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The Oncologist, Vol. 7, No. 6, 481–491, December 2002
© 2002 AlphaMed Press

The Use of Zoledronic Acid, a Novel, Highly Potent Bisphosphonate, for the Treatment of Hypercalcemia of Malignancy

Pierre Major

Department of Medicine, McMaster University, Hamilton, Ontario, Canada; Hamilton Regional Cancer Centre, Hamilton, Ontario, Canada

Correspondence: Pierre Major, M.D., Hamilton Regional Cancer Centre, 699 Concession Street, Hamilton, Ontario, Canada L8V 5C2. Telephone: 905-387-9495; Fax: 905-304-7334; e-mail: Pierre.major{at}hrcc.on.ca


   LEARNING OBJECTIVES
Top
 Learning Objectives
Abstract
 Introduction
 Summary
 References
 
After completing this course, the reader will be able to:

  1. Recognize the natural history and clinical presentation of hypercalcemia of malignancy (HCM).
  2. Compare the relative efficacy of available bisphosphonates in the treatment of HCM.
  3. Examine the efficacy and safety of zoledronic acid, a new-generation bisphosphonate.

Access and take the CME test online and receive one hour of AMA PRA category 1 credit at CME.TheOncologist.com


   ABSTRACT
Top
 Learning Objectives
 Abstract
Introduction
 Summary
 References
 
Background. Hypercalcemia of malignancy is a serious complication of cancer that affects patients with and without bone metastases. A single infusion of pamidronate disodium, a nitrogen-containing bisphosphonate, effectively normalizes serum calcium in the majority of patients treated for up to 1 month. Zoledronic acid is a new-generation, heterocyclic nitrogen-containing bisphosphonate and the most potent inhibitor of bone resorption identified to date.

Methods. The natural history, clinical presentation, and treatment of hypercalcemia of malignancy are reviewed, with a focus on the mechanisms of action and relative efficacy and safety of bisphosphonate therapies.

Results. The improved efficacy of zoledronic acid compared with pamidronate disodium has been demonstrated in a pooled analysis of two randomized clinical trials in patients with hypercalcemia of malignancy. In these trials, both zoledronic acid and pamidronate disodium were safe and well tolerated; however, zoledronic acid treatment resulted in a significantly higher number of complete responses, more rapid calcium normalization, and more durable responses compared with pamidronate disodium.

Conclusions. Given the superior efficacy and comparable safety profile of zoledronic acid compared with pamidronate disodium, zoledronic acid is likely to become the treatment of choice for hypercalcemia of malignancy.

Key Words. Bisphosphonate • Bone metastases • Hypercalcemia of malignancy • Pamidronate disodium • Zoledronic acid


   INTRODUCTION
Top
 Learning Objectives
 Abstract
 Introduction
Summary
 References
 
Hypercalcemia of Malignancy
Hypercalcemia of malignancy (HCM) is a serious skeletal complication of malignancy that affects approximately 10%-20% of all cancer patients at some point during the course of their disease and 20%-40% of patients with advanced disease [1–4]. Hypercalcemia of malignancy can occur in patients with or without bone metastases and is classified as either osteolytic (HCM with bone metastases) or humoral (HCM without skeletal involvement) [5]. Humoral HCM occurs most often in patients with squamous-cell malignancies of the lung or of the head and neck and in patients with renal cell carcinoma [6]. Among patients with skeletal involvement, HCM is most common in patients with multiple myeloma, affecting 30% to greater than 80% of these patients [7, 8]. Similarly, a high proportion (30%-65%) of patients with metastatic breast cancer develop HCM during the course of their disease compared with less than 15% of patients with lung cancer [1, 2, 9]. Hypercalcemia of malignancy is rare in patients with prostate cancer. The extent of metastatic bone disease correlates poorly with both the occurrence and severity of HCM [10].

