Official reprint from UpToDate®
www.uptodate.com ©2018 UpToDate, Inc. and/or its affiliates. All Rights Reserved.

Risks of therapy with bone antiresorptive agents in patients with advanced malignancy

James R Berenson, MD
Alison T Stopeck, MD
Section Editors
Robert A Kyle, MD
Reed E Drews, MD
Deputy Editor
Diane MF Savarese, MD


Parenteral administration of osteoclast inhibitors (bisphosphonates and denosumab) reduces the frequency of skeletal-related events among patients with multiple myeloma and in those with bone metastases from a variety of solid tumors, including breast, lung, and prostate cancer. Prolonged therapy with these antiresorptive agents in patients with advanced malignancy is generally well tolerated, but some side effects are potentially serious and require periodic monitoring [1-3].

This topic will provide an overview of the risks of therapy with antiresorptive agents in patients with skeletal involvement from advanced malignancy. The therapeutic use of bisphosphonates and denosumab in malignant disease, and their use and side effects in other conditions, such as osteoporosis and cancer treatment-related bone loss, are discussed separately, as is a more thorough discussion of medication-related osteonecrosis of the jaw (MRONJ). (See "Osteoclast inhibitors for patients with bone metastases from breast, prostate, and other solid tumors" and "The use of osteoclast inhibitors in patients with multiple myeloma" and "The use of bisphosphonates in postmenopausal women with osteoporosis" and "Denosumab for osteoporosis" and "Evaluation and management of aromatase inhibitor-induced bone loss" and "Overview of the use of osteoclast inhibitors in early breast cancer" and "Side effects of androgen deprivation therapy", section on 'Prevention' and "Bone metastases in advanced prostate cancer: Management" and "Medication-related osteonecrosis of the jaw in patients with cancer".)


Two classes of antiresorptive agents are used for prevention of skeletal events in patients with advanced malignancy:

Bisphosphonates pamidronate, zoledronic acid, and ibandronate are structural analogs of inorganic pyrophosphate. Pamidronate and zoledronic acid are approved in the United States, while ibandronate is approved in many European countries. Bisphosphonates inhibit osteoclastic bone resorption by attaching to hydroxyapatite binding sites within bone. The bisphosphonate that is released during bone resorption impairs the ability of the osteoclasts to adhere to the bony surface and resorb bone. In addition, bisphosphonates also reduce osteoclast activity by decreasing osteoclast progenitor development and recruitment, and by promoting osteoclast apoptosis. (See "Pharmacology of bisphosphonates".)

Denosumab is a fully human monoclonal antibody that inhibits osteoclastic bone resorption by specifically binding and inhibiting the receptor activator of nuclear factor-KB ligand (RANKL), a key regulator of osteoclast formation, function, and survival. (See "Normal skeletal development and regulation of bone formation and resorption".)

To continue reading this article, you must log in with your personal, hospital, or group practice subscription. For more information on subscription options, click below on the option that best describes you:

