Blood Biomarker May Track Bone Metastases in Medullary Thyroid Cancer

Medullary thyroid cancer (MTC) is a rare malignancy that often progresses silently, frequently going undetected until it reaches advanced stages. By the time it spreads to bone, it can produce unusual lesions marked by excessive bone formation, leaving patients vulnerable to pain and fracture. Yet noninvasive tools to detect and track this skeletal involvement remain limited, making early identification difficult. Addressing this gap, new findings demonstrate a blood-based approach for identifying and monitoring bone metastases in MTC.

Researchers at The University of Texas MD Anderson Cancer Center (Houston, TX, USA) describe measurement of circulating osteoprotegerin (OPG) as a potential blood test to detect and monitor bone metastasis in MTC. The work, published September 8, 2026, in Cell Reports Medicine, links elevated OPG with metastatic disease, particularly to bone. The approach focuses on quantifying OPG produced by tumor cells harboring mutations in the RET oncogene.

The team found that RET-mutant cancer cells produce higher levels of osteoprotegerin (OPG), a regulator of osteoclast development. Excess OPG disrupted normal bone remodeling by blocking bone resorption, favoring net mineral accumulation around metastatic deposits. This mechanism provides a biologic explanation for the abnormal bone-forming lesions that distinguish MTC metastases from the bone-destroying patterns more commonly seen with other thyroid cancers.

In preclinical models engineered with two common RET mutations, tumor growth in bone increased bone formation and mineralization while reducing osteoclast activity. Genetic and pharmacologic reduction of RET signaling lowered OPG levels, restored osteoclast activity, and diminished aberrant bone changes. Treatment with the investigational targeted therapy ONC201 also reduced RET expression, decreased tumor growth in bone, and further lowered OPG levels.

Analysis of tumor and blood specimens from 81 patients with MTC supported the experimental findings. Elevated tumor OPG expression was associated with metastatic disease, and circulating OPG concentrations were markedly higher in patients with bone metastases. Patients with higher blood OPG also had shorter overall survival, suggesting that OPG may reflect disease aggressiveness and help monitor treatment response.

Taken together, the data indicate that serum OPG measurement could provide a less invasive way to detect and monitor bone metastases in MTC. Additional studies are needed to validate OPG as a clinical biomarker and clarify how RET mutations drive OPG production and reshape the bone microenvironment. The team plans to further investigate these pathways.

“Our findings suggest that RET-mutant cancer cells may send signals that encourage new bone formation while stopping the breakdown of old bones, causing a pile-up. This imbalance could explain the unusual bone lesions uniquely seen in medullary thyroid cancer bone metastases and suggests that monitoring blood levels of the OPG protein could help identify and monitor patients who develop bone metastases,” said Theresa Guise, M.D., professor of Endocrine Neoplasia and Hormonal Disorders.

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