Tumor cells induce HCM by stimulating osteoclast activity, resulting in excessive bone resorption and release of calcium into circulation. Tumor cells produce several soluble factors, including parathyroid hormone-related protein (PTHrP), prostaglandins, and cathepsins, which can either directly or indirectly stimulate osteoclasts to degrade bone (Fig. 1Go) [9, 11]. Osteoprotegerin ligand (OPGL, also known as TRANCE and RANKL), secreted by either tumor cells, stromal cells, or activated immune cells, can also stimulate osteoclast activity [13–15].



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  		Figure 1. Diagram of the molecular interactions between osteoclasts and tumor cells. TGF = transforming growth factor; TNF = tumor necrosis factor; EGF = epidermal growth factor; PGs = prostaglandins; OIF = osteoclast inhibitory factor; OAF = osteoclast activating factor [12].

 
In humoral HCM, osteoclasts are stimulated by circulating tumor products including PTHrP, interleukin-1 (IL-1), IL-6, OPGL, and macrophage inflammatory protein-1-alpha [11]. These circulating soluble factors can affect the entire skeleton through their effects on osteoclasts. In addition, PTHrP stimulates increased renal tubular calcium reabsorption, resulting in further increases in serum calcium levels, and induces osteoclast formation through upregulation of OPGL. Approximately 25% of patients with HCM will have elevated PTHrP levels (>2 pmol/l), although patients with humoral HCM are more likely to have high circulating PTHrP levels than patients who have osteolytic HCM [6, 11, 16, 17].

HCM usually develops late in the natural history of the disease. Patients with HCM typically have advanced disease, are more likely to have distant metastases and renal failure, and generally have a poor prognosis [2, 6]. Patients who develop HCM generally have a short life expectancy, ranging from weeks to months, and management of HCM is a difficult clinical challenge.

Clinical Presentation of HCM
Excessive release of calcium into the blood as a consequence of bone resorption results in polyuria and gastrointestinal disturbances, with progressive dehydration and a decreased glomerular filtration rate [3, 6]. This results in increased renal resorption of calcium, setting up a cycle of worsening systemic hypercalcemia. Patients with HCM may present with a wide range of symptoms (Table 1Go) [12], but the development and severity of symptoms do not appear to be strictly correlated with serum calcium levels. The early symptoms of HCM are mild and can be difficult to distinguish from those of the underlying disease or the side effects of cancer therapy, especially if the rise in serum calcium levels occurs rapidly in the range of 2.7 to 3.0 mg/l. Recognition of the early symptoms of HCM is vital because, if left untreated, it can progress rapidly and may become severe or life threatening. Progression of HCM can be prevented with appropriate measures, including hydration, anticancer therapy, and treatment with bisphosphonates.


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  		Table 1. Symptoms and CSC levels in HCM
 
Treatment of HCM
Management of HCM involves effective anticancer therapy to reduce the production of humoral factors, particularly PTHrP, that can stimulate bone resorption and renal tubular calcium reabsorption. Recent improvements in anticancer therapy have reduced the incidence of HCM, and patients now typically develop HCM only in the late stages of advanced metastatic disease. Adequate hydration is key in the management of HCM to restore the 2- to 3-liter negative fluid balance and facilitate renal excretion of excess serum calcium. Hydration in conjunction with loop diuretics requires careful monitoring of fluid balance. In addition, an intervention to inhibit bone resorption can eliminate the primary source of excess serum calcium. A wide variety of agents have been used to reduce bone resorption, including phosphate, mithramycin, calcitonin, gallium nitrate, and bisphosphonates [18]. Administration of an i.v. bisphosphonate, coupled with adequate hydration, effectively normalizes serum calcium in the majority of cancer patients. However, patients with high serum calcium and PTHrP levels are more difficult to treat. In particular, high PTHrP levels are correlated with a poor response to most of the currently available bisphosphonates [6, 16].

