Karine Briot
email: karine.briot@aphp.fr

Christian Roux

Thierry Thomas

Hubert Blain

Daniel Buchon

Roland Chapurlat

Françoise Debiais

Jean Marc Feron

Jean Bernard Gauvain

Pascal Guggenbuhl

Eric Legrand

Anne Marie Lehr-Drylewicz

Eric Lespessailles

Françoise Tremollieres

Georges Weryha

Bernard Cortet

2018 Update of French Recommendations on the Management of Postmenopausal Osteoporosis

à la diffusion de documents scientifiques de niveau recherche, publiés ou non, émanant des établissements d'enseignement et de recherche français ou étrangers, des laboratoires publics ou privés.

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 A c c e p t e d M a n u s c r i p t

Objectives and methods

These updated recommendations are intended for all physicians involved in managing women who have, or are at risk for, postmenopausal osteoporosis. The objectives of the update are to review current epidemiological data on postmenopausal osteoporosis; identify the key criteria for evaluating patients at high risk for fractures; and clarify the principles of drug therapy for postmenopausal osteoporosis in the light of recent evidence about indications, efficacy, and safety. The content of the recommendations was discussed and elaborated according to the method advocated by the French National Authority for Health (HAS) then validated by a multidisciplinary study group. When published data were inadequate or incomplete, expert consensus formed the basis for the recommendations, to give due weight to current practice and expert opinion.

No recommendations can encompass every specific situation, the full spectrum of comorbidities, or all hospital care protocols. Therefore, the current update does not claim to cover all possible management strategies and should not serve as a substitute for individual physician responsibility regarding treatment decisions. The indications of the drugs and the information on reimbursement by the statutory health insurance system of drugs, bone absorptiometry, and serum 25-OH-vitamin D assays are valid for France. These updated recommendations were developed by a project manager and a scientific committee then discussed and revised by a multidisciplinary panel of reviewers. As part of the process of revising and validating the recommendations, advice was obtained from the following scientific societies: Collège National des Généralistes Enseignants, Collège

National des Gynécologues et Obstétriciens Français, Fédération Nationale des Collèges de

Epidemiology of osteoporosis and fractures

Epidemiology

Osteoporosis is a generalized bone disease in which bone strength is diminished, resulting in a risk of fractures [START_REF]NIH Consensus Development Panel on Osteoporosis[END_REF]. As a disease that increases the risk and frequency of several severe fractures associated with devastating consequences, osteoporosis is a major public health issue. The fracture risk increases substantially with age, and the burden placed by osteoporosis on public health is therefore heaviest in countries with long life expectancies.

The recommendations presented here apply to patients in whom causes of decreased bone strength other than postmenopausal osteoporosis have been ruled out.

Osteoporotic or fragility fractures are induced by low-energy trauma such as a fall from standing height while walking. The only bones where osteoporotic fractures do not occur are the skull, facial bones, cervical spine, first three thoracic vertebras, hand bones, and toes; fractures at these sites are due to either injuries or tumors. Falls from standing height are the leading cause of non-vertebral fragility fractures. Among these falls, 5% are responsible for fractures at any site (2) and 2% for hip fractures in individuals older than 65 years of age (3).

2.1.1.

Epidemiological data from France

A c c e p t e d M a n u s c r i p t [START_REF] Thomas | Évaluation de la prise en charge avant et après hospitalisation pour fracture de fragilité en France à partir des dossiers de la SNIIRAM[END_REF]. The number of patients admitted with osteoporotic fractures at any site was 177 000. Among these patients, three-quarters were female and twothirds were older than 70 years. The number of admissions for fractures of any type increased by 9% between 2011 and 2013. Direct annual costs totaled 771 million Euros. During the year following the admission, 6325 (7%) patients died, 12% experienced another fracture, and 40% were readmitted. The mortality rate was twice as high in males than in females. During the first year after the fracture, only 10% of patients underwent bone absorptiometry and only 15% were started on osteoporosis medication. Thus, over 80% of patients did not receive appropriate management after sustaining a fracture that required hospital admission. These data from France (6) are consistent with those reported worldwide (7).

2.1.2.

