Abstract
Great strides have been made over the last 20 years in the treatment of breast cancer and despite an increasing incidence, the number of deaths has fallen sharply since the late 1980s. The advent of new therapies, including taxanes and aromatase inhibitors, and exciting results announced recently using trastuzumab in the adjuvant treatment of HER2-positive patients should decrease this even further. However, although most patients present with disease that appears to be localized to the breast, a significant proportion of women will eventually develop metastatic breast cancer. Therefore, the detection and treatment of micrometastatic disease represents perhaps the most important remaining challenge in breast cancer management, and is the focus of extensive ongoing research. Bone is the most frequent site of distant relapse, accounting for approximately 40% of all first recurrences. In addition to the well recognized release of bone cell-activating factors from the tumor, it is now appreciated that the release of bone-derived growth factors and cytokines from resorbing bone can attract cancer cells to the bone surface and facilitate their growth and proliferation. Bisphosphonates are potent inhibitors of bone osteolysis and the inhibition of bone resorption could therefore have an effect on the development and progression of metastatic bone disease. They could represent an adjuvant therapeutic strategy of potential importance. Clinical trial results with the early bisphosphonate, clodronate, have proved inconclusive. A large, randomized, controlled trial has recently completed accrual and should provide the definitive answer to the question of the role of clodronate in this setting. More potent second- and third-generation bisphosphonates have also shown enhanced antitumor effects in preclinical evaluation and further studies are required to determine whether this antitumor potential of bisphosphonates translates to the clinical setting. Adjuvant bisphosphonates are, therefore, currently only recommended in the research setting and clinical trials evaluating the adjuvant use of these newer compounds are currently recruiting or being established. This article will review in more detail the rationale for the adjuvant use of bisphosphonates, the results of early trials, the progress of the later trials and the potential future role of bisphosphonates in the adjuvant treatment of breast cancer. In addition, it is increasingly acknowledged that many cancer treatments have detrimental effects on bone and can increase the risk of fracture. The increasing use of aromatase inhibitors, in particular, will become a major cause of treatment-induced bone loss. This bone loss can be prevented with bisphosphonate treatment and this will also be discussed.
There are 40,000 new cases of breast cancer diagnosed in the UK every year [101]. Although most patients present with disease that appears to be localized to the breast, a significant proportion of women will eventually develop metastatic breast cancer. Bone is the most frequent site of distant relapse, accounting for approximately 40% of first recurrence [1], and up to 80% of patients with breast cancer will develop bone secondaries [2].
The clinical course of metastatic bone disease in breast cancer is relatively long, with an average life expectancy from diagnosis of bone involvement of 2 years, with up to 20% of patients surviving for 5 years. Patients experience sequential skeletal-related events (SREs) over this period, with symptoms including bone pain, pathologic fractures, hypercalcemia and spinal cord compression, all of which may profoundly impair a patient's quality of life. The associated bone pain is thought to be generated by pain mediators released during osteolysis and causes serious morbidity for the patient. External-beam radiotherapy and systemic endocrine and cytotoxic therapies are the mainstays of treatment for advanced cancers. However, it is acknowledged that bisphosphonates are the current standard of care in patients with bone metastases, decreasing skeletal complications and reducing bone pain, leading to improved mobility and quality of life [3].
It can be seen that the prevention of metastasis to bone would have enormous therapeutic value and the detection and treatment of micrometastatic disease represents perhaps the most important remaining challenge in breast cancer management. This is the focus of extensive ongoing research and many preclinical studies are investigating the process of metastasis to establish why progression to bone is so prevalent in breast cancer.
This strategy should identify new targets, allowing evaluation and better understanding of existing therapeutic agents and the development of effective new compounds.
The process of metastasis to bone
Healthy bone is composed of outer hard, compact bone tissue and inner spongy tissue with a strong honeycomb-like structure. However, bone is not inert and is constantly undergoing a complex process of remodeling characterized by two opposing actions: the resorption of old bone by osteoclasts and the formation of new bone by osteoblasts.
