Clinical Opinion: The Biologic and Pharmacologic Principles for Age-Adjusted Long-term Estrogen Therapy

Morris Notelovitz, MD, PhD, MB BCh, FACOG, FRCOG

In This Article


Sufficient bone mass and an intact trabecular microarchitecture are 2 of the main factors responsible for bone strength and prevention of osteoporotic fracture. Prevention of falls is an additional factor that reduces fracture risk.

Achieving peak bone mass and maintaining bone mass depend on the balanced coupling of new bone formation (osteoblast function) and bone removal, or resorption (osteoclast activity) in the bone remodeling cycle. Osteocytes modulate the osteoclast/osteoblast interaction and play a role as 'mechanotransducers' in the positive effect of mechanical loading (exercise) on bone strength. The sex steroids are involved in development of peak bone mass and skeletal homeostasis.[1] Estrogens and androgens influence bone homeostasis through effects on osteoblasts and osteoclasts that are mediated by the steroid receptors[2] and through gene regulation (eg, estrogen-regulated genes with trabecular bone-sparing effects have been identified[3]).

Estrogen is synthesized endogenously in bone tissue in part by the aromatization of testosterone to estradiol (E2).[4] Estrogen upregulates steroid receptors,[5] and the estrogen receptors (ERs) are downregulated with aging and estrogen deprivation. Apoptosis of osteocytes is closely linked to estrogen deficiency and may be one reason why mechanical loading does not prevent bone loss in the presence of low E2 levels.[6] Estrogen also has important extracellular functions that influence bone health. There is evidence from animal studies that estrogen regulates genes involved in a vitamin D-independent transport of calcium from the intestines and renal tubules; estrogen increased the levels of activated vitamin D [1.25(OH)2D3] and vitamin D-binding protein.[7] There are specific vitamin D receptors in muscle,[8] and apart from its role in calcium metabolism, vitamin D improves muscle strength and prevents body sway.[9]

The literature is replete with randomized controlled clinical trials (RCTs) that have clearly demonstrated a positive effect of standard doses of estrogen on bone mass accrual and improvement in bone mineral density (BMD). In a study of postmenopausal women (> 65 years), those who had undetectable levels of endogenous estrogen (< 5 pg/mL) were found to be at increased risk of hip and vertebral fracture, as were postmenopausal women with higher endogenous serum concentrations of sex hormone binding globulin (SHBG).[10] The risk of fracture decreased with serum estrogen levels above 10 pg/mL but within normal postmenopausal concentrations (< 20 pg/mL), which the authors proposed could be achieved with low-dose ET without significant risk for endometrial or breast cancer.[10]

A series of studies have confirmed that exogenous estrogen can increase BMD in doses much lower than the standard dose of estrogen prescribed for menopausal symptoms (eg, conjugated equine estrogens [CEE], 0.625mg). These include oral micronized E2, 0.25 mg[11]; transdermal E2, 25 mcg[12]; CEE, 0.3 mg and 0.45 mg[13]; and ethinyl estradiol (EE), 5 mcg.[14] The increase in BMD achieved with these lower doses averaged about 1% to 3% over a 2-year study interval -- approximately half of that following standard doses of estrogen. However, none of the studies with these low-dose regimens evaluated fracture. More recently, an ultra low-dose regimen of unopposed transdermal E2 (14 mcg) reported a 2% increase in BMD in the lumbar spine of older postmenopausal women (mean age, 67 years) relative to placebo (P < .001) without causing endometrial hyperplasia.[15]

Urinary bone markers (deoxypyridinoline; type I collagen breakdown products) above the upper limit of normal for premenopausal women are predictive of hip fracture. The initial increase and subsequent gradual decrease in postmenopausal bone remodeling may influence clinical decisions regarding the timing and dose of ET. For example, in a study of healthy, recently postmenopausal women, the percentage of positive responders (ie, who had a positive change from baseline in lumbar BMD) on transdermal ET correlated with the ET dose: 59.6%, 25 mcg; 79.3%, 50 mcg; and 83.9%, 75 mcg.[12] A similar result was found for women on low-dose oral E2 therapy.[11] In clinical practice, the nonresponders could be identified by biochemical monitoring and their dose of ET could be titrated upwards to ensure a positive clinical response.

The estrogen-alone arm of the Women's Health Initiative (WHI) reported a 39% reduction in hip fracture and a 38% decrease in vertebral fractures.[16] The results are consistent with earlier observational studies and recent meta-analyses. It also links the biologic plausibility of improvement in BMD with a reduced risk of fracture as reported in other studies involving the use of nonhormonal antiresorptive agents. Notably, the protective effect of ET in the WHI study for hip fractures was confined to women older than 60 years of age, and particularly in the age 60 to 69 category: RR 0.33 (0.13-0.83) vs RR 0.62 (0.38-1.00) in women aged 70 to 79 years. The protective effect of ET on bone declines rapidly upon cessation of treatment.[17]

Given the asymptomatic nature of osteoporosis, screening with peripheral or axial dual energy x-ray absorptiometry (DXA) is recommended. Women with osteopenia are candidates for preventive therapy, especially if they have evidence of accelerated bone remodeling. In this context, pretreatment assessment of the biochemical bone markers,[18] especially if the values are above the premenopausal reference range, may be valuable for treatment decision making, selecting an ET dose, and monitoring the efficacy of ET. Reduction of the pretreatment bone turnover markers (eg, urinary collagen cross-linked N telopeptide) by 50% from the baseline value is indicative of biologic efficacy, and some studies, but not all, have found bone markers useful for predicting risk of future fracture.[18,19,20,21,22,23]

Timing of therapy and the dose of ET are more important than the choice of estrogen. The presence of other indications for ET and the effect of ET on SHBG should also be factored into the decision. On this basis, I would recommend that recently symptomatic menopausal women should be treated with either oral E2 (1 mg), CEE (0.45 mg), or the transdermal E2 patch (50 mcg). As indicated by the WHI study, the protective effect of estrogen occurs beyond the early menopausal period.[16] Guided by annual biochemical marker monitoring and 2-yearly DXA monitoring, the dose of ET may be gradually titrated downwards (eg, every 5 years) until a much lower maintenance (but clinically effective) dose of ET is achieved.


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