Jane A. Cauley, DrPH

I am the Clinical Site Principal Investigator of the Study of Osteoporotic Fractures (SOF) and the Osteoporotic Fractures in Men Study (MrOS), both large epidemiologic cohort studies designed to identify risk factors for fractures. These studies have had a major impact on the identification of women and men at high risk of fractures. The current clinical recommendation to use both clinical risk factors and BMD (see National Osteoporosis Foundation at www.http://nof.org) is in a large part based on prospective studies like SOF and MrOS. I have led large omnibus papers examining the correlates of both areal (DXA) and volumetric BMD in older men. I extended these studies to both men and women of African descent. I have published on risk factors for fracture in men of African descent and risk factors for the severity and type of fracture. I led a paper showing that lumbar spine BMD (but not hip BMD) and bone resorption markers (but not bone formation maker) measured pre-menopausally predicted fracture over the menopausal transition. I have also a major interest in the role that inflammation plays in fracture risk. I have also examined several lifestyle factors and risk of fractures. In MrOS, I showed that while self-reported physical activity was unrelated to hip fractures in men, objectively measured activity was indeed related both to falls and fractures. This work has improved our understanding of risk factors for fracture in older and mid- life women, in older men, in women across multiple ethnicities and in men of Afro-Caribbean descent.

I have had a major interest in improving our understanding of factors that underlie the 240-fold difference in hip fracture rates worldwide. I published an invited review on the geographic and ethnic disparities in osteoporotic fractures in Nature Endocrinology (2014). I served as Chair of the International Osteoporosis Foundation (IOF) review of the World Health Organization fracture risk assessment tool (FRAX). I also served on the Endocrine’s Society Task Force on Disparities in Endocrine Disorders: Biological and Clinical Differences (2014). I was the first to publish on the degree to which black/white differences in bone mineral density (BMD) is a function of differences in sex steroid hormones. I expanded my comparisons to include measures of hip geometry and bone quality as assessed by ultrasound. I was one of the first to compare hip geometry in US White and US Black women with women from West Africa. These studies demonstrated that the 50% lower risk of fracture among Blacks was not only due to higher bone density but also due to other important geometric and bone quality differences. I expanded my studies to a large population of Afro-Caribbean men and women, all with 100% African ancestry. I showed that the BMD of the Tobago men and women were one standard deviation higher than the BMD of African Americans, perhaps reflecting European admixture in US Blacks. Most of the studies of risk factors for fracture come from studies of Whites. I was one of the first to further examine these risk factors in non-White women and men. I was one of the first to show that despite the lower relative risk of fractures in Blacks, Hispanics and Asians, the absolute number of fractures exceeds the combined number of incident cases of myocardial infarction, breast cancer and stroke in women of all race/ethnicities. This finding emphasizes the growing public health impact of osteoporotic fractures across all racial groups. Finally, I have explored several factors that could underlie these race/ethnic differences including sex steroids, genetic factors, muscle, muscle fat infiltration, falls, adipose tissue, vitamin D and general determinants. This research has made significant contribution to our understanding of race/ethnic differences in fracture.

Another major thrust of my research has focused on the role of endogenous and exogenous hormones in multiple chronic diseases including osteoporosis, breast, and endometrial cancer, osteoarthritis and cognitive and physical functioning. I was the first to hypothesize that BMD could be used as a biological measure of a woman’s lifetime exposure to estrogen. I showed prospectively that indeed, women with higher BMD have an increased risk of breast cancer and that this varied by family history and stage of disease. I published several papers on sex steroid hormones and their metabolites and the risk of breast cancer. I am part of an ongoing collaborative group from Oxford that pulled many cohort studies to further examine the association between endogenous hormones, obesity and breast cancer. I have also been a co-author of several manuscripts examining the risk of breast cancer from exogenous estrogen therapy and testosterone therapy. A major thrust of my research on endogenous and exogenous hormones has focused on osteoporosis. I have studied the relationship between circulating estrogen levels and BMD. I was one of the first to publish on this association in both Black women and White women. In my 1988 JAMA paper, I showed that a lifetime of adequate calcium coupled with adequate levels of serum estrogens could maximize bone density after menopause. I have also shown that sex steroid hormones are predictors of fractures. One of my most highly cited papers was an in depth analysis of hormone replacement therapy and fracture from SOF. I further examined the timing of the estrogen replacement therapy for optimal osteoporosis prevention. I led several papers on exogenous estrogen and fracture from major trials including the Heart Estrogen and Progestin Study (HERS) and the WHI. I also showed that the reduction in fracture observed with hormone treatment in the WHI was independent of baseline estradiol levels and lean mass. My studies of circulating sex steroids, BMD and fracture also extend to men. I showed in the MrOS Study that serum estradiol was associated with higher BMD and slower bone loss, which is partially explained by weight loss. Although men with low testosterone were more likely to have osteoporosis, there was little association between testosterone and BMD and bone loss. Through my work on the Study of Women’s Health Across the Nation (SWAN), I have advanced the study of the menopausal transition.  Finally, I was PI of the Testosterone Trial at the University of Pittsburgh and Chair, Recruitment Committee.  I am an active member of the T Trial Steering, Bone, Physical Function and Publications Committees.

Another theme of my research is a focus on the health outcomes of calcium and vitamin D supplementation and the association between circulating vitamin D levels and diverse outcomes in older men and women. The WHI Calcium Vitamin D (CaD) Supplementation trial was designed to test the primary hypothesis that the CaD supplementation could prevent hip fractures. I served as the chair/co-chair of the CaD Osteoporosis working group for the entire duration of the trial. I led the 5-year extension paper of the CaD trial and showed that over the entire 11-year study, CaD reduced vertebral fractures. I was also part of a meta-analysis published in NEJM which showed that an intake >800 IU vitamin D prevents hip fracture. A major thrust of my research has also been on circulating levels of 25 hydroxyvitamin D 25(OH)D, the primary marker of vitamin D nutritional status. My publications showed that men and women with 25(OH)D <20 ng/ml have an increased risk of hip fracture. These findings contributed to the recent Institute of Medicine (IOM) conclusion that maintaining a vitamin D level >20 ng/ml will improve skeletal health. It is well established that Blacks have lower 25(OH)D levels than Whites and are more likely to be vitamin D deficient. Yet, most of the studies of “optimal” 25(OH)D levels have been carried out in Whites. I showed that Black women with higher levels of 25(OH)D have an increased risk of fractures suggesting that the “optimal” level may vary by race. Further information on whether the association between 25(OH)D and skeletal health differs by race is needed.