Advertisement
help button home button The Oncologist
HOME HELP CONTACT US SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
First Published Online January 29, 2009
The Oncologist, Vol. 14, No. 2, 181-191, February 2009; doi:10.1634/theoncologist.2008-0209
© 2009 AlphaMed Press

This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF)
Right arrow All Versions of this Article:
theoncologist.2008-0209v1
14/2/181    most recent
Right arrow eLetters: Submit a response to this article
Right arrow Purchase Article
Right arrow View Shopping Cart
Right arrow Alert me when this article is cited
Right arrow Alert me when eLetters are posted
Right arrow Alert me if a correction is posted
Right arrow Citation Map
Services
Right arrow E-mail this article link to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrow Reprints/Permissions
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Van den Wyngaert, T.
Right arrow Articles by Vermorken, J. B.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Van den Wyngaert, T.
Right arrow Articles by Vermorken, J. B.

Symptom Management and Supportive Care

Bisphosphonates in Oncology: Rising Stars or Fallen Heroes

Tim Van den Wyngaerta,b, Manon T. Huizinga, Eric Fossionc, Jan B. Vermorkena

aDepartment of Medical Oncology and bDepartment of Nuclear Medicine, Antwerp University Hospital, Edegem, Belgium; cDepartment of Oral and Maxillo-Facial Surgery, ZNA Middelheim, Wilrijk, Belgium

Key Words. Bisphosphonates • Palliative care • Adjuvant drug therapy • Osteonecrosis • Jaw

Correspondence: Tim Van den Wyngaert, M.D., Department of Medical Oncology, Antwerp University Hospital, Wilrijkstraat 10, 2650 Edegem, Belgium. Telephone (mobile): 32-473-542124; Fax: 32-3-8253308; e-mail: tim.van.den.wyngaert{at}skynet.be

Received September 19, 2008; accepted for publication January 2, 2009; first published online in THE ONCOLOGIST Express on January 29, 2009.

Disclosures: Tim van den Wyngaert: Consultant/advisory role: Novartis Pharmaceuticals Corporation; Honoraria: Novartis Pharmaceuticals Corporation; Manon T. Huizing: None; Eric Fossion: Consultant/advisory role: Novartis Pharmaceuticals Corporation; Jan B. Vermorken: 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 independent peer reviewers.


   ABSTRACT
Top
 Abstract
Introduction
 Current Evidence Supporting the...
 Emerging Evidence on the...
 Impact and Prevention of...
 Risk Stratification Using Bone...
 Conclusion
 Author Contributions
 References
 
The introduction of bisphosphonates in oncology has dramatically changed the management of patients with metastatic bone disease. In this manuscript, we thoroughly scrutinize the available body of clinical trials supporting the use of bisphosphonates in this setting and review new and ongoing research. Additionally, we summarize the data showing the benefits of bisphosphonate use in the prevention of treatment-induced bone loss and the intriguing emerging evidence on the antitumor potential of some of these agents when used in the adjuvant setting. Finally, we address the need for a careful consideration of potential benefits of bisphosphonate therapy and the risk for osteonecrosis of the jaw, a recently recognized late-toxicity of their use.


   INTRODUCTION
Top
 Abstract
 Introduction
Current Evidence Supporting the...
 Emerging Evidence on the...
 Impact and Prevention of...
 Risk Stratification Using Bone...
 Conclusion
 Author Contributions
 References
 
Recently, the 40th anniversary of the publication of a landmark paper by Herbert Fleisch and colleagues in 1968 passed, describing the in vitro and in vivo influence of bisphosphonates—erroneously called diphosphonates at that time—on the precipitation and dissolution of calcium phosphate [1, 2]. This research paved the way to the study of the effects of these agents on hydroxyapatite, and their first therapeutic application in a patient with myositis ossificans just 1 year later [3, 4]. In oncology, the introduction of bisphosphonate therapy has radically improved the management and prevention of skeletal-related events (SREs) associated with malignancy disseminated to the bones, including pathologic fractures, bone pain, impaired mobility, spinal cord compression, and hypercalcemia [5, 6].

Also, it is approximately 5 years ago that Robert Marx published a letter alerting the medical community to the increase in the number of patients presenting with nonhealing areas of exposed bone in the oral cavity. He termed the condition "osteonecrosis of the jaw" (ONJ) and noted that all these patients apparently shared a common denominator: bisphosphonate treatment [7]. Although the safety profile of the bisphosphonates was, until that time, considered to be favorable and well-understood, successive case series seemed to confirm this particular association, as previously reported in this journal [8–10].

Both the recognition of ONJ as a late toxicity of bisphosphonate treatment and the recent advances in basic and clinical research into the effects of bisphosphonate therapy in different malignancies warrant an update to redefine the balance of risks and benefits.


   CURRENT EVIDENCE SUPPORTING THE USE OF BISPHOSPHONATES IN CANCER
Top
 Abstract
 Introduction
 Current Evidence Supporting the...
Emerging Evidence on the...
 Impact and Prevention of...
 Risk Stratification Using Bone...
 Conclusion
 Author Contributions
 References
 
Multiple Myeloma
The older non-nitrogen-containing clodronate and the more potent aminobisphosphonates pamidronate, ibandronate, and zoledronic acid have been studied in multiple myeloma. Two large, placebo-controlled trials with oral clodronate are of interest, next to a larger number of smaller and mostly uncontrolled studies. One trial, using 2,400 mg/day for 24 months (n = 350), concluded a 50% proportional lower number of patients with progression of osteolytic bone lesions (24% versus 12%; p = .026) and found more patients attaining a pain-free state [11]. Patients in the second placebo-controlled clodronate trial (n = 536) received 1,600 mg/day and showed, at 1 year, a 50% lower occurrence of severe hypercalcemia (5% versus 10%; p = .06) and number of reported nonvertebral fractures (6.8% versus 13.2%; p = .04) [12].

In contrast, only one placebo-controlled trial has been conducted with i.v. pamidronate (90 mg 4 weekly) in stage III multiple myeloma patients (n = 392) with at least one osteolytic lesion, showing, at 9 months, a significantly lower proportion of patients with an SRE (24% versus 41%; p < .001) and a lower mean number of SREs per year (1.1 versus 2.2; p = .0006) [13]. However, a subsequent placebo-controlled study with oral pamidronate (300 mg/day) demonstrated no significant effect on SREs, presumably because of its very low and variable bioavailability [14].

In addition to a randomized phase II dose-seeking comparison with pamidronate (n = 280) demonstrating equal efficacy, the results of one randomized phase III trial (n = 518), showing the noninferiority of zoledronic acid versus pamidronate, form the basis for the use of this potent bisphosphonate in multiple myeloma. Both trials recruited a mixed population of breast cancer and stage III multiple myeloma patients [15, 16].

Finally, a large phase III trial with i.v. ibandronate (2 mg monthly) was negative, with no difference in bone morbidity or survival in stage II/III multiple myeloma patients [17].

Breast Cancer
Little new research has been performed in the last decade in the setting of bone metastatic breast cancer, with major research groups focusing on adjuvant bisphosphonate therapy instead. In metastatic disease, early evidence from three placebo-controlled trials (total n = 417) suggests that oral clodronate (800 mg/day or 1,600 mg/day) resulted in a significantly lower number/rate of skeletal events (hazard ratio [HR], 0.84; 95% confidence interval [CI], 0.72–0.98), longer time to first SRE, lower incidence of vertebral fractures and deformity, and lower total number of (terminal) hypercalcemic episodes, and leads to less pain and a lower use of analgesics (Fig. 1) [18–21].


