3.2.1. Bisphosphonates
Bisphosphonates are potent osteoclast inhibitors and an important class of bone-targeted agents used to reduce the frequency of SREs, improve bone pain and serve as an established treatment for hypercalcemia of malignancy [
22,
23] (
Table 1). Non-nitrogen containing bisphosphonates, such as clodronate and etidronate, are converted intracellularly into methylene-containing analogs of adenosine triphosphate (ATP), which accumulate within macrophages and osteoclasts causing direct apoptosis [
18]. Nitrogen-containing bisphosphonates, including pamidronate, ibandronate and zoledronic acid, also inhibit farnesyl diphosphate synthase, a rate-limiting enzyme of the mevalonate pathway, preventing protein prenylation of small guanosine triphosphatase (GTPase) such as Ras, Rho and Rab, which are important signaling proteins that regulate cell survival in osteoclasts [
18,
24].
In vitro, at higher concentrations, nitrogen-containing bisphosphonates inhibit osteoblasts, epithelial and endothelial cells as well as breast tumor cells, in part explaining their potential anti-tumor properties [
24].
Table 1.
Bisphosphonates are defined by their P-C-P conformation, which renders them high affinity to the hydroxyapatite in the bone mineral. Bisphosphonates contain two side chains, R1 being the variable structure that determines the potency of the compound (top left of each structure), and R2 being the short addition that increases the bone affinity (bottom left of each structure). Nitrogen-containing R1 improves the potency by at least 100 fold, and OH-containing R2 significantly increases the affinity to bone. Additional abbreviations: MBC, metastatic breast cancer; IV, intravenous; PO, oral. Reproduced with permission from the
Journal of Breast Cancer: Targets and Therapy [
18].
The effects of bisphosphonates on SREs have been extensively studied in metastatic breast cancer over the last two decades using a variety of agents. In a 2012 Cochrane systematic review and meta-analysis, data from 19 randomized controlled trials (RCTs) and 6646 patients were incorporated to evaluate the effects of bisphosphonates or denosumab on SREs from breast cancer bone metastases [
25] (
Figure 2). For women with advanced breast cancer and clinically evident bone metastases, bisphosphonates significantly reduced the incidence and rate of SREs (excluding hypercalcemia) by 15% as compared to placebo control (risk ratio (RR) 0.85; 95% CI 0.77–0.94;
p = 0.001) [
25]. Efficacy in reducing SREs was demonstrated for both parenteral (RR 0.83;
p = 0.008) and oral (RR 0.84;
p = 0.0007) routes of administration compared to control. Individual drug effects on SREs were shown for intravenous (IV) zoledronic acid 4 mg (RR 0.59), IV pamidronate 90 mg (RR 0.77), IV ibandronate 6 mg (RR 0.80), oral ibandronate (RR 0.86) and oral clodronate (RR 0.85) [
25]. Few trials have directly compared agents.
A large multi-center randomized, double-blind, placebo-controlled trial of patients with bone metastases from breast cancer and multiple myeloma (
n = 1130) led by Rosen
et al. [
26] compared 4 mg or 8 mg IV zoledronic acid to 90 mg IV pamidronate, every 3–4 weeks for up to two years. After a protocol modification due to concerns about renal toxicity with the 8 mg zoledronic acid, 4 mg zoledronic acid was shown to be equivalent in efficacy in terms of SREs and tolerability including incidence of renal impairment, when compared to pamidronate in the overall population [
26]. In the lytic metastases from breast cancer subgroup (
n = 528), zoledronic acid produced a significant prolongation of time to first skeletal related event (SRE) (310
versus 174 days;
p = 0.013), significant reduction in skeletal morbidity rate (1.2
versus 2.4 events;
p = 0.008) and a significant reduction in the SRE rate (
p = 0.010) when compared to pamidronate [
27]. Skeletal morbidity rate was significantly lower when zoledronic acid was combined with radiotherapy (0.47
versus 0.71 events,
p = 0.018) or with hormone therapy (0.33
versus 0.58 events,
p = 0.015), suggesting synergism between zoledronic acid and other anti-cancer therapies in preventing skeletal complications [
26]. In a more recent phase III trial, the zoledronic acid
versus oral ibandronate comparative evaluation (ZICE) study (
n = 1405), oral ibandronate was shown to be inferior to zoledronic acid in terms of the primary endpoint of SRE rate (0.543
versus 0.444, HR (hazard ratio) 1.22; 95% CI 1.04–1.45;
p = 0.017) [
28].
