Skip to main content

Advertisement

SpringerLink
Log in

Malignant bone pain: Pathophysiology and treatments

  • Published:
Current Review of Pain Aims and scope Submit manuscript

Abstract

Metastatic involvement of the bone is one of the most frequent causes of pain in cancer patients and represents one of the first signs of widespread neoplastic disease. The pain may originate directly from the bone, from nerve root compression, or from muscle spasms in the area of the lesions. The mechanism of metastatic bone pain is mainly somatic (nociceptive), even though, in some cases, neuropathic and visceral stimulations may overlap. The conventional symptomatic treatment of metastatic bone pain requires the use of multidisciplinary therapies, such as radiotherapy, in association with systemic treatment (hormonotherapy, chemotherapy, radioisotopes) with the support of analgesic therapy.

Recently, studies have indicated the use of bisphosphonates in the treatment of pain and in the prevention of skeletal complications in patients with metastatic bone disease. In some patients, pharmacologic treatment, radiotherapy, and radioisotopes administered alone or in association are not able to manage pain adequately. The role of neuroinvasive techniques in treating metastatic bone pain is debated. The clinical conditions of the patient, his life expectancy, and quality of life must guide the physician in the choice of the best possible therapy.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References and Recommended Reading

  1. Coleman RE, Rubens RD: The clinical course of bone metastases from breast cancer. Br J Cancer 1987, 55:61–66.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  2. Body JJ: Metastatic bone disease: clinical and therapeutical aspects. Bone 1992, 13:557–562.

    Article  Google Scholar 

  3. Hanks GW: The pharmacological treatment of bone pain. Cancer Surv 1988, 7:87–101.

    CAS  PubMed  Google Scholar 

  4. Chigira M, Watanabe H, Maehara S, Shinozaki T: Pain and internal hypertension in bone lesions. Acta Orthop Scand 1984, 55:375–377.

    Article  CAS  PubMed  Google Scholar 

  5. Ferreira SH: Prostaglandins, aspirin-like drugs and analgesia. Nature New Biol 1972, 240:200–203.

    Article  CAS  PubMed  Google Scholar 

  6. Bennet A: Role of biochemical mediators in peripheral nociception and bone pain. Cancer Surv 1988, 7:55–67.

    Google Scholar 

  7. Caraceni A, Mendoza TR, Mencaglia E, et al.: A validation study of an Italian version of the Brief Pain Inventory (Breve Questionario per la valutazione del dolore). Pain 1996, 65:87–92.

    Article  CAS  PubMed  Google Scholar 

  8. Cherny NI: Cancer pain: principles of assessment and syndromes. In Supportive Oncology. Edited by Berger AM et al. Philadelphia: Lippincott-Raven; 1997:3–42.

    Google Scholar 

  9. Portenoy RK, Payne D, Jacobsen P: Breakthrough pain: characteristics and impact in patients with cancer pain. Pain 1999, 81:129–134. An excellent review about incident pain.

    Article  CAS  PubMed  Google Scholar 

  10. Mercadante S: Malignant bone pain: pathophysiology and treatment. Pain 1997, 69:1–18. cribes the most important aspects regarding pathophysiology and treatment of malignant bone pain

    Article  CAS  PubMed  Google Scholar 

  11. Dodwell DJ: Malignant bone resorption: cellular and biochemical mechanisms. Ann Oncol 1992, 3:257–267.

    CAS  PubMed  Google Scholar 

  12. Mundy GR: Hypercalcemia of malignancy revisited. J Clin Invest 1988, 82:1–6.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  13. McBride WH: Phenotype and functions of intratumoral macrophages. Biochem Biophys Acta 1986, 865:27–41.

    CAS  PubMed  Google Scholar 

  14. Sabatini M, Chavez J, Mundy GR, Bonewald LF: Stimulation of tumor necrosis factor release from monocytic cells by the A375 human melanoma via granulocyte-macrophage colony-stimulating factor. Cancer Res 1990, 50:2673–2678.

    CAS  PubMed  Google Scholar 

  15. De Conno F, Caraceni A, Gamba A, et al.: Pain measurement in cancer patients: a comparison of six methods. Pain 1994, 57:161–166.

    Article  PubMed  Google Scholar 

  16. Cleeland CS, Ryan KM: Pain assessment: global use of the Brief Pain Inventory [review]. Ann Acad Med Singapore 1994, 23:129–138.

