73.1

Background

At the time of menopause, women often experience a significant bone loss with an increased risk of osteoporosis and fracture, as a result of the decline in ovarian estrogen production . The notion of idiopathic osteoporosis occurring in the perimenopause was first understood in 1940 and, soon thereafter, the relationship between 17β estradiol and bone pathology was solidified . Since then, estrogen therapy alone or combined hormone therapy (HT, estrogen and progesterone) has been one of the most effective therapies for the prevention and treatment of osteoporosis .

Historically, HT was the primary choice to both prevent and treat postmenopausal osteoporosis because it was the only real option before 1995 when Fosamax was approved . In 2002 the Women’s Health Initiative (WHI) study results were published, and thus began the doubt, paradigm and societal shift away from the use of HT for osteoporosis management because of increased health risks and failure to prevent heart disease . The WHI study was the largest randomized control trial (RCT) of HT conducted on postmenopausal women aged 50–79, however, the primary end point of the study was not the effects of HT on fracture risk, but rather its effects on the prevention of cardiovascular disease . The estrogen plus progestin [conjugated equine estrogen (CEE) and medroxyprogesterone acetate (MPA)] arm of the study was discontinued in 2002 after 5.6 years of follow-up due to an increase in risk of invasive breast cancer, cardiovascular events, stroke, and pulmonary embolism among treated women . Subsequently, the estrogen (CEE) alone arm of the study was discontinued in 2004, after nearly 7 years of follow-up due to an increased risk of stroke in the treatment group; however, unlike combined HT with estrogen and progestin, estrogen alone did not appear to have a negative effect on heart disease or risk of breast cancer. Of note, both CEE alone and CEE+MPA combined therapy showed a significant reduction in the risk of hip and all fractures .

Critics of the WHI study state that it was limited to the evaluation of one estrogen dose (CEE 0.625 mg daily), two hormone formulations (CEE 0.625 mg/day+MPA 2.5 mg/day or CEE 0.625 mg/day alone), and only an oral route of administration in a cohort of older women with an average age of 63 . With the reevaluation of the WHI study, by stratifying patients by age and time since menopause and along with other emerging data, it became evident that for healthy and recently postmenopausal women, the benefits of HT outweigh the risks . These women were seen to have a lower number of adverse cardiovascular events and a lower overall all-cause mortality than older postmenopausal women . We must acknowledge the reluctance and uneasiness of some clinicians as menopausal HT (MHT) has a complex pattern of risks and benefits, with increased risk of stroke and invasive breast cancer being considered a primary cause of concern. Of note, WHI data did show younger women (aged 50–59 years) on CEE alone had more favorable results than those on CEE+MPA, for all-cause mortality, myocardial infarction, and the global index (stroke, pulmonary embolism, colorectal cancer, endometrial cancer, hip fracture, and death). After 13 years of cumulative follow-up for younger women (aged 50–59 years) in the WHI study, absolute excess risks of stroke and invasive breast cancer in CEE+MPA arm versus placebo were 4 [HR (95% CI)=1.37 (0.89–2.11)] and 9 [HR (95% CI)=1.34 (1.03–1.75)] more cases per 10,000 women-year, respectively; In younger women on CEE alone arm, however, there were 1 [HR (95% CI)=0.96 (0.60–1.55)] and 7 [HR (95% CI)=0.76 (0.52–1.11)] less cases of stroke and invasive breast cancer per 10,000 women-year than placebo . Although risk profiles of HT vary by age, public misconceptions persist that HT use in postmenopausal women is unsafe, and that the original WHI study results are applicable to women at all ages, regardless of dosage, formulation, duration, and route of HT administration.

In May 2017 the American College of Physicians (ACP) updated their 2008 clinical guideline regarding osteoporosis management and recommended against the use of HT for osteoporosis treatment for women (recommendation 5) . This recommendation differs from the 2008 guidelines that recommended HT for women with osteoporosis with high-quality evidence for a reduced risk of vertebral, nonvertebral, and hip fractures . This change raised concern and has led to an extensive review and critical appraisal of all six published studies quoted in the ACP guideline as the supportive evidence for the recommendation 5, claiming that HT does not reduce fracture risk in postmenopausal women with established osteoporosis. This assertion is now being questioned and debated .

