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1 The Oncologist Symptom Management and Supportive Care High Incidence of Hypocalcemia and Serum Creatinine Increase in Patients with Bone Metastases Treated with Zoledronic Acid MONICA ZURADELLI, a GIOVANNA MASCI, a GIUSEPPE BIANCOFIORE, a GIUSEPPE GULLO, a MARTA SCORSETTI, b PIERINA NAVARRIA, b FLAVIO TANCIONI, c MARCO BERLUSCONI, d LAURA GIORDANO, e ARMANDO SANTORO a a Department of Medical Oncology and Hematology, b Radiotherapy Unit, c Neurosurgery Unit, d Trauma Unit, and e Statistics Unit, Istituto Clinico Humanitas, Rozzano, Milan, Italy Key Words. Bisphosphonates Laboratory abnormalities Bone metastasis Zoledronic acid Disclosure: Monica Zuradelli: None; Giovanna Masci: None; Giuseppe Biancofiore: None; Giuseppe Gullo: None; Marta Scorsetti: None; Pierina Navarria: None; Flavio Tancioni: None; Marco Berlusconi: None; Laura Giordano: None; Armando Santoro: None. The content of this article has been reviewed by independent peer reviewers to ensure that it is balanced, objective, and free from commercial bias. No financial relationships relevant to the content of this article have been disclosed by the authors or independent peer reviewers. ABSTRACT Background. Zoledronic acid belongs to the new generation of bisphosphonates with demonstrated clinical benefit for the treatment of bone metastases from different kinds of neoplasms. Hypocalcemia and serum creatinine elevation are expected adverse events during this therapy. The monitoring of serum calcium and creatinine is therefore recommended. The primary aim of this study was to establish the actual incidence of hypocalcemia and serum creatinine elevation during treatment with zoledronic acid. Skeletal-related events and side effects were also assessed. Methods. Serum creatinine and calcium levels were evaluated in 240 consecutive patients (83 males, 157 females; mean age, 62 years) with metastatic bone lesions from different solid tumors treated with zoledronic acid. Results. Overall, 93 of 240 patients (38.8%) developed hypocalcemia, which was grade (G)1 in 45 patients (48.4%), G2 in 37 patients (39.8%), G3 in 10 patients (10.8%), and G4 in one patient (1.1%). The median time to occurrence of hypocalcemia (any grade) was 2.3 months after the beginning of the treatment (range, months). Increased serum creatinine was observed in 33 of 240 patients (13.7%), of whom 19 had G1 (57.6%), 11 had G2 (33.3%), and three had G3 (9.1%). The median time to serum creatinine increase (for any grade) was 4.7 months (range, months). Conclusions. Our analysis shows a high incidence of hypocalcemia and increased serum creatinine level during treatment with zoledronic acid. These results strongly support the need for accurate monitoring of plasma calcium and creatinine levels. The Oncologist 2009;14: Correspondence: Monica Zuradelli, M.D., Dipartimento di Oncologia Medica ed Ematologia, Istituto Clinico Humanitas, Via Manzoni 56, Rozzano (Milano), Italy. Telephone: ; Fax: ; monica.zuradelli@ humanitas.it Received October 15, 2008; accepted for publication April 8, AlphaMed Press /2009/$30.00/0 doi: /theoncologist The Oncologist 2009;14:

2 2 Toxicity Profile of Zoledronic Acid Therapy INTRODUCTION Bone is the predominant site of breast and prostate cancer metastases, which occur in 65% 70% of patients with metastatic breast cancer and in 80% of men with advanced prostate cancer. Moreover, approximately 40% of patients with advanced lung cancer develop skeletal metastases. After detection of bone lesions, the median survival duration for patients with prostate cancer is 3 years, whereas for patients with breast cancer it is approximately months. These patients are at risk for developing complications; therefore, early detection and aggressive management of skeletal metastases are critical to maintaining a patient s quality of life and functional levels. Bisphosphonates, such as pamidronate and zoledronic acid, inhibit osteoclastic absorption of bone; therefore, they are used to reduce skeletal complications and to relieve bone pain. Of all the bisphosphonates available for the treatment of bone metastases, zoledronic acid is preferred because of the short infusion time (15 minutes). Furthermore, there is evidence