    CAS  PubMed  Google Scholar 

  17. Jensen MP, Turner JA, Romano JM, Fisher LD: Comparative reliability and validity of chronic pain intensity measures. Pain 1999, 83:157–162.

    Article  CAS  PubMed  Google Scholar 

  18. Uebelhart D, Gineyts E, Chapuy MC: Urinary excretion of pyridinium crosslinks: a new marker of bone resorption in metabolic bone disease. Bone Miner 1990, 8:87–96.

    Article  CAS  PubMed  Google Scholar 

  19. Vinholes JJ, Purohit OP, Abbey ME, et al.: Relationships between biochemical and symptomatic response in a doubleblind randomised trial of pamidronate for metastatic bone disease. Ann Oncol 1997, 8:1243–1250.

    Article  CAS  PubMed  Google Scholar 

  20. Coleman R: Management of bone metastases. In ASCO Educational Book. Philadelphia: W.B. Saunders; 1998:100–108.

    Google Scholar 

  21. Bruera E, Neumann CM: Bone pain. In ASCO Educational Book. Philadelphia: W.B. Saunders; 1999:393–401.

    Google Scholar 

  22. World Health Organization: Cancer Pain Relief. Geneva: WHO Office of Publication; 1986.

    Google Scholar 

  23. World Health Organization: Cancer Pain Relief, edn 2. Geneva: WHO Office of Publication; 1996.

    Google Scholar 

  24. McCormack K: Non-steroidal anti-inflammatory drugs and spinal nociceptive processing. Pain 1994, 59:9–43.

    Article  CAS  PubMed  Google Scholar 

  25. Jenkins CA, Bruera E: Non steroidal anti-inflammatory drugs as adjuvant analgesics in cancer patients. Palliat Med 1999, 13:183–196. A comprehensive survey about the use of NSAIDs in clinical practice, with particular attention to adverse effects.

    Article  CAS  PubMed  Google Scholar 

  26. Watanabe S, Bruera E: Corticosteroids as adjuvant analgesics. J Pain Symptom Manage 1994, 9:442–445.

    Article  CAS  PubMed  Google Scholar 

  27. Delattre JY, Arbit E, Thaler HT, et al.: A dose-response study of dexamethasone in a model of spinal cord compression caused by epidural tumor. J Neurosurg 1989, 70:920–925.

    Article  CAS  PubMed  Google Scholar 

  28. Sorensen PS, Helweg-Larsen S, Mouridsen H, et al.: Effect of high-dose dexamethasone in carcinomatous metastatic spinal cord compression treated with radiotherapy. A randomized trial. Eur J Cancer 1994, 30A:22–27.

    Article  CAS  PubMed  Google Scholar 

  29. Vecht CJ, Haaxma-Reiche H, van Putten WLJ, et al.: Initial bolus of conventional versus high-dose dexamethasone in metastatic spinal cord compression. Neurology 1989, 39:1255–1257.

    Article  CAS  PubMed  Google Scholar 

  30. Portenoy RK, Lipton RB, Foley KM: Back pain in the cancer patient: an algorithm for evaluation and management. Neurology 1987, 37:134–138.

    Article  CAS  PubMed  Google Scholar 

  31. Byrne TN, Waxman SG: Spinal Cord Compression: Diagnosis and Principles of Treatment. Philadelphia: Contemporary Neurology Series; 1990.

    Google Scholar 

  32. Harrington KD: Orthopaedic surgical management of skeletal complications of malignancy. Cancer 1997, 80(suppl):1614–1627.

    Article  CAS  PubMed  Google Scholar 

  33. Ripamonti C, Zecca E, De Conno F: Pharmacological treatment of cancer pain: alternative routes of opioid administration. Tumori 1998, 84:289–300.

    CAS  PubMed  Google Scholar 

  34. Mercadante S, Fulfaro F: Alternatives to oral opioids for cancer pain. Oncology 1999, 13:215–225.

    CAS  PubMed  Google Scholar 

  35. Bruera E, Macmillan K, Kuehn N, et al.: Circadian distribution of extra doses of narcotic analgesics in patients with cancer pain: a preliminary report. Pain 1992, 49:311–314.

    Article  CAS  PubMed  Google Scholar 

  36. Ripamonti C, Bruera E: Current status of patient-controlled analgesia in cancer patients. Oncology 1997, 11:373–380.

    CAS  PubMed  Google Scholar 

  37. Body JJ: Bisphosphonates for metastatic bone pain. Support Care Cancer 1999, 7:1–3.

    Article  CAS  PubMed  Google Scholar 

  38. 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.