Regardless of this controversy, estrogen-based HT for bone protection is supported by basic science, animal model, and clinical data. It has been proven that estrogen receptors (ERs) and their signaling pathways in bone are critical for maintaining good bone health. In addition to estrogen, selective ER modulators (SERMs) are a class of medications whose relative ER agonistic and antagonistic effects can differ between organ tissues . In this chapter, we review emerging evidence of the clinical use of estrogen and SERMs for the prevention and treatment of osteoporosis in the modern era.

73.2

Estrogen receptors in the bone

Estrogens are known to modulate and affect peripheral calcium homeostasis in the kidney and gastrointestinal tract (mainly the intestines); however, this activity is modest when compared to their substantial actions in bone . It is believed that postmenopausal osteoporosis is most likely a direct result of increases in the activity of both osteoblasts and osteoclasts with an imbalance in the strict control of osteoclastogenesis . Osteoblasts are known to lay bone matrix and osteoclasts breakdown or degrade bone . The ERα and ERβ subunits are found in osteoblasts, osteocytes, and osteoclasts . The ERα subunit was identified in the 1960s and is mostly seen in cortical bone, whereas the ERβ subunit was identified and first cloned in 1996 and is more prevalent in trabecular bone . An osteoporosis rodent model study found that a significant bone phenotype was not seen when a complete knockout of ERα and ERβ subunits was done . In bone, estrogen binds to ERα and ERβ in osteoclasts and induces the expression of the Fas ligand that in turn acts in an autocrine manner to start apoptosis in osteoclast cells . Meanwhile, estrogen stimulates the expression and activity of alkaline phosphatase (a marker of differentiated osteoblasts), in addition to osteoblast activating growth factors and cytokines . NFκB (nuclear factor kappa-light-chain-enhancer of activated B cells) is a protein complex that controls transcription of DNA, cytokine production, and cell survival. It has been noted that NFκB functions as an inhibitor of bone in differentiated osteoblasts . Interestingly, estrogen activated ERα is a powerful inhibitor of NFκB which in turn suppresses both osteoblast and osteocyte apoptosis . Therefore women going through menopause have declining estrogen levels and subsequently decreased osteoclast apoptosis and increased osteoblast apoptosis, which result in a decrease in bone mineral density (BMD) and an increase in vertebral, hip, and wrist fractures .

Of interest, ERs are also found in immune cells, including T cells and monocytes . Estrogen suppresses proosteoclastic cytokines [interleukin (IL)-1, IL-6, IL-7, and tumor necrosis factor alpha (TNFα)] in T cells and prevents TNFα-induced apoptosis in osteoblasts . A study by Roggia et al. showed that in response to an ovariectomy in mice, a resultant increase in the number of T cells was seen that caused the production of the RANKL (receptor activator for NFκB ligand) receptor, a major osteoclast differentiating factor . D’Amelio et al. highlighted the clinical importance of this by showing that there is an increase in the number of TNFα and RANKL producing T cells in postmenopausal women affected by osteoporosis .

73.3

Estrogen and combined hormone therapy

Estrogen therapy is only approved by the US Food and Drug Administration (FDA) for prevention but not treatment of osteoporosis, due to the lack of fracture efficacy data in women with osteoporosis from large population-based RCTs . With the availability of other antiosteoporosis medications, it may be unethical to conduct placebo-controlled HT trials in patients with established osteoporosis for long duration, which unfortunately is required by the drug regulatory agency. It may be impractical to conduct noninferiority or equivalence trials as an alternative since prohibitively large sample sizes may be required when the outcome is rare . From a clinical standpoint the prevention and treatment of osteoporosis share the same clinical objective that is to prevent fractures. In addition, osteoporosis drugs protect bone by preventing bone loss regardless whether patients have low bone mass or established osteoporosis. In both WHI papers by Cauley et al. (E+P) and Jackson et al. (E alone) , there was no evidence of a bone effect that differed across the strata after data were stratified by BMD and underlying risk of fractures. While the evidence for HT in osteoporosis prevention is not interchangeable with fracture efficacy data from a regulatory perspective, it may not be clinically prudent to refrain from using HT for the treatment of osteoporosis solely due to the lack of high-quality antifracture evidence in women with established osteoporosis.

