Assessment of Cardiovascular Safety of Anti-Osteoporosis Drugs.

The incidence of osteoporosis and cardiovascular disease increases with age, and there are potentially shared mechanistic associations between the two conditions. It is therefore highly relevant to understand the cardiovascular implications of osteoporosis medications. These are presented in this narrative review. Calcium supplementation could theoretically cause atheroma formation via calcium deposition, and in one study was found to be associated with myocardial infarction, but this has not been replicated. Vitamin D supplementation has been extensively investigated for cardiac benefit, but no consistent effect has been found. Despite findings in the early 21st century that menopausal hormone therapy was associated with coronary artery disease and venous thromboembolism (VTE), this therapy is now thought to be potentially safe (from a cardiac perspective) if started within the first 10 years of the menopause. Selective estrogen receptor modulators (SERMs) are associated with increased risk of VTE and may be related to fatal strokes (a subset of total strokes). Bisphosphonates could theoretically provide protection against atheroma. However, data from randomised trials and observational studies have neither robustly supported this nor consistently demonstrated the potential association with atrial fibrillation. Denosumab does not appear to be associated with cardiovascular disease and, although parathyroid hormone analogues are associated with palpitations and dizziness, no association with a defined cardiovascular pathology has been demonstrated. Finally, romosozumab has been shown to have a possible cardiovascular signal, and therefore post-market surveillance of this therapy will be vital.

Is there a role for menopausal hormone therapy in the management of postmenopausal osteoporosis?

We provide an evidence base and guidance for the use of menopausal hormone therapy (MHT) for the maintenance of skeletal health and prevention of future fractures in recently menopausal women. Despite controversy over associated side effects, which has limited its use in recent decades, the potential role for MHT soon after menopause in the management of postmenopausal osteoporosis is increasingly recognized. We present a narrative review of the benefits versus risks of using MHT in the management of postmenopausal osteoporosis. Current literature suggests robust anti-fracture efficacy of MHT in patients unselected for low BMD, regardless of concomitant use with progestogens, but with limited evidence of persisting skeletal benefits following cessation of therapy. Side effects include cardiovascular events, thromboembolic disease, stroke and breast cancer, but the benefit-risk profile differs according to the use of opposed versus unopposed oestrogens, type of oestrogen/progestogen, dose and route of delivery and, for cardiovascular events, timing of MHT use. Overall, the benefit-risk profile supports MHT treatment in women who have recently (< 10 years) become menopausal, who have menopausal symptoms and who are less than 60 years old, with a low baseline risk for adverse events. MHT should be considered as an option for the maintenance of skeletal health in women, specifically as an additional benefit in the context of treatment of menopausal symptoms, when commenced at the menopause, or shortly thereafter, in the context of a personalized benefit-risk evaluation.

[La ménopause et le traitement hormonal de la ménopause : une actualisation]. / Menopause and menopause hormonal treatment : an update.

Postmenopausal hormone therapy (MHT) is mainly used for the relief of menopausal symptoms. It can also be prescribed for the treatment of postmenopausal osteoporosis, but nowadays, other medications are given to older patients for this indication. Current, available data, demonstrates that MHT is beneficial as well as safe for postmenopausal, symptomatic women. Modern regimens of MHT comprise lower dosages of estrogens than in the past, either safer progestins or SERMs. These regimens should be the preferred option for women with a uterus. Non-androgenic progestin may present reduced thrombotic and breast cancer risks, and transdermal oestrogen could have a reduced thrombotic risk. Oestrogen-only therapy is the preferred option for women who underwent a hysterectomy. Vaginal oestrogen therapy is indicated for women with atrophic vaginitis and recurrent urinary tract infections.

Le traitement des symptômes vasomoteurs constitue l'indication principale du traitement hormonal de la ménopause (THM). La seconde indication est le traitement de l'ostéoporose après la ménopause. Toutefois, d'autres produits sont utilisés pour traiter des femmes plus âgées à cette même fin. La balance bénéfice-risque est en faveur du THM pour les femmes postménopausées et symptomatiques, mais les doses d'oestrogène ont été réduites dans les schémas de traitement actualisés. Par ailleurs, ces schémas préconisent l'utilisation soit de progestatifs moins androgéniques et ayant une moindre innocuité que les progestatifs anciens, soit des SERMs. Ces schémas constituent les premiers choix de traitement pour les femmes non-hystérectomisées. Les progestatifs nonandrogéniques sont associés à un risque diminué de thrombose veineuse et de cancer du sein alors que les oestrogènes par voie transdermique présentent un moindre risque de thrombose veineuse. Chez les femmes qui n'ont plus d'utérus, il convient de prescrire des oestrogènes sans progestatifs. Le traitement local par voie vaginale à base d'oestrogènes est indiqué chez les femmes souffrant de vaginite atrophique, entrainant des difficultés sexuelles ou des infections urinaires récidivantes.

