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

BMJ 2003; 327 doi: (Published 28 August 2003) Cite this as: BMJ 2003;327:469

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  1. J R Ross, research fellow (joy.ross{at},
  2. Y Saunders, research fellow1,
  3. P M Edmonds, consultant in palliative medicine2,
  4. S Patel, statistician3,
  5. K E Broadley, consultant in palliative medicine11,
  6. S R D Johnston, consultant oncologist4
  1. 1Department of Palliative Medicine, Royal Marsden Hospital, London SW36JJ,
  2. 2Department of Palliative Care and Policy, Kings College, London SE5 9RS
  3. 3Systematic Reviews Training Unit, Institute of Child Health, London WC1N 1EH
  4. 4Department of Medicine, Royal Marsden Hospital, London
  1. Correspondence to: J R Ross
  • Accepted 9 July 2003


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

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

Study selection Included trials were randomised controlled trials of patients withmalignant 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 ≥ 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.


  • Contributors JRR and YS contributed to the design of the study, collected and reviewed the papers, independently extracted the data, analysed the results, and prepared the manuscript for publication. PME supervised JRR and YS, contributed to the design of the study, randomly selected 10% of papers to check, and contributed to the manuscript for publication. SP performed all the statistical analysis and contributed to the design and methodology of the study. KEB developed the original idea, obtained funding, and contributed to the manuscript for publication. SRDJ contributed to the design of the study and interpretation of the results and contributed to the manuscript for publication. JRR is guarantor.

  • Funding This review was funded by the NHS Health and Technology Assessment Programme. The conclusions do not necessarily reflect the views of the funding body. The guarantor accepts full responsibility for the conduct of the study, had access to the data, and controlled the decision to publish.

  • Competing interests None declared

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