Bone is the most common location of metastatic disease most frequently associated with breast and prostate cancers 1. Breast and prostate tumours represent around 80% of all bone metastases and these metastases are involved in more than 300 000 deaths every year; thus, it is important to understand their pathophysiology and treatment. Essentially, bone metastases can be radiologically classified as lytic, blastic or mixed. However, from a pathogenic viewpoint, all cases show an increase in both bone resorption and osteoblastic activity 2.
Tumour cells secrete a series of factors that stimulate osteoclastic activity including prostaglandin E, transforming growth factor, epidermal growth factor, tumour necrosis factor and interleukin 1 3. As a consequence of this alteration in the bone metabolism, several serum markers are released, becoming detectable in blood. These serum markers related to bone formation–destruction turnover can provide information about loss of bone mass, which could be useful during adjuvant breast cancer treatment and for monitoring the response of metastatic bone disease to bisphosphonate (BP) treatment. This would be the case, for instance, with N-telopeptide of type I collagen, which could predict the risk of skeletal morbidity and death in patients with bone metastases and be used to determine response to treatment with zoledronic acid (ZA) 4. The symptoms related to bone metastases are associated with this osteoclastic activity involving bone resorption 5.
Bone metastases frequently affect the clinical course of the malignant disease and have a severe impact on quality of life (QoL). Therefore, the main goals of the treatment of metastatic bone disease are to control symptoms and increase QoL. The diagnosis of bone metastases can coincide with significant morbidity in female patients with the onset of events such as spinal cord compression, pathological fractures and hypercalcaemia 6. However, pain is the most common symptom related to bone metastases from breast cancer. It is usually the first sign of metastatic disease and can present in up to 80% of all cases 7. The pathogenesis of metastatic bone pain is not fully understood; mediators such as prostaglandins, histamine and bradykinin could be involved 8.
Bone-targeted therapy such as BP treatment reduces bone resorption and, therefore, related bone events, in addition to reducing bone mass loss related to the disease or its treatment. The mechanism of action of these drugs can be highly complex, even having a direct effect on tumour cells. Despite the available evidence confirming the efficacy of BP only in the metastatic setting, some data have suggested a potential benefit of adding BP to adjuvant therapy 9.
The American Society of Clinical Oncology (ASCO) has published guidelines on the use of bone-modifying agents in metastatic breast cancer 10,11. These agents include BPs and new osteoclast inhibitors. The first ASCO guidelines were published in the year 2000 and they were updated in 2003. Most of the recommendations remain unchanged. These compounds are recommended in bone metastases due to breast cancer with bone loss. It is also recommended that a dental examination be performed before BP administration, and that creatinine levels are monitored during BP therapy. Bone-modifying agents include the BPs ZA, pamidronate (PA) and denosumab.
This paper reviews the use of BPs in female patients with metastatic breast cancer, emphasizing the role of the most widely used BP, ZA. The phase III studies with this drug have provided first-class scientific evidence of the prevention of skeletal events in breast cancer patients with bone metastases and of its use as prophylaxis for bone mass loss related to cancer or its treatment.
Endpoints and objectives of studies with bisphosphonates
Around 70% of patients with advanced breast cancer present bone involvement, which is associated with a 2-year median survival rate, although ∼20% survive for 5 years or more. Bone metastases have a huge impact not only in terms of mortality but also in terms of morbidity. Pain is the most common symptom and is estimated to be present in 50–90% of all cases. The impact of BPs has to be effectively and homogeneously measured to study and quantify their benefit. The primary objective in most studies is the number or percentage and timing of skeletal-related events (SREs). They are usually defined as events that include one or more of the following: pathological fracture, need for radiotherapy or surgery for bone complications (pain, fractures) or spinal cord compression. Hypercalcaemia is occasionally included. However, as the different studies do not provide the same definition of SRE, they are not comparable. Other common limitations of trial design are that studies frequently do not consider other important issues such as pain, immobility or the use of analgesics. Moreover, most trials do not use the appropriate QoL assessments or cost-effectiveness analyses. Therefore, the primary endpoint in more recent studies tends to be mean skeletal morbidity rate, defined as number of SREs divided by the study time in years. Another alternative study objective is skeletal morbidity period rate, which refers to events within a specific period of time (usually 12 weeks). However, even with these methodological limitations, some important conclusions can be drawn about the efficacy of the oral BPs clodronate and ibandronate, and the intravenous (i.v.) BPs PA and ZA, as will be briefly discussed below.
