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The life expectancy of women has risen in the past century from 48years to more than 80. The decline of endogenous estrogen production (in particular, the principal circulating physiological hormone, 17β-estradiol) at menopause (which occurs at an average of 51years) is often accompanied by a series of functional disorders that affect quality of life (QoL). This estrogen deficiency affects different tissues and results in an increase in the prevalence of various disorders, including but not limited to osteoporosis and cardiovascular disease. Hormone therapy for menopause is a relatively recent biomedical challenge, which underwent a downturn after the Women Health Initiative study of older postmenopausal women. We will summarize the WHI findings in the first part of this article. At Inserm unit 1048, we are working on understanding the protective effects of estrogen against the development of atherosclerosis and type 2 diabetes in murine models. We have also focused in recent years on modeling the impact of estrogen in thrombosis models, to attempt to clarify the complex relation between estrogen and thrombotic risk. In part II of this article, we will describe a new strategy of hormone therapy for menopause, combining estrogens and selective estrogen receptor modulators (SERM). We review the scientific underpinnings of this strategy, which may enable the renewal of hormone therapy for menopause., (Copyright © 2015 Elsevier Masson SAS. All rights reserved.)

This document has been archived because it contains outdated information. It should not be consulted for clinical use, but for historical research only. Please visit the journal website for the most recent guidelines.

Osteoporosis is an increasing public health problem. The bisphophonates are the most useful treatment used through the world to prevent osteoporotic fractures. Their large prescription revealed an unpredictable side effect: the atypical fracture. These fractures appear in the subtrochanteric or diaphysal femoral proximal site, spontaneously or after a low trauma, and could be bilateral. X-rays shows a transversal or oblique fracture with a spur in the cortex and with a diffuse thickening of the cortical of the proximal femur. Expert's recommendations are current in progress to well understand and managed this problem. Here we report three cases of atypical femur fractures occurred in our Centre of bone diseases with some management and treatment propositions.

The results of the fracture risk assessment tool (FRAX) could be modulated. Calcium supplements are still in the middle of a cardiovascular controversy. New immunological properties of vitamin D are reported. Denosumab is effective for the prevention of all fractures and can be used without renal limitation. Atypical subtrochanteric femoral fractures are more frequent in case of treatment with bisphosphonates. The teriparatide is effective in various bone diseases. Bazedoxifene, a new SERM is now available. A meta-analysis fails to demonstrate the effectiveness of vertebroplasty on pain relief in case of osteoporotic vertebral fractures.

In this review article an update of the menopause hormone therapy is presented (MHT). MHT is the most efficient therapy for climacteric symptoms. It prevents also osteoporosis. Nevertheless, since prolonged use is associated with increased health risks, other therapies, combined with calcium and vitamin D, are preferred for women who suffer from osteoporosis without climacteric symptoms. Increased breast cancer risk has been reported, after 5 years of use, in women treated with a fixed combined regimen of oestrogen and progestin (0,625 mg conjugated estrogens (CEE) + 5 mg de medroxyprogesteron acetate (MPA) (WHI-EP), while a reduced risk has been reported in women using oestrogen only (0,625 mg conjugated estrogens) (WHI-E). In women without risk factors, the attributable risk of suffering from a stroke or thromboembolism, following using MHT, is slow in women younger than 60 years of age. While, MHT (WHI-EP), was associated with an increased risk of coronary disease, in women who started their treatment around the age of 67 years, oestrogen only treatment (WHI-E), has been associated with a reduced coronary risk in women who initiated the therapy at a younger age (between 50-60 years), suggesting that the risks vary in relation to the used regimen and the treated population.

The number of molecules acting on bone turn over rapidly increasing. The idea to use them on bones erosions is not new, however this year a new molecule confirms the suitability of such an approach with the demonstration of efficency in both postmenopausal osteoporosis as well as in the prevention of bone erosions in rheumatoid arthritis. Denosumab, a human monoclonal antibody against RANKL (Receptor Activator of Nuclear factor-KB ligand), decreases the fracture risk in postmenopausal osteoporosis and prevents new bone erosions in rheumatoid arthritis. Of simple use, it appears to act rapidly, to be efficient with a sustain benefit. The tolerance seems excellent, and now we'll have just to wait for its licensing.

Despite advances in the prevention and treatment of fragility fractures, their prevalence continues to grow. The identification and treatment of osteoporosis in these high-risk patients are widely reported to be inadequate. The results of the 2002 and 2006 "Orthopaedic Surgeon Survey" under the auspice of BJD and IOF have shown a better involvement of the orthopaedic surgeon in osteoporosis management during his routine clinical practice. The orthopaedic surgeons knew that fragility fractures in patient over 50 years old require investigation for osteoporosis. Although some surgeons agreed to initiate investigation and inform patient about new osteoporosis fracture risk, the majority did not institute medical treatment and thought that the patient primary care provider or rheumatologist should be responsible for medical care. This round table highlights the current aspect of management of fragility fractures and focuses on diagnosis imaging techniques, pharmacological treatment as well as recent advances in implant design and surgical techniques.

Background: Postmenopausal osteoporosis is especially female pathology, whose incidence increases with age., Aim: The purposes of this study are to evaluate the level of bone turnover by the determination of markers of bone formation (PAL, BAP) and marker of bone resorption (CTX) in the osteoporotic women, to study the correlations between bone biochemical markers, clinical parameters and radiological measurements and to assess the interest of biochemical markers therapeutic monitoring after 6 months of antiresorptive treatment., Methods: The authors report a prospective study of 134 osteoporotic women classified in two groups according to the presence of osteoporotic fracture. Patients of the first group G1 (n=102) with fractures, were treated by the bisphosphonates (risedronate), whereas the ones of the second group G2 (n=32) without fractures, were submited to calcic supplementation and vitamin D., Results: The analyses showed that the femoral and lumbar BMD were statistically lower in the presence of osteoporotic fractures. However, the values of CTX were statistically higher in the patients of G1 group compared to those of the G2 group (0,708 +/- 0,332 ng/ml versus 0,514 +/- 0,225 ng/ml). The CTX were statistically correlated with the femoral and lumbar BMD (r = -0,21, p<0,05 and r= -0,348, p<0,001). The hypovitminosis were observed in 50,98% (52/102) of women with ostéoporotic fractures, whereas it was only 25% (8/32) in women without fractures. After 6 months of treatment by the bisphosphonates, the PAL, the BAP and the CTX have decreased with an average of, respectively, 19%, 46,5% and 62,9%. These variations were significantly more important in G1 group., Conclusion: The biochemical markers of bone turnover, in particular those of the resorption (CTX), can predict the postmenopausal woman's bone loss evaluated by BMD, the risk of fractures and the efficiency of the bone treatments.

Post-menopausal osteoporosis is a public health problem, because of its extreme frequency and its related fractures. Gynaecologists play an important role in the early detection of patients whose bones are at risk. During the consultation, a routine examination, asking pertinent questions and taking height and weight measurements, allows for the discovery of modifiable risk factors - diet, life style: physical activity, alcohol and tobacco consumption, etc. Gynaecologists are in a particularly good position to intervene. Indeed, they can inform and advise these patients at risk, by recommending a diet rich in calcium, vitamin D and protein, maintaining a healthy BMI, a sufficient exposure to sunlight, daily physical activity with a preference for weight-bearing exercise, avoiding smoking and excessive alcohol. These simple changes for a healthy life style can slow down the loss of bone density, and this well before any loss due to estrogen deficiency.

Corticosteroid-induced osteoporosis is common but too often unrecognized, and its management remains insufficient. Bone loss is variable from one patient to another and thus difficult to predict, but all treated patients must be considered at risk. There are tools to assess absolute fracture risk in this case as there are for menopause-associated osteoporosis, and they may help guide the clinician in decision-making. Recent guidelines help the physician to define indications for bone mineral density testing and for therapeutic management. Bisphosphonates are currently the first-line treatment for patients with fractures or elevated fracture risk during corticosteroid treatment.

Every year in France, we observe 60,000 vertebral fractures, 50,000 hip fractures and 35,000 wrist fractures. However, only 20% of these patients receive adequate pharmacologic therapy to prevent new fractures and their complications. At the present time, clinicians have not a perfect knowledge of the therapeutic class of SERMs (Selective Estrogen Receptor Modulators). In this paper, the authors show the strong capacity of these drugs to produce, in osteoporotic postmenopausal women, major therapeutic effects on bone (reduction of fracture risk), on breast (reduction of cancer risk), and without any side effects on arterial diseases except an increased risk of venous thromboembolism.

Since the diffusion of the WHI's trial and MWS results, which reported a negative risk/benefit balance of hormone therapy, the management of postmenopausal women has deeply changed over the last 2-3 years. In particular, for the prevention of osteoporosis, the use of other efficient agents tends now to be more widely recommended rather than estrogens. The SERMs with raloxifene are new molecules that have estrogen agonist effects on bone and estrogen antagonist or neutral effects on endometrial and breast tissue. The efficacy of raloxifene to inhibit postmenopausal bone loss as well as to reduce the incidence of vertebral fractures has been demonstrated in women at high risk for osteoporosis through a large randomized placebo-controlled trial involving several thousands of postmenopausal women (MORE trial). Furthermore, the extraskeletal effects of raloxifene might represent an advantage for a global management approach of postmenopausal women, although to date, its exclusive indication is namely the prevention of osteoporosis. However, the estrogen antagonist effects of raloxifene on breast tissue as well as its good safety profile with regard to both the endometrium and the risk of heart diseases are likely to make raloxifene of particular interest for women around the age of 60 years old. Adverse events associated with raloxifene only included an increase in the absolute risk of venous thromboembolism in a comparable manner as with estrogen therapy. Also, its lack of efficacy in reducing hot flushes or preventing vaginal dryness may limit its use in young symptomatic postmenopausal women. Also, its lack of reimbursement in women with no prior fragility fracture must be taken into account.

Hormone replacement therapy prevents bone loss and the increase in bone resorption due to the hormone deficiency in oestrogen in postmenopausal women. The WHI (Women's Health Initiative) randomised, double-blind study against placebo, demonstrated that which all the epidemiological trials had already suggested: replacement therapy can reducing by around 30% the risk of fractures in postmenopausal women. Administration of hormone replacement therapy requires account being taken of (in view of the uncertainties regarding the anti-fracture effect of low dose therapy): the duration (in view of the absence of remnant effect of the product on bone loss and on the risk of fracture) and the benefit/risk ration (in view of the benefits demonstrated on climacteric disorders, but the increase in risk of breast cancer). The menopause is the occasion to assess individual risks, notably vascular and of fractures, taking into account the clinical risk factors and measurement of bone density.

Objective: Recent results put into question the risks/benefits ratio of hormone replacement therapy and emphasize the importance of precise knowledge of the effects of other treatments that exist for postmenopausal symptoms or diseases. Our aim is to analyze their effect., Methods: A review of randomized trials or epidemiological studies was undertaken., Results: Bisphophonates, calcitonin, parathormone, strontium ranelate, calcium and vitamin D have specific effects on bone. The efficacy of bisphophonates for prevention and treatment of osteoporosis has been proven and parathormone and strontium ranelate seem promising. These treatments are useful for women at high risk of osteoporosis who do not suffer from menopausal symptoms. Tibolone, SERMs and phytoestrogens exert effects on various tissues. SERMs are very promising, but they do not improve climacteric symptoms and their long term effects are still unknown. Tibolone has beneficial effects on climacteric symptoms and on bone loss, but recent results concerning its effects on the risk of breast cancer call into question its interest. The beneficial effects of phytoestrogens on bone and on vasomotor symptoms need to be confirmed., Conclusion: At this time, none of the existing treatments for postmenopausal symptoms or diseases is ideal. The existence of several options for treatments of symptoms or diseases of the postmenopause is helpful as it affords several choices for physicians and for women who sometimes need to be treated for many years. However several questions remain unanswered concerning the long term effects of these treatments.

Over the past two decades, multiple observational studies have suggested that hormone replacement therapy (HRT) reduced the risk of fracture, increased the quality of life and protected against the cardiovascular disease. HRT was often recommended, on the basis of this evidence, for that indications. But these recommendations were based entirely on observational evidence, which can sometimes be misleading. In the early 1990, several large randomized studies were initiated. The largest of these trials, the Women Health Initiative (WHI) was stopped prematurely last summer (only the group with estrogen plus progestin) because the disadvantages outweighted the advantages of treatment. The conclusions of that study were largely debated in the press and destabilised more than one patient or doctor. The Swiss menopausal society published some directive to precise the indications of HRT.

Raloxifene is a second generation Selective Estrogen Receptor Modulator. It is indicated in prevention and treatment of post-menopausal osteoporosis. This drug has an estrogen agonistic effect on bone tissue, an estrogen-antagonistic effect in breast and endometrial tissue. It inhibits estrogen induced breast cells proliferation and, in animal studies, it prevents the growth of chemically induced mammary tumors. Raloxifene has a limited effectiveness in women with advanced breast cancers. The effects of raloxifene after treated breast cancer and sequential use of tamoxifene after raloxifene (or the contrary) are not known and should be tested in specific pre-clinical and clinical studies. In osteoporotic women included in the MORE trial, the risk reduction of hormone-dependent breast cancer due to raloxifene raises the issue of some effectiveness of raloxifene in breast cancer prevention. The STAR trial is currently comparing tamoxifene vs raloxifene in breast cancer prevention in women at increased risk of breast cancer. Like tamoxifene, raloxifene increases the risk of venous thrombo-embolic events. On the other hand, in a subgroup of women at increased vascular risk in the MORE trial, the reduction of cardiovascular events raises the issue of an effect of raloxifene in the prevention of coronary events. The ongoing RUTH trial is testing this assumption and it is comparing raloxifene to a placebo in women at increased vascular risk. Today, in clinical practice, before the results of ongoing trail, raloxifene should be used in the setting of osteoporosis prevention and treatment.

Osteoporosis is a general disorder of the skeleton characterised by a decrease in bone mass, with damage to the microarchitecture leading to an increase in bone fragility and fracture risk. The incidence of this illness will increase in the future because of the aging of the population and increasing risk factors. Many guidelines have been proposed by qualified authorities--those of the European Agency for the Evaluation of Medicinal Products (EMEA) being the latest published. The aim of treatment of the osteoporosis is to increase, maintain or improve bone mass as well as its strength, with a view to decreasing the incidence of bone fractures. With regard to preclinical studies, in vitro studies--such as those using osteoblast or osteoclast cultures--allow a better understanding of the mechanism of action of drug treatment. The evaluation of bone quality should be performed in two species, such as the ovariectomised female rat model and larger animals (ewe, sow, primate etc.). Phase I studies are designed to enable determinations of pharmacokinetic profiles and bone diffusion and to offer indications of the putative clinical relevance of the dosages. For phase II studies (double-blind controlled studies versus placebo, ideally with a duration of 24 or sometimes 12 months), tests of three dosages are recommended, and the bone mass is considered as a relevant substitution criterion. The aim of secondary osteoporosis prevention studies (randomised double-blind and comparative controlled design versus placebo) is to avoid the occurrence of new bone fractures, and the main evaluation criterion is the number of patients with new fractures. The study length should not be less than 3 years. For evaluation of primary osteoporosis prevention, efficacy in the prevention of bone fracture is the prerequisite--before the use of bone mass as the main evaluation criterion. This criterion can be evaluated by alterations in bone mineral density at the rachis level. Reference drugs such as estrogens can be an alternative to placebo comparison. The tolerability of drugs for the treatment of osteoporosis requires evaluation in long-term studies and the collection of postmarketing data. The International Conference on Harmonisation (ICH) could lead to uniform guidelines for the US, Europe and Japan.

The currently reported data concerning the large WHI randomized controlled trial compare the impact of continuous combined conjugated estrogens + medroxyprogesterone acetate vs placebo in postmenopausal women. These results appear largely pessimistic. After 5.2 years of hormone replacement, an excess of coronary heart disease, cerebrovascular disease, venous thromboembolism, breast cancer incidence and extension, mild cognitive impairment and dementia is recorded. By contrast, osteoporotic fracture risk and colorectal cancer are decreased during hormone replacement. Accordingly, this hormonal treatment can no longer be recommended on a long term basis, except after extensive risk-benefit balance evaluation. It should no longer be prescribed for prevention of chronic diseases. It remains indicated during 4-5 years for relief of vasomotor symptoms, genital atrophy and, potentially, for some aspects of quality of life. HRT should probably be prescribed in minimal-effective dosages; new regimens, routes of administration, new compounds and associations should be envisaged in order to avoid cardiovascular or breast problems. However these new approaches ask for thorough validation studies.

The prevention and treatment of osteoporosis are now a necessary goal because of the aging of the population and the social and economic costs of fracture complications. The publication of guidelines by registration agencies during the last 10 years has provided precise rules for evaluating new drugs designed for the prevention and treatment of postmenopausal osteoporosis. The benefit of combination treatment with calcium and vitamin D in osteoporotic patients has clearly been proven, especially among the oldest patients, but results of prospective studies designed for the prevention of fracture risk are conflicting. In the Fracture Intervention Trial (FIT), treatment with alendronate 10 mg/day reduces the risk of vertebral fracture by 48% and increases bone mineral density (BMD) in patients with vertebral fractures. In the Vertebral Efficacy with Risedronate Therapy Multi-National (VERT-MN) and VERT-NA (North America) studies, treatment with risedronate 5 mg/day reduces the risk of vertebral fracture by 49% and 41%, respectively. Risedronate 5 mg daly for 3 years leads to an increase in BMD. The Prevent Recurrence Of Osteoporotic Fractures (PROOF) study has shown a significant decrease in the risk of vertebral fracture in patients treated with calcitonin 200 IU. However, numerous criticisms of the methodology of this study design have been identified. Selective estrogen receptor modulators could act as agonists or antagonists of estrogens, depending on the target tissue. In the Multiple Outcomes of Raloxifene Evaluation (MORE) study, treatment with raloxifene reduces the risk of vertebral fracture by 50% in patients without prevalent vertebral fracture and by 30% in patients with prevalent vertebral fracture. PTH treatment leads to an increase in BMD and reduces the risk of vertebral fracture by 65%. Strontium ranelate has a novel mechanism of action (stimulation of bone synthesis and decrease in bone resorption), and administration of 2 g daily has a proven positive effect, leading to an increase in bone mass among women with osteoporosis. This effect was especially evident in the Spinal Osteoporosis Therapeutic Intervention phase III (SOTI) study, in which a significant decrease in the incidence of vertebral fracture of 41% over 3 years has been shown. Thus, effective therapeutic strategies now enable improved treatment of postmenopausal osteoporosis. However, this condition is still poorly diagnosed and not all patients are correctly treated. Preventing the occurrence of the first fracture should remain the prime concern.

Osteoporosis in very elderly subjects is now considered, in most developed and several developing countries as a major social, clinical and financial burden. While many compounds have been investigated in the prevention or treatment of spinal fractures, few of them have unequivocally demonstrated their ability to reduce the risk of non vertebral and more specifically hip fractures in the very elderly. This situation may seem highly paradoxical since hip fractures are unanimously considered to be the most dramatic and disabling consequence of osteoporosis. The present article reviews the current evidence available to justify anti-osteoporotic medications to be recommended to very elderly subjects, in the perspective of reducing their risk of appendicular fractures.

Objective: Our purpose was to review with critical analysis, data from randomized controlled clinical trials comparing the effects on bone of conventional hormone replacement therapy (HRT) and tibolone. Their respective effects on bone were also reviewed and summarized. Materials and methods. Medline via PubMed was searched using a combination of the following key words "tibolone, estrogens and bone" to identify all randomized controlled trials tibolone versus HRT (1960-2001)., Results: Six randomized controlled trials that have been carried out to compare effects of tibolone and conventional HRT on prevention of postmenopausal bone loss were identified. Only one of these trials has been performed with a correct methodology (double-blind and with an adequate duration). In this trial over 2 years, the highest significant increase from baseline in bone mineral density (BMD) at all sites was observed with HRT; in addition, HRT showed a significantly greater increase in BMD at lumbar spine than tibolone. Randomized placebo-controlled trials have demonstrated that tibolone produces positive effects on BMD. Nevertheless, no clinical convincing data are available to support its efficacy in the prevention of osteoporotic fractures. The positive impact on BMD of conventional HRT to prevent postmenopausal bone loss and to treat established osteoporosis has been shown by many randomized controlled trials. Regarding fracture risk prevention, some clinical and epidemiological data suggest that HRT initiated in early or late postmenopause may prevent fractures if it is administered at standard doses and continued for a long time., Conclusion: HRT is always the reference treatment of postmenopausal symptoms related to estrogen deficiency.

The recent Women's Health Initiative study report evaluated the long-term benefits and risks of hormone replacement therapy among healthy postmenopausal women. The report showed that the risk-benefit profile of continuous combined hormone replacement therapy was not consistent with the primary prevention of coronary heart disease. The Women's Health Initiative study of continuous combined hormone replacement therapy is a landmark study and the results provide valuable information for patients and clinicians. However, the most common indication for hormone replacement therapy is menopausal symptoms, for which it is effective, not prevention of disease, and the most common use is for less than three years. Nevertheless, even short-term use has small effects on some outcomes. This statement discusses how the findings of the Women's Health Initiative study can be applied to reach appropriate clinical decisions.

INDIRECT MECHANISM OF ACTION: Tibolone (OD 14) is the precursor of its active principles that are its metabolites: 3 alpha and 3 beta hydroxylated derivatives. In vivo, the latter behave like estrogens. Certain tissues (liver, endometrium) may metabolize the 3 beta ol derivative into the delta 4 isomer with progestagenic and androgenic activity. The metabolism of the product in other tissues such as the breast and brain is unknown., Activity: At the dose of 2.5 mg/day, the product expresses an estrogen activity equivalent to that observed with classical doses of estrogens in the brain, genito-urinary tract, vascular endothelium and bone. In the brain and muscle, it also has a slightly androgenic effect and in the breast an antiestrogenic effect. ON METABOLIC LEVEL: The product acts like a minor androgen (lowering triglycerides and HDL cholesterol without interfering in the cholesterol cell flow) and it stimulates fibrinolysis. ON CLINICAL LEVEL: Tibolone treats the symptoms of estrogen privation and protects against bone loss, without inducing bleeding or mastodynia. There is a lack of large epidemiological studies on prevention of fracture risks, cardiovascular effects and breast. Tolerance in the population studied was excellent (healthy population). However, tolerance remains to be assessed in particular sub-groups (populations at risk of certains pathologies).

PRINCIPLE CHARACTERISTICS: Specific estrogen receptor modulators (SERMs) are non-steroid molecules that maintain some of the agonist properties of estrogens on bone tissue and cardiovascular system, but not their stimulating effects on the gynecological sphere. OLD AND NEW MOLECULES: SERMs were formerly known as "antiestrogens" in reference to their primary inhibition of breast tumor growth. Hence, tamoxifen has been used for many years as adjuvant treatment of breast cancer. However, its long-term use is limited by the risk of endometrial hyperplasia, which has led to the development of new molecules devoid of this side effect. Among these molecules, raloxifen, more specifically reserved for the prevention of osteoporosis in menopausal women, has been the subject of major pre-clinical and clinical developments. THE EFFECTS OF RALOXIFEN: In the prevention of postmenopausal bone loss and vertebral fractures, the effects of raloxifen have been established in several randomized, double-blind studies against placebo, which were the basis of its current marketing authorization. Moreover, raloxifen has a favorable effect on lipid profile and, contrary to oral estrogens, does not increase the C-Reactive protein. Endometrial tolerance is good and it is associated with a significant reduction in the incidence of breast cancer in elderly osteoporotic women. ITS PLACE IN THERAPY: Raloxifen's properties raise the question of its place, together with hormone replacement therapy (HRT), in the management of menopausal women. Its absence of efficacy in the control of the climacteric syndrome does not a priori make it a treatment of choice at the beginning of postmenopausal phase. However, its effects in the prevention of vertebral fracture, its good gynecological tolerance and the fact that it is easy to administer, are arguments for its administration in the prevention of osteoporosis in 60 year-old women or in relay to HRT. Its safety on gynecological level privileges its use in all women exhibiting benign breast or uterine pathologies at the origin of poor tolerance to HRT.

