Abstract
Bone is the most common organ for tumor metastasis, especially in patients with cancers of the breast or prostate. Bone metastases disrupt skeletal metabolism and result in considerable skeletal morbidity, including intractable, chronic bone pain, hypercalcemia of malignancy, pathologic fracture and spinal-cord compression. In addition to the chronic pain caused by bone metastases, skeletal-related events (SREs) such as pathologic fractures and spinal-cord compression can result in acute increases in pain. These effects can severely impair mobility and contribute to a general decrease in quality of life. Palliative options to treat bone metastases include radiotherapy, analgesics, surgery and bisphosphonates. These drugs bind to the surface of the bone and impair osteoclast-mediated bone resorption, and reduce the tumor-associated osteolysis that is initiated by the development of skeletal metastases. In addition to preventing SREs, bisphosphonates can palliate bone pain caused by a variety of solid tumors. This Review summarizes the clinical trial data of bisphosphonates for the prevention of SREs and the palliation of bone pain. Among these agents, nitrogen-containing bisphosphonates are recognized as the most effective, and zoledronic acid has demonstrated the broadest clinical utility.
Key Points
-
Bone metastases disrupt skeletal metabolism, which can result in disabling and potentially life-limiting skeletal-related events including pathologic fracture, spinal-cord compression, the requirement for surgery or radiation therapy to bone, and hypercalcemia of malignancy
-
Bone metastases are the most frequent source of severe pain in patients with advanced cancers
-
Skeletal-related events can reduce the functional independence of patients and undermine their quality of life
-
Through the inhibition of bone resorption, bisphosphonates have demonstrated efficacy in delaying the onset and reducing the risk of skeletal-related events, as well as palliating bone pain
-
Zoledronic acid is the only bisphosphonate that has demonstrated efficacy in reducing the risk of skeletal-related events in multiple cancer types, and in the long-term palliation of bone pain in patients with breast or prostate cancer
This is a preview of subscription content, access via your institution
Access options
Similar content being viewed by others
References
Van Poznak C and Nadal C (2006) Bone integrity and bone metastases in breast cancer. Curr Oncol Rep 8: 22–28
Saad F (2006) Bone-directed treatments for prostate cancer. Hematol Oncol Clin North Am 20: 947–963
Coleman RE (2004) Bisphosphonates: clinical experience. Oncologist 9 (Suppl 4): 14–27
Fourneau I and Broos P (1998) Pathologic fractures due to metastatic disease. A retrospective study of 160 surgically treated fractures. Acta Chir Belg 98: 255–260
Deng G and Cassileth BR (2005) Integrative oncology: complementary therapies for pain, anxiety, and mood disturbance. CA Cancer J Clin 55: 109–116
Mantyh PW (2004) A mechanism-based understanding of bone cancer pain. Novartis Found Symp 261: 194–214 discussion 214–219, 256–261
Ripamonti C and Fulfaro F (2001) Pathogenesis and pharmacological treatment of bone pain in skeletal metastases. QJ Nucl Med 45: 65–77
Sabino MA and Mantyh PW (2005) Pathophysiology of bone cancer pain. J Support Oncol 3: 15–24
Coleman RE (1997) Skeletal complications of malignancy. Cancer 80 (Suppl): 1588–1594
Weinfurt KP et al. (2005) The significance of skeletal-related events for the health-related quality of life of patients with metastatic prostate cancer. Ann Oncol 16: 579–584