from a large randomized trial on bone metastases from breast cancer and multiple myeloma that this drug (4 mg i.v.) is more effective than pamidronate in reducing the risk for skeletal complications both in the general population and in breast cancer patients [1 4]. Recently, bisphosphonates have increasingly been used as anticancer treatments, for osteoporosis therapy, and to prevent adverse effects on bone from aromatase inhibitors in the adjuvant treatment of breast cancer patients [5, 6]. Because of their spreading and prolonged use, it seems to be more and more necessary to give greater attention to their toxicity profile. Zoledronic acid is generally well tolerated and induces just mild transient side effects, such as flu-like symptoms (fever, bone pain, arthralgia, nausea and vomiting), following the initial infusion. Over the last years, concerns of bisphosphonate-induced osteonecrosis of the jaw have emerged. Furthermore, all bisphosphonates are known to be associated with laboratory abnormalities, particularly, elevated serum creatinine levels and hypocalcemia. Sporadic episodes of acute and subacute renal failure have been reported [7 13], whereas hypocalcemia has not yet been the subject of detailed research. The primary endpoint of our analysis was to assess the actual incidence of hypocalcemia and increased serum creatinine during long-term treatment with zoledronic acid in patients with different kinds of metastatic neoplasms. Secondary endpoints were assessments of other side effects and skeletal-related events (SREs). MATERIALS AND METHODS All consecutive patients with radiologically documented bone metastases from solid cancers treated with zoledronic acid at our institute from January 2002 to November 2006 were retrospectively analyzed. Bone metastases were generally diagnosed by bone scintigraphy and x-rays and were later investigated by magnetic resonance imaging (MRI) or computed tomography (CT), especially if the spine was involved. All patients with radiologically documented bone metastases from solid tumors were managed by a multidisciplinary team including medical oncologists, radiotherapists, orthopedic surgeons, neurosurgeons, and radiologists. All patients were evaluated very carefully, in order to prevent impending fractures or spinal cord compression. Based on the bone treatment program developed by the medical team, patients were eligible for treatment with bisphosphonates. All patients with bone metastases received zoledronic acid, except for those showing a single irradiated bone lesion or few osteoblastic lesions. During zoledronic acid therapy, patients were also treated with chemotherapy, biological, immunological, or hormonal therapy, and other supportive drugs at the treating physician s discretion. Bone metastases underwent periodic radiological examination to monitor the evolution of the disease and its response to treatment and to decide on further interventions, such as radiation or surgery, if required. Zoledronic Acid Treatment Four milligrams of zoledronic acid (Zometa ; Novartis Pharma AG, Basel, Switzerland/Novartis Pharmaceuticals Corporation, East Hanover NJ) was administered in 100 ml of 0.9% sodium chloride as a 15-minute i.v. infusion every 4 weeks. All patients were prescribed oral calcium and vitamin D supplements [Cacit (Procter and Gamble, Rome, Italy) vitamin D3 or Calcium Sandoz (Sandoz, Origgio, Varese, Italy) tablet, 500 mg/day, plus Diseon (Teva Pharma Italia, Milan, Italy) tablet 1 g/day] daily, throughout treatment. If evidence of grade (G)2 or G3 hypocalcemia was found at the time of zoledronic acid administration, i.v. calcium gluconate (1 g/10 ml) was given as well. For G1 hypocalcemia, administration of i.v. calcium gluconate was at the treating physician s discretion. According to the guidelines of the American Society of Clinical Oncology (ASCO), zoledronic acid was given until a substantial decline in the patient s performance status was observed [14]. Zoledronic acid was withheld if patients had G2 G3 creatinine and calcium abnormalities and was resumed when levels returned to normal or within the G1

