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Genetics Key to Value of Hormone Therapy for Reducing Fracture Risk

By Jamie Santa Cruz

A recent study shows hormone therapy offers the greatest benefit to women at highest genetic risk of fracture; however, personalized medicine based on genetics isn't broadly available.

Hormone therapy is known to prevent bone loss and reduce the risk of fractures in menopausal women.1,2 However, new research from the University at Buffalo has found that genetics is a key element in the equation. Specifically, the new study shows that women at the highest genetic risk of fracture receive the most benefit from hormone therapy—a finding the researchers say has important implications for personalized medicine and the use of genetics in medical decision making.3

"Women are different, and according to their genetics, women differ in their risk," says Heather Ochs-Balcom, PhD, an associate professor of epidemiology and environmental health in the University at Buffalo's School of Public Health and Health Professions and one of the study's authors. "It's important to recognize that if these drugs are broadly prescribed, not every woman will have the same risks and benefits from treatment."

A First-of-Its-Kind Clinical Trial
The findings, published in the Journal of Clinical Endocrinology and Metabolism, are based on data from the Women's Health Initiative (WHI), a large, multicenter study that began in 1993. Although the WHI enrolled approximately 162,000 women nationally, the new research relies on a smaller subsample of women from the WHI cohort—namely, those who were enrolled in one of two clinical trials that examined the risks and benefits of hormone therapy. Of this subsample, nearly 10,000 had had their genes assessed via a genomewide association study (GWAS). It was this population the University at Buffalo researchers used to determine whether the risk/benefit analysis of hormone therapy might vary based on an individual's genetic profile.

To establish genetic risk, the University at Buffalo researchers relied on a set of approximately 50 genes identified as being linked to fracture risk in a meta-analysis of GWAS.4 By tallying the total number of risk alleles of each study participant, they were able to establish a genetic risk score for each.

A key strength of the new study, Ochs-Balcom says, is its use of a clinical trial design. In the WHI cohort the University at Buffalo researchers used, women were randomly assigned to either hormone therapy or placebo so as to minimize confounding effects to the greatest extent possible. Although a clinical trial design is the gold standard in medical research, it is often difficult to achieve for gene-environmental interaction studies such as the current one. "Some other researchers who work in environmental health, for instance, want to look at genetic interactions with exposures such as benzene, etc. The problem is that everyone is exposed at some level (most at very low levels), and it's hard to find people who aren't exposed." Due to the randomization in the WHI trial, however, it is completely clear which women were exposed to hormone therapy and which were not. "It's an ideal setting in which to do this gene-environment interaction study," Ochs-Balcom says.

The finding that women at highest genetic risk of fracture receive the greatest benefit from hormone therapy came as no surprise, but such insight into the impact of genes is valuable information for aiding physicians in tailoring medical care to an individual, Ochs-Balcom says.

"If someone is really at low risk of fracture, she might not see a bone or fracture-related benefit from hormone therapy," she explains. "So you can protect her from harm—and the inefficiency—by not giving it to her."

Findings Don't Support Use of Hormone Therapy for Fracture Prevention
Importantly, the findings show only that genetics may be useful for determining which populations might receive the most benefit from hormone therapy. They do not suggest that hormone therapy is actually advisable for fracture prevention, says Jean Wactawski-Wende, PhD, dean of the School of Public Health and Health Professions at the University at Buffalo and a coauthor of the study.

Indeed, as Wactawski-Wende notes, both of the original clinical trials of hormone therapy in the WHI cohort were halted prematurely in the early 2000s due to the fact that hormone therapy in both cases proved to result in more harm than benefit. In the case of the first trial, which tested a combination of estrogen and progestin against placebo, women receiving hormone therapy had a lower risk of fracture and colorectal cancer but had a higher risk of heart disease, stroke, deep vein thrombosis, and breast cancer. In the case of the second trial, which tested estrogen alone against placebo, hormone therapy provided a benefit in terms of reducing fracture but was associated with increased stroke risk.

According to Wactawski-Wende, who is also a professor in the department of epidemiology and environmental health the University at Buffalo, the findings of the new study do not negate the findings of the original WHI trials: the risks of hormone therapy outweigh the benefit with respect to reduction of fracture risk—a statement she says remains true even for women at high genetic risk of fracture. Thus, hormone therapy is currently recommended only for women with moderate to severe hot flashes or other menopausal symptoms—and then only for short periods.

"Nobody is saying people should start taking hormone therapy for prevention of fracture. If you are taking it because you have severe menopausal symptoms, you will have fracture benefit, but without that indication, you should not be taking hormone therapy," Wactawski-Wende says.

Ultimately, Wactawski-Wende says, the new study is not meant to influence treatment decisions related to hormone therapy; rather, the purpose of the study is simply to gain insight into how genes could factor into the risk/benefit analysis for a given medication in an attempt to further the development of personalized medicine down the road. The question, she says, is, "Could you combine genetics with information from trials and try to give the right drug to the right person who would most benefit—and avoid those with risks?"

The Future of Genetics as a Decision-Making Aid
Currently, genetics is not commonly part of the decision-making process with respect to hormone therapy, and according to Wactawski-Wende, use of genetics for this purpose would not be feasible on a general basis at this point.

"Most physicians would not have access to a GWAS to even try to put together a genetic risk score on any of their patients," she says. "It's something that's done in a research setting. […] Intuitively, there may be people at higher or less risk, but we don't have the mechanism to do a test to be able to take what we know from this study and use it clinically."

One question of current interest is how closely family history is correlated with genetic risk score. The former is known to be a meaningful predictor of genetic risk, Ochs-Balcom says, and it is relatively easy to measure. "Family history probably isn't a perfect proxy for these 50 genetic markers, but how good is it?" Ochs-Balcom asks. "Is family history good enough?" Even if the correlation is quite strong, she adds, some women do not know their family history, so they would need a genetic test in order to reliably establish the risk—and that sort of test simply is not accessible to most at present.

Due to the fact that there is no readily available way to establish an individual's genetic risk score at this point, the findings of the new study have little application for practice, Wactawski-Wende says. Although the new research does suggest the value of genetics, and although it points to the possibilities of personalized medicine in the future, she maintains that it is currently "not actionable" for physicians.

"Precision medicine is something we all would love to see sooner rather than later, but it's going to take time, and it's more complicated than many people can appreciate," she says. Therefore, she adds, physicians should maintain adherence to current recommendations regarding hormone therapy. "These findings give us hope that we can eventually try to match the right medicine with the right person, but they should not change [physicians'] management of osteoporosis. Hormone therapy is still not recommended as a primary treatment because of the risk/benefit profile."

— Jamie Santa Cruz is a freelance writer based in Englewood, Colorado.

1. Jackson RD, Wactawski-Wende J, LaCroix AZ, et al. Effects of conjugated equine estrogen on risk of fractures and BMD in postmenopausal women with hysterectomy: results from the women's health initiative randomized trial. J Bone Miner Res. 2006;21(6):817-828.

2. Cauley JA, Robbins J, Chen Z, et al. Effects of estrogen plus progestin on risk of fracture and bone mineral density: the Women's Health Initiative randomized trial. JAMA.2003;290(13):1729-1738.

3. Wang Y, Wactawski-Wende J, Sucheston-Campbell LE, et al. Gene-hormone therapy interaction and fracture risk in postmenopausal women. J Clin Endocrinol Metab. 2017;102(6):1908-1916.

4. Estrada K, Styrkarsdottir U, Evangelou E, et al. Genome-wide meta-analysis identifies 56 bone mineral density loci and reveals 14 loci associated with risk of fracture. Nat Genet. 2012;44(5):491-501.