The Clinical Choice between Estrogen and Bisphosphonates to Prevent Bone Loss: Are Women Being Misled?

“… women at high risk of developing osteoporosis under the age of 60 years are prime treatment targets for estrogen in order to maximize the impact on prevention of osteoporosis.”

A progressively rising benchmark for quality of life has characterized the developed economies over the last 50 years. During the last two decades, access to the internet has revolutionized the way we, and those in the developing world, acquire knowledge. The reach of awareness of health-promoting concepts has grown and poses a challenge to health provision systems. In general, doctors are trained in curative medicine, but to a much lesser degree in preventative medicine. Areas of interest to women experiencing the climacteric and menopause transition are the cures of menopausal symptoms, management of sexual dysfunction, overcoming cognitive slowdown and prevention of osteoporosis. As women witness the appalling consequences of osteoporosis in our increasingly aging society, they become motivated to identify their own risks and methods of preventing bone loss.

Estrogen plays an essential role in skeletal growth and bone homeostasis in both men and women. Increased bone turnover during lactational amenorrhoea is one of the finest examples of modulating tissue compositions during reproduction. The associated hypo-estrogenic state tips the balance in favor of osteoclastic activity to enrich breast milk with calcium. When menstruation is resumed with rising estrogen levels, osteoclasts are suppressed, allowing osteoblasts to rebuild the skeleton in preparation for the next pregnancy [1]. Nature has adopted this efficient mechanism of providing the woman with a new wave of estrogenic action to rebuild her bones. Estrogen appears to have successfully survived the vicious randomized eliminating trials of nature over the last 1.2 billion years as an essential transactivating factor for myriad cellular and molecular processes [2].

Osteoporosis, characterized by low bone mass and increased susceptibility to fracture, is the consequence of inadequate peak bone mass, excessive bone resorption, reduced bone formation or a combination thereof. The disease is also influenced by genetic, hormonal and environmental factors. Metabolic changes may influence the more sensitive trabecular bone compared with the cortical bone. The prevention of bone loss, as opposed to the treatment of osteoporosis, should be the aim of an effective healthcare program.

Bone loss is inevitable as part of the aging process, commencing between the ages of 45 and 50 years, at a rate of approximately 1% per annum. However, the menopause does have its own impact on the rate of bone loss. During the first 4 years or so after the last menstrual period an average of 16% of bone mass is lost. The homeostatic mechanisms that regulate physiological bone turnover are tipped toward a higher osteoclastic activity, but unlike lactational amenorrhoea, the bone loss after the menopause is not followed by recovery, as the ovaries are no longer able to produce estrogen. If we were able to delay the additional loss of bone mass for 10–15 years, a major impact on the incidence of vertebral and femoral neck fractures and associated deformities and disabilities could be achieved. In a systematic review of randomized clinical trials, estrogen replacement commenced in the perimenopausal period for an average of 6.2 years reduced incident fractures by 52% (95% CI: 18–64%) cost effectively [3]. Indeed, the only noncontroversial result of the Women's Health Initiative publications is that estrogen-only treatment and combined hormonal therapy (HT) reduced the risk of clinical vertebral and hip fractures by 34% [4,5].

Long-term estrogen treatment at high doses not only blunts bone resorption, but also stimulates bone formation, leading to a net anabolic effect [6]. Histomorphometric studies on iliac crest biopsies showed that estrogen is unique in its ability to regenerate bone collagen after its disintegration in postmenopausal women receiving long-term estradiol implants [7], an effect that has not been shown with bisphosphonates.

The available advice includes calcium and vitamin D supplementation for those with deficiencies, and weight-bearing exercises. Weight-bearing exercises would help to stimulate bone repair, but more importantly these exercises improve muscle strength and enhance balance. Avoidance of smoking and excessive use of alcohol also helps to prevent deterioration of bone quality. These measures support the maintenance of peak bone mass and reduce an adverse lifestyle's impact on bone health.

The National Osteoporosis Foundation's guidelines (2010) lists, in alphabetical order, approved therapies for the treatment and prevention of osteoporosis with bisphosphonates, calcitonin, estrogen/HT, raloxifene (selective estrogen receptor modulator) and parathormone [101]. The clinician is left to choose. Not unexpectedly, most clinicians select the first item on the list – the bisphosphonates. By contrast, the NICE guidelines, TA160, have omitted estrogen/HT from the list of recommended treatments [102]. Notwithstanding the gastrointestinal adverse effects of the bisphosphonate family of compounds, they are associated with bone-specific problems, including the development of microcrack fractures [8] and poor healing of dental sockets after dental extraction, as well as the development of atypical spiral fractures of the femur. More importantly, the continuation rate with oral bisphosphonates is rather poor.