Consequences of severe fractures

Severe fractures are associated with an increase in mortality. Fractures are severe at the following sites: hip, proximal humerus, spine, pelvis, sacrum, femoral shaft, distal femur, ribcage involving at least three ribs, and proximal tibia [START_REF] Leblanc | Hip fracture and increased short-term but not long-term mortality in healthy older women[END_REF][START_REF] Melton Lj 3rd | Long-term mortality following fractures at different skeletal sites : a population-based cohort study[END_REF][START_REF] Bliuc | Mortality risk associated with low-trauma osteoporotic fracture and subsequent fracture in men and women[END_REF]. The excess mortality compared Epidemiological studies have confirmed that pelvic and humeral fractures are associated with increased mortality [START_REF] Clinton | Proximal humeral fracture as a risk factor for subsequent hip fractures[END_REF]. Furthermore, severe fractures are associated with a risk of further vertebral and non-vertebral fractures, which account for 25% of the excess mortality [START_REF] Bliuc | The impact of nonhip nonvertebral fractures in elderly women and men[END_REF].

Other common fractures, such as forearm fractures, are classified as non-severe because they are not associated with an increase in mortality, although their impact may be substantial. Non-severe fractures can be the first manifestation of osteoporosis and are associated with a risk of further fractures, which may be severe [START_REF] Cuddihy | Forearm fractures as predictors of subsequent osteoporotic fractures[END_REF].

Risk factors for fractures and short-term fracture risk

A recent fracture is a major risk factor for a further fracture in the short term. More specifically, after a vertebral fracture there is a 25% risk of sustaining another fracture within the following year [START_REF] Lindsay | Risk of new vertebral fracture in the year following a fracture[END_REF]. The risk of fracture is also increased during the 2 to 3 years after a non-vertebral fracture [START_REF] Van Geel | Clinical subsequent fractures cluster in time after first fractures[END_REF][START_REF] Van Geel | Development of a simple prognostic nomogram for individualising 5-year and 10-year absolute risks of fracture : a population-based prospective study among postmenopausal women[END_REF]. In addition to a recent fracture, risk factors for a repeat fracture in the short term include risk factors for falls [START_REF] Bonafede | Predicting imminent risk for fracture in patients aged 50 or older with osteoporosis using US claims data[END_REF][START_REF] Huntjens | The role of the combination of bone and fall related risk factors on short-term subsequent fracture risk and mortality[END_REF]. Patients who have these risk factors should be treated promptly to prevent further fractures.

Comorbidities and fracture risk

Patients with osteoporosis have an increased prevalence of chronic comorbidities such as dementia, Parkinson's disease, other neurological disorders, diabetes, and cardiovascular disease, and many are on multiple medications [START_REF] Amouzougan | High prevalence of dementia in women with osteoporosis[END_REF][START_REF] Laroche | Osteoporosis and ischemic cardiovascular disease[END_REF]. These comorbidities must receive appropriate attention, as they increase the fracture risk and the adverse impact of fractures.

Examples of situations in which fractures are particularly deleterious include hip fractures in patients with dementia and vertebral fractures in those with chronic obstructive pulmonary values; and comorbidity profile.

Fracture risk prediction tools

History of fractures in the patient

A history of fracture is the strongest predictor of further fractures [START_REF] Lindsay | Risk of new vertebral fracture in the year following a fracture[END_REF][START_REF] Van Geel | Clinical subsequent fractures cluster in time after first fractures[END_REF][START_REF] Huntjens | The role of the combination of bone and fall related risk factors on short-term subsequent fracture risk and mortality[END_REF][START_REF] Laroche | Osteoporosis and ischemic cardiovascular disease[END_REF][START_REF] Black | Prevalent vertebral deformities predict hip fractures and new vertebral deformities but nop wrist fractures[END_REF], regardless of fracture location at the spine or at a peripheral site. The period of greatest risk increase is 2 to 3 years after the first fracture. However, the risk increase remains significant for 10 to 15 years (particularly after vertebral and humeral fractures) [START_REF] Klotzbuecher | Patients with prior fractures have an increased risk of future fractures : a summary of the literature and statistical synthesis[END_REF][START_REF] Giangregorio | Manitoba Bone Density Program. Time since prior fracture is a risk modifier for 10-year osteoporotic fractures[END_REF]. The time since the fracture is important to note, as only recent fractures are associated with an increased short-term risk of fractures.

