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Recommendations for use of Bisphosphonates

Summary of Trial or Study Results

Bone health

Chemotherapy and some endocrine therapies (aromatase inhibitors and ovarian suppression) are associated with bone mineral density (BMD) loss. The majority of trials identified in the Cancer Australia systematic review32 reported that patients were assigned to receive calcium and vitamin D supplements, which could impact on their bone health. Eight trials reported that short-term use of bisphosphonates (up to four years) was associated with significantly reduced lumbar spine, hip and femoral neck BMD loss at follow-up. The patient populations and breast cancer treatment regimens used in each trial varied, and the follow-up periods ranged from one to five years after completion of bisphosphonates.

A meta-analysis32 of four trials showed that bisphosphonates significantly reduced the incidence of osteoporosis. All trials favoured the bisphosphonates group; however the results are largely influenced by the large ABCSG-12 trial23 of intravenous zoledronic acid in premenopausal women undergoing ovarian suppression (without adjuvant chemotherapy), which was the only individual trial to show a significant reduction in incidence of osteoporosis.

The effect of bisphosphonates on osteopenia (a condition where BMD is lower than normal but not low enough to be classified as osteoporosis) is unclear, as the results differ by trial. The ABCSG-12 trial23 reported a significant reduction in incidence of osteopenia at three-year follow-up for participants receiving zoledronic acid in addition to goserelin and anastrozole, or goserelin and tamoxifen; yet five-year follow-up results were only significant for addition of zoledronic acid to goserelin and anastrozole. Results from other trials of clodronate and risedronate were not significant.

A meta-analysis19 of 14 randomised controlled trials and meta-analysis32 of five randomised controlled trials showed that short-term use of bisphosphonates (up to five years) did not significantly reduce the incidence of fractures at follow-up. As the trials generally had short follow-up periods (one to five years), it is unknown whether improvements in BMD could have long-term effects on the incidence of fractures. Also, the studies were not powered to detect a significant difference for fracture outcome.

Australian guidelines36 on the prevention and management of osteoporosis state that there is high level evidence to support the effectiveness of bisphosphonates in reducing the risk of vertebral and non-vertebral fractures and increasing BMD in postmenopausal women with osteoporosis in the general population. The guidelines also state that healthy lifestyle choices (such as adequate vitamin D, healthy weight and body mass index, not smoking and limiting alcohol consumption) minimise the risk of developing osteoporosis.

The most appropriate protocol for monitoring bone mineral density has not been addressed as a clinical question. The trials included in the Cancer Australia systematic review monitored BMD at baseline and at regular intervals throughout the duration of the trials.  While not included in the scope of this guideline, secondary causes of low BMD, including vitamin D deficiency, hyperthyroidism and primary hyperparathyroidism, have been observed to be common in postmenopausal breast cancer patients.37A detailed analysis of secondary causes of low BMD was not undertaken for this guideline.

Overall survival

The evidence on overall survival is complex, as different trials with different patient populations and treatment regimens have reported varying results. The Cancer Australia meta-analysis32 of five randomised controlled trials found that bisphosphonates (clodronate, risedronate and zoledronic acid) do not significantly affect overall survival. An earlier Cochrane meta-analysis20 of three oral clodronate trials reported that oral clodronate may improve overall survival at follow-up of 4–5.5 years. More recent follow-up data from two of these trials was included in the Cancer Australia meta-analysis, which found no significant difference in overall survival associated with bisphosphonates, although the trials were not designed to show a significant difference in relation to mortality or overall survival. 

Subgroup analysis  of 1,100 out of 3,360 women of preliminary results from the AZURE trial showed that intravenous zoledronic acid had a significant effect on overall survival for women with well-established menopause (ie more than 5 years after menopause).38 Women in this trial had stage II/III breast cancer, scheduled to receive (neo) adjuvant chemotherapy and/or endocrine therapy.39 The full results on overall survival from this trial are not yet published.

