• 62% to 72% of patients experienced relief 9

Bone Metastases Pathophysiology

Tumor factors promote the formation of bone metastasis

  • Bone microenvironment is altered by a variety of factors, creating conditions favorable to the establishment of bone metastases
  • The balance between osteoblastic and osteolytic signaling is disrupted

Prostate cancer cell signals promote the formation of bone metastases1-3

Prostate Cancer

resorption of lamellar bone lamellar bone

Prostate cancer cells alter bone balance by secreting factors that regulate osteoblast differentiation and proliferation. This leads to formation of immature bone (new woven bone) that is ultimately converted to lamellar bone.3 Prostate cancer cells also produce pro-osteolytic signals that act on osteoclasts, such as RANKL and IL-6.2

Factors produced by prostate cancer cells Action
BMP Bone morphogenetic protein Induces osteoblast differentiation3
TGF Transforming growth factor TGF-beta increases osteoblast proliferation3, TGF-alpha and -beta, stimulate osteoclastic activity1
IGF Insulin-like growth factor Increases osteoblast differentiation and proliferation3
PDGF Platelet-derived growth factor Increases osteoblast proliferation3
FGF Fibroblast growth factor Increases osteoblast differentiation and proliferation3
VEGF Vascular endothelial growth factor Increases osteoblast proliferation3
PSA Prostate-specific antigen Increases osteoblast proliferation3
ET-1 Endothelin-1 Increases osteoblast differentiation and proliferation3
PGE Prostaglandin-E Stimulates osteoclastic activity1
EGF Epidermal growth factor Stimulates osteoclastic activity1
TNF Tumor necrosis factor Stimulates osteoclastic activity1
IL-1 Interleukin-1 Stimulates osteoclastic activity1
IL-6 Interleukin-6 Stimulates osteoclastic activity1
RANKL Receptor activator of NF-kappB ligand Initiate osteoclastogenesis2
PTHrP Parathyriod hormone-related protein Stimulates osteoclastic activity1

Complex signaling leads to fundamentally mixed lesions

While some sites may be characterized by their radiological appearance as predominantly osteoblastic or predominantly osteolytic, it is now understood that most of these lesions have both a blastic and lytic component 2,4

"[There is] an impressive body of evidence detailing a complex web of interactions between breast cancer cells, the mineralized bone matrix and host cells resident in bone; such as osteoblasts, osteoclasts and bone marrow endothelium." 5

Breast cancer cell signals, including osteoblast-mediated signals acting on osteoclasts, promote the formation of bone metastases. 5

Breast Cancer

resorption of lamellar bone lamellar bone

Breast cancer cells release cytokines that stimulate osteoclast-mediated bone resorption. In addition, stimulation of osteoblasts via PTHrP by cancer cells leads to the release of osteoclast-stimulating factors and growth factors that stimulate breast cancer cell proliferation. This altered bone microenvironment favors metastatic invasion.5

OPN: osteopontin.

"Although these two cell types arise independently from distinct precursors and regulate opposing functions, the differentiation and activity of osteoclasts are heavily influenced by osteoblast-derived factors." 5

  • Multiple myeloma cells also release cytokines that disrupt the balance between osteoblasts and osteoclasts, typically leading to severe bone resorption6
    • While this uncoupled signaling is conventionally seen as leading to purely lytic lesions, bone scans reveal that marked osteoblastic activity may be present 7
    • One characteristic of multiple myeloma is the early stimulation of osteoblasts, which produce high amounts of IL-6, a potent myeloma cell growth factor and a critical cytokine for the formation of osteoclasts in the bone marrow 8

REFERENCES:

  1. Coleman RE. Metastatic bone disease: clinical features, pathophysiology and treatment strategies. Cancer Treat Rev. 2001;27:165-176.
  2. Keller ET, Brown J. Prostate cancer bone metastases promote both osteolytic and osteoblastic activity. J Cell Biochem. 2004;91:718-729.
  3. Logothetis CJ, Lin SH. Osteoblasts in prostate cancer metastasis to bone. Nature Rev. 2005;5:21-28.
  4. Rodrigues P, Hering F, Campagnari JC. Use of bisphosphonates can dramatically improve pain in advanced hormone-refractory prostate cancer patients. Prostate Cancer Prostatic Dis. 2004;7:350-354.
  5. Rose AA, Siegel PM. Breast cancer-derived factors facilitate osteolytic bone metastasis. Bull Cancer. 2006;93:931-943.
  6. Terpos E, Dimopoulos MA. Myeloma bone disease: pathophysiology and management. Ann Oncol. 2005;16:1223-1231.
  7. Edwards GK, Santoro J, Taylor A Jr. Use of bone scintigraphy to select patients with multiple myeloma for treatment with strontium-89. J Nucl Med. 1994;35:1992-1993.
  8. Bataille R, Chappard D, Marcelli C, et al. Recruitment of new osteoblasts and osteoclasts is the earliest critical event in the pathogenesis of human multiple myeloma. J Clin Invest. 1991;88:62-66.
  9. 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.

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