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Symptom Management and Supportive Care

Efficacy and Safety of Zoledronic Acid in Patients with Breast Cancer Metastatic to Bone: A Multicenter Clinical Trial

^a A.O.R.N.A. Cardarelli, Napoli, Italy; ^b Ospedale Vittorio Emanuele II, Catania, Italy; ^c Istituto Oncologico, Bari, Italy; ^d Centro di Riferimento Oncologico, Aviano, Italy; ^e Novartis Farma S.p.A, Origgio, Italy; ^f Ospedale Morgagni-Pierantoni, Forlì, Italy

Key Words. Zoledronic acid • Bisphosphonates • Breast cancer • Bone metastases

Correspondence: Dino Amadori, M.D., Ospedale Morgagni-Pierantoni, Divisione di Oncologia Medica, Via Forlanini 34, Forlì, 47100 Italy. Telephone: +39-0543-731737; Fax: +39-0543-731736; e-mail: segronco{at}ausl.fo.it

Received March 9, 2006; accepted for publication May 18, 2006.

	ABSTRACT

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Purpose. This study evaluated the efficacy and safety of zoledronic acid in breast cancer patients with newly diagnosed bone metastases.

Materials and Methods. Patients diagnosed with bone metastases 6 weeks prior to first visit were enrolled. Zoledronic acid (4 mg) was administered via a 15-minute infusion every 3 or 4 weeks for 12 infusions. Skeletal-related events (SREs) were defined as pathologic bone fractures, spinal cord compression, surgery to bone, radiation therapy to bone, and hypercalcemia of malignancy. Primary efficacy end points were the proportion of patients with at least one SRE and the time to first SRE. Secondary end points included pain, analgesic use, and quality of life.

Results. Among 312 patients enrolled, 30% experienced at least one SRE during the 12-month study, and 22% experienced only one SRE. The median time to first SRE was not reached in the intent-to-treat population. Mean pain and analgesic scores declined from baseline, and quality-of-life scores remained stable to study end. The most frequently reported adverse events, regardless of relationship to study drug, were pyrexia (22%) and bone pain (10%). Serum creatinine levels did not significantly increase from baseline throughout the study.

Conclusions. Breast cancer patients with newly diagnosed bone metastases who were treated with zoledronic acid had a low incidence of SREs compared with patients who received placebo in randomized phase III trials, and pain was decreased from baseline. This study demonstrated the favorable risk:benefit ratio of zoledronic acid for the prevention of skeletal complications.

	INTRODUCTION

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Each year nearly 800,000 women worldwide are diagnosed with breast cancer, and 314,000 die from the disease [1]. Globally, breast cancer is the most common type of cancer and the leading cause of cancer-related mortality in women [1]. Approximately 70% of patients with advanced breast cancer develop bone metastases [2]. Bone metastases are a common cause of skeletal complications, including severe bone pain requiring palliative radiotherapy, pathologic fractures, spinal cord compression, and hypercalcemia of malignancy (HCM). Because the median survival time for patients with breast cancer is 18–26 months after diagnosis of bone metastases, these patients are at risk for long-term skeletal morbidity [3]. In fact, several studies have shown that, without effective bisphosphonate therapy, approximately 55% of patients are likely to experience at least one skeletal-related event (SRE) within 12 months of study entry [4–6].

Bisphosphonates are the current standard of care for the prevention of SREs in breast cancer patients with metastatic bone disease [7, 8]. These compounds reduce the incidence of skeletal complications by inhibiting bone resorption [9]. Zoledronic acid is a highly effective, nitrogen-containing bisphosphonate that has been approved for the treatment of HCM and for the prevention of skeletal complications secondary to multiple myeloma and bone metastases from any solid tumor [2, 9–11]. In a recent long-term, phase III, multicenter, comparative trial, zoledronic acid (4 mg via a 15-minute infusion) was shown to be at least as effective as pamidronate (90 mg via a 2-hour infusion), the previous standard of care, for the prevention of SREs in patients with stage III multiple myeloma or stage IV breast cancer [12]. Moreover, among breast cancer patients in that study, zoledronic acid reduced the risk for developing a skeletal complication (including HCM) by an additional 20% over the benefit provided by pamidronate [12]. More recently, a 12-month, placebo-controlled study in Japanese women with metastatic bone disease secondary to breast cancer demonstrated that zoledronic acid was significantly more effective than placebo in decreasing the incidence of SREs; 30% of patients treated with zoledronic acid experienced at least one SRE compared with 50% of patients in the placebo group [6]. Zoledronic acid also significantly delayed the onset of SREs and reduced the risk for SREs in that study.

