Advertisement

Malignancies of the Bone

  • Megan R. Crawford
  • Susan E. Williams
  • Leila Khan
  • Angelo LicataEmail author
Chapter

Abstract

Initial workup of malignant skeletal lesions includes obtaining a thorough clinical history, physical exam, imaging, and laboratory testing. Key findings that suggest underlying malignant bone pathology include the presence of hypercalcemia, history of pathologic fracture associated with a skeletal lesion, and locally aggressive behavior of a bone tumor on imaging. The optimal approach to patients with primary or metastatic bone neoplasm or a hematologic malignancy includes a multidisciplinary approach with a variety of subspecialists. Bone-modifying therapy including bisphosphonates and denosumab plays an important role in the management of pain related to metastatic malignancy of bone and multiple myeloma.

Keywords

Malignancy Skeletal metastases Multiple myeloma Pathologic fracture Bisphosphonates Denosumab Hypercalcemia 

Abbreviations

ASCO

American Society of Clinical Oncology

BAP

Bone-specific alkaline phosphatase

BMI

Body mass index

Bpm

Beats per minute

CT

Computed tomography

CTX

Carboxy-terminal telopeptide of type I collagen or C-telopeptide

dL

Deciliter

DPD

Deoxypyridinoline

EBCTCG

Early Breast Cancer Trialists’ Collaborative Group

ESR

Erythrocyte sedimentation rate

FDA

Food and drug administration

G

Gram

GFR

Glomerular filtration rate

h

Hour

IGF

Insulin-like growth factor

IL

Interleukin

IV

Intravenous

K

     Thousand

L

     Liter

Lb

    Pounds

mg

        Milligram

MGUS

    Monoclonal gammopathy of undetermined significance

mmHg

    Millimeters of mercury

mmol

      Millimoles

MRI

      Magnetic resonance imaging

Ng

       Nanogram

NTX

       Amino-terminal telopeptide of type I collagen or N-telopeptide

ONJ

        Osteonecrosis of the jaw

P1CP

      Procollagen type I intact C-terminal propeptide

P1NP

      Procollagen type I intact N-terminal propeptide

PET

       Positron emission tomography

Pg

        Picogram

POEMS

    Polyneuropathy, organomegaly, endocrinopathy, monoclonal proteins, and skin findings

