W9 - Biological markers of the effect of HT on risk of fractures in the Women's Health Initiative clinical trial

Investigator Names and Contact Information

Introduction/Intent

The primary objective of this project is to determine whether the effect of HT on risk of fracture depends on levels of sex hormones, bone turnover, or genetic markers of sex hormone metabolism and action before treatment. We also propose to test the hypothesis that women who experience the greatest reductions in bone turnover with HT will experience fewer fractures. To test these hypotheses, we propose that serum and DNA from the baseline exam be allocated for measurement of total estradiol (E2), bioavailable estradiol (or E2/SHBG), and 2 markers of bone turnover, a marker of resportion, C-Terminal cross linked (S-CTx) Teleopetide of Type I Collagen and a marker of bone formation, either N-terminal propetide (PINP) or bone specific alkaline phosphatase (bone ALP), and single nucleotide polymorphisms in 20 estrogen and progestin related genes

Aim 1: To test the hypothesis that women with the lowest serum levels of estradiol and bioavailable estradiol (or E2/SHBG) at baseline have the greatest decrease fracture risk during treatment with hormone therapy.

Aim 2: To test the hypothesis that women with the highest bone turnover at baseline will have the greatest reduction in fracture risk with hormone therapy.

Aim 3: To test the hypotheses that the women who experience the largest decrease in bone turnover (baseline to year 1) with hormone therapy experience the greatest decrease in fracture risk.

Aim 4: To test the hypothesis that allelic variation in genes related to estrogen and progestin metabolism and action identifies women who derive the greatest reduction in fracture risk during hormone therapy.

Several prospective studies have shown that serum estradiol and testosterone predict the risk of hip and vertebral fractures. In SOF, women with the highest estradiol had 50% lower risk of hip and 70% lower risk of vertebral fractures.(1) This association was independent of age, obesity and other risk factors for fracture. Obese women may have a lower risk of fracture because of their higher endogenous estrogen levels (2). In the E+P trial, there was some suggestion that the major effect of HT on fracture was primarily observed in women with a BMI <30.0 but the interaction was not statistically significant. We hypothesize that women with lower estradiol at baseline are at an increased risk of fracture and will experience the greatest decrease in fracture.

The efficacy of anti-resorptive therapy on fractures cannot be explained by changes in BMD. It has been estimated that < 20% of the observed fracture reduction is attributed to increases in BMD.(3) Riggs and Melton have suggested that much of the anti-fracture effect of anti-resorptive drugs results from normalization of the high level of bone turnover and thus prevention of further microdamage.(4) They also suggest that there may be different thresholds of decline of bone turnover that are required to reduce vertebral fractures (more trabecular bone) than hip fractures (more cortical bone).

In the Fracture Intervention Trial, greater reductions in bone turnover with alendronate therapy were independently related to a reduced risk of hip, vertebral and all non-spine fractures (5).

There is also convincing evidence of a powerful genetic influence on bone metabolism and fracture(6) and small preliminary studies suggest that polymorphisms in estrogen metabolism genes may contribute in part to bone health and the anti-fracture efficacy of hormone therapy. For example, we recently determined the association between estrogen receptor " (ESR1) genotype (XbaI) and bone mineral density (BMD) among postmenopausal participants in our Healthy Women Study.(7) We found no significant overall association between estrogen receptor " genotype and hip BMD. However, estrogen receptor " +/+ genotype was associated with 11% greater bone mass among women on hormone replacement (P=0.01 for hormone x genotype interaction). Other studies have confirmed these interactions.(8) {Salmen, 2000 #15652} Other recent small studies have also shown that estrogen receptor " genotype may predict the anti-fracture efficacy of hormone therapy.(9) We propose to further evaluate the impact of genetic variation in the estrogen receptor " gene and other estrogen and progestin metabolism genes on the anti-fracture efficacy of hormone therapy in the Women’s Health Initiative Clinical Trial.

Materials/Methods

We propose to use the same sampling strategy for this study as used by other WHI HT Biomarkers studies. We anticipate the design will be a case-cohort approach that includes women who fracture and a random sample of all participants in the E+P trial. We anticipate that the usual design is to include a random set of non-cases and we will defer to the case-control biomarker group on the design. Nevertheless, we have consulted statisticians to explore whether the non-cases would essentially cancel themselves out in the denominator of the E+P and placebo groups. If this is the case, and we can still compute risks and p-values, then limitation to the cases would be a much more efficient design, allowing us to measure estradiol and bone turnover markers in a larger number of women who fractured.

