Spin-Off Studies from Historic Women's Health Initiative Address Myriad Diverse Conditions in Men and Women

BUFFALO, NY - When University at Buffalo researchers began recruiting women to participate in the three-pronged Women's Health Initiative (WHI) national clinical trial in 1993, the relationship of gum disease to osteoporosis was not one of the questions they were seeking to answer.

In the "one-thing-leads-to-another" nature of scientific research, however, UB's WHI Clinical Vanguard Center has conducted a series of studies, funded for a total of $3 million dollars, on the link between the two. UB also is taking part in trials on the effect of estrogen on memory, Alzheimer's disease and macular degeneration and a study of benign breast disease, all of which are direct spin-offs of the original initiative.

Hundreds of like projects are underway at WHI clinical sites across the country, spawned in whole or in part by the 12-year, $625 million initiative funded by the National Institutes of Health. WHI is the largest clinical trial ever undertaken in the U.S. Approximately 162,000 women are enrolled at 40 centers across the U.S., including 4,000 in Buffalo.

Historically, clinical trials have been conducted on men only. As a result, treatments tested exclusively on men were prescribed for women without evidence that they would receive the same benefit.

The goal of WHI is to gather essential clinical data on the major diseases affecting women, using women as subjects. With that mission in mind, researchers set out to determine, once-and-for-all, if a women's risk of developing coronary heart disease, breast and colon cancer, and osteoporosis could be lowered through three particular interventions: hormone replacement (estrogen alone or with progesterone), vitamin D and calcium supplementation, or a low fat diet.

Myriad ancillary studies, meanwhile, are addressing questions that weren't even being asked in 1993.

"This is one of the legacies of WHI," said Jean Wactawski-Wende, Ph.D., co-director with Maurizio Trevisan, M.D., of UB's WHI Vanguard Center. (Fifteen of the 40 clinical centers were

designated Vanguard Centers and helped to plan the trial and establish the protocols.)

"With comprehensive health data on 162,000 women, we have an invaluable mine of information to use to advance public health," she said. "I think we'll be learning from it for 50 years."

UB's interest in the link between oral health and osteoporosis dates to the early 1990s. Researchers in the Department of Oral Biology in the UB School of Dental Medicine in 1995 reported results of a pilot study showing that women with increasing levels of periodontal disease showed corresponding loses of bone mineral density. That study, supported in part by the U.S. Public Health Service, led to a $750,000 grant from the U.S. Army to investigate this link in UB participants enrolled in one arm of the WHI study.

Based on those findings, which duplicated the pilot study results, UB received $2 million this summer from the National Institute of Dental Research to follow the women for four more years and document any gum disease-osteoporosis link.

Having a periodontal-disease clinic in place for this WHI spin-off study provided the opportunity for UB researchers to move forward quickly on another major investigation: the link between periodontal disease and heart disease.

Trevisan and co-principal investigator Robert J. Genco, D.D.S., Ph.D., UB vice provost and SUNY Distinguished Professor in the UB Department of Oral Biology, received $7 million from the National Institute of Dental and Craniofacial Research last October to plan and conduct a pilot study to determine if treating periodontal disease in patients who have had one heart attack will prevent a second.

Genco was one of the first scientists to show a connection between inflammation from periodontal disease and heart disease. He has been working for several years to further elucidate this connection and identify the particular oral pathogens involved in inflammation in the blood vessels. Inflammation now is considered an important cause of heart disease and research is progressing in this area on several fronts.

Perhaps the richest WHI vein available to be mined is the data bank of blood samples taken from all 162,000 participants at the start of the initiative. As various conditions and diseases develop in participants, these blood samples can be scanned for signal cues, or disease "markers," that could form the basis for future screening tests designed to catch diseases in the very early stages.

In one study, UB's Trevisan and another group of WHI investigators led by Paul Ridker, M.D., of Harvard University Medical School, are analyzing the samples of WHI participants who develop cardiovascular disease, looking for such clues. This research will help detect blood markers that can be used to identify people who are at risk of having a heart attack before any symptoms develop.

UB researchers and scientists at additional WHI clinical sites also are studying CA 125, a blood marker for ovarian cancer, using this large database.

The collection of blood samples could lead to the discovery of currently unknown disease markers and new methods of early identification for a wide variety of conditions, Trevisan said. "The fact that we can wait for a disease to show up and then look for clues in the specimens already collected and stored in the WHI blood-sample bank will give us better and quicker ways to identify disease markers," he said.

The studies of estrogen replacement and its relationship to Alzheimer's disease and macular degeneration are being carried out at UB and several other WHI clinical centers in participants over the age of 65. Even though the estrogen/progesterone arm of the trial has been halted, these women will continue to be followed to determine if hormone replacement was beneficial in preventing dementia or vision loss.

Women in the estrogen-alone arm of that trial, which was not halted, will continue their participation as scheduled. Results of those trials will begin to be released when the WHI ends in 2005.

Benign breast disease is the subject of yet another WHI spin-off study involving women in the low-fat-diet and hormone-replacement arms of the trial. UB and others are carrying out this research under contract with the Albert Einstein College of Medicine.

Certain forms of benign breast disease are thought to be precursors of breast cancer. Analyzing breast-tissue biopsies from participating women will allow researchers to catalog different types of benign disease and determine which types lead most frequently to malignancy.

"By following women on and off hormones and on and off a low fat diet, we will get a better sense of how cancer risk is enhanced in women with benign breast disease and if certain types of benign breast disease occur more often than others," said Wactawski-Wende.

As the end of the initial WHI trial approaches, UB and other WHI clinical centers will be applying for additional grants to follow participants into the future.

"The idea is to keep a data stream going," Wactawski-Wende said. "The intention is to keep the cohort together. I look at this as a life-span study. There is so much data, people will be analyzing it and learning from it for years. "