These increasingly important questions are on the minds of Mayo Clinic's osteoporosis research team whose insights about the causes of bone loss will likely revolutionize the way physicians understand the disease. Led by endocrinologist, Sundeep Khosla, M.D., the team's investigations indicate that osteoporosis can be prevented and even reversed. Their program is held as the model for translational research by the National Institutes of Health (NIH).

"The efforts of our group are closely aligned with the National Institutes of Health (NIH) Roadmap for Reengineering the Clinical Research Enterprise," says Dr. Khosla. "As we learn more about why bones fracture, we hope to develop tools that can accurately identify people at risk and ways to modulate their risk factors."

Updating the Definition of Osteoporosis

Epidemiologist, L. Joseph Melton, III, M.D., has a storied history in the field of bone loss epidemiology. His collection of data from residents of Olmsted County, Minn., which determined the incidence, complications and cost of osteoporotic fractures, led to a seminal paper, in 1992, which determined the enormous impact of osteoporosis on public health (Journal of Bone and Mineral Research 7:1005-1010, 1992). Dr. Melton's work also helped provide the basis for the first definition of osteoporosis by the World Health Organization (WHO). Today, he and other members of Mayo's osteoporosis research team are working with WHO to devise better ways to predict fractures.

Dr. Melton worked in concert with another pioneer in bone loss, endocrinologist Lawrence Riggs, M.D., whose early work introduced the concept of bone density and its measurement with the first densitometer. Before their work, the increased incidence of bone fractures and stooping was considered a natural consequence of aging rather than a disease. Later studies were the first to show that human bone has estrogen receptors, the first to demonstrate the efficacy of estrogen therapy, and the first to show that the use of fluoride increases bone density but also increases the incidence of fractures due to poor quality of the bone formed.

"Now we envision changing the entire notion of what osteoporosis is," says Dr. Melton. "For the first time, we are in the position of being able to understand how the risk factors for osteoporosis and fractures really operate, and how therapies might modulate them."

Dr. Khosla has an NIH research grant to study the epidemiology of age-related bone loss and fractures. His studies will delve further into the group's recent recognition that people may be at risk for fracture due to structural weaknesses in the bone even though they have normal bone density. The new insights mean that structural changes in the morphology of bone must be incorporated into a new definition of osteoporosis, which is currently defined by bone density levels alone.

"We have a scanner that does what we refer to as an 'in-vivo bone biopsy.' This is a high resolution computerized tomography (CT) device that allows us to visualize bone structure in patients at the wrist," says Dr. Khosla. "Until recently, bone strength and structure could only be measured after death."

This technology is combined with sophisticated computer-generated images of bone structure at the spine and hip using software, called Analyze, which was specifically adapted for this purpose by Richard Robb, Ph.D., an expert in biomedical image visualization and analysis, and director of Mayo's Biomedical Imaging Resource. Further collaborations between the Mayo group and computer-modeling groups at the University of California, Berkeley, and the University of Zurich, Switzerland, led to the development of mathematical models that electronically calculate the strength and fracture risk of bone. Studies comparing their model, which is called the finite element modeling method, to the actual breaking strength of the bone demonstrate a high degree of accuracy.

"We are currently conducting studies to validate the new methods," says Dr. Khosla. "We anticipate being able to provide physicians with better tools to identify persons at risk for fracture in the next five to seven years. We can then target treatments to help those at greatest risk, which will minimize both costs and side effects of treatment."

Bone Biology

Funded by a $1.2 million per year NIH Program Project grant, the osteoporosis research team is also taking their research to the genetic and molecular levels to study the physiology of bone metabolism in an aging population. Thomas Spelsberg, Ph.D., and Merry Oursler, Ph.D., members of the Mayo Clinic Bone Group, study estrogenic steroids and a growth factor tumor-suppressor gene, which was discovered at Mayo, called TGF-beta-Inducible Early Gene (TIEG).

