To identify evidence for the role of
bisphosphonates in
malignancy for the treatment of hypercalcaemia, prevention of skeletal morbidity and use in the adjuvant setting. To perform an economic review of current literature and model the cost effectiveness of
bisphosphonates in the treatment of hypercalcaemia and prevention of skeletal morbidity.
DATA SOURCES: Two independent reviewers assessed studies for inclusion, according to predetermined criteria, and extracted relevant data. Overall event rates were pooled in a meta-analysis, odds ratios (OR) were given with 95% confidence intervals (CI). Where data could not be combined, studies were reported individually and proportions compared using chi-squared analysis. Cost and cost-effectiveness were assessed by a decision analytic model comparing different
bisphosphonate regimens for the treatment of hypercalcaemia; Markov models were employed to evaluate the use of
bisphosphonates to prevent skeletal-related events (SRE) in patients with
breast cancer and
multiple myeloma.
RESULTS: For acute hypercalcaemia of
malignancy,
bisphosphonates normalised serum
calcium in >70% of patients within 2-6 days.
Pamidronate was more effective than control,
etidronate,
mithramycin and low-dose
clodronate, but equal to high dose
clodronate, in achieving normocalcaemia.
Pamidronate prolongs (doubles) the median time to relapse compared with
clodronate or
etidronate. For prevention of skeletal morbidity,
bisphosphonates compared with placebo, significantly reduced the OR for fractures (OR [95% CI], vertebral, 0.69 [0.57-0.84], non-vertebral, 0.65 [0.54-0.79], combined, 0.65 [0.55-0.78])
radiotherapy 0.67 [0.57-0.79] and hypercalcaemia 0.54 [0.36-0.81] but not orthopaedic surgery 0.70 [0.46-1.05] or
spinal cord compression 0.71 [0.47-1.08]. However, reduction in orthopaedic surgery was significant in studies that lasted over a year 0.59 [0.39-0.88].
Bisphosphonates significantly increased the time to first SRE but did not affect survival. Subanalyses were performed for disease groups, drugs and route of administration. Most evidence supports the use of intravenous aminobisphosphonates. For adjuvant use of
bisphosphonates,
Clodronate, given to patients with primary operable
breast cancer and no metastatic disease, significantly reduced the number of patients developing bone
metastases. This benefit was not maintained once regular administration had been discontinued. Two trials reported significant survival advantages in the treated groups.
Bisphosphonates reduce the number of bone
metastases in patients with both early and advanced
breast cancer.
Bisphosphonates are well tolerated with a low incidence of side-effects. Economic modelling showed that for acute hypercalcaemia, drugs with the longest cumulative duration of normocalcaemia were most cost-effective.
Zoledronate 4 mg was the most costly, but most cost-effective treatment. For skeletal morbidity, Markov models estimated that the overall cost of
bisphosphonate therapy to prevent an SRE was GBP250 and GBP1500 per event for patients with
breast cancer and
multiple myeloma, respectively.
Bisphosphonate treatment is sometimes cost-saving in
breast cancer patients where fractures are prevented.
CONCLUSIONS: