Update on the management of endometriosis-associated pain in France.

The French National College of Obstetricians and Gynecologists (CNGOF) published guidelines for managing endometriosis-associated pain in 2018. Given the development of new pharmacological therapies and a review that was published in 2021, most national and international guidelines now suggest a new therapeutic approach. In addition, a novel validated screening method based on patient questionnaires and analysis of 109-miRNA saliva signatures, which combines biomarkers and artificial intelligence, opens up new avenues for overcoming diagnostic challenges in patients with pelvic pain and for avoiding laparoscopic surgery when sonography and MRI are not conclusive. Dienogest (DNG) 2 mg has been a reimbursable healthcare expense in France since 2020, and, according to recent studies, it is at least as effective as combined hormonal contraception (CHC) and can be used as an alternative to CHC for first-line treatment of endometriosis-associated pain. Since 2018, the literature concerning the use of DNG has grown considerably, and the French guidelines should be modified accordingly. The levonorgestrel intrauterine system (LNG IUS) and other available progestins per os, including DNG, or the subcutaneous implant, can be offered as first-line therapy, gonadotropin-releasing hormone (GnRH) agonists with add-back therapy (ABT) as second-line therapy. Oral GnRH antagonists are promising new medical treatments for women with endometriosis-associated pain. They competitively bind to GnRH receptors in the anterior pituitary, preventing native GnRH from binding to GnRH receptors and from stimulating the secretion of luteinizing hormone and follicle-stimulating hormone. Consequently, estradiol and progesterone production is reduced. Oral GnRH antagonists will soon be on the market in France. Given their mode of action, their efficacy is comparable to that of GnRH agonists, with the advantage of oral administration and rapid action with no flare-up effect. Combination therapy with ABT is likely to allow long-term treatment with minimal impact on bone mass. GnRH antagonists with ABT may thus be offered as second-line treatment as an alternative to GnRH agonists with ABT. This article presents an update on the management of endometriosis-associated pain in women who do not have an immediate desire for pregnancy.

Sexual function and quality of life in women with idiopathic premature ovarian insufficiency.

BACKGROUND: Premature ovarian insufficiency (POI) is a disruptive diagnosis for women, with major consequences on fertility but also on quality of life and sexual functioning. AIM: The aim of this study was to evaluate the impact of vaginal symptoms from the genitourinary syndrome of menopause on the quality of life and sexual functioning of women with POI. METHODS: This cross-sectional observational study involved 88 women who were investigated in a specialized setting at the University Hospital of Toulouse (France) between 2014 and 2019. All women completed the Day-to-Day Impact of Vaginal Aging (DIVA) questionnaire on well-being and quality of life and the Female Sexual Function Index (FSFI) on sexual functioning. Analysis of total scores and subdomains of the questionnaire was performed and compared according to use of hormone replacement therapy or local low-dose estrogen treatment, age at POI, and use of antidepressant therapy or current psychological support. OUTCOMES: Outcomes included the DIVA questionnaire and the FSFI. RESULTS: Among the 88 women who fulfilled the inclusion criteria, 66 (75%) answered the questionnaires. Mean ± SD age at POI diagnosis was 32.6 ± 6.9 years and mean age at questionnaire time was 41.6 ± 6.9 years. The highest mean scores on the DIVA questionnaire were found in the self-perception and body image domain (2.05 ± 1.36), followed by the sexual functioning domain (1.52 ± 1.28). The mean FSFI score was 23.08 (95% CI, 21.43-24.73), with 32 women (78% of sexually active women) having a score <26.55, which defines sexual dysfunction. There was no difference in the FSFI score and for all DIVA domains whether or not women were taking hormone replacement therapy or local hormone therapy. CLINICAL IMPLICATIONS: This should encourage practitioners to systematically discuss the impact of POI on sexuality and vulvovaginal symptoms to provide women with specific care and advice to improve their quality of life. STRENGTHS AND LIMITATIONS: This is the first French study that aimed to assess the impact of the genitourinary syndrome of menopause on the quality of life and sexual well-being in women with POI by using standardized validated questionnaires with a very good participation rate (75%). The sample size was limited, and we could not eliminate selection bias due to university hospital recruitment. CONCLUSION: POI can have a negative impact on sexual quality of life, which raises the needs for specific advice and care.