In this study, we report the efficacy and safety of zoledronic acid (4 mg via a 15-minute infusion) over 12 months for the prevention of SREs in breast cancer patients with newly diagnosed bone metastases. Secondary objectives included evaluation of pain, analgesic use, and quality of life (QoL).

	MATERIALS AND METHODS

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Patients
Adult patients (aged 18 years) with a histologically confirmed diagnosis of breast cancer and at least one newly diagnosed (6 weeks prior to first visit) bone metastasis confirmed by conventional radiographs of bone (plain film) were eligible. Bone lesions could be purely osteolytic, purely osteoblastic, or mixed. Patients were required to have adequate liver function (as determined by total serum bilirubin), a baseline Eastern Cooperative Oncology Group (ECOG) performance status 2, and normal renal function as determined by serum creatinine <1.5 times the upper limit of normal and creatinine clearance >60 ml/minute. Patients were excluded if they had a previous diagnosis of bone metastasis (>6 weeks prior to first visit), had previously been treated with bisphosphonates for the current disease, or had a known hypersensitivity to bisphosphonates. Ongoing antineoplastic therapy or hormonal therapy was permitted for all patients at the time of inclusion but could be changed or discontinued at the discretion of the investigator. All patients provided written informed consent prior to screening. The study protocol was reviewed and approved by independent ethics committees and/or institutional review boards at each study site. This trial was conducted in accordance with good clinical practice and the Declaration of Helsinki. Patient participation was limited to 52 weeks.

Study Design and Treatment
This was a multicenter, open-label study. Patients were assigned to treatment with 4 mg zoledronic acid via a 15-minute infusion either every 3 weeks or every 4 weeks at the discretion of the investigator, for a total of 12 infusions (48 weeks). A protocol amendment (October 2002) allowed for continuing treatment until week 52 following a patient evaluation at week 36 for patients treated every 3 weeks and at week 48 for patients treated every 4 weeks. Patients received calcium supplements (500 mg) and multivitamin tablets containing 400–500 IU vitamin D at visit 1 and were instructed to take oral supplements once daily for the duration of the study. Patients received concomitant antineo-plastic therapy at the discretion of the treating physician, but use of other bisphosphonates was prohibited.

Assessments
SREs were defined as pathologic fractures, spinal cord compression, surgery to bone, radiation therapy to bone, and HCM. The skeletal morbidity rate (SMR) was defined as the number of SREs per patient per year. The primary efficacy variables were the proportion of patients who had at least one SRE inclusive of HCM, the time to first SRE, and the SMR. Secondary efficacy variables included pain as measured by the Brief Pain Inventory (BPI) composite pain score. The BPI composite pain score was defined as worst pain, average pain, and least pain over the last 7 days and pain right now; pain scores were recorded every 12 weeks up to 52 weeks. Other variables included analgesic use measured on a scale of 0 (none) to 4 (strong narcotics), ECOG performance status score, and QoL as assessed by the Functional Assessment of Cancer Therapy-General (FACT-G) questionnaire.

Adverse events (AEs) were defined according to the Medical Dictionary for Regulatory Activities (MedDRA^®, a registered trademark of the International Federation of Pharmaceutical Manufacturers and Associations). Renal safety was assessed by monitoring serum creatinine levels before each administration of zoledronic acid. Dosing was delayed if patients with baseline serum creatinine levels <1.4 mg/dl had an increase of 0.5 mg/dl, if patients with baseline serum creatinine levels 1.4 mg/dl had an increase of 1.0 mg/dl, or if there was any doubling of the baseline serum creatinine level. Treatment was resumed when serum creatinine levels returned to within 10% of baseline. Creatinine grade was defined according to the National Cancer Institute/National Institutes of Health Common Toxicity Criteria (NCI/NIH-CTC).