Bisphosphonates
Bisphosphonate compounds can be divided into two distinct pharmacologic classes with different mechanisms of action depending on whether they contain a nitrogen atom(s) in their side chains [19, 20] (Table 2Go). Non-nitrogen-containing bisphosphonates, including etidronate, clodronate, and tiludronate, are metabolized intracellularly to cytotoxic, nonhydrolyzable analogues of ATP. Nitrogen-containing bisphosphonates, including alendronate, ibandronate, pamidronate disodium, risedronate, and zoledronic acid, inhibit protein prenylation [21] and are more potent inhibitors of osteoclast-mediated bone resorption. Zoledronic acid is a new-generation, heterocyclic nitrogen-containing bisphosphonate and the most potent inhibitor of bone resorption identified to date.


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  		Table 2. Bisphosphonates
 
Bisphosphonates have proven to be effective inhibitors of bone resorption, particularly when administered i.v. [16], and the impact of various bisphosphonates on the inhibition of this process can be monitored by measuring several specific markers of bone resorption [22–26]. These specific markers include several unique breakdown products of type I collagen, including the pyridinium cross-links, pyridinoline and deoxypyridinoline, and the peptide-bound cross-links, N-telopeptide and C-telopeptide [22–26]. The effects of bisphosphonates on bone resorption were initially thought to result primarily from the physicochemical effect on the structure of hydroxyapatite crystals, but their molecular and cellular effects on osteoclasts have gradually been elucidated. Bisphosphonates are absorbed by bone due to their affinity for hydroxyapatite; they are released subsequently during the process of bone resorption and are then internalized by osteoclasts and inhibit the formation and osteolytic activity of osteoclasts. Once absorbed, bisphosphonates reduce osteoclast survival.

Nitrogen-containing bisphosphonates have a unique mechanism of action that is related to their ability to inhibit the mevalonate biosynthetic pathway [20, 21, 27,28]. The mevalonate pathway is responsible for biosynthesis of cholesterol, other sterols, and isoprenoid lipids. This latter group of compounds is required for the modification (prenylation) of small enzymes, guanosine triphosphatases (GTPases), that are critically important intracellular signaling proteins. Prenylation of GTPases (e.g., Ras and Rho) is necessary for them to regulate a variety of intracellular processes that are required for osteoclast cell morphology, function, and survival [28]. For example, responses to PTHrP, cytoskeletal arrangement, membrane ruffling, and apoptosis are all regulated by prenylated GTPases. Nitrogen-containing bisphosphonates inhibit prenylation of GTPases (primarily farnesylation of Ras) [21, 29–31], which disrupts osteoclast function, has cytostatic effects, and can induce apoptosis of osteoclasts [32]. Structural changes in the nitrogen-containing side chain of bisphosphonates can affect their potency with respect to inhibition of osteoclast-mediated bone resorption.

First-Generation Bisphosphonate Treatment for HCM
First-generation bisphosphonates (e.g., etidronate and clodronate), introduced almost 3 decades ago, are relatively weak inhibitors of bone resorption.

Clodronate Oral clodronate (1,600 to 3,200 mg) and i.v. etidronate (5 to 10 mg/kg/day) are non-nitrogen-containing bisphosphonates that have been used to treat HCM [33–36]. In a randomized trial in patients with multiple myeloma, clodronate decreased the proportion of patients experiencing severe HCM by 50%, although the difference between the clodronate group and the placebo group was not statistically significant (p = 0.06) [33]. Statistically significant reductions in hypercalcemic episodes were documented in patients with breast cancer treated with clodronate (1,600 mg/day, p <0.01) [34]. However, oral bisphosphonates have limited efficacy in the treatment of HCM compared with i.v. bisphosphonates, [37, 38] and their use is limited by poor bioavailability (<5%), necessitating administration of high doses, which are associated with gastrointestinal toxicity (primarily esophagitis) [37, 39]. Therefore, intravenous clodronate has also been studied at doses ranging from 300 mg/day for up to 7 days to a single 1,500-mg infusion over 4 hours and has been shown to normalize serum calcium in approximately 80% of patients (based on experience in approximately 200 patients) [40, 41]. A single infusion of 1,500 mg was shown to normalize serum calcium more rapidly than the approved regimen (300 mg/day x 5 days) [41]. However, the 1,500 mg clodronate i.v. dose was associated with increased serum creatinine in 5 of 21 (24%) patients in a comparative study with pamidronate [42]. Furthermore, i.v. clodronate was found to be less effective than pamidronate.