This is normally a tightly coordinated process in which initial osteoclast resorption takes place in discrete packets known as bone-remodeling units, over a period of approximately 8 days. This is followed by a more prolonged phase of bone formation (over approximately 3 months) to repair the defect mediated by osteoclasts. During this period, new osteoid tissue is laid down and calcium and other minerals are deposited, giving bones their hardness and final form. When healthy, there is a steady-state balance, or coupling, of osteoclastic bone resorption and osteoblastic bone formation.
This balance is lost when tumor cells enter the bone microenvironment and a vicious cycle is created, whereby complex multidirectional interactions between tumor cells, osteoblasts and osteoclasts lead both to increased osteolysis and tumor growth.
Actively resorbing bone releases a number of bone-derived growth factors and cytokines that attract circulating cancer cells to the bone surface. From in vitro studies, circulating metastatic breast cancer cells have been shown to be very responsive to these factors and have a high affinity for the bone microenvironment, accounting for the high levels of relapse in the skeleton. These growth factors also facilitate the tumor cells' growth and proliferation [4–6]. Once incorporated into the bone, the metastatic breast cancer cell interferes with bone homeostasis, releasing factors that increase osteoclast number and enhance their activity.
In the case of breast cancer-causing osteolysis, one of the main mediators is parathyroid hormone-related protein (PTHrP) [7]. Overexpression of PTHrP by breast cancer cells disrupts the osteoblast/osteoclast balance, increasing osteoclastogenesis via enhancement of osteoblastic receptor activator of nuclear factor (NF)-κB ligand (RANKL) production and downregulation of the osteoblastic osteoprotegerin (OPG) pathway, which normally inhibits osteoclast proliferation [6]. Other tumor-derived growth factors have also been shown to stimulate osteoclastogenesis and osteoclast activity [8–11], leading to increased bone resorption. As a result, the growth factor transforming growth factor (TGF)-β, a potent enhancer of PTHrP production, is released from the bone matrix in greater amounts and the vicious cycle continues. It can be seen that such a cycle potentiates the osteolytic potential of tumors once established in the bone (Figure 1).
The vicious cycle of bone metastasis.
Bisphosphonates are effective in the treatment of bone metastases as they are able to interrupt this vicious cycle by acting selectively upon the osteoclasts and altering the bone microenvironment.
The antiresorptive properties of bisphosphonates
Bisphosphonates bind avidly to the bone, where they deposit both in newly formed bone and under osteoclasts. The tight binding to bone immobilizes the bisphosphonate to give a prolonged biologic half-life which, for some agents, may be measurable in years. Their high affinity for bone mineral and subsequent uptake by activated osteoclasts during bone resorption ensures that cytotoxic concentrations only accumulate within osteoclasts, while systemic levels remain low. Uptake by these cells results in a shortened osteoclast lifespan due to programmed cell death (apoptosis) and reduced osteoclastic activity. These effects upon the osteoclasts therefore lead to a decrease in bone turnover that is secondary to the inhibition of bone resorption. However, it is thought that bisphosphonates may also accumulate within tumor cells growing in close proximity to osteoclasts that have been attracted to sites of osteolysis [12]. The effects of bisphosphonate administration are, therefore, to not only cause a reduction in osteolytic bone lesions, but also to decrease the tumor burden in bone [7,8]. How much of this is due to the inhibition of bone-derived growth factors stimulating tumor cell proliferation as opposed to direct effects on neighboring cancer cells remains an area of considerable controversy.
The development of bisphosphonates
Bisphosphonates have been used for over a century in industry as preventors of scaling, owing to their property of inhibiting calcium carbonate precipitation. However, it was not until 1968 that bisphosphonates were shown to have biologic effects [13]. Many bisphosphonates have been investigated in humans with respect to their effects on bone and a number of them are commercially available today for the treatment of bone disease.
All bisphosphonates contain a phosphorus–carbon–phosphorus central structure that promotes their binding to the bone matrix, and variable side chains that determine the specific effects on bone cells.
