Sometimes, it comes down to being in the right place at the right time. For Cheryl Conover, Ph.D., the "right place" happened to be the corridor outside her lab on Mayo Clinic's Rochester campus. Walking down that hallway nearly a decade ago, she ran into Sundeep Khosla, M.D., whose laboratory was across the hall. Dr. Khosla and an associate were discussing a patient with odd symptoms -- an elderly man who had aching limbs. His pain was treatable but Dr. Khosla wanted to find the cause. X-rays showed the man was essentially healthy, but despite his age, had experienced a sudden, rapid growth in bone density.

"And it was good bone," Dr. Conover says -- structurally strong and located in the spine and hips, areas typically vulnerable to osteoporosis. She later learned that another elderly patient with similar symptoms had been declared by a radiologist to have the bones of a 20-year-old.

In the corridor Dr. Conover heard Dr. Khosla speculate that insulin-like growth factors (IGFs) might be causing his patient's rapid bone growth. "It has to be the IGFs," Dr. Conover recalls saying "somewhat flippantly" as she walked past. Structurally similar to insulin, IGFs play a key role in growing bones and other systems throughout the body.

A conversation ensued between Dr. Conover, whose lab studies the actions of IGFs, and Dr. Khosla, whose clinical research and practice focus on osteoporosis. The eventual result: Mayo Clinic's discovery that a certain IGF and IGF binding protein (IGFBP) can indeed stimulate bone growth -- and possibly, a novel treatment for osteoporosis. For patients with osteoporosis, stimulating new bone formation is crucial.

"Up to now the drugs we had would prevent further loss of bone," Dr. Khosla says. But new therapies "provide the hope that you can reverse the disease. Osteoporosis will essentially become a curable disease."

Osteoporosis is a major health problem, affecting some 44 million men and women age 50 and older in the United States. Half of all women and 20 percent of men will experience an osteoporotic fracture during in their lives. The disease costs the U.S. healthcare system an estimated $17 billion a year. With the country's population aging, the problem will worsen. By 2010, 52 million women and men are expected to be have osteoporosis; by 2020, 61 million.

Mayo Clinic: A Leader in Bone-Loss Research

Mayo Clinic has long been a center for bone-loss research. Once considered an inevitable consequence of aging, osteoporosis was identified as a preventable and treatable disorder largely as a result of Mayo research. Mayo also has pioneered the use of innovative imaging techniques, population-based studies on age- and gender-specific patterns of bone loss, and the use of estrogen and other new therapies.

The clinic's success is due in part to "team science" like the cooperation between Drs. Conover and Khosla. Dr. Conover's biological research has enhanced physicians' understanding of how IGFs regulate bone growth.

"The more you do that," Dr. Khosla says, "the better you open up potential targets for intervention."

Such collaboration is routine at Mayo, where clinician researchers and basic scientists work in coordination..

"We always talk about taking research from the (lab) bench to the (hospital) bedside," Dr. Conover says. In this osteoporosis research, she adds with a smile, "we are going from the bedside to the bench and, I hope, back to the bedside."

New Bone Growth in Elderly Patient Leads to Discovery

That patient of Dr. Khosla's had a rare form of osteosclerosis associated with Hepatitis C. People with this syndrome experience an unusual increase in bone density in adulthood. Because IGFs are produced in the liver and stimulate bone formation, Dr. Conover agreed they were an obvious culprit in the bone growth. Her Mayo lab was one of the few in the world with the expertise to undertake a detailed analysis of the IGF system in patients with Hepatitis C-associated osteosclerosis.

Sure enough, after studying the IGF systems in Dr. Khosla's patient and a handful of others worldwide with the rare condition, Dr. Conover found something unique: an elevation in a precursor form of a certain IGF, known as IGF-II; and in an IGF binding protein called IGFBP-2. But how exactly might this IGF complex cause new bone growth?

To find out, she undertook in-vitro (lab dish)studies of the IGF complex and human bone cells grown in the lab. The experiments showed that, when acting alone, neither IGF-II nor IGFBP-2 showed significant bonding with the bone matrix. But when added together, the IGF-II/IGFBP-2 complex showed "a whopping 20-fold increase in binding" to bone matrix, Dr. Conover says. And once bound to the matrix, the IGF complex stimulated the production of bone-forming cells. In other words, the IGF complex helped grow new, healthy bone.

The next step was pre-clinical trials. Dr. Conover found that administering the IGF complex to laboratory animals with low bone-mineral density boosted that density about 10 percent. These "amazing results," she says, strengthened her belief that someday, osteoporosis might be prevented.

"We want to see if we can reverse osteoporosis," Dr. Conover says. "That's what's really needed. You'd decrease the incidence of fracture and prolong the quality of life."

So she decided to find out if the IGF complex could boost bone density in animal studies. Doing so, however, required a supply of animal IGFBP -- which wasn't readily available. Fortunately, a collaborator in Denmark recently discovered a way to produce the needed substance in his lab.

"At the time, with what we had, we couldn't do the studies that were critical," she says. "Now, we're getting enough to be able to do them," which also will help ascertain dosage and delivery methods."

So far, the IGF complex doesn't appear to cause side effects. Clinically-observed osteosclerosis patients and the lab animals "don't have hypoglycemia. They don't have increased tumors," Dr. Conover says. And "once they increase their bone mass, it stays up. It's not transient."

She hopes to eventually start clinical studies in human patients. All this might never have happened without a coincidental meeting and a flippant remark in a lab corridor.

"Mayo allows the flexibility of collaboration," Dr. Conover says. "We're not competing against each other." With a smile, she adds: "We do have fun."

- Barbara Toman, July 2008