British journal of radiology

Abstract

Over the last decade, hormone replacement therapy (HRT) has gone from being a first line treatment for postmenopausal osteoporosis to a last resort option. The place of this therapy in clinical practice is questionable. Despite being proven to have high efficacy as a treatment for both declining bone mass and climacteric symptoms in peri- and post-menopausal women, the general consensus is now that the risks of this treatment outweigh the benefits. However, the pharmaceutical companies have yet to develop a treatment for the symptoms of menopause that can fill the niche left by HRT, and so this population of women are left with few options that provide comparable results. In light of these issues, this essay reviews the basis, mechanisms, and efficacy of HRT, as well as giving consideration to the changes in it's use and the controversy surrounding the long-term risks of this treatment. The conclusions that can be drawn from this review of hormone replacement are that, while it has long-term problems and has been plagued with negative representation in the media, the basic mechanisms and efficacious results still provide promise. While HRT may never recover from the damages to it's reputation with both clinicians and patients, there is hope that modification of dosages and the forms of treatment given, along with alteration of factors such as the route of admission, will give a new lease of life to hormone replacement therapy.

Introduction

One of the most important health problems facing older women today is that of osteoporosis. Osteoporosis is defined as a 'loss of bony tissue resulting in bones that are brittle and liable to fracture' [1]. It is characterised by a decrease in bone mass, measured as bone mineral density (BMD). Osteoporosis can be diagnosed as such, using a DEXA (dual-energy x-ray absorptiometry) scan. In this setting, it is identified in subjects who have a BMD more than 2.5 standard deviations below the mean ('normal') BMD of a healthy young adult [2]. However, osteoporosis may also be diagnosed based simply on patient history, the presence of relevant risk factors, and the occurrence of fractures. It is not commonplace to carry out DEXA screening for osteoporosis prior to symptom presentation, and as a result it often exists as a 'silent' disease, going undiagnosed until an event (i.e. fracture) occurs.

Risk factors for osteoporosis include various conditions that affect a person's hormonal balance, either leading to a deficiency of oestrogens (and/or androgens), or having a direct effect on bone homeostasis e.g. conditions such as hyperthyroidism and hyperparathyroidism. There are also lifestyle factors which can increase the risk of osteoporosis, including smoking, excess alcohol and caffeine intake, inactivity, and malnutrition. Osteoporosis is more likely to affect women than men - this can be attributed to a variety of factors including lower peak bone mass, loss of oestrogen protection after menopause, and greater life expectancy [2].

It is estimated that osteoporosis affects around 3 million people in the UK [3]. 50% of women and 20% of men over 50 years old experience a bone fracture [4], and osteoporosis is a major causative factor of these events in older people. Various types of fractures have an increased risk with osteoporosis. Most commonly occurring is hip fracture, followed by vertebral fractures, and fractures of the distal wrist. Hip fracture has an estimated mortality of 24% over the first year [5], and those that survive are likely to suffer long-term morbidity and a decrease in their general quality of life. The majority of hip fractures, especially in the elderly, occur due to a fall from standing height or lower, i.e. are not due to major trauma [2]. This indicates fragility in the skeleton, such as that seen in osteoporosis.

Postmenopausal osteoporosis, the most common form of the disease, is low bone mineral density in women due to an acceleration in the natural age-dependent loss of bone mass. This acceleration is due to the loss of oestrogen-mediated protection of bone when circulating oestrogen levels drop during and after menopause.

In outlining the relevant bone physiology and mechanisms by which osteoporosis exerts its effects, and at which treatment can be targeted, this essay will review the mechanisms of hormone replacement therapy, and appraise it's use as a preventative and alleviating treatment for this disease. It aims to provide some insight into the future of HRT by examining the benefit and risks of the treatment and taking a look at the road map of it's use over the last 10 years.

The role of oestrogen in bone homeostasis

Both trabecular and cortical bone in the body is constantly being remodelled. Osteoblast cells facilitate the synthesis and mineralisation of bone, while osteoclasts act to resorb bone. The resorption and formation of bone within each bone-remodelling unit is said to be coupled, so that over the short term bone mass remains stable. Over the long term however, external influences can have an effect on the resorption and/or formation of bone, leading to an imbalance. In the case of osteoporosis, the formation of new bone drops below the resorption of existing bone, leading to a decrease in bone mineral density and overall bone mass [2].