Etidronate Etidronate, administered as a single 24-hour infusion (30 mg/kg) [35] or administered on 7 consecutive days (4.3 mg/kg/day) [36], has been demonstrated to reduce serum calcium levels after a mean of approximately 4 days [35]. Oral etidronate has also proven useful in some patients to maintain normocalcemia following i.v. treatment. Synergistic effects have been demonstrated after coadministration of 7.5 mg/kg etidronate with 100 IU subcutaneous calcitonin [43]. However, in comparative trials with gallium nitrate or pamidronate, etidronate was significantly less effective in reducing serum calcium levels than these later-generation treatments [44, 45].

As a class, bisphosphonates are well tolerated; however, rapid i.v. infusion of etidronate and clodronate to patients with HCM has been associated with renal failure [46]. Therefore, these bisphosphonates must be administered by slow i.v. infusion along with saline to avoid toxic renal effects, making outpatient treatment inconvenient.

Nitrogen-Containing Bisphosphonate

Alendronate and Ibandronate for the Treatment of HCM Both alendronate and ibandronate have been studied in phase II trials in patients with HCM. Alendronate (7.5 mg administered i.v.) was significantly more effective than 600 mg clodronate in controlling HCM, although neither treatment group achieved normocalcemia [47]. In contrast, a study by Nussbaum et al. [48] found that 2.5 to 15 mg alendronate did normalize corrected serum calcium (CSC) levels in a majority of 59 patients, with no dose-response effect above 5 mg. Neither study revealed significant side effects, suggesting that alendronate is well tolerated.

Ibandronate, a newer nitrogen-containing bisphosphonate, was similarly effective in two large phase II trials [49, 50], significantly lowering serum calcium levels in up to 77% of patients after 5 days. Normocalcemia was maintained for up to 36 days following treatment. Doses >=2 mg were comparable in efficacy with pamidronate and clodronate, and serious adverse events were minimal (three reports from 174 patients), consisting of fever, nausea, and thrombocytopenia [50].

Pamidronate Disodium for the Treatment of HCM Pamidronate disodium (60 to 90 mg) is an i.v. nitrogen-containing bisphosphonate that is currently used to restore and maintain normocalcemia in patients with HCM. In the initial clinical trials performed in groups of 20 to 65 patients, a single infusion of pamidronate disodium normalized calcium for an average of 1 month [51–53]. In a group of 10 patients with a mean (± standard error) plasma calcium concentration of 3.24 ± 0.14 mmol/l, a single 24-hour i.v. infusion of pamidronate disodium (60 mg) reduced calcium levels to 2.24 ± 0.06 mmol/l, (p <0.001, Fig. 2Go) [52]. All patients achieved normocalcemia lasting for >=14 days [52]. In a subsequent dose-response study, researchers determined that the patient’s initial plasma calcium concentration defined the optimal dose of bisphosphonate required to achieve normocalcemia. Body and Dumon [54] determined that doses of 0.5 to 1.5 mg/kg pamidronate were effective in normalizing CSC levels in 80%-94% of 160 patients. The authors suggested that 1.5 mg/kg pamidronate is the preferred dose for treatment of HCM, except in cases of mild HCM, in which 1 mg/kg appeared sufficient. A confirmatory dose-finding study concluded that a single 60-mg dose or 90-mg dose of pamidronate disodium was highly effective [55].



