California Pacific Currents 2003
Excellence in Research from Osteoporosis to Breast Cancer: California Pacific Recruits Steve Cummings, MD
Steven R. Cummings, MD, FACP, an internationally recognized expert on the epidemiology of osteoporosis and fractures, joined the ranks of researchers at California Pacific Medical Center in July 2003. Dr. Cummings has also begun work on his latest initiative, the Centers of Research in Clinical Excellence (CRCLE). These innovative, state-of-the-art programs are designed to advance the way in which the research community derives, assesses, and applies clinical data to enhance patient care.
Making Headway in Osteoporosis and Its Outcomes
“You recruited Steve Cummings? That’s a huge accomplishment,” says Stephen I. Katz, MD, PhD, Director of National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS). “Many institutions have tried to lure him over the years and failed. California Pacific is very fortunate.” Dr. Cummings’ work has focused largely on highly prevalent diseases such as osteoporosis and certain cancers affecting millions. For example, approximately eight million postmenopausal women, or roughly one in four, suffer from osteoporosis. An additional 22 million have osteopenia, a condition of low bone mass that places them at risk of fractures. By 2010, this number is expected to climb to an estimated 35 million. In particularly vulnerable or weakened individuals, a fracture can have far greater consequences than just the broken bone; hip fractures in the elderly can be a precipitating factor in the loss of life.
Menopause is the common signpost of changes in a woman’s physiology that can lead to osteoporosis. Long regarded as a “silent disease,” the first indication of brittle bones is often a fracture. And while the disease can be substantially ameliorated through intervention, osteoporosis has long presented a diagnostic challenge in terms of determining which women will be at the greatest risk of developing it.
Understanding that the waiting game, however, could increase morbidity and endanger lives, Dr. Cummings designed an ambitious study to correlate bone mass and fracture incidence among nearly 10,000 women over a 15-year period. Termed The Study of Osteoporotic Fractures, this work revealed that bone density in the hip can reliably predict a woman’s risk of future fractures. This information, coupled with effective treatments to retard bone loss and a major national campaign to encourage osteoporosis screening, provided a sound foundation to begin to change the course of osteoporosis in our society. Dr. Cummings has also been a principal investigator and played a major role in the design of clinical trials for two drugs, alendronate (Fosamax®) and raloxifene (Evista®), now used widely in the reduction of risk of fractures.
The Mr. OS Study
Men typically have greater bone mass than women, which helps protect them against brittle bones. Osteoporosis is not just a women’s disease, however, and as lifespan extends it becomes a concern for men as well. One of eight, or two million, American men of advanced age suffers from osteoporosis and one-third of hip fractures occur in men. In addition, a number of conditions that affect younger men (and women), such as bone cancer and impaired bone metabolism due to chronic glucosteroid treatment, require pharmacological intervention to offset the dangerous compromise to bone mass.
To explore the risk factors involved in osteoporosis and older men, the National Institutes of Health is funding the Mr. OS Study, which includes 6,000 older men. The object of this seven-year study-in-progress is to determine the extent to which the risk of fracture in men is related to bone mass and structure, biochemistry, lifestyle, tendency to fall, and other factors. The study, in which Dr. Cummings is a principal investigator, will also attempt to determine if bone mass is associated with an increased risk of prostate cancer.
The Role of Estrogen in Bone Health and Breast Cancer
Dr. Cummings’ research findings have indicated that higher estrogen levels are associated with a lower risk of fracture; this helps confirm that estrogen has a definite influence on bone health. Here’s how that influence plays out: Despite its appearance, bone is a highly dynamic organ, constantly undergoing a process called remodeling. As bone remodels, calcified deposits of microscopic sections of old or damaged bone are digested by specialized enzymes and re-sculpted with fresh bone mineral. Estrogen helps ensure that degraded bone is replaced with an equal amount of new bone. The decline of estrogens at menopause can consequently lead to a dwindling mass of healthy, strong bone.
Some estrogen-like synthetic molecules, collectively called SERMs (selective estrogen receptor modulators), have long been studied for their bone-building properties. These drugs showed promise as a potential means to prevent bone loss in postmenopausal women. However, it is known that, while estrogen and certain SERMs were beneficial for bone, they could potentially contribute to certain reproductive cancers.