PTH

       Parathyroid hormone

PTHrP

     Parathyroid hormone-related peptide

RANKL

   Receptor activator of nuclear factor κB ligand

RECIST

   Response Evaluation Criteria in Solid Tumors

SPECT

    Single-positron emission tomography

TGF-β

     Tumor growth factor-β

TRACP5b

 Isoform 5b of the osteoclast enzyme tartrate-resistant acid phosphatase

U

         Unit

References

  1. 1.
    Clines GA, Guise TA. Hypercalcaemia of malignancy and basic research on mechanisms responsible for osteolytic and osteoblastic metastasis to bone. Endocr Relat Cancer. 2005;12(3):549–83.PubMedCrossRefGoogle Scholar
  2. 2.
    Edwards CM, Zhuang J, Mundy GR. The pathogenesis of the bone disease of multiple myeloma. Bone. 2008;42(6):1007–13.PubMedPubMedCentralCrossRefGoogle Scholar
  3. 3.
    Mundy GR, Raisz LG, Cooper RA, Schechter GP, Salmon SE. Evidence for the secretion of an osteoclast stimulating factor in myeloma. N Engl J Med. 1974;291(20):1041–6.PubMedCrossRefGoogle Scholar
  4. 4.
    Bataille R, Chappard D, Marcelli C, Dessauw P, Baldet P, Sany J, Alexandre C. Recruitment of new osteoblasts and osteoclasts is the earliest critical event in the pathogenesis of human multiple myeloma. J Clin Investig. 1991;88(1):62–6.PubMedCrossRefGoogle Scholar
  5. 5.
    Woitge HW, Horn E, Keck AV, Auler B, Seibel MJ, Pecherstorfer M. Biochemical markers of bone formation in patients with plasma cell dyscrasias and benign osteoporosis. Clin Chem. 2001;47:686–93.PubMedGoogle Scholar
  6. 6.
    Guise TA, Yin JJ, Taylor SD, Kumagai Y, Dallas M, Boyce BF, Yoneda T, Mundy GR. Evidence for a causal role of parathyroid hormone-related protein in the pathogenesis of human breast cancer-mediated osteolysis. J Clin Investig. 1996;98(7):1544–9.PubMedCrossRefGoogle Scholar
  7. 7.
    Henderson MA, Danks JA, Slavin JL, Byrnes GB, Choong PF, Spillane JB, Hopper JL, Martin TJ. Parathyroid hormone-related protein localization in breast cancers predict improved prognosis. Cancer Res. 2006;66(4):2250–6.PubMedCrossRefGoogle Scholar
  8. 8.
    Lecouvet FE, Larbi A, Pasoglou V, Omoumi P, Tombal B, Michoux N, Malghem J, Lhommel R, Vande Berg BC. MRI for response assessment in metastatic bone disease. Eur Radiol. 2013;23(7):1986–97.PubMedCrossRefGoogle Scholar
  9. 9.
    Cook GJ. PET and PET/CT imaging of skeletal metastases. Cancer Imaging. 2010;10(1):101–8.CrossRefGoogle Scholar
  10. 10.
    Eisenhauer EA, Therasse P, Bogaerts J, Schwartz LH, Sargent D, Ford R, Dancey J, Arbuck S, Gwyther S, Mooney M, Rubinstein L, Shankar L, Dodd L, Kaplan R, Lacombe D, Verweij J. New response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1). Eur J Cancer. 2009;45(2):228–47.PubMedPubMedCentralCrossRefGoogle Scholar
  11. 11.
    Ueda T, Naka N, Araki N, Ishii T, Tsuchiya H, Yoshikawa H, et al. Validation of radiographic response evaluation criteria of preoperative chemotherapy for bone and soft tissue sarcomas: Japanese Orthopaedic Association Committee on musculoskeletal tumors cooperative study. J Orthop Sci. 2008;13(4):304–12.PubMedPubMedCentralCrossRefGoogle Scholar
  12. 12.
    Guise TA. Molecular mechanisms of osteolytic bone metastases. Cancer. 2000;88(S12):2892–8.PubMedCrossRefGoogle Scholar
  13. 13.