Role of bisphosphonates in bone disease
Multiple studies and several systematic reviews have assessed the role of BPs in stage IV breast cancer with bone metastases.
In the first systematic review of the literature in patients with bone disease, BP therapy reduces the odds ratio (OR) of nonvertebral fractures [OR 0.80; 95% confidence interval (CI) 0.64–0.99], fractures in general (OR 0.75; 95% CI 0.61–0.93), need for radiotherapy (OR 0.65; 95% CI 0.54–0.79) or orthopaedic surgery (OR 0.59; 95% CI 0.43–0.83) and hypercalcaemia (OR 0.43; 95% CI 0.29–0.63) versus placebo 12.
A subsequent Cochrane review analysed nine studies that included 2189 breast cancer patients with clinically evident bone metastases treated with BP. Whether compared with placebo or not, BPs showed a significant 17% reduction [risk ratio (RR) 0.83; 95% CI 0.78–0.89; P<0.00001] in the risk of SRE, including hypercalcemia. Moreover, BPs reduced the SRE rate by 28% and delayed its median time of onset. The RR was 0.77 (95% CI 0.69–0.87) for i.v. PA, 0.59 (95% CI 0.42–0.82) for i.v. ZA and 0.84 (95% CI 0.72–0.98) for oral clodronate. In seven studies versus or not versus placebo, BP showed better pain control and there was also an improvement in QoL in the few studies that analysed it. There was no benefit, however, in terms of overall survival (RR 0.99; 95% CI 0.93–1.05) or reduction in the incidence of SREs in patients with asymptomatic bone disease 13.
A more recent meta-analysis included 18 randomized studies in which bone metastases from different primary tumours had been treated with clodronate, PA or ZA. Unlike the previous review, each drug was analysed individually. The RR of SRE was 0.87 (95% CI 0.75–1.00) with clodronate, 0.81 (95% CI 0.73–0.91) with PA and 0.70 (95% CI 0.61–0.81) with ZA, which was significant versus placebo in the latter two and borderline with the former. Once again, there was no reduction in mortality versus placebo in any of the BPs 14. This study confirmed that, despite the absence of any effect on mortality, both PA and ZA significantly reduced the risk of SRE, with a greater benefit observed with ZA treatment (30% reduction in the risk of any SRE).
A very similar conclusion can be drawn from a more recent Cochrane review, published in 2012 15. This pooled analysis included nine studies comparing BPs with placebo or no BPs and included 2806 patients with breast cancer and clinically evident bone metastases. Again, BPs showed a significant reduction in the risk of SRE compared with placebo or no BPs (15% reduction; RR 0.85; 95% CI 0.77–0.94; P=0.001). The reduction in risk was most apparent with i.v. formulations, with an RR of 0.59 (95% CI 0.42–0.82) for i.v. ZA, 0.77 (95% CI 0.69–0.87) for i.v. PA and 0.80 (95% CI 0.67–0.96) for i.v. ibandronate.
Role of zoledronic acid in bone disease
Definitive conclusions on the efficacy of one BP over another should be avoided as there is a lack of a direct comparison among different BPs other than ZA versus PA. However, among the few studies available comparing the efficacy of oral BPs with ZA, a phase III study showed a similar efficacy of oral ibandronate to i.v. ZA 16. A second study comparing oral clodronate with i.v. PA also showed similar efficacy with both compounds 17.
