Is HRT still indicated for the primary prevention of osteoporosis?

Hormone replacement therapy for fracture prevention

Hormone replacement therapy

In most European countries, the actual guideline on the evaluation of new medicinal products in the treatment of primary osteoporosis is incomplete in that, unlike the previous Note for Guidance on Postmenopausal Osteoporosis in Women (EMEA 2001 Guidance), it fails to address the prevention of osteoporosis indication.

Early prevention of osteoporosis is essential because the majority of fractures occur in the non-osteoporotic population. Furthermore, it is well known that individuals who had one osteoporotic fracture approximately double their risk to have another. Although treatment of osteoporosis can reduce the risk for a subsequent fracture, it cannot eliminate the excess risk. It is therefore essential to maintain bone architecture and quality as early as in the peri- and early post-menopause. Gynecological endocrinologists are therefore greatly astonished that EMEA did not maintain the prevention of osteoporosis by estrogens as a first-line medical intervention in women with an increased risk of osteoporosis and bone fractures in its latest recommendations.

It is well known that the first 5–10 years after menopause are associated with an accelerated rate of bone loss. Primary prevention of osteoporosis is directed at women identified as being at increased risk for the disease but without established disease. Hormone replacement therapy (HRT) has been shown to reduce post-menopausal bone loss and reduce fracture incidence in several RCT studies, including the PEPI [1] and the HOPE trial [2] trial. More recently, the WHI trial, using a fixed combination of conjugated equine estrogens 0.625 mg and medroxyprogesterone acetate 2.5 mg, has shown that the resulting loss of bone architecture and quality preventable with hormone therapy and confirmed the fracture reduction efficacy of HRT, including hip and spine fractures [3],[4]. The WHI trial was of women aged between 50 and 80 years, who were not known to have increased fracture risk and who were supposed to be in general good health. In addition, the Women's Health Initiative [3] has demonstrated fracture prevention with hormone therapy in a non-osteoporotic population, too. This preventive effect is maintained: the PERF study [5] demonstrated that administration of hormone therapy in early post-menopause offers a long-lasting benefit for the prevention of post-menopausal bone loss and osteoporotic fracture. Lower doses than previously thought necessary are now proving effective [2],[6-8], and a very low dose estrogen product has recently been licensed for osteoporosis prevention by the US Food and Drugs Administration.

HRT is an effective treatment for the prevention of osteoporotic fractures in women without established disease. These women tend to be younger, as older women have an increasing prevalence of osteoporosis as defined by bone density criteria [9]. Are younger women with osteopenia, rather than osteoporosis, at increased fracture risk? In the age group of 50–80 years, around 36% of classical osteoporotic fractures occur in those below age 65 years [10],[11]. In the UK, this amounts to more than 100,000 fractures per year in women aged 50–65 years, over 9000 of which are hip fractures [10,11; www.uk2u.net].

There is no doubting the efficacy of HRT for the primary prevention of osteoporosis in post-menopausal women. Its current role in prevention of fractures seems best suited to those younger post-menopausal women with an increased risk. In such a population, HRT use for osteoporosis prevention would be cost-effective [12].

Alternatives to HRT

The currently licensed alternatives to HRT for the secondary prevention of osteoporosis, preventing fractures in women with existing osteoporosis, include bisphosphonates, raloxifene, teriparatide, strontium ranelate, calcitonin and anabolic steroids. Calcium supplements and Vitamin D are licensed as an adjunct to therapy.

Of these, only bisphosphonates such as alendronate, risedronate, ibandronate and zoledronate have been shown to reduce the incidence of hip fractures, yet hip fracture is the most important osteoporotic fracture. However, both alendronate [13] and risedronate [14] and other bisphoshonates have only been shown to prevent hip fracture in elderly women, mean age above 65 years, who already had osteoporosis, with bone density T-score in either hip or spine below –2.5, and in many cases had already sustained a fracture. Hip fractures occur most commonly in elderly women. However, bisphosphonates have not been shown in prospective studies to prevent hip fractures in younger women with increased risk rather than established disease. Furthermore, there are no data available in precocious and in early menopause or in longstanding amenorrhea. However, today, there is an agreement that bisphosphonate use is more appropriate in asymptomatic elderly women being 10 or more years after their menopause than HRT regimens.