Vertebral fractures are common, but their frequency is underestimated, as they are missed in two-thirds of cases due to the paucity of the symptoms or to a mistaken diagnosis of disk disease as the source of pain, in the absence of a radiographic assessment. Vertebral fractures are a key risk factor for vertebral and non-vertebral fractures. (expert consensus).

Bone mineral density (BMD) measurement

Dual-energy X-ray absorptiometry (DXA) is the reference method for measuring BMD at the lumbar spine and hip. Bone strength correlates strongly with BMD. In postmenopausal women, BMD results are reported as T-scores. The T-score is the number of standard deviations (SDs) of the measured BMD value above or below the same-site mean BMD in young women. The World Health Organization defines osteoporosis as a T-score ≤-2.5 at the femoral neck [START_REF]Assessment of fracture risk and its application to screening for postmenopausal osteoporosis : report of a WHO study group[END_REF]. Since July 1, 2006, the French health insurance system reimburses DXA in women meeting the criteria listed in Box 1.

3.1.2.1.

Selecting the BMD measurement site and reference curve BMD should be measured at two sites, the lumbar spine and proximal femur (femoral neck and total hip). BMD measurement at the radius is not indicated for the evaluation of postmenopausal osteoporosis [START_REF] Lewiecki | Official position of the International Society for Clinical Densitometry[END_REF]. According to the International Osteoporosis Foundation, if

DXA is performed at a single site, the femoral neck or total hip should be selected and the NHANES III reference curve used [START_REF] Kanis | A reference standard for the description of osteoporosis[END_REF][START_REF] Paggiosi | International variation in proximal femur bone mineral density[END_REF]. BMD at the femoral neck correlates more The fracture risk increases as BMD decreases: for each BMD decrease by 1 SD, the fracture risk increases 2-fold [START_REF] Marshall | Metanalysis of how well measures of bone mineral density predict occurrence of osteoporotic fractures[END_REF][START_REF] Fujiwara | Fracture prediction from bone mineral density in Japanese men and women[END_REF][START_REF] Sornay-Rendu | Identification of osteopenic women at high risk of fracture : the OFELY study[END_REF]. As the T-score value declines, the risk of osteoporotic hip fracture increases [START_REF] Johnell | Predictive value of BMD for hip and other fractures[END_REF][START_REF] Bates | Clinical use of bone densitometry : clinical applications[END_REF]. BMD decrease at any site is associated with a higher risk of fracture at any site. Nevertheless, a decline in BMD measured at the femur strongly predicts the risk of fracture at any site and at the femur (32, 33).

Limitations of using a T-score cutoff

Defining osteoporosis based on BMD criteria fails to identify all women at risk for fractures. Thus, over 50% of non-vertebral fractures occur in women whose T-score is above -2.5 [START_REF] Sornay-Rendu | Identification of osteopenic women at high risk of fracture : the OFELY study[END_REF][START_REF] Sc | Fracture incidence and association with bone mineral density in elderly men and women : the Rotterdam Study[END_REF][START_REF] Siris | Bone mineral density threshold for pharmacological intervention to prevent fractures[END_REF][START_REF] Wainwright | Hip fracture in women without osteoporosis[END_REF]. Among patients with osteoporosis diagnosed based on a fracture after a trivial trauma although they do not meet BMD criteria for the disease, bone tissue assessments show specific alterations responsible for decreased bone strength. For instance, obese individuals may have BMD values that are too low for their body weight, diabetic patients exhibit bone matrix abnormalities related to protein glycation, and women starting aromatase inhibitor therapy experience excessive bone resorption (37-41).

Evaluating the fall risk

Risk factors for falls play a central role in the occurrence of non-vertebral fractures in very elderly and/or frail patients [START_REF] Dargent-Molina | Fall-related factors and risk of hip fracture : the EPIDOS prospective study[END_REF]. Recommendations about identifying individuals at high risk for falls were issued by the HAS in 2005 (http://www.hassante.fr/portail/upload/docs/application/pdf/prevention_des_chutes-argumentaire.pdf).

