Estradiol for Prevention of Osteoporosis

17-beta estradiol is synthetic bioidentical human estrogen derived from soybeans in most cases. It is one of the two prime sex steroid hormones, the other being testosterone. Sex steroid hormones become deficient at menopause and this leads to a number of chronic medical disorders including osteoporosis. It is easily treated, treatment is inexpensive, is safe when done properly and started early in the menopause, is readily available, and effectively prevents the problems caused by the hormone deficiency.

US FDA Indications and Usage for Estradiol Generic Label
Prevention of osteoporosis.

When prescribing solely for the prevention of postmenopausal osteoporosis, therapy should only be considered for women at significant risk of osteoporosis and for whom non-estrogen medications are not considered appropriate.

Treatment of moderate to severe vasomotor symptoms associated with the menopause
Treatment of moderate to severe symptoms of vulvar and vaginal atrophy associated with the menopause. When prescribing solely for the treatment of symptoms of vulvar and vaginal atrophy, topical vaginal products should be considered.
Treatment of hypoestrogenism due to hypogonadism, castration, or primary ovarian failure.
Treatment of breast cancer (for palliation only) in appropriately selected women and men with metastatic disease
Treatment of advanced androgen-dependent carcinoma of the prostate (for palliation only).

Estradiol for Osteoporosis Prevention

The best data for estradiol’s effect on bone health comes from the Women’s Health Initiative. 27,000 postmenopausal women enrolled in this study. There average age was 63 and 84% were white. There were divided into two groups one with their uterus (16,600) and one without (9,400). In the one with a uterus, half were given PremPro (equine estrogen and MPA) and half a matching placebo. In those whose uterus had been surgically removed, half were given Premarin (equine estrogen without MPA) and the other half a matching placebo.

After 5 years in 2002, the trial was halted due to cardiovascular and cancer side effects in the PremPro group only. There were no side such side effects reported in the Premarin only group and those women continued in the study.

The following statistically significant osteoporosis outcomes found in the study. In the women treated with PremPro hip fracture was reduced by 34%, spine fractures by 34% and peripheral fractures by 23%.

Statistically Significant Treatment Harms and Benefits
Seen in Women’s Health Initiative in Women on PremPro


Rate per year


Heart Attack

7 per 10,000


8 per 10,000

Pulmonary Embolism

8 per 10,000

Breast Cancer

8 per 10,000


2.2 per 1,000

Venous Thromboembolism

1.3 per 1.000


Prevention of Colon Cancer

-6 per 10,000

Prevention of Hip Fracture

-5 per 10,000

Prevention of Vertebral Fractures

-6 per 10,000

Global Harm/Benefit Outcome Analysis

4.9 per 1,000 residual harm

The table above is a summary of the important adverse and beneficial outcomes seen in the WHI trial. The number in the rate column is the expected incidence of the event each year. For example, the event rate for stroke was 8 per 10,000 woman years. That is about 1 in a 1,000 each year had a stroke attributable to oral PremPro. It is important to bear in mind that the women in the WHI were 63 years old on average when the started PremPro, they took it orally, the raw data in the table provides no insight into their diet, tobacco use, or exercise habits. The dementia data in the table was taken from a WHI sub-study that included 5,500 women started on PremPro that were on average 73 years old when the began the study so they are different that the other patients in the table but this is an important harm that women need to consider so I included it.

One of the lesions learned from the WHI is that the risks seen in the table above were much higher in women who were started on PremPro after 65 years of age than earlier. When sex hormones are begun much earlier, especially soon after menopause the harms are much lower.

The women without a uterus who were treated with Premarin only did not have heart attacks and their risk for breast cancer was reduced by about 30% not increased. Their overall Global Harm/Benefit Outcome Analysis would have been neutral or positive if the study principal investigator had allowed the study to complete its planned 8 years but he decided to end it one year early because the incidence for stroke had become statistically significant. It is important to note how small these numbers are on both the harm and benefit side of the ledger.

The findings of the WHI has been enormously influential and despite its flaws have overshadowed the findings of all previous studies that showed substantial benefits of hormone use after menopause. The WHI has had chilling effect on use of hormones in women after menopause. One unfortunate adverse consequence stemming from the study’s findings is that they preclude funding of large-scale studies of different forms of and combinations of hormones delivered by other routes of administration that could have less harm and results that are more beneficial. For instance in my opinion a bioidentical formulation of estradiol, progesterone, and testosterone could be administered at the equivalent of 1/10th the WHI dose, have significantly better benefits and harms resulting in a positive Global Outcome Assessment.