Study finds elevated circulating osteoprotegerin correlates with RET mutations, unusual bone lesions, and reduced survival in patients.
Measuring blood levels of the osteoprotegerin (OPG) protein could provide a less invasive method to detect and monitor bone metastasis in patients with medullary thyroid cancer, according to a study from The University of Texas MD Anderson Cancer Center published in Cell Reports Medicine.
Medullary thyroid cancer is a rare malignancy originating from thyroid C cells that regulate calcium metabolism, the authors note. Roughly half of all cases are driven by mutations in the RET oncogene, and patients often do not experience symptoms until the cancer has advanced. When the disease metastasizes to bone, it produces abnormal bone accumulation, pain, and fractures, contrasting with other thyroid cancers that typically cause bone destruction.
In the study, researchers found that cancer cells harboring RET mutations produce elevated levels of OPG, a naturally occurring protein that regulates osteoclasts. Excess OPG suppresses osteoclast activity and diminishes normal bone resorption, resulting in a dense accumulation of bone surrounding metastatic lesions.
“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,” says Theresa Guise, MD, professor of endocrine neoplasia and hormonal disorders at MD Anderson and lead author of the study, in a release. “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.”
Clinical and Preclinical Findings
To evaluate clinical relevance, the research team analyzed tumor and blood samples from 81 patients with medullary thyroid cancer. According to the study, elevated OPG expression in tumor tissue was associated with metastatic disease, while circulating blood concentrations of OPG were significantly higher in patients with confirmed bone metastases. Furthermore, patients with high circulating OPG levels exhibited shorter overall survival, indicating that the circulating protein may serve as an indicator of aggressive progression and treatment response.
In preclinical models engineered with two common RET mutations linked to aggressive disease, reducing RET activity through genetic inhibition or targeted pharmacological agents lowered OPG levels, restored osteoclast activity, and reduced bone abnormalities. Additionally, treatment with ONC201, an investigational targeted therapy that decreases RET expression, curtailed tumor growth in bone and lowered OPG concentrations, according to the researchers.
Implications for Clinical Laboratories
The findings point toward blood-based OPG testing as a potential tool for clinical laboratories—aligned with broader advances in liquid biopsy cancer detection—to assist in tracking disease trajectory and therapeutic response without relying solely on serial imaging.
The study authors emphasize that further clinical studies are necessary to validate OPG assays as standardized biomarkers for routine patient care. Future research will focus on detailing the precise molecular mechanisms by which RET mutations drive OPG production and influence the bone microenvironment.
The study received support from the Cancer Prevention and Research Institute of Texas, the Bone Disease Program of Texas, the National Cancer Institute, Dive into the Pink, and MD Anderson institutional funding.
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