Multiple research studies, both observational and RCTs, have shown the efficacy of HT on fracture reduction in postmenopausal women, with and without osteoporosis (lower risk women) . In the WHI HT trials a statistically significant reduction in hip fractures was reported in both intervention arms combined , and the antifracture benefit of HT remains after a median of 13 years’ cumulative follow-up across intervention and posttrial follow-up . Despite the compelling evidence supporting the efficacy of HT for the prevention and treatment of postmenopausal osteoporosis, HT is being gradually disregarded and eliminated from our medical toolbox for postmenopausal osteoporosis management, largely due to safety concerns with HT use. Several more current osteoporosis treatment guidelines continue to be based upon the original WHI safety data published in 2002, either recommending HT use only when other first-line antiosteoporotic medications are contraindicated or simply recommending against its use . However, after reanalyzing the WHI data with study participants stratified by time since menopause and age, it was found that for healthy recently postmenopausal women the benefits of HT outweigh adverse risks . In this young cohort, fewer cardiovascular events and all-cause mortality were reported, with a more favorable overall safety profile for estrogen therapy than estrogen plus progestin therapy, specifically concerning breast cancer risk . In 2013 Manson et al. examined total and cause-specific cumulative mortality, including during the intervention and extended postintervention follow-up, of the two WHI-HT trials and concluded that HT with CEE plus MPA for a median of 5.6 years or with CEE alone for a median of 7.2 years, among postmenopausal women, was not associated with risk of all-cause, cardiovascular, or cancer mortality during a cumulative follow-up of 18 years . In 2016 the International Menopause Society recommendations for MHT state that for women ages 50–60 years or within 10 years after menopause, the benefits of HT outweigh the risks and could be considered as first-line therapy in preventing fractures . The 2017 HT position statement of The North American Menopause Society states that HT may be considered as a primary therapy for prevention of bone loss and fracture in postmenopausal women at elevated risk of osteoporosis or fractures, primarily for women aged younger than 60 years or who are within 10 years of menopause onset . However, it should be noted that after 60 years of age or more than 10 years following menopause, the risk–benefit analysis for HT should be weighted toward avoidance .

While the safety profile of estrogen therapy differs depending on the age of patients and time since onset of menopause, various side effects of estrogen can occur depending on dose, duration, route, and type of estrogen administered. Among the types of estrogen, oral micronized 17β-estradiol is structurally identical to the main product of the premenopausal ovary. In general, 1 mg micronized 17β-estradiol is considered equivalent to 0.625 mg of CEEs, 0.625 mg of esterified estrogens (EEs), 0.05 mg of transdermal 17β-estradiol, or 5 µg of ethinyl estradiol . When estrogen was used in a dose of 0.625 mg/day for both oral CEEs and EEs, EEs were associated with less risk of venous thromboembolism (VTE) relative to CEEs in a dose adjusted analysis, with a positive dose–response relationship with VTE risk only seen in CEEs, even though they produce similar blood levels of estrone and estradiol . Lower doses of estrogen are often used to minimize the adverse effects of estrogen, while treatment efficacy is still preserved. In an RCT, 406 recently postmenopausal women were randomly assigned to unopposed EEs (0.3, 0.625, and 1.25 mg/day) or placebo. Although all three doses prevented bone loss and produced positive changes on lipids, only the 0.3 mg dose did not induce endometrial hyperplasia . It was found in another RCT that oral ultralow dose micronized 17β-estradiol at 0.25 mg/day reduced bone turnover makers to a degree similar to that seen with 1 mg 17β-estradiol, but it had a more favorable side effect profile similar to that of placebo . A systematic review and meta-analysis of 15 observational studies along with other multicenter studies reported that transdermal estrogen may be associated with less risk of VTE and DVT when compared to oral estrogen, even in women with obesity or women who carry a prothrombotic mutation . Transdermal estrogen avoids first-pass hepatic metabolism, thereby allowing administration of lower doses and provides more stable blood levels than oral estrogen. Transdermal estrogen does not increase the production of triglycerides and confers a more favorable lipid profile than oral estrogen . The American College of Obstetricians and Gynecologists (ACOG) recommends that clinicians should take into consideration the possible thrombosis-sparing properties of transdermal estrogen when prescribing estrogen therapy .