    Tian E, Zhan F, Walker R, Rasmussen E, Ma Y, Barlogie B, Shaughnessy JD. The role of the Wnt-signaling antagonist DKK1 in the development of osteolytic lesions in multiple myeloma. N Engl J Med. 2003;349(26):2483–94.PubMedCrossRefGoogle Scholar
  14. 14.
    Guise TA, Mohammad KS, Clines G, Stebbins EG, Wong DH, Higgins LS, et al. Basic mechanisms responsible for osteolytic and osteoblastic bone metastases. Clin Cancer Res. 2006;12(20 Pt 2):6213s–6s.PubMedCrossRefGoogle Scholar
  15. 15.
    Bonica JJ. Management of cancer pain. Acta Anaest Scand Suppl. 1982;74:75–82.CrossRefGoogle Scholar
  16. 16.
    Downie A, Williams CM, Henschke N, Hancock MJ, Ostelo RW, de Vet HC, et al. Red flags to screen for malignancy and fracture in patients with low back pain: systematic review. BMJ. 2013;347:f7095.PubMedPubMedCentralCrossRefGoogle Scholar
  17. 17.
    Schaberg J, Gainor BJ. A profile of metastatic carcinoma of the spine. Spine. 1985;10(1):19–20.PubMedCrossRefGoogle Scholar
  18. 18.
    Healey JH, Brown HK. Complications of bone metastases: surgical management. Cancer. 2000;88(12 Suppl):2940–51.PubMedCrossRefGoogle Scholar
  19. 19.
    Buggay D, Jaffe K. Metastatic bone tumors of the pelvis and lower extremity. J Surg Orthop Adv. 2004;12(4):192–9.Google Scholar
  20. 20.
    Biermann JS, Holt GE, Lewis VO, Schwartz HS, Yaszemski MJ. Metastatic bone disease: diagnosis, evaluation, and treatment. J Bone Joint Surg Am. 2009;91(6):1518–30.PubMedGoogle Scholar
  21. 21.
    Papanastassiou ID, Filis AK, Gerochristou MA, Vrionis FD. Controversial issues in kyphoplasty and vertebroplasty in malignant vertebral fractures. Cancer Control. 2014;21(2):151–7.PubMedCrossRefGoogle Scholar
  22. 22.
    Health Quality Ontario. Vertebral augmentation involving vertebroplasty or kyphoplasty for cancer-related vertebral compression fractures: a systematic review. Ont Health Technol Assess Ser. 2016;16(11):1–202.PubMedCentralGoogle Scholar
  23. 23.
    Gainor BJ, Buchert P. Fracture healing in metastatic bone disease. Clin Orthop. 1983;178:297–302.Google Scholar
  24. 24.
    Harting MT, Lally KP, Andrassy RJ, Vaporciyan AA, Cox CS, Hayes-Jordan A, Blakely ML. Age as a prognostic factor for patients with osteosarcoma: an analysis of 438 patients. J Cancer Res Clin Oncol. 2010;136(4):561–70.PubMedCrossRefGoogle Scholar
  25. 25.
    Lee J, Hoang BH, Ziogas A, Zell JA. Analysis of prognostic factors in Ewing sarcoma using a population-based cancer registry. Cancer. 2010;116(8):1964–73.PubMedCrossRefGoogle Scholar
  26. 26.
    Kyle RA, Durie BGM, Rajkumar SV, Landgren O, Blade J, Merlini G, Kröger N, Einsele H, Vesole DH, Dimopoulos M, San Miguel J, Avet-Loiseau H, Hajek R, Chen WM, Anderson KC, Ludwig H, Sonneveld P, Pavlovsky S, Palumbo A, Richardson PG, Barlogie B, Greipp P, Vescio R, Turesson I, Westin J, Boccadoro M. Monoclonal Gammopathy of Undetermined Significance (MGUS) and smoldering (asymptomatic) multiple myeloma: IMWG consensus perspectives risk factors for progression and guidelines for monitoring and management. Leukemia. 2010;24(6):1121–7.PubMedCrossRefGoogle Scholar
  27. 27.
    Piot JM, Royer M, Schmidt-Tanguy A, Hoppé E, Gardembas M, Bourrée T, et al. Factors associated with an increased risk of vertebral fracture in monoclonal gammopathies of undetermined significance. Blood Cancer J. 2015;5:e345.PubMedPubMedCentralCrossRefGoogle Scholar
  28. 28.
