In bone metastases, a “vicious cycle” occurs in which tumor cells produce factors that directly or indirectly induce the formation of osteoclasts. In turn, bone resorption by osteoclasts releases growth factor from the bone matrix that stimulate tumor growth and bone destruction. This reciprocal interaction between tumor cells and the bone microenvironment results in bone destruction and increased tumor burden. Stephan Paget’s 1889 proposal that metastasis depends on multiple interactions (“cross-talk”) between selected cancer cells (the “seeds”) and specific organ microenvironments (the “soil”) still holds today: ¹ It is now known that the potential of a tumor cell to metastasize depends on its interactions with the homeostatic factors that promote tumor cell growth, survival, angiogenesis, invasion, and metastasis. ¹

Although some cancers are more likely than others to spread to the bone, bone metastases (“bone mets”) can occur whenever cancer cells from a primary tumor relocate to the bone.²

Prevalence and Impact

With more than 10 million new cases every year, cancer has become one of the most devastating diseases worldwide. Estimates of new cancer cases range from 2.2 million cases in China (20.3% of the world total) and 1.6 million in North America (14.4%) to about 1,400 in Micronesia/Polynesia.³ Approximately 50% to 80% of all those diagnosed with carcinoma are predicted to have metastasis to bone at the time of their death. Some cancers are more likely to spread to bone than others. ² Those most likely to metastasize to the bone are breast, prostate, kidney, thyroid, and lung cancers. In breast and prostate cancer, bone is most often the initial site of metastasis. The spine is most commonly affected by bone metastasis, followed by the pelvis, hip, upper leg bones (femurs), and the skull.

Source: Coleman RE. Skeletal Complications of Malignancy. Cancer. 1997;80(suppl 8):1588-94.

Current Treatments and Guidelines

For the majority of patients, external beam radiotherapy provides palliation for localized metastatic bone pain. In most clinical situations, this can be achieved with a short treatment schedule of one to five fractions (portions of a dose given over a period of time). Radiopharmaceuticals are now also available for the palliation of metastatic bone pain.

Bisphosphonates are used in the management of cancer-related bone metastases, particularly monthly infusions of pamidronate or zoledonic acid. American Society of Clinical Oncology guidelines recommend intravenous pamidronate in patients with metastatic breast cancer who have imaging evidence of lytic destruction of bone and who are concurrently receiving systemic therapy with hormonal therapy or chemotherapy.¹⁶

Localized treatment of bone metastases with radiotherapy and/or surgery is also used for sites of progressive disease that compromise function.

Role of RANKL in Bone Metastases

The receptor activator of nuclear factor kappa B ligand (RANKL) plays a key role in bone destruction across a range of conditions and fuels a vicious cycle of bone destruction and tumor growth in metastatic disease.^4,5

• The body maintains a normal level of RANKL activity in healthy bone that regulates normal bone remodeling. ^5,6
• In cancer-induced bone disease, however, RANKL overwhelms the effects of OPG, causing an imbalance in the remodeling process. ^6,7
• Malignancies such as breast and prostate cancer alter the natural balance between RANKL and OPG activity. ⁶

In preclinical models of metastatic disease, it is believed RANKL contributes to a vicious cycle of bone destruction and tumor growth. When tumor cells invade bone, they secrete parathyroid-hormone-related peptide (PTHrP), which induces osteoblast production of RANKL. ⁸ RANKL promotes the differentiation, activation, and survival of osteoclasts, leading to bone resorption. ^5,9 Bone resorption leads to the release of bone-derived growth factors and calcium (Ca 2+) that promote tumor growth and establish a vicious cycle. ^5,8,10 RANKL may also have a direct effect on the metastatic behavior of RANK-expressing tumor cells. ¹¹

In preclinical models of multiple myeloma, breast, or prostate cancer, inhibiting RANKL by increasing OPG levels:

• interrupted the vicious cycle of bone destruction¹²
• decreased total skeletal tumor burden and the associated indices of bone pain^12-14
• provided sustained (84 days) suppression of bone resorption¹⁵

These findings suggest that the inhibition of RANKL may provide a new therapeutic approach to inhibiting the processes involved in bone metastases.

References

1. Fidler IJ. The pathogenesis of cancer metastasis: the ‘seed and soil’ hypothesis revisited. Nat Rev Cancer. 2003;3:453-458.
2. Canale, Terry S. Campbell’s Operative Orthopedics. 10th ed. St. Louis, Mo: Mosby; 2003:848.
3. Parkin DM, Bray F, Ferlay J, Pisani P. Global cancer statistics, 2002.CA Cancer J Clin. 2005;55:74-108. Available at: http://caonline.amcancersoc.org. Accessed March 22, 2006.
4. Fuller K, Wong B, Fox S, Choi Y, Chambers TJ. TRANCE is necessary and sufficient for osteoblast-mediated activation of bone resorption in osteoclasts. J Exp Med. 1998;188:997-1001.
5. Roodman GD. Mechanisms of bone metastasis. N Engl J Med. 2004;350:1655-1664.
6. Hofbauer LC, Schoppet M. Clinical implications of the osteoprotegerin/RANKL/RANK system for bone and vascular diseases. JAMA. 2004;292:490-495.
7. Pearse RN, Sordillo EM, Yaccoby S, et al. Multiple myeloma disrupts the TRANCE/osteoprotegerin cytokine axis to trigger bone destruction and promote tumor progression. Proc Natl Acad Sci USA. 2001;98:11581-11586.
8. Thomas RJ, Gulse TA, Yin JJ, et al. Breast cancer cells interact with osteoblasts to support osteoclast formation. Endocrinology. 1999;140:4451-4458.
9. Boyle WJ, Simonet WS, Lacey DL. Osteoclast differentiation and activation. Nature. 2003;423:337-342.
10. Sanders JL, Chattopadhyay N, Kifor O, Yamaguchi T, Butters RR, Brown EM. Extracellular calcium-sensing receptor expression and its potential role in regulating parathyroid hormone-related peptide secretion in human beast cancer cell lines. Endocrinology. 2000;141:4357-4364.
11. Tometsko M, Armstrong A, Miller R, et al. RANK Ligand directly induces osteoclastogenic, angiogenic, chemoattractive and invasive factors on RANK-expressing human cancer cells MDA-MB-231 and PC3. Presented at: The 25th Annual Meeting of the American Society for Bone and Mineral Research; October 1-5, 2004; Seattle, Wash. Abstract 1095.
12. Morony S, Capparelli C, Sarosi I, Lacey DL, Dunstan CR, Kostenuik PJ . Osteoprotegerin inhibits osteolysis and decreases skeletal tumor burden in syngeneic and nude mouse models of experimental bone metastasis. Cancer Res. 2001;61:4432-4436.
13. Honore P, Luger NM, Sabino MAC, et al. Osteoprotegerin blocks bone cancer-induced skeletal destruction, skeletal pain and pain-related neurochemical reorganization of the spinal cord. Nat Med. 2000;6:521-528.
14. Luger NM, Honore P, Sabino MAC, et al. Osteoprotegerin diminishes advanced bone cancer pain. Cancer Res. 2001;61:4038-4047.
15. Body J-J, Greipp P, Coleman RE, et al. A phase 1 study of AMGN-0007, a recombinant osteoprotegerin construct, in patients with multiple myeloma or breast carcinoma related bone metastases. Cancer. 2003;97(suppl 3):887-892.
16. American Society of Clinical Oncology. Available at http://www.asco.org.