Figure 2.
Forest plot of comparison: Overall risk of SREs (excluding hypercalcemia) from breast cancer bone metastases: bisphosphonate
versus control. Reproduced with permission from the
©Cochrane Collaboration [
25].
Figure 2.
Forest plot of comparison: Overall risk of SREs (excluding hypercalcemia) from breast cancer bone metastases: bisphosphonate
versus control. Reproduced with permission from the
©Cochrane Collaboration [
25].
The question of when to start a bisphosphonate, and when to stop have, yet to be answered by RCTs. In the exploratory retrospective analysis of the zoledronic acid
versus pamidronate trial led by Rosen
et al. [
26], patients with one prior SRE were found to be at significantly higher risk (HR 2.08) of developing an on-study SRE than patients with no prior SRE [
29]. This suggests starting bisphosphonates early may be warranted rather than waiting for a SRE to occur [
18]. The American Society of Clinical Oncology (ASCO) guidelines, the Cancer Australia National Breast and Ovarian Cancer Centre (NBOCC) guidelines and the International Expert Panel guidelines all recommend starting bisphosphonates at the first radiographic sign of bone metastasis [
30,
31,
32] (
Table 2). As for the duration of bisphosphonates, there is currently a paucity of data on their use beyond 2 years, which is the treatment duration most commonly set in RCTs. However, this should not be a contraindication to continual therapy in individual patients and is encouraged by consensus guidelines [
30,
31,
32]. The standard dosing of zoledronic acid is 4 mg every 3–4 weeks [
30]. A recent randomized controlled trial (RCT) from Italy demonstrated non-inferiority of reduced frequency dosing at every 12 weeks in the second year [
33].
In the 2012 Cochrane meta-analysis, few serious adverse events were reported and many were disease or chemotherapy related. Fever and asymptomatic hypocalcemia were the most commonly reported side-effects in women receiving IV pamidronate. Gastrointestinal toxicity was the most frequently reported side-effect of oral bisphosphonates, while acute-phase reactions were more common with IV bisphosphonates [
25]. When calcium and vitamin D supplementation were not given, hypocalcemia was more common with zoledronic acid (39%
versus 7%) compared to placebo [
34], however no significant hypocalcemia was seen when calcium and vitamin D supplementation was instituted [
27]. Renal toxicity was the main issue with IV zoledronic acid with incidence at 8.5% [
35] and was related to dose and infusion time [
26]. Osteonecrosis of the jaw (ONJ) was rare at 1.4% after objective assessment [
35]. Established guidelines recommend cessation of bisphosphonates prior to invasive dental treatments or avoidance of such procedures during bisphosphonate therapy [
36].
Table 2.
Existing guideline recommendations for bisphosphonate use in metastatic breast cancer patients with bone metastases. Additional abbreviations: CT, computed tomography; MR, magnetic resonance; ZOL, zoledronic acid; IBA, ibandronate; PAM, pamidronate; CLO, clodronate; DMB, denosumab. Reproduced with permission from the
Journal of Breast Cancer: Targets and Therapy [
18].
Table 2.