Cancer recurrence and metastases

The Cancer Australia meta-analysis32 of six randomised controlled trials of clodronate, risedronate and zoledronic acid showed that bisphosphonates did not significantly affect overall cancer recurrence.

The Cochrane systematic review20 and three randomised controlled trials8,11,21 reported that the risk of developing bone metastases was not significantly reduced with bisphosphonates (clodronate, pamidronate, zoledronic acid). The Cochrane systematic review20 and recent follow-up data from one randomised controlled trial21 reported that oral clodronate does not significantly reduce risk of developing visceral metastases.  

Disease-free survival, recurrence-free survival and survival without metastasis

The evidence on disease-free survival is complex, as different trials with different patient populations and treatment regimens have reported varying results. The large ABCSG-12 trial11 in premenopausal women undergoing ovarian suppression in combination with endocrine therapy (without adjuvant chemotherapy) found that intravenous zoledronic acid significantly improved disease-free survival and recurrence-free survival. Longer follow-up data recently reported from this trial support these findings.22 The primary end point of this trial was disease-free survival, defined as time from randomisation to the first occurrence of one or more of the following: a local or regional recurrence, cancer in the contralateral breast, distant metastasis, second primary carcinoma, or death from any cause.

Preliminary results from the large AZURE trial of women with stage II/III breast cancer, scheduled to receive (neo) adjuvant chemotherapy and/or endocrine therapy found no significant effect of intravenous zoledronic acid on disease-free survival after a median follow-up of 59 months.39 The full results on disease-free survival from this trial are not yet published.

A trial8 comparing oral pamidronate with standard care in pre- and postmenopausal women reported no significant impact on survival without bone metastasis.  

Schedule and duration of administration

No bisphosphonate is currently subsidised on the Pharmaceutical Benefits Scheme for women with early breast cancer.40 Doses and schedules identified in this guideline are based on individual trials in women with early breast cancer; however there are no standard schedules and there is much variation among trials.

Most trials administered bisphosphonates over a period of one to five years. No studies comparing different durations of bisphosphonate use, or use beyond five years were identified.

Three trials13,18,24,29-30 compared upfront to delayed intravenous zoledronic acid, in combination with aromatase inhibitors for postmenopausal women with early breast cancer. Upfront zoledronic acid significantly improved disease-free survival29 and significantly reduced BMD loss associated with treatment for early breast cancer.13,18,24,30 However, the addition of upfront zoledronic acid to aromatase inhibitors was associated with increased adverse events, such as pyrexia (fever), bone pain and headache. An integrated analysis13 of two trials and recent follow-up data from the ZO-FAST trial29 found that upfront zoledronic acid significantly reduced the incidence of severe osteopenia/osteoporosis (T score less than -2.0) in premenopausal women with mild-moderate osteopenia (T score of -1.0 or lower and -2.0 or greater) when compared to delayed zoledronic acid. This effect was significant at one and three year follow-up.

Recent results from the CALGB 79809 trial41 report that zoledronic acid prevents bone loss in premenopausal women who develop ovarian failure due to chemotherapy. The upfront addition of intravenous zoledronic acid to adjuvant chemotherapy (within 1–3 months of randomisation) led to a significantly greater reduction in BMD loss compared to delaying addition of zoledronic acid for one year.

Adverse events

Ten trials32 reported on adverse events or toxicity. Minimal serious toxicity was reported, with serious adverse events reported for <1% to 10.4% of women taking bisphosphonates. In these trials, there were no statistically significant differences in reported toxicity between women taking bisphosphonates and no bisphosphonates. Trials of ibandronate,7 pamidronate,8 risedronate9-10,25 and zoledronic acid12 found that bisphosphonates were well tolerated compared with placebo. One trial25 found that risedronate benefited patients by reducing incidence of arthralgia and chest pain, compared with placebo. The ABCSG-12 trial11 of zoledronic acid in premenopausal women with ovarian suppression (without adjuvant chemotherapy) reported a significant increase in adverse events associated with zoledronic acid, including arthralgia, bone pain, fever and nausea/vomiting. There were no confirmed cases of osteonecrosis of the jaw (ONJ) in this trial.