    Kyle RA, Durie BG, Rajkumar SV, Landgren O, Blade J, Merlini G, et al. Criteria for the classification of monoclonal gammopathies, multiple myeloma and related disorders: a report of the international myeloma working group. Br J Haematol. 2003;121(5):749–57.CrossRefGoogle Scholar
  29. 29.
    Wiltshaw E. The natural history of extramedually plasmacytoma and its relation to soliray myeloma of bone and myelomatosis. Medicine. 1976;55(3):217–38.PubMedCrossRefGoogle Scholar
  30. 30.
    Kilciksiz S, Karakoyun-Celik O, Agaoglu FY, Haydaroglu A. A review for solitary plasmacytoma of bone and extramedullary plasmacytoma. Sci World J. 2012;2012:895765.CrossRefGoogle Scholar
  31. 31.
    Dispenzieri A. POEMS syndrome: 2014 update on diagnosis, risk-stratification, and management. Am J Hematol. 2014;89(2):213–23.CrossRefGoogle Scholar
  32. 32.
    Dimopoulos M, Kyle R, Fermand J-P, Rajkumar SV, San Miguel J, Chanan-Khan A, Ludwig H, Joshua D, Mehta J, Gertz M, Avet-Loiseau H, Beksac M, Anderson KC, Moreau P, Singhal S, Goldschmidt H, Boccadoro M, Kumar S, Giralt S, Munshi NC, Jagannath S. Consensus recommendations for standard investigative workup: report of the international myeloma workshop consensus panel 3. Blood. 2011;117(18):4701–5.PubMedCrossRefGoogle Scholar
  33. 33.
    Fletcher CD, Brigde JA, Hogendoorn PC, Mertens F. World Health Organization classification of tumours of soft tissue and bone. Lyon: IARC Press; 2013.Google Scholar
  34. 34.
    Dubey P, Ha CS, Besa PC, Fuller L, Cabanillas F, Murray J, Hess MA, Cox JD. Localized primary malignant lymphoma of bone. Int J Radiat Oncol Biol Phys. 1997;37(5):1087–93.PubMedCrossRefGoogle Scholar
  35. 35.
    Limb D, Dreghorn C, Murphy JK, Mannion R. Primary lymphoma of bone. Int Orthop. 1994;18(3):180–3.PubMedCrossRefGoogle Scholar
  36. 36.
    Ramadan K, Shenkier T, Sehn L, Gascoyne R, Connors J. A clinicopathological retrospective study of 131 patients with primary bone lymphoma: a population-based study of successively treated cohorts from the British Columbia Cancer Agency. Ann Oncol. 2006;18(1):129–35.PubMedCrossRefGoogle Scholar
  37. 37.
    Zhang X, Zhu J, Song Y, Ping L, Zheng W. Clinical characterization and outcome of primary bone lymphoma: a retrospective study of 61 Chinese patients. Sci Rep. 2016;6:28834.PubMedPubMedCentralCrossRefGoogle Scholar
  38. 38.
    Freeman C, Berg JW, Cutler SJ. Occurrence and prognosis of extranodal lymphomas. Cancer. 1972;29(1):252–60.PubMedCrossRefGoogle Scholar
  39. 39.
    Rudders RA, Ross ME, Delellis RA. Primary extranodal lymphoma. Response to treatment and factors influencing prognosis. Cancer. 1978;42(2):406–16.PubMedCrossRefGoogle Scholar
  40. 40.
    Van Der Pluijm G, Sijmons B, Vloedgraven H, Deckers M, Papapoulos S, Löwik C. Monitoring metastatic behavior of human tumor cells in mice with species-specific polymerase chain reaction: elevated expression of angiogenesis and bone resorption stimulators by breast cancer in bone metastases. J Bone Miner Res. 2001;16(6):1077–91.PubMedCrossRefGoogle Scholar
  41. 41.
    Juárez P, Guise TA. TGF-Î2 in cancer and bone: implications for treatment of bone metastases. Bone. 2011;48(1):23–9.PubMedCrossRefGoogle Scholar
  42. 42.
    Takai H, Kanematsu M, Yano K, Tsuda E, Higashio K, Ikeda K, Watanabe K, Yamada Y. Transforming growth factor-Î2 stimulates the production of osteoprotegerin/osteoclastogenesis inhibitory factor by bone marrow stromal cells. J Biol Chem. 1998;273(42):27091–6.PubMedCrossRefGoogle Scholar
