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Metastatic Bone Disease

Developing Strategies to Optimize Management

  • Therapy in Practice
  • Published:
American Journal of Cancer

Abstract

The cancer patient with skeletal metastases now has a much improved range of treatment options with major advances in bone-specific drug therapy as well as radiotherapy and radiopharmaceuticals, orthopaedic surgery, and systemic anticancer therapy with cytotoxic and endocrine agents.

Recent advances in the understanding of bone remodeling mechanisms and the interdependence of cancer cells and bone have been closely associated with development of the bisphosphonate drugs and newer agents such as osteoprotegerin (OPG). The bisphosphonates are potent inhibitors of osteoclast mediated bone resorption and appear to function either by induction of apoptosis in mature osteoclasts or by inhibition of formation of osteoclasts from progenitor cells. Bisphosphonates are the treatment of choice in tumor-induced hypercalcemia. Bisphosphonates have a clear role in reducing bone pain and skeletal complications, such as pathological fracture and are being evaluated in the prevention of bone metastases.

Until recently, intravenous (IV) pamidronate has been the drug most commonly prescribed for oncological indications and oral clodronate has also been widely used in some countries outside the US. However, newer and more potent drugs, such as zoledronate, are increasingly having a major impact on routine therapy. Three of the largest ever bisphosphonate trials, using zoledronate in metastatic bone disease have recently been completed. In a breast and multiple myeloma trial in 1648 patients, zoledronate (4mg IV) was shown to be equivalent to pamidronate (90mg IV) in reducing skeletal events and was more convenient to administer. In trials in prostate cancer and a wide range of other solid tumor types affecting bone, both the number of patients with skeletal-related events and the rate of bone complications were reduced. The indications for bisphosphonates are, therefore, no longer constrained by tumor type.

The assessment of response to therapy is a vital part of management of metastatic bone disease. Plain radiographs and the isotope bone scan remain widely used but have many limitations. Newer imaging techniques such as computerized tomography, magnetic resonance imaging, and positron emission tomography may be useful in selected situations. Recent research suggests that measurement of tumor markers and bone-specific markers will play an increasingly important role in assessment of response. In particular, bone resorption markers measuring collagen breakdown have potential as rapid, convenient, and inexpensive measures of response, with suppression of bone resorption into the normal range being an important aim of bone-specific treatments.

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References

  1. Schottenfeld D, Fraumeni JF, editors. Cancer epidermiology and prevention. 2nd ed. New York: Oxford University Press, 1996

    Google Scholar 

  2. DeVita VT, Hellman S, Rosenberg SA. Cancer: principles and practice of oncology. Philadelphia (PA): Williams and Wilkins, 2001

    Google Scholar 

  3. Coleman RE. Skeletal_complications of malignancy. Cancer 1998; 80: 158894

    Google Scholar 

  4. MacVicar D. Radiology and magnetic resonance imaging. In: Rubens RD, Mundy GR, editors. Cancer and the skeleton. London: Martin Dunitz, 2000: 113–36

    Google Scholar 

  5. Lipton A, Costa L, Ali S, et al. Use of bone turnover formonitoring bone metastases and the response to therapy. Semin Oncol 2001; 4Suppl. 11: 54–9

    Article  Google Scholar 

  6. Lipton A, Theriault RL, Hortobagyi GH, et al. Pamidronate prevents skeletal complications and is effective palliative treatment in women with breast carcinoma and osteolytic bone metastases; long-term follow up of two randomised, placebo controlled trials. Cancer 2000; 88: 1082–90

    Article  PubMed  CAS  Google Scholar 

  7. Berenson JR, Lichtenstein A, Porter L, et al. Efficacy of pamidronate in reducing skeletal events in patients with advanced multiple myeloma, Myeloma Aredia Study Group. N Engl J Med 1996; 334: 488–93