Statistical Analysis
Data summaries for continuously scaled parameters included descriptive statistics of n, mean, median, standard deviation (SD), minimum, and maximum. Qualitative parameters were reported as frequencies and percentages. The proportion of patients who had an SRE (including HCM) was expressed as a percentage, and time to first SRE was analyzed by Kaplan-Meier estimates. Changes from baseline were calculated for the composite BPI pain score, ECOG performance status score, and QoL score. Change from baseline use of analgesics was summarized in shift tables. Tolerability, measured as an assessment of safety, was based on the frequency of AEs and abnormal laboratory values.

	RESULTS

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Patients
Three hundred twelve patients were enrolled at 58 centers in Italy and were assigned to treatment with 4 mg zoledronic acid every 3 weeks (n = 135) or every 4 weeks (n = 177) at the discretion of the investigator (Fig. 1). One patient was excluded from the intent-to-treat (ITT) analysis because, although he received study drug, he was not evaluated for SREs. Overall, 195 (63%) patients completed the study. Patients who prematurely discontinued the study were followed for 56 weeks or until death.

Baseline demographics and disease characteristics are shown in Table 1. The mean age was 59 years, and the majority (87%) of patients had an ECOG performance status score 1. The mean time from initial diagnosis of cancer to study entry was 53 months, and the time from diagnosis of bone metastases to study entry was 1.7 months. Prior to study entry, 9% of the patients had experienced an SRE. At study entry, 79% of the patients reported pain, 51.6% of the patients used analgesics (from minor to strong), and the mean composite baseline BPI pain score was 3.3 (on a scale of 0–10). At study entry, 44% and 45% of patients were receiving hormonal therapy or chemotherapy, respectively, with an additional 5% of patients receiving both hormonal therapy and chemotherapy. More than 99% of patients had a normal serum creatinine level in accordance with the normal range of local laboratories. Serum calcium levels were above normal in 7% of patients.

Efficacy—SREs
Within the ITT population (n = 311), 30% of patients experienced at least one SRE during the study; most patients (22%) experienced only one SRE (Fig. 2). The most common SRE was radiation to bone (22%), followed by pathologic nonvertebral fractures (4.8%) (Fig. 3). The median time to first SRE was not reached in the ITT population; the time to the 25th percentile was 170 days (Fig. 4). The time to the 25th percentile for radiation to bone was 198 days. The SMR (mean ± SD) up to week 52 was 0.9 ± 3.8.

Efficacy—Bone Pain and Analgesic Use
At the end of treatment, 272 patients were evaluated for pain for any reason. The mean (± SD) composite BPI pain score decreased from 3.3 ± 2.2 at baseline to 2.6 ± 2.3 at the end of treatment. Among the 247 patients with pain at baseline, 237 were evaluable at the end of treatment. Of these 237 patients, 138 (58%) had a decrease in pain score, 19% had no change from baseline, and 23% had an increase in pain (Fig. 5A). Among the 157 patients using analgesics at baseline, analgesic use decreased in 37% of patients, whereas 46% of patients recorded no change (Fig. 5B). For those patients (n = 148) with no analgesic use at baseline, 82% reported no change in their use of analgesics, and 17% reported an increased use of analgesics for any reason at the end of treatment.

Efficacy—Performance Status and QoL
Mean (± SD) ECOG performance status score increased from 0.6 ± 0.7 at baseline to 0.9 ± 1.2 at the end of treatment. Among 157 patients with a baseline score of 0, the majority (70%) experienced no change in performance status (Fig. 5C). Among 148 patients with a baseline performance status score 1, 32% had a worsening of performance status and 32% had improved performance status. For the QoL analysis, the total FACT-G score (mean ± SD) was 65 ± 17 at baseline and 66 ± 18 at the end of study, indicating no change in overall QoL. Patients reported a mean increase from baseline in the physical well-being sub-scale (+0.86), the emotional well-being subscale (+1.07), and the functional well-being subscale (+0.35), whereas the social/family well-being subscale decreased slightly (–0.25) from baseline to the end of study.

