When it comes to bones and what makes them break, Mayo Clinic researchers have a habit of shattering conventional wisdom.
It was Mayo investigators who, in the early 1970s, first identified osteoporosis as a preventable and treatable disorder, not an inevitable consequence of aging. Subsequent osteoporosis research focused on women and estrogen, the hormone that regulates female bone metabolism. Testosterone, the primary male sex hormone, was assumed to regulate bone metabolism in men.
But a decade ago, endocrinologist Sundeep Khosla, M.D., made another profound discovery: Estrogen regulates bone metabolism in men as well as women. Moreover, declining estrogen levels can lead to osteoporosis in aging men just as in postmenopausal women. [J. Clin. Invest. (2000)106(12), 1553-1560]. Dr. Khosla's finding that men need estradiol, the primary form of estrogen, drew attention to male osteoporosis. Now, collaborating with other Mayo researchers, Dr. Khosla's laboratory team is uncovering solutions.
"This finding is leading to some important changes in our diagnostic evaluation and, potentially, treatment approaches for men with osteoporosis," Dr. Khosla says. Although many clinicians continue to focus on testosterone levels in men with symptoms of osteoporosis, "we really ought to be looking at estradiol levels in those men," Dr. Khosla says. "Measuring estradiol levels in older men might be a useful tool to identify those at increased risk of bone loss or fractures."
Translating basic science such as Dr Khosla's estrogen research into patient care is a cornerstone of Mayo's approach to medicine. Lab discoveries lead to innovative treatments; patients' needs raise questions about cell structure and suggest improvements in imaging technology. When a disease like osteoporosis is examined from all these angles, the results are striking. "The progress in the past 10 to 15 years has been enormous," Dr. Khosla says. "Our understanding of how bone is regulated has exploded, and out of that has come a whole host of new treatments. There's great excitement in osteoporosis."
Although aging men have only about one-third the fracture rate of postmenopausal women, the number of men affected is still high. About one in eight men over age 50 will suffer an osteoporotic fracture. Moreover, the consequences can be more serious in men; they are twice as likely as women to die in hospital after a hip fracture. About 20 percent of people with hip fracture die within a year of their injury.
Dr. Khosla considers his team's findings in male osteoporosis to be some of their most significant work. After the initial discovery, the investigators wanted to learn precisely how estrogen regulates bone metabolism. They studied knockout mice in which estrogen receptors, which promote bone growth, were unable to bind to DNA. Blocking the estrogen receptors "had a very profound effect on bone," particularly in males, Dr. Khosla says.
Cancer and Osteoporosis
Unlike postmenopausal women, most men don't experience a sharp decline in estrogen. However, subgroups of men can be estrogen-deficient, such as prostate cancer patients. Treating prostate cancer requires suppressing testosterone production. Since most estrogen in men is converted from testosterone, suppressing testosterone also reduces estrogen. Low estrogen can cause vertebral compression fractures or hip fractures that, in turn, can lead to severe disability or even death from fracture complications. So although suppressing testosterone treats patients' prostate cancer, "you really impair their quality of life," Dr. Khosla says.
At Mayo, prostate cancer patients are often referred to osteoporosis specialists. "There are plenty of reasons to have their bone density treated," says Mayo Clinic urologist R. Jeffrey Karnes, M.D. "When we're proactive, they don't develop symptoms. It's a phenomenon that is really starting to weave its way into the fabric of advanced prostate cancer therapy."
Women with osteoporosis are frequently treated with a group of drugs known as selective estrogen receptor modulators. SERMs stimulate estrogen-like action in tissue. Because too much estrogen can result in feminizing effects in men, such as breast enlargement, the FDA hasn't yet approved SERMs for use in men. But Dr. Khosla's team conducted the first study of a SERM in men, and their findings were significant: The drug, called Raloxifene, had protective effects on bone without feminizing side effects. The study results indicate that for estrogen-deficient men treatment with selective estrogen receptor modulators would be a useful option.
The Raloxafine study yielded another interesting result. The drug had little effect on bone density in men with normal estradiol levels; the reduction in bone breakdown was seen mostly in estrogen-deficient men. "So above a certain threshold, adding estrogenic activity as treatment doesn't really help," Dr. Khosla says. "But if you truly are low in estrogen, then giving an estrogen-like compound does, in fact, help." Finding Affordable Options
Finding this threshold is important not only in treating patients but also in restraining health-care costs. "There are going to be a lot of treatment options for patients with osteoporosis. But some of them are quite expensive," Dr. Khosla says. "So you really have to identify those who are at greatest risk and target them for these expensive treatments."
Another aid to identifying at-risk patients, both male and female, is better imaging technology. The current method, called DEXA (Dual Energy X-ray Absorptiometry), measures bone density but can't assess the bone's structure or strength. "If you were going to put a bridge across a chasm, and you used just a two-dimensional plank, that might be an analogy for DEXA," says Richard Robb, Ph.D., a computer scientist and biomedical engineer at Mayo. "If you put up a bridge with pillars and tiers and cross-struts "a much stronger three-dimensional structure "that might be an analogy for bone-volume CT scans."
Dr. Robb is collaborating with the Khosla lab on developing and analyzing these high-tech 3D images. The bridge analogy is particularly apt because like bridges, bone strength is related to its three-dimensional structure. "We look at the entire volume of bone," Dr. Robb says, including the outer cortical and inner trabecular tissue, as both play an important role in bone strength. Using mathematical algorithms and "finite element models" similar to those that civil engineers use to predict bridge strength, Dr. Robb's team can quantify volumetric bone mineral density and calculate associated bio-mechanical parameters for assessing fracture risk as related to age, gender and hormonal levels. "We can model a patient's specific 3D scan information and compute the fracture risk," Dr. Robb says.
Another diagnostic tool is computer simulations of various types of falls. Dr. Khosla is working with bio-mechanical specialists at Mayo to create these simulations, which can help researchers determine precisely how bones break. "If you can better understand that, then maybe you can understand what kinds of treatments need to be targeted for specific weaknesses in bone," Dr. Khosla says.
Collaboration between engineers and clinicians is common at Mayo. "It's exciting to be a research scientist or engineer working at Mayo," Dr. Robb says. "There's just this natural opportunity to interact with physicians and surgeons in building solutions we're mutually interested in. Underneath all this patient care is a lot of fundamental science and engineering."
Indeed, the list of Dr. Khosla's research colleagues reads like a directory of scientific and medical departments: biomedical engineering, bio-mechanics, cell biology and radiology, to name just a few. "If you enjoy doing what I do, which is looking at a question like osteoporosis at many different levels, you just don't have the skill set to do it all. No single person does," Dr. Khosla says. He is quick to credit the young researchers who run his lab on a daily basis, allowing him time to treat patients and supervise the lab's numerous projects.
For Dr. Khosla, the dual roles of clinician and researcher are inseparable. "I very much enjoy seeing patients. That's why I became a physician," he says. In addition, "that interaction is absolutely critical for my research. It keeps me in tune with the current clinical issues.
"That's also what makes working at Mayo fun," he adds. "The environment is very difficult to replicate. There's no place else I can work as effectively as I do it here."
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