Kinnane N (2007) Burden of bone disease. Eur J Oncol Nurs 11 (Suppl 2): S28–S31
Reich CD (2003) Advances in the treatment of bone metastases. Clin J Oncol Nurs 7: 641–646
Diel IJ (2007) Effectiveness of bisphosphonates on bone pain and quality of life in breast cancer patients with metastatic bone disease: a review. Support Care Cancer 15: 1243–1249
Cleeland CS and Ryan KM (1994) Pain assessment: global use of the Brief Pain Inventory. Ann Acad Med Singapore 23: 129–138
Cella DF et al. (1993) The Functional Assessment of Cancer Therapy scale: development and validation of the general measure. J Clin Oncol 11: 570–579
Spitzer WO et al. (1981) Measuring the quality of life of cancer patients: a concise QL-index for use by physicians. J Chronic Dis 34: 585–597
Aaronson NK et al. (1993) The European Organisation for Research and Treatment of Cancer QLQ-C30: a quality-of-life instrument for use in international clinical trials in oncology. J Natl Cancer Inst 85: 365–376
EuroQol Group (1990) EuroQol—a new facility for the measurement of health-related quality of life. Health Policy 16: 199–208
Adrover E et al. (2005) Development of a questionnaire to measure health-related quality of life (HRQoL) in patients with bone metastases (BOMET-QoL). J Outcomes Res 9: 15–27
Harris K and Chow E (online 2006) Bone metastases module [http://groups.eortc.be/qol/downloads/2006_southampton/ chow_bone_mets_module_short_nov2006.pdf] (accessed 15 December 2008)
Sureda A et al. (2007) Final development and validation of the BOMET-QoL questionnaire for assessing quality of life in patients with malignant bone disease due to neoplasia. J Med Econ 10: 27–39
Lipton A (2005) Management of bone metastases in breast cancer. Curr Treat Options Oncol 6: 161–171
Rosen LS et al. (2003) Long-term efficacy and safety of zoledronic acid compared with pamidronate disodium in the treatment of skeletal complications in patients with advanced multiple myeloma or breast carcinoma: a randomized, double-blind, multicenter, comparative trial. Cancer 98: 1735–1744
Saad F et al. (2004) Long-term efficacy of zoledronic acid for the prevention of skeletal complications in patients with metastatic hormone-refractory prostate cancer. J Natl Cancer Inst 96: 879–882
Licata AA (2005) Discovery, clinical development, and therapeutic uses of bisphosphonates. Ann Pharmacother 39: 668–677
Jagdev SP et al. (2001) The bisphosphonate, zoledronic acid, induces apoptosis of breast cancer cells: evidence for synergy with paclitaxel. Br J Cancer 84: 1126–1134
Caraglia M et al. (2006) Emerging anti-cancer molecular mechanisms of aminobisphosphonates. Endocr Relat Cancer 13: 7–26
Boissier S et al. (1997) Bisphosphonates inhibit prostate and breast carcinoma cell adhesion to unmineralized and mineralized bone extracellular matrices. Cancer Res 57: 3890–3894
Berger W et al. (2006) The N-containing bisphosphonate zoledronic acid exerts potent anticancer activity against non-small cell lung cancer cells by inhibition of protein geranylgeranylation [abstract #4981]. Proc Am Assoc Cancer Res 46
Fournier P et al. (2002) Bisphosphonates inhibit angiogenesis in vitro and testosterone-stimulated vascular regrowth in the ventral prostate in castrated rats. Cancer Res 62: 6538–6544
Saad F (2006) The role of bisphosphonates in the management of prostate cancer. Curr Oncol Rep 8: 221–227
Pavlakis N et al. (2005) Bisphosphonates for breast cancer. Cochrane Database of Systematic Reviews 2005, Issue 3. Art. No.: CD003474. 10.1002/14651858.CD003474.pub2.