Safety
Zoledronic acid was well tolerated (Table 2). Within the safety-evaluable population (n = 312), AEs were reported by 256 (82%) patients. These events were generally mild to moderate in severity and were consistent with the known safety profile of i.v. bisphosphonates. The most frequently reported events were pyrexia (22%), bone pain (10%), and hypocalcemia (9%). Of patients reporting pyrexia, 85% had only a single episode following the first infusion of the study drug. The majority (79%) of hypocalcemia AEs were NCI/NIH-CTC grade 1, and only one episode led to study discontinuation. Although serious AEs were reported by 70 patients, only nine serious AEs were suspected to be related to the study drug. These nine serious AEs occurred in four patients: the first patient experienced musculoskeletal pain and generalized edema after the first infusion and stopped zoledronic acid treatment; the second patient experienced hypocalcemia after the first infusion, and approximately 4 weeks later had vomiting and diarrhea, and went off study; the third patient completed the study despite serious AEs after the first infusion that included nausea and vomiting, which resolved after 2 days of symptom management, and vertigo, which spontaneously resolved within 1 day; the fourth patient was accidentally administered a zoledronic acid overdose in the 13th week of treatment, but this patient also completed the study.

Overall, there was no change in the mean serum creatinine level over 12 months. The mean (± SD) baseline serum creatinine level was 0.79 ± 0.18 mg/dl, and at the end of week 52, the mean serum creatinine level was 0.80 ± 0.22 mg/dl. Nearly all patients (n = 270) had NCI/NIH-CTC grade 0 creatinine levels at the end of study. No grade 3 or 4 serum creatinine levels were reported at any time during the study. An NCI/NIH-CTC grade 1 or grade 2 serum creatinine increase occurred in 4.8% and 0.3% of patients, respectively. For patients with grade 1 serum creatinine increases, the mean value of serum creatinine during the study was 1.5 mg/dl (range, 1.32–1.59 mg/dl); in the patient with a grade 2 serum creatinine increase, the mean value was 2.1 mg/dl. Only one patient discontinued treatment (in the 16th week on study) because of a serum creatinine increase that coincided with progression of disease at the same assessment.

	DISCUSSION AND CONCLUSION

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Patients diagnosed with bone metastases from advanced breast cancer are at high risk for developing skeletal complications [2, 13]. SREs, such as severe bone pain requiring palliative radiotherapy, pathologic fractures, and spinal cord compression, significantly reduce a patient’s QoL [14]. This is particularly meaningful for patients with metastatic breast cancer, considering their relatively long median survival time after diagnosis of bone metastases [3]. Zoledronic acid has been shown to reduce the incidence of SREs and to delay the time to first SRE in patients with bone metastases from advanced breast cancer [6, 15].

The results of this open-label trial confirm both the efficacy and safety of zoledronic acid in the treatment of patients with bone metastases from advanced breast cancer. Within the ITT population, only 30% of patients experienced an SRE during the 12-month study. These results are consistent with those reported in a randomized, placebo-controlled trial of zoledronic acid in 228 Japanese women with breast cancer metastatic to bone [6]. In that study, 31% of patients treated with zoledronic acid experienced at least SRE over the 12-month study period. It is noteworthy that the patient populations in this study and in the study reported by Kohno et al. [6] were similar; eligible patients had all types of bone lesions, and the median time from diagnosis of bone metastases to study entry was relatively short (1.7 months in this study and 3.9 months in the Kohno et al. study).

Other randomized, placebo-controlled trials also have demonstrated the benefits of bisphosphonate therapy for the prevention of skeletal complications in patients with metastatic breast cancer. In studies reported by Hortobagyi et al. [4] and Theriault et al. [5], significantly fewer patients treated with pamidronate experienced an SRE over 12 months compared with patients in the placebo group [4, 5]. In those studies, approximately 56% of patients receiving placebo experienced at least one SRE compared with approximately 45% of patients treated with pamidronate [4, 5]. However, patients in those studies had more advanced disease and they had predominantly osteolytic bone lesions; 34% of patients had an ECOG performance status score 2, and the time from diagnosis of bone metastases to study entry was nearly 2 years.

In the comparative trial of zoledronic acid and pamidronate reported by Rosen et al. [16], the percentage of breast cancer patients treated with zoledronic acid who had an SRE at 13 months also was higher than what was seen in this study. However, those patients also had more advanced disease, and approximately 62% had experienced an SRE prior to study entry [15]. Therefore, early intervention with zoledronic acid soon after diagnosis of bone metastases and before skeletal complications occur appears to result in a better clinical outcome (i.e., lower incidence of SREs, particularly pathologic fractures).

Bisphosphonates also have demonstrated efficacy in delaying the time to first SRE. In this study, the median time to first SRE was not reached after 1 year of follow-up. Similarly, Kohno et al. [6] reported that the median time to first SRE was not reached in patients treated with zoledronic acid, whereas the median time to first SRE for patients in the placebo group was 360 days (including HCM). Therefore, the current study is consistent with the trial reported by Kohno et al. [6] in terms of time to first SRE.