Bone mass increases during growth, and is then maintained until around 30 years of age, at which point bone mass is said to be at it's peak. After the 3rd or 4th decade of life, age-dependent loss of bone mass begins. This is a slow, steady and progressing process, and is irreversible. It follows that the higher one's bone mass is at it's peak, the longer it will take for bone mineral density and mass to become depleted to an osteoporotic level [2]. Fortunately, although loss of bone mass is irreversible, the rate of loss can be decreased, for example by stimulation of oestrogen receptors.

Oestrogen is a steroid hormone, produced by pre-ovulatory and luteinised granules, and the theca interna cells, of the ovaries. It is the single most important factor in the maintenance of bone mass in women [7]. Oestrogen has various regulatory effects on bone metabolism during different phases of life:

  1. Activation of oestrogen receptors stimulates the GH/IGF-1 axis, which is involved in growth regulation. Oestrogen is thereby indirectly involved in the stimulation of growth in puberty. [8]
  2. Oestrogen acts, along with GH, to meet increased demand for calcium and phosphate when there is a high rate of bone mineralisation e.g. during maturation of bone in the pubertal growth spurt. It does this by increasing the activity of enzyme 1a-OHase in the proximal kidney tubules, which increases the levels of calcitrol (active vitamin D) [8].
  3. Oestrogen receptors are present on the epiphyseal growth plate of maturing bone. When oestrogen is present at these receptors, ossification of newly laid cartilage matrix occurs, causing fusion of the growth plates and termination of longitudinal bone growth. In this way oestrogen has a role to play in determining 'bone-age' [8].
  4. Oestrogen protects bone mass via stimulation of the C-cells of the thyroid gland, which induces an increase in plasma calcitonin levels. Calcitonin directly inhibits osteoclasts, and so decreases resorption of bone [8].
  5. Oestrogen activates nuclear oestrogen receptors on osteoblasts, resulting in inhibition of osteoblast production of TNF-a and IL-1 cytokines. This in turn inhibits the production of other cytokines, namely IL-6 and GM-CSF. Oestrogen also decreases the level of IL-1 and TNF- a cytokines via inhibitory action on blood leukocytes. The net effect of this reduction in cytokine production is to decrease the rate of bone resorption [8].

However, not all these effects of oestrogen are relevant to the development (and therefore treatment) of primary, postmenopausal osteoporosis. For example, in primary osteoporosis decreased plasma calcium levels are not observed [2], which limits the therapeutic value of oestrogen's influence on calcium-phosphate homeostasis. Conversely, in secondary osteoporosis, e.g. due to malnutrition, GI disorders of malabsorption, or hypoparathyroidism etc., depleted plasma calcium levels may be a causative factor, in which case the influence of oestrogen on vitamin D activation (and therefore it's indirect enhancement of plasma calcium levels) could be useful.

The most relevant effects of oestrogen, in terms of primary postmenopausal osteoporosis and treatment with HRT, are therefore it's action on calcitonin and cytokine levels. The decreased levels of oestrogen experienced in women during/after the menopause are thought to interfere with immune-regulation, the primary effect of which is an increase in the production of certain cytokines, namely IL-1, IL-6, TNF-a and GM-CSF.

Il-1 (interleukin-1) and TNF-a (tumour necrosis factor-a) are both cytokines produced by monocytes and osteoblasts. They activate osteoclast differentiation from precursor cells, and are also thought to indirectly increase resorption via osteoblasts. In addition they stimulate the production of IL-6 and GM-CSF. IL-6 (interleukin-6) and GM-CSF (granulocyte macrophage-colony stimulating factor) are cytokines produced indirectly from osteoblast cells. They also activate osteoclast differentiation from haemopoetic stem cells [2][8].

By increasing the circulating levels of these cytokines, the menopausal reduction in oestrogen interferes with the immune-mediated mechanism of control over bone resorption, and the coupling of formation to resorption becomes imbalanced.

In addition to this, decreased levels of oestrogen also mean that the stimulation of C-cells in the thyroid gland seen in pre-menopausal women does not occur, and protective levels of calcitonin (for bone mass) are not produced.

