Estimated impact for the NHS

Other treatments

In the trials in the EBCTCG meta-analysis (2015), bisphosphonates were administered in addition to other treatments for breast cancer; for example, chemotherapy and surgery.

In the trials included in the meta-analysis, 9,290 women received zoledronic acid, 5,053 women received clodronate, 3,072 women received ibandronic acid, 953 women received pamidronate and 398 women received risedronate sodium. The bisphosphonates were usually administered at the following dosages, for the listed durations:

  • intravenous (IV) zoledronic acid 4 mg 3- or 4-weekly or 6-monthly for 3–5 years (some trials used intermediate frequencies such as 3-monthly, or monthly for an initial period then 6-monthly)

  • oral clodronate 1,600 mg daily for 2–3 years

  • oral ibandronic acid 50 mg daily for 2 years

  • oral pamidronate 150 mg twice daily for 4 years

  • oral risedronate 35 mg weekly for 1–2 years.

Based on the evidence, the CCO/ASCO guideline generally recommends IV 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, and calcium and vitamin D supplementation). The lower dose of zoledronic acid is recommended because the EBCTCG meta-analysis found no statistically significant difference between less- and more-intensive dosage schedules in terms of bone recurrence, and adverse effects are less common and less severe with less-intensive regimens.

European consensus guidance on adjuvant bisphosphonates for early breast cancer also recommends that IV zoledronic acid (4 mg every 6 months) or oral clodronate (1,600 mg daily) are the preferred agents for preventing recurrence of breast cancer and improving disease outcomes. The guideline states that the potential risks and benefits of 3–5 years of adjuvant bisphosphonate treatment (plus vitamin D supplementation and adequate calcium intake) should be discussed with relevant women.

Costs of bisphosphonates used most often in the meta-analysis

No cost-effectiveness studies were found considering bisphosphonates for preventing recurrence and improving survival in people with early breast cancer.

Table 4 shows the costs of bisphosphonates at the dosages most commonly used in the EBCTCG meta-analysis. The dosages shown do not represent the full range that can be used and they do not imply therapeutic equivalence. Oral pamidronate is not included in the table because the meta-analysis found it was ineffective and it is not currently available in the UK. Risedronate is not included because relatively few women took this medicine in the trials in the meta-analysis.

The costs shown in the table are for the medicines only (excluding VAT) and do not include any local procurement discounts or other costs incurred, such as dilution and administration, or any costs associated with attendance for day case treatment. Calcium and vitamin D supplementation is generally recommended when bisphosphonates are used, particularly if dietary intake is low; the cost of this is not included in the table.

Table 4 Annual costs of bisphosphonates commonly used in the EBCTCG meta-analysis

Medicine

Usual dosage

Cost per unit, excluding VAT

Annual cost, excluding VAT

IV zoledronic acid 4 mg/100 ml

4 mg monthly for 3–5 years

£3.94b per vial

£47.28

4 mg 6-monthly for 3–5 years

£3.94b per vial

£7.88

Oral sodium clodronate 800 mg

1,600 mg daily for 2–3 years

£136.67c per 56 tablets

£1781.59

Oral ibandronic acid 50 mg

50 mg daily for 2 years

£6.27c per 28 tablets

£81.73

a The dosages shown reflect those most commonly used in the EBCTCG meta-analysis. They do not represent the full range that can be used and do not imply therapeutic equivalence

b Average price paid in English NHS hospital trusts over the last 4 months of 2015 taken from Drugs and pharmaceutical electronic market information; excluding VAT

c Costs taken from the Drug Tariff, April 2017; excluding VAT

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 (see the NICE guideline on early and locally advanced breast cancer: diagnosis and treatment), or by reducing the number of people with metastatic disease.

Current or estimated usage

Estimating the current usage off-label usage of bisphosphonates as adjuvant treatments for preventing the recurrence of early breast cancer and improving survival is difficult because bisphosphonates are used to treat various conditions. No information on prescribing adjuvant bisphosphonates for early breast cancer was available at the time this evidence summary was prepared.

Likely place in therapy

Local decision makers need to take safety, efficacy, cost and patient factors into account when considering the likely place in therapy of adjuvant bisphosphonates for preventing recurrence and improving survival in people with early breast cancer.

In the EBCTCG meta-analysis, in women with early breast cancer treated with adjuvant bisphosphonates, there were small, borderline statistically significant reductions in distant recurrence, bone recurrence and breast cancer mortality, but not breast cancer recurrence, at 10 years compared with control. No information is available on adjuvant bisphosphonates for preventing recurrence or improving survival in men with early breast cancer.

When prespecified subgroup analyses according to menopausal status were undertaken, no benefits were seen in premenopausal women, but the benefits were found to be higher than in the general study population for postmenopausal women. At 10 years compared with control, the absolute reductions in the risk of breast cancer death and bone recurrence in postmenopausal women were 3.3% (14.7% compared with 18.0%; p=0.002; number needed to treat [NNT] 31) and 2.2% (6.6% compared with 8.8%; p=0.0002; NNT 46) respectively. Benefits appeared to be independent of the type and dosage of bisphosphonate, the tumour characteristics and the use of concomitant chemotherapy.

The CCO/ASCO guideline 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 of breast cancer (3.3% at 10 years) seen in the meta-analysis is similar to the benefit seen with anthracycline polychemotherapy versus nonanthracycline polychemotherapy.

The evidence is insufficient to determine precise subgroups of postmenopausal women who would or would not benefit. The authors of the CCO/ASCO guideline consider that the benefits of bisphosphonates 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, when the European consensus guidance on adjuvant bisphosphonates for early breast cancer was developed, although the panel agreed that data supported the use of adjuvant bisphosphonates in postmenopausal (whether natural or induced) women, 58% of the experts (14/24) suggested restricting use to women considered at intermediate- or high-risk of recurrence of breast cancer rather than unselected use across all risk groups.

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 available evidence, the CCO/ASCO guideline generally recommends IV 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 IV zoledronic acid or daily oral clodronate first-line for preventing metastases and improving disease outcomes in postmenopausal women with early breast cancer. There is less evidence to support the use of monthly IV 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. Adverse effects vary among bisphosphonates. Oral bisphosphonates such as clodronate are more likely to cause gastrointestinal adverse effects than IV 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 IV treatment, rather than daily oral treatment. Zoledronic acid infusion can cause an acute response resulting in flu-like symptoms. More serious, less common 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.

The annual cost of zoledronic acid given at the dosages generally used in the meta-analysis ranges from around £8 to £47 (excluding VAT), not including 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. Clodronate costs around £1780 per year and ibandronic acid costs around £80 per year (excluding VAT).