Menopausal hormone therapy in the prevention and treatment of osteoporosis

INTRODUCTION — Women have menopause at a mean age of 51 years. The resulting lack of estrogen is associated with rapid bone loss due to increased bone resorption and often consequent osteoporosis. (See "Pathogenesis of osteoporosis".)

Although menopausal hormone therapy (MHT) is not a first-line option for the prevention of osteoporosis, because of concerns of adverse effects, women who are already taking estrogen for menopausal symptom relief have the additional benefit of skeletal protection. This topic will review the efficacy of estrogen therapy on the prevention and treatment of postmenopausal bone loss. The approach to osteoporosis management, the benefits and risks of estrogen therapy, and our current recommendations for estrogen use are discussed separately. (See "Overview of the management of low bone mass and osteoporosis in postmenopausal women" and "Treatment of menopausal symptoms with hormone therapy" and "Menopausal hormone therapy: Benefits and risks".)

GENERAL PRINCIPLES — In the past, menopausal hormone therapy (MHT) was often prescribed for prevention of osteoporosis and coronary heart disease (CHD), based upon epidemiologic data demonstrating a protective effect of estrogen on the heart and bone. However, data from the Women's Health Initiative (WHI), which evaluated oral conjugated equine estrogen (0.625 mg/day) with or without medroxyprogesterone acetate (2.5 mg/day) in postmenopausal women (mean age 63 to 64 years at beginning of study and not selected on the basis of low bone mineral density [BMD]), showed a number of adverse outcomes, including an excess risk of CHD, stroke, venous thromboembolism (VTE), and breast cancer [1,2]. In light of the WHI data and the efficacy of other osteoporosis drugs, MHT (in particular the regimens used in the WHI) are no longer used for the prevention of chronic conditions. (See "Menopausal hormone therapy: Benefits and risks", section on 'Overview'.)

The increased risk of adverse events in the WHI was largely due to the older age of the study population. Follow-up analyses from the WHI and other studies have since demonstrated that the benefits of MHT outweigh the risks for women who are in their 50s, or less than 10 years from menopause. MHT is currently used in this population for management of menopausal symptoms, most importantly, hot flashes. Current regimens of MHT most often include 17-beta estradiol and micronized progesterone, preparations that have a number of advantages over those used in the WHI. The duration of therapy is typically up to four to five years, although some women with persistent symptoms are treated for longer. (See "Menopausal hormone therapy: Benefits and risks", section on 'Estimates of risk in women 50 to 59 years' and "Treatment of menopausal symptoms with hormone therapy".)

Women who seek MHT for menopausal symptoms in their late 40s or early 50s will have the additional benefit of a reduced risk of bone loss and fracture [3,4]. In such women, a separate first-line drug for prevention or treatment of osteoporosis is usually not required with estrogen (estradiol) doses equivalent to or higher than 25 mcg/day of transdermal or 0.5 mg/day oral. Lower doses of transdermal estradiol (14 mcg) have also been shown to have skeletal benefits. With this ultra-low dose of transdermal estrogen, bone density should be monitored in women at high risk for osteoporosis and fracture as another agent (eg, a bisphosphonate) may be needed. (See "Preparations for menopausal hormone therapy" and 'Prevention of osteoporosis' below.)

Women who desire osteoporosis preventive therapy, but do not need MHT for menopausal symptoms, are prescribed other antiresorptive drugs (eg, bisphosphonates, raloxifene). (See "Overview of the management of low bone mass and osteoporosis in postmenopausal women".)

EFFICACY OF ESTROGEN THERAPY

Prevention of osteoporosis — Numerous randomized, placebo-controlled studies, including the Women's Health Initiative (WHI) and the Postmenopausal Estrogen/Progestin Interventions (PEPI) trial [5], have established that the postmenopausal decrease in bone density is attenuated by estrogen, resulting in a lower risk of fracture [1,5-10]. Nevertheless, most experts no longer recommend estrogen as first-line therapy for prevention of osteoporosis, given the results of the WHI. For women using MHT for relief of symptomatic hot flashes, however, a separate first-line drug for prevention of osteoporosis is usually not required. (See 'General principles' above and "Overview of the management of low bone mass and osteoporosis in postmenopausal women" and "Treatment of menopausal symptoms with hormone therapy".)