Subscribers log in here

Literature review current through: Dec 2017. | This topic last updated: Apr 28, 2017.
The content on the UpToDate website is not intended nor recommended as a substitute for medical advice, diagnosis, or treatment. Always seek the advice of your own physician or other qualified health care professional regarding any medical questions or conditions. The use of this website is governed by the UpToDate Terms of Use ©2018 UpToDate, Inc.
  1. Tralongo P, Repetto L, Di Mari A, et al. Safety of long-term administration of bisphosphonates in elderly cancer patients. Oncology 2004; 67:112.
  2. Mehrotra B, Ruggiero S. Bisphosphonate complications including osteonecrosis of the jaw. Hematology Am Soc Hematol Educ Program 2006; :356.
  3. Dunstan CR, Felsenberg D, Seibel MJ. Therapy insight: the risks and benefits of bisphosphonates for the treatment of tumor-induced bone disease. Nat Clin Pract Oncol 2007; 4:42.
  4. Stopeck AT, Lipton A, Body JJ, et al. Denosumab compared with zoledronic acid for the treatment of bone metastases in patients with advanced breast cancer: a randomized, double-blind study. J Clin Oncol 2010; 28:5132.
  5. Henry DH, Costa L, Goldwasser F, et al. Randomized, double-blind study of denosumab versus zoledronic acid in the treatment of bone metastases in patients with advanced cancer (excluding breast and prostate cancer) or multiple myeloma. J Clin Oncol 2011; 29:1125.
  6. Fizazi K, Carducci M, Smith M, et al. Denosumab versus zoledronic acid for treatment of bone metastases in men with castration-resistant prostate cancer: a randomised, double-blind study. Lancet 2011; 377:813.
  7. Edwards BJ, Gounder M, McKoy JM, et al. Pharmacovigilance and reporting oversight in US FDA fast-track process: bisphosphonates and osteonecrosis of the jaw. Lancet Oncol 2008; 9:1166.
  8. Medication-Related Osteonecrosis of the Jaw - 2014 Update. American Association of Oral and Maxillofacial Surgeons. http://www.aaoms.org/docs/position_papers/mronj_position_paper.pdf?pdf=MRONJ-Position-Paper (Accessed on September 04, 2014).
  9. Van Poznak CH, Temin S, Yee GC, et al. American Society of Clinical Oncology executive summary of the clinical practice guideline update on the role of bone-modifying agents in metastatic breast cancer. J Clin Oncol 2011; 29:1221.
  10. Kyle RA, Yee GC, Somerfield MR, et al. American Society of Clinical Oncology 2007 clinical practice guideline update on the role of bisphosphonates in multiple myeloma. J Clin Oncol 2007; 25:2464.
  11. European Medicines Agency. CHMP Assessment Report on Bisphosphonates and Osteonecrosis of the Jaw. London: EMA/CHMP 2011. http://www.ema.europa.eu/docs/en_GB/document_library/Other/2010/01/WC500051383.pdf (Accessed on October 16, 2014).
  12. Blair HC, Robinson LJ, Huang CL, et al. Calcium and bone disease. Biofactors 2011; 37:159.
  13. Peter R, Mishra V, Fraser WD. Severe hypocalcaemia after being given intravenous bisphosphonate. BMJ 2004; 328:335.
  14. Chennuru S, Koduri J, Baumann MA. Risk factors for symptomatic hypocalcaemia complicating treatment with zoledronic acid. Intern Med J 2008; 38:635.
  15. Body JJ, Lipton A, Gralow J, et al. Effects of denosumab in patients with bone metastases with and without previous bisphosphonate exposure. J Bone Miner Res 2010; 25:440.
  16. Lipton A, Fizazi K, Stopeck AT, et al. Superiority of denosumab to zoledronic acid for prevention of skeletal-related events: a combined analysis of 3 pivotal, randomised, phase 3 trials. Eur J Cancer 2012; 48:3082.
  17. Body JJ, Bone HG, de Boer RH, et al. Hypocalcaemia in patients with metastatic bone disease treated with denosumab. Eur J Cancer 2015; 51:1812.
  18. Block GA, Bone HG, Fang L, et al. A single-dose study of denosumab in patients with various degrees of renal impairment. J Bone Miner Res 2012; 27:1471.
  19. Yang SP, Kim TW, Boland PJ, Farooki A. Retrospective Review of Atypical Femoral Fracture in Metastatic Bone Disease Patients Receiving Denosumab Therapy. Oncologist 2017; 22:438.
  20. Hayashi K, Aono M, Shintani K, Kazuki K. Bisphosphonate-related atypical femoral fracture with bone metastasis of breast cancer: case report and review. Anticancer Res 2014; 34:1245.
  21. Puhaindran ME, Farooki A, Steensma MR, et al. Atypical subtrochanteric femoral fractures in patients with skeletal malignant involvement treated with intravenous bisphosphonates. J Bone Joint Surg Am 2011; 93:1235.
  22. Chang ST, Tenforde AS, Grimsrud CD, et al. Atypical femur fractures among breast cancer and multiple myeloma patients receiving intravenous bisphosphonate therapy. Bone 2012; 51:524.
  23. Adam Z, Sprláková-Puková A, Chaloupka R, et al. [Atypical fracture of metatarsal bone in a patient with multiple myeloma who was treated long-term with bisphosphonates]. Vnitr Lek 2013; 59:1022.
  24. Waterman GN, Yellin O, Jamshidinia K, et al. Metatarsal stress fractures in patients with multiple myeloma treated with long-term bisphosphonates: a report of six cases. J Bone Joint Surg Am 2011; 93:e106.
  25. Markowitz GS, Appel GB, Fine PL, et al. Collapsing focal segmental glomerulosclerosis following treatment with high-dose pamidronate. J Am Soc Nephrol 2001; 12:1164.
  26. Sauter M, Jülg B, Porubsky S, et al. Nephrotic-range proteinuria following pamidronate therapy in a patient with metastatic breast cancer: mitochondrial toxicity as a pathogenetic concept? Am J Kidney Dis 2006; 47:1075.