Figure 1
View larger version (22K):
[in this window]
[in a new window]

  		Figure 1. Overview of the benefit of treatment with bisphosphonates over placebo on the risk of a skeletal-related event in bone metastatic breast cancer (hazard ratios with 95% confidence intervals). Pooled data for clodronate and pamidronate are taken from a Cochrane review by Pavlakis et al. [21].

Abbreviation: PO, orally.

 
However, the methodology used in one of these studies may have overestimated treatment effects [18], the subsequent availability of more robust data demonstrating similar activity of pamidronate, and the lack of U.S. Food and Drug Administration approval in the U.S. have all contributed to the rather limited use of clodronate in these patients [22]. Indeed, four placebo-controlled trials (n = 1,453) concluded that i.v. pamidronate (45–90 mg 3–4 weekly) results in a significantly longer time (12.7 versus 7.0 months; p < .001) to the occurrence of the first SRE (HR, 0.77; 95% CI, 0.69–0.87), lower incidence of SREs (53% versus 68%; p < .001), and longer time to progression of bone lesions (8.3 versus 5.6 months; p = .02) [21, 23–27]. Moreover, evidence from a head-to-head comparison suggests its superiority over clodronate in both controlling symptoms and suppressing bone resorption [28].

The most recent data available are on the newer bisphosphonates zoledronic acid and ibandronate. Besides the previously cited phase II trial in a mixed population of breast cancer and multiple myeloma patients, the firm body of evidence supporting zoledronic acid comes from both a positive placebo-controlled trial (n = 228) and a phase III noninferiority head-to-head comparison with pamidronate in patients with predominantly breast cancer (n = 1,130) [16, 29]. At 1 year of follow-up and excluding hypercalcemia of malignancy, zoledronic acid resulted in a 20% lower percentage of patients with at least one SRE (30% versus 50%; p = .003), 39% lower rate of SREs (p = .027), longer median time to first SRE (median, not reached versus 12 months; p = .007), and 41% lower risk for SREs in a multiple-event analysis (HR, 0.59; 95% CI, 0.37–0.91; p = .019), compared with placebo [29]. Furthermore, zoledronic acid was found to provide a 20% additional lower risk for skeletal events (HR, 0.80; 95% CI, 0.65–0.98; p = .037) compared with pamidronate (multiple-event analysis), and even greater benefit in patients with at least one osteolytic lesion [30]. Additional evidence suggesting the superiority of zoledronic acid comes from a phase II study showing that zoledronic acid, used as a salvage therapy in patients failing clodronate or pamidronate, can significantly improve pain control [31].

The oral and i.v. use of ibandronate has been studied in three placebo-controlled trials, all using a primary efficacy parameter that hampers comparison of the results with other studies. The skeletal morbidity period rate (SMPR) was defined as the number of 12-week periods with new bone complications divided by the number of periods on study, and excluding SREs that occurred during the first 12 weeks.

The i.v. trial (MF4265) randomized 466 patients to ibandronate (2 mg or 6 mg) or placebo every 3–4 weeks for up to 2 years. Only the group receiving 6 mg showed a statistically significant advantage in terms of the SMPR (p = .004), the number of new bone events, and the time to first event [32]. The efficacy of oral ibandronate was reported in a pooled analysis of two smaller phase III trials (MF4434 and MF4414) randomizing patients with bone metastases from breast cancer to 50 mg/day ibandronate (n = 287) or placebo (n = 277) for up to 96 weeks. It concluded that ibandronate produced a significantly lower mean SMPR (0.95 versus 1.18; p = .004), lower risk for a skeletal event (HR, 0.62; 95% CI, 0.48–0.79; p = .0001), lower mean number of events requiring radiotherapy (0.73 versus 0.98; p < .001), and fewer events requiring surgery (0.47 versus 0.53; p = .037) [33].

However, the difference in the proportion of patients with an SRE, which is a straightforward and conservative endpoint that is considered statistically more rigorous for assessing the clinical benefit of bisphosphonate therapy, was not significant in the i.v. trial (51% versus 62%; p = .052) and was not reported in the oral trial [34]. Therefore, the results of two ongoing phase III trials comparing ibandronate with zoledronic acid are eagerly awaited [35, 36].

Prostate Cancer
In patients with prostate cancer, the effect of clodronate on bone metastasis–free survival in the nonmetastatic setting and bone pain and bone progression–free survival in metastatic disease has been well studied. Although the results from smaller uncontrolled trials had been encouraging, all large controlled studies, with a total of 1,214 patients randomized, have reported negative findings (Table 1) [37].


View this table:
[in this window]
[in a new window]

  		Table 1. Overview of randomized, placebo-controlled trials evaluating the benefit of clodronate in prostate cancer

 
Similarly, a randomized, prospective, double-blind, placebo-controlled study (n = 57) with i.v. etidronate followed by oral maintenance therapy in patients with hormone-refractory metastatic prostatic cancer showed no significant difference in pain control between the two groups [38].

In the treatment and prevention of SREs, pamidronate has been prospectively evaluated with disappointing results as well. A pooled analysis of two multicenter, double-blind, randomized, placebo-controlled trials (n = 378) in hormone-refractory prostate cancer patients with bone metastases failed to demonstrate an overall treatment benefit of 3-weekly i.v. pamidronate (90 mg) on self-reported pain measurements, analgesic use, proportion of patients with an SRE, or mobility [39].

Treatment with 3-weekly i.v. zoledronic acid (4 mg), on the other hand, has effectively demonstrated a benefit in hormone-refractory prostate cancer patients with metastatic bone disease. In a large prospective, randomized, controlled trial (n = 422), there was a significant absolute 11% lower proportion of patients who experienced one or more SREs (p = .028) and a significantly longer time until the first SRE of 5.5 months (p = .009). In addition, an absolute lower mean skeletal morbidity rate of 0.7 SREs per year (p = .005) was observed, compared with the placebo group in which at 2 years of follow-up 49% of patients experienced one or more SREs and had on average 1.47 SREs per year [40, 41]. Looking beyond first-event analyses, zoledronic acid also resulted in a 36% lower ongoing relative risk for SREs (HR, 0.64; 95% CI, 0.43–0.81; p = .002), compared with placebo [42]. Interestingly, patients without pain appeared to benefit most, and therefore treatment with zoledronic acid should probably not be postponed until symptoms develop [43].

Data on ibandronate, the latest addition in the constellation of the bisphosphonates, are still maturing, and placebo-controlled trials are required before it can be considered [44].

Other Solid Tumors
Data on the efficacy of zoledronic acid in small cell and non-small cell lung cancer, renal cell carcinoma, and a variety of other histologies (including head and neck, thyroid, and unknown primary cancer) are derived from a large (n = 773), placebo-controlled trial demonstrating a significantly lower proportion (39% versus 48%; p = .04) of patients with an SRE (HR, 0.69; 95% CI, 0.54–0.89; p = .003), a longer median time to first SRE (7.9 versus 5.2 months; p = .009), and a 36% lower annual incidence of SREs (mean, 1.74 versus 2.71 SREs per year; p = .01), compared with placebo at 21 months of follow-up [45, 46]. A subset analysis of renal cell carcinoma patients in that trial was in agreement with this, with a significantly lower proportion (37% versus 74%; p = .015) of patients with an SRE (HR, 0.39; 95% CI, 0.19–0.81; p = .008) [47]. The whole of these data has led to zoledronic acid being the only bisphosphonate to have worldwide regulatory approval for use in patients with bone metastases secondary to solid tumors other than breast cancer. Moreover, a randomized phase III study recruiting patients (n = 287) with a broad range of malignancies demonstrated the superiority of zoledronic acid over pamidronate in the treatment of hypercalcemia [48].