Hormone Replacement Therapy

In this setting, HRT refers to the replacement of oestrogen. HRT can be given as a treatment for problems arising from the decreased level of circulating oestrogen during and after the menopause in women. The exogenous oestrogens used in HRT can be synthetic, derived from plants, or equine [9], and are structurally very similar to the oestrogen found naturally in the body. The two figures below show the almost identical structures of oestradiol and a conjugated oestrogen. Oestradiol is one of three endogenous form of oestrogen found in the human circulation [10], while the conjugated oestrogen is made up of oestrone sulphate - the sulphated form of another endogenously produced oestrogen, and equilin sulphate - the sulphated form of an oestrogen found in horses [11]. As can be seen, the only structural difference between the two compounds is the addition of a sulphate group to the conjugated oestrogen, in the place of an OH group on the oestradiol.

In hysterectomised women oestrogen replacement can be given alone, whereas in non-hysterectomised women it is generally prescribed with progestogen. The progestogen opposes the action of oestrogen on the endometrium, preventing the increased risk of endometrial cancer that would usually be carried with oestrogen replacement, and this form of treatment is known as opposed HRT [12]. Progestogen can be derived from progesterone or testosterone.

Postmenopausal osteoporosis arises due to low levels of circulating oestrogen. Thus far, almost all of the most effective methods of treating osteoporosis have been anti-resorptive [13] i.e. methods which aim to correct the imbalance of bone resorption over formation, and therefore help to maintain bone mass. HRT is one of the anti-resorptive agents that have been used as such, and treatment with HRT after the menopause can prevent the accelerated depletion of bone mass that is observed in women at this time. It does this by restoring levels of circulating oestrogen towards the pre-menopausal parameters, which helps to restore immune-mediated control over bone resorption, decreasing cytokine levels and hence bone resorption. It also allows physiological stimulation of the C-cells of the thyroid gland to increase circulating calcitonin levels. HRT is therefore used as an anti-osteoporotic, aimed to decrease the prevalence of low bone mineral density, and most importantly, to reduce the occurrence of fractures as a result of abnormal fragility of the skeleton. It is important however, to appreciate that neither HRT, nor any of the other anti-resorptive treatment agents available, can reverse the effects of low oestrogen levels prior to treatment i.e. they can not reverse the loss of bone mass.

Treatment with HRT
  • Length of treatment
  • HRT is not prescribed as a permanent fix for osteoporotic loss of bone mass. During the treatment period it can decrease the rate of bone mass depletion for a number of years, effectively 'buying time' for the skeleton and hence delaying the onset of osteoporosis until later life. While this is obviously beneficial, if HRT treatment is begun at the onset of menopause the patient will need a fairly long period of treatment in order to reduce the risk of suffering an osteoporotic fracture [2]. The average age of menopause in the UK is 52 years [14], and the average life expectancy for women in the UK is now 81.6 years [15], which leaves a long period of time over which bone mass can decrease, and osteoporosis can develop. Unfortunately, the longer periods of treatment that would be necessary to completely prevent this are associated with an increased risk of side effects, and so are not recommended.

    It is logical that with cessation of oestrogen treatment the rate of bone resorption should revert to that of a post-menopausal woman prior to treatment, as is common with many of the competing anti-resorptive agents [2]. However, Bagger et al. [16] carried out a randomized controlled trial of the BMD and fracture risk in women who had received relatively short-term treatment with HRT (2-3yrs) compared to women who received no treatment. They found that even with short-term treatment the risk of fracture was significantly reduced, with an odds ratio of 0.48 (95% CI, 0.26-0.88). In addition to this, the calculated 'number needed to treat' (NNT) was 7, i.e. 7 postmenopausal women need to be treated with HRT for 2-3yrs to prevent one fracture, suggesting that HRT has an exceptionally high efficacy, particularly when taking into account that, as yet, there are no permanent treatments for osteoporosis.

  • Routes of administration
  • There are numerous methods of administration of HRT including subcutaneous implants, nasal sprays, oral administration and transdermal patches [17]. Although in theory, these different routes all act in a similar fashion to release oestrogen into the blood stream, they have been shown to have slightly different effects. For example, the results of the E3N cohort study [18], which looked at the difference in side effects between oral and transdermal oestrogen therapy, show that while oral therapies were associated with a significantly increased risk of venous thromboembolism, transdermal oestrogens were not associated with a significantly increased risk. Similarly, a case-control study into the effect of HRT on the risk of venous thromboembolism in women with a prothrombotic mutation, by Straczek et al. [19], found that while oral oestrogen therapy carried an increased risk of VTE, with an odds ratio of 4.3 (95% CI: 2.6 - 7.2) transdermal oestrogen therapy did not carry significantly increased risk (odds ratio 1.2 (95% CI; 0.8 - 1.7).