Hansen-Algenstaedt N et al. (2006) Sequential changes in vessel formation and micro-vascular function during bone repair. Acta Orthop 77: 429–439
Vogt U et al. (2004) Breast tumour growth inhibition in vitro through the combination of cyclophosphamide/metotrexate/5-fluorouracil, epirubicin/cyclophosphamide, epirubicin/paclitaxel, and epirubicin/docetaxel with the bisphosphonates ibandronate and zoledronic acid. Oncol Rep 12: 1109–1114
Budman DR and Calabro A (2006) Zoledronic acid (Zometa) enhances the cytotoxic effect of gemcitabine and fluvastatin: in vitro isobologram studies with conventional and nonconventional cytotoxic agents. Oncology 70: 147–153
Ozturk OH et al. (2007) Cisplatin cytotoxicity is enhanced with zoledronic acid in A549 lung cancer cell line: preliminary results of an in vitro study. Cell Biol Int 31: 1069–1071
Bertelli G et al. (2006) Weekly docetaxel and zoledronic acid every 4 weeks in hormone-refractory prostate cancer patients. Cancer Chemother Pharmacol 57: 46–51
Neville-Webbe HL et al. (2005) Sequence- and schedule-dependent enhancement of zoledronic acid induced apoptosis by doxorubicin in breast and prostate cancer cells. Int J Cancer 113: 364–371
Ullén A et al. (2005) Additive/synergistic antitumoral effects on prostate cancer cells in vitro following treatment with a combination of docetaxel and zoledronic acid. Acta Oncol 44: 644–650
Winter MC et al. (2008) Exploring the anti-tumour activity of bisphosphonates in early breast cancer. Cancer Treat Rev 34: 453–475
Ballantyne JC (2007) Opioid analgesia: perspectives on right use and utility. Pain Physician 10: 479–491
Panchal SJ et al. (2007) Opioid-induced bowel dysfunction: prevalence, pathophysiology and burden. Int J Clin Pract 61: 1181–1187
Loberg RD et al. (2007) The lethal phenotype of cancer: the molecular basis of death due to malignancy. CA Cancer J Clin 57: 225–241
Meuser T et al. (2001) Symptoms during cancer pain treatment following WHO-guidelines: a longitudinal follow-up study of symptom prevalence, severity and etiology. Pain 93: 247–257
Yoshida K and Hiratsuka J (2006) Palliative radiotherapy for metastatic bone tumor [Japanese]. Clin Calcium 16: 641–645
Fairchild A et al. (2008) The rapid access palliative radiotherapy program: blueprint for initiation of a one-stop multidisciplinary bone metastases clinic. Support Care Cancer [10.1007/s00520-008-0468-3]
Smeland S et al. (2003) Role of strontium-89 as adjuvant to palliative external beam radiotherapy is questionable: results of a double-blind randomized study. Int J Radiat Oncol Biol Phys 56: 1397–1404
Chow E et al. (2005) Pain flare following external beam radiotherapy and meaningful change in pain scores in the treatment of bone metastases. Radiother Oncol 75: 64–69
Hellman RS and Krasnow AZ (1998) Radionuclide therapy for palliation of pain due to osteoblastic metastases. J Palliat Med 1: 277–283
Lewington VJ (2005) Bone-seeking radionuclides for therapy. J Nucl Med 46 (Suppl 1): 38S–47S
Delea T et al. (2004) The cost of treatment of skeletal-related events in patients with bone metastases from lung cancer. Oncology 67: 390–396
Green JR (2004) Bisphosphonates: preclinical review. Oncologist 9 (Suppl 4): 3–13
Iwamoto J et al. (2002) Transient relief of metastatic cancer bone pain by oral administration of etidronate. J Bone Miner Metab 20: 228–234
Heidenreich A et al. (2001) The use of bisphosphonate for the palliative treatment of painful bone metastasis due to hormone refractory prostate cancer. J Urol 165: 136–140
Tubiana-Hulin M et al. (2001) Double-blinded controlled study comparing clodronate versus placebo in patients with breast cancer bone metastases [French]. Bull Cancer 88: 701–707
Ernst DS et al. (2003) Randomized, double-blind, controlled trial of mitoxantrone/prednisone and clodronate versus mitoxantrone/prednisone and placebo in patients with hormone-refractory prostate cancer and pain. J Clin Oncol 21: 3335–3342