Fracture risk prediction tools for specialists

These tools can be helpful to all physicians trained in interpreting their results and experienced in managing bone diseases.

Absolute fracture risk estimation using the FRAX 

The identification of individuals at risk for fractures requires a multifactorial assessment including BMD measurement and an evaluation of the clinical risk factors associated with the fracture risk (Box 2). The roles played by the various risk factors varies with age. The Fracture Risk Assessment Tool FRAX  was developed to quantify the fracture risk [START_REF] Kanis | FRAX® and the assessment of fracture probability in men and women from the UK[END_REF] (www.sheffield.ac.uk/FRAX). The tool estimates the 10-year probability of a hip fracture and of major fracture defined as a fracture of the hip, humerus, wrist or a clinical vertebral fracture. The FRAX  tool has been tested in several cohorts in France [START_REF] Briot | update of French guidelines for the pharmacological treatment of postmenopausal osteoporosis[END_REF][START_REF] Briot | FRAX®: prediction of major osteoporotic fractures in women from the general population : the OPUS study[END_REF][START_REF] Sornay-Rendu | The FRAX tool in French women : How well does it describe the real incidence of fracture in the OFELY cohort?[END_REF][START_REF] Trémollieres | Fracture risk prediction using BMD and clinical risk factors in early postmenopausal women. Sensitivity of the WHO FRAX tool[END_REF][START_REF] Couris | FRAX® probabilities and risk of major osteoporotic fracture in France[END_REF]. The -

The FRAX  tool is not useful when there is a clear indication to start osteoporosis therapy, for instance a history of severe fracture or a T-score -3 at the lumbar spine and at the total hip and/or femoral neck.

-The FRAX  cutoff above which osteoporosis treatment is appropriate varies with age. For a given age, the FRAX  cutoff for treatment is the value in same-age women with a history of fracture (risk of repeat fracture) [START_REF] Kanis | FRAX® and the assessment of fracture probability in men and women from the UK[END_REF]. Figure 1 shows the cutoffs according to age (consensus of experts).

The trabecular bone score (TBS)

The trabecular bone score (TBS) is a measure of bone texture that is automatically computed from DXA data at the lumbar spine. TBS values are lower in patients with than without fragility fractures and have been found effective in discriminating between these two groups. Combining the BMD and TBS values predicts the fracture risk more effectively than does the lumbar BMD value alone. Nevertheless, in prospective studies, femoral BMD was the strongest predictor. Routine TBS measurement for fracture risk prediction and treatment monitoring is not recommended, as the ability of the TBS to reclassify patients has not been firmly established [START_REF] Bousson | Trabecular Bone Score : Where are we now?[END_REF]52). The TBS is associated with the risk of osteoporotic hip fractures after adjustment on the FRAX ® probability [START_REF] Leslie | Lumbar spine texture enhances 10-year fracture probability assessment[END_REF][START_REF] Leslie | Spine bone texture assessed by trabecular bone score (TBS) predicts osteoporotic fractures in men : the Manitoba Bone Density Program[END_REF]. A metaanalysis of 14 prospective studies showed that adjustment on the TBS did not substantially improve the predictive performance of the FRAX ® tool [START_REF] Mccloskey | A Meta-Analysis of Trabecular Bone Score[END_REF][START_REF] Vasikaran | Fracture Risk Prediction and Its Relationship to FRAX. Markers of bone turnover for the prediction of fracture risk and monitoring of osteoporosis treatment : a need for international reference standards[END_REF]. In situations where the appropriateness of osteoporosis therapy is not obvious, the TBS[AW5] can be used in the same way as the FRAX  and with the same treatment-initiation cutoffs.

A c c e p t e d M a n u s c r i p t 14

Bone turnover markers

Several laboratory markers are available for noninvasively assessing bone turnover.

Among them, some reflect bone formation (osteocalcin, bone alkaline phosphatase, procollagen I extension peptides) and others bone resorption (degradation peptides).

