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Recommendations for use of Bisphosphonates

Statements of evidence

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

STATEMENTS LEVEL OF EVIDENCE5 REFERENCE
In women with advanced breast cancer without clinically evident bone metastases, bisphosphonates do not reduce the incidence of skeletal metastases I Cochrane2
In women with advanced breast cancer and clinically evident bone metastases
(who may or may not be having systemic therapy):

Bone health

The following bisphosphonates significantly reduce the risk of developing a skeletal event:

  • intravenous zoledronic acid
  • intravenous pamidronate
  • oral clodronate
I Cochrane2
Bisphosphonates significantly reduce the risk of hypercalcaemia I Ross10
Bisphosphonates reduce the rate (frequency) of skeletal events I Cochrane2

The following bisphosphonates significantly delay time to a skeletal event:

  • intravenous ibandronate
  • intravenous pamidronate
  • intravenous zoledronic acid
  • oral clodronate
I Cochrane2

Bone pain

The following bisphosphonates significantly reduce bone pain:

  • intravenous or oral ibandronate
  • intravenous pamidronate
  • intravenous zoledronic acid
I Cochrane2

Overall survival
Treatment with bisphosphonates does not affect overall survival I Cochrane,2 Ha11
Oral clodronate does not affect bone metastasis-free survival or non-skeletal metastasis-free survival I Ha11
Quality of life
Ibandronate (oral or intravenous) significantly improves quality of life II Body12-13
There are insufficient data to indicate a significant difference in quality of life with other bisphosphonates

Type of bisphosphonate and mode of administration

There is no significant difference between treatment with intravenous zoledronic acid or intravenous pamidronate in:

  • risk of developing a skeletal event,
  • time to first skeletal event
  • skeletal morbidity rate

However, for women with osteolytic lesions, zoledronic acid is associated with longer time to first skeletal event and lower skeletal morbidity rate than pamidronate

II Rosen9
There are insufficient data to indicate a significant difference in relation to type of bisphosphonate
Intravenous and oral bisphosphonates both significantly reduce the risk of developing a skeletal event I Cochrane2
Schedule and duration of administration

The clinical studies evaluating bisphosphonates were limited to therapy no greater than 23 years

However, many women with advanced breast cancer can have disease control with modern bisphosphonates for longer periods of time

There are no formal data evaluating the cumulative effect of bisphosphonates or reduced frequency of administration

The optimal schedule of bisphosphonates is unknown and there are no studies evaluating long-term bisphosphonate use, or shorter versus longer-term bisphosphonate use


Adverse events
Bisphosphonates are associated with mild and infrequent toxicity I Cochrane2
Mild gastrointestinal toxicity is associated with oral bisphosphonates Cochrane2
Oral ibandronate appears to have fewer side effects than intravenous zoledronic acid II Body14
Renal toxicity is associated with intravenous zoledronic acid and is related to dose and infusion time Cochrane2

The evidence on risk factors predisposing to osteonecrosis of the jaw is weak

Some suggested risk factors include intravenous bisphosphonates and duration of exposure to bisphosphonate treatment, tooth extraction and invasive dental work, and pre-existing dental or periodontal disease

Khosla8
Dental preventive measures (baseline mouth assessment with a dental visit to detect potential dental conditions and dental care if required) before bisphosphonate therapy significantly lower rates of osteonecrosis of the jaw in patients taking bisphosphonates III-3 Ripamonti7

Other new emerging therapies
Evidence from one large study has indicated greater benefit with denosumab, a new bone agent, compared to zoledronic acid in delaying or preventing skeletal events II Stopeck15

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