In WHI, fracture outcomes include all fractures except those of the ribs, chest/sternum, skull/face, fingers, toes and cervical vertebral. There were a total of 1629 fractures, E+P group, n=733; placebo group, n=896. We have insufficient funding to include all the fractures for analyses of analyses of hormones and bone turnover markers. Therefore, we propose to include all cases of hip fractures (E+P group n=52 and placebo group n=73) and a random sample of the other non-spine fractures, the exact number of which will be determined by the sample size estimates. For analyses of genetic markers, we will include all hip and non-spine fractures.

All hip fractures are included because they have the most serious consequences. Hip fractures are associated with a 12-20% excess in mortality (10) and also have major impact on physical function, quality of life and an increase in disability (11). We considered including all vertebral fractures, since vertebral fractures are the most common osteoporotic fracture and are also associated with an increase in mortality (12,13) and loss of physical function (14). However, in WHI, we are limited to clinical vertebral fractures which are diagnosed when they come to medical attention because of back pain or other symptoms. We do not have information on radiographic vertebral fractures which require systematic assessment from spinal radiographs. All non-spine fractures are related to low bone mineral density(11,15,16). In the Fracture Intervention Trial, greater reductions in bone turnover with alendronate therapy were independently associated with fewer non-spine fractures (5). Hence, non-spine fractures represent a reasonable outcome in this Biomarker study.

Results/Findings

See Publications: 433. WHI publications by study lists published WHI papers that have been generated by ancillary studies. A complete list of WHI papers is available in the Papers of this website.

References

1. Cummings S, Browner W, Bauer D, et al. 1998 Endogenous hormones and the risk of hip and vertebral fractures among older women. N Engl J Med 339(11):733-8.
2. Cauley J, Gutai J, Kuller L, et al. 1994 Black-white differences in serum sex hormones and bone mineral density. Am J Epidemiol 139(10):1035-46.
3. Cummings SR, Karpf DB, Harris F, et al. 2002 Improvement in spine bone density and reduction in risk of vertebral fractures during treatment with antiresorptive drugs. Am J Med 112(4):281-9.
4. Riggs BL, Melton III LJ 2002 Bone turnover matters: the raloxifene treatment paradox of dramatic decreases in vertebral fractures without commensurate increases in bone density. J Bone Miner Res 17:11-4.
5. Bauer DC, Black DM, Garnero P, et al. 2002 Reduction in bone turnover predicts hip, non-spine, and vertebral fracture in alendronate treated women: the Fracture Interventional Trial. J Bone Miner Res 2002 Program & Abstracts 17(Suppl 1):S187.
6. Zmuda JM, Cauley JA, Ferrell RE 1999 Recent progress in understanding the genetic susceptibility to osteoporosis. Genetic Epidemiology 16:356-67.
7. Lee M, Zmuda J, Cauley J, et al. 1999 Bone Mineral Density (BMD) in Postmenopausal Women: Interaction Between Estrogen Receptor (ER) Genotypes and Hormone Use. Journal of Bone and Mineral Research 14(Suppl 1):S453(Abstract).
8. Ongphiphadhanakul B, Chanprasertyothin S, Payatikul P, et al. 2000 Oestrogen-receptor-alpha gene polymorphism affects response in bone mineral density to oestrogen in post-menopausal women. Clinical Endocrinology 52(5):581-5.
9. Salmen T, Heikkinen AM, Mahonen A, et al. 2000 The protective effect of hormone-replacement therapy on fracture risk is modulated by estrogen receptor alpa genotype in early postmenopausal women. Journal of Bone and Mineral Research 15(2):315-21.
10. Browner WS, Pressman AR, Nevitt MC, et al. 1996 Mortality following fractures in older women. The Study of Osteoporotic Fractures. Archives of Internal Medicine 156(14):1521-5.
11. Magaziner J, Simonsick EM, Kashner TM, et al. 1990 Predictors of functional recovery one year following hospital discharge for hip fracture: a prospective study. J Gerontol Soc of America 45(3):M101-7.
12. Kado DM, Palermo WS, Nevitt MC, et al. 1999 Vertebral fractures and mortality in older women: a prospective study. Study of Osteoporotic Fractures Research Group. Arch Intern Med 159(11):1215-20.
13. Cauley JA, Thompson DE, Ensrud KC, et al. 2000 Risk of mortality following clinical fractures. Osteoporosis International 11(7):556-61.
14. Nevitt MC, Ettinger B, Black DM, et al. 1998 The association of radiographically detected vertebral fractures with back pain and function: a prospective study. Annals of Internal Medicine 128(10):793-800.
15. Black DM, Cummings SR, Genant HK, et al. 1992 Axial and appendicular bone density predict fractures in older women. Journal of Bone & Mineral Research 7(6):633-8.
16. Seeley DG, Browner WS, Nevitt MC, et al. 1991 Which fractures are associated with low appendicular bone mass in elderly women? Ann Intern Med 115:837-42.