A lineage of sorts connects Karl L. Insogna, MD, FACP, to renowned endocrinologist Frederic C. Bartter. The connection has recently come full circle, as Insogna is the 2021 recipient of the Frederic C. Bartter Award, an esteemed award from the American Society for Bone and Mineral Research (ASBMR).
The award is given to an ASBMR member in recognition of outstanding clinical investigation in disorders of bone and mineral metabolism. The award includes an honorarium and a plaque that is presented at ASBMR’s annual meeting in October.
Insogna is associated with Bartter through his long-time mentor, Arthur E. Broadus, MD, PhD, who trained with Bartter. Broadus received the Bartter Award in 1989 while serving as chief of the Section of Endocrinology at Yale School of Medicine (YSM), a position he held for nearly 30 years.
Receiving the Bartter award is “one of the greatest academic accolades I've had the great good fortune to receive,” said Insogna, Ensign Professor of Medicine (endocrinology) at YSM.
Both his Ensign professorship, which Insogna inherited from Broadus, and the Bartter award, “are particularly meaningful,” Insogna said.
“I feel like I'm in some way connected to Dr. Bartter because my mentor trained with him, and my whole career evolved entirely based on the guidance and teaching that [Broadus] gave me as a fellow and junior faculty member,” Insogna said. That guidance, he said, was “to be exquisitely careful in understanding the clinical features of a disease, because that would inform any subsequent investigative efforts.”
During Insogna’s 40-year medical career, he has contributed to advances in the treatment of several skeletal diseases including osteoporosis and X-Linked hypophosphatemia (XLH).
Thomas Carpenter, MD, professor of pediatrics (endocrinology) at YSM and a close collaborator, nominated Insogna for the Bartter Award. “Once you get to know Karl, you realize his incredible depth of intellectual prowess in many, many areas, his capacity to integrate information in a very detailed and rigorous manner, and his incredible generosity in sharing his intellect and his interest with you,” Carpenter said. “This really ends up focusing on him because those traits that are so hard to develop require a lot of discipline and rigor.”
Carpenter also credits Insogna for maintaining a research infrastructure at YSM. “He's been a model citizen in that regard, running a core facility for bone research for 15 years, and also providing a very well-informed service in the Yale Bone Center for performing and reading bone density that's still very much the sought-after site for that procedure,” Carpenter said.
Rocks in Urine
As a resident and a chief resident at the University of Rochester, Insogna was fascinated with the process by which calcium and phosphorus are regulated in the body, and how diseases influence the economy of these ions. In a clinic treating patients with kidney stone disease, Insogna learned that metabolic perturbations put a person at risk for kidney stones.
Around this time, Broadus published an influential paper in The New England Journal of Medicine, “The Metabolic Basis of Kidney Stone Disease,” that explained the hormonal regulation of calcium economy.
“As a medical student, I thought kidney stones were the most boring, uninteresting possible things,” Insogna said. “What could be more uninspiring than rocks in your urine?”
However, soon he was borrowing a key technique from Broadus, an assay to measure the bioactivity parathyroid hormone (PTH). PTH controls the amount of calcium in the blood and bones.
“As Chief Resident at Rochester I began looking at how pregnancy and aging affected the bioactivity parathyroid hormone,” Insogna explained. Since those initial studies, his work has focused on acquired and inherited disorders that disrupt calcium and phosphate economy. A major theme of his bench research has been understanding the mechanisms by which PTH acts in the bone. He hopes that some of his most recent scientific insights in this arena will have a direct clinical impact in the not-too-distant future, he said.
Sinking While Swimming
That’s something I learned from Arthur Broadus, that you will learn a tremendous amount from your patients if you pay careful attention, and that if you plan to study those patients, you need to carefully define the clinical syndrome first.
Karl L. Insogna, MD, FACP
In 1999 Insogna was referred a patient with incredibly dense but largely normal-appearing bones. The patient was part of a larger family that had been cared for by Joseph Belsky, MD, an internal medicine specialist in Danbury. The affected members of the family had bone density values that were up to five times higher than a normal person's.