   EMERGING EVIDENCE ON THE FUTURE ROLE OF BISPHOSPHONATES IN CANCER
Top
 Abstract
 Introduction
 Current Evidence Supporting the...
 Emerging Evidence on the...
Impact and Prevention of...
 Risk Stratification Using Bone...
 Conclusion
 Author Contributions
 References
 
Prevention of Treatment-Induced Bone Loss
The potential benefit of bisphosphonates to prevent the bone loss caused by endocrine therapy in breast and prostate cancer has previously been reviewed in this journal [49].

In summary, androgen-deprivation therapy (ADT) in prostate cancer patients leads to a clinically significant bone loss that translates into a higher fracture risk at 5 years of 19.4%, compared with 12.6% in nonusers (p < .001) [50, 51]. Placebo-controlled trials have shown that pamidronate (60 mg i.v. every 3 months) can maintain bone mineral density (BMD) in patients (n = 43) with nonmetastatic prostate cancer receiving a gonadotropin-releasing hormone agonist, and that oral alendronate (70 mg once weekly) not only prevents bone loss but actually improves BMD in patients (n = 112) on ADT [52, 53].

However, zoledronic acid (4 mg i.v. once or every 3 months) currently has the most impressive bulk of evidence, with four published randomized controlled trials (n = 439) consistently demonstrating an increase in BMD, even after a single administration [54–57].

Likewise, breast cancer patients with chemotherapy-induced ovarian failure or receiving aromatase inhibitor treatment have a greater annual bone loss that results in a higher fracture incidence (11%) than in patients treated with tamoxifen (8%) [58, 59]. Previous studies into the benefit of bisphosphonate treatment in these patients have shown that the oral bisphosphonates clodronate (n = 148) and risedronate (n = 53) can reduce this bone loss, but not completely prevent it [60, 61].

The most convincing results, however, are available for zoledronic acid, with three randomized trials (n = 2,068), providing evidence that zoledronic acid (4 mg i.v. every 6 months) effectively inhibits aromatase inhibitor–associated bone loss. Moreover, in postmenopausal women with early-stage breast cancer receiving letrozole, upfront zoledronic acid prevents bone loss more effectively than when treatment is delayed until bone loss has been documented [62, 63].

Prevention of Bone Metastases
With nearly every trial with bisphosphonates in patients with skeletal metastases from breast cancer being positive, studies investigating the impact of clodronate on metastasis-free and overall survival in patients without bone metastases have produced very conflicting results, with two positive and one negative randomized trial [64–67]. A recent meta-analysis of these trials concluded that there was no evidence to suggest that adjuvant clodronate therapy improves 5-year overall (HR, 0.75; 95% CI, 0.31–1.82), bone metastasis-free (HR, 0.68; 95% CI, 0.38–1.23), or nonskeletal metastasis-free (HR, 0.89; 95% CI, 0.40–1.98) survival in breast cancer patients [68]. Hopefully, a more definitive judgment on clodronate can be rendered when the eagerly awaited National Surgical Adjuvant Breast and Bowel Project B34 trial, which has accrued 3,000 patients, investigating adjuvant oral clodronate in patients with resected stage I–II breast cancer, has accumulated enough events to be reported, probably later this year [69].

The effect of newer and more potent bisphosphonates on disease-free and overall survival in this setting is actively being investigated. A large open-label study, randomizing 953 women with primary breast cancer to either adjuvant oral pamidronate (150 mg twice daily for 4 years) or no bisphosphonate, failed to demonstrate a beneficial effect on the occurrence of bone metastases [70]. In contrast, zoledronic acid has shown very promising antitumor activity in preclinical animal and in vitro research, as well as synergistic effects with the sequential administration of chemotherapy [71, 72]. Recently, the exciting first efficacy results of the Austrian Breast and Colorectal Cancer Study Group Trial 12 have been reported, suggesting that the use of adjuvant zoledronic acid can improve disease-free survival (DFS) in premenopausal women who are receiving endocrine treatment with ovarian suppression and tamoxifen or anastrozole. This open-label, multicenter study investigated whether anastrozole is superior to tamoxifen in these patients, and whether adding zoledronic acid to endocrine therapy improves the outcome over endocrine therapy alone (Fig. 2). After a median follow-up of 60 months, there was no statistically significant difference in DFS between the tamoxifen (65 events) and anastrozole (72 events) groups (HR, 1.10; 95% CI, 0.79–1.54; p = .59).


Figure 2
View larger version (62K):
[in this window]
[in a new window]

  		Figure 2. Design of the Austrian Breast and Colorectal Cancer Study Group Trial 12 that recruited 1,803 premenopausal women between 1999 and 2006 with stage I or II and ER- and/or PR-positive breast cancer. All patients were chemotherapy naive, except for neoadjuvant treatment.

Abbreviations: ANA, anastrozole; ER, estrogen receptor; PR, progesterone receptor; q28d, every 28 days; q6m, every 6 months; TAM, tamoxifen; ZOL, zoledronic acid.

 
However, women who received zoledronic acid had significantly fewer DFS events (54 versus 83) than those who had not received the bisphosphonate (HR, 0.64; 95% CI, 0.46–0.91; p = .01). Intriguingly, this benefit of zoledronic acid treatment was not only limited to the bone but also resulted in a lower incidence of contralateral breast cancer, locoregional recurrence, and distant nonbone recurrence [73].

Equally promising results have been reported in an early subset analysis of the Breast International Group 1–04/Does Adjuvant Zoledronic acid redUce REcurrence study. This large, multicenter trial randomized a total of 3,360 women with stage II–III breast cancer to standard (neo)adjuvant therapy alone or combined with zoledronic acid (monthly for 6 months, then every 3 months for 2 years, then every 6 months for 2.5 years) with a planned follow-up of 5 years [74]. In the 205 women who received neoadjuvant chemotherapy, the addition of zoledronic acid significantly improved the pathological response rate of the primary tumor [75]. Whether these benefits will impact disease-free survival is yet to be reported.

Finally, of the other ongoing adjuvant bisphosphonate trials, including GAIN (German Adjuvant Intergroup Node-positive) (n = 3,000) and ICE (Ibandronate with or without Capecitabine in Elderly patients) (n = 1,400), the Southwest Oncology Group S0307 study that started recruitment in 2005 is of particular interest. This ambitious phase III, randomized trial is seeking to recruit 4,500 participants, comparing adjuvant zoledronic acid (4 mg i.v. monthly for 6 months, then 3 monthly for 2.5 years) with clodronate (1,600 mg/day orally [PO] for 3 years) and with ibandronate (50 mg/day PO for 3 years) in patients with resected stage I–III breast cancer, and follow them for 10 years [76].


   IMPACT AND PREVENTION OF ONJ
Top
 Abstract
 Introduction
 Current Evidence Supporting the...
 Emerging Evidence on the...
 Impact and Prevention of...
Risk Stratification Using Bone...
 Conclusion
 Author Contributions
 References
 
ONJ has officially been defined by consensus as the persistence of exposed bone in the oral cavity, despite adequate treatment for 8 weeks, without local evidence of malignancy and no prior radiotherapy to the affected region [77].

Our current understanding of the underlying pathophysiology is limited, but in particular, the potent nitrogen-containing bisphosphonates have been associated with this rare disorder, suggesting that their powerful inhibition of bone resorption and the subsequent reduction in remodeling capacity are important. Additionally, in approximately 80% of patients with ONJ, an invasive dental procedure was performed at the affected site, implicating trauma as a pivotal factor in the disease etiology [78]. Nonetheless, other factors, including superinfection, inhibition of angiogenesis by bisphosphonates or concomitant treatments, and impaired wound healing resulting from cytotoxic or steroid therapy, have been suggested to play a role as well [79].