  43. 43.
    Mohan S, Baylink DJ. Bone growth factors. Clin Orthop Relat Res. 1991;263:30–48.Google Scholar
  44. 44.
    Coleman RE, Rubens RD. The clinical course of bone metastases from breast cancer. Br J Cancer. 1987;55(1):61–6.PubMedPubMedCentralCrossRefGoogle Scholar
  45. 45.
    Rubens RD, Mundy GR, editors. Bone metastases- incidence and complications. Cancer and the skeleton. London: Martin Dunitz; 2000. p. 33–42.Google Scholar
  46. 46.
    Fulfaro F, Casuccio A, Ticozzi C, Ripamonti C. The role of bisphosphonates in the treatment of painful metastatic bone disease: a review of phase III trials. Pain. 1998;78(3):157–69.PubMedCrossRefGoogle Scholar
  47. 47.
    Fizazi K, Carducci M, Smith M, Damiao R, Brown J, Karsh L, 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;377:813–22.PubMedPubMedCentralCrossRefGoogle Scholar
  48. 48.
    Henry DH, Costa L, Goldwasser F, Hirsh V, Hungria V, Prausova J, Scagliotti GV, Sleeboom H, Spencer A, Vadhan-Raj S, von Moos R, Willenbacher W, Woll PJ, Wang J, Qi J, Jun S, Dansey R, Yeh H. 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(9):1125–32.PubMedCrossRefGoogle Scholar
  49. 49.
    Stopeck AT, Lipton A, Body J-J, Steger GG, Tonkin K, de Boer RH, Lichinitser M, Fujiwara Y, Yardley DA, Viniegra M, Fan M, Jiang Q, Dansey R, Jun S, Braun A. 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(35):5132–9.PubMedCrossRefGoogle Scholar
  50. 50.
    Rosen LS, Gordon D, Kaminski M, Howell A, Belch A, MacKey J, 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.PubMedGoogle Scholar
  51. 51.
    Barrett-Lee P, Casbard A, Abraham J, Hood K, Coleman R, Simmonds P, Timmins H, Wheatley D, Grieve R, Griffiths G, Murray N. Oral ibandronic acid versus intravenous zoledronic acid in treatment of bone metastases from breast cancer: a randomised, open label, non-inferiority phase 3 trial. Lancet Oncol. 2014;15(1):114–22.PubMedCrossRefGoogle Scholar
  52. 52.
    Irelli A, Cocciolone V, Cannita K, Zugaro L, Di Staso M, Baldi PL, Paradisi S, Sidoni T, Ricevuto E, Ficorella C. Bone targeted therapy for preventing skeletal-related events in metastatic breast cancer. Bone. 2016;87:169–75.PubMedCrossRefGoogle Scholar
  53. 53.
    Kyle RA, Yee GC, Somerfield MR, Flynn PJ, Halabi S, Jagannath S, Orlowski RZ, Roodman DG, Twilde P, Anderson K. American Society of Clinical Oncology 2007 clinical practice guideline update on the role of bisphosphonates in multiple myeloma. J Clin Oncol. 2007;25(17):2464–72.PubMedCrossRefGoogle Scholar
  54. 54.
    Van Poznak CH, Temin S, Yee GC, Janjan NA, Barlow WE, Biermann JS, Bosserman LD, Geoghegan C, Hillner BE, Theriault RL, Zuckerman DS, Von Roenn JH. 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(9):1221–7.PubMedCrossRefGoogle Scholar
  55. 55.
    Powles T, Paterson S, Kanis JA, McCloskey E, Ashley S, Tidy A, Rosenqvist K, Smith I, Ottestad L, Legault S, Pajunen M, Nevantaus A, Männistö E, Suovuori A, Atula S, Nevalainen J, Pylkkänen L. Randomized, placebo-controlled trial of clodronate in patients with primary operable breast cancer. J Clin Oncol. 2002;20(15):3219–24.PubMedCrossRefGoogle Scholar
  56. 56.