3 Zuradelli, Masci, Biancofiore et al. 3 range. Treatment was stopped in cases of persistent G2 electrolyte abnormalities, gradual worsening of these parameters, or whenever any adverse event occurred that the treating physician deemed significant. Definition of Side Effects Serum calcium and creatinine levels were monitored before each dose of zoledronic acid. Abnormal calcium and creatinine serum levels were assessed according to the National Cancer Institute (NCI) Common Toxicity Criteria, Version 3.0. Normal serum calcium is in the range of mmol/l. Hypocalcemia was defined as G1 when serum calcium levels were mmol/l, G2 when they were mmol/l, G3 when they were mmol/l, and G4 when they were 1.5 mmol/l. The creatinine normal range is mg/dl. Increased serum creatinine was classified as follows based on the NCI Common Toxicity Criteria, Version 3.0: G1 when the creatinine level was 1.5 the upper limit of normal (ULN), G2 when the creatinine level was ULN, G3 when the creatinine level was ULN, and G4 when the creatinine level was 6.0 ULN. SREs were assessed during zoledronic acid therapy and included pathological fractures, malignancy-associated hypercalcemia, spinal cord compression, bone surgery, or radiotherapy. We considered as SREs any of the above events occurring during zoledronic acid therapy. Statistical Analysis Medical oncologists entered data into a Microsoft Access database. They included patient age at the start of zoledronic acid treatment, type of tumor, nature of skeletal lesions (purely osteolytic, purely osteoblastic, or mixed), number of skeletal sites involved (defined as disseminated bone disease, more than three skeletal sites involved, and one to three sites involved), specific antineoplastic therapy at the beginning of zoledronic acid treatment and related changes, any bone events (fractures, radiation, surgery), the electrolyte value at each zoledronic acid administration, and any side effects. Data were described as number and percentage or median and range. The Pearson 2 test was used to compare categorical data; a p-value.05 was regarded as significant. Analyses were performed with Stata 9.0 ( RESULTS Two hundred forty consecutive patients treated with zoledronic acid were evaluated. Table 1 shows the baseline disease characteristics of the study population. The median age at the start of treatment was 62 years (range, years); the group included 157 females (65.4%) and 83 Table 1. Patient characteristics Characteristic n (%)/median (range) Total 240 (100) Gender Male 83 (34.6) Female 157 (65.4) Age, years 62 (29 88) Primary cancer Breast 122 (50.9) Lung 59 (24.6) Prostate 14 (5.9) Colon/rectum 13 (4.1) Kidney 7 (2.9) Sarcoma 8 (2.9) Others 17 (8.7) Treatment reason Bone lesions 235 (98.0) Osteolytic 120 (50.0) Osteoblastic 7 (3.0) Mixed 68 (29.1) Unknown 40 (17.1) Hypercalcemia 5 (2.0) n of lesions a (28.3) 3 41 (17.1) Diffuse 126 (52.5) a The sum is not equal to the total because of missing values. males (34.6%). Regarding the type of tumor, the group comprised 122 primary breast cancer patients (50.9%), 59 primary lung cancer patients (24.6%), and 14 primary prostate cancer patients (5.9%). The remaining 45 patients (18.7%) had primitive tumors at other sites. The type of skeletal lesion was specified in 195 patients (81.2%). It was osteolytic in 120 (50.0%), mixed in 68 (29.1%), and osteoblastic in seven (3.0%) patients. Finally, despite negative baseline radiological examinations, the bone scan detected multiple painful lesions in 15 cases (6.5%). One hundred twenty-six patients (52.5%) evidenced disseminated bone lesions; in 41 cases (17.1%) the disease involved more than three sites, and 68 patients (28.3%) had one to three sites involved. Five patients (2.0%) had no evidence of bone lesions but were treated with a bisphosphonate because of hypercalcemia. Forty-one patients (17.1%) had received previous pamidronate and had then switched to zoledronic acid. The duration of treatment with

