Table 1. Meta-analysis results of study outcomes from the Cochrane Review2
|Outcome||No. studies||No. participants||Relative risk
|Overall risk of skeletal events (including hypercalcaemia)||8||2189||0.83 (0.78, 0.89)|
|Overall risk of skeletal events (excluding hypercalcaemia)||8||2656||0.85 (0.79, 0.91)|
|Overall risk of skeletal events by drug route of administration:|
||5||1918||0.83 (0.78, 0.89)|
||5||1147||0.84 (0.76, 0.93)|
|Overall risk of skeletal events by individual drug at recommended dosing:|
||1||227||0.59 (0.42, 0.82)|
||1||751||0.77 (0.69, 0.87)|
||3||422||0.84 (0.72, 0.98)|
||1||312||0.82 (0.67, 1.00)|
||1||564||0.86 (0.73, 1.02)|
|Incidence of bone metastases (in women without prior bone metastases)||3||320||0.99 (0.67, 1.47)|
|Survival||10||2255||0.99 (0.93, 1.05)|
A Cochrane pooled analysis2 of eight studies of women with advanced breast cancer and clinically evident bone metastases showed that bisphosphonates reduced the risk of developing a skeletal event, including hypercalcaemia, by 17% (p<0.00001) compared to no bisphosphonate. A Cochrane meta-analysis2of risk of skeletal events by individual drug at recommended dosing showed a statistically significant reduction in risk with intravenous zoledronic acid, intravenous pamidronate and oral clodronate. A reduced risk was reported for oral and intravenous ibandronate; however this was not statistically significant (Table 1).
Twelve studies identified in the Cochrane Review2reported lower skeletal event rates with bisphosphonates and ten of these studies reported a statistically significant reduction in skeletal event rate with all bisphosphonates. The definition and measurement of skeletal event rate varied across studies and included skeletal morbidity rate (number of events per year), cumulative events in the follow-up period, cumulative proportion of skeletal events and total events per study group.
Thirteen studies2 assessed the effect of bisphosphonates on time to skeletal event. Of these, seven studies of intravenous pamidronate, intravenous ibandronate, oral clodronate and intravenous zoledronic acid reported that bisphosphonates significantly delayed time to skeletal event compared to no bisphosphonates. Studies on oral ibandronate and oral pamidronate reported that bisphosphonates delayed time to skeletal events compared to no bisphosphonates; however this was not statistically significant.
Three studies of bisphosphonates in women without clinically evident bone metastases identified in the Cochrane Review2 did not show a significant reduction in the incidence of skeletal metastases associated with the use of bisphosphonates (Table 1).
The Cochrane Review2 identified 11 studies that reported the effect of bisphosphonates on bone pain, compared with no bisphosphonate or placebo. A significant reduction in bone pain was reported in four large studies of ibandronate (intravenous and oral), intravenous pamidronate and intravenous zoledronic acid and two smaller studies (n<150) on oral pamidronate and oral clodronate.
Another Cochrane review16 on the use of bisphosphonates for bone pain for patients with multiple primary disease sites (including breast) concluded that bisphosphonates provide modest pain relief for patients with painful bone metastases and that bisphosphonates should be considered where analgesics and/or radiotherapy are inadequate.
Ten studies identified in a Cochrane Review meta-analysis2 reported overall survival, with no study reporting a significant difference between women taking bisphosphonates compared with no bisphosphonates or placebo (Table 1). Similarly, a separate meta-analysis11 showed that oral clodronate did not affect overall survival for women with advanced breast cancer.
The meta-analysis of oral clodronate also reported that bisphosphonates did not significantly affect bone metastasis-free survival and non-skeletal metastasis-free survival.
Quality of life
Patient-rated quality of life data was reported in seven bisphosphonate studies.2 Of these, two studies on ibandronate showed statistically significant improvements in quality of life for the women taking bisphosphonates. However, the remaining studies reported no significant differences in quality of life with bisphosphonates compared to no bisphosphonates.
Type of bisphosphonate and mode of administration
A randomised study comparing intravenous zoledronic acid with intravenous pamidronate9 did not show a significant difference between the two bisphosphonates with regard to developing a skeletal event, time to first skeletal event or skeletal morbidity rate.
The efficacy of intravenous and oral bisphosphonates was assessed in two Cochrane pooled analyses2 of women with advanced breast cancer and clinically evident bone metastases. A pooled analysis of five studies showed that intravenous bisphosphonates significantly reduced the risk of developing a skeletal event by 17% (p<0.00001) and a separate pooled analysis of five studies showed that oral bisphosphonates significantly reduced risk of developing a skeletal event by 16% (p=0.001) (Table 1).