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  		Figure 2. Plasma calcium concentration (mean ± standard error) in patients treated with a single dose of (A) 30 mg, (B) 45 mg, (C) 60 mg, or (D) 90 mg pamidronate disodium. The open bar indicates the time of pamidronate disodium infusion. The shaded area highlights the normal plasma calcium concentration range. Serum calcium levels were corrected for albumin. Adapted with permission [52].

 
Comparative studies in patients with HCM suggest that pamidronate disodium is superior to etidronate [53] and clodronate [42]. In the clodronate study, the median duration of normocalcemia following pamidronate treatment was twice as long as the duration achieved for clodronate (28 days versus 14 days, respectively; p < 0.01). The superiority of pamidronate over clodronate for the treatment of HCM was confirmed in a second study by Vinholes et al. [56] in which 90 mg pamidronate or 1,500 mg clodronate administered i.v. over 4 hours restored normocalcemia with a median time of 3 to 4 days. However, the duration of response was significantly greater for patients receiving pamidronate compared with patients receiving clodronate. Patients administered clodronate began to experience a relapse in CSC levels after day 4, becoming statistically higher than the pamidronate group after day 10.

Other studies confirmed that a 2-hour infusion time was as safe and effective as the 24-hour infusion, thereby making pamidronate disodium somewhat more convenient than clodronate and etidronate for the treatment of HCM [57]. In all of these studies, pamidronate disodium was well tolerated; some patients reported a self-limiting, influenza-like syndrome, usually after the first pamidronate disodium infusion, and most patients’ general health improved as the symptoms of HCM were relieved.

Zoledronic Acid for the Treatment of HCM Zoledronic acid is a highly potent, new-generation, nitrogen-containing bisphosphonate [58] that was approved by the U.S. Food and Drug Administration (http://www.fda.gov) for the treatment of HCM in 2001 and for the treatment of bone metastases in February 2002. Zoledronic acid has been extensively investigated in cancer patients with HCM and has demonstrated superior efficacy compared with pamidronate disodium [16]. The clinical potency of zoledronic acid was demonstrated in early HCM clinical trials; doses as low as 1 mg effectively normalized CSC levels [59, 60]. Therefore, an open-label, dose-finding study was conducted in 33 hypercalcemic cancer patients to determine a tolerable dose of zoledronic acid that would normalize calcium levels in at least 80% of patients with HCM (>=2.75 mmol/l) [59]. Doses as low as 0.02 mg/kg normalized CSC levels and calcium/creatinine ratios in the majority of patients within 2 to 3 days, and the duration of normocalcemia in the 0.04-mg/kg group exceeded 21 days (Fig. 3Go) [59]. The most common adverse events were transient fever and hypophosphatemia, adverse events that are typically associated with bisphosphonate therapy. Therefore, low-dose zoledronic acid was safe, well tolerated, and effectively normalized serum calcium levels.



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  		Figure 3. Effects of i.v. zoledronic acid after saline rehydration on serum calcium levels in 20 patients with HCM. Open circles (n = 5) represent treatment with 0.02 mg/kg zoledronic acid and filled squares (n = 15) represent treatment with 0.04 mg/kg zoledronic acid. The gray bar indicates the normal plasma concentration range. Serum calcium levels were corrected for albumin. Adapted with permission [59].

 

Pivotal Trials The superior efficacy of zoledronic acid (4 or 8 mg) compared with pamidronate disodium (90 mg) was recently established in a pooled analysis of two large, randomized, phase III trials in patients with moderate to severe HCM [16]. These are the largest comparative trials of bisphosphonate therapy ever conducted in patients with HCM. Patients with HCM received a single i.v. dose of either zoledronic acid (4 or 8 mg), administered via a 5-minute infusion, or pamidronate disodium (90 mg), administered via a 2-hour infusion. The doses of zoledronic acid (4 and 8 mg) for the comparative trials were chosen based on effective suppression of markers of bone resorption established in phase I and phase II trials in patients with bone metastases [60, 61]. Patients who relapsed or were refractory to initial treatment with either zoledronic acid or pamidronate disodium were eligible for retreatment with 8 mg zoledronic acid in the second phase of the trial. Patients were followed for 56 days or until their CSC levels were >=2.9 mmol/l. Complete response (CR) was defined as a CSC level <2.7 mmol/l by day 10.