Value of the 68Ga-DOTATATE PET-CT in the diagnosis of endometriosis. A pilot study.

OBJECTIVE: The non-invasive diagnosis of endometriosis remains challenging. Recent data suggested that somatostatin might be involved in its pathogenesis. High sensitive visualization of somatostatin receptors expression is possible using PET-CT imaging after the administration of a 68Ga-labeled somatostatin analog (DOTATATE) that will bind to the somatostatin receptor sub-types 2 and 5. The aim of the present study was to assess the usefulness of 68Ga-DOTATATE PET-CT in the diagnosis of endometriosis. STUDY DESIGN: This is a prospective, single center pilot study. A pre operative 68Ga-DOTATATE PET-CT was performed in all of the patients who presented with suspected endometriosis and who were scheduled for a laparoscopy. Surgical endometriosis staging and histopathological analysis, including somatostatin receptors SST1, 2 and 5 immunohistochemistry (IHC) of removed specimens, were confronted to the results of the 68Ga-DOTATATE PET-CT. RESULTS: 12 patients were included in this study. 68Ga-DOTATATE PET-CT performed pre operatively showed increased pathologic uptake in four patients with a deep infiltrating endometriosis (DIE) recto-vaginal lesion and in another patient with an adenomyoma. Expression of SST1, 2 and 5 receptors in surgical specimens was confirmed by IHC in these five lesions. Neither superficial peritoneal endometriosis, nor ovarian endometrioma were found to show an increased pathologic uptake on 68Ga-DOTATATE PET-CT. IHC analysis confirmed that SST1, 2, and 5 receptors were not present in these lesions. CONCLUSION: The results observed in this small size series of patients seem to confirm expression of somatostatin receptors only in recto-vaginal DIE and focal adenomyosis lesions. The usefulness of 68Ga-DOTATATE PET-CT in the diagnosis of this entity is uncertain. Future research should concentrate on studying the role of somatostatin in the pathogenesis of DIE.

Osteoporosis in Frail Patients: A Consensus Paper of the Belgian Bone Club.

In this consensus paper, the Belgian Bone Club aims to provide a state of the art on the epidemiology, diagnosis, and management of osteoporosis in frail individuals, including patients with anorexia nervosa, patients on dialysis, cancer patients, persons with sarcopenia, and the oldest old. All these conditions may indeed induce bone loss that is superimposed on physiological bone loss and often remains under-recognized and under-treated. This is of particular concern because of the major burden of osteoporotic fractures in terms of morbidity, mortality, and economic cost. Therefore, there is an urgent need to appreciate bone loss associated with these conditions, as this may improve diagnosis and management of bone loss and fracture risk in clinical practice.

Coping with menopausal symptoms: An internet survey of Belgian postmenopausal women.

OBJECTIVES: An internet survey was performed to obtain data on the current use in Belgium of hormone replacement therapy and alternative treatments for the alleviation of menopausal symptoms. A supplementary aim was to assess the use of opt-in internet opinion panels (TalkToChange, http://www.talktochange.com, and GMI, http://www.gmi-mr.com/global-panel) as a potential new way to obtain data on menopausal issues. STUDY DESIGN: Data were collected via an internet platform from 696 postmenopausal women aged 45-60 years. OUTCOME MEASURES: Respondents were asked questions about their socio-demographic profile, their experience of the menopause, the burden of the menopause, its impact on their quality of life and the treatment of menopausal symptoms (if any). RESULTS: The opt-in internet opinion panels proved a quick way (19days) to obtain reliable information with a low error margin (3.7%). The online survey collected detailed socio-demographic data. Almost all of the women (98%) had heard about the menopause before. Sixty-one percent perceived the menopause as a temporary phase (17% thought it lasted for one or two years and 44% thought it lasted for three to five years) and only 39% realized the menopause would last for the rest of their life. Twenty-three percent of the women reported any kind of impact of the menopause on their quality of life. However, for the other 77% the menopause had resulted in complaints. No differences according to the women's age, level of education or professional status were found in this respect. Sixty-nine percent of the women had 'ever' used some type of treatment for menopausal symptoms and 53% were currently using a treatment. Forty percent of those with more than three symptoms were currently untreated. Of those who were not on hormone replacement therapy (HRT), 61% would not consider taking it (54% were 'strongly opposed' and 7% simply 'opposed'), while 8% would consider asking their doctor for HRT. Among those women who were opposed to HRT, 25% indicated that they were afraid of the increased risk of breast cancer, 34% cited cardiovascular risks and 26% were worried about weight gain. In this Belgian sample, HRT was used significantly more often by French-speaking women (32%) than by Dutch-speaking women (9%) (OR 4.4, p<0.0001). The alternatives to HRT had a high satisfaction rate among users. Relaxation techniques, regular physical activity, acupuncture and avoiding stress had satisfaction rates similar to that with HRT. It was not possible to compare the alternatives in the same women. Nor was it possible to assess whether more pronounced symptoms required a specific treatment. CONCLUSION: Opt-in internet opinion panels proved a quick and efficient way to gather data on menopausal issues in Belgium. Despite the high levels of awareness and knowledge, there is some confusion concerning the duration of the menopause, and its common perception as a temporary condition is likely to mean that the menopausal burden is substantially underestimated. Many symptomatic women are untreated.

The role of biochemical of bone turnover markers in osteoporosis and metabolic bone disease: a consensus paper of the Belgian Bone Club.

The exact role of biochemical markers of bone turnover in the management of metabolic bone diseases remains a topic of controversy. In this consensus paper, the Belgian Bone Club aimed to provide a state of the art on the use of these biomarkers in different clinical or physiological situations like in postmenopausal women, osteoporosis in men, in elderly patients, in patients suffering from bone metastasis, in patients with chronic renal failure, in pregnant or lactating women, in intensive care patients, and in diabetics. We also gave our considerations on the analytical issues linked to the use of these biomarkers, on potential new emerging biomarkers, and on the use of bone turnover biomarkers in the follow-up of patients treated with new drugs for osteoporosis.

[State of contraception in 2016]. / Etat de la contraception en 2016.

INTRODUCTION: The Pill and other forms of hormonal contraception, if taken correctly, are very effective and safe for millions of women, but since a few years, due to the debates and controversies about the third- and fourth-generation pills, other options have gained in popularity. OBJECTIVES: to provide a review of oestroprogestative contraception (OP), progesta-tive contraception, IUDs with a focus on their advantages and side-effects according to the specific needs of women. METHODS: literature review and lessons learned from clinical practice. RESULTS: The importance of family and individual history, the life-style and socio-economic conditions are critical factors for advising women on the 15 contraceptive choices available to them. The risk/benefit ratio of OP contraception needs a yearly follow-up. The progestative contraception is the preferred option for women who have contraindication for oestrogen, are older than forty, and/or have risk factors such as a history of venous thromboembolism, overweight and smoking. The IUD usually is well tolerated and causes few side effects. Among the other contraceptive methods, sterilization and diaphragms are briefly discussed. CONCLUSION: Among the many safe and effective contraceptive methods, it is important for general practitioners to know the advantages and the side effects of each method, as well as the specific conditions of the woman, to propose the best options available. In case of difficulties of follow up or adherence to daily uptake, in particular among adolescents, long-acting methods such as IDU or implants are preferable.

INTRODUCTION: Longtemps préférées des femmes, les pilules sont en recul en Belgique depuis les polémiques sur les pilules de 3e et 4e génération. Si le recours à la contraception orale a diminué, d'autres prat iques contraceptives se sont renforcées. OBJECTIFS: fournir une description détaillée des contraceptifs oestroprogestatifs (OP), des contraceptifs à base de progestatifs seuls et des dispositifs intra-utérins, en soulignant leur intérêt mais aussi les risques de leur utilisation. METHODE: revue de la littérature et expérience clinique. RESULTATS: l'importance des antécédents personnels, familiaux, et du style de vie est déterminante pour évaluer les indications des différentes méthodes. En ce qui concerne les contraceptifs OP, le rapport risque/bénéfice nécessite un suivi annuel. La contraception progestative est une option choisie par de nombreuses femmes, particulièrement celles qui ont plus de 40 ans, et/ou des facteurs de risque comme le tabac, le surpoids ou des antécédents de TEV. Le dispositif intra-utérin est généralement bien toléré comme méthode contraceptive car il présente peu d'effets secondaires ou de complications. Parmi les autres méthodes contraceptives, la stérilisation féminine et le diaphragme sont brièvement discutés. CONCLUSION: Parmi les nombreuses possibilités de choix contraceptifs, il est important de faire connaître les indications et contre-indications en tenant compte de la situation de la personne. En cas de difficulté de suivi et d'observance, en particulier chez les adolescentes, la prescription des méthodes à longue durée d'action est préférable.