Current estimates on the prevalence of ONJ in bisphosphonate-treated multiple myeloma patients vary between 2.3% and 11%, with smaller series and Greek authors [80–82] reporting higher numbers than in larger retrospective cohort studies [9, 83] or studies originating from other parts of the world. Despite this broad range, this risk does seem consistently higher than the 1.2%–6.5% reported for breast or prostate cancer patients (Table 2). The cause of this greater susceptibility remains unknown, although some evidence suggests a higher incidence of dental problems requiring surgery in myeloma patients. In addition, the longer duration of remissions in comparison with other malignancies may increase the prevalence of ONJ, as well as regional differences in oral comorbidities [84].


View this table:
[in this window]
[in a new window]

  		Table 2. Available evidence estimating the prevalence of ONJ in different tumor types

 
In response, existing treatment guidelines published by the American Society of Clinical Oncology (ASCO) and the Mayo Clinic have been revised, suggesting a limit to the duration of bisphosphonate therapy of 2 years in patients who respond to therapy or have stable disease, instead of continued use until there is evidence of a substantial decline in a patient's general performance status [85–87]. The results of LOTUZ (LOng-Term Use of Zometa), an ongoing, multicenter, prospective, pharmacoepidemiological trial studying the safety and efficacy of the long-term use of zoledronic acid beyond 2 years in patients with solid and hematologic malignancies, will probably provide valuable data to assess the strength of this recommendation [88].

Also, a lower frequency of bisphosphonate administration (e.g., 3 monthly) has been suggested in patients who have minimal disease requiring active therapy, although no trial data on efficacy and effect on ONJ occurrence exist to support this claim [86]. An even more controversial topic is the preferred bisphosphonate in myeloma patients, with ASCO suggesting either pamidronate or zoledronic acid and the Mayo Clinic choosing the former as the agent of choice in newly diagnosed patients [86, 87]. Indeed, some cohort studies have suggested a higher risk for ONJ in patients treated with zoledronic acid, compared with pamidronate [9, 80]. However, uncertainties regarding the statistical validity of one such report exist [89], whereas another had an unusually high incidence of ONJ [82], and more recent reports studying a larger number of patients could not replicate this finding [83]. Moreover, most of these reports were published before adequate prevention strategies for ONJ were implemented and prior to the publication of a consensus definition of ONJ.

Indeed, the only intervention with a proven benefit in reducing the occurrence of ONJ is prevention, effectively reducing the incidence of ONJ in one study from 3.2% to 1.3% in patients with solid tumors [90]. Similar benefits have also been reported in multiple myeloma patients [91]. Recent data emerging from ongoing prospective trials with zoledronic acid have been rather reassuring and did not document any case of ONJ [63, 73].

Consensus-based prevention guidelines recommend a panoramic radiograph to help in the diagnosis of caries and periodontal disease, the evaluation of third molars, and the identification of metastatic cancer and other bony pathology [92]. If bisphosphonate therapy can be delayed, preventive surgery to eliminate potential sites of infection should be performed. Only after the mucosa has completely healed should bisphosphonate therapy be started. Finally, dentures should be adjusted to relieve pressure on mucosal surfaces.

Optimal dental health during treatment is essential, and all patients should be informed of the importance of good oral hygiene and the use of chlorhexidine rinses. In addition, regular visual inspections by the treating physician and routine assessments (at least annually) by a dental specialist are warranted.

Whenever dental treatment is necessary, the less invasive endodontic techniques with preservation of the dental root are preferred over total tooth extraction. Only when teeth have a mobility score ≥3 should extraction be considered, and it should be performed as atraumatically as possible [92]. To prevent local infection, the use of antibiotics may be indicated. Otherwise, any elective jaw procedure requiring bone healing should be avoided.

Some authors suggest the withdrawal of bisphosphonate therapy for 1–3 months before performing invasive dental procedures [86, 93]. Considering the long half-life of bisphosphonates in bone, however, it remains doubtful if adequate osteoclast recovery is realistic [94].


   RISK STRATIFICATION USING BONE TURNOVER MARKERS
Top
 Abstract
 Introduction
 Current Evidence Supporting the...
 Emerging Evidence on the...
 Impact and Prevention of...
 Risk Stratification Using Bone...
Conclusion
 Author Contributions
 References
 
When bone is resorbed by osteoclast activity, the collagen remnants of the organic matrix can be detected in the serum or urine [95]. These degradation products, including the aminoterminal (NTX-I) and carboxyterminal (CTX-I) crosslinked telopeptide, have been shown to be specific biochemical markers of osteoclast function and hence of bone turnover [96]. Although initially used in clinical trials to assess the effect of bisphosphonate therapy on bone turnover, the use of serum CTX-I has recently been proposed to predict the risk for ONJ after an invasive dental procedure in patients receiving oral bisphosphonate therapy. Patients with morning fasting serum CTX-I levels >150 pg/ml are considered to have adequate residual bone remodeling capacity and to be only at minimal risk of developing ONJ [97].

However, the technique is subject to considerable variability, both subject and assay related, and most patients on bisphosphonate therapy will not have had a baseline CTX-I measurement. Moreover, known sources of CTX-I variability include, amongst others, the circadian cycle, gender, age, food intake, renal and liver function, and concomitant medication use [98]. Therefore, it can be questioned whether an arbitrarily defined cutoff of 150 pg/ml that does not take into account pretherapy baseline CTX-I levels is universally appropriate. In fact, recently published reports cast doubt on the reliability of CTX-I by failing to demonstrate a significant relationship between the marker and the severity of ONJ and the fact that some patients with ONJ have bone markers that are within the normal range [99, 100].

In patients with skeletal metastases, the theoretical merit of bone turnover markers is lacking, and they should thus not be used to guide clinical management decisions. Indeed, bone markers give an overall impression of bone turnover in the whole skeleton, and in cancer patients this will largely be determined by the number and activity of metastatic tumor deposits in the skeleton. A serum CTX-I sample with a value above a predefined threshold is, in these patients, not a measure of adequate residual osteoclast capacity, but rather of poor disease control.

In addition, the increase in bone turnover markers caused by skeletal metastases varies greatly among different malignancies. This was elegantly demonstrated in a pooled analysis of three randomized, controlled, phase III clinical trials of cancer patients (n = 1,462) receiving zoledronic acid. Approximately 44% of prostate cancer patients had highly elevated urinary NTX-I/creatinine levels at baseline, compared with 37% of breast cancer patients and only 20% of multiple myeloma patients. Moreover, bone resorption markers have been found to provide prognostic information in patients with bone metastases. Persisting high or moderate NTX-I/creatinine levels in patients with solid tumors during bisphosphonate treatment were associated with a 4.8-fold (95% CI, 3.9–5.9; p < .001) and 3.1-fold (95% CI, 2.5–3.8; p < .001) higher risk for death, respectively, compared with patients with low bone turnover markers [101]. Consequently, the use of marker-directed therapy is prospectively being investigated in the BISMARK (BISphosphonates in metastatic bone disease: MARKer directed therapy with zoledronic acid) trial [102].

In summary, although the theoretical concept of risk stratification using CTX-I in osteoporosis patients is appealing, the current evidence is still limited and requires further validation before its widespread clinical use is warranted. In contrast, in cancer patients with metastatic bone disease, who will ultimately represent 95% of ONJ cases, we see no role for bone markers to guide management decisions as yet.