4 4 Toxicity Profile of Zoledronic Acid Therapy % Hypocalcemia G0 G1 G2 G3 G4 Figure 1. Distribution of hypocalcemia according to the National Cancer Institute Common Toxicity Criteria, Version 3.0. Abbreviation: G, grade. zoledronic acid was 6 months in 143 patients (59.6%), 6 12 months in 55 patients (22.9%), months in 29 patients (12.1%), and 24 months in 13 patients (5.4%). The mean initial diagnosis-to-treatment interval was 3 weeks. The mean and median numbers of zoledronic acid infusions were eight and six, respectively, with a range of Seventy-six (82.0%) of 93 patients with hypocalcemia received i.v. calcium gluconate supplements (1 g/10 ml). Forty-two patients (17.0%) did not take oral calcium supplements because of noncompliance or intolerance. Calcium Safety Assessment The median baseline serum calcium level was 2.34 mmol/l (range, mmol/l); at the end of treatment with zoledronic acid, the mean serum calcium level was 2.13 mmol/l, with a median value of 2.1 mmol/l (range, mmol/l). At baseline, 13 patients (5.4%) had hypercalcemia and seven patients (3.0%) had hypocalcemia. As shown in Figure 1, during treatment, 93 patients (38.8%) demonstrated hypocalcemia levels that were classified as G1 in 45 cases (48.4%), G2 in 37 cases (39.8%), G3 in 10 cases (10.8%), and G4 in one case (1.1%). The median time to occurrence of hypocalcemia (any grade) was 2.3 months (range, months) after the beginning of treatment with zoledronic acid; G1 and G2 hypocalcemia levels were seen after 2.3 months (range, months and months, respectively) and G3 levels were seen after 3.4 months (range months). We observed a G4 level only for one patient; the time to occurrence was 23 months. In 54 patients (58.0%), hypocalcemia occurred once, in 18 (19.3%) it occurred twice, in eight (8.6%) it occurred three times, and in 13 (13.9%) it occurred more than three times. Although serum albumin levels are not routinely evaluated, data were available for 56 of 93 patients (60.2%) with hypocalcemia. Levels were normal in 31 of these 56 patients (55.4%). Regarding the remaining 25 patients % Hypercreatininemia G0 G1 G2 G3 Figure 2. Distribution of increased serum creatinine according to the National Cancer Institute Common Toxicity Criteria, Version 3.0. Abbreviation: G, grade. (44.6%), we observed G1 hypoalbuminemia in six patients (10.7%), G2 hypoalbuminemia in 16 patients (28.5%), and G3 hypoalbuminemia in three patients (5.3%). Applying the specific formula for hypocalcemia correction in the presence of hypoalbuminemia, 17 of 25 patients (68.0%) had factitious hypocalcemia, whereas in eight patients (32.0%) calcium levels were abnormal (five patients had G3 hypocalcemia and three patients had G2 hypocalcemia). No significant correlation was found between grade of hypoalbuminemia and severity of hypocalcemia or among plasma calcium abnormalities, type and number of bone metastases, patient age, and number of zoledronic acid infusions. There was a significant correlation (p.006) between hypocalcemia and prostate cancer and a significant inverse correlation between hypocalcemia and breast cancer (p.006). Serum levels returned to normal in 39 of 45 patients with G1 hypocalcemia after zoledronic acid withdrawal. The same was observed in 21 (44.0%) of 47 patients with G2 G3 hypocalcemia levels; in the remainder, hypocalcemia decreased to G1 in four patients, remained stable in 10 patients, and was not evaluable in 12 patients who died from their disease. Renal Safety Assessment The mean baseline serum creatinine level was 0.90 mg/dl (range, mg/dl); when treatment ended, the mean and median creatinine levels were 1.22 mg/dl (range, mg/dl) and 1.09 mg/dl, respectively. The baseline serum creatinine level was above normal in 13 patients (5.4%). As shown in Figure 2, during zoledronic acid treatment, 33 patients (13.7%) developed an increased serum creatinine concentration that was G1 in 19 cases (57.6%), G2 in 11 cases (33.3%), and G3 in the remaining three cases (9.1%). The median time to maximum increased serum creatinine level (any grade) was 4.7 months (range, months) after

