Systematic review of role of bisphosphonates on skeletal morbidity in metastatic cancer

Abstract

Objective: To review the evidence for the use of bisphosphonates to reduce skeletal morbidity in cancer patients with bone metastases.

Data sources: Electronic databases, scanning reference lists, and consultation with experts and pharmaceutical companies. Foreign language papers were included.

Study selection: Included trials were randomised controlled trials of patients with malignant disease and bone metastases who were treated with oral or intravenous bisphosphonate compared with another bisphosphonate, placebo, or standard care. All trials measured at least one outcome of skeletal morbidity.

Results: 95 articles were identified; 30 studies fulfilled inclusion criteria. In studies that lasted > or = 6 months, compared with placebo bisphosphonates significantly reduced the odds ratio for fractures (vertebral 0.69, 95% confidence interval 0.57 to 0.84, P < 0.0001; non-vertebral 0.65, 0.54 to 0.79, P < 0.0001; combined 0.65, 0.55 to 0.78, P < 0.0001), radiotherapy (0.67, 0.57 to 0.79, P < 0.0001), and hypercalcaemia (0.54, 0.36 to 0.81, P = 0.003) but not for orthopaedic surgery (0.70, 0.46 to 1.05, P = 0.086) or spinal cord compression (0.71, 0.47 to 1.08, P = 0.113). The reduction in orthopaedic surgery was significant in studies that lasted over a year (0.59, 0.39 to 0.88, P = 0.009). Use of bisphosphonates significantly increased time to first skeletal related event but did not increase survival. Subanalyses showed that most evidence supports use of intravenous aminobisphosphonates.

Conclusions: In people with metastatic bone disease bisphosphonates significantly decrease skeletal morbidity, except for spinal cord compression and increased time to first skeletal related event. Treatment should start when bone metastases are diagnosed and continue until it is no longer clinically relevant.

Fig 1

Flow diagram of studies (see table A on bmj.com for full details of the 47 included studies and table B on bmj.com for details of the 48 excluded studies)

Fig 2

Forest plot for vertebral fractures (3238 patients)

Fig 3

Forest plot for non-vertebral fractures (3376 patients)

Fig 4

Forest plot for combined fractures (2587 patients)

Fig 5

Forest plot for radiotherapy (3140 patients)

Fig 6

Forest plot for hypercalcaemia (3894 patients)

Fig 7

Forest plot for orthopaedic surgery (2556 patients)

Fig 8

Forest plot for spinal cord compression (2628 patients)