Role of menopausal hormone therapy in the prevention of postmenopausal osteoporosis Original paper

What was reviewed?

This review explains how menopausal hormone therapy for osteoporosis prevention works, which women benefit most, and how dose and route affect safety. The authors summarize evidence that systemic estrogen prevents postmenopausal bone loss and lowers fractures, while risks vary by age, time since menopause, and oral versus transdermal delivery. They describe how estrogen restrains osteoclast activity through the RANKL–OPG axis and reduces inflammatory cytokines that drive bone resorption. They note that benefits often fade after stopping therapy, and that decisions must weigh fracture reduction against rare vascular and breast risks.

Who was reviewed?

The guidance focuses on peri- and early postmenopausal women with vasomotor symptoms who are under 60 years or within 10 years of menopause and have low baseline risks for cardiovascular disease, stroke, thromboembolism, and breast cancer. It also covers women with premature ovarian insufficiency who need longer replacement and women after hysterectomy who can use estrogen alone. The review includes data from large randomized trials and cohort studies, such as Women’s Health Initiative analyses, and it addresses women who use oral or transdermal estradiol with or without a progestogen, as well as users of tibolone or tissue-selective estrogen complexes. The paper emphasizes that fracture reduction appears across baseline bone mineral density strata and progestogen use, while persistence of benefit after discontinuation remains uncertain.

Most important findings

The evidence shows that menopausal hormone therapy increases bone mineral density and reduces hip, vertebral, and other osteoporotic fractures in average-risk postmenopausal women, with a hip fracture reduction of around one-third in a major trial using conjugated equine estrogens plus medroxyprogesterone acetate. Transdermal estradiol avoids first-pass hepatic effects and does not raise venous thromboembolism and stroke risk to the same degree as oral estrogen, which supports transdermal use in women with vascular or metabolic risk. Estrogen restrains osteoclastogenesis by increasing osteoprotegerin and lowering RANKL signaling and by dampening IL-1, IL-6, and TNF activity; these immune shifts align with lower bone resorption and suggest indirect ties to gut microbiome–immune crosstalk, although the review reports no microbial taxa. Bone loss resumes after stopping therapy, yet prior users can retain a higher bone mineral density for some years; the fracture risk benefit may not persist. Lower-dose oral and transdermal regimens improve bone mineral density, but definitive fracture outcomes remain limited. Calcium and vitamin D with hormone therapy further lowers hip fractures versus either alone.

Key implications

Clinicians should consider menopausal hormone therapy for symptomatic women who are younger than 60 years or within 10 years of menopause and who have low baseline vascular and breast risks, with transdermal estradiol preferred when thrombotic risk exists. You should add a progestogen for women with a uterus to protect the endometrium and tailor the dose and route to symptoms and risk. You should not use menopausal hormone therapy as first-line primary prevention in older, asymptomatic women more than a decade past menopause. You should explain that fracture protection wanes after stopping and plan a long-term bone strategy. Because the review maps cytokine and RANKL–OPG shifts, teams building a microbiome signatures database can flag these immune changes as mechanistic links between estrogen status and bone, while noting that this review does not profile microbes.