A tightly coupled cellular function involving the osteoclasts and osteoblasts ensures that, concomitant with osteoclastic bone resorption, osteoblastic bone formation is maintained [9–11]. As a result, the pronounced inhibition of osteoclastic activity can be detrimental to bone formation, leading to changes in bone quality and strength [12]. This is illustrated in trials of combination therapy of alendronate with teriparatide 1–34 and parathyroid hormone 1–84, and showed that the bisphosphonate blunted the anabolic effects of parathyroid hormones, while the less potent suppressor of osteoclastic activity, raloxifene, did not impair the anabolic effects [13,14].

Raloxifene prevents vertebral fractures, but not femoral neck fractures. Furthermore, raloxifene is associated with an increased incidence of venous thrombosis similar to oral estrogens and may increase the incidence of vasomotor symptoms. In this context, transdermal estradiol is not associated with increased risks of venous thrombosis. Due to the reported stroke in the RUTH study, the recommendation also includes an assessment of the risk for developing stroke before prescribing raloxifene [15,16].

Estrogen exerts positive effects on calcium balance as it improves its absorption, facilitates vitamin D activation and reduces renal tubular loss of calcium which occurs after the menopause. Furthermore, estrogen exerts other effects on calcium balance by promoting the induction of vitamin D receptor, a process that is suppressed by estrogen deficiency and reactivated by estrogen administration [17]. Furthermore, estrogen replacement increases the synthesis of calcitonin [18].

Prevention of bone loss in young postmenopausal women under the age of 60 years using estrogen-based regimens may have other advantages. Contrary to the adverse publicity promoted by the publication of the Women's Health Initiative study results, estrogen treatment resulted in the reductions in the incidence of coronary heart disease and dementia, which are primary examples; while the breast cancer risk was not raised in hysterectomized women who used estrogen-only therapy compared with a placebo [19]. Indeed, there was a reduction of 21% in the incidence of breast cancer in this group of women. Estrogen does not increase the proliferation of breast glandular epithelium, while synthetic progestins and progestogens do [20]. Postmenopausal estrogen use is not a mammary carcinogen [19], but it could promote a pre-existing cancer, while the dose and duration of progestogen/progestin used in HRT appear to be responsible for the increased incidence of breast cancer reported with continuous combined HT. It follows that sequential combined estrogen and micronized progesterone is a safer HRT compared with continuous combined HRT. The main resentment to the use of sequential combined hormonal supplementation in postmenopausal women, it appears, is that withdrawal bleeding is re-established [21].

Women, particularly when suffering estrogen deficiency symptoms, may accept withdrawal bleeding if they understand the safety reasons and that the dose of hormones can be adjusted to minimize the inconvenience. However, doctors in primary care do not appear to be keen on the management of irregular bleeding associated with HRT, should it happen. Furthermore, the economic considerations that underlie the need for endometrial surveillance discourage the regulatory authorities and primary care physicians from such engagement with HRT-related bleeding [22,23].

Since the average age of starting the menopause is approximately 51 years (range: 40–60 years), it follows that women at high risk of developing osteoporosis under the age of 60 years are prime treatment targets for estrogen in order to maximize the impact on prevention of osteoporosis. To adopt this rational strategy is to mimic nature's design to rebuild bone structure and strength; a natural treatment design that has been rendered safe and effective during evolution.

Conclusion

In preventing postmenopausal bone loss, the most effective method is to promote a premenopausal estrogen milieu. This is particularly relevant to women in the first decade after the menopause. The target population is, therefore, the young postmenopausal woman with high risks of developing osteoporosis. Estrogen-based therapies are confirmed to reduce fractures. Where estrogen was thought to be contraindicated or feared for its adverse effects on breast cancer, heart attacks and stroke, it became reasonable to seek an alternative. The literature that followed the initial Women's Health Initiative reports has illustrated the safety of estrogen and the neutral effects of estrogen-only therapy on breast carcinogenesis [24]. Educating women to understand the safety and efficacy of estrogen will enable them to make informed health choices.