Persistent gap in menopause care 20 years after the WHI: a population-based study of menopause-related symptoms and their management.

OBJECTIVES: To assess the current management of menopause in France with regard to menopause-related and genitourinary symptoms, with a focus on use of menopause hormone therapy (MHT). DESIGN, SETTING, AND PARTICIPANTS: The ELISA Study is a population-based survey of 5004 French representative women aged 50 to 65 years. From July to August 2020, the participating women answered an online computer-assisted web interview on menopause-related and genitourinary symptoms and their management, including use of MHT. MAIN OUTCOMES AND MEASURES: Prevalence of menopause-related and genitourinary symptoms in postmenopausal women. Management of these symptoms, including the reasons for not doing so, management by health care providers, and use of MHT. RESULTS: Among the 5004 selected women, 4041 whose postmenopausal status was confirmed were included in the final analyses. Of the untreated 3685 women, 87 % reported at least 1 menopausal symptom, with a significantly higher percentage of symptomatic women in the 50-54 age group (92 %, p < 0.05) than in the other two age groups (55-59 years: 89 % and 60-64 years: 82 %). 68 % of the surveyed women experienced on average 2.5 symptoms of the genitourinary syndrome of menopause (GSM). Using a visual analogue scale (VAS) from 0 (no impact) to 10 (high impact) to evaluate the impact of menopausal/GSM symptoms on their quality of life, mean VAS score was 5.9 (SD: 2.2), with 25 % of the women aged 55-59 years rating their quality of life between 8 and 10. 61 % of the surveyed women reported being regularly followed by a health care professional. 44 % of women reported never having discussed their menopausal/GSM symptoms with a health care provider. The main reasons were because menopause is "a normal part of women's lives", because it was not "necessary to do so", or their symptoms were "not serious enough". Only 242 women (6 %) were current MHT users, of whom 49 % were using estrogen-alone therapy and 71 % were using transdermal estrogens. Fear of hormones (35 %) and MHT side-effects (25 %) were the main reasons given for not using MHT. 62 % of the women reported that the decision not to take MHT was supported by their physician. CONCLUSIONS AND RELEVANCE: This large population-based survey confirmed not only the high prevalence of menopause-related and GSM symptoms in postmenopausal women within the first 10-15 years after menopause, but also the very low percentage of MHT users in France. Twenty years after the publication of the initial Women's Health Initiative (WHI) results, management of postmenopausal women is still characterized by unmet needs in menopausal care. Therefore, there is a strong need to educate the public and health care providers about menopause-related problems and possible solutions, including MHT, through dedicated educational programs.

Interactions between antiseizure medications and contraception: A study about the knowledge of patients and their specialist physicians.

Planning pregnancy is very important for women with epilepsy (WWE), because of the potential teratogenic effects and neurodevelopmental disorders of different antiseizure medications (ASMs). Nevertheless, contraception in WWE can be challenging due to the existence of drug interactions between ASMs and hormonal contraception. The aim of this study was to assess women's knowledge of potential interactions between their ASMs and contraceptive options. The second objective was to assess neurologist's knowledge of the potential interactions between ASMs and contraceptive methods. An anonymous online survey was proposed to reproductive-age WWE during consultation with their neurologist. Another online survey was proposed to neurologists. These surveys were performed through a French regional medical network. A total of 79 patients agreed to respond to the survey. Forty-nine women used lamotrigine alone or in combination, 15 used an enzyme-inducing ASM alone or in combination, 13 used non-enzyme-inducing ASM and 2 used both lamotrigine and an enzyme-inducing ASM. Half of the WWE had mistaken beliefs about interactions between their ASM and contraception. Among them, 35% of the women treated with an enzyme-inducing ASM were unaware of a potential decreased efficacy of hormonal contraception. Moreover, 51% of the women who were taking lamotrigine did not know that combined hormonal contraception might decrease the efficacy of their ASM. On the other hand, 64.5% of WWE without an enzyme-inducing ASM wrongly thought that their ASM can decrease their hormonal contraceptive efficacy. A total of 20 neurologists answered the online survey. It revealed specific gaps concerning interactions between ASM and contraceptives; in fact, 35% of answers concerning the identification of specific enzyme-inducing ASMs were wrong. This study therefore highlights the need for educational efforts for both WWE and their physicians regarding drug interactions between ASMs and hormonal contraceptives.