  • Progestogen use

Progestogen is generally prescribed with oestrogen in non-hysterectomised woman in order to protect the endometrium from high levels of oestrogen. This also means that treatment can be organised cyclically in women who still have regular or irregular periods, so that their menstrual cycle is maintained until cessation occurs naturally [17]. There are various forms of progestogens, and while they all have similarly beneficial effects on the endometrium, some forms have been associated with detrimental side effects. Fournier et al. [20] carried out a cohort study to evaluate the link between HRT and the risk of breast cancer in postmenopausal women. Their findings were that the risk of breast cancer was significantly increased with HRT containing synthetic progestins, with a relative risk of 1.4 (95% CI; 1.2-1.7). In contrast, when treated with HRT containing micronized progesterone, there was no significant increase, with a relative risk of 0.9 (95% CI; 0.7-1.2). As breast cancer is one of most well publicised risks of HRT, the choice of lower risk forms of progestogen for opposed-HRT should be considered important to good clinical use.

Efficacy of HRT

HRT is the only treatment available for osteoporosis that has been shown to significantly reduce the risk of hip fracture in younger women, and those at risk of osteoporosis, rather than with established osteoporosis [21]. In trials carried out by the Womens Health Initiatve [22] to evaluate the effect of HRT on BMD and fracture rates, treatment with oestrogen plus progestin was shown to reduce the hip fracture risk by 33% (Hazard Ratio; 0.67, 95% CI; 0.47-0.96) in their trial group of post-menopausal women between 50 and 79 years old. While there is evidence that bisphosphonate alendronate reduces the risk of hip fracture, the effect is only significant in women with established osteoporosis i.e. with a bone mineral density more than 2.5 standard deviations from the young adult mean, and did not show a significant decrease in fracture risk in women with a higher BMD [23]. Similarly, another biphosphonate risedronate has been shown to reduce risk of hip fracture in elderly women (70-79 years old), [24] but has not been proven to have significant effects in a younger trial group [22]. Another study, by Komulainen et al. [25], assessed fracture risk in postmenopausal women with an average age of 53 yrs. this study shows similar results to the WHI trials, finding a significantly lower rate of non-vertebral fractures (relative risk 0.43, 95% CI; 0.20-0.91) with HRT treatment compared to placebo.

HRT and SERMs

New agents for the treatment of osteoporosis are constantly under development. Particularly relevant is the development and release of selective oestrogen receptor modulators (SERMS). SERMs such as raloxifene have a similar effect on bone homeostasis as oestrogen itself. Weinstein et al. [26] compared the effects of both raloxifene and HRT on bone turnover in a randomised controlled trial on postmenopausal women, and concluded that both treatment options have a similarly significant beneficial effect on bone turnover when compared to placebo. Due to their selective nature, SERMS do not stimulate the oestrogen receptors in breast tissue, and hence do not carry the risk of breast cancer that is associated with oestrogen therapy, which is the major advantage of this mode of treatment [2]. However, they are likely to carry a similar risk venous thromboembolism as HRT. Lasofoxifene, for example, is one of the newer SERMS being developed, and has been associated with a significantly increased risk of VTE with a hazard ratio of 2.06 (95% CI; 1.17-3.60), even at a lower dose [27]. The major disadvantage of SERMs is that they do not tackle the other, vasomotor, symptoms of menopause. In fact, studies have shown that they can actually increase some symptoms such as hot flashes [28]. Currently, HRT is the only treatment agent for osteoporosis that also addresses these climacteric symptoms, including hot flashes, night sweats, vaginal dryness, sleep disturbance and recurrent UTIs [29]. These symptoms can dramatically affect the well being and quality of life of peri- and post-menopausal women, and so the benefit gained from HRT can be invaluable. Additionally, addressing these symptoms could have a positive effect on treatment adherence, particularly since depletion of bone mass is not symptomatic and so patients are likely to feel little benefit from treatment which is purely anti-osteoporotic.