●Prevention of bone loss – Estrogen therapy prevents bone loss. In one study, as an example, 43 postmenopausal women were randomly assigned to treatment with percutaneous 17-beta estradiol, calcium, or placebo for two years and followed with sequential measurements of bone density by dual photon absorptiometry [6]. Treatment with estrogen prevented bone loss in the forearm and whole body and increased bone density of the spine; it was significantly more effective than calcium or placebo.

The results were similar in a placebo-controlled study of 120 postmenopausal women with low bone density who were randomly assigned to treatment with exercise plus either placebo, calcium, or estrogen (1.25 mg estropipate); these women were followed with sequential measurements of forearm bone density [7]. Although calcium supplementation reduced bone loss at the distal forearm compared with placebo, treatment with estrogen was much more effective in preventing loss of bone density in the proximal, middle, and distal forearm than were the other treatments (figure 1).

Among postmenopausal women not taking estrogen, those with low (but detectable) serum estradiol concentrations have higher bone density than those with undetectable concentrations [11]. Based upon this observation, lower doses of estrogen have been explored as a strategy to prevent bone loss while minimizing side effects and breast cancer risk [12-14]. Almost all studies suggest that lower doses of estrogen also prevent bone loss, particularly when adequate vitamin D and calcium intake are provided. (See "Calcium and vitamin D supplementation in osteoporosis".)

•In one study, 406 recently postmenopausal women were randomly assigned to unopposed esterified estrogen at one of three doses (0.3, 0.625, and 1.25 mg/day) or placebo [15]. All three doses prevented bone loss, while endometrial hyperplasia occurred only at the two higher doses (figure 2).

•There is evidence that even ultra-low doses of estrogen (roughly equivalent to oral estradiol 0.25 mg/day or conjugated estrogens 0.15 mg/day) provide some protection against bone loss. A 0.014 mg/day transdermal estradiol patch and oral estradiol (0.25 mg/day) both appear to prevent bone loss [16-18]. (See "Preparations for menopausal hormone therapy".)

●Prevention of fracture – The WHI provides the best evidence that estrogen reduces fracture risk. In the WHI trial, both unopposed estrogen and combined estrogen-progestin treatment reduced fracture risk. In this study, hip fracture was a secondary outcome, and women were not selected based upon osteoporosis history or risk factors. While bone mineral density (BMD) was not measured, estrogen-progestin therapy was associated with significant reductions in [1]:

•Hip fracture (10 versus 15 per 10,000 person-years, hazard ratio [HR] 0.66, unadjusted 95% CI 0.45-0.98) (figure 3).

•Vertebral (0.5 versus 0.7 percent, HR 0.66, unadjusted 95% CI 0.44-0.98) and other osteoporotic fractures (6.8 versus 8.6 percent, HR 0.77, 95% CI 0.69-0.86, respectively).

Similar risk reductions were seen in the unopposed estrogen arm of the WHI trial for hip fracture (HR 0.61, 95% CI 0.41-0.91) and vertebral fracture (HR 0.62, 95% CI 0.42-0.93) [2]. Other results of the trial are reviewed elsewhere. (See "Menopausal hormone therapy: Benefits and risks".)

A limitation of the WHI is that BMD was not a criterion for randomization. Thus, the results are not conclusive, because the bone density in the two groups may have been different at baseline.

All types of postmenopausal hormone therapy appear to confer benefit. In a prospective, cohort study of over one million women (the Million Women Study), current users of postmenopausal hormone therapy had a significantly lower risk of any fracture than nonusers (relative risk [RR] 0.62, 95% CI 0.58-0.66) [19]. The protective effect was seen for all types of postmenopausal hormone therapy (unopposed estrogen, combined estrogen-progestin, different estrogen and progestin formulations, different routes of administration [oral versus transdermal], and different patterns of administration [cyclic versus continuous]).

Concomitant administration of a progestin to prevent endometrial hyperplasia does not interfere with the beneficial effect of estrogen on bone, whether given as cyclic or continuous therapy [5,20]. (See "Preparations for menopausal hormone therapy" and "Treatment of menopausal symptoms with hormone therapy".)