Santangelo A et al. (2006) The use of bisphosphonates in palliative treatment of bone metastases in a terminally ill, oncological elderly population. Arch Gerontol Geriatr 43: 187–192
Ozyuvaci E et al. (2005) The effects of clodronate for the pain treatment of bone metastasis due to prostate cancer [Turkish]. Agri 17: 49–53
Donat DA et al. (2005) Low-dose clodronate as adjunctive therapy in breast cancer patients with bone metastases [abstract #27P]. Ann Oncol 16 (Suppl 2): ii278
Rodrigues P et al. (2004) Use of bisphosphonates can dramatically improve pain in advanced hormone-refractory prostate cancer patients. Prostate Cancer Prostatic Dis 7: 350–354
Hering F et al. (2003) Clodronate for treatment of bone metastases in hormone refractory prostate cancer. Int Braz J Urol 29: 228–233
Strang P et al. (1997) The analgesic efficacy of clodronate compared with placebo in patients with painful bone metastases from prostatic cancer. Anticancer Res 17: 4717–4721
Hortobagyi GN et al. (1996) Efficacy of pamidronate in reducing skeletal complications in patients with breast cancer and lytic bone metastases. Protocol 19 Aredia Breast Cancer Study Group. N Engl J Med 335: 1785–1791
Hortobagyi GN et al. (1998) Long-term prevention of skeletal complications of metastatic breast cancer with pamidronate. Protocol 19 Aredia Breast Cancer Study Group. J Clin Oncol 16: 2038–2044
Theriault RL et al. (1999) Pamidronate reduces skeletal morbidity in women with advanced breast cancer and lytic bone lesions: a randomized, placebo-controlled trial. Protocol 18 Aredia Breast Cancer Study Group. J Clin Oncol 17: 846–854
Small EJ et al. (2003) Combined analysis of two multicenter, randomized, placebo-controlled studies of pamidronate disodium for the palliation of bone pain in men with metastatic prostate cancer. J Clin Oncol 21: 4277–4284
Wong R et al. (2003) A randomized double blind placebo controlled trial of radiotherapy (XRT) with or without single dose pamidronate (PAM) for pain relief in patients with painful bone metastases [abstract #3099]. Proc Am Soc Clin Oncol 22 (Suppl): 77
Groff L et al. (2001) The role of disodium pamidronate in the management of bone pain due to malignancy. Palliat Med 15: 297–307
Vitale G et al. (2001) Pamidronate improves the quality of life and induces clinical remission of bone metastases in patients with thyroid cancer. Br J Cancer 84: 1586–1590
Body JJ et al. (2004) Oral ibandronate improves bone pain and preserves quality of life in patients with skeletal metastases due to breast cancer. Pain 111: 306–312
Body JJ et al. (2003) Intravenous ibandronate reduces the incidence of skeletal complications in patients with breast cancer and bone metastases. Ann Oncol 14: 1399–1405
Tripathy D and Bergström B (2005) Effect of intravenous and oral ibandronate on the need for analgesic interventions for metastatic bone pain: phase III trial results [abstract #404]. Eur J Cancer Suppl 3: 113
Menssen HD et al. (2002) Effects of long-term intravenous ibandronate therapy on skeletal-related events, survival, and bone resorption markers in patients with advanced multiple myeloma. J Clin Oncol 20: 2353–2359
Tripathy D et al. (2004) Oral ibandronate for the treatment of metastatic bone disease in breast cancer: efficacy and safety results from a randomized, double-blind, placebo-controlled trial. Ann Oncol 15: 743–750
Body JJ et al. (2005) Acute and long-term relief from metastatic bone pain with intravenous ibandronate: phase III and phase II trial results [abstract #26P]. Ann Oncol 16 (Suppl 2): ii277
Heidenreich A et al. (2005) Ibandronate in the management of painful osseous metastases due to hormone refractory prostate cancer [poster #279]. Presented at the 2005 ASCO Prostate Cancer Symposium: 2005 February 17–19, Orlando, FL
