On the road from clinical need to effective therapy, osteoporosis has come a long way.
“When I jointed Mayo in 1988, I could offer calcium, vitamin D, estrogen,” says Sundeep Khosla, M.D., “and that was pretty much it.”
Clinician, Researcher, Leader
Dr. Khosla is a practicing endocrinologist at Mayo Clinic, as well as the Dr. Francis Chucker and Nathan Landow research professor of medicine and physiology, a Mayo Foundation distinguished investigator, the director of the Center for Clinical and Translational Science, and dean for Clinical and Translational Science at Mayo Clinic.
He is also one of the top experts in the world on osteoporosis, and a past president of the American Society for Bone and Mineral Research (ASBMR). Dr. Khosla will present the Louis V. Avioli Lecture to the organization’s conference attendees on September 17. Dr. Avioli was ASBMR’s first president in 1978 and speakers chosen for this plenary talk are society members who have made notable lifetime contributions to the field. The ASBMR is an international organization that leads the field of bone and mineral metabolism.
“It’s a huge honor to be giving this lecture,” says Dr. Khosla. “Everyone attends and it’s a chance to stand before your colleagues and really in my case, highlight key aspects of decades of work.”
In his talk, Dr. Khosla will highlight three areas that capture the essence of the breadth and width of his work, and point toward new therapeutic directions for osteoporosis patients.
“The osteoporosis field over the past 25-plus years is really a great example of how a better understanding of the fundamental biology drives new therapeutics,” says Dr. Khosla, “and it continues today.”
Estrogen Effects in Men
Take estrogen for example. While estrogen’s role in bone metabolism is well-known for women, only in the last 16 years was it recognized as a bone regulator in men. “It was all testosterone,” says Dr. Khosla. But studies from Dr. Khosla’s group and others found that estrogen was a better predictor of fracture risk and provided a stronger link to bone density in men than testosterone. These findings were especially important for prostate cancer patients taking medication to block tumor-feeding testosterone, a type of androgen.
“I see [prostate cancer] patients who urologists treat with androgen-deprivation therapy getting fractures,” says Dr. Khosla. “These patients are living longer and longer, and they’re beginning to actually suffer fractures and diabetes and other complications from the treatment.”
That, according to Dr. Khosla, should spur the field to think about new approaches, like using very low doses of estrogen to offset the effects of therapy on some prostate cancer patients. But he says, “we haven’t harnessed that thinking as of yet.”
Directing the Conversation between Bone Cells
Other avenues of treatment may also exist in the cross-talk between osteoclasts and osteoblasts, cells responsible for bone breakdown and bone formation, respectively. In collaboration with Merry Jo Oursler, Ph.D., Dr. Khosla began examining the communication between these types of cells.
What they found according to Dr. Khosla, demonstrates that osteoclasts signal to the osteoblasts that form bone and stimulate those cells in a process called coupling. This osteoclast-osteoblast coupling provided a new option for drug intervention and led to the development of an early prototype drug. But, Dr. Khosla says, “there may be opportunities there for other novel therapeutics that really take advantage of these concepts.”
From osteoclast-osteoblast coupling, Drs. Oursler and Khosla became more interested in aging research as they examined how this cell-to-cell communication could be derailed by aging. “That really focused our efforts much more on fundamental aging mechanisms in bone,” says Dr. Khosla. “So more recently we’ve gotten into the whole field of cell senescence in bone.”
Role of Senescent Cells in Osteoporosis
Cell senescence is the name for cells in the body that are not functioning properly and lapse into a state of dormancy. These cells, although unable to divide, can drive chronic inflammation and tissue dysfunction linked to aging and chronic disease. Currently several groups, including Mayo Clinic, are investigating novel therapeutics to kill senescent cells in different tissues. Dr. Khosla and his team worked with James L. Kirkland, M.D., Ph.D, director of the Robert and Arelene Kogod Center on Aging to investigate this therapeutic opportunity.
“Our work,” says Dr. Khosla, “suggests that these drugs may also have beneficial skeletal effects, so that’s particularly exciting because you could then develop a class of drugs that treats not only osteoporosis but multiple aging comorbidities like muscle loss, cardiovascular function, and prevention of cataracts.”
Experts, Working Together
It has been, Dr. Khosla says, a logical progression starting with the unmet needs of the patients he sees in practice, to questions one phase of research raised that required new tools, and then answers that led Dr. Khosla’ s team in new directions and to new partnerships.
“Having the right teams around you can allow you to ask questions in much greater depth and breadth than if you were working more in isolation,” says Dr. Khosla. “The Mayo environment is particularly conducive to this.”
– Sara Tiner