Existing guideline recommendations for bisphosphonate use in metastatic breast cancer patients with bone metastases. Additional abbreviations: CT, computed tomography; MR, magnetic resonance; ZOL, zoledronic acid; IBA, ibandronate; PAM, pamidronate; CLO, clodronate; DMB, denosumab. Reproduced with permission from the Journal of Breast Cancer: Targets and Therapy [18].
| When to start? | Which bisphosphonate? | When to stop? |
---|
ASCO Guidelines 2011 [30] | Breast cancer + radiographic evidence of bone destruction: | IV PAM 90 mg every 3–4 weeks OR IV ZOL 4 mg every 3–4 weeks OR SC DMB 120 mg every 4 weeks
| Until evidence of substantial decline in patient’s general performance status |
International Expert Panel Guidelines 2008 [32] | Breast cancer + first sign of radiographic evidence of bone metastases, even if patient is asymptomatic |
Nitrogen-Bisphosphonate
IV preferable (ZOL, IBA, PAM) PO for patients who cannot or need not attend hospital care (CLO, IBA)
| Continue beyond 2 years but always based on individual risk assessment; should not discontinue treatment once SRE occurs |
While bisphosphonates as a group significantly reduced incidence and rates of SREs, they do not affect survival in women with bone metastases from breast cancer (RR 1.01; 95% CI 0.92–1.11) [
25].
3.2.2. Denosumab
Denosumab, a fully human monoclonal antibody to RANK-L, has been shown in preclinical studies and clinical trials to inhibit osteoclast-mediated bone destruction [
37].
Its superior suppression of bone turnover (urinary N-telopeptide <50 nM) compared to zoledronic acid (71%
versus 29%) was demonstrated in a randomized Phase II trial involving breast cancer, prostate cancer and multiple myeloma patients [
38]. In a landmark Phase III trial led by Stopeck
et al. [
35], 2046 patients with bone metastases from breast cancer were randomized to subcutaneous (SC) denosumab 120 mg or IV zoledronic acid 4 mg every 4 weeks. Denosumab significantly delayed first on-study SREs compared to zoledronic acid and the study met both its primary endpoint of non-inferiority (HR 0.82, 95% CI 0.71–0.95;
p < 0.001) and secondary endpoint of superiority (HR 0.82,
p = 0.01). Denosumab extended the median time to development of first on-study SRE compared to zoledronic acid (32.4
versus 26.4 months) [
35]. In addition, denosumab prolonged the time to developing moderate or severe pain compared to zoledronic acid (HR 0.78;
p = 0.002) [
39]. The 2012 Cochrane meta-analysis included 3 RCTs and 2345 patients comparing denosumab and IV bisphosphonates, showed a significant reduction in the risk of developing a SRE by 22% favoring denosumab (RR 0.78; 95% CI 0.72–0.85;
p < 0.00001) [
25] (
Figure 3).
Figure 3.
Forest plot of comparison: Overall risk of SREs in breast cancer bone metastases: denosumab
versus bisphosphonate. Reproduced with permission from
©Cochrane Collaboration [
25].
Figure 3.
Forest plot of comparison: Overall risk of SREs in breast cancer bone metastases: denosumab
versus bisphosphonate. Reproduced with permission from
©Cochrane Collaboration [
25].
The incidence of adverse events were similar between denosumab and zoledronic acid in the study by Stopeck
et al. [
35]. There was no significant difference in the rate of ONJ (2%
versus 1.4%,
p = 0.39) and denosumab was associated with significantly less renal toxicity (4.9%
versus 8.5%,
p = 0.001) and fewer acute-phase reactions (10.4%
versus 27.3%) [
35]. Toothache and hypocalcemia were more common with denosumab and for the latter, adequate daily calcium and vitamin supplementation was emphasized. The most common adverse reactions in patients receiving denosumab were fatigue, asthenia, hypophosphatemia and nausea [
35].
Denosumab’s improved efficacy over zoledronic acid, ease of administration and more favorable renal toxicity profile have resulted in the ASCO guidelines recommending it as a first-line option in the management of bone metastases from breast cancer [
30].
Key points for clinical practice:
Zoledronic acid is the most potent and effective bisphosphonate in preventing SREs. Standard dose is given IV 4 mg every 3–4 weeks for 2 years and to continue if performance status remains adequate;
Denosumab given 120 mg SC every 4 weeks, has superior efficacy over zoledronic acid in preventing SREs;
Calcium and vitamin D supplementation could prevent treatment related hypocalcemia;
While ONJ is rare at 2% or less, invasive dental procedures should be avoided during bisphosphonate or denosumab therapy;
Bisphosphonates do not improve survival in women with metastatic breast cancer.