Estrogen hormone therapy and postmenopausal osteoporosis: does it really take two to tango?

Osteoporosis is a chronic disease characterized by compromised bone strength, predisposing to an increased susceptibility to fracture (Compston, McClung, and Leslie 2019). The prevalence of osteoporosis, defined as a bone mineral density (BMD) T-score by DXA of ≤ −2.5, increases from 6.8 percent in women aged 50–59 years, to 25.7 percent for those aged 70–79 years, and to 34.9 percent in women aged 80 years and older (Cappola et al. 2023). Approximately, 50 percent of women will experience an osteoporotic fracture in their lifetime, and both hip and vertebral fractures are associated with substantial morbidity and mortality (Cappola et al. 2023).

The aging process, along with estrogen deficiency, detrimentally affects bone health, leading to decreased bone mass and increased risk of osteoporotic fractures in postmenopausal women. Although the precise role of each factor in postmenopausal osteoporosis remains uncertain, their combined influence is undeniable. In addition to the negative effects on bone health, the loss of ovarian function and the subsequent decline in estrogen levels result in a cluster of bothersome symptoms such as hot flashes, sweating, insomnia, mood swings, irritability, vaginal dryness, and pain during sexual intercourse. Concurrently, the postmenopausal state is associated with greater amounts of visceral fat and an increased risk of metabolic and cardiovascular diseases (Greendale et al. 2021; Leeners et al. 2017).

The role of estrogen in bone physiology and pathophysiology is complex and results of its direct activity on osteoblasts, osteoclasts, and osteocytes (Drake and Khosla, 2018; Rozenberg et al. 2020). Estrogens increase osteoblast differentiation and activity and limit both osteoblast and osteocyte apoptosis. In addition, estrogens have a suppressive action on bone resorption by promoting osteoclastic apoptosis and reducing osteoclast function (Almeida et al. 2017). Estrogen reduction during the menopausal transition results in increased bone remodeling, with a greater augmentation of bone resorption than formation, leading to a loss of BMD and increased fracture risk (Drake and Khosla, 2018; Rozenberg et al. 2020).

Beneficial effects of estrogen therapy with or without progestogen on bone mass and fracture reduction have been largely demonstrated (Cauley et al. 2003; PEPI Trial, 1996; Rossouw et al. 2002). Data from the Women’s Health Initiative (WHI) trial showed that therapy with conjugated estrogens plus medroxyprogesterone acetate prevents osteoporosis fractures in postmenopausal women, with a 34 percent reduction in the incidence of hip fracture and 24 percent reduction in all fractures, regardless of baseline BMD (Rossouw et al. 2002). In agreement with these findings, a meta-analysis of 28 studies including 33,426 participants showed that menopausal hormone therapy (MHT) reduces the risk of hip, vertebral, and all fractures by 28 percent, 37 percent, and 26 percent, respectively (Zhu et al. 2016). Furthermore, although studies have shown an increase in the risk of osteoporotic fractures following the cessation of MHT, the benefit of MHT on BMD may persist for at least 2 years after treatment discontinuation. Nonetheless, the recurrence of menopausal symptoms in women who discontinue MHT can negatively affect their quality of life (Papadakis et al. 2016).

While many randomized controlled trials (RCTs) showed fracture risk reduction with standard doses of oral estrogen therapy, there is a paucity of studies with the transdermal route of hormone administration. A prospective study in postmenopausal women with low bone mass demonstrated that transdermic estradiol combined with levonorgestrel increased BMD at the lumbar spine and hip by 8 percent and 6 percent, respectively (Warming, Ravn, and Christiansen 2005). Recently, Park et al. in a prospective, open-label, randomized trial, of 281 postmenopausal women with a recent hip fracture, showed a similar risk of a secondary fracture in the group treated with percutaneous estradiol gel (1.5 mg/day) plus oral micronized progesterone (100 mg/day), compared to the group treated with risedronate for 4 years. BMD at the total hip increased by 2.8 percent in the MHT group and remained unchanged in those treated with risedronate (Park et al. 2021).

Despite the anti-fracture efficacy of estrogen therapy, indications for MHT approved by the US Food and Drug Administration (FDA) and recommended by the Menopause Societies are limited to the treatment of menopausal symptoms and the prevention of postmenopausal osteoporosis (Force USPST, 2022; NAMS, 2022). Hormonal therapy is also recommended to treat women with hypoestrogenism resulting from hypogonadism, bilateral oophorectomy, primary ovarian insufficiency, and those with symptoms of vulvovaginal atrophy (Baber et al. 2016; Davis and Baber 2022; Flores, Pal, and Manson 2021; NAMS, 2022). MHT-related adverse events observed in RCTs, including the WHI, raised a question regarding the safety profile of the MHT (NAMS, 2022; Rossouw et al. 2002). Hence, concerns related to an increased risk of adverse events such as venous thromboembolism, coronary heart disease, stroke, and breast cancer, only for estroprogestative regimen, led to a huge reduction in medical prescriptions and scrapped MHT to treat osteoporosis (Anagnostis et al. 2021). Indeed, current guidelines of different medical societies, including the International Menopause Society (IMS) and the North American Menopause Society (NAMS), recommend MHT as an alternative to first-line therapies to treat osteoporosis in patients with vasomotor symptoms of menopause (Baber et al. 2016; Camacho et al. 2020; Eastell et al. 2019; NAMS, 2021, 2022). Similarly, in women without menopausal vasomotor symptoms who require fracture risk reduction, other first-line therapies are preferred. Thus, MHT has been reserved for women with low or moderate risk of fracture in the context of menopausal symptoms (Kanis et al. 2020; NAMS, 2021), or as an alternative to first-line therapies to treat osteoporosis (Eastell et al. 2019).

While concerns regarding the safety profile of the MHT have limited its use in the management of postmenopausal osteoporosis, it is crucial to recognize that when MHT is initiated in women under the age of 60 or within 10 years following their final menstrual period, the benefits outweigh the risks. This time frame is the cornerstone for the concept of the “timing hypothesis” that the effects of MHT on atherosclerosis and clinical outcomes depend upon the timing of MHT initiation in relation to a woman’s chronological age and the duration since her menopause (Flores, Pal, and Manson 2021; Hodis and Mack 2022).

Therefore, considering the unequivocal action of estrogen to reduce fracture risk, associated with a favorable safety profile of MHT in selected early postmenopausal women, it is urgent to revisit the debate regarding the use of estrogen therapy, either as a standalone intervention or in combination with progestogens, in women with postmenopausal osteoporosis irrespective of bothersome menopausal symptoms. Furthermore, estrogen therapy should be used not only for the prevention of postmenopausal osteoporosis but also as the first line in the treatment of early postmenopausal women at high risk of osteoporotic fracture.