HOUSTON, SEPTEMBER 8, 2026 ― Researchers at The University of Texas MD Anderson Cancer Center have uncovered a possible reason why metastatic medullary thyroid cancer causes abnormal bone growth, pointing to a new opportunity to detect and monitor bone metastases in patients.
The study, published today in Cell Reports Medicine , was led by Theresa Guise, M.D. , professor of Endocrine Neoplasia and Hormonal Disorders . The researchers discovered that cancer cells with RET mutations produce higher levels of the OPG protein, which disrupts the balance of bone renewal, blocking destruction and favoring the accumulation of bone. The findings suggest that measuring OPG levels via blood tests could identify and monitor patients that develop aggressive disease.
"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," Guise said. "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."
Why is medullary thyroid cancer difficult to treat once it spreads?
Medullary thyroid cancer is a rare and silent cancer formed from thyroid C cells that help control calcium metabolism. Patients often do not show any symptoms until the disease is in advanced stages, and roughly half of all cases are caused by mutations in the RET oncogene.
While many patients initially respond to treatment, many also develop metastases. These cancers can metastasize to the bone, resulting in excessive bone accumulation, which is distinct from other thyroid cancers that typically cause bone destruction. These patients often experience pain, fractures and other complications that affect quality of life and survival, but the underlying process behind this abnormal bone formation is largely unknown.
What did the researchers discover in preclinical models?
The researchers developed preclinical models carrying two common RET mutations associated with aggressive disease. When the cancer cells grew in bone, they caused an increase in bone formation and mineralization while also reducing the activity of osteoclasts, the cells responsible for breaking down and removing old bone.
The researchers identified a key driver of these effects, osteoprotegerin (OPG), which is a naturally occurring protein that controls the development of osteoclasts. When too much OPG was present, osteoclast activity dropped. RET-mutant cancer cells produced higher levels of OPG, leading to reduced bone resorption and excessive bone accumulation around metastatic tumors.
How did targeting RET affect bone metastasis in preclinical models?
The researchers reduced RET activity both genetically and pharmacologically, which, in both cases, reduced OPG levels, increased osteoclast activity and diminished the formation of bone abnormalities. Additionally, reducing RET expression with a new investigational targeted therapy, called ONC201, also reduced tumor growth in bones and resulted in lower levels of OPG, improving signs of bone disease in preclinical models.
These findings suggest that RET affects both tumor growth and the interactions between cancer cells and the bone microenvironment.
Were these results consistent in medullary thyroid cancer patients?
To confirm these preclinical results, the researchers analyzed tumor and blood samples from 81 patients with medullary thyroid cancer. Elevated OPG expression in tumors was associated with metastatic disease, while circulating OPG levels in the blood were much higher in patients who had developed bone metastasis. Patients with high blood levels of OPG also had shorter overall survival, suggesting the protein may reflect treatment response.
Taken together, these results suggest that measuring OPG blood levels may be a less invasive way to monitor bone metastasis and aggressive disease progression for patients with medullary thyroid cancer. However, future studies will be needed to validate the potential for this process to be used as a biomarker for clinical care. The researchers also plan to further investigate how RET mutations drive OPG production and affect the bone microenvironment.