Schedule and duration of administration
Most studies of bisphosphonates in women with advanced breast cancer identified in the Cochrane Review2 administered bisphosphonates over a period of two to three years. However, the optimal schedule and duration of bisphosphonates is not known.
Seventeen studies identified in the Cochrane Review2reported adverse events or toxicity but little serious toxicity was reported. Gastrointestinal toxicity (nausea and vomiting) was the most frequent side effect reported by women in oral clodronate studies, and an oral pamidronate study17 reported a withdrawal rate of 25% of pamidronate participants due to gastrointestinal toxicity. Serum creatinine, serum calcium and bilirubin levels were identified in most studies to determine patient eligibility or exclusion on the basis of renal function, calcium levels and liver function. In one study9comparing intravenous pamidronate with zoledronic acid, renal toxicity was reported more frequently for zoledronic acid participants (4 30% depending on treatment group). In the same study, calcium and vitamin D supplements were given to all participants and there was no reported hypocalcaemia. A separate study18of intravenous zoledronic acid without calcium and vitamin D supplements showed a higher incidence of grade I hypocalcaemia with zoledronic acid than placebo. A literature review19 on adverse effects associated with bisphosphonates identified renal toxicity with intravenous bisphosphonates, mainly zoledronic acid and to a lesser extent pamidronate. Intravenous ibandronate and oral bisphosphonates were identified as having a safety profile similar to placebo with regard to renal toxicity.
A taskforce of the American Society for Bone and Mineral Research conducted a review of bisphosphonate-associated osteonecrosis of the jaw (BP ONJ) in 2007.8 While the taskforce recognised that the evidence on risk factors predisposing to BP ONJ was weak, some risk factors were suggested, including intravenous bisphosphonates and duration of exposure to bisphosphonate treatment, tooth extraction and invasive dental work, and pre-existing dental or periodontal disease.
Most studies identified in the Cochrane Review2pre-dated recognition of BP ONJ as a potential adverse event; therefore the true incidence of BP ONJ in women with advanced breast cancer is unknown. More recent prospective studies in the adjuvant breast cancer setting may provide an indication of the incidence of BP ONJ. One systematic review and meta-analysis20 of 15 randomised controlled trials reported that osteonecrosis of the jaw was a rare event in women with early breast cancer, occurring in 13 of the 5,312 patients receiving bisphosphonates (0.2%). All thirteen occurrences were in patients taking zoledronic acid, and the meta-analysis showed a significant increase in osteonecrosis of the jaw with zoledronic acid compared with no bisphosphonates.
Limited information is available evaluating the effect of dental preventive measures and incidence of BP ONJ in cancer patients. A non-randomised study by the National Cancer Institute of Milan7found that patients who underwent dental preventive measures (baseline mouth assessment with a dental visit to detect potential dental conditions and dental care if required) before bisphosphonate therapy had significantly lower rates of BP ONJ than patients who did not receive any preventive measures (1.7% vs 7.8% respectively, p=0.016). American expert panels21-22have suggested that patients should have a dental examination before beginning therapy with bisphosphonates and that patients should be informed on the importance of maintaining good oral hygiene and having regular dental assessments.
Table 2. Bisphosphonates and their side effects2-3,6
Please see the statements of evidence for further evidence on adverse effects of bisphosphonates.
|Agent||Characteristic side effects|
|Clodronate||Gastrointestinal toxicity (diarrhoea), hypocalcaemia (abnormally low calcium levels)|
|Ibandronate||Gastrointestinal toxicity, arthralgia (joint pain)|
|Pamidronate||Gastrointestinal toxicity, fever, hypocalcaemia (abnormally low calcium levels), phlebitis (inflammation of a vein), flu-like symptoms, hypophosphataemia (abnormally low phosphate levels)|
|Zoledronic acid||Anaemia, fever, nausea, fatigue, hypocalcaemia (abnormally low calcium levels), renal toxicity, nervous system disorders, flu-like symptoms, arthralgia (joint pain), myalgia (muscle pain), hypophosphataemia (abnormally low phosphate levels)|
Other new emerging therapies
Denosumab is a monoclonal antibody that binds to receptor activator of nuclear factor kappa-B ligand (RANKL), thereby inhibiting osteoclast function and bone resorption. Evidence from a large study15 suggests that denosumab may result in improved outcomes in delaying or preventing skeletal-related events compared to zoledronic acid, with similar toxicity. The study identified fewer adverse events potentially associated with renal toxicity (5% vs 9%) for patients taking denosumab.
c 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