"Using both cell cultures and genetically engineered mice, our team is examining the role of estrogens and partial estrogen antagonists (SERMs) in the loss of bone in osteoporotic post-menopausal women and aging men and related diseases," says Dr. Spelsberg. "Estrogens have been one of the most promising drugs for the therapeutic prevention of bone loss in these diseases. We are examining the important regulatory steps of estrogen action at the gene or genomic level in hopes of identifying the origins of bone loss and targets for prevention of bone loss."

Dr. Spelsberg's lab received a patent for developing cell lines of a type of human bone cell called an osteoblast, which is responsible for bone formation. The cell lines can differentiate into osteoblasts and form bone—an invaluable resource for further research. The TIEG studies investigate the gene's role in bone and skeletal disorders such as osteoporosis and breast cancer metastasis to the bone. TIEG codes for a gene-regulating protein (transcription factor), which appears to generate severe bone loss when it is inactive or missing in laboratory mice.

"The identification of the genes and signal pathways would allow scientists to better diagnose the predisposition of bone loss diseases before fractures occur and then prevent bone loss through the development of newer and better estrogen-related drugs," says Dr. Spelsberg.

In related studies, Dr. Khosla's group has recently shown that the precursors of osteoblast cells circulate in the peripheral blood in much greater numbers that previously thought, especially during times of increased bone formation, such as puberty (N Engl J Med. 2005 May 12;352(19):1959-66). Their study may have discovered an important component in the process of bone formation.

Patient-focused Investigations

Mayo is uniquely positioned to integrate epidemiology, intensive human studies and basic bone biology because of our highly synergistic system. A major focus of Dr. Khosla's leadership is to develop innovative methods from basic research that can be applied to human investigation.

"Because Mayo is very patient-focused, research is always driven by the question of how what you investigate is likely to translate into clinical care," says Dr. Khosla. "We are now working with the National Osteoporosis Foundation to help develop new guidelines for the prevention and treatment of osteoporosis."

Mayo Clinic's CTSA Clinical Research Unit (CRU) is considered one of the best clinical research facilities in the country. The center hosts more than 200 human studies each year, many of them by the osteoporosis group, which is currently conducting a bone marrow aspirate study on post-menopausal women to examine the effect of estrogen on osteoclasts—bone cells responsible for breaking down bone. They are also looking at the way gene variations in individuals change estrogen action which, in turn, affects bone composition. The hope is to develop markers that will be able to predict osteoporosis risk. Other studies are testing the effect of drugs to treat and prevent osteoporosis in women undergoing chemotherapy for breast cancer, which can cause early menopause and loss of bone density.

"We have established a unique group of investigators that conduct population studies, intensive clinical investigations in humans, and basic research of bone biology," says Dr. Khosla. "It's exciting to be part of such a cohesive group because the sum of what we do is so much greater than what our individual labs can produce."

Osteoporosis Stats

• Osteoporosis and/or low bone mass is present in 44 million U.S. women and men age 50 and older
• One in 2 women and 1 in 5 men will experience an osteoporotic fracture during the course of aging
• Estimated annual cost to the US healthcare system: $17 billion (2001)
• By 2010, 52 million and by 2020, 61 million women and men will be affected

Landmark Bone Loss Research at Mayo

• Largely responsible for the identification of osteoporosis as a preventable and treatable disorder, rather than an inevitable consequence of growing old
• First use of bone densitometry (Dual Energy X-ray Absorptiometry (DEXA) scanning) and later bone biochemical markers in population-based studies
• First population-based studies on the age- and gender-specific patterns of bone loss, the relationship of bone density to fractures, and the economic impact of hip fractures
• First demonstration of sex steroid receptors in bone cells
• Role of estrogen deficiency in late post-menopausal bone loss in women
• Critical role of estrogen in the male skeleton
• Development/assessment of new therapies (calcitonin, bisphosphonates, fluoride, transdermal estrogen, SERMs)
• Application of new imaging techniques to potentially redefine current approaches to fracture risk assessment
• Development of novel paradigms:
  • Concept of type I and type II osteoporosis
  • Unitary model for pathogenesis