   CONCLUSION
Top
 Abstract
 Introduction
 Current Evidence Supporting the...
 Emerging Evidence on the...
 Impact and Prevention of...
 Risk Stratification Using Bone...
 Conclusion
Author Contributions
 References
 
The bisphosphonates have been proven to be an important asset in the treatment and prevention of SREs in cancer patients with bone metastases. Although the results in the adjuvant setting are very promising, in particular in the prevention of bone metastases, they are as yet not practice changing. With the results of a number of large trials set to be reported in the near future, the final verdict on the adjuvant use of bisphosphonates in breast cancer is still out. Nonetheless, it seems reasonable to assume that some of this research will translate into new indications for bisphosphonate use in oncology.

With the increasing use of bisphosphonates, ONJ has to be recognized as a potential side effect that is rare, but can have a high impact on quality of life. However, when implementing a set of straightforward preventative measures, ONJ should not deter the clinician from using this powerful tool in daily practice and recognizing the rising stars that the bisphosphonates continue to be in oncology.


   AUTHOR CONTRIBUTIONS
Top
 Abstract
 Introduction
 Current Evidence Supporting the...
 Emerging Evidence on the...
 Impact and Prevention of...
 Risk Stratification Using Bone...
 Conclusion
 Author Contributions
References
 
Conception/design: Tim Van den Wyngaert

Collection/assembly of data: Tim Van den Wyngaert

Data analysis: Tim Van den Wyngaert, Manon T. Huizing, Eric Fossion, Jan B. Vermorken

Manuscript writing: Tim Van den Wyngaert

Final approval of manuscript: Manon T. Huizing, Eric Fossion, Jan B. Vermorken


   REFERENCES
Top
 Abstract
 Introduction
 Current Evidence Supporting the...
 Emerging Evidence on the...
 Impact and Prevention of...
 Risk Stratification Using Bone...
 Conclusion
 Author Contributions
 References
 

