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Recommendations for use of Bisphosphonates

Statements of Evidence

Below are the statements of evidence on which the clinical practice recommendations are based.

STATEMENTS LEVEL OF EVIDENCE4 REFERENCE
In women with early breast cancer who are receiving or have received systemic therapy:
Bone health
Short-term use of any bisphosphonate (up to 4 years) can reduce lumbar spine, hip and femoral neck bone mineral density loss associated with treatment for early breast cancer at follow-up (1 5 years) II

McCloskey,5
Saarto,6
ARIBON,7

Kristensen,8
REBBeCa,9
SABRE,10
ABCSG-12,11
Hershman12

Bisphosphonates (clodronate, ibandronate, risedronate and zoledronic acid) significantly reduce the incidence of osteoporosis I CA32a

The short-term use of bisphosphonates does not significantly affect the incidence of bone fractures within a follow-up period of 1 5 years

The longer-term impact of bisphosphonates on bone fractures is unknown

I Valachis19
Overall survivalb
Bisphosphonates (clodronate, risedronate and zoledronic acid) do not significantly affect overall survival I CA32a
Cancer recurrence and metastases
Oral bisphosphonates (clodronate and risedronate) do not significantly affect cancer recurrence I CA32a
Bisphosphonates (clodronate, pamidronate and zoledronic acid) do not significantly reduce the risk of developing bone metastases

I

II

Cochrane20

Diel,21
Kristensen,8
ABCSG-1211

Oral clodronate does not significantly reduce the risk of developing visceral metastases

I

II

Cochrane20

Diel21

Disease-free survival and recurrence-free survivalb
In premenopausal women undergoing ovarian suppression in combination with endocrine therapy (without adjuvant chemotherapy), zoledronic acid is associated with significantly longer disease-free survival and recurrence-free survival II ABCSG-1211,22
Quality of life
There are no studies on bisphosphonates in early breast cancer that report on quality of life
Type of bisphosphonate
There are no studies comparing different types of bisphosphonate
Schedule and duration of administration
There are no studies comparing different durations of bisphosphonate use

Clinical studies evaluating bisphosphonates have been limited to therapy no greater than 5 years

There is no evidence on the continuation of bisphosphonates beyond 5 years

The administration schedules used in trials of bisphosphonate are:

  • Intravenous zoledronic acid:
- 4mg every 6 months for 3 yearsc ABCSG-1211,23
- 4mg every 3 months for 1 year Hershman12
- 4mg every 6 months for 5 years Hines 2009b,24
Z-FAST,17
ZO-FAST18
  • Oral clodronate: 1600mg daily for 2 3 years
Saarto,6
McCloskey5
  • Oral ibandronate: 150mg every 4 weeks for 2 years
ARIBON7
  • Oral pamidronate: 150mg twice daily for 4 years
Kristensen8
  • Oral risedronate: 35mg weekly for 1 2 years
Hines 2009a,25
REBBeCA,9,26-28
SABRE10

In postmenopausal women, the upfrontd addition of intravenous zoledronic acid (4mg every 6 months) to aromatase inhibitors has the following benefits when compared to delayede treatment:

  • significantly improves disease-free survival
  • significantly reduces bone mineral density loss

However, it may be associated with increased adverse events

II

ZO-FAST29

Hines 2009b,24
Z-FAST,30
ZO-FAST,18
Z-FAST/ZO-FAST13

In postmenopausal women with osteopenia, the upfront addition of intravenous zoledronic acid to aromatase inhibitors significantly reduces the incidence of osteoporosis at 1 and 3 years follow-up Z-FAST/ZO-FAST,13
ZO-FAST29
Adverse eventsf

Bisphosphonates are associated with mild and infrequent toxicity

Serious adverse events reported in bisphosphonate-treated populations ranged from <1% to 10.4%; however no statistically significant differences were reported between women taking bisphosphonates and no bisphosphonates in these trials

II

ARIBON,7
Kristensen,8
Hines 2009a,25
REBBeCa,9

SABRE,10

ABCSG-12,11
Hershman,12
Hines 2009b,24
Z-FAST,30
ZO-FAST,18
Z-FAST/ZO-FAST13

Intravenous zoledronic acid significantly increases the incidence of osteonecrosis of the jaw; although the overall incidence is extremely low in women with early breast cancer (13 out of 5,312 women taking bisphosphonates; 0.2%) I Mauri 200931
In premenopausal women undergoing ovarian suppression in combination with endocrine therapy, intravenous zoledronic acid may increase adverse events including bone pain, arthralgia, fever and nausea/vomiting II ABCSG-1211
All patients were screened for adequate renal function before inclusion to the adjuvant trials on zoledronic acid, and renal monitoring was conducted regularly throughout trial duration ABCSG-12,11
Hershman,12
Hines 2009b,24
Z-FAST,30
ZO-FAST18

a Statement based on a meta-analysis undertaken as part of the Cancer Australia systematic review32

b The Cancer Australia systematic review does not include preliminary results from the AZURE trial. Further information can be found in the summary of results section of the guideline

c Protocol amendments, after 254 patients had been enrolled, reduced the dose of intravenous zoledronic acid from 8mg every 4 weeks to 4mg every 6 months

d The upfront groups received intravenous zoledronic acid immediately after random assignment

e The delayed groups received intravenous zoledronic acid when either post-baseline lumbar spine or total hip T score decreased to less than -2.0 or a non-traumatic clinical fracture occurred

f Precautionary information for bisphosphonates mentioned in this guideline is available in the product information (PI) on the Pharmaceutical Benefits Scheme website at www.pbs.gov.au

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