Elsevier

Cancer Treatment Reviews

Volume 36, Issue 8, December 2010, Pages 615-620
Cancer Treatment Reviews

Anti-Tumour Treatment
Metastasis and bone loss: Advancing treatment and prevention

https://doi.org/10.1016/j.ctrv.2010.04.003Get rights and content

Abstract

Tumor metastasis to the skeleton affects over 400,000 individuals in the United States annually, more than any other site of metastasis, including significant proportions of patients with breast, prostate, lung and other solid tumors. Research on the bone microenvironment and its role in metastasis suggests a complex role in tumor growth. Parallel preclinical and clinical investigations into the role of adjuvant bone-targeted agents in preventing metastasis and avoiding cancer therapy-induced bone loss have recently reported exciting and intriguing results. A multidisciplinary consensus conference convened to review recent progress in basic and clinical research, assess gaps in current knowledge and prioritize recommendations to advance research over the next 5 years. The program addressed three topics: advancing understanding of metastasis prevention in the context of bone pathophysiology; developing therapeutic approaches to prevent metastasis and defining strategies to prevent cancer therapy-induced bone loss. Several priorities were identified: (1) further investigate the effects of bone-targeted therapies on tumor and immune cell interactions within the bone microenvironment; (2) utilize and further develop preclinical models to study combination therapies; (3) conduct clinical studies of bone-targeted therapies with radiation and chemotherapy across a range of solid tumors; (4) develop biomarkers to identify patients most likely to benefit from bone-targeted therapies; (5) educate physicians on bone loss and fracture risk; (6) define optimal endpoints and new measures of efficacy for future clinical trials; and (7) define the optimum type, dose and schedule of adjuvant bone-targeted therapy.

Introduction

Despite the improvements in screening, early diagnosis and cancer treatments, death from cancer remains the major cause of mortality worldwide. New therapeutic strategies based on improved understanding of cancer biology, targeted treatments and personalized therapies are urgently needed. The success of future therapeutic options is likely to target key interactions between cancer cells and a range of host cells within the bone microenvironment. Bone targeted treatments have the potential to prevent not only bone metastasis but also to impair the ability of tumor cells to remain dormant. We need to realize this potential through relevant preclinical research, high quality clinical trials and improved understanding of cancer and bone cell biology. Priorities were identified in basic and preclinical research, clinical assessment of bone-targeted therapies and physician education.

Section snippets

Influence of the bone microenvironment on growth of tumor cells in bone

When tumor cells are resident in bone, they change their patterns of gene expression and modify their phenotype. These changes may lead to important interactions with the normal host cells, not only with other bone cells, but also with primitive hematopoietic (stem) cells and other cells abundant in the bone microenvironment. It is proposed that one of the major factors responsible for this change in behavior is the physical microenvironment the tumor cells experience when they encounter the

Developing therapeutic approaches to prevent metastasis

Several randomized clinical trials suggest that BPs may prevent not only the development of bone metastases but also extraskeletal metastases and locoregional recurrence. The mechanisms underlying these observations are uncertain but may include a silencing and suppressive effect on dormant micrometastases in the bone marrow that, with conventional therapies only targeting the tumor cell, remain able to seed to extra-skeletal sites. Several small trials have evaluated the impact of monthly

Breast cancer

Aromatase Inhibitors (AIs) have become the standard of care for the endocrine treatment of breast cancer in postmenopausal women. All AIs are associated with loss of bone density and concomitant increased risk of fracture in unselected populations.44 The necessity to address accelerated bone loss in these at-risk populations is highlighted by studies showing the negative impact of fractures on patient independence and quality of life.45 Therefore, reducing the associated costs of treatment and

Conclusion

Prevention of bone metastasis and bone loss are at the intersection of multiple avenues of basic and clinical research and exciting new insights into tumor and bone biology and pathogenesis. Table 1 summarizes recommended priorities to advance understanding of bone metastasis, critically evaluate bone-targeted therapies to prevent metastasis and bone loss, and advance physician education.

Conflict of interest statement

Brendan F. Boyce: Nothing to disclose.

Adam M. Brufsky: Consultant: Novartis; Honoraria: Novartis; Research Funding: Novartis; Royalties: Novartis.

Philippe Clézardin: Honoraria: Novartis; Research Funding: Novartis.

Robert E. ColemanConsultant: Novartis, Amgen; Research Funding: Novartis; Speakers’ Bureau: Novartis , Amgen; Expert Testimony: Novartis.

Peter I. Croucher: Research Funding: Acceleron Pharma; Speakers’ Bureau: Amgen.

Julie R. Gralow: Research Funding: Abraxane, Amgen, Bristol-Myers

Acknowledgements

The consensus conference was supported by educational grants provided by Amgen Inc. and Novartis Pharmaceuticals. Editorial assistance was provided by Melinda Lindquist of InforMEDical Communications, Inc., Carlisle, MA.

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