Fertility-sparing management of gynecological cancers.

Fifteen to 21% of women diagnosed with genital tract tumors are younger than 40. Adequate counseling of these patients must be conducted to decide whether fertility-sparing treatment is allowed and what would be the oncological, fertility and obstetrical outcomes. We performed a comprehensive PubMed literature search using the terms "Uterine Cervical Neoplasms"[Mesh], "Trachelectomy", "Endometrial Neoplasms"[Mesh], "Ovarian Neoplasms"[Mesh] and "Fertility"[Mesh]. The following review reports available evidence for the conservative management of cervical, endometrial and ovarian cancer. Data regarding the selection of patients, surgical techniques, obstetrical issues and cancer prognosis are summarized. The level of evidence is low in most of the available reports. The therapeutic options presented in this paper should not therefore be considered as a standard of care. Nevertheless, fertility-sparing treatments of gynecological malignancies should be discussed in a multidisciplinary team and suggested to eligible patients who are younger than 40 and wish to become pregnant further.

Should we abstain from treating women with endometriosis using menopausal hormone therapy, for fear of an increased ovarian cancer risk?

Women suffering from endometriosis often have an early menopause, resulting in severe menopausal symptoms and an increased risk of osteoporosis. They are therefore candidates for menopausal hormone therapy (MHT). Unfortunately, MHT may increase the risk of endometriosis recurrence. Moreover, endometriosis patients are at increased risk of ovarian cancer, which may be further enhanced by MHT use. It is unknown, however, whether MHT more frequently increases type I (low-grade serous tumors), which seem to be increased when endometriosis is present, or type II (the more aggressive high-grade serous) tumors. We propose the following decision-making algorithm for endometriosis patients considering MHT. Those who have been treated with bilateral salpingo-oophorectomy, and in whom there is no residual endometriotic disease, can probably be treated using MHT without risk of endometriosis recurrence or fear of ovarian cancer. For women with significant, residual endometriosis lesions, the benefit may outweigh the risks, when menopause is reached before the age of 45 years or when severe symptoms are present.

Systematic review about breast cancer incidence in relation to hormone replacement therapy use.

BACKGROUND: Several studies report a decrease in breast cancer incidence subsequent to the decrease in hormone replacement therapy (HRT) use. But its magnitude and the time-lag may vary between countries. This may reflect differences in populations, previous type and prevalence of HRT use and breast cancer screening. AIM: To review systematically studies assessing the relation between breast cancer incidence and change of HRT use. MATERIAL AND METHOD: Descriptive analysis of the methodology of the studies including design limitations and presence of confounding factors, data sources for breast cancer and HRT and regimens of HRT used. RESULTS AND DISCUSSION: Eighteen articles were selected. Most studies were ecological and confounding factors such as mammography screening and changes in reproductive and lifestyle habits could not be excluded. Sources of data on breast cancer and HRT were heterogeneous and only few data on HRT regimens used were available. Most studies concluded that the decrease in HRT use during the last decade was probably associated with a decrease in breast cancer incidence, especially for women aged 50 years or more. CONCLUSIONS: Data, mostly from epidemiological studies, suggest that the decrease in breast cancer incidence can be partly attributed to the drop in HRT use. Nevertheless, available studies are hampered by a number of limitations and it remains difficult to evaluate the exact impact of the drop in HRT use on the decrease in breast cancer incidence. Especially, the studies are seldom based on detailed individual data and do not provide information on regimens used, type of cancers and possible confounding factors.

Extraskeletal benefits and risks of calcium, vitamin D and anti-osteoporosis medications.