    Article  PubMed  CAS  Google Scholar 

  8. Saad F, Gleason D, Murray R, et al. A randomised, placebo controlled trial of zoledronic acid in patients with hormone refractory metastatic prostate carcinoma. J Natl Cancer Inst 2002; 94: 1458–68

    Article  PubMed  CAS  Google Scholar 

  9. Rosen L, Gordon D, Tchekmedyian S, et al. Zometa significantly increases the median time to first skeletal related event (SRE) in patients with osteolytic bone metastases from non-small cell lung cancer (NSCLC) and other solid tumours (OST) [abstract]. Lung Cancer 2001; 34Suppl. 1: 67

    Google Scholar 

  10. Pantel K, Core RJ, Fostad O. Detection and clinical importance of micrometastatic disease. J Natl Cancer Inst 1999; 91: 1113–24

    Article  PubMed  CAS  Google Scholar 

  11. Orr FW, Lee J, Duivenvoorden WCM, et al. Pathophysiologic interactions in skeletal metastases. Cancer Suppl 2000; 88: 2912–8

    CAS  Google Scholar 

  12. Mundy GR. Mechanisms of bone metastasis. Cancer 1997; 80Suppl. 8: 1546–56

    Article  PubMed  CAS  Google Scholar 

  13. Kanis JA, McCloskey EV. Bone turnover and biochemical markers in malignancy. Cancer 1997; 80Suppl. 8: 1538–45

    Article  PubMed  CAS  Google Scholar 

  14. Fleisch H. Development of bisphosphonates. Breast Cancer Res 2002; 4: 30–4

    Article  PubMed  CAS  Google Scholar 

  15. 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: 377–87

    PubMed  CAS  Google Scholar 

  16. Body JJ, Bartl R, Burckhardt P, et al. Current use of bisphosphonates in oncology: International Bone and Cancer Study Group. J Clin Oncol 1998; 16: 3890–9

    PubMed  CAS  Google Scholar 

  17. Major P, Lortholary A, Hon J, et al. Zoledronic acid is superior to pamidronate in the treatment of hypercalcemia of malignancy: a pooled analysis of two randomised, controlled clinical trials. J Clin Oncol 2001; 19: 558–67

    PubMed  CAS  Google Scholar 

  18. Coleman RE. Management of bone metastases. Oncologist 2000; 5: 463–70

    Article  PubMed  CAS  Google Scholar 

  19. Body JJ, Lichinitser MR, Diel IE, et al. Double-blind placebo controlled trial of ibandronate in breast cancer metastatic to bone [abstract 2222]. Proc Am Soc Clin Oncol 1999; 18: 575a

    Google Scholar 

  20. Berenson JR, Rosen LS, Howell A, et al. Zoledronic acid reduces skeletal events in patients with osteolytic metastases. Cancer 2001; 91: 1191–200

    Article  PubMed  CAS  Google Scholar 

  21. Diel IJ, Marschner M, Kindler O, et al. Continual oral versus intravenous interval therapy with bisphosphonates in patients with breast cancer and bone metastases [abstract 488]. Proc Am Soc Clin Oncol 1999; 18: 128a

    Google Scholar 

  22. Jagdev SP, Purohit OP, Heatley S, et al. Comparison of the effects of intravenous pamidronate and oral clodronate on symptoms and bone resorption in patients with metastatic bone disease. Ann Oncol 2001; 12: 1433–8

    Article  PubMed  CAS  Google Scholar 

  23. Van Holten-Verzantvoort AT, Bijvoet OLM, Cleton FJ, et al. Reduced morbidity from skeletal metastases in breast cancer patients during long term bisphosphonate (APD) treatment. Lancet 1987; II: 983–5

    Google Scholar 

  24. Paterson AHG, Powles TJ, Kanis JA, et al. Double-blind controlled trial of oral clodronate in patients with bone metastases from breast cancer. J Clin Oncol 1993; 11: 59–65