Menopausal hormone therapy for the management of osteoporosis.

Postmenopausal osteoporosis is a frequent clinical condition which affects nearly 1 in 3 women. Estrogen deficiency leads to rapid bone loss which is maximal within the first 2-3 years after the menopause transition and can be prevented by menopause hormone therapy (MHT). Not only, MHT prevents bone loss and the degradation of the bone microarchitecture but it significantly reduces the risk of fracture at all bone sites by 20-40%. It is the only anti-osteoporotic therapy that has a proven efficacy regardless of basal level of risk, even in low-risk women for fracture. Following the publication of the WHI results, use of MHT has considerably declined due to safety concerns which raise the question as to whether it might still be used in the prevention of osteoporosis. Over the last years, subsequent re-analyses of the WHI and further trials have challenged the initial conclusions of the WHI. It is now clearer that the individual benefit-risk balance of MHT is dependent on the individual risk profile in each woman as well as whether estrogen is opposed or unopposed, the type of estrogens and progestogens or doses and routes of administration. It must be also reminded that to date osteoporosis is a chronic disease that cannot be cured. The choice of the 1st treatment option should thus always be made in the context of a more comprehensive long-term strategy. This is particular true in early postmenopausal women found to be at low/moderate risk of fragility fracture over the first 10 years after menopause but who may have a much greater lifetime risk. In the absence of contraindication, use of MHT should be considered as a 1st option for the maintenance of bone health in those women where specific bone active medications are not warranted. Subsequent reassessment of the individual benefit-risk balance of MHT is thereafter recommended, with the possibility of switching to another osteoporosis treatment if the balance is not considered as favourable as at the beginning of the menopause for women still at high risk of fracture.

TBS in early postmenopausal women with severe vertebral osteoporosis.

INTRODUCTION/BACKGROUND: Severe vertebral osteoporosis is a rare condition in early postmenopausal women. We seek to determine whether Trabecular Bone Score (TBS), which is a new bone texture measurement, could be of additional value in evaluating trabecular bone properties in this population. METHODOLOGY: Lumbar spine (LS) and femoral neck (FN) bone mineral densities (BMDs) and TBS were measured in 105 early postmenopausal women (group 1: "cases", mean age: 53.1 ± 2.6 yrs.) with severe vertebral osteoporosis defined as a vertebral BMD T-score ≤ 3, as well as in 105 healthy postmenopausal women matched for age (group 2) and 105 older osteoporotic women matched for vertebral BMD (group 3, mean age: 63.9 ± 4 yrs.). None of the women had a secondary cause for osteoporosis. Correlations between TBS values and BMD were calculated after controlling for clinical characteristics. RESULTS: The women in group 1 (cases) were significantly smaller and thinner and had a history of more fractures than the age-matched controls (p < 0.05). Mean LS and FN BMD values were significantly lower in the cases than in the age-matched controls (0.770 ± 0.05 vs 1.106 ± 0.11 g/cm2 and 0.700 ± 0.07 vs 0.872 ± 0.12 g/cm2, for LS and FN, respectively; p < 0.001). The mean TBS value was also significantly lower in the cases than in the age-matched controls (1.24 ± 0.08 vs 1.37 ± 0.07, p < 0.001) but significantly higher than in the older osteoporotic controls (1.20 ± 0.07, p < 0.05). After adjustment for vertebral BMD, the difference in TBS values between the cases and the age-matched controls was no longer significant although it remained significantly higher than in the older osteoporotic controls. This would suggest that in group 1, osteoporosis is rather the consequence of a low peak bone mass than of further bone degradation while the greater decrease in TBS value in elderly osteoporotic controls is more likely to reflect additional damage in bone microarchitecture associated with aging. In a multivariate analysis including age, vertebral and femoral neck BMD, height and weight (R2 = 0.60, p < 0.0001), TBS was found to be negatively and independently associated with age (r = -0.31 p < 0.0001) and height (r = -0.20 p < 0.001). The FRAX score was significantly higher in group 1 and group 3 women than in the healthy control women (group 2). There were no changes in the results after adjustment for TBS. CONCLUSIONS: Women presenting with severe vertebral osteoporosis at the beginning of menopause have TBS values that are, first and foremost, proportional to their BMD. Whether this indicates that osteoporosis in this population is the consequence of a low peak bone mass remains to be determined and further studies are required. Nevertheless, the value of measuring TBS in addition to BMD appears to be relatively negligible in early postmenopausal women with severe vertebral osteoporosis.

Bone mineral density in women with deep infiltrating endometriosis who have undergone early bilateral oophorectomy.

OBJECTIVE: To study bone mineral density (BMD) in women with and without pelvic deep infiltrating endometriosis (DIE) who underwent early bilateral oophorectomy (BO). METHODS: A case-control study was performed in 83 women who underwent early BO before the age of 45 years, 31 for DIE and 52 for another clinical condition. All the women answered a standardized computer-assisted questionnaire to record their clinical and historical data and were medically examined. Lumbar spine and femoral neck BMDs were measured by dual-energy X-ray absorptiometry after early BO. Simultaneously, serum calcium, intact parathyroid, 25-hydroxyvitamin D, and cross-linked C-telopeptide were also measured. Unadjusted and adjusted odds ratios (with 95% confidence intervals [CI]) for endometriosis were calculated using logistic regression. RESULTS: The mean lumbar spine and femoral neck BMDs were significantly higher in women who underwent early BO for DIE than in those who underwent early BO for another clinical condition. After adjusting for age at BMD measurement, years since menopause, age at menarche and body mass index, odds ratio for endometriosis associated with a 1-SD increase in lumbar spine and femoral neck BMD was 2.59 (95% CI: 1.45-4.62) and 2.16 (95% CI: 1.23-3.81), respectively. CONCLUSION: Higher lumbar spine and femoral neck BMDs are associated with an increase in the likelihood of pelvic DIE in women who underwent early BO. This might be expected to the extent that endometriosis is itself associated with enhanced estrogen status, although further studies are needed to confirm such a hypothesis. These findings suggest that BMD measurement could contribute to the hormonal management of surgical menopause in women with DIE.

French recommendations on strategies for preventing and treating osteoporosis induced by adjuvant breast cancer therapies.

Standard adjuvant therapies for breast cancer such as chemotherapy or aromatase inhibitor and LH-RH agonist hormone therapy are associated with significant survival gains but also induce bone loss by aggravating the estrogen deprivation. The bone loss may be substantial, notably during early treatment, and occurs regardless of the baseline bone mineral density values. The objective of developing these recommendations was to achieve a practical consensus among various scientific societies, based on literature review, about osteoporosis prevention and treatment in these patients. The following scientific societies contributed to the work: Société Française de Rhumatologie (SFR), Groupe de Recherche et d'Information sur les Ostéoporoses (GRIO), Groupe Européen d'Etudes des Métastases Osseuses (GEMO), Association Francophone pour les Soins Oncologiques de Support (AFSOS), Société Française de Sénologie et de Pathologie Mammaire (SFSPM), Société Française de Radiothérapie Oncologique (SFRO). Drug prescription and reimbursement modalities in France were taken into account. These recommendations apply to postmenopausal women taking systemic chemotherapy and/or aromatase inhibitor therapy, non-postmenopausal women taking LH-RH agonist therapy, and non-postmenopausal women with persistent amenorrhea 1 year after chemotherapy completion. All women in these three categories should undergo an evaluation of bone health and receive interventions to combat risk factors for bone loss. Patients with a history of severe osteoporotic fracture and/or a T-score value <-2.5 should receive osteoporosis drug therapy. The FRAX® score should be used to guide treatment decisions in patients whose T-score is between -1 and -2.5. General osteoporosis prevention measures should be applied in patients without criteria for osteoporosis drug therapy, who should undergo bone mineral density measurements 18-24 months later if the baseline T-score is<-1 and 3-5 years later if the baseline T-score is>-1. The anti-tumor effect of bisphosphonates and denosumab was not considered when establishing these recommendations.