Selective estrogen receptor modulators (SERMs) are licensed for the prevention and treatment of spinal osteoporosis in post-menopausal women. They have not been shown to reduce hip fracture risk. There is good evidence (level 1) for a reduction in estrogen receptor-positive breast cancers in users of SERMs. Therefore, there is an indication for SERMs in women with an increased risk for breast cancer. Currently, available SERMs are not able to relieve climacteric symptoms in early post-menopausal women and may make them worse. SERMs have the same thromboembolic risk as per-oral HRT.

Main non-skeletal benefits and riks for HRT

Climacteric syndrome

The uncontested main indication for HRT remains the relief of post-menopausal symptoms, which brings a major improvement in quality of life [15-18]. No other therapy has proved to be more effective than HRT in this respect.

Cardiovascular risk

EMEA expressed concern because of a possible increase of the cardiovascular (CVD ) risk of HRT in December 2003, mainly based on the publication of the first analysis of the WHI data in the combined in the estrogen-only arm [4],[19],]. In fact, the WHI study was not designed, and therefore was not powered, to investigate the consequences of HRT in women below 60 years of age. Therefore, any attempt to present the results of the study as indicating that HRT may inflict damage to the heart in general is profoundly wrong and must be amended.

It should be noted that the recent final analysis of WHI data [20], as well as the latest update of the results of the Nurses' Health Study [21],[22] have uniformly suggest that HRT, when started soon after menopause, does not increase the risk of CVD but may even protect against myocardial infarction. The outcomes in the youngest cohort of the WHI study (age 50–59 years or within 10 years of menopause) confirms previous evidence regarding a favourable effects on cardiovascular risk factors, vascular structure and function in nonatherosclerotic vessels, a reduced insulin resistance and reduction in the risk of diabetes and the preventative benefit of HRT for CHD in the majority of pre-clinical and observational studies. Young healthy post-menopausal women can be started on HRT when clinically warranted without fear of increased cardiovascular disease risk.

Thromboembolism and Stroke

The risks of ET for venous thromboembolism have been overstated in the WHI [23] for the younger study participants. The VTE risk was age-dependent and significantly higher in the older and in obese women (BMI > 25). The same has been found for stroke [24]. As Canonico et al. [25] have shown, there is no significantly increased venous thromboembolic risk in women with parenteral estrogen application. Women seeking HRT who have potential or confirmed risk factors for venous thromboembolism and stroke need individualised counselling; in these situations, transdermal HRT might be preferable to oral formulations.

Breast cancer risk

The intention to eliminate the use of HRT from the prevention of osteoporsis/osteoporotic fractures, as expressed e.g. by EMEA in December 2003, is largely the consequence of the believe that HRT should increase the risk of breast cancer, mainly deduced again from the first publications of the WHI data [26],[27]. However, newer publications from the WHI are showing a quite different picture. Because of its inherent weaknesses, we believe that the MWS ([28]; an observational study and not an RCT) should not be used as part of an evidence base for HRT and should be discounted by regulatory authorities.

The new sub-analysis of the unopposed estrogen arm of the WHI study has modified further the original alarmist messages [29]. The WHI study investigators have released the details of breast cancer and mammography screening data for 10,739 women with prior hysterectomy, who received either estrogen replacement treatment (ERT) or placebo for a mean follow-up of 7.1 years [29]. Thirty percent of the subjects were aged 50–59 years and 24% were 70–79 years old at study entry; over half had never taken ERT prior to the study. The initial report on the estrogen-only arm [4] concluded that there was a non-significant (p < 0.06) decreased risk for breast cancer in ERT users, but subgroup analyses now reveal that first lifetime exposure to ERT at the trial was associated with fewer breast cancer cases as compared to placebo (hazard ratio (HR), 0.76; 95% confidence interval (CI), 0.58–0.99; p < 0.05). On the other hand, mammographic breast density increased in ERT users, with 9.2% having abnormalities in the ERT group versus 5.5% in the placebo group at 1 year (p < 0.001) and a cumulative percentage of 36.2% and 28.1%, respectively, leading to more breast biopsies.