A total of 287 patients were randomized in these two trials: 138 patients in the U.S./Canadian trials and 149 in the European/Australian trials. Demographic and baseline clinical characteristics were similar among the three treatment groups. Overall, 59% of patients were male, with a mean age of 59 years and a mean baseline CSC level of 3.47 mmol/l [16]. The CR rate was significantly higher for zoledronic-acid-treated patients (88.4% for 4 mg and 86.7% for 8 mg) than for pamidronate disodium-treated patients (69.7%, Fig. 4Go) [16]. Furthermore, patients treated with zoledronic acid had a more rapid normalization of CSC levels than those in the pamidronate disodium group (Fig. 5Go) [16]. Mean CSC levels at days 4, 7, and 10 were significantly lower (p <= 0.05) in patients treated with 4 or 8 mg zoledronic acid than in pamidronate disodium-treated patients [16]. Finally, the median time to relapse (Table 3Go) [16], median duration of CR, median duration of response, and time to relapse (Fig. 6Go) [16] were all longer in the zoledronic acid groups than in the pamidronate disodium group. Although the 8-mg dose of zoledronic acid normalized calcium by day 4 in a slightly greater proportion of patients and was associated with a longer duration of response and time to relapse, the 4-mg dose was nearly as effective, and the differences between the two doses were not statistically significant. Because the patient population studied had high mean baseline CSC levels and many patients in clinical practice may have less severe hypercalcemia, the 4-mg dose is recommended for initial therapy in most patients.



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  		Figure 4. Proportion of patients achieving a complete response by treatment group. Adapted with permission [16].

 


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  		Figure 5. Mean CSC levels at baseline and days 4, 7, and 10 for patients treated with zoledronic acid, 4 mg (filled circles) or 8 mg (filled squares), or pamidronate disodium, 90 mg (filled triangles). Per-protocol entrance criteria (mean CSC >=3.0 mmol/l [12.0 mg/dl], solid line) and normalization value (mean CSC <=2.7 mmol/l [10.8 mg/dl], dashed line) are indicated. Adapted with permission [16].

 

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  		Table 3. Time to relapse and duration of complete response
 


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  		Figure 6. Kaplan-Meier estimates of time to hypercalcemia of malignancy relapse in combined analysis of Protocols 036 and 037. Zol = zoledronic acid; Pam = pamidronate disodium. Adapted with permission [16].

 
Patients who relapsed or were refractory to zoledronic acid or pamidronate were retreated with 8 mg zoledronic acid. Sixty-nine patients were evaluable after retreatment with 8 mg zoledronic acid, and 36 (52%) patients achieved a CR by day 10. Following retreatment with 8 mg zoledronic acid, mean CSC values decreased from 3.17 mmol/l to 2.71 mmol/l at day 10. Median duration of CR was 10.5 days, median duration of response was 15 days, and median time to relapse was 8 days. Although the 52% retreatment response rate observed in this study by Major et al. [16] was not as impressive as the effect of initial therapy, this response rate is meaningful in this patient population. In studies with other bisphosphonates, relapsing patients have often exhibited diminished serum calcium responsiveness to bisphosphonate therapy [48, 62].