Fertility preservation, contraception and menopause hormone therapy in women treated for rare ovarian tumours: guidelines from the French national network dedicated to rare gynaecological cancers.

INTRODUCTION: Rare ovarian tumours include complex borderline ovarian tumours, sex-cord tumours, germ cell tumours and rare epithelial tumours. Indications and modalities of fertility preservation (FP), infertility management, contraindications for hormonal contraception or menopause hormone therapy are frequent issues in clinical practice. A panel of experts from the French national network dedicated to rare gynaecological cancers, and experts in reproductive medicine and gynaecology have built guidelines on FP, contraception and menopause hormone therapy in women treated for ovarian rare tumours. MATERIAL AND METHODS: A panel of 35 experts from different specialties contributed to the preparation of the guidelines, following the DELPHI method (formal consensus method). Statements were drafted after a systematic literature review and then rated through two successive rounds. RESULTS: Thirty-five recommendations were identified, concerning indications for FP, contraindications for ovarian stimulation, contraceptive options and menopause hormone therapy for each tumour type. DISCUSSION: Overall, caution has been recommended in the case of potentially hormone-sensitive tumours such as sex-cord tumours, serous and endometrioid low-grade adenocarcinomas, as well as for high-risk serous borderline ovarian tumours. CONCLUSION: In the context of a scarce literature, a formal consensus method allowed the elaboration of guidelines, which will help clinicians in the management of these patients.

2018 update of French recommendations on the management of postmenopausal osteoporosis.

OBJECTIVES: To update the 2012 recommendations on pharmacotherapy for postmenopausal osteoporosis, under the aegis of the Bone Task Force of the French Society for Rheumatology (SFR) and of the Osteoporosis Research and Information Group (GRIO), in collaboration with scientific societies (Collège national des généralistes enseignants, Collège national des gynécologues et obstétriciens français, Fédération nationale des collèges de gynécologie médicale, Groupe d'étude de la ménopause et du vieillissement hormonal, Société française de chirurgie orthopédique, Société française d'endocrinologie, and Société française de gériatrie et de gérontologie). METHODS: Updated recommendations were developed by a task force whose members represented the medical specialties involved in the management of postmenopausal osteoporosis. The update was based on a literature review and developed using the method advocated by the French National Authority for Health (HAS). DISCUSSION AND CONCLUSION: The updated recommendations place strong emphasis on the treatment of women with severe fractures, in whom the use of osteoporosis medications is recommended. All the available osteoporosis medications are suitable in patients with severe fractures; zoledronic acid deserves preference as the fist-line drug after a hip fracture. In patients with or without non-severe fractures, the decision to use osteoporosis medications is based on bone mineral density values and in challenging cases, on probabilities supplied by prediction tools such as FRAX®. All osteoporosis medications are suitable; raloxifene should be reserved for patients at low risk for peripheral fractures. The fracture risk should be reevaluated every 2 to 3 years to decide on the best follow-up treatment. These updated recommendations discuss the selection of first-line osteoporosis medications and treatment sequences.

[Fertility preservation, contraception and menopause hormone therapy in women treated for rare ovarian tumors: Guidelines from the French national network dedicated to rare gynaecological cancer]. / Préservation de la fertilité, contraception et traitement hormonal de la ménopause chez les femmes traitées pour tumeurs malignes rares de l'ovaire : recommandations du réseau national dédié aux cancers gynécologiques rares (TMRG/GINECO).

INTRODUCTION: Rare ovarian tumors include complex borderline ovarian tumors, sex-cord tumors, germ cell tumors, and rare epithelial tumors. Indications and modalities of fertility preservation, infertility management and contraindications for hormonal contraception or menopause hormone therapy are frequent issues in clinical practice. A panel of experts from the French national network dedicated to rare gynaecological cancers, and of experts in reproductive medicine and gynaecology have worked on guidelines about fertility preservation, contraception and menopause hormone therapy in women treated for ovarian rare tumors. METHODS: A panel of 39 experts from different specialties contributed to the preparation of the guidelines, following the DELPHI method (formal consensus method). Statements were drafted after a systematic literature review, and then rated through two successive rounds. RESULTS: Thirty-five recommendations were selected, and concerned indications for fertility preservation, contraindications for ovarian stimulation (in the context of fertility preservation or for infertility management), contraceptive options (especially hormonal ones), and menopause hormone therapy for each tumor type. Overall, prudence has been recommended in the case of potentially hormone-sensitive tumors such as sex cord tumors, serous and endometrioid low-grade adenocarcinomas, as well as for high-risk serous borderline ovarian tumors. DISCUSSION: In the context of a scarce literature, a formal consensus method allowed the elaboration of guidelines, which will help clinicians in the management of these patients.