  1. Fleisch H, Russell RG, Bisaz S et al. The influence of pyrophosphate analogues (diphosphonates) on the precipitation and dissolution of calcium phosphate in vitro and in vivo. Calcif Tissue Res 1968;2(suppl):10–10a.[Medline]
  2. Van den Wyngaert T, Huizing MT, Vermorken JB. Disambiguating the bisphosphonates. Ann Oncol 2008;19:1357–1359.[Free Full Text]
  3. Bassett CA, Donath A, Macagno F et al. Diphosphonates in the treatment of myositis ossificans. Lancet 1969;2:845.[Medline]
  4. Fleisch H, Russell RG, Francis MD. Diphosphonates inhibit hydroxyapatite dissolution in vitro and bone resorption in tissue culture and in vivo. Science 1969;165:1262–1264.[Abstract/Free Full Text]
  5. Mundy GR. Mechanisms of bone metastasis. Cancer 1997;80;(8) (suppl):1546–1556.[CrossRef][Medline]
  6. Ross JR, Saunders Y, Edmonds PM et al. Systematic review of role of bisphosphonates on skeletal morbidity in metastatic cancer. BMJ 2003;327:469–474.[Abstract/Free Full Text]
  7. Marx RE. Pamidronate (Aredia) and zoledronate (Zometa) induced avascular necrosis of the jaws: A growing epidemic. J Oral Maxillofac Surg 2003;61:1115–1117.[CrossRef][Medline]
  8. Conte P, Guarneri V. Safety of intravenous and oral bisphosphonates and compliance with dosing regimens. The Oncologist 2004;9(suppl 4):28–37.[Abstract/Free Full Text]
  9. Estilo CL, Van Poznak CH, Wiliams T et al. Osteonecrosis of the maxilla and mandible in patients with advanced cancer treated with bisphosphonate therapy. The Oncologist 2008;13:911–920.[Abstract/Free Full Text]
  10. Ibrahim T, Barbanti F, Giorgio-Marrano G et al. Osteonecrosis of the jaw in patients with bone metastases treated with bisphosphonates: A retrospective study. The Oncologist 2008;13:330–336.[Abstract/Free Full Text]
  11. Lahtinen R, Laakso M, Palva I et al. Finnish Leukaemia Group. Randomised, placebo-controlled multicentre trial of clodronate in multiple myeloma. Lancet 1992;340:1049–1052.[CrossRef][Medline]
  12. McCloskey EV, MacLennan IC, Drayson MT et al. MRC Working Party on Leukaemia in Adults. A randomized trial of the effect of clodronate on skeletal morbidity in multiple myeloma. Br J Haematol 1998;100:317–325.[CrossRef][Medline]
  13. Berenson JR, Lichtenstein A, Porter L et al. Myeloma Aredia Study Group. Efficacy of pamidronate in reducing skeletal events in patients with advanced multiple myeloma. N Engl J Med 1996;334:488–493.[Abstract/Free Full Text]
  14. Brincker H, Westin J, Abildgaard N et al. Danish-Swedish co-operative study group. Failure of oral pamidronate to reduce skeletal morbidity in multiple myeloma: A double-blind placebo-controlled trial. Br J Haematol 1998;101:280–286.[CrossRef][Medline]
  15. Berenson JR, Rosen LS, Howell A et al. Zoledronic acid reduces skeletal-related events in patients with osteolytic metastases. Cancer 2001;91:1191–1200.[CrossRef][Medline]
  16. Rosen LS, Gordon D, Kaminski M et al. Zoledronic acid versus pamidronate in the treatment of skeletal metastases in patients with breast cancer or osteolytic lesions of multiple myeloma: A phase III, double-blind, comparative trial. Cancer J 2001;7:377–387.[Medline]
  17. Menssen HD, Sakalova A, Fontana A et al. Effects of long-term intravenous ibandronate therapy on skeletal-related events, survival, and bone resorption markers in patients with advanced multiple myeloma. J Clin Oncol 2002;20:2353–2359.[Abstract/Free Full Text]
  18. Paterson AH, Powles TJ, Kanis JA et al. Double-blind controlled trial of oral clodronate in patients with bone metastases from breast cancer. J Clin Oncol 1993;11:59–65.[Abstract]
  19. Kristensen B, Ejlertsen B, Groenvold M et al. Oral clodronate in breast cancer patients with bone metastases: A randomized study. J Intern Med 1999;246:67–74.[CrossRef][Medline]
  20. Tubiana-Hulin M, Beuzeboc P, Mauriac L et al. [Double-blinded controlled study comparing clodronate versus placebo in patients with breast cancer bone metastases]. Bull Cancer 2001;88:701–707.[Medline]
  21. Pavlakis N, Schmidt R, Stockler M. Bisphosphonates for breast cancer. Cochrane Database Syst Rev 2005;(3):CD003474.
  22. Coleman RE. Bisphosphonates in breast cancer. Ann Oncol 2005;16:687–695.[Abstract/Free Full Text]
  23. Conte PF, Latreille J, Mauriac L et al. The Aredia Multinational Cooperative Group. Delay in progression of bone metastases in breast cancer patients treated with intravenous pamidronate: Results from a multinational randomized controlled trial. J Clin Oncol 1996;14:2552–2559.[Abstract]
  24. Hortobagyi GN, Theriault RL, Lipton A et al. Protocol 19 Aredia Breast Cancer Study Group. Long-term prevention of skeletal complications of metastatic breast cancer with pamidronate. J Clin Oncol 1998;16:2038–2044.[Abstract]
  25. Hultborn R, Gundersen S, Ryden S et al. Efficacy of pamidronate in breast cancer with bone metastases: A randomized, double-blind placebo-controlled multicenter study. Anticancer Res 1999;19:3383–3392.[Medline]
  26. Theriault RL, Lipton A, Hortobagyi GN et al. Protocol 18 Aredia Breast Cancer Study Group. Pamidronate reduces skeletal morbidity in women with advanced breast cancer and lytic bone lesions: A randomized, placebo-controlled trial. J Clin Oncol 1999;17:846–854.[Abstract/Free Full Text]
  27. Lipton A, Theriault RL, Hortobagyi GN et al. Pamidronate prevents skeletal complications and is effective palliative treatment in women with breast carcinoma and osteolytic bone metastases: Long term follow-up of two randomized, placebo-controlled trials. Cancer 2000;88:1082–1090.[CrossRef][Medline]
  28. Jagdev SP, Purohit P, Heatley S et al. Comparison of the effects of intravenous pamidronate and oral clodronate on symptoms and bone resorption in patients with metastatic bone disease. Ann Oncol 2001;12:1433–1438.[Abstract/Free Full Text]
  29. Kohno N, Aogi K, Minami H et al. Zoledronic acid significantly reduces skeletal complications compared with placebo in Japanese women with bone metastases from breast cancer: A randomized, placebo-controlled trial. J Clin Oncol 2005;23:3314–3321.[Abstract/Free Full Text]
  30. Rosen LS, Gordon DH, Dugan W Jr et al. Zoledronic acid is superior to pamidronate for the treatment of bone metastases in breast carcinoma patients with at least one osteolytic lesion. Cancer 2004;100:36–43.[CrossRef][Medline]
  31. Clemons MJ, Dranitsaris G, Ooi WS et al. Phase II trial evaluating the palliative benefit of second-line zoledronic acid in breast cancer patients with either a skeletal-related event or progressive bone metastases despite first-line bisphosphonate therapy. J Clin Oncol 2006;24:4895–4900.[Abstract/Free Full Text]
  32. Body JJ, Diel IJ, Lichinitser MR et al. Intravenous ibandronate reduces the incidence of skeletal complications in patients with breast cancer and bone metastases. Ann Oncol 2003;14:1399–1405.[Abstract/Free Full Text]
  33. Body JJ, Diel IJ, Lichinitzer M et al. Oral ibandronate reduces the risk of skeletal complications in breast cancer patients with metastatic bone disease: Results from two randomised, placebo-controlled phase III studies. Br J Cancer 2004;90:1133–1137.[CrossRef][Medline]
  34. Cook RJ, Major P. Methodology for treatment evaluation in patients with cancer metastatic to bone. J Natl Cancer Inst 2001;93:534–538.[Abstract/Free Full Text]
  35. Barrett-Lee PJ, Murray N. Zoledronic acid versus ibandronate comparative evaluation in breast cancer patients with bone metastases: The NCRI ZICE trial. Bone 2006;38(suppl 1):67.[Medline]
  36. Rivkin S. Oral ibandronate versus intravenous zoledronic acid for breast cancer patients with skeletal complications: The SWOG trial. Bone 2006;38(suppl 1):82.
  37. Berry S, Waldron T, Winquist E et al. The use of bisphosphonates in men with hormone-refractory prostate cancer: A systematic review of randomized trials. Can J Urol 2006;13:3180–3188.[Medline]
  38. Smith JA Jr. Palliation of painful bone metastases from prostate cancer using sodium etidronate: Results of a randomized, prospective, double-blind, placebo-controlled study. J Urol 1989;141:85–87.[Medline]
  39. Small EJ, Smith MR, Seaman JJ et al. Combined analysis of two multicenter, randomized, placebo-controlled studies of pamidronate disodium for the palliation of bone pain in men with metastatic prostate cancer. J Clin Oncol 2003;21:4277–4284.[Abstract/Free Full Text]
  40. Saad F, Gleason DM, Murray R et al. A randomized, placebo-controlled trial of zoledronic acid in patients with hormone-refractory metastatic prostate carcinoma. J Natl Cancer Inst 2002;94:1458–1468.[Abstract/Free Full Text]
