BA9 - Biochemical antecedents of fracture in minority women

Investigator Names and Contact Information

Jane Cauley (jcauley@pitt.edu)

Introduction/Intent

This study will examine risk markers for fracture in groups of minority and white women. This study will be the first comprehensive investigation of biochemical factors leading to fracture in minority women. The results promise to explain differences in fracture rates and to help target prevention strategies.

The recently released Surgeon General’s Report on Bone Health and Osteoporosis noted that one in two American’s over age 50 will be at risk for fractures from osteoporosis (1). Although fracture rates are lower among non-white women (2-4), the report emphasizes that osteoporosis is a real risk for any aging women and noted an area of particular concern regarding the lack of information on ethnic and racial minorities. The consequences of fracture may be greater among minority populations. Ethnic variation in fractures cannot be explained by differences in bone mineral density (BMD) alone or clinical risk factors. The factors that underlie these ethnic variations in fracture remain poorly defined.

The goal of the proposed project is to improve our understanding of the biochemical factors that predict the risk of fracture in minority women and to test whether these biochemical factors are independent of other risk factors such as body weight, smoking, and physical activity. We will test whether these risk factors contribute to ethnic differences in fracture. Closing the gap between what is known about osteoporosis in minority women and effective prevention will not be possible without a better understanding of the risk factors and biochemical measures that predict fractures in minority women. The long range goal is to develop a set of risk factors that may help to identify minority women at high risk of fracture who could be targeted for screening and intervention.

Hypotheses: We are proposing to measure serum sex steroid, growth, and calciotropic hormones, bone turnover, renal function, pro-inflammatory cytokines, and osteoprotegrin to test several hypotheses about the etiology of fractures in minority women. The specific hypotheses to be addressed in this study are:

1. A greater risk of fracture will be associated with:
   • a. Lower concentrations of serum estradiol and testosterone;
   • b. Lower concentrations of insulin like growth factor – (IGF);
   • c. Greater bone turnover as measured by markers of bone formation, serum aminoterminal pro-collagen extension propeptide, (PINP) and bone resorption, serum c-terminal telopeptide of type 1 collagen, (CTx);
   • d. Lower Vitamin D nutritional status as measured by circulating 25(OH)D3;
   • e. Higher levels of intact parathyroid hormone (iPTH);
   • f. Greater levels of the pro-inflammatory cytokines: Tumor necrosis Factor –  Soluble Receptor I and II (TNF-sRI and II) and interleukin -6 soluble receptor (IL-6sR);
   • g. Lower levels of Osteoprotegrin (OPG);
   • h. Decreased renal function as assessed by higher serum levels of cystatin – c.
2. These associations will be independent of other risk factors such as age, physical activity, body weight.
3. Ethnic differences in fracture rates will be in part mediated by ethnic differences in these biochemical factors.

A1.2 Exploratory hypothesis

1. Low levels of estradiol lead to an increased risk of fracture because of the inability to oppose the action of the pro-inflammatory cytokines on bone turnover. In these models, we will examine the joint effect of estradiol, inflammatory cytokines and bone turnover on the risk of fracture. We hypothesize that inclusion of estradiol in the model will attenuate the association between cytokines and bone turnover to fracture risk.
2. Higher estradiol levels among Black and Hispanic women compensates for their low 25(OH)D and higher PTH levels.
3. Impairment of renal function results in an increase in fracture partially because of its’ effect on Vitamin D metabolism and the increase in inflammatory markers associated with renal impairment.
4. Low levels of IGF are associated with an increase in fracture because of low concentrations of sex steroid hormones.
5. The association between Vitamin D insufficiency and higher serum PTH with fractures is mediated in part by the occurrence of falls and physical activity.

A1.3 Specific Aims

1. To identify a set of biochemical factors that predict the occurrence of fracture in multi-ethnic postmenopausal women;
2. To determine whether the biochemical factors associated with fractures differs across ethnicity;
3. To test whether these associations are independent of clinical risk factors;
4. To determine if these biochemical factors contribute to ethnic differences in fracture.

Results/Findings

See Publications: 841, 863, 945. For a complete, up-to-date list of WHI papers related to this ancillary study, please use the searchable Papers section of this website.

References

1 - U.S. Department of Health and Human Services. Bone Health and Osteoporosis: A Report of the Surgeon General. Rockville, MD: U.S. Department of Health and Human Services, Office of the Surgeon General, 2004.

2 - Farmer ME, White LR, Brody JA, Bailey KR. Race and sex differences in hip fracture incidence. Am J Public Health 1984;74:1374-80.

3 - Baron J, Karagas M, Barrett J, Kniffen W, Malenka D, Mayor M, et al. Basic epidemiology of fractures of the upper and lower limb among Americans over 65 years of age. Epidemiology 1996;7:612-8.

4 - Baron JA, Barrett J, Malenka D, Fisher E, Kniffin W, Bubolz T, et al. Racial differences in fracture risk. Epidemiology 1994;5:42-7