Bone metastases cause morbidity and mortality in multiple malignancies. In addition to portending a dire prognosis, bone metastases cause bone pain, fractures, hypercalcemia, spinal cord compression, and other nerve compression syndromes. Improved understanding of the mechanisms that predispose tumor metastases to bone is needed to improve patients’ therapeutic options, maintain their quality of life, and improve their survival.
Methods
This review discusses selected preclinical and clinical data regarding bone metastasis development and cytokine/molecular interactions predisposing to bone metastases formation. Potential interventions for reducing bone metastases are also described.
Results
Biologic mechanisms resulting in metastases of tumor cells to bone are being studied. Among these are the RANKL pathway, osteoclast activation via cytokines (produced by tumor cell and cells in the bone microenvironment), interactions with transient and stromal cells in the bone microenvironment, and molecules such as PTHrP and endothelin-1. These molecules offer important opportunities for targeted interventions to decrease bone metastases-associated morbidity.
Conclusions
Knowledge of the pathophysiology of bone and cancer is developing rapidly. Relationships among cancer cells, bone-derived cells, and cytokines provide opportunities for the development of new interventions. Therapy targeting osteoclast/osteoblast interactions has proven benefit for patients with bone metastases.
References
1.
RubensR.D.. Bone metastases: incidence and complications. In: RubensR.D., MundyG.R., eds. Cancer and the Skeleton.London: Martin Dunitz; 2000: 33–42.
2.
RosenL.S., GordonD., TchekmedyianS.. 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(16): 3150–3157.
3.
RosenL.S., GordonD., KaminskiM.. 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(8): 1735–1744.
4.
RoodmanG.D.. Mechanisms of bone metastasis.N Engl J Med.2004; 350(16): 1655–1664.
5.
BussardK.M., GayC.V., MastroA.M.. The bone microenvironment in metastasis; what is special about bone?Cancer Metastasis Rev.2008; 27(1): 41–55.
6.
ChambersA.F., GroomA.C., MacDonaldI.C.. Dissemination and growth of cancer cells in metastatic sites.Nat Rev Cancer.2002; 2(8): 563–572.
7.
MichigamiT., ShimizuN., WilliamsP.J.. Cell-cell contact between marrow stromal cells and myeloma cells via VCAM-1 and alpha(4) beta(1)-integrin enhances production of osteoclast-stimulating activity.Blood.2000; 96(5): 1953–1960.
8.
MaedaT., AlexanderC.M., FriedlA.. Induction of syndecan-1 expression in stromal fibroblasts promotes proliferation of human breast cancer cells.Cancer Res.2004; 64(2): 612–621.
9.
LiptonA.. Implications of bone metastases and the benefits of bone-targeted therapy.Semin Oncol.2010; 37(suppl 2): S15–S29.
10.
SasakiA., BoyceB.F., StoryB.. Bisphosphonate risedronate reduces metastatic human breast cancer burden in bone in nude mice.Cancer Res.1995; 55(16): 3551–3557.
11.
PowlesT., PatersonS., KanisJ.A.. Randomized, placebo-controlled trial of clodronate in patients with primary operable breast cancer.J Clin Oncol.2002; 20(15): 3219–3224.
12.
GuiseT.A., YinJ.J., MohammadK.S.. Role of endothelin-1 in osteoblastic bone metastases.Cancer.2003; 97(3 suppl): 779–784.
13.
NelsonJ.B., HedicanS.P., GeorgeD.J.. Identification of endothe-lin-1 in the pathophysiology of metastatic adenocarcinoma of the prostate.Nat Med.1995; 1(9): 944–949.
14.
YiB., WilliamsP.J., NiewolnaM.. Tumor-derived platelet-derived growth factor-BB plays a critical role in osteosclerotic bone metastasis in an animal model of human breast cancer.Cancer Res.2002; 62(3): 917–923.
15.
YonedaT., HiragaT.. Crosstalk between cancer cells and bone microenvironment in bone metastasis.Biochem Biophys Res Commun.2005; 328(3): 679–687.
16.
GuiseT.A., YinJ.J., TaylorS.D.. Evidence for a causal role of parathyroid hormone-related protein in the pathogenesis of human breast cancer-mediated osteolysis.J Clin Invest.1996; 98(7): 1544–1549.
17.
AdwanH., BäuerleT.J., BergerM.R.. Downregulation of osteopontin and bone sialoprotein II is related to reduced colony formation and metastasis formation of MDA-MB-231 human breast cancer cells.Cancer Gene Ther.2004; 11(2): 109–120.
18.
ClinesG.A., GuiseT.A.. Molecular mechanisms and treatment of bone metastasis.Expert Rev Mol Med.2008; 10: e7.
19.
BurtonD.W., GellerJ., YangM.. Monitoring of skeletal progression of prostate cancer by GFP imaging, X-ray, and serum OPG and PTHrP.Prostate.2005; 62(3): 275–281.
20.
FulcinitiM., TassoneP., HideshimaT.. Anti-DKK1 mAb (BHQ880) as a potential therapeutic agent for multiple myeloma.Blood.2009; 114(2): 371–379.
21.