●Current versus past therapy – The maximum protection of bone mass appears to occur when estrogen therapy is begun soon after menopause and then continued indefinitely (although this is no longer the way MHT is prescribed). As an example, cross-sectional data from the Rancho Bernardo study found that women who had taken estrogen in the past and then discontinued it had slightly higher bone density than women who had never taken estrogen, but their bone density was substantially lower than women currently taking estrogen (figure 4) [21]. Other studies have noted similar findings: higher bone mass in women currently taking estrogen [22] and in those treated long term [23-25].

The limited efficacy of past estrogen therapy may reflect "catch-up" bone loss, although data have been conflicting [26-28]:

•One study in 43 postmenopausal women found that those not treated with estrogen after oophorectomy initially lost bone at a rate of 2.6 percent per year, which later fell to 0.8 percent per year (figure 5) [26]. Those treated with estrogen for four years lost no bone, but after it was discontinued, they lost bone at a rate of 2.5 percent per year for the next four years. There was no significant difference in bone loss between the two groups at eight years.

•In one study of postmenopausal women posthysterectomy, the women were randomly assigned to receive alendronate, estrogen, combination therapy, or placebo for two years, followed by further randomization to continued drug therapy or placebo in year 3. Bone density decreased in year 3 after stopping estrogen (-4.5, 1.8, and 2.4 percent in the spine, total hip, and femoral neck, respectively) but not after stopping alendronate or combined alendronate-estrogen treatment [29].

•In contrast, in the much larger PEPI trial, postmenopausal women who discontinued estrogen did not lose bone at an unusually fast rate. In this study of 495 women who had measurements of BMD for an average of three years during and four years after the trial, annual rates of BMD loss in the women who took estrogen and then stopped it and those who never took estrogen were the same (approximately 1 percent per year) [28].

Thus, data on accelerated bone loss after stopping estrogen therapy are inconsistent. Even if there is accelerated bone loss after stopping estrogen, it is unlikely to cause loss of all of the BMD preserved on treatment, as most studies show that postmenopausal women who have taken estrogen in the past have higher BMD than those who have never taken it [30].

Treatment of established osteoporosis — Estrogen is not a first-line treatment of established osteoporosis in postmenopausal women due to the availability of more potent agents. In postmenopausal women taking estrogen therapy to treat menopausal symptoms, estrogen may be sufficient to treat osteoporosis. Bone density should be monitored in women at high risk for fracture as another agent (eg, a bisphosphonate) may be needed. (See 'General principles' above and "Overview of the management of low bone mass and osteoporosis in postmenopausal women", section on 'Choice of initial therapy'.)

Although estrogen therapy is US Food and Drug Administration (FDA) approved for prevention but not treatment of osteoporosis, data suggest that estrogen is effective in postmenopausal women with established osteoporosis and vertebral fractures. In one study, 75 such women were randomly assigned to treatment with transdermal estradiol (0.1 mg) or placebo; calcium supplements were given to both groups [31]. Estrogen was associated with an increase in bone density in the spine and proximal femur and no change in bone density in the mid-radius. It also lowered the risk of vertebral fractures by more than 50 percent (23 versus 58 fractures per 100 patient-years).

Estrogen appears to be effective even when started after age 75 years, although this is not recommended. As an example, in 67 frail older women (over age 75 years), administration of estrogen for nine months increased bone density at the lumbar spine and hip as compared with placebo (4.3 versus 0.4 percent in the spine; 1.7 versus -0.1 percent in the hip) [32].

Estrogen versus bisphosphonate therapy — Estrogen with medroxyprogesterone acetate was similar in efficacy to alendronate therapy for preventing bone loss in one study of women ages 45 to 59 years (figure 6) [33], and in a study of older women [34], while alendronate was superior to combination hormone replacement in one study of older postmenopausal women (ages 65 to 90 years) [35]. Bone loss may be greater after stopping estrogen than alendronate [29].