A literature review42 on bisphosphonate-related adverse effects identified gastrointestinal toxicity, acute-phase reactions and renal toxicity as the most common adverse events of bisphosphonates. Renal toxicity was associated with intravenous bisphosphonates, mainly zoledronic acid and to a lesser extent pamidronate, while intravenous ibandronate and oral bisphosphonates were identified as having a safety profile similar to placebo with regard to renal toxicity. The trials identified in the Cancer Australia systematic review32 reported no incidences of renal toxicity; however this is likely influenced by the trial exclusion criteria, as many studies excluded patients with renal dysfunction.

Some side effects of bisphosphonates, which may affect women on an individual basis, are presented in Table 2.

Table 2. Bisphosphonates and their side effects20,32,40,43

See the statements of evidence for further evidence on adverse effects of bisphosphonates.

Agent Characteristic side effects
Clodronate Gastrointestinal toxicity, hypocalcaemia
Ibandronate Gastrointestinal toxicity, arthralgia
Pamidronate Gastrointestinal toxicity, fever, hypocalcaemia, phlebitis, flu-like symptoms, hypophosphataemia
Risedronate Gastrointestinal toxicity, arthralgia, chest pain
Zoledronic acid Anaemia, fever, nausea, fatigue, hypocalcaemia, renal toxicity, nervous system disorders, flu-like symptoms, arthralgia, myalgia, hypophosphataemia

Osteonecrosis of the jaw

A taskforce of the American Society for Bone and Mineral Research conducted a review of bisphosphonate-associated ONJ in 2007.16 The true incidence of bisphosphonate-associated ONJ is unknown; however the estimated incidence in patients with malignancy seems to range between 1% and 10%. While the taskforce recognised that the evidence on risk factors predisposing to bisphosphonate-associated 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.

One systematic review and meta-analysis31 of 15 randomised controlled trials assessed the relationship between ONJ and bisphosphonate use as adjuvant breast cancer treatment. ONJ was identified in the review as a rare event, occurring in 13 of the 5,312 patients receiving bisphosphonates (0.2%) and occurring in one of the 5,382 patients in the control group (0.02%). All 13 ONJ occurrences in the bisphosphonates group were in patients taking zoledronic acid, and the meta-analysis showed a significant increase in ONJ with zoledronic acid compared with no bisphosphonates. Further published data from the AZURE trial44 on the safety profile of zoledronic acid reported 11 confirmed cases of ONJ from a total of 1,665 women receiving zoledronic acid (0.7%). No cases of ONJ were reported in the group of women not receiving zoledronic acid.

Limited information is available evaluating the effect of dental preventive measures on incidence of bisphosphonate-associated ONJ in cancer patients. In the advanced cancer setting, a retrospective non-randomised study45 found 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 intravenous zoledronic acid therapy had significantly lower rates of bisphosphonate-associated ONJ than patients who did not receive any preventive measures (1.7% vs. 7.8% respectively, p=0.016). American expert panels14-15 have 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.

Atypical fractures

While not included in the scope of this guideline, atypical femoral fractures have been reported to be associated with bisphosphonate use. A recent Swedish analysis46 of women aged 55 years and older with a fracture identified that bisphosphonate use was associated with atypical fractures; however the absolute risk was small [0.0005 (0.0004-0.0007)]. A detailed analysis of atypical fractures was not undertaken for this guideline.

Quality of life

Quality of life, including the impact of adverse events on quality of life, was not a reported outcome in the trials identified in the systematic review. Further research is required to determine the short- and long-term effects of bisphosphonates on quality of life.

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. There are ongoing studies comparing denosumab with placebo in women with early breast cancer (D-CARE,47 ABCSG-18,48 NCT0008966149), and evidence from one large study50 in the advanced breast cancer setting has found that denosumab may result in improved outcomes in delaying or preventing skeletal-related events compared to zoledronic acid, with similar toxicity.  

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