5 Zuradelli, Masci, Biancofiore et al. 5 treatment with zoledronic acid: 4.8 months (range, months) for G1 elevation, 3.1 months (range, months) for G2 elevation, and 2.5 months (range, months) for G3 elevation. In 20 patients (60.6%), the increase in serum creatinine level occurred once, in nine patients (27.3%) it occurred twice, in two patients (6.1%) it occurred three times, and in two patients (6.1%) it occurred more than three times. In 17 of 19 patients with G1 hypercreatininemia, serum levels returned to normal after zoledronic acid withdrawal. Of 11 patients with G2 hypercreatininemia, creatinine levels returned to normal in one patient, regressed to G1 levels in two patients, remained stable in four patients, and were not detectable in four patients. Of the three patients with G3 hypercreatininemia, serum levels regressed to a G2 concentration in one patient and were not evaluable in the remaining two patients. When serum creatinine concentrations increased, 14 of 33 patients (42.2%) were receiving chemotherapy: six (18.1%) were receiving a potentially nephrotoxic chemotherapy (cisplatin or pemetrexed), three (9.0%) were receiving a fluoropyrimidine-based chemotherapy, two (6.0%) were receiving an anthracycline-based chemotherapy, two (6.0%) were receiving a taxane, and one (3.0%) was receiving gemcitabine. Eight patients (24.2%) were receiving hormonal treatment, six patients (18.2%) were receiving supportive care, and five patients (15.1%) were receiving biological therapy or immunotherapy. No significant correlation was found between abnormal creatinine level and primary tumor or type and number of bone metastases. Advanced age and male sex were associated with increased creatinine levels (p.001 and p.006, respectively). Table 2. Incidence of SREs SRE n %in population % of total SREs Pathologic fracture Bone radiation Bone surgery Spinal cord compression HCM Abbreviations: HCM, hypercalcemia of malignancy; SRE, skeletal-related event. SREs Seventy-seven of the 240 patients (32.1%) experienced at least one SRE following the beginning of zoledronic acid therapy (Table 2). Overall, 91 SREs were recorded. Fortyseven patients (19.6%) had skeletal fractures vertebral in 24 patients (10.0%) and nonvertebral in 23 patients (9.6%). They were initially detected by X-rays in 30 patients (63.9%); all but rib fractures were confirmed by MRI or CT scan. In the other 17 patients, fractures were detected by MRI in 13 (27.6%) and by CT scan in the remaining four (8.5%). Thirty-four of the 240 patients (14.2%) received palliative bone radiotherapy during zoledronic acid therapy. According to the internal procedures of our oncology unit, we indicate such treatment in cases of spinal cord compression or high fracture risk, or when the patient has bone pain severity of seven on a visual analog scale that is nonresponsive to optimal analgesic therapy given according the World Health Organization criteria. Six patients (2.5%) had bone surgery and four patients (1.7%) had spinal cord compression (Fig. 3). The median time to first skeletal event was 7 months (range, 0 28 months). Twelve patients of 77 (15.6%) had more than one SRE. A significant correlation between skeletal fractures and disseminated bone disease was observed (p.001). It should be noted that 39 patients underwent programmed treatments just before or within a month after the first zoledronic acid infusion. Twenty-nine patients underwent radiotherapy, eight patients had percutaneous vertebroplasty, and two patients had planned bone surgery to avoid fractures rather than to treat acute occurrences. Side Effects Table 3 and Figure 4 show the most frequent side effects. They were bone pain in 27 patients (11.3%) and fever in 23 patients (9.6%). Three patients (1.3%) developed shivers, four (1.7%) had vomiting, and two (0.8%) experienced nausea. Two patients (0.8%) reported muscle pain, one developed dysuria, and one had an episode of paralytic ileus that was considered zoledronic acid related; another patient developed an allergic reaction during the first infusion. After administration of steroid therapy, symptoms resolved rapidly. Four patients (1.6%), three with breast cancer and one with kidney cancer, developed osteonecrosis of the jaw after a median treatment duration of 12 months (range, months). At the time of the jaw osteonecrosis, two breast cancer patients were receiving aromatase inhibitors and the other was on docetaxel plus trastuzumab, whereas the renal cancer patient was being treated with interferon. All the patients underwent jaw surgery, and histology confirmed the absence of neoplasm and the presence of necrosis. One patient was diagnosed with osteoradionecrosis because she had undergone palliative radiotherapy to the maxillary sinus and zigomatic bone 6 months earlier (36 Gy total dose).