[Towards an optimization of the modulation of the estrogen receptor during menopausal hormonal therapy]. / Vers une optimisation de la modulation du récepteur des œstrogènes dans le traitement hormonal de la ménopause.

Women now live more than a third of their lives after the onset of menopause. The decline in endogenous estrogen production during this period is accompanied by functional disorders that affect quality of life. These symptoms may be relieved by menopausal hormone therapy (MHT) initially based on the administration of equine conjugated estrogens (mainly in the United States, oral route) or the natural estrogen, 17ß-estradiol (in Europe, transdermal route). Estrogen receptor α (ERα), but not ERß, mediates most of the physiological effects of estrogens. ERα belongs to the superfamily of nuclear receptors and regulates the transcription of genes via its activation functions AF1 and AF2. In addition to these classical genomic actions, estrogens can activate a subpopulation of ERα present at the cell membrane and thereby induce rapid signals. In this review, we will summarize the evolution of MHTs in last decades, as well as treatments that use various selective estrogen receptor modulators (SERMs). Next, we will describe recent advances in the understanding of the mechanisms of estrogen action, in particular the respective roles of nuclear and membrane ERα as well as the potential implications for future therapies.

Estetrol, a Fetal Selective Estrogen Receptor Modulator, Acts on the Vagina of Mice through Nuclear Estrogen Receptor α Activation.

The genitourinary syndrome of menopause has a negative impact on quality of life of postmenopausal women. The treatment of vulvovaginal atrophy includes administration of estrogens. However, oral estrogen treatment is controversial because of its potential risks on venous thrombosis and breast cancer. Estetrol (E4) is a natural estrogen synthesized exclusively during pregnancy by the human fetal liver and initially considered as a weak estrogen. However, E4 was recently evaluated in phase 1 to 2 clinical studies and found to act as an oral contraceptive in combination with a progestin, without increasing the level of coagulation factors. We recently showed that E4 stimulates uterine epithelial proliferation through nuclear estrogen receptor (ER) α, but failed to elicit endothelial responses. Herein, we first evaluated the morphological and functional impacts of E4 on the vagina of ovariectomized mice, and we determined the molecular mechanism mediating these effects. Vaginal epithelial proliferation and lubrication after stimulation were found to increase after E4 chronic treatment. Using a combination of pharmacological and genetic approaches, we demonstrated that these E4 effects on the vagina are mediated by nuclear ERα activation. Altogether, we demonstrate that the selective activation of nuclear ERα is both necessary and sufficient to elicit functional and structural effects on the vagina, and therefore E4 appears promising as a therapeutic option to improve vulvovaginal atrophy.

Drug holidays from bisphosphonates and denosumab in postmenopausal osteoporosis: EMAS position statement.

BACKGROUND: Bisphosphonates and denosumab are used extensively in the treatment of postmenopausal osteoporosis. Despite their proven efficacy in the reduction of vertebral and non-vertebral fractures, their optimal duration of use has not been determined. The occurrence of adverse effects, such as osteonecrosis of the jaw (ONJ) and atypical femoral fractures (AFF), has raised the issue of bisphosphonate or denosumab discontinuation ("drug holiday") after a certain treatment period. AIM: To assess the effect of bisphosphonate and denosumab discontinuation on fracture risk, as well as its possible benefits in reducing the risk of adverse effects. METHODS: Systematic review and consensus of expert opinion. RESULTS AND CONCLUSIONS: Discontinuation of bisphosphonates should be considered in all patients who have beentreated for more than five years with alendronate, risedronate or zoledronic acid. In view of the limited evidence, no robust recommendations can be made for ibandronate and denosumab. If the patient has not experienced fractures before or during therapy and the fracture risk is low, a "drug holiday" canbe recommended. Although there is no solid evidence, 1-2 years for risedronate, 3-5 years for alendronate and 3-6 years for zoledronic acid are suggested. After this time, the patient should be reassessed. If a new fracture is experienced, or fracture risk has increased or BMD remains low (femoral neck T-score ≤-2.5), anti-osteoporotic treatment should be resumed. In the case of denosumab discontinuation, close monitoring is suggested, due to the possibility of rebound fractures.

