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In Vivo
PUBLIC HEALTH

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Photo: Charles Manley
John Bilezikian
John Bilezikian
Many disorders have the potential to cause great suffering but are not well known because they don’t affect large numbers of people. Primary hyperparathyroidism is such a disease. The disease results when the parathyroid glands produce too much parathyroid hormone, causing bones to lose calcium and thus to be prone, at least in theory, to fracture. Patients with primary hyperparathyroidism can also develop kidney stones and a constellation of nonspecific symptoms such as weakness and easy fatigability.
   Even though this bone disease is much less common than osteoporosis – it still affects about 4 million people around the world. Physicians in the Metabolic Bone Disease Program at CUMC are acknowledged leaders in the diagnosis and care of people with hyperparathyroidism. So much so that John P. Bilezikian, M.D., chief of the Division of Endocrinology and director of the Metabolic Bone Disease Program, says, “it sometimes seems as if we see all 4 million patients in our unit on Harkness 9.”
   Dr. Bilezikian has been studying hyperparathyroidism with other CUMC clinical investigators since 1980. This group, in fact, has the distinction of studying this disease under the longest, continually running grant on this disorder that the NIH has ever funded.
   John T. Potts Jr. M.D., director of research and physician-in-chief emeritus at Massachusetts General Hospital, describes the group’s expertise with hyperparathyroidism this way: ”John Bilezikian and his group at Columbia are the world’s authorities on primary hyperparathyroidism. They have described the natural history of the disease after years of careful study of Columbia patients and because of that they’ve been the ones to settle the question of which patients should have surgery to remove the gland. Doctors are able to make a more rational decision for their patients based on Columbia’s research.”
   Dr. Bilezikian says the bone researchers at the Metabolic Bone Disease Program focus on primary hyperparathyroidism and other bone diseases for a simple reason: “Not all bone loss is osteoporosis! A group that is generally well-versed in all the metabolic bone diseases is better equipped to ferret out and to treat other causes of bone loss.”
   The program is home to one of the world’s top experts in Paget’s disease, another metabolic bone disease. Ethel Siris, M.D., the Madeline C. Stabile Professor of Clinical Medicine, is a world authority and has published widely on this subject. As well as speaking and writing on the subject, Dr. Siris cares for a large number of patients with Paget’s disease.
   Another disorder in which the Columbia group has developed a unique expertise through their research is hypoparathyroidism – the opposite of hyperparathyroidism – in which the parathyroid glands produce no parathyroid hormone. The disease is very rare but, “it’s a perfect model from the point of view of understanding bone, and how important parathyroid hormone is to bone,” says Dr. Bilezikian.
   Osteoporosis, of course, is a major focus of Columbia’s Metabolic Bone Disease Program but physicians here perceive the disease from a broader perspective – not only as an older woman’s disease, but also as a complication of other conditions in both women and men.
   “When Columbia first started doing heart transplants, for example, surgeons would come to us with their male patients who were four inches shorter and stooped over only a few years after the operation,” Dr. Bilezikian says. “Elizabeth Shane [professor of clinical medicine] was the first to describe osteoporosis in these patients and she showed that if treated with Fosamax after the transplant, the bone loss and the fractures could be prevented.”
   The new challenge is to understand how metabolic bone diseases, including osteoporosis, affect bone quality, a term used to describe properties of bone that include but are not limited to bone density. “There’s more to bone quality than just density, for example, the overall size and shape of bone, bone turnover, microarchitecture and bone collagen,” Dr. Bilezikian says. “When bone quality is poor, we’d like to understand why and which drugs can restore bone quality.”
   Four new faculty members, who are bone biologists, have been recently added to the CUMC roster of bone experts. They include Gerard Karsenty, M.D., Ph.D., the new chairman of the Department of Genetics and Development. With these new outstanding bone biologists; stellar clinical investigator-physicians – many of whom are national and international leaders – and a state-of-the art high resolution new bone imaging instrument, Dr. Bilezikian says the Metabolic Bone Disease Program is ideally suited to make even greater contributions to the understanding and treatment of metabolic bone diseases.