    Coleman R, Powles A, Paterson M, Gnant S, Anderson I, Diel J, et al. Early Breast Cancer Trialists’ Collaborative Group (EBCTCG). Adjuvant bisphosphonate treatment in early breast cancer: meta-analyses of individual patient data from randomised trials. Lancet. 2015;386(10001):1353–61.Google Scholar
  57. 57.
    Jones DH, Nakashima T, Sanchez OH, Kozieradzki I, Komarova SV, Sarosi I, Morony S, Rubin E, Sarao R, Hojilla CV, Komnenovic V, Kong Y-Y, Schreiber M, Dixon SJ, Sims SM, Khokha R, Wada T, Penninger JM. Regulation of cancer cell migration and bone metastasis by RANKL. Nature. 2006;440(7084):692–6.PubMedCrossRefGoogle Scholar
  58. 58.
    Gnant M, Pfeiler G, Dubsky PC, Hubalek M, Greil R, Jakesz R, Wette V, Balic M, Haslbauer F, Melbinger E, Bjelic-Radisic V, Artner-Matuschek S, Fitzal F, Marth C, Sevelda P, Mlineritsch B, Steger GG, Manfreda D, Exner R, Egle D, Bergh J, Kainberger F, Talbot S, Warner D, Fesl C, Singer CF. Adjuvant denosumab in breast cancer (ABCSG-18): a multicentre, randomised, double-blind, placebo-controlled trial. Lancet. 2015;386(9992):433–43.PubMedCrossRefPubMedCentralGoogle Scholar
  59. 59.
    Blomqvist C, Risteli L, Risteli J, Virkkunen P, Sarna S, Elomaa I. Markers of type I collagen degradation and synthesis in the monitoring of treatment response in bone metastases from breast carcinoma. Br J Cancer. 1996;73(9):1074–9.PubMedPubMedCentralCrossRefGoogle Scholar
  60. 60.
    Koizumi M, Matsumoto S, Takahashi S, Yamashita T, Ogata EM. Bone metabolic markers in the evaluation of bone scan flare phenomenon in bone metastases of breast cancer. Clin Nucl Med. 1994;24(1):15–20.CrossRefGoogle Scholar
  61. 61.
    Maeda H, Koizumi M, Yoshimura K, Yamauchi T, Kawai T, Ogata E. Correlation between bone metabolic markers and bone scan in prostatic cancer. J Urol. 1997;157(2):539–43.PubMedCrossRefGoogle Scholar
  62. 62.
    Demers LM, Costa L, Lipton A. Biochemical markers and skeletal metastases. Cancer. 2000;88(12 Suppl):2919–26.PubMedCrossRefGoogle Scholar
  63. 63.
    Costa L, Demers LM, Speicher T, Gouveia T, Curley E, Harvey H, et al. Biochemical markers of bone turnover correlate with the extent of metastatic bone disease. Cancer. 2000;88(12 Suppl):2919–26.PubMedGoogle Scholar
  64. 64.
    Withold W, Friedrich W, Reinauer H. Comparison of biochemical markers of bone resorption in patients with metabolic and malignant bone diseases. Ann Clin Biochem. 1996;33(Pt 5):421–7.PubMedCrossRefGoogle Scholar
  65. 65.
    Lumachi F, Basso SMM, Camozzi V, Tozzoli R, Spaziante R, Ermani M. Bone turnover markers in women with early stage breast cancer who developed bone metastases. A prospective study with multivariate logistic regression analysis of accuracy. Clin Chim Acta. 2016;460:227–30.PubMedCrossRefGoogle Scholar
  66. 66.
    Lipton A, Smith MR, Fizazi K, Stopeck AT, Henry D, Brown JE, et al. Changes in bone turnover marker levels and clinical outcomes in patients with advanced cancer and bone metastases treated with bone antiresorptive agents. Clin Cancer Res. 2016;22(23):5713–21.PubMedCrossRefGoogle Scholar

Copyright information

© Springer Nature Switzerland AG 2019

Authors and Affiliations

  • Megan R. Crawford
    • 1
  • Susan E. Williams
    • 1
  • Leila Khan
    • 1
  • Angelo Licata
    • 1
    Email author
  1. 1.Department of Endocrinology, Diabetes and MetabolismCleveland Clinic FoundationClevelandUSA

Personalised recommendations