There are two classes of bisphosphonates: those that contain nitrogen compounds and those that do not. The first generation of non-nitrogen-containing bisphosphonates, including etidronate and clodronate, have an effect upon ATP in osteoclasts, causing cytotoxic ATP analogs to accumulate within the cells. The intelligent design of bisphosphonates over the past 30 years has led to the development of more potent second- and third-generation nitrogen-containing aminobisphosphonates (N-BPs), including alendronate, risedronate, pamidronate, ibandronate and zoledronic acid. These N-BPs affect osteoclast activity and survival via a different mechanism. Following internalization, these compounds inhibit a key enzyme in the biosynthetic mevalonate pathway, farnesyl diphosphonate (FPP) synthase. As a result, N-BPs interfere with a variety of cellular functions essential for the bone-resorbing activity and survival of osteoclasts [12]. These drugs have greater affinity for bone and are far more potent than the non-nitrogen-containing bisphosphonates.
Clodronate (usually administered orally) and pamidronate (by intravenous infusion) were, until recently, the two drugs most commonly used for oncologic indications. Both have been shown to reduce pain and SREs from metastatic bone disease [14–16]. Two relatively new bisphosphonates, ibandronate and zoledronic acid, have now been approved for the treatment of bone metastases in patients with breast cancer and are steadily replacing the older drugs.
Both oral and intravenous formulations of ibandronate have received approval in Europe, based on results from randomized trials comparing oral ibandronate (50 mg) [17] or intravenous ibandronate (2 or 6 mg) [18] with placebo. Zoledronic acid has yielded impressive results in the treatment of hypercalcemia and bone pain associated with bone metastases and has been compared directly with pamidronate. Zoledronic acid was significantly more effective at reducing the risk of SREs among breast cancer patients by an additional 20% over that achieved with pamidronate [19].
Only intravenous pamidronate and zoledronic acid have been approved in the USA and are recommended by the American Society of Clinical Oncology (ASCO) for the treatment of breast cancer patients with bone metastases [20].
There is currently considerable interest in personalizing bisphosphonate treatment in metastatic bone disease following the observation that the risk of SREs is related to the rate of bone resorption [21]. These data suggest that a single fixed schedule may not be the most cost-effective approach to treatment. Marker-directed therapy is being evaluated in a UK randomized Phase III trial – cost-effective use of BISphosphonates in metastatic bone disease: a comparison of bone MARKer directed zoledronic acid therapy versus a standard schedule (BISMARK).
Adjuvant clodronate clinical trials
Experiments in animals and preliminary clinical observations indicated that early clodronate therapy might reduce the incidence of new bony metastases in breast cancer patients [22]. These observations formed the basis for three randomized clinical trials with clodronate which have unfortunately yielded conflicting results (Table 1).
Breast cancer: adjuvant clodronate trials (ASCO 2004 update).
Primary breast cancer patients (T1 to T4 and NO to N2) with micrometastases in the bone marrow
Subgroup primary operable stage II–III breast cancer patients with no evidence of metastatic disease.
ASCO: American Society of Clinical Oncology; BM: Bone metastasis; ER: Estrogen receptor; LN: Lymph node; NS: Not significant.
Over an 11-year period, Powles and colleagues recruited to a randomized, double-blind, placebo-controlled, multicenter trial evaluating the efficacy and safety of oral clodronate in 1069 patients with primary operable stage I–III breast cancer between 1989 and 2000 [23]. Patients received oral clodronate (1600 mg/day) or placebo for 2 years, starting within 6 months of primary treatment (surgery, radiotherapy and tamoxifen). The ad hoc analysis in 2002 demonstrated that fewer women who received clodronate developed bone metastases compared with those receiving placebo (2.3 vs 5.2%; p = 0.016). An updated analysis of the results presented at the ASCO in 2004 demonstrated that oral clodronate significantly reduced the risk of bone metastases by 45% in all patients during the medication period (2 years: hazard ratio [HR]: 0.546; p = 0.031) and by 31% during the study period (5 years: HR: 0.692; p = 0.043) compared with placebo [24]. Similarly, clodronate significantly reduced the risk of bone metastases in patients with stage II/III disease during the medication (2 years: 50%, HR: 0.496, p = 0.020) and study (5 years: 41%, HR: 0.592, p = 0.009) periods. Oral clodronate versus placebo significantly improved overall survival (OS) (23% reduction in risk of death: HR: 0.768, p = 0.048) and survival for stage II/III patients (26% reduction in risk of death: HR: 0.743, p = 0.041). Oral clodronate was well tolerated, with mild-to-moderate diarrhea being the most frequently reported adverse event.