  41. Saad F, Gleason DM, Murray R et al. Long-term efficacy of zoledronic acid for the prevention of skeletal complications in patients with metastatic hormone-refractory prostate cancer. J Natl Cancer Inst 2004;96:879–882.[Abstract/Free Full Text]
  42. Saad F, Lipton A. Zoledronic acid is effective in preventing and delaying skeletal events in patients with bone metastases secondary to genitourinary cancers. BJU Int 2005;96:964–969.[CrossRef][Medline]
  43. Saad F. Bisphosphonates can prevent skeletal complications of malignant bone disease from prostate cancer and renal cell carcinoma. Eur Urol Suppl 2007;6:683–688.[CrossRef]
  44. Heidenreich A, Elert A, Hofmann R et al. Ibandronate in the treatment of prostate cancer associated painful osseous metastases. Prostate Cancer Prostatic Dis 2002;5:231–235.[CrossRef][Medline]
  45. Rosen LS, Gordon D, Tchekmedyian S et al. Zoledronic acid versus placebo in the treatment of skeletal metastases in patients with lung cancer and other solid tumors: A phase III, double-blind, randomized trial—the Zoledronic Acid Lung Cancer and Other Solid Tumors Study Group. J Clin Oncol 2003;21:3150–3157.[Abstract/Free Full Text]
  46. Rosen LS, Gordon D, Tchekmedyian NS et al. Long-term efficacy and safety of zoledronic acid in the treatment of skeletal metastases in patients with nonsmall cell lung carcinoma and other solid tumors: A randomized, phase III, double-blind, placebo-controlled trial. Cancer 2004;100:2613–2621.[CrossRef][Medline]
  47. Lipton A, Zheng M, Seaman J. Zoledronic acid delays the onset of skeletal-related events and progression of skeletal disease in patients with advanced renal cell carcinoma. Cancer 2003;98:962–969.[CrossRef][Medline]
  48. Major P, Lortholary A, Hon J et al. Zoledronic acid is superior to pamidronate in the treatment of hypercalcemia of malignancy: A pooled analysis of two randomized, controlled clinical trials. J Clin Oncol 2001;19:558–567.[Abstract/Free Full Text]
  49. Brufsky AM. Cancer treatment-induced bone loss: Pathophysiology and clinical perspectives. The Oncologist 2008;13:187–195.[Abstract/Free Full Text]
  50. Shahinian VB, Kuo YF, Freeman JL et al. Risk of fracture after androgen deprivation for prostate cancer. N Engl J Med 2005;352:154–164.[Abstract/Free Full Text]
  51. Polascik TJ. Bone health in prostate cancer patients receiving androgen-deprivation therapy: The role of bisphosphonates. Prostate Cancer Prostatic Dis 2008;11:13–19.[CrossRef][Medline]
  52. Smith MR, McGovern FJ, Zietman AL et al. Pamidronate to prevent bone loss during androgen-deprivation therapy for prostate cancer. N Engl J Med 2001;345:948–955.[Abstract/Free Full Text]
  53. Greenspan SL, Nelson JB, Trump DL et al. Effect of once-weekly oral alendronate on bone loss in men receiving androgen deprivation therapy for prostate cancer: A randomized trial. Ann Intern Med 2007;146:416–424.[Abstract/Free Full Text]
  54. Smith MR, Eastham J, Gleason DM et al. Randomized controlled trial of zoledronic acid to prevent bone loss in men receiving androgen deprivation therapy for nonmetastatic prostate cancer. J Urol 2003;169:2008–2012.[CrossRef][Medline]
  55. Ryan CW, Huo D, Demers LM et al. Zoledronic acid initiated during the first year of androgen deprivation therapy increases bone mineral density in patients with prostate cancer. J Urol 2006;176:972–978.[CrossRef][Medline]
  56. Israeli RS, Rosenberg SJ, Saltzstein DR et al. The effect of zoledronic acid on bone mineral density in patients undergoing androgen deprivation therapy. Clin Genitourin Cancer 2007;5:271–277.[CrossRef][Medline]
  57. Michaelson MD, Kaufman DS, Lee H et al. Randomized controlled trial of annual zoledronic acid to prevent gonadotropin-releasing hormone agonist-induced bone loss in men with prostate cancer. J Clin Oncol 2007;25:1038–1042.[Abstract/Free Full Text]
  58. Howell A, Cuzick J, Baum M et al. Results of the ATAC (Arimidex, Tamoxifen, Alone or in Combination) trial after completion of 5 years' adjuvant treatment for breast cancer. Lancet 2005;365:60–62.[CrossRef][Medline]
  59. McCloskey E. Effects of third-generation aromatase inhibitors on bone. Eur J Cancer 2006;42:1044–1051.[CrossRef][Medline]
  60. Delmas PD, Balena R, Confravreux E et al. Bisphosphonate risedronate prevents bone loss in women with artificial menopause due to chemotherapy of breast cancer: A double-blind, placebo-controlled study. J Clin Oncol 1997;15:955–962.[Abstract/Free Full Text]
  61. Saarto T, Blomqvist C, Valimaki M et al. Chemical castration induced by adjuvant cyclophosphamide, methotrexate, and fluorouracil chemotherapy causes rapid bone loss that is reduced by clodronate: A randomized study in premenopausal breast cancer patients. J Clin Oncol 1997;15:1341–1347.[Abstract/Free Full Text]
  62. Gnant M, Mlineritsch B, Luschin-Ebengreuth G et al. Adjuvant endocrine therapy plus zoledronic acid in premenopausal women with early-stage breast cancer: 5-year follow-up of the ABCSG-12 bone-mineral density substudy. Lancet Oncol 2008;9:840–849.[CrossRef][Medline]
  63. Brufsky A, Bundred N, Coleman R et al. Integrated analysis of zoledronic acid for prevention of aromatase inhibitor-associated bone loss in postmenopausal women with early breast cancer receiving adjuvant letrozole. The Oncologist 2008;13:503–514.[Abstract/Free Full Text]
  64. Diel IJ, Solomayer EF, Costa SD et al. Reduction in new metastases in breast cancer with adjuvant clodronate treatment. N Engl J Med 1998;339:357–363.[Abstract/Free Full Text]
  65. Saarto T, Blomqvist C, Virkkunen P et al. Adjuvant clodronate treatment does not reduce the frequency of skeletal metastases in node-positive breast cancer patients: 5-year results of a randomized controlled trial. J Clin Oncol 2001;19:10–17.[Abstract/Free Full Text]
  66. Powles T, Paterson S, Kanis JA et al. Randomized, placebo-controlled trial of clodronate in patients with primary operable breast cancer. J Clin Oncol 2002;20:3219–3224.[Abstract/Free Full Text]
  67. Diel IJ, Jaschke A, Solomayer EF et al. Adjuvant oral clodronate improves the overall survival of primary breast cancer patients with micrometastases to the bone marrow: A long-term follow-up. Ann Oncol 2008;19:2007–2011.[Abstract/Free Full Text]
  68. Ha TC, Li H. Meta-analysis of clodronate and breast cancer survival. Br J Cancer 2007;96:1796–1801.[CrossRef][Medline]
  69. Mamounas EP. NSABP breast cancer clinical trials: Recent results and future directions. Clin Med Res 2003;1:309–326.[Abstract/Free Full Text]
  70. Kristensen B, Ejlertsen B, Mouridsen HT et al. Bisphosphonate treatment in primary breast cancer: Results from a randomised comparison of oral pamidronate versus no pamidronate in patients with primary breast cancer. Acta Oncol 2008;47:740–746.[CrossRef][Medline]
  71. Daubine F, Le Gall C, Gasser J et al. Antitumor effects of clinical dosing regimens of bisphosphonates in experimental breast cancer bone metastasis. J Natl Cancer Inst 2007;99:322–330.[Abstract/Free Full Text]
  72. Ottewell PD, Monkkonen H, Jones M et al. Antitumor effects of doxorubicin followed by zoledronic acid in a mouse model of breast cancer. J Natl Cancer Inst 2008;100:1167–1178.[Abstract/Free Full Text]
  73. Gnant M, Mlineritsch B, Schippinger W et al. Adjuvant ovarian suppression combined with tamoxifen or anastrozole, alone or in combination with zoledronic acid, in premenopausal women with hormone-responsive, stage I and II breast cancer: First efficacy results from ABCSG-12. J Clin Oncol 2008;26;(15) (suppl):LBA4.
  74. Burkinshawa R, Thorpe H, Pollard S et al. The AZURE trial—Does Adjuvant Zoledronic acid redUce REcurrence in patients with high-risk localised breast cancer? Bone 2006;38(suppl 1):70–71.
  75. Winter M, Thorpe H, Burkinshaw R et al. The addition of zoledronic acid to neoadjuvant chemotherapy may influence pathological response exploratory evidence for direct anti-tumor activity in breast cancer. Presented at the San Antonio Breast Cancer Symposium; December 10–14, 2008; San Antonio, TX.
  76. Paterson AH. The role of bisphosphonates in early breast cancer. The Oncologist 2006;11(suppl 1):13–19.[Abstract/Free Full Text]
  77. Advisory Task Force on Bisphosphonate-Related Osteonecrosis of the Jaws, American Association of Oral and Maxillofacial Surgeons. American Association of Oral and Maxillofacial Surgeons position paper on bisphosphonate-related osteonecrosis of the jaws. J Oral Maxillofac Surg 2007;65:369–376.[CrossRef][Medline]
  78. Van den Wyngaert T, Huizing MT, Vermorken JB. Bisphosphonates and osteonecrosis of the jaw: Cause and effect or a post hoc fallacy? Ann Oncol 2006;17:1197–1204.[Abstract/Free Full Text]