In a Japanese phase III study in 228 patients with at least one osteolytic bone metastasis from breast cancer, ZA (4 mg/month for 15 months) showed a significant benefit versus placebo in SRE reduction [hazard ratio (HR) 0.61; P=0.027] in patients with at least one SRE (30 vs. 50%) and in time to first event (Table 1) 23. Some studies also compared different i.v. BPs. In a randomized, double-blind study in 280 patients with osteolytic lesions from breast cancer or myeloma, ZA was at least as effective as PA in reducing SREs, including hypercalcaemia 18. In a combined analysis of two randomized studies (287 patients), ZA was superior to PA in control of hypercalcaemia (Table 1) 19.
A pivotal phase III noninferiority study compared ZA and PA in 1648 patients with breast cancer (69%) or myeloma (31%) and osteolytic or mixed metastases receiving active cancer therapy 20. They were randomized to ZA 4 or 8 mg (after finding no differences, the final dose was 4 mg) or PA every 3–4 weeks, both for 12 months (Table 1). The patients were stratified into three groups: those with myeloma, those with breast cancer receiving chemotherapy and those with breast cancer receiving hormone therapy. The percentages of patients with at least one SRE were similar between ZA and PA treatment (43 vs. 45%), as was the median time to first event (around 12 months), although ZA tended to control pain better and presented a significantly smaller proportion of patients requiring radiotherapy (15 vs. 20%), especially in patients with breast cancer and hormone therapy (16 vs. 25%). There were no differences in overall survival or time to progression 20. In an analysis of this study on the 1130 breast cancer patients, time to first SRE was significantly longer with ZA than with PA (310 vs. 174 days; P=0.013), with a tendency to reduce the percentage of patients with one SRE in the population with at least one osteolytic metastasis (n=528; 48 vs. 58%; P=0.058), although there were no differences in the total population 22. In a subsequent analysis of the original study, with data at 25 months, the results continued to show similar percentages of SREs (47 vs. 51%) and time to first SRE, together with a significant reduction in the need for bone radiotherapy with ZA (19 vs. 24%); there were no differences in overall survival 21. After a preplanned multiple event analysis, ZA was significantly more effective than PA in SRE reduction (RR 0.841; 95% CI 0.719–0.983; P=0.030), being particularly beneficial in breast cancer patients (RR 0.799; 95% CI 0.657–0.972; P=0.025). In the patients receiving hormone treatment, the benefit with ZA was even more significant, increasing time to first SRE (415 vs. 370 days) and reducing the risk of SRE by a further 30%. The authors believe that the longer survival rate in these patients is associated with an increased time at risk of an SRE, suggesting that prompt intervention with ZA could be responsible for the difference 21.
Efficacy in control of bone pain
Bone pain is the earliest and most frequent symptom of bone metastases. This symptom could be invalidating and have a significant negative impact on QoL. Despite this, bone pain relief is not a common primary endpoint in clinical trials; however, several studies have shown an improvement in bone pain with the use of ZA 20,23–25.
A randomized study that compared ZA with PA, the primary objective of which was the proportion of patients with SRE, included patients with bone metastases from breast cancer or osteolytic lesions from multiple myeloma. It found an improvement in pain scores in both groups, even with the stable or decreasing use of analgesics. Pain assessment was one of the study’s secondary objectives. The differences in pain control between ZA and PA were not significant 20.
Moreover, a randomized study that included Japanese patients with bone metastases from breast cancer compared the efficacy of ZA versus placebo. The primary objective was the SRE ratio. The patients who received ZA experienced pain relief and the differences were significant after 4 weeks of treatment 23.
Another randomized, cross-over study compared the efficacy of ZA administered in the ‘community’ setting versus in the ‘hospital’ setting. There was better pain control after initiating ZA treatment, with a greater reduction in bone pain observed in the ‘community’ setting, with no difference in safety 25.
Finally, in a phase II study, Clemons et al.24 assessed the efficacy of ZA in patients with bone disease from breast cancer who had already presented with an SRE or in whom bone metastases had progressed in the context of previous BP treatment (PA or clodronate). Treatment with ZA for 3 months was effective in improving pain control by week 8 of treatment. Thus, this study confirmed the efficacy of ZA in pain control even as second-line treatment after the failure to previous BPs 24.