Diel and colleagues recruited 302 patients between 1990 and 1995 with primary breast cancer and tumor cells in the bone marrow [22]. This is a known risk factor for recurrence, as confirmed recently by Braun and colleagues [25]. They demonstrated that the presence of micrometastases in bone marrow at the time of diagnosis of breast cancer is associated with a poor prognosis, these cells presumably providing the seeds for later macroscopic bone disease. If prophylactic bisphosphonates decreased these micrometastases, it could follow that they might decrease progression to bone metastases and impact positively on survival.
Patients in the Diel study were randomly assigned to receive clodronate at a dose of 1600 mg/day orally for 2 years (157 patients) or standard follow-up (145 patients). The incidence of both osseous and visceral metastases was significantly lower in the clodronate group than the control group (p = 0.003 for both osseous and visceral metastases). The mean number of bone metastases per patient in the clodronate group was roughly half that in the control group (3.1 vs 6.3). In a reanalysis performed at a follow-up time of 103 ± 12 months, the incidence of osseous and visceral metastases was found to be similar in both groups [26]. Although the advantage in terms of disease-free survival (DFS) with clodronate was no longer statistically significant, a significant OS advantage for the clodronate-treated group persisted (p < 0.01). In order to establish whether the effect on OS will also diminish with time, even longer follow-up will be required.
In a study by Saarto and colleagues, 299 women with primary node-positive breast cancer were recruited between 1990 and 1993 and randomized to oral clodronate 1600 mg/day for 3 years (n = 149) or placebo (n = 150) [27]. All patients received adjuvant chemotherapy or endocrine therapy. Bone metastases were more common in the control group, although the difference did not reach statistical significance (p = 0.27). Clodronate was also associated with an increased risk of nonskeletal recurrence (p = 0.0007). Patients treated with clodronate had worse outcomes in terms of OS (p = 0.009) and DFS (p = 0.07). After a 10-year follow-up period, the incidence in bone metastases was similar in the clodronate and control groups: 44 (32%) versus 42 (29%), respectively (p = 0.35) [28,29]. However, the frequency of nonskeletal recurrences (visceral and local) was significantly higher in the clodronate group, 69 (50%), compared with 51 (36%) in the controls, (p = 0.005), and the DFS remained significantly lower in the clodronate group (45 vs 58%; p = 0.01, respectively). In estrogen receptor (ER)-positive patients, 10-year DFS was 55% in the clodronate group and 59% in the control group, with no difference between the groups (p = 0.47); however, in the ER-negative patients, the DFS difference was highly significant in favor of the controls: 25 versus 58% (p = 0.004), respectively.
In this study, patients were stratified by menopausal status rather than hormone receptor status, so that premenopausal women received chemotherapy while postmenopausal patients (both ER-positive and -negative) were randomized again in another trial to receive tamoxifen or toremifene. Significantly more patients with ER-negative and progesterone receptor (PR)-negative cancers (and therefore a worse prognosis) were randomized to the clodronate group compared with the control group. In addition, none of the postmenopausal patients, including ER- and PR-negative cases, received adjuvant chemotherapy, further compounding the imbalance between the two groups.
To try to address these imbalances, multivariate analyses of factors influencing outcomes were performed. DFS, nodal status, tumor size, PR status and study treatment group (clodronate or placebo) retained statistically significant effects on outcome. However, study treatment no longer had a significant influence on OS.
There is no biologic rationale for a worsening of outcome with an adjuvant bisphosphonate to explain these results and the imbalance in prognostic factors, the somewhat unconventional use of endocrine treatments due to secondary randomizations and the small size of the trial are more plausible reasons for the outcomes observed.
Based on these limited and somewhat conflicting data, the ASCO, in their guidance on bisphosphonate use in breast cancer, did not recommend the use of adjuvant bisphosphonates for the prevention of bone metastases in patients with breast cancer [20].
With such conflicting data, clarification of the role of clodronate was required, and a large, randomized, controlled trial run under the auspices of the National Surgical Adjuvant Breast and bowel Project (NSABP) B-34 has recently completed accrual (Figure 2). The study compared the effects of oral clodronate 1600 mg/day with those of placebo on disease progression in 3400 patients with stage I or II breast cancer. Preliminary analyses of data are expected in 2008 and should provide the definitive answer regarding the role of clodronate in this setting.
