AS181 - Estradiol, Cytokines, and Bone Turnover – Effects on Fracture

This page provides study documentation for AS181. For description of the specimen results, see Specimen Results Description (open to public). Data sets of the specimen results are included in the existing WHI datasets located on the WHI Data on this site (sign in and a completed Data Distribution Agreement are required; see details on the Data site).

Investigator Names and Contact Information

Jane A. Cauley, DrPH, Dept. of Epidemiology, University of Pittsburgh


Osteoporosis is a major public health problem that over a lifetime results in fractures in 40% of aging women.  Hip fracture is a main endpoint in WHI and is the most important manifestation of osteoporosis.  Hip fractures are one of the most important causes of disability and death in older women.  Estrogen deficiency is a major cause of osteoporosis.  The mediators of the effects of estrogen are unclear, but recent research suggests that pro-inflammatory cytokines play a major role.  In preliminary analyses, we found that men and women enrolled in the Health, Aging and Body Composition (HABC) study who have the highest cytokine soluble receptor levels experience almost a twofold faster rate of bone loss and are at a 60-70% increased likelihood of experiencing a fracture in comparison to participants with lower cytokine soluble receptor concentrations.  In the current proposal, we plan to confirm these findings, to extend them to include two novel cytokines and to test whether increased bone turnover predicts hip fracture.  Our goal is to substantially improve our understanding of the hormonal factors and the paracrine mediators that contribute to hip fracture in older women.

As part of the WHI-OS Hip Fracture Umbrella Study, we have received funding to test several important hypotheses concerning the hormonal and genetic causes of hip fracture in older women (Steven R. Cummings, Principal Investigator).  Specifically, we will test the hypothesis that postmenopausal women with very low baseline concentrations of total and bioavailable estradiol, high levels of sex hormone binding globulin (SHBG), and low levels of insulin like growth factor (IGF-1) are at an increased risk of hip fracture.  In addition, we are testing the hypothesis that specific polymorphisms of several genes are associated with an increased risk of hip fracture.  These studies are being carried out in the WHI-OS using a nested case-control approach.  A total of 400 women with hip fracture will be compared to 400 matched controls. 

As part of this WHI-OS Blood Competition, we are proposing to use additional serum in these same cases and controls to test several additional hypotheses.  We propose to use an additional 0.75 ml of stored serum to measure bone turnover, cytokine soluble receptors, and two recently discovered cytokines that form the essential pathway through which osteoblast (bone forming cells) precursors direct osteoclast (bone resorption cells) development. 


1.     Women with the greatest cytokine soluble receptor levels will have an increased risk of subsequent hip fracture.

2.     Women with very low baseline concentrations of osteoprotegerin (OPG) will have an increased risk of hip fracture.

3.     Women with high levels of RANKL (receptor activator of NF-Kappa B ligand) will have increased risk of subsequent fracture. 

4.     It is possible that the balance between the stimulator of osteoclastgenesis, RANKL, and of the inhibitor, OPG, will determine the effects on hip fracture.  Therefore, we will also test the hypothesis that the ratio of OPG to RANKL is an important predictor of hip fracture.

5.     Women with increased bone turnover at baseline will have an increased risk of fracture.  We propose to measure serum aminoterminal procollagen extension propetide (PINP) as a marker of bone formation and serum C-terminal telopeptide of type I collagen (CTx) as a marker of bone resorption. It’s possible that the balance between bone formation and bone resorption predicts hip fracture.  Therefore, we will form an “uncoupling” index (PINP/CTx) and test whether this is related to hip fracture. 

6.     The link between low estradiol and an increased rate of bone turnover and risk of hip fracture will be mediated by cytokine soluble receptors, OPG and RANKL. 


Some of the publications related to this ancillary study are: 

Ms634 - Cauley JA, LaCroix AZ, Wu L, Horwitz M, Danielson ME, Bauer DC, Lee JS, Jackson RD, Robbins JA, Wu C, Stanczyk FZ, LeBoff MS, Wactawski-Wende J, Sarto G, Ockene J, Cummings SR. Serum 25 hydroxyvitamin D concentrations and the risk of hip fractures: The Women's Health Initiative. Ann Intern Med. 2008 Aug;149(4):242-50.

Ms714 - Barbour KE, Boudreau R, Danielson ME, Youk AO, Wactawski-Wende J, Greep NC, Lacroix AZ, Jackson RD, Wallace RB, Bauer DC, Allison MA, Cauley JA. J Bone Miner Res. Inflammatory markers and  risk of hip fracture: The Women’s Health Initiative. 2012 Jan 27. [Epub ahead of print]

Ms878 - Eaton CB, Young A, Allison MA, Robinson J, Martin LW, Kuller LH, Johnson KC, Curb JD, Van Horn L, McTiernan A, Liu S, and Manson JE. Prospective association of vitamin D concentrations with mortality in postmenopausal women: results from the Women's Health Initiative (WHI). Am J Clin Nutr. 2011 Oct 26. [Epub ahead of print]

Ms910 - Robinson JG, Manson JE, Larson J, Liu S, Song Y, Howard BV, Phillips L, Shikany JM, Allison M, Curb JD, Johnson KC, Watts N. Lack of association between 25(OH)D levels and incident type 2 diabetes in older women. Diabetes Care. 2011 Feb 2. [Epub ahead of print]

For a complete, up-to-date list of WHI papers related to this ancillary study, please use the searchable Bibliography section of this website. To search for papers by study number, access the Simple Search, and enter the study number in the “Related Studies” field.