    PubMed  CAS  Google Scholar 

  25. Conte PF, Latreille J, Mauriac L, et al. Delay in progression of bone metastases treated with intravenous pamidronate: results from a multicentre randomised controlled trial. J Clin Oncol 1996; 14: 2552–9

    PubMed  CAS  Google Scholar 

  26. Hortobagyi GN, Theriault RL, Porter L. Efficacy of pamidronate in reducing skeletal complications in patients with breast cancer and lytic bone metastases. New Engl J Med 1996; 335: 1785–91

    Article  PubMed  CAS  Google Scholar 

  27. Hultborn R, Ryden S, Gunderson S, et al. Efficacy of pamidronate on skeletal complications from breast cancer metastases: a randomised prospective double blind placebo controlled trial. Acta Oncologica 1996; 35Suppl. 5: 73–4

    Article  PubMed  Google Scholar 

  28. Theriault RL, Lipton A, Hortobagyi GN, et al. Pamidronate reduces skeletal morbidity in women with advance breast cancer and lytic bone lesions: a randomised, placebo-controlled trial. J Clin Oncol 1999; 17: 846–54

    PubMed  CAS  Google Scholar 

  29. Lahtinen R, Laasko M, Palva I, et al. Randomised placebo controlled multicentre trial of clodronate in multiple myeloma. Lancet 1992; 340: 1049–52

    Article  PubMed  CAS  Google Scholar 

  30. Berenson JR, Lichtenstein A, Porter L, et al. Long-term pamidronate treatment of advanced multiple myeloma patients reduces skeletal events. J Clin Oncol 1998; 16: 593–602

    PubMed  CAS  Google Scholar 

  31. McCloskey EV, MacLennan ICM, Drayson MT, et al. A randomized trial of the effect of clodronate on skeletal morbidity in multiple myeloma. Br J Haematol 1998; 100: 317–25

    Article  PubMed  CAS  Google Scholar 

  32. Dearnaley DP, Sydes MR, on behalf of the MRC PR05 collaborators. Preliminary evidence that oral clodronate delays symptomatic progression of bone metastases from prostate cancer: first results of the MRC PR05 trial [abstract 693]. Proc Am Soc Clin Oncol 2001; 20: 174a

    Google Scholar 

  33. Lipton A, Costa L, Ali SM, et al. Bone markers in the management of metastatic bone disease. Cancer Treat Rev 2001; 27: 181–5

    Article  PubMed  CAS  Google Scholar 

  34. Paterson AHG, Powles TJ, Kanis J, et al. Double-blind controlled trial of oral clodronate in patients with bone metastases from breast cancer. J Clin Oncol 1998; 11: 59–65

    Google Scholar 

  35. Hortobagyi GN, Thierault RL, Porter L, et al. Efficacy of pamidronate in reducing skeletal complications on patients with breast cancer and lytic bone metastases. N Engl J Med 1996; 335: 1785–91

    Article  PubMed  CAS  Google Scholar 

  36. Pavlakis N, Stockler M. Bisphosphonates for breast cancer. Available in: The Cochrane Library [database on disk and CD ROM]. Updated quarterly. The Cochrane Collaboration; issue 1. Oxford: Update Software, 2002

  37. National Institutes of Health Concensus Development Conference Statement. Adjuvant therapy for breast cancer. 2000 Nov 1–3. J Natl Cancer Inst Monogr 2001; 30: 5–15

    Article  Google Scholar 

  38. Bolla M, Gonzalez D, Wardle P, et al. Improved survival in patients with locally advanced prostate cancer treated with radiotherapy and goserelin. N Engl J Med 1997; 337: 295–300

    Article  PubMed  CAS  Google Scholar 

  39. Goldhirsch A, Gelber RD, Price KN, et al. Effect of systemic adjuvant treatment on first sites of breast cancer relapse. Lancet 1994; 343: 377–81

    Article  PubMed  CAS  Google Scholar 

  40. Jagdev SP, Coleman RE, Shipman CM, et al. The bisphosphonate zoledronic acid induces apoptosis of breast cancer cells: evidence for synergy with paclitaxel. Br J Cancer 2001; 84: 1126–34