NSABP B34: clodronate as adjuvant therapy for primary breast cancer.
Treatment with bisphosphonates at nonskeletal recurrence
Several small studies with oral clodronate or oral pamidronate have been conducted in patients who had a local or distant relapse at extraskeletal sites but did not have bone metastases at study entry. In a small, randomized, double-blind study of 133 breast cancer patients receiving 1600 mg clodronate or placebo for 3 years, Kanis showed a significant reduction in the total number of bone metastases in the clodronate group (32 vs 63; p < 0.005) [30]. However, the number of patients with bone metastases was not significantly reduced (15 vs 19 patients). There was no effect on OS. A similar study of oral pamidronate (150–300 mg/day) failed to show any effect on the appearance of bone metastases in breast cancer patients treated at recurrence [31]. This outcome may have been due to the poor bioavailability of oral pamidronate and/or the fact that this population may not be ideal for testing the potential of bisphosphonates to prevent bone metastases.
The enhanced antitumor properties of the nitrogen-containing bisphosphonates
The more potent intravenous aminobisphosphonates may have the greatest potential to prevent bone metastases. Pamidronate, ibandronate and zoledronic acid are significantly more potent than clodronate, with zoledronic acid being the most potent. They have been shown to inhibit bone resorption in micromolar concentrations [3]. The N-BPs work through the inhibition of FPP synthase in the mevalonate pathway and, as a result, they interfere with a variety of cellular functions essential for the survival of osteoclasts and, possibly, associated cancer cells.
There have been comprehensive reviews of the antitumor effects of bisphosphonates showing extensive in vitro and in vivo preclinical evidence that bisphosphonates, particularly the more potent N-BPs, have antitumor activity and can reduce the skeletal tumor burden [12,32]. In addition to indirect effects on tumor growth in bone via inhibition of bone resorption and osteoclastogenesis, bisphosphonates have the potential to directly induce apoptosis of tumor cells, inhibit tumor cell adhesion to extracellular bone matrix, reduce the metastatic potential of tumor cells and inhibit angiogenesis. It has also been demonstrated that bisphosphonates antagonize the stimulatory effects of growth factors on human breast cancer cell survival and reduce protective effects against apoptotic cell death. They also have effects on immune function, with stimulation of γδT lymphocytes [33], although the clinical relevance of these actions is uncertain.
Jagdev and colleagues demonstrated that the combination of zoledronic acid plus the commonly used chemotherapeutic paclitaxel enhanced apoptosis of MCF-7 breast cancer cells fourfold compared with either agent alone [34].
Subsequently, Neville-Webbe and colleagues found that clinically relevant concentrations of either doxorubicin [35] or paclitaxel [36] and zoledronic acid induced sequence- and schedule-dependent synergistic apoptosis of breast cancer cells. Replacing zoledronic acid with clodronate did not induce increased apoptosis (Figure 3).
Sequential treatment of MCF-7 breast cancer cells with doxorubicin and zoledronic acid enhances apoptosis.
They concluded that these findings may have relevance in the clinical setting, particularly for breast cancer patients receiving these commonly used chemotherapy agents in the adjuvant setting.
To take account of this potential benefit, one of the ongoing adjuvant studies, Adjuvant Zoledronic acid to redUce REcurrence (AZURE), has mandated that doses of zoledronic acid are given immediately postchemotherapy.
The literature clearly shows the potential and impressive antineoplastic properties of bisphosphonates in vitro and sheds new light on the biologic applications of such compounds in the clinical setting. However, as bisphosphonates are bound so tightly to bone, the relevance of their in vitro antitumor effects upon circulating metastatic cells is unclear [12]. Further studies are needed to determine whether the antitumor potential of bisphosphonates translates to the clinical setting.
Adjuvant trials with aminobisphosphonates
There are no informative randomized trials of aminobisphosphonates in the adjuvant setting. A small, nonrandomized trial of intravenous pamidronate conducted in Japan suggested effective inhibition of bone metastases [37]. However, the selection of treatment based on patient preference and the longer duration of follow-up in the control arm of this study makes interpretation of these findings impossible. In addition, a larger study of 429 patients with stage I–III breast cancer reported on 258 patients treated with adjuvant intravenous and oral pamidronate therapy and 171 patients who did not receive bisphosphonates (nonrandomized) [38]. The median follow-up duration was 3.5 years. The incidence of bone metastases was 2.3% in the pamidronate group and 8.7% in the control group. The authors concluded that adjuvant pamidronate therapy significantly reduced the development of bone metastases in perimenopausal women with primary breast cancer. However, significant imbalances between the two study groups prevent definitive conclusions.