In addition to reducing SREs, bisphosphonates have been shown to positively effect health-related quality of life (HRQoL) [17]. A recent study by Weinfurt et al. [17] sought to assess HRQoL in patients with metastatic breast cancer. They found that patients with a history of SREs began the study with significantly lower QoL scores. However, patients receiving zoledronic acid or pamidronate over the course of the 12-month study reported an improvement in QoL [17]. In the present study, both pain and analgesic use decreased from baseline, and QoL scores improved in the areas of physical, functional, and emotional well-being. These results suggest that by preventing SREs through treatment with zoledronic acid, HRQoL is likely to improve. Overall QoL scores did not reflect any change; however, this is likely because of the low incidence of SREs in the overall patient population.

Zoledronic acid was extremely well tolerated in this trial. The incidence of AEs was notably lower than that reported for other phase III trials of zoledronic acid [15]. There were no unexpected or clinically significant AEs, suggesting that zoledronic acid 4 mg infused over 15 minutes every 3 or 4 weeks for up to 52 weeks is well tolerated. All patients maintained good renal function, as evidenced by no change in serum creatinine levels throughout the study, and renal adverse events were infrequent. Grade 1 hypocalcemia, an expected result of bone resorption inhibition, was lower than in the study of Kohno et al. [6] (9% vs. 39%), in which the daily use of calcium and vitamin D supplements was not recommended. Together with the results of the international trials with zoledronic acid, this confirms that hypocalcemia may be prevented with routine use of calcium and vitamin D.

In summary, this study has confirmed the favorable risk: benefit ratio of zoledronic acid for the prevention of SREs in patients with newly diagnosed bone metastases from breast cancer and supports the routine use of zoledronic acid for this indication. Based on previously published phase III trials, the American Society of Clinical Oncology consensus treatment guidelines for the use of bisphosphonates in patients with breast cancer recommend therapy with zoledronic acid or pamidronate for the prevention of skeletal complications in patients with radiologic evidence of bone lesions [7]. These results also confirm and extend previous findings demonstrating that zoledronic acid reduces pain associated with malignant bone disease. Given the low incidence of skeletal complications in this study, especially with respect to pathologic fractures, it appears that early intervention with zoledronic acid results in better long-term outcomes and may improve or preserve QoL in patients with newly diagnosed bone metastases from breast cancer.

	AUTHORS' NOTE

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This work was supported by Novartis Farma S.p.A.

	DISCLOSURE OF POTENTIAL CONFLICTS OF INTEREST

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R. R. and V. V. are employees of Novartis.

View this table: [in this window] [in a new window]   Table 2. Most frequently reported adverse events occurring in 2% of patients

View larger version (19K): [in this window] [in a new window]   Figure 1. Flow diagram of patients in an open-label trial of zoledronic acid 4 mg.

View larger version (6K): [in this window] [in a new window]   Figure 2. Percentage of patients who experienced a skeletal-related event by frequency (intent-to-treat population).

View larger version (11K): [in this window] [in a new window]   Figure 3. Distribution of skeletal-related events by event type (intent-to-treat population).

View larger version (10K): [in this window] [in a new window]   Figure 4. Kaplan-Meier estimate of time to first skeletal-related event (intent-to-treat population).

View larger version (16K): [in this window] [in a new window]   Figure 5. Change in pain score (A), analgesic use (B), and ECOG performance status score (C) (intent-to-treat population).

