Bone metastases in thyroid cancer
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Lymph node and lung metastases is standard-of-care in thyroid cancer patients, bone metastases are less well studied and are often neglected in thyroid cancer patient surveillance. Bone metastases in thyroid cancer are, however, independently associated with poor/worse prognosis with a median overall survival detection of only 4 years despite an otherwise excellent prognosis for the vast majority of thyroid cancer patients.

In particular, bone metastasis pathogenesis appears to reflect cooperatively between cancer and the bone microenvironment creating a “vicious cycle” of bone destruction rather than due exclusively to tumor invasion into bone. Additionally, bone metastases are more frequent in follicular and medullary thyroid cancers, requiring closer bone surveillance in patients with these histologies. Emerging data also suggest that treatments such as multikinase inhibitors (MKIs) can be less effective in controlling bone, as opposed to other (e.g. lung), metastases in thyroid cancers, making special attention to bone critical even in the setting of active MKI therapy. Although locoregional therapies including surgery, radiotherapy and ablation play important roles in palliation, antiresorptive agents including bisphosphonates and denosumab appear individually to delay and/or lessen skeletal morbidity and complications, with dosing frequency of every 3 months appearing optimal; their early application should therefore be strongly considered.

The “vicious cycle” of osteolytic bone metastases

Bone is unique, in that it is a large repository of immobilized growth factors, and calcium. Perhaps unexpectedly, osteolysis is triggered principally by tumor-stimulated osteoclast differentiation and activation - rather than by replacement of bone by tumor per se. Tumor-associated macrophages and metastatic cancer cells often overexpress osteoclast-inducing factors to prompt bone resorption/osteolysis, this osteolysis in turn, leads to the release of active matrix-embedded cytokines/growth factors, like TGFβ and IGFs, thereby promoting tumor growth in bone in a “vicious cycle”.

Primary and metastatic tumors are frequently heterogeneous, with metastases often clonally distinct their primary tumors and sometimes better suited to preferential adhesion and metastasis formation at specific anatomical sites. The ability of tumor cells to recruit blood supply is critical to the development of macrometastases; >80% of DTC OMs are located in the axial skeleton red marrow - where blood flow is highest, with vertebrae, pelvis, ribs, and femur representing the most common sites of metastases. Bone also contains niches wherein vascular sinusoids lacking basement membranes are permissive of invasion. Moreover, cancer subclonal cells that exchange biological information with the bone are best able to establish OMs via disrupting a normally tightly regulated process called “coupling” linking bone resorption to bone formation.

The presence of OMs in advanced TC conveys a worse prognosis, high morbidity, therapeutic challenges, and difficulties in assessing OM response to applied therapies. As the risk of OM development is increased in MTC, FTC, and HCC, proactive surveillance of patients with these TC histologies in especially important. In this regard, RAI imaging (iodine avid follicular cell-derived thyroid cancers only), FDG-PET, or gallium dotatate-PET, are preferable imaging approaches with regard to detecting OMs.

Although kinase inhibitors have proven clinical activity in DTC and MTC, MKI effects in controlling OMs appear attenuated relative to effects at other metastatic sites. Early use of antiresorptive palliative therapy (e.g. zoledronic acid, denosumab) is thus favored based upon an analogy to data other cancers and limited data specific to TCs – and also given that advanced DTC patients are usually treated with TSH-suppressive doses of levothyroxine with consequently heightened risk for bone loss. Providers should, therefore, have a low threshold for institutions of antiresorptive therapy to supplement other therapeutic approaches, with data general supporting similar efficacy and lessened toxicities with every three-monthly, versus monthly, dosing. Still, much work is needed to develop more effective systemic therapeutic approaches to preventing and managing OMs.