The role of adjuvant pamidronate will probably be further elucidated by a large Danish study of more than 1000 patients randomized to oral pamidronate or placebo. This study completed recruitment in the mid 1990s but to date no results are available.
The 5-year AZURE trial is currently recruiting across Europe and Australasia and will accrue 3300 patients with stage II/III breast cancer and no evidence of metastatic disease (Figure 4). This study will assess DFS and time to bone and distant metastasis in patients treated with standard anticancer therapy alone and those treated with standard therapy plus zoledronic acid (4 mg), administered monthly for six doses, every 3 months for eight doses and subsequently every 6 months for five doses. It is hoped that the added potency of zoledronic acid may have beneficial effects, not only through the inhibition of bone resorption and reduction in growth factors and cytokines that appear to promote the development of a metastasis in the bone marrow microenvironment, but also through direct effects on tumor cells in the bone marrow and possible suppression of angiogenesis. Other end points include OS and incidence of skeletal morbidity. If the current recruitment rate continues the trial will close by January 2006, with the interim analysis of data expected in 2008.
Breast cancer: adjuvant zoledronic acid (AZURE®).
The South West Oncology Group (SWOG) in the USA is currently setting up a large, randomized, three-arm trial (SWOG 0307/Intergroup) to compare the effects of intravenous zoledronic acid (4 mg via a 15-minute intravenous infusion every month for six doses, then every 3 months), oral clodronate (1600 mg/day) and oral ibandronate (50 mg/day) on DFS in 6000 patients with stage I, II or IIIA breast cancer (Figure 5). Secondary end points include OS, bone mineral density (MBMD), quality of life and bone markers as predictors of recurrent disease. This study assumes that either the B-34 or AZURE trials will show an advantage for an adjuvant bisphosphonate and will clarify the choice of agent.
SWOG 0307/Intergroup trial.
Approximately 50% of new diagnoses of early breast cancer are made in patients over the age of 65 years, but since this age group has not been eligible to participate in most trials in the past, the effect of adjuvant therapy is still unclear in elderly patients. An ongoing study in Germany, the Breast InterGroup (BIG) 4–04/GBG 32, using Ibandronate with or without Capecitabine in Elderly patients (ICE) aims to determine, in the presence of a bisphosphonate, the role of adjuvant chemotherapy with capecitabine in patients aged 65 years and older. A total of 1394 patients will be randomized to receive 50 mg oral ibandonate daily or 6 mg intravenous ibandronate monthly (according to patient choice), with or without capecitabine.
Bisphosphonates in the treatment & prevention of cancer treatment-induced bone loss
Recent advances in systemic adjuvant therapies for breast cancer are improving survival; however, many treatments are detrimental to bone and can increase the risk of fracture [39]. Most of the effects on bone are mediated by endocrine changes, either induction of an early menopause by chemotherapy and ovarian ablation, or further suppression of postmenopausal circulating estrogens by aromatase inhibitors. The causes and treatment of bone loss associated with carcinoma of the breast are reviewed comprehensively by Lester and colleagues [40].
A number of studies have shown that cancer treatment-induced bone loss (CTIBL) can be prevented with bisphosphonate treatment. Saarto and colleagues studied 121 postmenopausal breast cancer patients who were treated with adjuvant endocrine therapy (tamoxifen or toremifine) and randomized to treatment with clodronate 1600 mg/day or placebo [41]. After 2 years, there was a 2.9% increase in BMD at the lumbar spine and a 3.7% increase at the femoral neck, in comparison with placebo patients, who showed little change in their BMDs. The changes were significant in both the lumbar spine (p = 0.004) and femoral neck (p < 0.0001).
