Anti-Tumour TreatmentMetastasis and bone loss: Advancing treatment and prevention
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.
References (61)
- et al.
Matrix elasticity directs stem cell lineage specification
Cell
(2006) - et al.
Antibody-based inhibition of DKK1 suppresses tumor-induced bone resorption and multiple myeloma growth in vivo
Blood
(2007) - et al.
Increasing Wnt signaling in the bone marrow microenvironment inhibits the development of myeloma bone disease and reduces tumor burden in bone in vivo
Blood
(2008) - et al.
BPs in cancer therapy
Cancer Lett
(2007) - et al.
Macrophage inflammatory protein 1-alpha is a potential osteoclast stimulatory factor in multiple myeloma
Blood
(2000) - et al.
Osteoclasts are important for bone angiogenesis
Blood
(2010) - et al.
Zoledronic acid effectively prevents aromatase inhibitor-associated bone loss in postmenopausal women with early breast cancer receiving adjuvant letrozole: Z-FAST study 36-month follow-up results
Clin Breast Cancer
(2009) - et al.
Practical guidance for the management of aromatase inhibitor-associated bone loss
Ann Oncol
(2008) - et al.
Randomized controlled trial of zoledronic acid to prevent bone loss in men undergoing androgen deprivation therapy for nonmetastatic prostate cancer
J Urol
(2003) - et al.
Toremifene increases bone mineral density in men receiving androgen deprivation therapy for prostate cancer: interim analysis of a multicenter phase 3 clinical study
J Urol
(2008)
Evidence for a causal role of parathyroid hormone-related protein in the pathogenesis of human breast cancer-mediated osteolysis
J Clin Invest
The hedgegog signaling molecule Gli2 induces parathyroid hormone-related peptide expression and osteolysis in metastaic human breast cancer cells
Cancer Res
The role of the Wnt-signaling antagonist DKK1 in the development of osteolytic lesions in multiple myeloma
N Engl J Med
Inhibiting Dickkopf-1 (Dkk1) removes suppression of bone formation and prevents the development of osteolytic bone disease in multiple myeloma
J Bone Miner Res
Insights into the antitumor effects of BPs from preclinical models and potential clinical implications
IBMS BoneKE
Antitumor effects of clinical dosing regimens of BPs in experimental breast cancer bone metastasis
J Natl Cancer Inst
Lowering bone mineral affinity of BPs as a therapeutic strategy to optimize skeletal tumor growth inhibition in vivo
Cancer Res
Mechanisms of bone metastasis
N Engl J Med
Therapeutic efficacy of a soluble receptor activator of nuclear factor kappaB-IgG Fc fusion protein in suppressing bone resorption and hypercalcemia in a model of humoral hypercalcemia of malignancy
Cancer Res
Recombinant osteoprotegerin decreases tumor burden and increases survival in a murine model of multiple myeloma
Cancer Res
Antisense inhibition of macrophage inflammatory protein 1-alpha blocks bone destruction in a model of myeloma bone disease
J Clin Invest
Role of CCR1 and CCR5 in homing and growth of multiple myeloma and in the development of osteolytic lesions: a study in the 5TMM model
Clin Exp Metastasis
An experimental model of bone metastasis by human lung cancer cells: the role of parathyroid hormone-related protein in bone metastasis
Cancer Res
TGF-beta signaling blockade inhibits PTHrP secretion by breast cancer cells and bone metastases development
J Clin Invest
Ki26894, a novel transforming growth factor-beta type I receptor kinase inhibitor, inhibits in vitro invasion and in vivo bone metastasis of a human breast cancer cell line
Cancer Sci
Zerumbone abolishes RANKL-induced NF-kappaB activation, inhibits osteoclastogenesis, and suppresses human breast cancer-induced bone loss in athymic nude mice
Cancer Res
Cathepsin K inhibitors as treatment of bone metastasis
Cancer Res
Inhibition of protein kinase c-Src reduces the incidence of breast cancer metastases and increases survival in mice. Implications for therapy
J Pharmacol Exp Ther
Extracellular engagement of alpha6 integrin inhibited urokinase-type plasminogen activator-mediated cleavage and delayed human prostate bone metastasis
Cancer Res
A causal role for endothelin-1 in the pathogenesis of osteoblastic bone metastases
Proc Natl Acad Sci USA
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Chinese expert consensus on the diagnosis and treatment of bone metastasis in lung cancer (2022 edition)
2023, Journal of the National Cancer CenterMulticenter study on atypical femoral fractures in patients with bone metastases taking bone- modifying agents
2023, Journal of Bone OncologySystemic effects of abnormal bone resorption on muscle, metabolism, and cognition
2022, BoneCitation Excerpt :Pathological bone resorption due to bone metastases or due to metabolic bone diseases causes fractures, pain, and poor patient outcome [2]. Bone-targeting therapeutics are a primary mode of treatment that act on the local bone microenvironment to reduce the risk of skeletal-related events [62]. Use of bisphosphonates is a well-established bone-targeting therapy for skeletal complications such as pain, fractures, and hypercalcemia in tumor- or nontumor-associated bone diseases [63,64].
Non-bone metastatic cancers promote osteocyte-induced bone destruction
2021, Cancer LettersCitation Excerpt :Osteoclastic bone destruction is driven by metastatic tumor cells that invade bone tissue to begin a complex interaction with the bone microenvironment [16,17]. Bone lesions result in bone pain, fractures, hypercalcemia and muscle weakness that often receive palliative interventions [18,19]. It has also been shown that bone loss can occur in patients with non-bone metastatic tumors.
Bone metastases from lung cancer: A paradigm for multidisciplinary onco-rheumatology management
2019, Revue du Rhumatisme (Edition Francaise)
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