  79. Van den Wyngaert T, Huizing MT, Vermorken JB. Osteonecrosis of the jaw related to the use of bisphosphonates. Curr Opin Oncol 2007;19:315–322.[CrossRef][Medline]
  80. Bamias A, Kastritis E, Bamia C et al. Osteonecrosis of the jaw in cancer after treatment with bisphosphonates: Incidence and risk factors. J Clin Oncol 2005;23:8580–8587.[Abstract/Free Full Text]
  81. Dimopoulos MA, Kastritis E, Anagnostopoulos A et al. Osteonecrosis of the jaw in patients with multiple myeloma treated with bisphosphonates: Evidence of increased risk after treatment with zoledronic acid. Haematologica 2006;91:968–971.[Abstract/Free Full Text]
  82. Zervas K, Verrou E, Teleioudis Z et al. Incidence, risk factors and management of osteonecrosis of the jaw in patients with multiple myeloma: A single-centre experience in 303 patients. Br J Haematol 2006;134:620–623.[CrossRef][Medline]
  83. Hoff AO, Toth BB, Altundag K et al. Frequency and risk factors associated with osteonecrosis of the jaw in cancer patients treated with intravenous bisphosphonates. J Bone Miner Res 2008;23:826–836.[CrossRef][Medline]
  84. Van den Wyngaert T. Osteonecrosis of the jaw (ONJ) might explain the increased oral surgery risk in cancer patients treated with bisphosphonates. J Evid Based Dent Pract 2007;7:132–135.[CrossRef][Medline]
  85. Berenson JR, Hillner BE, Kyle RA et al. American Society of Clinical Oncology clinical practice guidelines: The role of bisphosphonates in multiple myeloma. J Clin Oncol 2002;20:3719–3736.[Abstract/Free Full Text]
  86. Lacy MQ, Dispenzieri A, Gertz MA et al. Mayo Clinic consensus statement for the use of bisphosphonates in multiple myeloma. Mayo Clin Proc 2006;81:1047–1053.[Abstract/Free Full Text]
  87. Kyle RA, Yee GC, Somerfield MR et al. American Society of Clinical Oncology 2007 clinical practice guideline update on the role of bisphosphonates in multiple myeloma. J Clin Oncol 2007;25:2464–2472.[Abstract/Free Full Text]
  88. Wildiers H, Duck L, Delforge M et al. Baseline characteristics, prior bisphosphonate (BPH) therapy (Rx), and clinical parameters of patients in LOTUZ, a prospective pharmacoepidemiological study of long-term zoledronic acid (ZOL) treatment (>2 years) in patients (pts) with solid and hema. J Clin Oncol 2008;26;(15) (15 suppl):20597.
  89. Durie BG, Katz M, Crowley J. Osteonecrosis of the jaw and bisphosphonates. N Engl J Med 2005;353:99–102; discussion 99–102.[Free Full Text]
  90. Ripamonti CI, Maniezzo M, Campa T et al. Decreased occurrence of osteonecrosis of the jaw after implementation of dental preventive measures in solid tumour patients with bone metastases treated with bisphosphonates. The experience of the National Cancer Institute of Milan. Ann Oncol 2009;20:137–145.[Abstract/Free Full Text]
  91. Dimopoulos MA, Kastritis E, Bamia C et al. Reduction of osteonecrosis of the jaw (ONJ) after implementation of preventive measures in patients with multiple myeloma treated with zoledronic acid. Ann Oncol 2009;20:117–120.[Abstract/Free Full Text]
  92. Migliorati CA, Casiglia J, Epstein J et al. Managing the care of patients with bisphosphonate-associated osteonecrosis: An American Academy of Oral Medicine position paper. J Am Dent Assoc 2005;136:1658–1668.[Abstract/Free Full Text]
  93. Thakkar SG, Isada C, Smith J et al. Jaw complications associated with bisphosphonate use in patients with plasma cell dyscrasias. Med Oncol 2006;23:51–56.[CrossRef][Medline]
  94. Papapoulos SE, Cremers SC. Prolonged bisphosphonate release after treatment in children. N Engl J Med 2007;356:1075–1076.[Free Full Text]
  95. Fleisch H. Bisphosphonates in Bone Disease. Second Edition. New York: The Parthenon Publishing Group, 1995:27.
  96. Calvo MS, Eyre DR, Gundberg CM. Molecular basis and clinical application of biological markers of bone turnover. Endocr Rev 1996;17:333–368.[Abstract/Free Full Text]
  97. Marx RE, Cillo JE Jr, Ulloa JJ. Oral bisphosphonate-induced osteonecrosis: Risk factors, prediction of risk using serum CTX testing, prevention, and treatment. J Oral Maxillofac Surg 2007;65:2397–2410.[CrossRef][Medline]
  98. Seibel MJ. Biochemical markers of bone turnover: Part I: Biochemistry and variability. Clin Biochem Rev 2005;26:97–122.[Medline]
  99. Bagan JV, Jimenez Y, Gomez D et al. Collagen telopeptide (serum CTX) and its relationship with the size and number of lesions in osteonecrosis of the jaws in cancer patients on intravenous bisphosphonates. Oral Oncol 2008;44:1088–1089.[CrossRef]
  100. Lehrer S, Montazem A, Ramanathan L et al. Normal serum bone markers in bisphosphonate-induced osteonecrosis of the jaws. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 2008;106:389–391.[CrossRef][Medline]
  101. Coleman RE, Major P, Lipton A et al. Predictive value of bone resorption and formation markers in cancer patients with bone metastases receiving the bisphosphonate zoledronic acid. J Clin Oncol 2005;23:4925–4935.[Abstract/Free Full Text]
  102. Lipton A. Biochemical bone markers in breast cancer. Cancer Treat Rev 2006;32(suppl 1):20–22.[CrossRef][Medline]
  103. Mason MD, Sydes MR, Glaholm J et al. Oral sodium clodronate for nonmetastatic prostate cancer–results of a randomized double-blind placebo-controlled trial: Medical Research Council PR04 (ISRCTN61384873). J Natl Cancer Inst 2007;99:765–776.[Abstract/Free Full Text]
  104. Dearnaley DP, Sydes MR, Mason MD et al. A double-blind, placebo-controlled, randomized trial of oral sodium clodronate for metastatic prostate cancer (MRC PR05 Trial). J Natl Cancer Inst 2003;95:1300–1311.[Abstract/Free Full Text]
  105. Ernst DS, Tannock IF, Winquist EW et al. Randomized, double-blind, controlled trial of mitoxantrone/prednisone and clodronate versus mitoxantrone/prednisone and placebo in patients with hormone-refractory prostate cancer and pain. J Clin Oncol 2003;21:3335–3342.[Abstract/Free Full Text]
  106. Kylmala T, Taube T, Tammela TL et al. Concomitant i.v. and oral clodronate in the relief of bone pain—a double-blind placebo-controlled study in patients with prostate cancer. Br J Cancer 1997;76:939–942.[Medline]
  107. Strang P, Nilsson S, Brandstedt S et al. The analgesic efficacy of clodronate compared with placebo in patients with painful bone metastases from prostatic cancer. Anticancer Res 1997;17:4717–4721.[Medline]
  108. Elomaa I, Kylmala T, Tammela T et al. Effect of oral clodronate on bone pain. A controlled study in patients with metastatic prostatic cancer. Int Urol Nephrol 1992;24:159–166.[Medline]
  109. Badros A, Weikel D, Salama A et al. Osteonecrosis of the jaw in multiple myeloma patients: Clinical features and risk factors. J Clin Oncol 2006;24:945–952.[Abstract/Free Full Text]
  110. Ortega C, Faggiuolo R, Vormola R et al. Jaw complications in breast and prostate cancer patients treated with zoledronic acid. Acta Oncol 2006;45:216–217.[Medline]
  111. Wang EP, Kaban LB, Strewler GJ et al. Incidence of osteonecrosis of the jaw in patients with multiple myeloma and breast or prostate cancer on intravenous bisphosphonate therapy. J Oral Maxillofac Surg 2007;65:1328–1331.[CrossRef][Medline]
  112. Jadu F, Lee L, Pharoah M et al. A retrospective study assessing the incidence, risk factors and comorbidities of pamidronate-related necrosis of the jaws in multiple myeloma patients. Ann Oncol 2007;18:2015–2019.[Abstract/Free Full Text]



This article has been cited by other articles:


Home page
 Anticancer ResHome page
G. SPIZZO, A. SEEBER, and M. MITTERER
Routine Use of Pamidronate in NSCLC Patients with Bone Metastasis: Results from a Retrospective Analysis
Anticancer Res, December 1, 2009; 29(12): 5245 - 5249.
[Abstract] [Full Text] [PDF]

This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF)
Right arrow All Versions of this Article:
theoncologist.2008-0209v1
14/2/181    most recent
Right arrow eLetters: Submit a response to this article
Right arrow Purchase Article
Right arrow View Shopping Cart
Right arrow Alert me when this article is cited
Right arrow Alert me when eLetters are posted
Right arrow Alert me if a correction is posted
Right arrow Citation Map
Services
Right arrow E-mail this article link to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrow Reprints/Permissions
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Van den Wyngaert, T.
Right arrow Articles by Vermorken, J. B.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Van den Wyngaert, T.
Right arrow Articles by Vermorken, J. B.

HOME HELP CONTACT US SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
THE ONCOLOGIST STEM CELLS CME ALPHAMED PRESS JOURNALS