Vassiliou V et al. (2005) Combination of radiotherapy and ibandronate for the treatment of bone metastases: clinical evaluation and radiological assessment [abstract 21-160]. Support Care Cancer 13: 467
Mancini I et al. (2004) Efficacy and safety of ibandronate in the treatment of opioid-resistant bone pain associated with metastatic bone disease: a pilot study. J Clin Oncol 22: 3587–3592
Lipton A et al. (2000) Pamidronate prevents skeletal complications and is effective palliative treatment in women with breast carcinoma and osteolytic bone metastases: long term follow-up of two randomized, placebo-controlled trials. Cancer 88: 1082–1090
Body JJ et al. (2004) Oral ibandronate reduces the risk of skeletal complications in breast cancer patients with metastatic bone disease: results from two randomised, placebo-controlled phase III studies. Br J Cancer 90: 1133–1137
Vogel CL et al. (2004) Safety and pain palliation of zoledronic acid in patients with breast cancer, prostate cancer, or multiple myeloma who previously received bisphosphonate therapy. Oncologist 9: 687–695
Kohno N et al. (2005) Zoledronic acid significantly reduces skeletal complications compared with placebo in Japanese women with bone metastases from breast cancer: a randomized, placebo-controlled trial. J Clin Oncol 23: 3314–3321
Saad F et al. (2002) A randomized, placebo-controlled trial of zoledronic acid in patients with hormone-refractory metastatic prostate carcinoma. J Natl Cancer Inst 94: 1458–1468
Weinfurt KP et al. (2006) Effect of zoledronic acid on pain associated with bone metastasis in patients with prostate cancer. Ann Oncol 17: 986–989
Rosen LS et al. (2003) Zoledronic acid versus placebo in the treatment of skeletal metastases in patients with lung cancer and other solid tumors: a phase III, double-blind, randomized trial—the Zoledronic Acid Lung Cancer and Other Solid Tumors Study Group. J Clin Oncol 21: 3150–3157
Rosen LS et al. (2004) Long-term efficacy and safety of zoledronic acid in the treatment of skeletal metastases in patients with nonsmall cell lung carcinoma and other solid tumors: a randomized, phase III, double-blind, placebo-controlled trial. Cancer 100: 2613–2621
Rosen LS et al. (2001) Zoledronic acid versus pamidronate in the treatment of skeletal metastases in patients with breast cancer or osteolytic lesions of multiple myeloma: a phase III, double-blind, comparative trial. Cancer J 7: 377–387
Rosen LS et al. (2004) Zoledronic acid is superior to pamidronate for the treatment of bone metastases in breast carcinoma patients with at least one osteolytic lesion. Cancer 100: 36–43
Wardley A et al. (2005) Zoledronic acid significantly improves pain scores and quality of life in breast cancer patients with bone metastases: a randomised, crossover study of community vs hospital bisphosphonate administration. Br J Cancer 92: 1869–1876
Wiktor-Jedrzejczak W (2005) Reduction of pain as the primary determinant of improved quality of life of cancer patients receiving zoledronic acid (Zol) for bone involvement [abstract #8022]. J Clin Oncol 23 (Suppl): 734s
Ripamonti C et al. (2007) Decreases in pain at rest and movement-related pain during zoledronic acid treatment in patients with bone metastases due to breast or prostate cancer: a pilot study. Support Care Cancer 15: 1117–1184
Stanculeanu DL et al. (2006) Zoledronic acid treatment in osteocondensant bone metastasis prostate cancer patients [poster #289]. Presented at the 2006 ASCO Prostate Cancer Symposium: 2006 February 24–26, San Francisco, CA
Efstathiou E et al. (2005) Combination of docetaxel, estramustine phosphate, and zoledronic acid in androgen-independent metastatic prostate cancer: efficacy, safety, and clinical benefit assessment. Urology 65: 126–130
Clemons MJ et al. (2006) Phase II trial evaluating the palliative benefit of second-line zoledronic acid in breast cancer patients with either a skeletal-related event or progressive bone metastases despite first-line bisphosphonate therapy. J Clin Oncol 24: 4895–4900