	ACKNOWLEDGMENT

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Prof. M. Aglietta, Istituto per la Ricerca e la Cura del Cancro, Candiolo; Dr. B. Agostara, Osp. Oncologico M. Ascoli, Palermo; Prof. O. Alabiso, Osp. Maggiore della Carità, Novara;Dr. D. Amadori, Ospedale Morgagni-Pierantoni, Forlì; Prof. M. Antimi, Osp. S. Eugenio, Roma; Dr. A. Ardizzoia, Osp. S. Gerardo, Monza; Prof. E. Bajetta, Istituto Nazionale dei Tumori, Milano; Dr. S. Barni, A.O. di Treviglio-Caravaggio, Treviglio; Prof. C. Barone, Policlinico A. Gemelli, Roma; Dr. G. Bernardo, Fondazione S. Maugeri, Pavia; Dr. O. Bertetto, Ospedale Molinette, Torino; Prof. A.R. Bianco, Policlinico Federico II, Napoli; Dr. R. Bordonaro, P.O.U. S. Currò, Catania; Dr. S. Cariello, A.O. S. Giovanni di Dio e Ruggi D’Aragona, Salerno; Dr. G. Cartenì, A.O.R.N. A. Cardarelli, Napoli; Dr. G. Catalano, A.O. San Salvatore, Pesaro; Dr. G. Cavazzini, Istituti Ospedalieri C. Poma, Mantova; Prof. G. Colucci, Istituto Oncologico, Bari; Dr. G. Comella, Fondazione G. Pascale, Napoli; Dr. B. Coria, Osp. S. Bortolo, Vicenza; Prof. E. Cortesi, Policlinico Umberto I, Roma; Dr. L. Crinò, Osp. Bellaria, Bologna; Prof. F. Dammacco, A. O. Consorziale, Bari; Dr. A.M. D’Arco, Presidio Ospedaliero Umberto I, Nocera Inferiore;Prof. A. De Matteis, Fondazione G. Pascale, Napoli; Dr. A. Falcone, Spedali Riuniti, Livorno;Dr. V. Ferrari, A.O. Spedali Civili, Brescia; Dr. G. Gasparini, Osp. S. Filippo Neri, Roma; Dr. V. Gebbia, Osp. La Maddalena, Palermo; Prof. G. Giardina, Osp. S. Anna, Torino; Dr. S. Gori, Osp. A.O. Policlinico, Perugia; Dr. C. Graiff, Osp. Regionale, Bolzano; Dr. E. Greco, Presidio Ospedaliero di Lamezia Terme; Prof. S. Iacobelli, Osp. Clinicizzato Colle Dell’Ara, Chieti; Prof. R. Labianca, Osp. Riuniti, Bergamo; Prof. F. La Torre, Policlinico Universitario, Messina; Dr. V. Lorusso, Istituto Oncologico, Bari; Dr. P. Manente, Osp. Civile, Castelfranco Veneto; Dr. L. Manzione, A. O. S. Carlo, Potenza; Prof. M. Marangolo, A.O. S. Maria delle Croci, Ravenna; Prof. M. Merlano, A.O. S. Croce e Carle, Cuneo; Dr. S. Molica, A.O. Pugliese-Ciaccio, Catanzaro; Prof. S. Monfardini, A.O. di Padova, Padova; Dr. F. Montinari, A.O. di Vimercate-Presidio di Desio, Desio; Dr. G. Mustacchi, Ospedali Riuniti, Trieste; Dr. G. Palmiotti, Osp. Di Venere, Carbonara di Bari; Dr. G. Pandoli, Osp. Civile dello Spirito Santo, Pescara; Dr. F. Patrone, Osp. S. Martino, Genova; Prof. A. Riccardi, Policlinico S. Matteo, Pavia; Dr. S. Romito, Presidio Ospedaliero A. Cardarelli, Campobasso; Dr. A. Santoro, Istituto Clinico Humanitas, Rozzano; Dr. A. Scanni, Osp. Fatebenefratelli, Milano; Dr. G. Serravezza, Presidio Ospedaliero F. Ferrari, Casarano; Dr. G. Tonini, Policlinico Universitario-Campus Biomedico, Roma; Dr. Ucci/Dr. Visini, Osp. A. Manzoni, Lecco; Dr. A. Veronesi, Centro di Riferimento Oncologico, Aviano; Dr. R. Vicelli, Osp. S. Anna, Torino; Dr. V. Zagonel, Osp. Fatebenefratelli, Roma.

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	ADDITIONAL READING

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Pavlakis N, Schmidt, Stockler M. Bisphosphonates for breast cancer. Cochrane Database Syst Rev 2005;(3):CD003474.

Lipton L. Bisphosphonate therapy for patients with breast cancer. Current Cancer Ther Rev 2005;1:217–225.[CrossRef]

Fulfaro F, Casuccio A, Ticozzi C et al. The role of bisphosphonates in the treatment of painful metastatic bone disease: a review of phase III trials. Pain 1998;78:157–169.[CrossRef][Medline]

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