Combination therapy (estrogen plus bisphosphonate) has been more effective in raising BMD than either agent alone in some [35,36], but not all [34], studies. We prefer not to use combination therapy for preventing bone loss as the additional BMD benefits are small and there is no proven additional fracture benefit. (See "Overview of the management of low bone mass and osteoporosis in postmenopausal women".)

PROGESTIN THERAPY — Progesterone inhibits bone resorption and has some beneficial effects on bone density when given to estrogen-deficient women [37,38]. However, the beneficial effect of progesterone on bone mineral density (BMD) is small compared with that of estrogen.

As an example, in one study in postmenopausal women who took either conjugated estrogens (0.625 mg per day), high doses of medroxyprogesterone (20 mg per day), or placebo, spine BMD fell 7 percent in those treated with placebo but fell only 5 percent in women receiving medroxyprogesterone [20]. On the other hand, BMD increased by 2 percent in women taking conjugated estrogens.

Combined estrogen-progestin therapy does not increase the efficacy of estrogen alone on bone [5,9]. This issue was best addressed in the Postmenopausal Estrogen/Progestin Interventions (PEPI) trial in which 875 women were randomly assigned to placebo or one of four treatment arms consisting of conjugated estrogens (0.625 mg/day) alone or with cyclic or continuous medroxyprogesterone or cyclic micronized progesterone (200 mg/day for 12 days per month) [5]. At three years, bone density increased similarly in all treatment groups by 3.5 to 5.0 percent at the spine and 1.7 percent at the hip; in contrast, bone density fell at these sites by 1.8 and 1.7 percent, respectively, in the placebo group.

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Osteoporosis" and "Society guideline links: Menopause".)

SUMMARY AND RECOMMENDATIONS

●General principles – Although menopausal hormone therapy (MHT) is an option for the prevention of osteoporosis in perimenopausal women, we no longer consider it a first-line therapy, since data from the Women's Health Initiative (WHI) suggest that in older menopausal women, estrogen-progestin therapy reduces fracture risk at a cost of increases in the incidence of breast cancer, coronary heart disease (CHD), stroke, and venous thromboembolism (VTE), or in the case of unopposed estrogen, an increase in stroke and thromboembolism risk (but not CHD or breast cancer). (See 'General principles' above and "Menopausal hormone therapy: Benefits and risks".)

●Prevention of osteoporosis

•Women taking MHT for menopausal symptoms – Although MHT is no longer prescribed for chronic conditions, it is indicated for the treatment of menopausal hot flashes in younger menopausal women. Women who seek MHT for menopausal symptoms in their late 40s or early 50s will have the additional benefit of a reduced risk of bone loss and fracture. (See 'General principles' above and 'Prevention of osteoporosis' above.)

In such women, a separate first-line drug for prevention of osteoporosis is usually not required with estrogen (estradiol) doses equal to or higher than 25 mcg/day of transdermal or 0.5 mg/day oral. Lower doses of transdermal estradiol (14 mcg) have also been shown to have skeletal benefits. We monitor bone density in women at high risk for osteoporosis and fracture who are taking ultra-low-dose transdermal estrogen as another agent (eg, a bisphosphonate) may be needed. (See 'General principles' above and 'Prevention of osteoporosis' above.)

•Women not taking MHT for menopausal symptoms – Women who desire osteoporosis preventive therapy, but do not need MHT for menopausal symptoms, are prescribed other antiresorptive drugs (eg, bisphosphonates, raloxifene). (See 'General principles' above and "Overview of the management of low bone mass and osteoporosis in postmenopausal women".)

●Treatment of established osteoporosis – Estrogen is not a first-line approach for the treatment of established osteoporosis in postmenopausal women due to availability of more potent agents. In postmenopausal women taking estrogen to treat persistent menopausal symptoms, estrogen may be sufficient to treat osteoporosis. Bone density should be monitored in women at high risk for fracture as another agent (eg, a bisphosphonate) may be needed. (See 'General principles' above and 'Treatment of established osteoporosis' above and "Overview of the management of low bone mass and osteoporosis in postmenopausal women", section on 'Choice of initial therapy'.)

ACKNOWLEDGMENT — The UpToDate editorial staff acknowledges Marc K Drezner, MD, who contributed to earlier versions of this topic review.