UNLABELLED: Drugs used for the prevention and the treatment of osteoporosis exert various favourable and unfavourable extra-skeletal effects whose importance is increasingly recognized notably for treatment selection. INTRODUCTION: The therapeutic armamentarium for the prevention and the treatment of osteoporosis is increasingly large, and possible extra-skeletal effects of available drugs could influence the choice of a particular compound. METHODS: The present document is the result of a national consensus, based on a systematic and critical review of the literature. RESULTS: Observational research has suggested an inverse relationship between calcium intake and cardiovascular diseases, notably through an effect on blood pressure, but recent data suggest a possible deleterious effect of calcium supplements on cardiovascular risk. Many diverse studies have implicated vitamin D in the pathogenesis of clinically important non-skeletal functions or diseases, especially muscle function, cardiovascular disease, autoimmune diseases and common cancers. The possible effects of oral or intravenous bisphosphonates are well-known. They have been associated with an increased risk of oesophageal cancer or atrial fibrillation, but large-scale studies have not found any association with bisphosphonate use. Selective oestrogen receptor modulators have demonstrated favourable or unfavourable extra-skeletal effects that vary between compounds. Strontium ranelate has a limited number of non-skeletal effects. A reported increase in the risk of venous thromboembolism is not found in observational studies, and very rare cases of cutaneous hypersensitivity reactions have been reported. Denosumab has been introduced recently, and its extra-skeletal effects still have to be assessed. CONCLUSION: Several non-skeletal effects of bone drugs are well demonstrated and influence treatment choices.

[Menopausal hormone treatment in 2011]. / Réactualisation du traitement hormonal a la ménopause en 2011.

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.

Evolution of breast cancer incidence in relation to hormone replacement therapy use in Belgium.

BACKGROUND: Recent randomized studies concluded that an increased risk of breast cancer is associated with hormone replacement therapy (HRT). Since then, HRT use has decreased in many countries. Several studies have reported a subsequent decrease in breast cancer incidence. AIM: As Belgium has one of the highest incidences of breast cancer in Europe and has a high rate of HRT use, with differences between regions, we assessed the evolution of breast cancer incidence and HRT sales per region and per regimen. MATERIALS AND METHODS: Breast cancer incidence rates (provided by the Belgian Cancer Registry) and HRT sales data (provided by IMS Health®) were analyzed by region, age class and HRT regimens. We also calculated the correlation between breast cancer incidence and HRT sales. RESULTS: Breast cancer incidence decreased from 2003 onwards in Flanders, Brussels and Wallonia, especially in the age group 50-69 years. In the same three regions, HRT use decreased by half from 2002 onwards. Greater decreases were observed for estrogens combined with androgenic progestins, estrogens only and estrogens prescribed with a separate progestin. The correlation between breast cancer incidence rates and HRT sales in the previous year was 0.55 (p=0.04), but, when adjusted for the number of women in the age class 40-69 years in each region, the correlation was no longer statistically significant (r=0.39, p=0.17). CONCLUSION: Although many arguments support the hypothesis that the drop in breast cancer incidence can be partly explained by the decrease in HRT use, we were unable to find a strong association between the two in Belgium.

Non-pharmacological management of osteoporosis: a consensus of the Belgian Bone Club.

This consensus article reviews the various aspects of the non-pharmacological management of osteoporosis, including the effects of nutriments, physical exercise, lifestyle, fall prevention, and hip protectors. Vertebroplasty is also briefly reviewed. Non-pharmacological management of osteoporosis is a broad concept. It must be viewed as an essential part of the prevention of fractures from childhood through adulthood and the old age. The topic also includes surgical procedures for the treatment of peripheral and vertebral fractures and the post-fracture rehabilitation. The present document is the result of a consensus, based on a systematic review and a critical appraisal of the literature. Diets deficient in calcium, proteins or vitamin D impair skeletal integrity. The effect of other nutriments is less clear, although an excessive consumption of sodium, caffeine, or fibres exerts negative effects on calcium balance. The deleterious effects of tobacco, excessive alcohol consumption and a low BMI are well accepted. Physical activity is of primary importance to reach optimal peak bone mass but, if numerous studies have shown the beneficial effects of various types of exercise on bone mass, fracture data as an endpoint are scanty. Fall prevention strategies are especially efficient in the community setting, but less evidence is available about their effectiveness in preventing fall-related injuries and fractures. The efficacy of hip protectors remains controversial. This is also true for vertebroplasty and kyphoplasty. Several randomized controlled studies had reported a short-term advantage of vertebroplasty over medical treatment for pain relief, but these findings have been questioned by recent sham-controlled randomized clinical studies.

Evaluation of 18FDG PET-CT in the diagnosis of endometriosis: a prospective study.

