Clinical Practice Guidelines for the management of locally advanced ...

Recently, there have been reports of osteonecrosis of the jaw in patients undergoing treatment with
bisphosphonates. In a case series of patients undergoing treatment with bisphosphonates for a variety
of cancers, Bamias et al 2005 43 reported an incidence of 6.7% for osteonecrosis of the jaw, and an
incidence of this condition in 6.5% of men with prostate cancer. They identified length of exposure as
the most important risk factor and that zoledronic acid may be more prone to produce this
complication than pamidronate. In a recent publication of a cohort study with matched controls,
Wilkinson et al 2007 44 have confirmed the earlier case series reports. They showed that cancer
patients treated with intravenously administered nitrogen containing bisphosphonates had an absolute
risk at six years for any jaw toxicity of 5.48% compared with matched controls, who had an absolute
risk of 0.30%. When adjustments were made for a number of potential confounders, the hazard ratio
was 11.48 (95% CI = 6.49 to 20.33). They also confirmed that length of exposure was a risk factor for
jaw toxicity with those receiving 14–21 infusions of bisphosphonates significantly more likely to
experience jaw toxicity than those who received less than three infusions (hazard ratio = 3.02 with
95% CI = 1.28 to 7.10). They were unable to find a clear association between types of cancer,
comorbidities, or with known risk factors for jaw and facial bone disease such as diabetes, alcoholism,
smoking, obesity, hyperlipidaemia or parenteral corticosteroids.
Atrial fibrillation may also be a concern. In a RCT of once-yearly infusions of zoledronic acid for the
treatment of post-menopausal osteoporosis, there was a significant increase in ‘serious’ atrial
fibrillation. 45
Recommendations
Zoledronic acid may be considered for the prevention of skeletal-related events in men with
asymptomatic or mildly symptomatic hormone-resistant or castrate-resistant metastatic
prostate cancer. Men, as part of the informed consent process, should be made aware that
nine men will need to be treated for one to achieve a benefit, and that there is a risk of
osteonecrosis of the jaw occurring during treatment. Dental review is advised and be sought
before commencing treatment.
Renal function needs to be monitored during treatment. Ideally treatment should be
confined to men whose serum creatinine is less than 265umol/L at the time of starting
treatment.
Grade B
On the basis of the available evidence, bisphosphonates are not recommended for routine
palliation of symptomatic bone disease in men, with hormone-resistant prostate cancer with
a possible exception of zoledronic acid, where there is some evidence of a benefit in
castrate-resistant men.
Grade C
In Australia, zoledronic acid (4mg in 5ml) is the only bisphosphonate listed on the PBS for ‘bone
metastases from hormone-resistant prostate cancer with demonstration of biochemical progression of
disease despite maximal therapy with hormonal treatments’. It is also listed along with clodronate for
the ‘treatment of hypercalcemia of malignancy refractory to anti-neoplastic therapy’.
( accessed 3/06/2009).
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Castration-resistant prostate cancer