Compliance and adherence
When recommending BPs for treatment, several aspects apart from efficacy should be taken into account. Compliance, adherence and safety are important issues to be considered before deciding the appropriate strategy 26. Of note, compliance (implementation of administration regimen as indicated on product label with respect to frequency and dosage) and adherence (degree to which patients follow clinicians’ recommendations with respect to duration and schedule) are very important issues.
Oral BPs have relatively poor adherence and compliance. This is mainly because of administration issues. When taking oral BPs, patients must fast overnight, remain upright and continue to fast for at least 30 min and for up to 2 h after ingesting the BP to minimize gastrointestinal side effects. These requirements are both associated with reduced adherence and compliance. A retrospective German insurance analysis confirmed that the duration of treatment with BPs in the real world is relatively low, with a median duration of treatment with oral BPs of 112 days 27. Furthermore, after 6 months, 64% of patients had stopped treatment 27. A second study compared the adherence of oral versus i.v. BPs. At 6 months, the adherence for oral compounds was 36 versus 92% for the i.v. formulations (P=0.012) 28. In this context, i.v. ZA shows several advantages in terms of regimen convenience (fast infusion of 15 vs. 90 min) and was preferred in one microcost study 29.
Impact of zoledronic acid on quality of life
In addition to controlling symptoms, improving QoL is a priority objective in advanced disease management. Several studies have included analyses of the impact of BPs, particularly ZA, on QoL (Table 2) 25,30–32.
A randomized, controlled clinical trial prospectively assessed QoL in breast cancer patients receiving treatment with ZA or PA. QoL was measured by standard questionnaires such as the Functional Assessment of Cancer Therapy-General (FACT-G) scale. An overall improvement in QoL was found with both ZA and PA 31.
Another study that compared ZA administration in the ‘community’ versus ‘hospital’ setting also assessed QoL using the European Organisation for Research and Treatment of Cancer Quality of Life Core Questionnaire 30 (EORTC QLQ-C30). ZA therapy showed an improvement in QoL in all cases; the improvement was greater if the therapy was administered in the ‘community’ versus the ‘hospital’ setting 25.
Finally, an Italian nonrandomized, multicentre study in 312 breast cancer patients showed a reduction in pain scores and an improvement in certain QoL subscales (measured by FACT-G) 32.
However, not all QoL studies obtained positive results. A 2004 study in 638 cancer patients with bone metastases found pain relief with ZA, but failed to detect an improvement in QoL (measured by FACT-G) 30.
Optimal duration and appropriate zoledronic acid therapy regimen
Both duration of ZA therapy and the maintenance over time of either a 21-day or a 28-day regimen are subjects of debate.
In a small study in 22 patients who received PA or ZA for a median of 3.6 years, prevention of SREs and symptom relief was maintained. This suggests that prolonged BP treatment may have a benefit that is maintained over time 33. Similarly, an exploratory analysis of subgroups of breast cancer patients in the second year of treatment showed a 41% reduction in the risk of SRE with ZA, a reduction that was similar to that seen in the first year of treatment. Furthermore, patients receiving ZA showed a significant increase in the time to first SRE versus PA 34. In a retrospective analysis of an American database of 4546 patients with bone metastases (breast, lung, prostate) who had presented with one or more SREs and who received ZA, persistence (defined as time between doses of<45 days) in the treatment with ZA was associated with lower rates of bone complications compared with patients who did not follow this treatment regimen and those who did not receive ZA, suggesting the importance of maintaining adherence to the correct posology 35.
A subsequent report of 2394 breast cancer patients (714 treated with ZA) confirmed that the risk of SRE was significantly lower in patients who adhered to the recommended regimen and received treatment for a longer time period (HR 0.576; P<0.05) 36. Finally, a Spanish retrospective study communicated as abstract form, including 366 breast cancer patients, analysed the effect of adherence. Suboptimal adherence to the recommended dose was found in 50% of patients in the first year and 68% in the second year. It also showed that the group treated with optimal/regular administration of ZA had a significantly increased time to progression and overall survival versus the cohort treated with a suboptimal ZA schedule 37.