    CAS  PubMed  Google Scholar 

  39. Hortobagyi GN, Theriault RL, Lipton A, et al.: Long-term prevention of skeletal complications of metastatic breast cancer with pamidronate. J Clin Oncol 1998, 16:2038–2044.

    CAS  PubMed  Google Scholar 

  40. Conte PF, Latreille J, Mauriac L, et al.: Delay in progression of bone metastases in breast cancer patients treated with intravenous pamidronate: results from a multinational randomized, controlled trial. J Clin Oncol 1996, 14:2552–2559.

    CAS  PubMed  Google Scholar 

  41. Bloomfield DJ: Should bisphosphonates be part of the standard therapy of patients with multiple myeloma or bone metastases from other cancers? An evidence-based review. J Clin Oncol 1998, 16:1218–1225. This is of outstanding interest for researchers because it is an evidence-based review.

    CAS  PubMed  Google Scholar 

  42. Berenson JR, Lipton A: Pharmacology and clinical efficacy of bisphosphonates. Curr Opin Oncol 1998, 10:566–571.

    Article  CAS  PubMed  Google Scholar 

  43. Kylmala T, Taube T, Tammela TL, et al.: Concomitant i.v. and oral clodronate in the relief of bone pain-a double-blind placebo-controlled study in patients with prostate cancer. Br J Cancer 1997, 76:939–942.

    Article  CAS  PubMed  Google Scholar 

  44. Ernst DS, Brasher P, Hagen N, et al.: A randomized, controlled trial of intravenous clodronate in patients with metastatic bone disease and pain. J Pain Symptom Manage 1997, 13:319–326.

    Article  CAS  PubMed  Google Scholar 

  45. Piga A, Bracci R, Ferretti B, et al.: A double blind randomized study of oral clodronate in the treatment of bone metastases from tumors poorly responsive to chemotherapy. J Exp Clin Cancer Res 1998, 17:213–217.

    CAS  PubMed  Google Scholar 

  46. McCloskey EV, MacLennan IC, Drayson MT, et al.: A randomized trial of the effect of clodronate on skeletal morbidity in multiple myeloma. MRC Working Party on Leukaemia in Adults. Br J Haematol 1998, 100:317–325.

    Article  CAS  PubMed  Google Scholar 

  47. Kristensen B, Ejlertsen B, Groenvold M, et al.: Oral clodronate in breast cancer patients with bone metastases: a randomized study. J Intern Med 1999, 246:67–74.

    Article  CAS  PubMed  Google Scholar 

  48. Diel IJ, Solomayer EF, Costa SD, et al.: Reduction in new metastases in breast cancer with adjuvant clodronate treatment. N Engl J Med 1998, 339:357–363.

    Article  CAS  PubMed  Google Scholar 

  49. Ripamonti C, Fulfaro F, Ticozzi C, et al.: Role of pamidronate disodium in the treatment of metastatic bone disease. Tumori 1998, 84:442–455.

    CAS  PubMed  Google Scholar 

  50. Cascinu S, Graziano F, Alessandroni P, et al.: Different doses of pamidronate in patients with painful osteolytic bone metastases. Support Care Cancer 1998, 6:139–143.

    Article  CAS  PubMed  Google Scholar 

  51. Theriault RL, Lipton A, Hortobagyi GN, et al.: Pamidronate reduces skeletal morbidity in women with advanced breast cancer and lytic bone lesions: a randomized, placebocontrolled trial. J Clin Oncol 1999, 17:846–854.

    CAS  PubMed  Google Scholar 

  52. Koeberle D, Bacchus L, Thuerlimann B, Senn HJ: Pamidronate treatment in patients with malignant osteolytic bone disease and pain: a prospective randomized double-blind trial. Support Care Cancer 1999, 7:21–27.

    Article  CAS  PubMed  Google Scholar 

  53. Pecherstorfer M, Herrmann Z, Body JJ, et al.: Randomized phase II trial comparing different doses of the bisphosphonate Ibandronate in the treatment of hypercalcemia of malignancy. J Clin Oncol 1996, 14:268–276.

    CAS  PubMed  Google Scholar 

  54. Body JJ, Lichinitser MR, Dihel I, et al.: Double-blind placebocontrolled trial of intravenous ibandronate in breast cancer metastatic to bone [abstract]. Proc Am Soc Clin Oncol 1999, 18:575a.

