Efficacy and safety of estrogen therapy for prevention of osteoporosis in postmenopausal women

Multiple randomized controlled trials and observational studies have demonstrated that estrogens reduce the risk of osteoporotic-related fractures, including hip and vertebral and nonvertebral fractures, in postmenopausal women. However, many clinicians have concerns about adverse effects of estrogen, particularly those related to breast cancer and cardiovascular disease (CVD). The US Food and Drug Administration (FDA) was concerned about the negative impact that their “black box warning” was having on the use of estrogen products. In November 2025, the FDA removed the “black box warning” on estrogen products, arguing that in 30 trials with 26,708 women participants, menopausal hormone therapy (HT) was not associated with increased cancer mortality. In fact, women who start HT before age 60 appear to have a decreased mortality risk. The present manuscript discusses the biologic effects of estrogens on bone, and its efficacy and safety. Although it is generally accepted that knowing the circulating estradiol (E 2 ) concentration in a patient is not essential to initiate treatment for osteoporosis prevention, E 2 testing can still play an important role in the treatment process. A number of studies have reported threshold E 2 concentrations for preventing postmenopausal bone loss and osteoporosis. However, most studies that have reported these threshold concentrations utilized inaccurate E 2 assay methodology and, therefore, the conclusions are not valid. An accurate representation of the risk and benefits of estrogen therapy to women in menopausal transition and postmenopausal women is fundamental to improving their care, quality of life, and health.