FinlayI.G., MasonM.D., ShelleyM.. Radioisotopes for the palliation of metastatic bone cancer: a systematic review.Lancet Oncol.2005; 6(6): 392–400.
22.
DafermouA., ColamussiP., GigantiM.. A multicentre observational study of radionuclide therapy in patients with painful bone metastases of prostate cancer.Eur J Nucl Med.2001; 28(7): 788–798.
23.
BerensonJ.R., LichtensteinA., PorterL.. Efficacy of pamidronate in reducing skeletal events in patients with advanced multiple myeloma. Myeloma Aredia Study Group.N Engl J Med.1996; 334(8): 488–493.
24.
HortobagyiG.N., TheriaultR.L., PorterL.. 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.1996; 335(24): 1785–1791.
25.
RosenL.S., GordonD., KaminskiM.. 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(5): 377–387.
26.
SaadF., GleasonD.M., MurrayR.. A randomized, placebo-controlled trial of zoledronic acid in patients with hormone-refractory metastatic prostate carcinoma.J Natl Cancer Inst.2002; 94(19): 1458–1468.
27.
PatersonA.H., PowlesT.J., KanisJ.A.. Double-blind controlled trial of oral clodronate in patients with bone metastases from breast cancer.J Clin Oncol.1993; 11(1): 59–65.
28.
RobertsonA.G., ReedN.S., RalstonS.H.. Effect of oral clodronate on metastatic bone pain: a double-blind, placebo-controlled study.J Clin Oncol.1995; 13(9): 2427–2430.
29.
ColemanR.E., PurohitO.P., BlackC.. Double-blind, randomised, placebo-controlled, dose-finding study of oral ibandronate in patients with metastatic bone disease.Ann Oncol.1999; 10(3): 311–316.
30.
BodyJ.J., DielI.J., LichinitzerM.. 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.2004; 90(6): 1133–1137.
31.
FilleulO., CrompotE., SaussezS.. Bisphosphonate-induced osteonecrosis of the jaw: a review of 2,400 patient cases.J Cancer Res Clin Oncol.2010; 136(8): 1117–1124.
32.
PalaskaP.K., CartsosV., ZavrasA.I.. Bisphosphonates and time to osteonecrosis development.Oncologist.2009; 14(11): 1154–1166.
33.
FehmT., FelsenbergD., KrimmelM.. Bisphosphonate-associ-ated osteonecrosis of the jaw in breast cancer patients: recommendations for prevention and treatment.Breast.2009; 18(4): 213–217.
34.
LiptonA., StegerG.G., FigueroaJ.. Randomized active-controlled phase II study of denosumab efficacy and safety in patients with breast cancer-related bone metastases.J Clin Oncol.2007; 25(28): 4431–4437.
35.
StopeckA.T., LiptonA., BodyJ.J.. 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): 5132–5139.
36.
OgataE.. Parathyroid hormone-related protein as a potential target of therapy for cancer-associated morbidity.Cancer.2000; 88(12 suppl): 2909–2911.
37.
GallwitzW.E., GuiseT.A., MundyG.R.. Guanosine nucleotides inhibit different syndromes of PTHrP excess caused by human cancers in vivo.J Clin Invest.2002; 110(10): 1559–1572.
38.
YinJ.J., SelanderK., ChirgwinJ.M.. TGF-beta signaling blockade inhibits PTHrP secretion by breast cancer cells and bone metastases development.J Clin Invest.1999; 103(2): 197–206.
39.
JensenA.B., WynneC., RamirezG.. The cathepsin K inhibitor odanacatib suppresses bone resorption in women with breast cancer and established bone metastases: results of a 4-week, double-blind, randomized, controlled trial.Clin Breast Cancer.2010; 10(6): 452–458.
40.
ZhaoY., BachelierR., TreilleuxI.. Tumor alphavbeta3 integrin is a therapeutic target for breast cancer bone metastases.Cancer Res.2007; 67(12): 5821–5830.
41.
YinJ.J., MohammadK.S., KäkönenS.M.. A causal role for endo-thelin-1 in the pathogenesis of osteoblastic bone metastases.Proc Natl Acad Sci U S A.2003; 100(19): 10954–10959.
42.
CarducciM.A., PadleyR.J., BreulJ.. Effect of endothelin-A receptor blockade with atrasentan on tumor progression in men with hormone-refractory prostate cancer: a randomized, phase II, placebo-controlled trial.J Clin Oncol.2003; 21(4): 679–689.
43.
RoodmanG.D.. Pathogenesis of myeloma bone disease.J Cell Biochem.2010; 109(2): 283–291.
44.
BreitkreutzI., RaabM.S., ValletS.. Lenalidomide inhibits osteo-clastogenesis, survival factors and bone-remodeling markers in multiple myeloma.Leukemia.2008; 22(10): 1925–1932.
45.
DielI.J., SolomayerE.F., CostaS.D.. Reduction in new metastases in breast cancer with adjuvant clodronate treatment.N Engl J Med.1998; 339(6): 357–363.
46.
