Key points

Key points

The content of this evidence summary was up-to-date in July 2017. See summaries of product characteristics (SPCs), British national formulary (BNF) or the MHRA or NICE websites for up-to-date information.

Regulatory status: Bisphosphonates reduce the rate of bone turnover. Six bisphosphonates are available in the UK (alendronic acid, ibandronic acid, pamidronate, risedronate, clodronate and zoledronic acid), which have various indications. Bisphosphonates may be used in some people with breast cancer, within the terms of their licenses, to prevent and treat osteoporosis or skeletal events, or manage osteolytic lesions, bone pain or hypercalcaemia of malignancy. However, these treatments are not licensed for preventing recurrence or improving survival in people with early breast cancer, and use for this indication is off-label.

Overview

This evidence summary discusses a meta-analysis of individual participant data from 26 randomised controlled trials (RCTs) including 18,766 women with early breast cancer (the Early Breast Cancer Trialists' Collaborative Group [EBCTCG] meta-analysis 2015). The meta-analysis found that, at 10 years compared with control, adjuvant bisphosphonates (in addition to standard breast cancer treatments) produced small, borderline statistically significant reductions in distant recurrence (recurrence in the bone or elsewhere, not in the breasts or regional lymph nodes), bone recurrence and breast cancer mortality (absolute reductions 1.4%, 1.1% and 1.7% respectively), but not breast cancer recurrence or all-cause mortality.

When prespecified subgroup analyses according to menopausal status were undertaken, no benefits were seen in premenopausal women, but the benefits in postmenopausal women were found to be greater than in the general study population. At 10 years compared with control, the absolute reductions in the risk of breast cancer mortality, bone recurrence and all-cause mortality in postmenopausal women were 3.3%, 2.2% and 2.3%, respectively.

The Cancer Care Ontario and the American Society of Clinical Oncology (CCO/ASCO) guideline on the Use of adjuvant bisphosphonates and other bone-modifying agents in breast cancer states that, although the EBCTCG meta-analysis found bisphosphonate treatment reduced the risk of bone recurrence and subsequently improved survival in postmenopausal women with early breast cancer, the absolute benefits were small compared with control and may not result in a clinically meaningful effect. Nevertheless, a Lancet comment accompanying the EBCTCG meta-analysis notes that the absolute reduction in the risk of dying from breast cancer among postmenopausal women (3.3% at 10 years) seen in the meta-analysis is similar to the benefit seen with anthracycline polychemotherapy versus nonanthracycline polychemotherapy.

The meta-analysis has limitations, primarily because the methods used were poorly reported. For example, there is no information on how trials were identified, no assessment of trial quality or risk of bias, no citations for publications for the included and excluded trials, and no indication whether the populations and treatments studied were homogeneous or not. It is also unclear what standard treatments were used for breast cancer in the included trials, whether standard treatment differed between pre- and postmenopausal women, and whether the treatments used reflect current clinical practice. Combining the data for all bisphosphonates in the meta-analysis was controversial, as was including small trials not designed to measure the outcomes of interest and performing a meta-analysis of subgroups. See the evidence strengths and limitations section of this evidence summary for more details.

The results of the meta-analysis suggest that bisphosphonates may be beneficial in postmenopausal women and provide an estimate of the average effects of bisphosphonates across the whole subgroup. However, evidence is insufficient to determine precise subgroups of postmenopausal women who would or would not benefit. The authors of the CCO/ASCO guideline note that the benefits might be less in women with low-risk cancers, which might be a factor in deciding whether to use treatment, particularly when balanced against the risk of adverse events with bisphosphonates. Similarly, more than half of the experts involved in developing European consensus guidance on adjuvant bisphosphonates for early breast cancer considered that bisphosphonates should be used only in postmenopausal women at intermediate- or high-risk of recurrence of cancer.

Several decision-making tools such as Adjuvant! Online, PREDICT and the Nottingham Prognostic Index are available to help estimate the risk of recurrence and mortality, and the benefits of standard adjuvant treatments based on various clinical parameters. According to the CCO/ASCO guideline, similar parameters may be relevant when deciding whether or not bisphosphonates should be used. If treatment with bisphosphonates is considered appropriate, it should be discussed with each woman, taking their individual risk of recurrence and death into account and balancing this against their risk of adverse effects from bisphosphonates.

The optimal choice, dosage and duration of bisphosphonate treatment for preventing recurrence and improving survival in women with early breast cancer is unclear. Based on the evidence from the meta-analysis, the CCO/ASCO guideline generally recommends intravenous zoledronic acid (4 mg every 6 months for 3–5 years) or oral clodronate (1,600 mg daily for 2–3 years) for postmenopausal women with breast cancer deemed candidates for adjuvant bisphosphonate therapy (in addition to standard breast cancer treatments). The European consensus guideline also recommends 6-monthly intravenous zoledronic acid or daily oral clodronate for preventing metastases and improving disease outcomes in postmenopausal women with early breast cancer. There is less evidence to support the use of monthly intravenous zoledronic acid and daily oral ibandronic acid, and little or no evidence to support the use of risedronate and alendronic acid.

Different adverse effect profiles, frequency and route of administration, and cost may affect the choice of treatment. The EBCTCG meta-analysis did not report adverse effects, but the adverse effects of bisphosphonates are well-established. An older Cochrane review that considered the use of bisphosphonates in a broader population with breast cancer concluded that the adverse effects of bisphosphonates were generally mild and infrequent. Serious, rare adverse events associated with bisphosphonates include serious oesophageal reactions, osteonecrosis of the jaw, atypical stress fractures and renal impairment. The MHRA has issued guidance on preventing and managing these.

