Background     Bisphosphonates are a class of medications that are primarily indicated to prevent and treat osteoporosis.  They work by interfering with bone resorption.  All bisphosphonates inhibit osteoclast activity and some also inhibit the maturation of mononuclear precursors into active osteoclasts. This leads to less bone turnover and improved bone density. Examples of bisphosphonates include alendronate, pamidronate, zoledronic acid, and ibandronate. Bisphosphonates are also used for the treatment or prophylaxis of cancer-related bone complications, including pain.  Therefore, its important for all clinicians who care for patients with cancer related bone pain to be aware of benefits and tradeoffs of utilizing bisphosphonates to treat cancer-related bone pain.

Analgesic therapy   Most of the studies evaluating bisphosphonates to treat cancer-related bone pain are phase II studies.  Breast cancer and multiple myeloma have been found to be the most responsive tumors to bisphosphonates.  Pain relief has been shown to a lesser degree in prostate cancer.  Their role in reducing bone pain in other types of cancers that are known to metastasize to the bone (e.g., colon, kidney, lung cancers) is less clear.  Standard starting doses include: zoledronic acid 4 mg IV over 15 minutes and pamidronate 90 mg IV administered over 2 hours.  Alendronate is available as a pill usually given 70 mg weekly and ibandronate usually given 150 mg as a monthly pill. About 50-70% of patients achieve a 30% reduction in pain within a week.  Most placebo-controlled studies did not a significant analgesic benefit from bisphosphonates.  If pain relief occurs, the average duration of pain relief is 12 weeks.  If analgesia is not achieved within a week, the patient can be retreated. Analgesic effect is related both to the dose per week and the total dose per infusion. Typically, patients are treated every 3-4 weeks by an oncologist or endocrinologist to achieve maximal effect.  If the pain is well controlled the dosing interval can be extended to a longer period without change in effect.

Prophylaxis   In patients with breast cancer or multiple myeloma, and asymptomatic bone metastases, monthly bisphosphonates decrease skeletal-related events (SRE) (pathologic fractures, spinal cord compression, surgery to bone, or radiation therapy to bone) by 30%. It may even help prolong survival modestly in patients with breast cancer. Bisphosphonates may also reduce the risk of SRE in prostate cancer with bone metastases, but the data is little less clear. The dosages of pamidronate and zoledronic acid are the same as used in analgesic therapy. There is no evidence that these medications prevent SRE in patients without known bone involvement. 

Toxicity   Bisphosphonates can cause an injection site reaction when given parenterally and a flu-like syndrome that responds well to acetaminophen.  Less common side effects include hypocalcemia and scleritis.  Renal dysfunction is a side effect of long-term, high dose or short interval/frequency use of bisphosphonates; this is typically reversible with discontinuation of the drug. Bisphosphonates are contraindicated in renal failure and with patients who experience an increase in creatinine (>0.5 mg/dl over baseline or >1.0 in patients with pre-existing renal insufficiency).  In moderate renal dysfunction (Cr > 3.0 mg/dl) the dose of both agents should either be reduced and/or the infusion time increased. Osteonecrosis is a recognized adverse effect of bisphosphonates and is covered in more detail in Fast Fact #196. Other concerning toxicities that warrant more investigation include a higher rate of disease recurrence seen in some studies of patients given bisphosphonates, neutropenic fever, pyrexia, and rash. 

Denosumab    While denosumab is not a bisphosphonate, it is commonly utilized to treat the same conditions, namely osteoporosis, cancer related bone pain, and prevention of SREs.  Denosumab is an antibody that blocks proteins that destroy bone tissue. It is usually given 120 mg subcutaneously every 4 weeks.  It seems to be well tolerated but is quite expensive. Osteonecrosis of the jaw, hypocalcemia, and vertebral fractures are known adverse events but they are thought to be rare. It may be more effective at preventing SREs but it is not clear if there is an analgesic benefit of denosumab compared with bisphosphonates for cancer bone pain. Its role in cancer care is evolving.

Cost   Many bisphosphonates are available as generic medications.  The average annual cost of intravenous zoledronic acid is about $335 (pamidronate is likely less expensive) and $716 for denosumab.   Oral bisphosphonates, especially those available as generics are likely less expensive.

References 

1. Hillner B, Ingle J, Chlebowski RT, et al. ASCO 2003 update on the role of bisphosphonates and bone health issues in women with breast cancer. J Clin Oncol. 2003; 21(21):4042-4057.
2. Pereira J. Management of Bone Pain. In: Portenoy RK, Bruera E, eds. Topics in Palliative Care, Volume 3.  New York, NY: Oxford University Press: 1998.
3. Body JJ, Mancini I. Bisphosphonates for cancer patients: why, how and when? Support Care Cancer.  2002; 10(5):399-407.
4. Body JJ. Dosing regimens and main adverse events of bisphosphonates. Semin Oncol. 2001; 28(4, Suppl 11):49-53.
5. Strang P. Analgesic effect of bisphosphonates on bone pain in breast cancer patients: a review article. Acta Oncol. 1996; 35(Suppl 5):50-54.
6. Berenson JR, Rosen LS Howell A, et al: Zoledronic acid reduces skeletal-related events in patients with osteolytic metastases. Cancer. 2001; 91:1191-1200.
7. DesHarnais CL, Bajwa K, Markle JP, et al. A microcosting analysis of zoledronic acid and pamidronate therapy in patients with metastatic bone disease.  Support Cancer Care. 2001; 9:545-551.
8. Palmieri C, Fullarton J, Brown J.  Comparative efficacy of bisphosphonates in metastatic breast and prostate cancer and multiple myeloma:  A mixed-treatment meta-analysis.  Cancer Res 2013; 19(24): 6863-72.
9. Wong MHF, Stockler MR, Pavlakis N.  Bisphosphonates and other bone agents for breast cancer (Review).  Cochrane Database of Systematic Reviews.  2012, Issue 2. Art. No.: CD003474.DOI: 10.1002/14651858.CD003474.pube.
10. Porta-Sales J, Garzon-Rodriguez C, Caraceni A.  Evidence on the analgesic role of bisphosphonates and denosumab in the treatment of pain due to bone metastases: a systemic review within the European Association for Palliative Care guidelines project.  Palliative Medicine 2016; 31(1):5-25.
11. Cadieux B, Coleman R, Jafarinasabian P, et al.  Experience with denosumab for prevention of skeletal-related events in the 10 years after approval.  J Bone Oncol 2022; 33:100416.

Version History:  This Fast Fact was originally edited by David E Weissman MD and published in April 2004. Re-copy-edited in April 2009; reviewed and updated again by Dr. Sam Maiser in June 2015; reviewed and updated in October 2025. 
Conflicts of Interest: None to report.