Powles and colleagues evaluated BMD changes in more than 300 women with primary operable breast cancer included in the adjuvant clodronate trial [42]. Patients were randomized equally between treatment with clodronate or placebo and followed up with yearly dual x-ray absorptiometry (DXA) scans for 2 years. After 2 years, patients treated with placebo lost, on average, 1.88% of their lumbar spine BMD. Clodronate-treated patients, however, lost just 0.16% (p = 0.04). BMD at the hip increased by 1.13% compared with patients in the placebo group, who lost 0.72% (p = 0.008). Postmenopausal women receiving placebo had relatively little bone loss during the study, probably since most were taking tamoxifen, which has bone-protective effects in this age group. Clodronate in this group was responsible for a mean improvement in BMD of 1.86% after 2 years compared with placebo (p = 0.04). Significant improvements in spine BMD were seen after 1 year in both pre- and postmenopausal women, although this was not maintained at 2 years. Patients who received chemotherapy without clodronate lost, on average, 3.07% of their BMD after 2 years; this improved by 1.72% in the treated patients.
Vehmanen presented 5-year results of the effect of adjuvant chemotherapy on BMD and the efficacy of clodronate in the prevention of bone loss in 73 premenopausal women with primary breast cancer [43]. All patients were treated with cyclophosphamide, methotrexate and 5-fluorouracil (CMF) chemotherapy. The patients were randomized to oral clodronate 1600 mg daily for 3 years or to a control group. At 5 years, patients were divided into those with preserved menstruation and those with amenorrhea. Changes in BMD correlated significantly with the menstrual function after chemotherapy. The changes in the lumbar spine BMD at 3 and 5 years were +0.6 and −1.3% in the menstruating group and −7.5 and −10.4% in the amenorrheic group (p = 0.0001 and p = 0.0001, respectively); and in the femoral neck the changes in BMD were +1.7 and −0.3%, and −3.5 and −5.8% (p = 0.002 and p = 0.001, respectively). Clodronate treatment for 3 years significantly reduced the bone loss in the lumbar spine (−3.0%) compared with controls (−7.4%) at 3 years (p = 0.003), but no significant difference was found in the femoral neck: −1.7% versus −2.8%, respectively (p = 0.86). These differences between the study groups were still seen at 5 years: in the lumbar spine −5.8% versus −9.7% (p = 0.008) and in the femoral neck −3.5% versus −5.1% (p = 0.91). The authors concluded that chemotherapy-induced ovarian failure in premenopausal women caused a temporary accelerated bone loss in the lumbar spine. Adjuvant clodronate treatment significantly reduced this bone loss. Bone loss was still significantly lower in the clodronate group compared with the control group 2 years after the termination of treatment.
Following encouraging results from recent adjuvant studies of aromatase inhibitors, their use is set to rise and the bone consequences of profound estrogen suppression will become increasingly important. Strategies to prevent bone loss are currently under investigation. The Austrian Breast and Colorectal Cancer Study Group (ABCSG) ran a 3-year randomized trial (ABCSG-012) to investigate the effects of zoledronic acid (4 mg via 15-min infusion every 6 months) on bone loss in premenopausal women receiving adjuvant therapy with goserelin (to induce an early menopause) in combination with anastrozole or tamoxifen [44]. BMD results are available in 400 patients and demonstrate profound bone loss in the goserelin plus anastrozole group (16% loss in 2 years) and also significant, although less severe, bone loss following goserelin and tamoxifen. However, bone loss with both treatment approaches was largely prevented with intravenous zoledronic acid given at a dose of 4 mg every 6 months.
The Zometa-Femara Adjuvant Synergy Trial (Z-FAST) has recently completed accrual and is one of the first studies designed to prevent the bone loss that occurs with aromatase inhibitors in the typical postmenopausal setting. In this study, patients treated with adjuvant letrozole are randomized to either immediate treatment with zoledronic acid (4 mg every 6 months) or to a delayed treatment strategy. Patients randomized to the delayed strategy are then treated with zoledronic acid if their number of standard deviations below peak bone mass (T-score) declines below −2, a fracture occurs unrelated to trauma, or a new vertebral fracture is found on radiography after 36 months. Preliminary 12-month BMD data have been presented, which showed that upfront zoledronic acid preserves bone density [45]. However, further follow-up is required to assess the clinical importance of this compared with the wait-and-see policy.