Results from ongoing trials may provide more evidence on the effects of bisphosphonates on breast cancer recurrence and survival in premenopausal women, allow more stable estimates of the 10-year outcomes in postmenopausal women, and provide comparisons of different bisphosphonate regimens.

A summary to inform local decision-making is shown in table 1.

Table 1 Summary of the evidence on effectiveness, safety, patient factors and resource implications

Effectiveness

  • In all women in the EBCTCG meta-analysis (n=18,766), the absolute 10-year risk with bisphosphonates compared with control was reduced by:

    • 1.4% for distant recurrence (20.4% compared with 21.8%, p=0.03)

    • 1.1% for bone recurrence (7.8% compared with 9.0%, p=0.004), and

    • 1.7% for breast cancer mortality (16.6% compared with 18.4%, p=0.04).

There was no statistically significant reduction in the risk of all-cause mortality or all breast cancer recurrence.

  • A subgroup analysis found that in postmenopausal women (n=11,767) the absolute 10-year risk with bisphosphonates compared with control was reduced by:

    • 3.0% for breast cancer recurrence (22.8% compared with 25.8%, p=0.002)

    • 3.4% for distant recurrence (17.9% compared with 21.2%, p=0.0003)

    • 2.2% for bone recurrence (6.6% compared with 8.8%, p=0.0002) and

    • 3.3% for breast cancer mortality (14.7% compared with 18.0%, p=0.002)

    • 2.3% for all-cause mortality (21.1% compared with 23.5%, p=0.005).

  • Bisphosphonate use had no statistically significant effect on distant recurrence other than bone recurrence, or on locoregional recurrence (in the same site as the original tumour or in the regional lymph nodes) or contralateral breast cancer (in the opposite breast).

  • Subgroup analyses suggested that benefits were independent of the type and dosage of bisphosphonate, the tumour characteristics and the use of concomitant chemotherapy. No subgroup analyses assessed bisphosphonates according to women's estimated risk of breast cancer recurrence or mortality.

Safety

  • Common adverse effects include gastrointestinal effects (such as nausea, dyspepsia, mild oesophagitis and abdominal pain) and bone, joint or muscle pain. Adverse effects vary among bisphosphonates, and some are related to the method of administration. See the individual summaries of product characteristics for more information.

  • In 12 trials (n=10,124) in early breast cancer included in the Cochrane review, the incidence of osteonecrosis of the jaw was found to be from 0% to 0.7%.

  • The MHRA has issued guidance on the use and safety of bisphosphonates, which summarises important safety issues with bisphosphonates, including oesophageal reactions, osteonecrosis of the jaw, atypical femoral fractures and adverse effects on renal function. The MHRA has also warned that osteonecrosis of the external auditory canal has been reported very rarely with bisphosphonates.

Patient factors

  • Some people with breast cancer will be eligible for bisphosphonate treatment according to the licensed indications; for example, to reduce the risk of osteoporosis associated with aromatase inhibitors or chemotherapy-induced premature menopause (see the NICE guideline on early and locally advanced breast cancer: diagnosis and treatment).

  • No information is available on adjuvant bisphosphonates for preventing recurrence or improving survival in men with early breast cancer.

  • The optimal choice, dosage and duration of bisphosphonate treatment for preventing recurrence and improving survival is unclear. Most trials included in the meta-analysis lasted 2–5 years.

  • The bisphosphonates used most commonly in the trials were zoledronic acid (50%), clodronate (27%) and ibandronic acid (16%). There is little or no evidence to support the use of risedronate, alendronic acid or pamidronate for preventing recurrence and improving survival in people with early breast cancer.

  • Although serious adverse effects are rare, they should be discussed with women considering adjuvant bisphosphonate therapy and measures should be taken to reduce the risk of them occurring (see the MHRA guidance).

  • Oral bisphosphonates such as clodronate are more likely to cause gastrointestinal adverse effects than intravenous bisphosphonates and some people may find them difficult to swallow. Nevertheless, some people may prefer oral medication because a hospital visit is not required.

  • Zoledronic acid is administered intravenously and, it may be easier for some people to adhere to 6-monthly intravenous treatment, rather than daily oral treatment. Zoledronic acid infusion can cause an acute response resulting in flu-like symptoms.

  • Calcium and vitamin D supplementation is generally recommended when bisphosphonates are used, particularly if dietary intake is low.

Resource implications

  • The annual cost (excluding VAT) of zoledronic acid given at the dosages generally used in the meta-analysis ranges from around £8 to £47. Clodronate costs around £1780 per year and ibandronic acid costs around £80 per year (costs taken from Drugs and pharmaceutical electronic market information and the Drug Tariff; excluding VAT). These costs do not include any local procurement discounts or other costs incurred, such as dilution and administration, standard supportive therapy (such as calcium and vitamin D), or any costs associated with attendance for day case treatment.

  • Depending on the bisphosphonate used, additional costs that need to be considered include dental check-ups and monitoring of renal function and vitamin D levels (see the MHRA guidance).

  • It is unclear how many additional appointments and investigations will be required with bisphosphonate treatment on top of those required for standard management of breast cancer. It is also unclear what savings might be seen as a result of such treatment; for example, due to a reduction in the need for dual energy X-ray absorptiometry (DEXA) scans in people taking breast cancer treatments that are associated with osteoporosis, or by reducing the number of people needing treatment for metastatic disease.