In summary, although the risk–benefit ratio of continued BP treatment for more than 2 years has not been studied extensively, it seems advisable to continue with an every 21–28-day regimen in the absence of significant toxicity. In this respect, ASCO guidelines recommend starting BP therapy when there is radiological evidence of bone destruction (simple radiograph, computed tomography scan or MRI), even if there are no symptoms, and continuing therapy until the patient’s performance status worsens 10,11. In our opinion, in patients in good condition, it seems reasonable to maintain long-term ZA with an appropriate control of potential side effects, mainly dental surveillance and renal function monitoring.
Monitoring zoledronic acid efficacy: bone resorption markers
The study carried out by Rosen et al.20, which compared ZA versus PA, also assessed bone resorption markers such as N-telopeptide, pyridinoline, deoxypyridinoline and bone alkaline phosphatase. The levels of the three markers (primarily N-telopeptide) decreased with both BPs. Moreover, ZA was more effective than PA in reducing N-telopeptide levels, with statistically significant differences reported.
The study carried out by Clemons et al.24, which assessed the efficacy of ZA as theoretical second-line treatment with BP (after PA or clodronate), also measured N-telopeptide levels in urine. It showed a reduction in the marker’s levels and also found a positive correlation between pain relief and N-telopeptide reduction 1 week after starting the therapy. N-telopeptide levels in urine could therefore be an early efficacy marker 24.
Tolerability of zoledronic acid
ZA was generally well tolerated in patients with bone metastases secondary to breast cancer, with most adverse events being generally mild to moderate in severity 20,23,32. Furthermore, the tolerability profile of ZA during long-term treatment (≤24 months) was generally similar to that observed during shorter term therapy (≤15 months) 21. The most common suspected drug-related adverse events in ZA recipients were back pain, pyrexia, fatigue and nausea 21,23,32. Furthermore, flu-like symptoms, such as fever, chills, bone pain, arthralgias and myalgias, have been observed but are usually associated with the first administration of ZA 38. Other adverse events, including vertigo, asthenia and renal tubular necrosis, have been observed at a lower incidence with ZA 38. Finally, few (<3%) patients receiving ZA have reported grade 3 or 4 hypocalcaemia, hypomagnesaemia, hypermagnesaemia or an increase in serum creatinine levels 38.
Osteonecrosis of the jaw can occur with long exposure to BPs. A large, retrospective study carried out by the M.D. Anderson Cancer Center in over 4000 patients with bone metastases showed that the rate of frequency of osteonecrosis was 1.2% in patients with breast cancer who received i.v. BPs 39. There have been some reports of osteonecrosis (usually of the jaw) in cancer patients receiving ZA therapy in several postmarketing studies 38,40–43, where the majority of cases were associated with dental procedures 42.
Treatment of malignant bone disease with BPs has been shown to reduce bone events and delay their onset. Several reviews and meta-analyses have confirmed the benefit of these drugs in controlling bone metastases. ZA has shown superior efficacy, with a favourable toxicity profile and a convenient administration regimen, making it the treatment of choice for this indication.
In patients with breast cancer and bone metastases, ZA therapy significantly reduces the SRE rate and the risk of SRE, and also delays the time to onset of SREs. ZA leads to better pain control and various studies also suggest an improvement in QoL, although with no impact on overall survival. The duration and optimal regimen for long-term ZA therapy have not yet been defined, but some studies suggest that continuing ZA therapy for more than two years could also extend its beneficial effect. Finally, exploratory studies suggest that the efficacy of ZA could be monitored by bone resorption markers, especially N-telopeptide levels.
Editorial and native English editing assistance and styling of the manuscript were provided by Simone Boniface of inScience Communications, Springer Healthcare. Support for this assistance was funded by Novartis Farmacéutica S.A. The development of this manuscript was supported by a grant from Novartis Farmacéutica S.A., who neither participated in the discussion nor reviewed the expert’s opinion before publication.
Conflicts of interest
There are no conflicts of interest.
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