  27. Kunin M, Kopolovic J, Avigdor A, Holtzman EJ. Collapsing glomerulopathy induced by long-term treatment with standard-dose pamidronate in a myeloma patient. Nephrol Dial Transplant 2004; 19:723.
  28. Perazella MA, Markowitz GS. Bisphosphonate nephrotoxicity. Kidney Int 2008; 74:1385.
  29. Gokden N, Zangari M, Elici F, et al. Potential effect of zoledronate therapy in heavy proteinuria. Clin Nephrol 2007; 67:263.
  30. Rosen LS, Gordon D, Kaminski M, et al. 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 2001; 7:377.
  31. Rosen LS, Gordon D, Kaminski M, et al. 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 2003; 98:1735.
  32. Chang JT, Green L, Beitz J. Renal failure with the use of zoledronic acid. N Engl J Med 2003; 349:1676.
  33. Jones SG, Dolan G, Lengyel K, Myers B. Severe increase in creatinine with hypocalcaemia in thalidomide-treated myeloma patients receiving zoledronic acid infusions. Br J Haematol 2002; 119:576.
  34. Markowitz GS, Fine PL, Stack JI, et al. Toxic acute tubular necrosis following treatment with zoledronate (Zometa). Kidney Int 2003; 64:281.
  35. Munier A, Gras V, Andrejak M, et al. Zoledronic Acid and renal toxicity: data from French adverse effect reporting database. Ann Pharmacother 2005; 39:1194.
  36. Berenson JR, Yellin O, Crowley J, et al. Prognostic factors and jaw and renal complications among multiple myeloma patients treated with zoledronic acid. Am J Hematol 2011; 86:25.
  37. McDermott RS, Kloth DD, Wang H, et al. Impact of zoledronic acid on renal function in patients with cancer: Clinical significance and development of a predictive model. J Support Oncol 2006; 4:524.
  38. Morgan GJ, Davies FE, Gregory WM, et al. First-line treatment with zoledronic acid as compared with clodronic acid in multiple myeloma (MRC Myeloma IX): a randomised controlled trial. Lancet 2010; 376:1989.
  39. Saad F, Gleason DM, Murray R, et al. A randomized, placebo-controlled trial of zoledronic acid in patients with hormone-refractory metastatic prostate carcinoma. J Natl Cancer Inst 2002; 94:1458.
  40. Rosen LS, Gordon D, Tchekmedyian S, et al. 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 2003; 21:3150.
  41. Berenson JR, Rosen L, Vescio R, et al. Pharmacokinetics of pamidronate disodium in patients with cancer with normal or impaired renal function. J Clin Pharmacol 1997; 37:285.
  42. Berenson JR, Boccia R, Lopez T, et al. Results of a multicenter open-label randomized trial evaluating infusion duration of zoledronic acid in multiple myeloma patients (the ZMAX trial). J Support Oncol 2011; 9:32.
  43. Himelstein AL, Qin R, Novotny PJ, et al. CALGB 90604 (Alliance): A randomized phase III study of standard dosing vs. longer interval dising of zoledronic acid in metastatic cancer (abstr). J Clin Oncol 33, 2015 (suppl; abstr 9501). Abstract available at http://meetinglibrary.asco.org/content/147845-156 (Accessed on July 09, 2015).
  44. Diel IJ, Bergner R, Grötz KA. Adverse effects of bisphosphonates: current issues. J Support Oncol 2007; 5:475.
  45. Olson K, Van Poznak C. Significance and impact of bisphosphonate-induced acute phase responses. J Oncol Pharm Pract 2007; 13:223.
  46. Fizazi K, Lipton A, Mariette X, et al. Randomized phase II trial of denosumab in patients with bone metastases from prostate cancer, breast cancer, or other neoplasms after intravenous bisphosphonates. J Clin Oncol 2009; 27:1564.
  47. Tanvetyanon T, Stiff PJ. Management of the adverse effects associated with intravenous bisphosphonates. Ann Oncol 2006; 17:897.
  48. Tan YL, Sims J, Chee SP. Bilateral uveitis secondary to bisphosphonate therapy. Ophthalmologica 2009; 223:215.
  49. www.fda.gov/Drugs/DrugSafety/PostmarketDrugSafetyInformationforPatientsandProviders/ucm101551.htm (Accessed on August 08, 2011).
  50. Wilkinson GS, Baillargeon J, Kuo YF, et al. Atrial fibrillation and stroke associated with intravenous bisphosphonate therapy in older patients with cancer. J Clin Oncol 2010; 28:4898.
  51. Erichsen R, Christiansen CF, Frøslev T, et al. Intravenous bisphosphonate therapy and atrial fibrillation/flutter risk in cancer patients: a nationwide cohort study. Br J Cancer 2011; 105:881.
  52. Block G, Bone HG, Fang L, et al. A single dose study of denosumab in patients with various degrees of renal impairment. Presented at the National Kidney Foundation, Orlando FL, April 2010.
  53. Watkins KR, Rogers JE, Atkinson B. Tolerability of denosumab in metastatic solid tumor patients with renal insufficiency. Support Care Cancer 2015; 23:1657.
  54. Leibbrandt A, Penninger JM. RANK/RANKL: regulators of immune responses and bone physiology. Ann N Y Acad Sci 2008; 1143:123.
  55. Kong YY, Yoshida H, Sarosi I, et al. OPGL is a key regulator of osteoclastogenesis, lymphocyte development and lymph-node organogenesis. Nature 1999; 397:315.
  56. Bekker PJ, Holloway DL, Rasmussen AS, et al. A single-dose placebo-controlled study of AMG 162, a fully human monoclonal antibody to RANKL, in postmenopausal women. J Bone Miner Res 2004; 19:1059.
  57. Cummings SR, San Martin J, McClung MR, et al. Denosumab for prevention of fractures in postmenopausal women with osteoporosis. N Engl J Med 2009; 361:756.
  58. Smith MR, Egerdie B, Hernández Toriz N, et al. Denosumab in men receiving androgen-deprivation therapy for prostate cancer. N Engl J Med 2009; 361:745.
  59. Saad F, Brown JE, Van Poznak C, et al. Incidence, risk factors, and outcomes of osteonecrosis of the jaw: integrated analysis from three blinded active-controlled phase III trials in cancer patients with bone metastases. Ann Oncol 2012; 23:1341.