    Google Scholar 

  55. Gatti D, Adami S: New bisphosphonates in the treatment of bone diseases. Drugs Aging 1999, 15:285–296.

    Article  CAS  PubMed  Google Scholar 

  56. Berenson JR, Lipton A, Rosen LS, et al.: Phase I clinical study of a new bisphosphonate, zoledronate (CGP-42446), in patients with osteolytic bone metastases. Blood 1996, 88(suppl 1):586a.

    Google Scholar 

  57. Kreeger L, Hutton-Potts J: The use of calcitonin in the treatment of metastatic bone pain. J Pain Symptom Manage 1999, 17:2–5.

    Article  CAS  PubMed  Google Scholar 

  58. Mystakidou K, Befon S, Hondros K, et al.: Continuous subcutaneous administration of high-dose salmon calcitonin in bone metastases: Pain control and beta-endorphin plasma levels. J Pain Symptom Manage 1999, 18:323–330.

    Article  CAS  PubMed  Google Scholar 

  59. Warrel RP Jr: Gallium nitrate for the treatment of bone metastases. Cancer 1997, 80(suppl 8):1680–1685.

    Article  Google Scholar 

  60. Senderowicz AM, Reid R, Headlee D, et al.: A phase II trial of gallium nitrate in patients with androgen-metastatic prostate cancer. Urol Int 1999, 63:120–125.

    Article  CAS  PubMed  Google Scholar 

  61. Matsubayashi T, Koga H, Nishiyama Y, et al.: The reparative process of metastatic bone lesions after radiotherapy. Jpn J Clin Oncol 1987, 11:253–264.

    Google Scholar 

  62. Koswig S, Budach V: Remineralization and pain relief in bone metastases after different radiotherapy fractions (10 times 3Gy vs. 1 time 8Gy). A prospective study. Strahlenther Onkol 1999, 175:500–508.

    Article  CAS  PubMed  Google Scholar 

  63. Stenland E, Leer J, van Houwelingen H, et al.: The effect of a single fraction compared to multiple fractions on painful bone metastases: a global analysis of the Dutch Bone Metastasis Study. Radiother Oncol 1999, 52:101–109.

    Article  Google Scholar 

  64. Nielsen OS, Bentzen SM, Sandberg E, et al.: Randomized trial of single dose versus fractionated palliative radiotherapy of bone metastases. Radiother Oncol 1998, 47:233–240.

    Article  CAS  PubMed  Google Scholar 

  65. Jeremic B, Shibamoto Y, Acimovic L, et al.: A randomized trial of three single-dose radiation therapy regimens in the treatment of metastatic bone. Int J Radiat Oncol Biol Phys 1998, 42:161–167.

    Article  CAS  PubMed  Google Scholar 

  66. Gaze MN, Kelly CG, Kerr GR, et al.: Pain relief and quality of life following radiotherapy for bone metastases: a randomised trial of two fractionation schedules. Radiother Oncol 1997, 45:109–116.

    Article  CAS  PubMed  Google Scholar 

  67. Dawson R, Currow D, Stevens G, et al.: Radiotherapy for bone metastases: a critical appraisal of outcome measures. J Pain Symptom Manage 1999, 17:208–218.

    Article  CAS  PubMed  Google Scholar 

  68. McQuay HJ, Carroll D, Moore RA: Radiotherapy for painful bone metastases: a systematic review. Clin Oncol (R Coll Radiol) 1997, 9:150–154. Evidence-based metanalysis that outlines the methodologic concerns and limitations of clinical trials about the use of radiotherapy for painful bone metastases.

    Article  CAS  Google Scholar 

  69. Ratanatharathorn V, Powers WE, Moss WT, Perez CA: Bone metastasis: review and critical analysis of random allocation trials of local field treatment. Int J Radiat Oncol Biol Phys 1999, 44:1–18.

    Article  CAS  PubMed  Google Scholar 

  70. Papatheofanis FJ: Variation in oncologic opinion regarding management of metastatic bone pain with systemic radionuclide therapy. J Nucl Med 1999, 40:1420–1423.

    CAS  PubMed  Google Scholar 

  71. Mertens WC, Filipczak LA, Ben-Josef E, et al.: Systemic bone-seeking radionuclides for palliation of painful osseous metastases: current concepts. CA Cancer J Clin 1998, 48:361–374. Reviews the recent advances in radioisotope therapy for metastatic bone pain.

    Article  CAS  PubMed  Google Scholar 

  72. Shah Syed GM, Maken RN, Muzzaffar N, et al.: Effective and economical option for pain palliation in prostate cancer with skeletal metastases: 32P therapy revisited. Nucl Med Commun 1999, 20:697–702.

