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Update on Hypercalcemia of Malignancy Builds on Earlier Yale Discovery

April 14, 2022
by Jane E. Dee

In a “Clinical Practice” review article in the New England Journal of Medicine, John Wysolmerski, MD, professor of medicine (endocrinology) at Yale School of Medicine provides a clinical update on hypercalcemia in malignancy, which often complicates the care of cancer patients.

“This is an update of a syndrome that led to the discovery of parathyroid hormone-related protein in our endocrine section at Yale,” said Wysolmerski, chief of the Endocrinology & Metabolism Section in the Department of Internal Medicine.

The review article, “Cancer-Associated Hypercalcemia,” by Wysolmerski and Theresa A. Guise, MD, of the MD Anderson Cancer Center, appeared April 14 in the New England Journal of Medicine. It is the first update on hypercalcemia in malignancy that the NEJM has published since 2005.

“This is a Yale story,” Wysolmerski said. “When our former section chief Arthur Broadus was recruited in 1976 to set up a clinical program in bone and mineral metabolism, one of the questions that they tackled was this mystery of why cancer patients developed high calcium levels.”

That question led to the discovery of the hormone called parathyroid hormone-related protein, or PTHRP. In addition to Broadus, the discovery involved Karl Insogna, MD, FACP, Ensign Professor of Medicine (endocrinology) and director of the Yale Bone Center as well as Andrew Stewart, MD, formerly of Yale and currently the director of the Diabetes, Obesity and Metabolism Institute at Icahn School of Medicine at Mount Sinai.

“When I was a medical student, I worked in Dr. Stewart's laboratory, and then as a fellow in Arthur Broadus' laboratory,” Wysolmerski said. “So I've been involved with PTHRP for a long time, and this is a review of the clinical disease that gave birth to many subsequent discoveries.”

His and Guise’s “Clinical Practice” offers new insight into the causes of the disorder. “Over the years, the frequency of the different types of hypercalcemia malignancy have changed somewhat, and there is some blurring of the original characterization of the humoral version of hypercalcemia of malignancy, in that some solid tumors seem to secrete both PTHrP and 1,25 Vitamin D, which originally was considered a rare event,” Wysolmerski said. Also, the distinction between hypercalcemia caused by bone metastases versus a purely humoral form of hypercalcemia is likely more of a spectrum than specific set categories. “We emphasize in this version that those initial distinctions are not quite as hard and fast as once thought,” he said.

The authors also emphasize that despite the improvements in controlling high calcium levels, the patient mortality rate is still 30 to 50 days. “Although this syndrome was thought to be a solved problem, I really believe that the stubborn high mortality rate indicates that there's still a need for more research to try to understand whether we should be treating the elevations in PTHRP, rather than just simply lowering the calcium,” Wysolmerski said.

Yale’s Section of Endocrinology & Metabolism works to improve the health of individuals with endocrine and metabolic diseases by advancing scientific knowledge; applying new information to patient care; and training the next generation of physicians and scientists to become leaders in the field. To learn more about their work, visit Endocrinology & Metabolism.

Submitted by Jane E. Dee on April 14, 2022