Other benefits seen with HRT

Treatment with HRT can also reduce the risk of cancer of the colon and rectum. Rennert et al. [30], reported a significant reduction in the relative risk of colorectal cancer in a case-control study of peri- and post-menopausal women in Israel. There was an odds ratio of 0.67 (95% CI; 0.51 - 0.89) for women receiving oral HRT compared to those not receiving treatment. However, it is worth noting that this decreased risk was not associated with non-oral HRT, and was subject to modulation by external factors such as aspirin intake and exercise levels. Furthermore, the California Teachers Study reported a 51% reduction in the risk (RR = 0.49, 95% CI; 0.35-0.68) of invasive colon cancers with between 5 and 15 years of hormone therapy [31].

Adherence and economic value

The combined benefits to osteoporosis risk and menopausal symptoms means that HRT is also a cost-effective method of treatment, as it can tackle both clinical issues. In a pharmacoeconomic appraisal of HRT treatment, Whittington et al. found it "both medically and economically justified in women with severe menopausal symptoms"[32], with a positive effect on QALY (quality-adjusted life years) of up to 0.5 in 10 years. However, HRT can only be considered cost-effective if patient concordance with treatment is high. Unfortunately, adherence to HRT has been reported to be lower than that seen with other treatments of osteoporosis in recent years, at just 70% patient concordance, compared to 88% with SERMs and 91% with bisphosphonates [33]. However, this low adherence could be attributed to the currently negative representation of HRT in media and public opinion after the WHI trials and the Million Women Study, which took place in 2002 and 2003 respectively. These studies reported dramatic breast cancer and cardiovascular risks associated with HRT, and promoted the adjustment of national and international guidelines for its use for the treatment of both menopausal symptoms and osteoporosis, and hence had a profound effect on the use of HRT. Reflecting these events, the use of HRT was seen to drop by a staggering 50% between 2001 and 2007 in Israeli women over 45 years of age [34].

Side effects of HRT

Like any treatment, HRT is associated with certain side effects, including fluid retention and bloating, indigestion, nausea, breast tenderness, and headaches. In addition to these problems, women using opposed-HRT (i.e. combined oestrogen and progestogen) may also suffer from mood swings and depression [14]. It is however, worth noting that these side effects do not occur in all women, and are likely to improve over time. Alternatives to HRT also come with side effects, for example SERMs are associated with hot flashes, night sweats, vaginal discharge, mood swings and fatigue [35].

Long-term risks of HRT

The long-term risks associated with HRT are the major disadvantage of this mode of treatment. It had long been theorised that HRT may be linked to an increased risk of breast cancer, but until 2002 there was no clear consensus on the risks involved. In 2002 the Women's Health Initiative carried out a randomised controlled trial to assess the risks and benefits of HRT treatment [36]. The trial included over 16000 women in the US ranging from 50 to 79 years of age, and compared the occurrence of two primary outcomes - invasive breast cancer and coronary heart disease, in the intervention group (who received opposed-oestrogen therapy) compared with the placebo group (who received no treatment). The results of the trial were dramatic, and the study was halted prematurely, after an average follow up of the participants for 5.2 years, as the risks of the treatment were considered to exceed the benefit to participants. The outcomes were as follows: coronary heart disease had an estimated hazard ratio of 1.29 (95% CI; 1.02-1.63), and breast cancer an estimated hazard ratio of 1.26 (95% CI; 1.00-1.59). This shows an increased risk of both outcomes with HRT treatment. In addition to this, the risk of stroke and pulmonary embolism was also increased, and the overall estimated hazard ratio for cardiovascular disease with HRT was calculated to be 1.22 (95% CI; 1.09-1.36).

Another study, the Million Women Study [37], was carried out in 2003 to further investigate the link between breast cancer risk and HRT. This was a cohort study, which looked at over 1 million women in the UK between 50 and 64 years of age, and compared their history of HRT use, cancer incidence, and death. The results of the study were as follow: women currently using HRT had a significantly increased risk of developing breast cancer, with an adjusted relative risk of 166 (95% CI; 158-175). This risk was higher when using opposed-oestrogen therapy than with unopposed HRT. However, the study did not show a significant increase in the risk of breast cancer in women who had used HRT in the past, suggesting that the risk is temporary.