Though osteoporosis usually affects women over 65, it is not uncommon for Elizabeth Shane, M.D., professor of clinical medicine, to find 30-year-olds in her office.
“A young woman may have put her finger into a bone density scanner at the local drugstore, gotten a low score, and now somebody wants to put her on Fosamax,” she says. “For a young woman, however, low density doesn’t necessarily mean she’s at risk for fracture. Some women are smaller, so they naturally have lower bone density. Or they have genetic reasons for low density.”
   When dual X-ray absorptiometry (DXA) machines became available in the 1980s, bone density scores gave doctors insight into bone health and fracture risk for older women. In fact, in many people DXA scores fail to predict fracture risk. These scores often appear normal in people with chronic kidney disease, hyperparathyroidism, or those who’ve received heart transplants, yet these patients experience a high incidence of broken bones. “People are recognizing that bone density doesn’t tell you everything,” Dr. Shane says.
   Bone researchers are now shifting their focus to bone strength to look for different methods to predict fracture. One reason for the shift is to find an end point for clinical studies other than fracture. “Fractures are relatively rare events, which means you have to study many, many people to see a difference between those taking drugs and the untreated population.” Dr. Shane says.

Appreciating Bone Complexity
Focusing on strength, rather than density, also makes sense from a biomechanical perspective, which is how Edward Guo, Ph.D., associate professor of biomedical engineering, looks at bone health. “At the end of the day, what determines whether or not a bone breaks is how strong it is,” Dr. Guo says.
   One of the most important factors contributing to bone strength, Dr. Guo says,
is the complex structure of bone. Bone has two components – an outer part consisting of a tube of very dense material and an inside that looks like a sea sponge, filled with finely interlaced struts, called trabeculae, which are about as wide as a human hair.
   Both types contribute to overall strength, but DXA machines cannot distinguish between the outer cortical bone and the lacy interior. The only way to see a person’s bone microarchitecture is by removing a piece during a bone biopsy, which is sometimes done to diagnosis bone disease.
   Recently, however, more powerful CT scanners have been developed to non-invasively capture the fine details of bone microarchitecture. A scanner acquired by the Division of Endocrinology – only the third such machine in use in the United States – allows Dr. Shane, Dr. Guo, Adi Cohen, M.D., assistant professor of clinical medicine, and their colleagues to study how bone structure affects fracture risk and how drugs alter bone structure over time. The scanner is being used in several groups of patients – premenopausal women, heart transplant patients, people with chronic kidney disease, those with primary hyper– and hypo– parathyroidism, and in men with osteoporosis.
   “What we want ultimately from these structural images is a better measure of bone strength for the purpose of fracture prediction in young premenopausal women and other groups of patients,” Dr. Cohen says.
   For young women with very low bone density scores, limited data collected with invasive bone biopsies suggest very small structural differences in trabecular bone can distinguish women who experience fractures from those who do not.
   With the new scanner, Drs. Shane and Cohen can noninvasively measure aspects of bone’s inner structure, including the number of thin struts inside the bone, the number of connections they make to each other, and how thick they are.
   The images are also undergoing an engineering analysis – finite element analysis – that is typically used in airplane design. With finite element analysis Dr. Guo can calculate a bone’s overall stiffness. In osteoporosis, bones lose stiffness not just because they lose mass, but also because of tiny changes in trabecular bone.
   Trabeculae in the bone’s interior come in two different shapes: rods and plates. When the bone is healthy, there are lots of plates. During osteoporosis plates change into rods over time.
   “In our computer simulations, plates are very important to stiffness,” Dr. Guo says, “so we’re very interested in looking at the new images to see if this is also true in people.”
   For now, the new CT scanner is strictly a research tool, so this technology is not routinely available to patients at risk. But when regulations do permit, it will be available to patients and their physicians, promising a new dimension of key information that will be helpful in decision-making. Physicians, however, should expect their view of bone to change.
Structural Changes Detected with New CT Scanner
Structural Changes Detected with New CT Scanner Structural Changes Detected with New CT Scanner
Osteoporotic Bone
Normal Bone
Unlike a DXA machine, the new CT bone scanner in the Division of Endocrinology can clearly detect changes in the tiny "struts," called trabeculae, inside bone. The CT image at left shows a loss of trabeculae in a cross section of the forearm from a patient with osteoporosis. The CT image at right shows normal forearm bone structure.
   “As a doctor, I’ve always looked at bone as an endocrine organ, but engineers see it as a structure,” Dr. Shane says. “The new emphasis on bone strength has made doctors realize that bone has mechanical properties and that looking at blood and urine tests only gives us part of the picture. There’s been a huge change in doctors’ appreciation of the engineering aspects of the skeleton in the last five years and machines like this will continue to support that change.”
   The acquisition of the XtremeCT bone scanner was made possible by a donation from Thomas Kempner and Katheryn Patterson.

—Susan Conova

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