Symptoms may appear during the perimenopause, but it is often difficult to treat them at that time. Progestins are used to treat abnormal bleeding. Low dose hormone replacement therapy (HRT) or oral contraception are often used also. HRT can be used to maintain the bone density even in elderly women. Nevertheless, the treatment is often not taken for sufficient time. In order to improve compliance, a number of low dose HRT have been developed. For most patients these medications will preserve the bone mass, but data showing a fracture protection are missing. The exact role of HRT on cardiovascular pathologies is controversial. Observational data indicated a protective effect on atherosclerosis. But randomised studies contradicted these results: the latest randomised trial involving a continuous combined regimen of estrogen and progestin reported an increased risk in cardiovascular events as compared to placebo. It is still possible that estrogen decreases atheromatosis but that it increases the risk of thrombosis. SERM (Selective Estrogen Receptor Modulators) have agonistic and antagonistic proprieties to estrogens on selective tissues. They have a proven protective effect on bone and possibly also on cardiovascular system. Nevertheless, the risk of thrombosis seems to be similar to that of estrogens. The risk of breast cancer seems to be increased in long term HRT users but this subject is also controversial since discordant results have been reported. Furthermore, breast cancer mortality in HRT users seems to be lower than in non users.

After menopause, especially after bilateral oophorectomy, androgens are significantly reduced in blood and this would influence the well-being of the woman. A Female Androgen Deficiency Syndrome has been described and it is logical to add androgens to the classical oestrogen replacement therapy. There are several advantages of such combined treatment including higher bone density, better sexual function, improved mood and general sense of well-being, less depression and enhanced cognitive functioning. Side effects upon lipids are minimal and without any long-term effect on cardiovascular morbidity as long as low dosage is used. It seems that low dose of androgen therapy is a very interesting treatment option for menopausal women but further studies are needed before clinical use is recommended.

Unlabelled: VARIOUS THERAPEUTIC POSSIBILITIES: Treatment of osteoporosis has greatly progressed over the past few years and, in parallel with hormone replacement therapy (HRT), new drugs (2nd and 3rd generation bisphosphonates and raloxifen) are now available, not only for primary prevention but also for secondary prevention of fractures. WHAT INDICATIONS?: The anti-fracture efficacy that has been demonstrated in large clinical trials, conducted according to the requirements of modern methodology, only appear patent in women at "high risk" for osteoporosis, i.e., those presenting a t-score < -2.5 and a prevalent fracture (particularly vertebral crushing), situation which is relatively rare at the onset of the menopause., In Practice: The initiation of such treatment in a women approaching the menopause should only be considered after prior measurement of her bone density, using a validated technique, measurement that is not always officially recognized by our Health Authorities. This problem, together with the varying conditions of prescription and reimbursement, explain some of the problems encountered in the use of these new therapeutics, notably in women at high risk of osteoporosis, who have not yet presented a fracture due to their bone fragility.

The small but significant increase in risk of discovering breast cancer in women with hormone replacement therapy and the recent discussion of coronary benefit of this treatment have led many authors to insist on the necessity to evaluate the benefit/risks ratio before administration. This evaluation is particularly important for women that are already at high risk of breast cancer because of some genetic predisposition, family history or some benign breast diseases. In these cases, it is important to evaluate the absolute risk of breast cancer, to define the patient's needs more precisely, to specify menopausal symptoms; it is also important to evaluate the risk of osteoporosis, to review the various therapeutic possibilities, which are not only estrogen/progestin treatments (there are alternative treatments), and to give the patients honest information. Before obtaining the results of current trials, we are proposing here a pragmatic attitude and a decision algorithm to adopt a therapeutic attitude more easily which will be decided together by both patients and their physicians.