“The bone density was so high that the thin members of the family couldn't swim, they couldn't float, they sunk to the bottom of the pool,” Insogna said. Through a detailed clinical and genetic analysis of that family, Insogna, in collaboration with Richard P. Lifton, MD, PhD, who at the time was chief of the Department of Genetics at YSM, identified a mutation in a gene called LRP5 that was the cause of this syndrome. This led, along with the work of other investigators, to the realization that gain-of-function in Wnt signaling could increase bone mass.
Said Carpenter: “He's kept the laboratory going with very directed aspects of looking at bone cell function, and he had, I think, a major breakthrough in his role in identifying the gene, LRP5, which encodes a molecule that has a major function in the limb of bone turnover that builds up bone, the anabolic limb of bone turnover.” This work ultimately led to the approval of the drug romsozumab for severe osteoporosis.
A Bone Hormone Gone Awry
X-linked hypophosphatemia (XLH), which causes rickets in children, and soft bone and fractures in adults, as well as hearing loss, arthritis, and calcification around joints was an interest to another Yale endocrinologist, Howard Rasmussen, MD, PhD, section chief of Yale Endocrinology before Broadus, from 1976 to 1986.
“X-linked hypophosphatemia is a disorder of phosphate metabolism due to a mutation in a gene called PHEX that leads by a mechanism we don't know to the overproduction of a bone hormone, called the FGF23,” Insogna explained. “What could be more exciting to a bone-head than a hormone that actually comes from the skeleton?” Insogna said. “We're always talking about hormones that come from the pancreas, the thyroid and the adrenal gland, but this is a skeletal hormone that's made by cells in bone, and regulates your blood phosphate.”
The overproduction of FGF23 causes chronic renal phosphate wasting. Shortly after he joined the YSM faculty, Insogna took over the treatment of Rassmussen’s patients with XLH. Carpenter arrived at Yale in the mid-1980s from Boston Children’s Hospital, where he had worked with a close colleague of Rasmussen’s. Insogna and Carpenter have been investigative partners and friends since. Insogna refers to himself and Carpenter as “the Bobbsey Twins of XLH.”
As leaders of the Yale Center for X-Linked Hypophosphatemia, they have cared for several generations of patients from one family with XLH. “Tom [Carpenter] and I were the first to report the efficacy of conventional therapy, which was calcitriol and phosphorus, in treating adults with this disease and prove that it could partially heal the disease,” Insogna said. In subsequent studies they defined the natural history, did detailed hormonal analyses and conducted therapeutic trials in patients with XLH. Because of their prominence in the field they were involved in the development of study protocols that led directly to the international clinical trials supporting the approval in 2018 of the drug, burosumab, to treat XLH.
Bone As Living Tissue
“Bone is living tissue,” Insogna explained. It builds up and breaks down throughout life. It’s not an inert Erector Set - you need to repair old or damaged bone. If you get a little micro-crack from a stumble, your body has to remove that damaged bone and replace it with new bone in a process called remodeling.”
After menopause, the cells that are responsible for digging out the old bone become overactive. They dig the hole too deep, they dig too many holes, and you can't fill them in fast enough. That process keeps going over time and with aging can occur in men as well, Insogna said.
Consequently, he noted that there is a great deal of interest in maintaining skeletal health through diet, particularly as we age. “Diet has a huge impact on the skeleton, but it's very difficult to study because the effect of diet on bone is small over the life span of a typical NIH grant. Nonetheless, because we eat our entire lives, what we eat has an enormous impact,” he said.
Insogna has made major contributions to a reassessment of the impact of dietary protein on bone metabolism. His work has helped to change the appreciation of where dietary protein fits in the diet of healthy women. It had been previously thought that protein was “bad for bone,” but his work has shown that within the range of usual dietary protein intakes it does not adversely affect bone and instead improves dietary calcium absorption. In contrast, a chronically low dietary protein intake can rob calcium from bone. He is also interested in the role of hyperparathyroidism in causing bone loss, and why certain patients who have abnormal parathyroid function tend to lose bone more than others.
“The two avenues of investigation that have bookended our work in osteoporosis are the work on the very high bone mass family, and the work on how PTH acts in bone,” he said.
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