    Article  PubMed  CAS  Google Scholar 

  41. Shipman CM, Rogers MJ, Apperley JE, et al. Bisphosphonates induce apoptosis in human myeloma cell lines: a novel anti-tumour activity. Br J Haematol 1997; 98: 665–72

    Article  PubMed  CAS  Google Scholar 

  42. Shipman CM, Croucher PI, Russell RG, et al. The bisphosphonate incadronate (YM175) causes apoptosis of human myeloma cells in vitro by inhibiting the mevalonate pathway. Cancer Res 1998; 58: 5294–7

    PubMed  CAS  Google Scholar 

  43. Powles TJ, Paterson AHG, Nevantaus A, et al. Adjuvant clodronate reduces the incidence of bone metastases in patients with primary operable breast cancer [abstract]. 34th Proc Am Soc Clin Oncol 1998: 17; 123a

    Google Scholar 

  44. Diel IJ, Solomayer E, Gollan C, et al. Bisphosphonates in the reduction of metastases in breast cancer: results of the extended follow-up of the first study population [abstract 314]. Proc Am Soc Clin Oncol 2000; 19: 82a

    Google Scholar 

  45. Saarto T, Blomqvist C, Virkkunen P, et al. Adjuvant clodronate treatment does not reduce the frequency of skeletal metastases in node-positive breast cancer patients: 5 year results of randomised controlled trial. J Clin Oncol 2001; 19: 10–7

    PubMed  CAS  Google Scholar 

  46. Smith MR, McGovern FR, Zeitman AI, et al. Pamidronate to prevent bone loss during androgen-deprivation therapy for prostate cancer. N Engl J Med 2001; 345: 948–54

    Article  PubMed  CAS  Google Scholar 

  47. Saarto T, Blomquist C, Valimaki M, et al. Chemical castration induced by adjuvant cyclophosphamide, methotraxate and fluorouracil chemotherapy causes rapid bone loss that is reduced by clodronate: a randomized study in premenopausal breast cancer patients. J Clin Oncol 1997; 15: 1341–7

    PubMed  CAS  Google Scholar 

  48. Hillner BE. Pharmacoeconomic issues in bisphosphonate treatment of metastatic bone disease. Semin Oncol 2001; 28Suppl. 11: 64–8

    Article  PubMed  CAS  Google Scholar 

  49. McCloskey E, Guest JF, Kanis JA. The clinical and cost considerations of bisphosphonates in preventing bone complications in patients with metastatic breast cancer or multiple myeloma. Drugs 2001; 61: 1253–74

    Article  PubMed  CAS  Google Scholar 

  50. Honore P, Luger NM, Sabino AC, et al. Osteoprotegerin blocks bone cancerinduced skeletal destruction: skeletal pain and pain-related neurochemical reorganisation of the spinal cord. Nat Med 2000; 6: 521–8

    Article  PubMed  CAS  Google Scholar 

  51. Body JJ, Greipp P, Coleman RE, et al. A phase 1 study of AMGN-0007: a recombinant osteoprotogerin construct in patients with multiple myeloma or breast carcinoma related bone metastases. Cancer 2003; 97: 887–92

    Article  PubMed  Google Scholar 

  52. Mirrels H. Metastatic disease in long bones: a proposed scoring system for diagnosing impending pathological fracture. Clin Orthop 1989; 249: 256–64

    Google Scholar 

  53. Hardman PDJ, Robb JE, Kerr GR, et al. The value of internal fixation and radiotherapy in the management of upper and lower limb bone metastases. Clin Oncol 1992; 4: 244–8

    Article  CAS  Google Scholar 

  54. Janjan NA. Radiation for bone metastases: conventional techniques and the role of systemic radiopharmaceuticals. Cancer 2000; 89: 363–8