Estrogen therapy increases BMD at the lumbar spine, hip, and total body in a dose-dependent fashion . Evidence supports that even ultralow doses of transdermal 17β-estradiol at 0.014 mg/day or oral micronized 17β-estradiol at 0.25 mg/day both appear to prevent bone loss . The lowest doses of estrogen currently approved by the FDA for prevention of postmenopausal osteoporosis include oral 0.3 mg/day CEEs, oral 0.3 mg/day EEs, oral 0.5 mg/day micronized 17β-estradiol, and 0.014 mg/day 17β-transdermal estradiol (1 patch/week), with cyclic progestins administered for endometrial protection for women with intact uterus .

The maximum bone protection appears to occur when estrogen therapy is initiated soon after menopause and then continued indefinitely . However, HT use in older postmenopausal women should be generally avoided due to the results shown in the WHI suggesting that the risks of HT outweigh the benefits. If there is an indication or shared decision made by women and their providers to discontinue estrogen therapy, clinicians should be mindful of the data that bone protection effect dissipates rapidly after stopping estrogen . Of note, emerging evidence suggests that there appears to be no accelerated bone loss or rebound fracture risk after HT discontinuation . Long-term residual skeletal benefit may extend for years after HT discontinuation, not only in bone but also in paraspinal muscles and intervertebral discs , where estrogen may play a key role in the prevention of vertebral fracture and age-related hyperkyphosis .

73.4

Selective estrogen receptor modulators

SERMs are known to be synthetic nonsteroidal agents noted to have both estrogen agonistic and antagonistic properties in differing tissues . Research has shown that SERMs are able to elicit varying gene expression profiles in differing tissues . SERMs work as agonists in the bone by altering the activity of osteoclasts and osteoblasts. They cause a decrease in osteoclast differentiation and bone resorption activity while stimulating osteoblast activity and proliferation by stimulating osteoprotegerin expression and decreasing RANKL levels, as shown in mice models .

The first-generation SERM, tamoxifen, is used as first-line treatment for ER-positive breast cancer in premenopausal women. Of note, bone density should be monitored while on therapy since tamoxifen blocks estrogen action on bone and can cause a decrease in BMD in premenopausal women. In postmenopausal women, tamoxifen has an agonistic effect on bone and fracture reduction; however, an increased risk of stroke, endometrial cancer, pulmonary emboli, and deep vein thrombosis was noted in women above the age of 50 years, limiting its use for bone protection in postmenopausal women .