However, the clinical meaning of bone marker levels must be interpreted in the light of

potential

Strategies for preventing and treating postmenopausal osteoporosis

The diagnosis of osteoporosis requires the elimination of other causes of bone fragility, which include metabolic diseases, malignancies, and genetic disorders. This diagnostic step must be completed before starting osteoporosis therapy. Fracture prevention is the treatment goal. Therefore, osteoporosis therapy should aim both to increase bone strength and to decrease the risk of falls. The management strategy thus combines pharmacological and 2 and3) [START_REF] Cauley | Effects of estrogen plus progestin on risk of fracture and bone mineral density. The women's Health Initiative randomized trial[END_REF][START_REF] Ettinger | Reduction of vertebral fracture risk in postmenopausal women with osteoporosis treated with raloxifEne. Results from a 3 years randomized clinical trial[END_REF][START_REF] Black | Randomised trial of effect of alendronate on risk of fracture in women with existing vertebral fractures. Fracture intervention Trial Research Group[END_REF][START_REF] Cummings | Effect of alendronate on risk of fracture in women with low bone density but without vertebral fractures : results from the Fracture Intervention trial[END_REF][START_REF] Cranney | Meta-analysis of alendronate for the treatment of postmenopausal women[END_REF][START_REF] Wells | Alendronate for the primary and secondary prevention of osteoporotic fractures in postmenopausal women[END_REF][START_REF] Harris | Effect of risedronate treatment on vertebral and nonvertebral fractures in women with postmenopausal osteoporosis. A randomized controlled trial[END_REF][START_REF] Reginster | Randomized trial of the effects of risedronate on vertebral fractures in women with established postmenopausal osteoporosis[END_REF][START_REF] Wells | Risedronate for the primary and secondary prevention of osteoporotic fractures in postmenopausal women[END_REF][START_REF] Boonen | Safety and efficacy of risedronate in reducing fracture risk in osteoporotic women aged 80 and older : implications for the use of antiresorptive agents in the old and oldest old[END_REF][START_REF] Black | Once-yearly zoledronic acid for treatment of postmenopausal osteoporosis[END_REF][START_REF] Lyles | Zoledronic Acid in Reducing Clinical Fracture and Mortality after Hip Fracture[END_REF][START_REF] Boonen | Efficacy and safety of a once-yearly intravenous zoledronic acid 5 mg for fracture prevention in elderly postmenopausal women with osteoporosis aged 75 and older[END_REF][START_REF] Neer | Effect of parathyroid hormone (1-34) on fractures and bone mineral density in postmenopausal women with osteoporosis[END_REF][START_REF] Cummings | Denosumab for prevention of fractures in postmenopausal women with osteoporosis[END_REF][START_REF] Karpf | Prevention of non vertebral fractures by alendronate. A meta-analysis. Alendronate Osteoporosis Treatment Study groups[END_REF][START_REF] Clung | Effect of risedronate on the risk of hip fracture in elderly women[END_REF][START_REF] Papapoulos | Metaanalysis of the efficacy of alendronate for the prevention of hip fractures in postmenopausal women[END_REF].

No head-to-head comparisons of the antifracture efficacy of osteoporosis medications are available. Neither BMD values nor biochemical parameters can serve to compare efficacy.

Important considerations when selecting the drug include beneficial or undesirable extraskeletal effects, specific contraindications of each drug, constraints for patients, and decisionsharing with patients. Taking the drugs exactly as ordered may contribute to minimize the risk of certain adverse events. Factors relevant to drug selection include age, the risk of vertebral and/or non-vertebral fractures, and fracture severity (consensus of experts). Finally, the conditions under which each drug is reimbursed by the health insurance system must be respected.

In every case, the patient should be informed about the disease and its treatments.

Emphasis should be placed on treatment adherence as part of the process of shared decision making. Adherence should be monitored throughout follow-up.

If osteoporosis drug therapy fails or raises challenges, advice should be sought from a bone disease specialist (consensus of experts). Management by a multidisciplinary network for fracture patients has been shown to improve the quality of care [START_REF] Ganda | Models of care for the secondary prevention of osteoporotic fractures : a systematic review and meta-analysis[END_REF][START_REF] Huntjens | Fracture liaison service : impact on subsequent nonv ertebral fracture incidence and mortality[END_REF]. The if the T-score is ≤-1 (consensus of experts) (Figure 2). DXA provides a quantitative assessment of bone fragility, confirms that the T-score is ≤-1, and serves as a reference for monitoring the treatment (Figure 2). If the T-score is >-1, it may be best to seek advice from a bone disease specialist and to use fracture prediction tools (FRAX ® , TBS, and bone turnover markers).