6 6 Toxicity Profile of Zoledronic Acid Therapy Skeletal-Related Events % Pathologic fractures Bone radiation Figure 3. Distribution of skeletal-related events. Abbreviation: HCM, hypercalcemia of malignancy. Table 3. Incidence of adverse events Adverse event n %in population Bone pain Pyrexia Shivers Vomiting Nausea Other Adverse events % of total adverse events Bone pain Pyrexia Shivers Vomiting Nausea Others Figure 4. Distribution of adverse events. Bone surgery After surgery, one patient experienced severe depression; another patient required multiple surgeries to correct complications. No other complications occurred. DISCUSSION The use of bisphosphonates in oncology has had a profound beneficial effect on the management of metastatic bone disease and the prevention of treatment-induced bone loss Spinal cord compression HCM Their use should be considered in all patients with bone metastases, and the ASCO panel recommends that this therapy, once started, should be continued until evidence of a substantial decline in a patient s general performance status occurs [14]. Although the ASCO guidelines recommend either zoledronic acid or pamidronate in patients affected by myeloma or breast cancer with osteolytic bone lesions, the first one is considered more convenient to administer than pamidronate because of its shorter infusion time (15 minutes versus 90 minutes). In addition, zoledronic acid is the only bisphosphonate that demonstrated superiority (by 20%) over pamidronate in a head-to-head study in breast cancer patients [1]. All of these data confirm the feasibility of zoledronic acid administration for a long time, especially in breast or prostate cancer patients, who can survive for several years after the diagnosis of bone metastases. Furthermore, recent trials demonstrated that, in breast cancer patients receiving adjuvant therapy with aromatase inhibitors, early zoledronic acid therapy administered every 6 months could preserve bone mineral density and prevent fractures, and might have additional antitumor and antineoplastic properties [5, 6]. Although its use in this population requires further study in order to define the most appropriate timing and duration of therapy, as well as its long-term efficacy and safety, it seems to be suitable for more and more prolonged and diffuse indications. Since 2003, several reports have been published highlighting the adverse event profile of these agents, though

7 Zuradelli, Masci, Biancofiore et al. 7 they are usually well tolerated and not associated with permanent systemic side effects because of their selective action. We know from many randomized clinical trials in the literature that electrolyte abnormalities are expected events following treatment with zoledronic acid; therefore, serum creatinine and calcium levels should be closely monitored. The aim of our analysis was to verify the incidence of the same events in the general population, outside clinical trials. In the literature, there is a well-known direct association between the risk for renal failure and drug infusion time and dose [7, 15, 16]. In fact, high-dose zoledronic acid (8 mg i.v.) with a short infusion time (5 minutes) is strongly nephrotoxic [2, 4, 17]. Using the recommended infusion time and dosage (15 minutes and 4 mg i.v., respectively), this drug showed a favorable renal safety profile, comparable with that of placebo, in several long-term, prospective, randomized trials involving 3,000 patients with different neoplasms [2, 3, 18]. Overall, the incidence of renal impairment is 9% 10% in patients with multiple myelomas or breast cancers [1]. Outside clinical trials, the incidence of renal failure associated with zoledronic acid therapy is in the range of 10% 20%. However, these results should be evaluated according to progression of the underlying disease, mainly in patients affected by multiple myeloma [19 21]. In our series, the overall incidence of increased serum creatinine was 13.7%, which reached G2 and G3 levels in 5.8% of patients. Similar results were reported by Guarneri et al. [22], who described a considerable increase in creatinine levels (12.2%) in a small group of 57 patients treated with long-term zoledronic acid or pamidronate. Furthermore, in our analysis, only six patients received nephrotoxic agents concomitantly with a bisphosphonate, and it can therefore be inferred that, in patients receiving zoledronic acid, creatinine concentrations were not affected by other treatments; hence, hypercreatininemia was caused, or at least influenced, by zoledronic acid alone. Finally, it must be stressed that creatinine increases are most frequent in older patients (p.001). Unlike creatinine levels, alterations in calcium levels have not received the same attention in literature. In a study by Saad et al. [3], G3 and G4 hypocalcemia was observed in only 2% of patients treated with 4 mg zoledronic acid as a 15-minute infusion. Henley et al. [23] described three cases of symptomatic hypocalcemia and renal impairment in patients with multiple myeloma. Furthermore, Kohno et al. [24] reported a high global incidence of hypocalcemia (39%), but no G2 G3 cases were found. Our analysis showed a similar overall incidence of hypocalcemia (38.8% of patients), namely, G1 in 18.8% of patients and G2 G3 in 19.6% of patients. Whereas the routine assessment of calcemia and serum creatinine is strongly suggested by zoledronic acid manufacturers, assessment of the albumin level is not required. For this reason, according to hospital policy, we assess calcemia and creatininemia before each zoledronic acid administration, whereas we do not routinely assess albuminemia. It is therefore likely that some of the hypocalcemia occurrences we registered were dependent on hypoalbuminemia, as proven by calcium levels corrected for albumin, but not all of them. It is therefore important that the albumin level is assessed in patients presenting with hypocalcemia during zoledronic acid therapy before making any decision regarding treatment. Alternatively, assessing ionized calcium may be useful in decision making. Data from the literature suggest close monitoring of plasma electrolytes as well as the use of vitamin D and calcium supplements during treatment with zoledronic acid, although hypocalcemia is often asymptomatic. In our series, not only was it asymptomatic but it developed despite daily calcium and vitamin D supplements. Patients with high-grade hypocalcemia were also supported with i.v. calcium gluconate. Even though, in our series, we found a correlation between hypocalcemia and prostate cancer (p.006) and an inverse correlation between the same electrolyte abnormality and breast cancer (p.006), we are unable to explain these phenomena and strongly suggest further evaluations in order to verify these data. In our analysis, 1.6% of patients developed osteonecrosis of the jaw. This side effect was recently reported in patients on prolonged bisphosphonate therapy; in fact, it seems to be the most serious adverse event associated with this type of treatment, and the risk for its development increases with the duration of bisphosphonate use. The incidence is, at present, uncertain in the literature because most cases are self-reported or are found on retrospective analysis; the estimated incidence varies in the range of 0.03% 11% [25 28]. The 32.1% incidence of skeletal events also aligns with rates reported in the literature, which are in the range of 30% 49% [2, 3, 29 31]. As expected, most bone fractures were seen in patients with disseminated disease (p.001) and were equally divided between vertebral and nonvertebral. Other zoledronic acid related adverse events were also within the reported ranges. In conclusion, our analysis shows a high incidence of hypocalcemia and serum creatinine elevation during treat-

8 8 Toxicity Profile of Zoledronic Acid Therapy ment with zoledronic acid. These results strongly support the need for accurate monitoring of plasma calcium and creatinine levels and, in cases of hypocalcemia, suggest measuring serum albumin in order to verify the actual occurrence of this side effect. According to the latest ASCO guidelines, zoledronic acid should be given until the patient shows a poor performance status. Because long-term use of the drug seems to be associated with a higher number of side effects, a randomized trial might be useful to assess whether short-term administration yields the same results as long-term treatment with milder side effects. AUTHOR CONTRIBUTIONS Conception/Design: Monica Zuradelli, Giovanna Masci Provision of study materials: Monica Zuradelli, Giovanna Masci, Giuseppe Biancofiore, Giuseppe Gullo, Marta Scorsetti, Pierina Navarria, Flavio Tancioni, Marco Berlusconi Collection/assembly of data: Monica Zuradelli Data analysis: Laura Giordano Manuscript writing: Monica Zuradelli, Giovanna Masci Final approval of manuscript: Armando Santoro REFERENCES 1 Rosen LS, Gordon D, Kaminski M et al. Long-term efficacy and safety of zoledronic acid compared with pamidronate disodium in the treatment of skeletal complications in patients with advanced multiple myeloma or breast carcinoma: A randomized, double-blind, multicenter, comparative trial. Cancer 2003;98: Rosen LS, Gordon D, Tchekmedyian S et al. 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