Fulfaro F et al. (2005) The use of zoledronic acid in patients with bone metastases from prostate carcinoma: effect on analgesic response and bone metabolism biomarkers. J Chemother 17: 555–559
Major PP et al. (2004) Zoledronic acid reduces the need for radiation to bone in patients with breast or prostate cancer metastatic to bone: a survival-adjusted cumulative incidence analysis [poster #8058]. Presented at the 40th Annual Meeting of the American Society of Clinical Oncology: 2004 June 5–8, New Orleans, LA
Saad F et al. (2003) Long-term reduction of bone pain with zoledronic acid in patients with advanced prostate cancer metastatic to bone [poster #1473]. Presented at the American Urological Association Annual Meeting: 2003 April 26–May 1, Chicago, IL
Costa L and Chen YM (2006) Breast cancer patients without pain are at risk for skeletal-related events and may have better outcomes with zoledronic acid compared with pamidronate [abstract #1071]. Breast Cancer Res Treat 100: S62
Hirsh V et al. (2004) Clinical benefit of zoledronic acid in patients with lung cancer and other solid tumors: analysis based on history of skeletal complications. Clin Lung Cancer 6: 170–174
Rosen L et al. Long-term zoledronic acid therapy is effective and safe for reducing the risk of skeletal complications in patients with non-small lung cancer (NSCLC) and bone metastases [poster #73]. Presented at the What is New in Bisphosphonates? Seventh Workshop on Bisphosphonates—From the Laboratory to the Patient: 2004 March 24–26, Davos, Switzerland
Saad F et al. (2005) Long-term reduction of bone pain and skeletal morbidity with zoledronic acid in patients with prostate cancer and bone metastases [abstract #572]. Eur Urol 3 (Suppl 4): 145
Saad F et al. Zoledronic acid is well tolerated for up to 24 months and significantly reduces skeletal complications in patients with advanced prostate cancer metastatic to bone [poster #1472]. Presented at the American Urological Association Annual Meeting: 2003 April 26–May 1, Chicago, IL
Acknowledgements
Funding for medical editorial assistance was provided by Novartis Pharmaceuticals Corporation. We thank Carol Sledz, PhD, ProEd Communications, Inc., for her editorial assistance with this manuscript.
Author information
Authors and Affiliations
Corresponding author
Ethics declarations
Competing interests
L Costa has declared associations with the following companies: Amgen, Novartis and Roche. PP Major has declared associations with the following companies: Amgen and Novartis. See the article online for full details of the relationships.
Supplementary information
Supplementary Table 2
Summary of trials with nitrogen-containing bisphosphonates* (DOC 99 kb)
Supplementary Table 3
Summary of Trials With Zoledronic Acid (4 mg) (DOC 99 kb)
Rights and permissions
About this article
Cite this article
Costa, L., Major, P. Effect of bisphosphonates on pain and quality of life in patients with bone metastases. Nat Rev Clin Oncol 6, 163–174 (2009). https://doi.org/10.1038/ncponc1323
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1038/ncponc1323
This article is cited by
-
Modelling skeletal pain harnessing tissue engineering
In vitro models (2022)
-
Photodynamic therapy outcome modelling for patients with spinal metastases: a simulation-based study
Scientific Reports (2021)
-
Current treatment strategies for patients with advanced gastroenteropancreatic neuroendocrine tumors (GEP-NETs)
Clinical Diabetes and Endocrinology (2018)
-
Radiopharmaceuticals for metastatic bone pain palliation: available options in the clinical domain and their comparisons
Clinical & Experimental Metastasis (2017)
-
Combined Vertebral Augmentation and Radiofrequency Ablation in the Management of Spinal Metastases: an Update
Current Treatment Options in Oncology (2017)