The result of the publication of the WHI trials and the MWS, and the media frenzy that ensued, was that the use of HRT for the treatment of both osteoporosis and menopausal symptoms decreased dramatically. Both the UK Committee on Safety of Medicines (CSM) and the European Agency for the Evaluation of Medicinal Products (EMEA) have advised against the use of HRT since the end of 2003 due to safety concerns. While the benefit:risk ratio of HRT treatment for climacteric symptoms is considered to be positive, the balance is not considered favourable for the treatment of osteoporosis [21]. Therefore, general protocol in the UK is now that HRT should only be considered for use in women with severe symptoms of menopause, and should be used at the lowest possible dose for the shortest possible time [38], effectively preventing it's use for the treatment of osteoporosis, and resulting in a dramatic decrease in it's use. The situation is similar in most parts of Europe, for example, in the Rhones-Alpes area of France, prescriptions of HRT decreased by 39% between 2004 and 2006, while prescriptions for bisphosphonates and raloxifene (a selective oestrogen receptor modulator) increased by 21% and 18% respectively [39].

However, the accuracy of both the WHI trials and the MWS has been scrutinized, and the validity of the results questioned. The design and findings of the WHI trials [36] have numerous important flaws. Firstly, the administration of HRT treatment did not wholly reflect how HRT would be prescribed in clinical practice, with 66% of the intervention group participants falling between 60 and 79 years of age, meaning the majority of participants began HRT at least 10 years after the average age of menopause in the US [40]. In addition to this, the participants showed a low level of adherence to prescribed treatment, with 42% of participants in the intervention group stopping treatment at some point. There was also a high number of participants included in the trial with pre-existing health problems and risk factors for disease, for example 35% of the intervention group were being treated for, or suffered from hypertension, and 34% had a body mass index over 30, with the average lying at 28.5. In addition, just over a quarter of all the participants in the trial were recorded as having prior hormone use, meaning that some women in the intervention group were not receiving HRT for the first time. It has been established that longer-term treatment increases the associated risks of HRT, and so inclusion of these participants is detrimental to the validity of the results, particularly when applied to the use of HRT in practice [41]. In terms of the statistical results from the trial, neither the risk of invasive, nor in-situ, breast cancers was increased to a nominally significant level when comparing intervention and control groups. Although there was a significant increase in the risk of CHD in the intervention group, there was no significant increase in the number of deaths due to CHD.

The Million Women Study [37] has similar flaws. Firstly, as a cohort study, the results can be given less inherent reliability than those of a randomised controlled trial or meta-analysis. Secondly, the cohort of women involved in the trial could not be considered wholly representative of the population at the time, as the method of recruitment was somewhat biased - an invitation to enrol upon scheduling a mammography [42]. This selection bias can be seen in the number of participants in the study who were currently using HRT, which was much higher than in the general population at over 26%. There were also various inconsistencies with the results of the study, for example, although the relative risk of breast cancer in current users of HRT was stated to be statistically significant at 1.66 (95% CI; 1.60-1.72), the risk in past users, even in those for whom the last use was less than 5 years ago, was not increased significantly, which seems unlikely, if not completely implausible.

The flaws in the design and implementation of both these trials mean that is important to look elsewhere for evidence in respect to the associated long-term risks of HRT. A population based cohort study carried out by Pentti et al. [43], looked at the link between HRT and mortality rates in over 11 000 women from 52 to 70 years old. The results of the study showed that the use of HRT was not linked to a significant increase in general mortality, or mortality due to CHD. This confirms the results of the WHI trial in respect to CHD mortality, and provides further support of the theory that although HRT may increase the risk of CHD, the associated disease cases are mild in severity, and unlikely to be fatal. There was also no significant increase in the mortality from breast cancer with use of HRT for 5 years or less. However, in women who received HRT treatment for 5 years or more, the adjusted hazard ratio of mortality due to breast cancer was 2.62 (95% CI: 0.98 - 7.00), providing more evidence that longer-term HRT might increase this risk. In further support of the association between HRT and breast cancer is the correlation between the decrease in HRT use, and the declining incidence of beast carcinoma seen in many populations across Europe and the US between 2001 and 2006. Although this correlation merely confirms an association, rather than causation, the fact that the most dramatic decline has been seen in oestrogen-receptor positive tumours, and in the 50-60 years age group, suggests a more causative relationship between HRT and breast carcinomas [44]. More detailed investigation is necessary to provide a reliable insight into the cardiovascular risk carried with HRT, and the effect of shorter-term treatment on breast tissue.