Zoledronic acid was equally effective regardless of gender, age, tumor type, presence or absence of bone metastases, or serum level of PTHrP. In contrast, pamidronate disodium was less effective in patients with humoral HCM (61% CR rate) than in patients with osteolytic HCM (80% CR rate) [16]. It has been previously reported that high levels of PTHrP are correlated with a poor response to pamidronate disodium [6]. The response rate to pamidronate disodium (90 mg) in these trials was 69.7%, lower than the response rates observed in previous trials [16]. In the earlier trials, pamidronate disodium (90 mg) normalized CSC levels in most patients (up to 100%) [42, 55, 63]. Changes in cancer treatment regimens and the restrictions on patient selection since the early trials and differences in study design may have contributed to this difference. The previous studies with pamidronate disodium involved smaller numbers of patients, and the mean baseline CSC levels of the patients were lower (3.17 to 3.33 mmol/l) than those evaluated in the pivotal zoledronic acid trials (3.42 to 3.49 mmol/l) [16]. The small sample size and the lower elevation of serum calcium may have accounted for the higher responses to pamidronate disodium observed in the early trials. In a heterogeneous patient population, such as patients with HCM, a large sample size is required due to high interpatient variability. In the earlier studies, patients also underwent a 48-hour hydration period prior to bisphosphonate treatment. Finally, it is unlikely that the shorter 2-hour infusion time for pamidronate disodium in the zoledronic acid trials played a significant role in the efficacy difference. Previous studies that directly compared different bisphosphonate infusion times in HCM demonstrated that the efficacy of pamidronate disodium and alendronate is independent of infusion duration [48, 64]. Therefore, the large patient population evaluated in the pivotal zoledronic acid trials provided the basis for concluding that zoledronic acid is superior to pamidronate disodium for the treatment of HCM.

In phase III trials, zoledronic acid was safe and well tolerated at both the 4-mg and 8-mg doses. The most common adverse events were fever, anemia, nausea, constipation, and dyspnea, and there were no statistically significant differences among treatment groups (Table 4Go) [16]. Adverse events suspected to be drug related included fever, hypophosphatemia, and hypocalcemia, which are known to occur with bisphosphonate therapy, and were similar in nature and frequency among all three treatment groups. No renal adverse event was suspected to be study drug related. Although there was a higher incidence of abnormal renal function, uremia, and urinary retention in the zoledronic acid groups, when the laboratory findings for serum creatinine were examined, there were no differences in the frequencies of grade 3 or 4 clinical toxicity criteria findings among the three primary treatment or retreatment groups.


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  		Table 4. Frequency of adverse events reported by >20% of patients in any group
 
Whereas some bisphosphonates have been associated with impairment of renal function in humans [40, 65], zoledronic acid has exhibited a mild renal toxicity profile [66]. However, in zoledronic acid clinical trials in patients with skeletal metastases, some increases in serum creatinine, comparable with those noted with a 2-hour infusion of pamidronate disodium (90 mg), were seen in patients receiving a 5-minute infusion after repeated administrations [67]. Therefore, the recommended infusion rate for zoledronic acid was increased from 5 to 15 minutes to reduce the potential for impairment of renal function in patients who require repeated or chronic drug administration. After extension of the infusion rate, observed increases in serum creatinine levels were similar to placebo in patients with metastatic bone disease [68].


   SUMMARY
Top
 Learning Objectives
 Abstract
 Introduction
 Summary
References
 
Preclinical and clinical studies have demonstrated that zoledronic acid is a potent inhibitor of bone resorption and has a favorable tolerability profile [58, 59, 66, 69]. The available clinical data have demonstrated that zoledronic acid is safe and highly effective in normalizing serum calcium. The pivotal trials in patients with moderate to severe HCM demonstrated statistically significant superiority of zoledronic acid over pamidronate disodium with respect to the proportion of patients who achieved a CR (i.e., normalization of CSC level <10.8 mg/dl) by day 10 and with respect to the duration of calcium normalization. Incidences of adverse events were similar between zoledronic acid and pamidronate. The superior efficacy and convenience of zoledronic acid, which can be safely infused over 15 minutes, suggest that zoledronic acid will be the first-line therapy of choice for the treatment of HCM.


   REFERENCES
Top
 Learning Objectives
 Abstract
 Introduction
 Summary
 References
 

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Received May 15, 2002; accepted for publication September 3, 2002.




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