of malignancy (HCM) showed that single-dose infusions of zoledronic acid are associated with decreases in serum calcium and phosphorus and increases in urinary calcium and phosphorus excretion.
Osteoclastic hyperactivity resulting in excessive bone resorption is the underlying pathophysiologic derangement in hypercalcemia of malignancy (HCM, tumor-induced hypercalcemia) and metastatic bone disease. Excessive release of calcium into the blood as bone is resorbed results in polyuria and gastrointestinal disturbances, with progressive dehydration and decreasing glomerular filtration rate. This, in turn, results in increased renal resorption of calcium, setting up a cycle of worsening systemic hypercalcemia. Reducing excessive bone resorption and maintaining adequate fluid administration are, therefore, essential to the management of hypercalcemia of malignancy.
Patients who have hypercalcemia of malignancy can generally be divided into two groups according to the pathophysiologic mechanism involved: humoral hypercalcemia and hypercalcemia due to tumor invasion of bone. In humoral hypercalcemia, osteoclasts are activated and bone resorption is stimulated by factors such as parathyroid hormone related protein, which are elaborated by the tumor and circulate systemically. Humoral hypercalcemia usually occurs in squamous-cell malignancies of the lung or head and neck or in genitourinary tumors such as renal-cell carcinoma or ovarian cancer. Skeletal metastases may be absent or minimal in these patients.
Extensive invasion of bone by tumor cells can also result in hypercalcemia due to local tumor products that stimulate bone resorption by osteoclasts. Tumors commonly associated with locally mediated hypercalcemia include breast cancer and multiple myeloma.

Dosage and administration of zoledronic acid

The maximum recommended dose of zoledronic acid is 4 mg as a single intravenous infusion administered over no less than 15 minutes. In patients with multiple myeloma and metastatic bone lesions from solid tumors, zoledronic acid should be infused every 3 or 4 weeks. Duration of treatment in the clinical studies was 15 months for prostate cancer, 12 months for breast cancer and multiple myeloma, and 9 months for other solid tumors.
Serum creatinine should be measured before each zoledronic acid dose, and treatment should be withheld for renal deterioration. In clinical studies, renal deterioration was defined as follows
For patients with normal baseline creatinine, increase of 0.5 mg/dL.
For patients with abnormal baseline creatinine, increase of 1.0 mg/dL
In the clinical studies, zoledronic acid treatment was resumed only when serum creatinine
returned to within 10% of the baseline value.

The anti tumor activity

Several in vitro studies have demonstrated that zoledronic acid and some other nitrogen-containing bisphosphonates have dose-dependent effects on the viability of human breast cancer, prostate cancer, and myeloma cell lines
In addition to the direct effects of zoledronic acid on osteoclasts and bone resorption, preclinical studies suggest that zoledronic acid has potent antitumor activity.

Zoledronic acid was the most potent bisphosphonate in this assay, achieving a 50% inhibition of cell viability relative to control cultures at a concentration of 15 µM. In contrast, pamidronate disodium and clodronate demonstrated a 50% inhibition of cell viability at 40 and 700 µM respectively.
Dose-dependent increases in the proportion of apoptotic cells have also been observed when Hs-578t breast cancer cells were incubated with zoledronic acid, with the maximum effect observed at 100 µM. At a concentration of 100 µM, zoledronic acid induced 84% DNA fragmentation compared with 32% for pamidronate disodium.
Various studies have shown that concentrations of zoledronic acid in the range of 100 to 500 µM reduced the viability of human myeloma cells with a concomitant increase in the number of apoptotic cells (Derenne et al, 1999).
Zoledronic acid may also interfere with the metastatic process. Based on results from an in vitro Matrigel-based invasion assay, zoledronic acid appears to inhibit the ability of human prostate and breast cancer cells to invade the extracellular matrix.
Zoledronic acid is superior to pamidronate; 4 mg is the dose recommended for initial treatment of HCM and 8 mg for relapsed or refractory hypercalcemia.
The 52% re treatment response rate observed in patients with relapsed or refractory HCM, although not as impressive as the effect of initial therapy, is still meaningful in this patient population. Diminished responsiveness of HCM to re treatment with bisphosphonates has been suggested by other trials with small numbers of re-treated patients (Thiebaud et al 1990.Nussbaum et al, 1993).

Safety Profile / Adverse effects

The safety profile of zoledronic acid was similar to that of pamidronate disodium. The commonly reported adverse events are not unexpected in patients with advanced cancer, and the frequency of each type of adverse event was generally similar among the zoledronic acid 4-mg, 8-mg, and Pamidronate disodium groups.
Zoledronic acid was well tolerated at all dose levels tested. Commonly reported adverse events included skeletal pain, fever, anorexia, constipation, and nausea, which were experienced by a similar proportion of patients in each treatment group (Berenson et al 2001.Major et al 2001).
The most commonly reported adverse events in zoledronic acid were skeletal pain, fever, arthralgia, and myalgia, which are all associated with an acute-phase reaction (Berenson et al, 2001).
No renal adverse event was considered related to study drug, and the multifactorial nature of renal dysfunction in this patient population makes it difficult to attribute causality. However, as with bisphosphonates in general, monitoring of renal function should be routine practice. No evidence of organ toxicity was observed based on renal and liver function tests, including urinary levels of N-acetyl--glucosaminidase.

Conclusion

In the treatment of hypercalcemia of malignancy for Serum calcium normalization, the complete response rate was significantly higher with zoledronic acid than with pamidronate disodium.
Zoledronic acid was effective regardless of the baseline CSC level, baseline parathyroid hormone-related protein level, blood urea nitrogen/creatinine ratio, or the presence or absence of bone metastases. In contrast, pamidronate disodium was much less effective in patients with humoral HCM.
Zoledronic acid is equally effective regardless of gender, age, tumor type, presence or absence of bone metastases, or serum level of parathyroid hormone-related protein. The superior efficacy and convenience of zoledronic acid, which can be safely infused over 15 minutes, provide the scientific basis for potential use of as the new standard for the first-line zoledronic acid treatment of HCM.
A single Lv. dose of either zoledronic acid (4 or 8 mg) infusion administered over a period of 15 minutes as compared to pamidronate disodium (90 mg), administered over a time of 2-hour infusion.
The potential benefits of the shorter infusion time for zoledronic acid include greater patient convenience and less nurse monitoring time.

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First Published April 2007

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