Raloxifene, a well-known second-generation SERM, is FDA approved for the prevention and treatment of osteoporosis in postmenopausal women and to reduce the risk of invasive breast cancer in postmenopausal women with osteoporosis or at high risk of breast cancer . Similar to tamoxifen, the effects of raloxifene on bone differ in pre- and postmenopausal women. In premenopausal women, raloxifene is associated with a decrease in BMD and an increase in all markers of bone turnover . However, raloxifene inhibits bone resorption and reduces the risk of vertebral fracture in postmenopausal women with osteoporosis . The most common side effects with raloxifene are hot flashes; however, it is not associated with vaginal bleeding or increased risk of endometrial hyperplasia or cancer . Raloxifene increases the risk of VTE that appears comparable to that reported with estrogen–progestin use . Raloxifene also increases the risk of fatal stroke in women with heart disease or risk factors for heart disease . Due to the lack of an effect on nonvertebral fracture, raloxifene may be used for the prevention of vertebral fractures in postmenopausal women with or at high risk of osteoporosis, who are not at high risk for nonvertebral fractures, especially when there is an independent need for breast cancer prophylaxis. Like estrogen, bone protection efficacy dissipates after discontinuing raloxifene; and the rate of bone loss after discontinuation is similar to that of placebo-treated women . Raloxifene has only 8 years of safety and efficacy data, therefore some providers prefer to discontinue raloxifene after 8 years and switch to an alternative antiosteoporosis agent .

The third-generation SERM, bazedoxifene (BZA), is approved in the European Union and other countries for the treatment of postmenopausal osteoporosis in women at increased risk for fracture . BZA is similar to raloxifene with regard to efficacy in preventing and treating postmenopausal osteoporosis . In a 5-year, randomized, placebo-controlled study in postmenopausal women with osteoporosis, the cumulative incidence of new vertebral fractures was significantly lower in women randomly assigned to BZA (20 or 40 mg daily) versus placebo . The incidences of short-term side effects such as hot flashes, leg cramps, and DVT are similar between two drugs, but long-term safety data is rather limited for BZA. Although an animal model showed that the growth of both tamoxifen-sensitive and -resistant breast cancer cells was inhibited by BZA , data in women for breast cancer prevention remains insufficient.

In contrast to bisphosphonates that work to inhibit osteoclast activity, SERMs behave more similarly to estrogen and are therefore considered more physiological than bisphosphonates . A combination of an SERM and estrogen may also be given to women who are at increased risk of fractures and are experiencing vasomotor symptoms . The FDA recently approved the first tissue-selective estrogen complex, specifically combining 0.45 mg CEEs with 20 mg of BZA (CEE/BZA), to relieve estrogen deficiency symptoms and prevent bone loss . CEE/BZA is indicated for the treatment of vasomotor symptoms and the prevention of osteoporosis in women with a uterus but without the need of a progestin for endometrial protection . CEE/BZA does not cause endometrial hyperplasia since BZA inhibits the stimulatory activity of CEE in the endometrium . BZA also inhibits the activity of CEE in breast tissue; however, the clinical efficacy of CEE/BZA on breast cancer risk reduction remains unclear.

Lasofoxifene has been shown to have similar or better skeletal benefit than raloxifene. It is not available in the United States and no longer available in the European Union. After 5 years in a randomized trial, lasofoxifene was associated with a decrease in both vertebral and nonvertebral fractures but did not reduce the risk of hip fracture . The same study showed a reduction in the risk of ER-positive breast cancer as well as an increase in the risk of thromboembolic events, hot flashes, and leg cramps . However, lasofoxifene may have more endometrial side effects (vaginal bleeding, endometrial polyp, and endometrial hyperplasia) than raloxifene.

73.5

Special population considerations

HT should be considered as a primary treatment option for both bone protection and for other health benefits in specific populations of women as outlined next .

73.6

Conclusion

The use of HT for the management of bone health may be considered an option for the primary prevention and treatment of osteoporosis in young women (within 10 years of menopause and before age 60). Furthermore, the knowledge of adequate dosing and mode of administration should be understood in order to give the appropriate dose of estrogen for the appropriate duration of time, without focusing only on the lowest dose for the shortest period of time . Annual reevaluation of a woman’s health status and shared decision-making is of utmost importance for the continued use of HT for bone health.

Conflict of interest

Drs. Jiang and Bhandari , none. Dr. Kagan is a consultant to or on the advisory boards of Allergan, Amgen, AMAG, Lupin, Merck, Noven, Radius Health, and Therapeutics MD. Research grants from Therapeutics MD and Endoceutics paid to Sutter Research Institute (last 3 years).