PowlesT., PatersonA., McCloskeyE.. Reduction in bone relapse and improved survival with oral clodronate for adjuvant treatment of operable breast cancer [ISRCTN83688026].Breast Cancer Res.2006; 8(2): R13.
47.
SaartoT., BlomqvistC., VirkkunenP.. Adjuvant clodronate treatment does not reduce the frequency of skeletal metastases in node-positive breast cancer patients: 5-year results of a randomized controlled trial.J Clin Oncol.2001; 19(1): 10–17.
48.
SaartoT., VehmanenL., VirkkunenP.. Ten-year follow-up of a randomized controlled trial of adjuvant clodronate treatment in node-positive breast cancer patients.Acta Oncol.2004; 43(7): 650–656.
49.
GnantM.. Bisphosphonates in the prevention of disease recurrence: current results and ongoing trials.Curr Cancer Drug Targets.2009; 9(7): 824–833.
50.
ColemanR., WoodwardE., BrownJ.. Safety of zoledronic acid and incidence of osteonecrosis of the jaw (ONJ) during adjuvant therapy in a randomised phase III trial (AZURE: BIG 01-04) for women with stage II/ III breast cancer.Breast Cancer Res Treat.2011; 127(2): 429–438.
51.
ColemanR.E.. Emerging strategies in bone health management for the adjuvant patient.Semin Oncol.2007; 34(6 suppl 4): S11–S16.
52.
van Holten-VerzantvoortA.T., BijvoetO.L., CletonF.J.. Reduced morbidity from skeletal metastases in breast cancer patients during longterm bisphosphonate (APD) treatment.Lancet.1987; 2(8566): 983–985.
53.
van Holten-VerzantvoortA.T., KroonH.M., BijvoetO.L.. Palliative pamidronate treatment in patients with bone metastases from breast cancer.J Clin Oncol.1993; 11(3): 491–498.
54.
van Holten-VerzantvoortA.T., ZwindermanA.H., AaronsonN.K.. The effect of supportive pamidronate treatment on aspects of quality of life of patients with advanced breast cancer.Eur J Cancer.1991; 27(5): 544–549.
55.
van Holten-VerzantvoortA.T., HermansJ., BeexL.V.. Does supportive pamidronate treatment prevent or delay the first manifestation of bone metastases in breast cancer patients?Eur J Cancer.1996; 32A(3): 450–454.
56.
ConteP.F., LatreilleJ., MauriacL.. Delay in progression of bone metastases in breast cancer patients treated with intravenous pamidronate: results from a multinational randomized controlled trial. The Aredia Multinational Cooperative Group.J Clin Oncol.1996; 14(9): 2552–2559.
57.
TheriaultR.L., LiptonA., HortobagyiG.N.. 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.1999; 17(3): 846–854.
58.
LiptonA., TheriaultR.L., HortobagyiG.N.. 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.2000; 88(5): 1082–1090.
59.
BerensonJ.R., RosenL.S., HowellA.. Zoledronic acid reduces skeletal-related events in patients with osteolytic metastases.Cancer.2001; 91(7): 1191–1200.
60.
RosenL.S., GordonD.H., DuganWJr. Zoledronic acid is superior to pamidronate for the treatment of bone metastases in breast carcinoma patients with at least one osteolytic lesion.Cancer.2004; 100(1): 36–43.
61.
HerasP., KaragiannisS., KritikosK.. Ibandronate is effective in preventing skeletal events in patients with bone metastases from colorectal cancer.Eur J Cancer Care (Engl).2007; 16(6): 539–542.
62.
HerasP., KritikosK., HatzopoulosA.. Efficacy of ibandronate for the treatment of skeletal events in patients with metastatic breast cancer.Eur J Cancer Care (Engl).2009; 18(6): 653–656.
63.
PecherstorferM., HerrmannZ., BodyJ.J.. 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.
64.
PecherstorferM., SteinhauerE.U., RizzoliR.. Efficacy and safety of ibandronate in the treatment of hypercalcemia of malignancy: a randomized multicentric comparison to pamidronate.Support Care Cancer.2003; 11(8): 539–547.
65.
BodyJ.J., DielI.J., LichinitserM.R.. Intravenous ibandronate reduces the incidence of skeletal complications in patients with breast cancer and bone metastases.Ann Oncol.2003; 14(9): 1399–1405.
66.
DearnaleyD.P., SydesM.R., MasonM.D.. A double-blind, placebo-controlled, randomized trial of oral sodium clodronate for metastatic prostate cancer (MRC PR05 Trial).J Natl Cancer Inst.2003; 95(17): 1300–1311.
67.
Tubiana-HulinM., BeuzebocP., MauriacL.. Double-blinded controlled study comparing clodronate versus placebo in patients with breast cancer bone metastases [Article in French].Bull Cancer.2001; 88(7): 701–707.
68.
PigaA., BracciR., FerrettiB.. 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(2): 213–217.
69.
FizaziK., CarducciM., SmithM.. Denosumab versus zoledronic acid for treatment of bone metastases in men with castration-resistant prostate cancer: a randomised, double-blind study.Lancet.2011; 377(9768): 813–822.
70.
FizaziK., LiptonA., MarietteX.. 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(10): 1564–1571.