    Article  Google Scholar 

  55. Houston SJ. Clinical use of radioisotopes for bone metastases. In: Rubens RD, Mundy GR, editors. Cancer and the Skeleton. London: Martin Dunitz, 2000: 172–82

    Google Scholar 

  56. Janjan N. Bone Metastases: approaches to management. Semin Oncol 2001; 28: 28–34

    Article  PubMed  CAS  Google Scholar 

  57. Portnow J, Grossman SA. Pain: mechanisms, assessment and management. In: Rubens RD, Mundy GR, editors. Cancer and the skeleton. London: Martin Dunitz, 2000: 183–99

    Google Scholar 

  58. Edelstyn GA, Gillespie PJ, Grebbel FS. The radiological demonstration of osseus metastases: experimental observations. Clin Radiol 1967; 18: 158–62

    Article  PubMed  CAS  Google Scholar 

  59. Howell A, Mackintosh J, Jones M, et al. The definition of the ‘no change’ category in patients treated with endocrine therapy and chemotherapy for advanced carcinoma of the breast. Eur J Cancer 1988; 24A: 1567–72

    Google Scholar 

  60. Robertson JFR, Jaeger W, Syzmendera JJ, et al. The objective measurement of remission and progression in metastatic breast cancer by use of serum tumour markers. Eur J Cancer 1999; 35: 47–53

    Article  PubMed  CAS  Google Scholar 

  61. Berruti A, Torta M, Piovesan A, et al. Biochemical picture of bone metabolism in breast cancer patients with bone metastases. Anticancer Res 1995; 15: 2871–6

    PubMed  CAS  Google Scholar 

  62. Costa L, Demers LM, Gouveia A, et al. Biochemical markers of bone turnover correlate with the extent of metastatic bone disease [abstract 2375]. Proc Am Soc Clin Oncol 1999; 18: 615a

    Google Scholar 

  63. Ali SM, Demers LM, Leitzel K, et al. Elevated serum N-telopeptide predicts poor prognosis in breats cancer patients with bone metastases [abstract 2549]. Proc Am Soc Clin Oncol 2000; 19: 646a

    Google Scholar 

  64. Walls J, Assiri A, Howell A, et al. Measurement of urinary collagen crosslinks indicate response to therapy in patients with breast cancer and bone metastases. Br J Cancer 1999; 80: 1265–70

    Article  PubMed  CAS  Google Scholar 

  65. Vinholes JJF, Purohit OP, Abbey ME, et al. Relationships between biochemical and symptomatic response in a double blind randomised trial of pamidronate for metastatic bone disease. Ann Oncol 1997; 8: 1243–50

    Article  PubMed  CAS  Google Scholar 

  66. Lipton A, Demers L, Curley E, et al. Markers of bone resorption in patients treated with pamidronate. Eur J Cancer 1998; 34: 2021–6

    Article  PubMed  CAS  Google Scholar 

  67. Brown JE, Ellis S, Gutcher S, et al. The bone resorption marker Ntx is strongly correlated with skeletal events in metastatic bone disease and is influenced by dose escalation of clodronate [abstract 1537]. Proc Am Soc Clin Oncol 2002; 21: 385a

    Google Scholar 

  68. Coleman RE, Rosen LS, Gordon D, et al. Zoledronic acid (4mg) significantly reduces the relative risk of developing a skeletal-related event compared with pamidronate (90mg) in patients with breast cancer and bone metastasis [abstract 355]. Breast Cancer Res Treat 2002; 76Suppl. 1: S95

    Google Scholar 

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  1. Yorkshire Cancer Research Academic Unit of Clinical Oncology Cancer Research Centre, Weston Park Hospital, Sheffield, S10 2SJ, UK

    Janet E. Brown &  Robert E. Coleman

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Brown, J.E., Coleman, R.E. Metastatic Bone Disease. Am J Cancer 2, 269–281 (2003). https://doi.org/10.2165/00024669-200302040-00005

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