The future of HRT

The standard protocol for the use of HRT is now generally based around the idea of giving the lowest possible dose for the shortest possible time, in order to minimize the risk of long-term side effects. It is not generally recommended as an anti-osteoporotic, rather for the treatment of climacteric symptoms [38]. Due to this new protocol, there has been a lot of research into the effects of 'low dose' oestrogens, and their efficacy as a treatment method.

Administration of low dose oral HRT (1mg/day of 17-estradiol) has been shown to provide a significant reduction in hot flashes and cyclical bleeding time in perimenopausal women, suggesting that a lower dose could be effective. In addition, a significant reduction in the levels of triglycerides, fibrinogen, and total and LDL-cholesterol has been observed with this mode of treatment [45]. Eilertsen et al. [46] found that while conventional HRT (2mg/day of 17-estradiol) caused a significant increase in the circulating levels of D-dimers, a marker of activated coagulation, low dose HRT (1mg/day of 17-estradiol) did not cause an increase. The findings of both studies provide evidence for a dose-response relationship between cardiovascular risks such as venous thromboembolism and HRT. A review of randomised clinical trials showed that low dose HRT had similar effects on bone mineral density and various menopausal symptoms to a conventional HRT [47]. In support of this, Gass et al. [48], found that over 1 year both low dose (0.3mg conjugated equine oestrogen) and conventional dose (0.625mg conjugated equine oestrogen) HRT preserved bone mineral density, measured at the spine, femur and trochanter, in postmenopausal women. In summary, the research up until this point has been positive in respect to the efficacy of lower dose HRT. However, further investigation into its association with fracture risk, long-term cardiovascular and breast cancer risk is needed to be able to draw firm conclusions concerning its suitability for clinical use [49].

In addition to dosage levels, the route of hormone administration can have an impact on its efficacy and the risks of certain associated side effects. This is therefore another important factor to consider in the future use of HRT. As has been previously discussed, studies have shown that transdermal oestrogen therapy is not associated with the significant increase in risk of venous thromboembolism seen with oral oestrogen therapies [18][19]. It has also been shown that transdermal oestrogen therapy can decrease both diastolic and mean blood pressure in postmenopausal women over a 2 years treatment period [50], which would allow control of blood pressure and minimize the cardiovascular risks that has been associated with HRT. In a comparative trial of oral oestrogen therapy versus transdermal oestrogen therapy [51], low dose transdermal HRT was associated with an increase in IGF-1, and positive modulation of bone metabolism, which resulted in a significant increase in bone mineral density (p<0.01) over 12 months, whereas oral HRT was associated with a significant decrease in IGF-1 levels over 12 months, and a statistically insignificant increase in bone mineral density. Although numerous other trials have shown oral HRT to have a significant effect on bone mineral density, suggesting that the results of this study may not be in keeping with the norm, the higher efficacy of transdermal therapy observed could still be considered important. Transdermal HRT has also been shown to be more effective in treating certain climacteric symptoms than other forms of HRT, for example Odabasi et al. [52], found that transdermal therapy produced a significant improvement in vaginal atrophy over 12 weeks of treatment that was not seen with intranasal oestrogen therapy. Again, further investigation into the efficacy and the level of long-term risk associated with transdermal HRT is desirable, however, the research up until this point suggests that this route of administration could not only maximize the efficiency of treatment, but also minimize the risks involved, and hence could be a key component of HRT in the future.

Conclusion

The mechanisms of hormone replacement therapy are well based, providing one of the most 'natural' forms of treatment for postmenopausal osteoporosis and climacteric symptoms by simply compensating for the causative decline in oestrogen seen during and after menopause. However, this favourable mechanism and its proven efficacy are not enough to justify dismissal of the risks involved. While the 2 main studies investigating the long-term risks of HRT (Women's Health Initiative trials and the Million Women Study) may have been flawed, it would be foolish to disregard the findings completely, particularly concerning the risk of breast cancer, which is currently the second most prevalent form of female cancer in the UK population [53]. Nevertheless, the place of HRT and it's use in practice should not be abandoned, particularly as, as yet, there are few suitable options to fill it's role. The recent studies into the efficacy of lower doses provide promising results. In addition, simple variations in the type of progesterone used in opposed treatment, and the route of administration of therapy can have a substantial affect on the risks involved with HRT. With further investigations into the long-term risks, it is the author's belief that hormone replacement therapy still has a place in the treatment of postmenopausal osteoporosis, and that, in fact, it is worth saving.

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