Overall, the WHI study is in line with older observational data [30],[31] and carries the message that ERT for post-menopausal women does not increase the risk of breast cancer up to 7 years. The incidence of diagnosis of breast cancer is increased with prolonged use of estrogen and, to a greater extent, with estrogen/progestogen treatment. Whether all progestogens are associated with an increase in breast cancer risk is currently unclear.

There is evidence that there may be some differences between the various estrogens, progestogens and progesterone in terms of their effect on the risk of breast cancer, but this requires more studies to confirm.

In conclusion, patients should be reassured that the possible risk of breast cancer after longterm HRT use (47 years in the WHI) is small and is comparable to the risk of a 1-year delay in menopause. Breast cancer risk is influenced by the total duration of exposure to endogenous and exogenous estrogens and progestogens. Some progestogens may increase the estrogen-dependent proliferation of mammary tissue. The WHI found no increase in breast cancer risk for duration of 7 years in participants with no prior use of HRT [32].

HRT and total mortality

There is no increase in total all-cause mortality in women using HRT [33], as might be the case if there were a significant increase in the risk of CVD and breast cancer. In contrast, in younger women (50–60 years, or starting HRT less than 10 years after menopause), a recent metaanalysis [33] suggests a significantly decreased risk of all-cause mortality. This supports the ‘window of opportunity’ theory where early use of HRT is associated with preventative cardiovascular benefits and is in agreement with the latest data from both the WHI and the Nurses' Health Study.

Conclusions

Once again, it is apparent that the alarmist reports that spreads worldwide when the first results of the WHI study were published in 2002 were unjustified based on the more recent further analyses, particularly in peri- and early post-menopausal women. It is very regrettable that, as a result, so many women and their medical advisors have lost confidence in the merits of HRT, which will now be difficult to redress. Nevertheless, they should be reassured that, once recommended for an approved indication, with correct timing and after proper individual considerations, ERT/HRT is an effective therapy that may even have some extra benefits (cardiac, metabolic) in certain subgroups of women, for the period of time investigated in the WHI study. The risks of ERT/HRT have been overstated. Lower or ultra-low dosages of ERT/HRT may have an even better safety profile.

Finally, HRT is less expensive than any of the alternatives, and thus its use for primary prevention should be actively encouraged targeting women in their early post-menopause at high risk for fracture, such as those with osteopenia, with a family history of hip fracture, with a low body mass index or with a history of corticosteroid use. Bisphosphonates may be the more cost-effective intervention for elderly osteoporotic women. However, new data from a long-term prospective study suggest that even limited HRT use in women during early menopause may result in fracture reduction later [5]. A recent analysis of the WHI study data also showed that overall fracture benefit was maintained 16 months after discontinuation of estrogen plus progestogen [34]. Both these findings need to be confirmed.

With regard to safety issues, some regulatory authorities may have misinterpreted the new data from the recent studies such as the WHI.

HRT should be started with the lowest appropriate dose and increased if necessary.

Although low and ultra-low doses have been shown to be effective for menopause symptom, relief data on reduction of fracture risk are missing. Women with premature ovarian failure generally require higher doses of HRT than those conventionally used in peri- and post-menopausal women. Arbitrary limitations on duration of therapy should be avoided. Benefits, risks and patient preferences should be discussed at least annually. Counselling should include discussion of benefits and risks in terms of absolute numbers of events rather than percentage changes.

In conclusion, HRT should be considered a first-line option for the primary prevention of osteoporosis-related fracture in precocious menopause even if asymptomatic as it has been postulated already in 2006 by the International Group on HRT and Regulatory issues (35). In the absence of data for the efficacy and safety of alternative preparations, HRT should be recommended in post-menopausal women at risk of osteoporosis-related fractures below the age of 60 as a first-line therapy. It should also be available to those older women with increased risk who either have persisting menopausal symptoms or who make an informed choice to use it.