What is the role of estrogen in osteoporosis?

Role of Estrogen in Osteoporosis

Estrogen plays a critical role in maintaining bone health, and its decline during menopause directly contributes to accelerated bone loss and increased risk of osteoporosis in women. The postmenopausal decline of estrogen production is associated with reduction of bone mineral density (BMD), with bone density decreasing by approximately 2% each year during the first 5 years after menopause, followed by an annual loss of approximately 1% thereafter 1.

Mechanisms of Estrogen's Effect on Bone

• Estrogen binds to estrogen receptors to promote the expression of osteoprotegerin (OPG) and suppress nuclear factor-κβ ligand (RANKL), thereby inhibiting osteoclast formation and bone resorptive activity 2
• Estrogen directly inhibits osteoclastic bone resorption and induces osteoclast apoptosis through an estrogen receptor-mediated mechanism 3
• Estrogen activates Wnt/β-catenin signaling to increase osteogenesis and upregulates BMP signaling to promote mesenchymal stem cell differentiation into osteoblasts rather than adipocytes 2
• When estrogen levels decline, there is increased secretion of inflammatory cytokines like IL-1, IL-6, and tumor necrosis factor (TNF), which further promote bone resorption 2

Epidemiology of Estrogen Deficiency and Osteoporosis

• The median age of menopause in women in the United States is 51 years, but ovarian production of estrogen begins to decrease years before the complete cessation of menses 1
• Lower levels of circulating estrogen contribute to accelerated bone loss and increased low-density lipoprotein levels around menopause 1
• Up to 70% of women older than 80 years of age have osteoporosis based on commonly used criteria 1
• The lifetime risk of hip fracture for a menopausal woman is estimated to be 15% 1

Evidence for Estrogen's Protective Effect

• Good evidence from observational studies and randomized clinical trials demonstrates that estrogen therapy increases bone density and reduces risk for fractures 1
• A meta-analysis of 22 trials reported an overall 27% reduction in nonvertebral fractures (RR, 0.73 [95% CI, 0.56 to 0.94]) with estrogen therapy 1
• Observational studies have demonstrated reductions in fractures of the vertebrae (RR for ever use, 0.6 [95% CI, 0.36 to 0.99]), wrist (RR for current use, 0.39 [95% CI, 0.24 to 0.64]), and possibly hip (RR for current use, 0.64 [95% CI, 0.32 to 1.04]) among women taking hormone replacement therapy (HRT) 1
• The Women's Health Initiative (WHI) found significant reductions in total fracture risk (RH, 0.76 [95% CI, 0.63 to 0.92]) among healthy women taking estrogen and progestin 1

Clinical Application of Estrogen Therapy for Osteoporosis

• For maximum benefit, preventive therapy should begin as early as possible after ovarian failure begins to occur 4
• The minimum effective dose is probably that which achieves circulating estrogen levels in the mid-follicular range 4
• Estrogen therapy is effective in increasing bone mineral density at the hip, lumbar spine, and peripheral sites 1
• The FDA has approved conjugated estrogens for the prevention of postmenopausal osteoporosis 5
• Estrogen therapy can be effective regardless of age (51 to 80 years) in retarding bone loss, with the rate of bone loss in estrogen users being approximately one-third that of non-users 6

Limitations and Considerations

• Despite the benefits, estrogen therapy has important risks that must be considered, including increased rates of thromboembolic events, stroke, and when combined with progestin, increased risk for coronary heart disease and breast cancer 1
• The U.S. Preventive Services Task Force recommends against using HRT routinely for the specific purpose of preventing chronic disease in women 1
• Women who discontinue estrogen therapy after age 65 may experience more rapid bone loss than women of similar age who never took estrogen 6
• Even with estrogen therapy, bone loss can still occur in later postmenopausal years, suggesting that periodic reevaluation of bone density and other fracture risks may be appropriate 7

Alternative Approaches

• For women who cannot or choose not to use estrogen therapy, other pharmacological treatments include bisphosphonates, teriparatide, and RANKL inhibitors 2
• Weight-bearing exercise and adequate calcium and vitamin D intake are mainstays for decreasing the risk of postmenopausal osteoporosis 5
• Postmenopausal women require an average of 1500 mg per day of elemental calcium and 400-800 IU per day of vitamin D 5

Clinical Decision Making

• When considering estrogen therapy solely for the prevention of postmenopausal osteoporosis, treatment should only be considered for women at significant risk of osteoporosis, and non-estrogen medications should be carefully considered 5
• For women with a uterus in place, a progestin is usually provided to protect the endometrium; progestins do not interfere with the effects of estrogen on the skeleton 4
• For patients with established osteoporosis, estrogen can be used as first-line therapy since it has a skeletal stabilizing effect and reduces the risk of recurrent fracture 4