With osteoporosis prevention still a priority, Dr. Cummings began to asses the risk factors that lead to breast cancer. He explains, “In osteoporosis, we have made headway with diagnosis and treatment of the disease. We are now looking at ways to combine current treatments to cure the disease, while providing education on the importance of osteoporosis screening to identify those at risk. In breast cancer, we have the challenge of needing to develop reliable predictive tests, as well as efficacious interventions.” Dr. Cummings is encouraged by the expansion of available drugs that help prevent breast cancer. “The introduction of agents that decrease the amount of estrogen stimulation are important developments in reducing the risk of first or recurrent breast cancer. The challenge remains, however, to better identify the women who are at risk and in need of these preventive options.”
With support of the Daniel and Phyllis Da Costa Fund, generous donors whose trust left money to support research in the US and the UK, Dr. Cummings will further this work at California Pacific. He will be collaborating with researchers at the Royal Marsden Hospital in London, whose mission is to find ways to identify women at high risk for breast cancer. Together, the two institutions plan to develop new methods that can predict a woman’s chance of developing the disease, as well as learn about potential means for prevention.
While Dr. Cummings has been repeatedly honored for his highly intuitive and excellent research, he is quick to acknowledge the contribution of others. “The best clinical research is collaborative,” he notes. “I have worked, and will continue to work, with clinical researchers throughout the Bay Area and the global research community with the hope of creating strong collaborative bridges among institutions.” For example, for two decades prior to joining California Pacific, Dr. Cummings periodically combined efforts with California Pacific’s Warren Browner, MD, MPH, Scientific Director of the Research Institute and Vice President Academic Affairs. “My long-standing relationship with Dr. Cummings has been a productive one,” says Dr. Browner. “We see eye-to-eye on many things, including research directions of interest and the importance of well-designed clinical research. I was fortunate to have Dr. Cummings as a mentor in the early stages of my career and to have worked with him on an ongoing basis.”
Most recently, the two researchers have set their sights on defining the association between certain novel proteins and disorders such as diabetes and cardiovascular disease. Osteoprotegerin, for example, is a hormone involved in digesting the calcium-containing mineral of old bone in need of repair. Could this protein also be involved with, or a marker of, vascular calcification, a process that leads to hardening of the arteries and cardiovascular mortality? The investigators are designing studies to find out.
Drs. Cummings and Browner are also involved in The Longevity Consortium, an ambitious international collaboration designed to uncover genes that influence how long one might live. Knowledge gained from research on mice and simple organisms, such as worms, will be integrated with data from nearly 100,000 older men and women. Genetic determinants of metabolism, inflammatory responses, resistance to cell stressors, and other factors that contribute to longevity will be analyzed.
Coming Full CRCLE
Dr. Cummings’ initiative, California Pacific’s new Centers of Research in Clinical Excellence (CRCLE), is designed to help pave the way for hard-won clinical results to be translated into everyday patient care. He also hopes that CRCLE will accelerate advances in clinical trial design and serve as a prototype for other such projects. “Clinical investigators at California Pacific share my vision of a strong program of clinical research,” says Dr. Cummings. “The large and high-quality clinical programs being developed and implemented here are a strong foundation on which to build state-of-the-art clinical and translational research.”
And such a foundation firmly supports the goals that Dr. Cummings feels strongly about and works to attain. “I care deeply about prevention and limiting the toll of breast cancer and fractures. I also care about helping other researchers achieve all that they envision in their own clinical work. I believe that we are making headway but I always feel that there is something more that I can—and should—be accomplishing before the end of the day.”
Through the concerted efforts of Dr. Cummings and other scientists, great strides have been made in preventing and treating two major diseases of our time—osteoporosis and breast cancer. No doubt, programs such as CRCLE will help convert the findings of past and future research into improved medical care. “We are thrilled to have someone of Dr. Cummings’ caliber join California Pacific at the helm of the CRCLE program,” adds Dr. Browner. “CRCLE will enable California Pacific to couple state-of-the-art clinical care with advanced information gathering to the benefit of our patients.”