In patients with severe non-vertebral fractures, the following drugs are reimbursed in France: alendronate, 70 mg/week or 10 mg/day; risedronate, 35 mg/week or 75 mg on 2 consecutive days once a month or 5 mg/day; zoledronic acid, 5 mg as a single intravenous infusion per year; and denosumab, 60 mg subcutaneously every 6 months (reimbursed only when used after a bisphosphonate). Zoledronic acid is the only osteoporosis drug that has been proven effective in postmenopausal patients with hip fractures [START_REF] Lyles | Zoledronic Acid in Reducing Clinical Fracture and Mortality after Hip Fracture[END_REF].

The

Recommendations for patients without fractures

Osteoporosis screening using DXA is recommended in postmenopausal women with risk factors for osteoporosis (Grade A). The test is reimbursed in this situation. Falls and osteoporosis are independent risk factors for non-vertebral fractures, and osteoporosis is common in patients who fall. Therefore, screening DXA should be performed in elderly patients at risk for falls (consensus of experts) [START_REF] Blain | Usefulness of bone density measurement in fallers[END_REF]. When osteoporosis drug therapy is indicated, the treatment options are those listed for non-severe fractures.

The criteria for using raloxifene and menopausal hormone replacement therapy are described in the previous section.

Treatment measures to be used in combination with osteoporosis drug therapy

Fall prevention

Calcium intake

The recommended calcium intake for postmenopausal women older than 50 years of age is at least 1000 to 1200 mg. Preference should be given to dietary calcium (dairy products and calcium-rich mineral water) (consensus of experts). Calcium-deficient patients at risk for fractures should ingest at least 1000 mg of calcium per day according to the PNNS. In practice, the dietary calcium intake can be assessed using a food frequency self-questionnaire available online (www.grio.org) [Appendix A, Table S1; See the supplementary material associated with this article online]. Calcium supplements alone have not been proven effective in decreasing the risk of osteoporotic fractures. Calcium supplementation was associated with a higher risk of cardiovascular events in older women [START_REF] Bolland | Vascular events in healthy older women receiving calcium supplementation : randomised controlled trial[END_REF][START_REF] Bolland | Effect of calcium supplements on risk of myocardial infarction and cardiovascular events : meta-analysis[END_REF][START_REF] Pentti | Use of calcium supplementation and the risk of coronary heart disease in 52-62-year-old women : the Kuopio Osteoporosis Risk Factor and Prevention Study[END_REF]. This adverse effect occurred chiefly among women whose baseline dietary calcium intake was adequate [START_REF] Bolland | Calcium supplements with or without vitamin D and risk of cardiovascular events : reanalysis of the Women's Health Initiative limited access dataset and meta-analysis[END_REF]. Vitamin D-deficient patients should receive vitamin D supplements.

Vitamin D

Current recommendations state that the serum 25-OH-vitamin D level should be kept at or above 30 ng/mL (75 nmol/L) (consensus of experts) [START_REF] Kanis | FRAX® and the assessment of fracture probability in men and women from the UK[END_REF]. A serum 25-OH-vitamin D assay should be performed to rule out other causes of bone fragility (osteomalacia), as well as in patients who fall and are scheduled for osteoporosis medication therapy. In both these indications, the assay is reimbursed in France. The assay may need to be repeated during follow-up to check that the target is met, particularly in patients at high risk for vitamin D Follow-up assays are recommended in patients who require osteoporosis medication therapy (consensus of experts).

In patients with vitamin D deficiency or insufficiency, initial high-dose supplementation can rapidly increase the serum 25-OH-vitamin D level above 30 ng/mL [START_REF] Kanis | FRAX® and the assessment of fracture probability in men and women from the UK[END_REF]. The vitamin D dosage for maintenance therapy is 800 to 1200 IU/day. Instead of daily supplementation, a dose of 80 000 to 100 000 IU can be given every 2 to 3 months [START_REF] Kanis | FRAX® and the assessment of fracture probability in men and women from the UK[END_REF]. Currently available data suggest that high doses of 500 000 to 600 000 IU once or twice a year may be deleterious and consequently are not recommended (87) (consensus of experts).

