Page 23 - Mathematical Techniques of Fractional Order Systems

Variable Order Fractional Derivatives and Bone Remodeling Chapter | 1 13

The presence of metastatic cancer cells (breast, prostate, lung, renal, and
myeloma among others) accelerates the remodeling process and disturbs the
balance between bone cells by disrupting its biochemical regulation (Lerner,
2006). Bone integrity is consequently lost. These sites of cancer metastasis
are usually those where bone remodeling rates are high, such as the pelvis,
the axial skeleton, or bones with abundant bone marrow (Boyce, 2012;
Schneider et al., 2005).
Bone metastases can be osteolytic (increased bone resorption), or osteo-
blastic (bone formation is stimulated in an unstructured way). However, both
are still present in any case, although out of balance, resulting in loss of
bone resistance and integrity. Breast cancer metastases are prone to develop
osteolytic metastasis and prostate cancer ones are usually osteoblastic (Suva
et al., 2011).
For osteolytic metastases, tumor cells stimulate osteoclast activity and
receive, in return, positive feedback from factors released by the bone micro-
environment during bone destruction (Casimiro et al., 2016; Chen et al.,
2010). As TGF-β is released from the bone matrix during resorption, it sti-
mulates tumor growth and parathyroid hormone-related protein (PTHrP) pro-
duction in metastatic cells. By binding to PTH receptors on cells of
osteoblastic lineage, RANKL levels are then enhanced. Subsequently, osteo-
clasts are activated, leading to increased bone resorption (Casimiro et al.,
2016). Osteoclasts activity, in turn, will result in the release of TGF-β from
the degraded bone, which further stimulates tumor growth and PTHrP secre-
tion, giving rise to the vicious cycle.
In osteoblastic metastases, tumorous cells grow as bone expresses
endothelin-1 (ET-1). ET-1 stimulates osteoblasts through the endothelin A
receptor (ETR), activating Wnt-signaling. Tumor-derived proteases contrib-
ute to the release of osteoblastic factors from the extracellular matrix, includ-
ing TGF-β and IGF-I. RANKL is increased due to tumor-induced osteoblast
activity, leading to the release of PTH and promoting osteoclast activity
(Casimiro et al., 2016). Thus, tumor microenvironment leads to the accumu-
lation of new formed bone.
Several approaches, that treat primary and metastatic bone tumors, have
the potential to affect both tumor affected and healthy cells. However, strate-
gies can be oriented to effectively inhibit tumor growth by targeting the bone
and its microenvironment rather than the tumor alone. Antiresorptive therapy
targets osteoclasts, when an osteolytic metastatic bone disease is present.
Bisphosphonates such as alendronate or zoledronic acid (Zometas -
Zoledronic Acid for Injection, 2017; Chen et al., 2002), and monoclonal
antibodies like denosumab (Sohn et al., 2014; Gibiansky et al., 2012), are
effective treatments currently being administrated. While bisphosphonates
lodge in bone and poison osteoclasts as they degrade bone, monoclonal anti-
bodies in turn bind exclusively to RANKL, increasing the OPG/RANKL
ratio and inhibiting osteoclast formation. For other diseases, such as multiple