Diagnostic accuracy of FRAX in predicting the 10-year risk of osteoporotic fractures using the USA treatment thresholds: A systematic review and meta-analysis.

OBJECTIVES: The aim of this study was to conduct a systematic review and meta-analysis on the performance of the WHO's Fracture Risk Assessment (FRAX) instrument in predicting 10-year risk of Major Osteoporotic Fractures (MOF) and Hip Fractures (HF), using the USA treatment thresholds, in populations other than their derivation cohorts. DESIGN: EMBASE and MEDLINE database were searched with search engine PubMed and OVID as well as Google Scholar for the English-language literature from July 2008 to July 2016. Limiting our search to articles that analyzed only MOF and/or HF as an outcome, 7 longitudinal cohorts from 5 countries (USA, Poland, France, Canada, New Zealand) were identified and included in the meta-analysis. SAS NLMIXED procedure (SAS v 9.3) was applied to fit the Hierarchical Summary Receiver Operating Characteristics (HSROC) model for meta-analysis. Forest plot and HSROC plot was generated by Review Manager (RevMan v 5.3). RESULTS: Seven studies (n=57,027) were analyzed to assess diagnostic accuracy of FRAX in predicting MOF, using 20% as the 10-year fracture risk threshold for intervention, the mean sensitivity, specificity, and diagnostic odds ratio (DOR) along with their 95% confidence intervals (CI) were 10.25% (3.76%-25.06%), 97.02% (91.17%-99.03%) and 3.71 (2.73-5.05), respectively. For HF prediction, using 3% as the 10-year fracture risk threshold, six studies (n=50,944) were analyzed. The mean sensitivity, specificity, and DOR along with their 95% confidence intervals (CI) were 45.70% (24.88%-68.13%), 84.70% (76.41%-90.44%) and 4.66 (2.39-9.08), respectively. CONCLUSIONS: Overall, using the 10year intervention thresholds of 20% for MOF and 3% for HF, FRAX performed better in identifying patients who will not have a MOF or HF within 10years, than those who will. A substantial number of patients who developed fractures, especially MOF within 10years of follow up, were missed by the baseline FRAX assessment.

Osteoporosis management in patients with breast cancer: EMAS position statement.

Aromatase inhibitors (AIs) are the first-line recommended standard of care for postmenopausal estrogen receptor-positive breast cancer. Because they cause a profound suppression of estrogen levels, concerns regarding their potential to increase the risk of fracture were rapidly raised. There is currently a general consensus that a careful baseline evaluation is needed of the risk of fracture in postmenopausal women about to start treatment with AIs but also in all premenopausal women with early disease. Bisphosphonates have been shown in several phase III trials to prevent the bone loss induced by cancer treatment, although no fracture data are available. Even though they do not have regulatory approval for this indication, their use must be discussed with women at high risk of fracture. Accordingly, several guidelines recommend considering treatment in women with a T-score ≤-2 or those with two or more clinical risk factors. Moreover, recent data suggest that bisphosphonates, especially intravenous zoledronic acid, may have an anticancer effect, in that they reduce bone recurrence as well as extra-skeletal metastasis and breast cancer mortality in postmenopausal women. The anti-RANK ligand antibody denosumab is also emerging as a new adjuvant therapeutic option to prevent AI-induced bone loss. It has been shown to extend the time to first fracture in postmenopausal women treated with AIs. Several issues still need to be addressed regarding the use of these different agents in an adjuvant setting. The purpose of this position statement is to review the literature on antifracture therapy and to discuss the current guidelines for the management of osteoporosis in women with early breast cancer.