Toxicity of bisphosphonates
The side effects of bisphosphonates are generally mild and well described, with patients experiencing only mild adverse events and occasional instances of decreased renal function [19]. However, recent retrospective case studies have reported an association between long-term bisphosphonate therapy and osteonecrosis of the jaw [46]. The typical presentation is a nonhealing extraction socket or exposed jawbone with localized swelling and purulent discharge. The incidence of osteonecrosis appears to be low, with an estimate of approximately 0.1–1%. However, patients receiving high doses for several years may be at a higher risk than this and, as bisphosphonates are administered to increasing numbers of cancer patients, and earlier in the course of their disease, problems may become more important.
Historically, the risk of developing osteonecrosis (at any site) is four-times higher in cancer patients than in the normal population and has multiple risk factors, including previous/concomitant chemotherapy, steroid therapy or radiation therapy, as well as trauma, infection and a history of dental procedures [47]. The emphasis for management is based on awareness of the problem and prevention. Dental procedures, such as extractions, should be kept to a minimum during bisphosphonate treatment and, when necessary, may prompt temporary interruption of treatment until it is clear the lesion is healing satisfactorily.
Future perspective
The current trials should enable us to determine whether there is a true benefit in terms of disease progression with the use of bisphosphonates as adjuvant agents, although further research may be required to determine whether the doses derived from the treatment of metastatic disease are required for prevention or whether lower doses would suffice.
Incorporated into the current adjuvant bisphosphonate trials are correlative studies investigating the use of markers to select high-risk women. This could lead to the selection of the breast cancer patients who might benefit most from adjuvant bisphosphonates, by evaluating tumor characteristics, bone marrow findings or urine or serum markers that predict who is at highest risk of bone recurrence. Bisphosphonates are relatively expensive drugs and a more targeted use would contribute to cost-effectiveness.
New agents are constantly under development and future bone-specific agents, such as antibodies to RANKL (AMG 162 and denusomab), are in the late stages of clinical development. Others, such as inhibitors of Src signalling or cathepsin K, could also prove to be clinically useful over the coming years. Elucidation of the mechanisms of action of the bisphosphonates has also raised the possibility of combination therapy with novel agents, for example, tyrosine kinase inhibitors, such as imatinib.
Finally, there is a growing role for the use of bisphosphonates in the prevention and treatment of osteoporosis. This is a major treatment issue in women undergoing systemic adjuvant therapy, due to the induction of a premature menopause in many young women and the expanding use of aromatase inhibitors in postmenopausal women, both of which have detrimental effects on the bones.
Executive summary
Bisphosphonates are potent inhibitors of bone resorption.
They are used extensively in the treatment of bone metastases for the prevention of skeletal complications and relief of bone pain.
First-generation non-nitrogen-containing bisphosphonates, for example, clodronate, reduce osteoclast activity by causing cytotoxic ATP analogs to accumulate in the cells.
More potent second- and third-generation nitrogen-containing bisphosphonates, for example, pamidronate, ibandronate and zoledronic acid, act via a different mechanism to inhibit a key enzyme, farnesyl diphosphonate synthase, in the biosynthetic mevalonate pathway.
Extensive in vitro and in vivo preclinical evidence exists demonstrating that bisphosphonates, particularly the nitrogen-containing bisphosphonates, have direct antitumor activity and synergy with chemotoxic agents.
There are conflicting results from adjuvant trials with oral clodronate. Further adjuvant bisphosphonate studies are required.
A large, randomized, controlled trial of adjuvant clodronate, the National Surgical Adjuvant Breast and bowel Project (NSABP) B-34, has completed accrual and should give the definitive answer regarding the use of clodronate in the adjuvant setting.
Ongoing Phase III clinical trials of adjuvant bisphosphonates are taking place, including; Adjuvant Zoledronic acid to redUce REcurrence (AZURE), South West Oncology Group (SWOG) 0307/Intergroup and Ibandronate with or without Capecitabine in Elderly patients (ICE).
The use of bisphosphonates for the treatment/prevention of cancer treatment-induced bone loss is expanding. This is of particular importance, owing to increasing use of aromatase inhibitors.
Physicians should be aware of osteonecrosis of the jaw as an occasional complication of long-term bisphosphonate use.