BACKGROUND: Noninvasive techniques have poor sensitivity and specificity in diagnosing endometriosis, which is often associated with an inflammatory process. In several benign diseases, measurement of hypermetabolism using fluorodeoxyglucose (18F 18FDG) reflects the degree of inflammation and aggressiveness of the disease. This prospective study evaluated the value of (18)FDG positron emission tomography (PET)-computed tomography (CT) in assessing the presence of endometriosis. METHODS: Ten consecutive patients suspected with endometriosis were prospectively included in this study. A preoperative 18FDG PET-CT was performed in all the patients during the follicular phase of their cycle, which preceded laparoscopic surgery. Surgical endometriosis staging and histopathological analysis of removed tissue were confronted with the results from 18FDG PET-CT. RESULTS: Of the 10 patients, 9 had endometriosis confirmed by laparoscopy; 6 had advanced stage of the disease and 5 had histologically proven lesions. Nevertheless, none of the patients had 18FDG-demonstrated hypermetabolism at PET-CT. CONCLUSIONS: In this preliminary series, we did not observe hypermetabolic activity in relation to endometriosis using 18FDG PET-CT. This study's most important limitation is the use of 18FDG as an isotopic tracer, which is not specific to endometrial tissue.

Evidence-based guidelines for the pharmacological treatment of postmenopausal osteoporosis: a consensus document by the Belgian Bone Club.

Several drugs are available for the management of postmenopausal osteoporosis. This may, in daily practice, confuse the clinician. This manuscript offers an evidence-based update of previous treatment guidelines, with a critical assessment of the currently available efficacy data on all new chemical entities which were granted a marketing authorization. Osteoporosis is widely recognized as a major public health concern. The availability of new therapeutic agents makes clinical decision-making in osteoporosis more complex. Nation-specific guidelines are needed to take into consideration the specificities of each and every health care environment. The present manuscript is the result of a National Consensus, based on a systematic review and a critical appraisal of the currently available literature. It offers an evidence-based update of previous treatment guidelines, with the aim of providing clinicians with an unbiased assessment of osteoporosis treatment effect.

Breast cancer screening in the older woman: an effective way to reduce mortality?

The value of systematic mammographic screening has been studied in a total of 11 randomized trials - some of doubtful methodological quality - on various populations of women; the earliest dates from the 1960s. However, older women have been under-represented in these trials, as only six of them registered patients over 60 years of age. The proportion of women aged over 70 years was low and there are no data for patients older than 74. Several meta-analyses have been conducted and a plausible estimate of the impact of screening is a 16% reduction in breast cancer mortality (95% confidence interval 9-23%). Some meta-analyses provide "post hoc subgroup analyses" by age and these have found a greater benefit of screening for women of older age, with estimates of risk reductions of 17%, 27% and 22% for cohorts of women aged 55-64, 60-69 and 65-74; these figures are significantly different from 0. In comparison, for women in the age groups 40-49, 45-54 and 50-59 the estimated risk reductions were 9%, 7% and 12%. Nevertheless, there has been no formal demonstration of an interaction with age. When these estimates are translated into the number of women who need to be screened in order to avoid one death from breast cancer during 15 years of follow-up, the figure lies between 1370 and 4120. The probability of not dying from breast cancer within 15 years of screening for a 65-year-old woman is estimated to be in the range 98.85-99.11%, compared with 98.73% for a woman who does not undergo screening. These benefits should be balanced against the possible disadvantages of screening, including false positive results, overdiagnosis and overtreatment. One of the meta-analyses concluded that the rate of total mastectomies was significantly increased after screening. Although most scientific recommendations agree that screening should be proposed to all women aged 50-69 years, the benefits and disadvantages of mammography should be fully explained, in order to allow them to make a truly informed decision.

Loading and skeletal development and maintenance.

Mechanical loading is a major regulator of bone mass and geometry. The osteocytes network is considered the main sensor of loads, through the shear stress generated by strain induced fluid flow in the lacuno-canalicular system. Intracellular transduction implies several kinases and phosphorylation of the estrogen receptor. Several extra-cellular mediators, among which NO and prostaglandins are transducing the signal to the effector cells. Disuse results in osteocytes apoptosis and rapid imbalanced bone resorption, leading to severe osteoporosis. Exercising during growth increases peak bone mass, and could be beneficial with regards to osteoporosis later in life, but the gain could be lost if training is abandoned. Exercise programs in adults and seniors have barely significant effects on bone mass and geometry at least at short term. There are few data on a possible additive effect of exercise and drugs in osteoporosis treatment, but disuse could decrease drugs action. Exercise programs proposed for bone health are tedious and compliance is usually low. The most practical advice for patients is to walk a minimum of 30 to 60 minutes per day. Other exercises like swimming or cycling have less effect on bone, but could reduce fracture risk indirectly by maintaining muscle mass and force.