    Article  PubMed  Google Scholar 

  73. Brundage MD, Crook JM, Lukka H: Use of strontium-89 in endocrine-refractory prostate cancer metastatic to bone. Provincial genitourinary Cancer Disease Site Group. Cancer Prev Control 1998, 2:79–87.

    CAS  PubMed  Google Scholar 

  74. Kasalicky J, Krajska V: The effect of repeated strontium-89 chloride therapy on bone pain palliation in patients with skeletal cancer metastases. Eur J Nucl Med 1998, 25:1362–1367.

    Article  CAS  PubMed  Google Scholar 

  75. Schmeler K, Bastin K: Strontium-89 for symptomatic metastatic prostate cancer to bone: recommendations for hospice patients. Hosp J 1996, 11:1–10.

    CAS  PubMed  Google Scholar 

  76. Serafini AN, Houston SJ, Resche I, et al.: Palliation of pain associated with metastatic bone cancer using samarium-153 lexidronam: a double-blind placebo-controlled clinical trial. J Clin Oncol 1998, 16:1574–1581.

    CAS  PubMed  Google Scholar 

  77. Tian JH, Zhang JM, Hou QT, et al.: Multicentre trial on the efficacy and toxicity of single-dose samarium-153-ethylene diamine tetramethylene phosphonate as a palliative treatment for painful skeletal metastases in China. Eur J Nucl Med 1999, 26:2–7.

    Article  CAS  PubMed  Google Scholar 

  78. Arner S, Rawal N, Gustafsson L: Clinical experience of longterm treatment with epidural and intrathecal opioids—a nationwide survey. Acta Anaesthesiol Scand 1988, 32:253–259.

    Article  CAS  PubMed  Google Scholar 

  79. Krames E: Intrathecal infusional therapies for intractable pain: patient management guidelines. J Pain Symptom Manage 1993, 8:36–46.

    Article  CAS  PubMed  Google Scholar 

  80. Mercadante S: Problems of long-term spinal opioid treatment in advanced cancer patients. Pain 1999, 79:1–13.

    Article  CAS  PubMed  Google Scholar 

  81. Hogan Q, Haddox JD, Abram S, et al.: Epidural opiates and local anesthetics for the management of cancer pain. Pain 1984, 46:271–279.

    Article  Google Scholar 

  82. Vainio A, Tigerstedt I: Opioid treatment for radiating cancer pain: oral administration vs epidural techniques. Acta Anaesthesiol Scand 1988, 32:179–180.

    Article  CAS  PubMed  Google Scholar 

  83. Sjogren P, Banning A: Pain, sedation, and reaction time during long-term treatment of cancer patients with oral and epidural opioids. Pain 1989, 39:5–11.

    Article  CAS  PubMed  Google Scholar 

  84. Arner S, Arner B: Differential effects of epidural morphine in the treatment of cancer-related pain. Acta Anaesthesiol Scand 1985, 29:32–36.

    Article  CAS  PubMed  Google Scholar 

  85. Kalso E, Heiskanen T, Rantio M, et al.: Epidural and subcutaneous morphine in the management of cancer pain: a double-blind cross-over study. Pain 1996, 67:443–449.

    Article  CAS  PubMed  Google Scholar 

  86. De Conno F, Ripamonti C, Ticozzi C: Intraspinal opioids and local anaesthetics for cancer pain. Eur J Palliat Care 1994, 1:162–168.

    Google Scholar 

  87. Rawal N: Indication for the use of intraspinal opioids. In Spinal Narcotics. Edited by Rawal N, Coombs DW. Boston: Kluwer; 1990:43–61.

    Chapter  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Rehabilitation, Pain Therapy and Palliative Care Division, National Cancer Institute, via Venezian, 1, 20133, Milano, Italy

    Carla Ripamonti MD

  2. SAMOT, Societá per l’Assistenza al Malato Oncologico Terminale, via Libertá 191, 90141, Palermo, Italy

    Fabio Fulfaro MD

Authors
  1. Carla Ripamonti MD
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Fabio Fulfaro MD
    View author publications

    You can also search for this author in PubMed Google Scholar

Rights and permissions

Reprints and permissions

About this article

Cite this article

Ripamonti, C., Fulfaro, F. Malignant bone pain: Pathophysiology and treatments. Current Review of Pain 4, 187–196 (2000). https://doi.org/10.1007/s11916-000-0078-3

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11916-000-0078-3

Keywords

Search

Navigation