Elimination of modifiable risk factors

Whenever possible, risk factors for fractures and falls should be eliminated. Examples include smoking cessation and discontinuation of non-essential medications associated with falls such as opiates and hypnotic agents [START_REF] Richardson | Polypharmacy including falls risk-increasing medications and subsequent falls in community-dwelling middle-aged and older adults[END_REF][START_REF] Teng | Opioids contribute to fracture risk : a meta-analysis of 8 cohort studies[END_REF]. Oral glucocorticoid therapy should be discontinued or reduced to the minimal effective dosage. Restraint regarding alcohol consumption should be encouraged.

Follow-up of patients with postmenopausal osteoporosis

Table 4 lists the main follow-up measures needed according to the nature of the osteoporosis treatment.

Clinical follow-up

Role for bone mineral density (BMD) measurement during follow-up

Frequency of BMD measurement

BMD measurements can be performed 2 to 3 years after treatment initiation and whenever a treatment change is considered (discontinuation of osteoporosis drug therapy or switch to a different drug). The goal is to check the absence of bone loss (defined as a greater than 0.03 g/cm 2 BMD decrease) (94) (Grade B). BMD measurement is also appropriate when the treatment must be stopped prematurely due to drug-related adverse events.

Recent data on zoledronic acid indicate that 40% to 61% of the decrease in the risk of vertebral and non-vertebral fractures is attributable to the BMD increase at the total hip [START_REF] Jacques | Relationship of changes in total hip bone mineral density to vertebral and nonvertebral fracture risk in women with postmenopausal osteoporosis treated with once-yearly zoledronic acid 5 mg : the HORIZON-Pivotal Fracture Trial (PFT)[END_REF].

With denosumab, the proportion of the anti-fracture effect ascribable to the same-site BMD increase is over 50% at vertebral and 72% at non-vertebral sites [START_REF] Austin | Relationship between bone mineral density changes with denosumab treatment and risk reduction for vertebral and nonvertebral fractures[END_REF]. Similar results have been obtained with teriparatide. Given these data, serial BMD measurements during followup are now intended not only to detect non-responders, but also to assess the bone response to treatment with the goal of achieving tight disease control.

BMD values at the end of a treatment course is among the criteria used to assess the risk of fractures over the next few years. The femoral BMD value after 5 years of alendronate or 3 years of zoledronic acid has been shown to predict the fracture risk over the following years [START_REF] Bauer | Fracture prediction after discontinuation of 4 to 5 years of alendronate therapy : the FLEX study[END_REF][START_REF] Cosman | Reassessment of fracture risk in women after 3 years of treatment with zoledronic acid : when is it reasonable to discontinue treatment?[END_REF]. In women whose hip T-score is <-2.5 after 3 years of zoledronic acid, 5 years of alendronate, or 4 years of denosumab, further treatment is beneficial to decrease the risk of vertebral fractures with zoledronic acid or of non-vertebral fractures with alendronate and denosumab [START_REF] Ferrari | Further reductions in nonvertebral fracture rate with longterm denosumab treatment in the FREEDOM open-label extension and influence of hip bone mineral density after 3 years[END_REF]. One possible BMD target is the value above which the fracture risk is decreased to an acceptable level. The target may vary with age and with the site at greatest risk for fracture. In all patients, the minimum treatment objective is absence of bone loss (BMD change ≤0.03 g/cm²). After a severe fracture in a patient with a very low femoral BMD value, the goal is a significant BMD increase, to a T-score value ≥-2.5 or -2 at the femur [START_REF] Bauer | Fracture prediction after discontinuation of 4 to 5 years of alendronate therapy : the FLEX study[END_REF][START_REF] Cosman | Reassessment of fracture risk in women after 3 years of treatment with zoledronic acid : when is it reasonable to discontinue treatment?[END_REF][START_REF] Ferrari | Further reductions in nonvertebral fracture rate with longterm denosumab treatment in the FREEDOM open-label extension and influence of hip bone mineral density after 3 years[END_REF]. Achieving this goal may require treatment adjustments (consensus of experts).

Role for bone turnover markers during follow-up

When treatment is recommended with an antiresorptive agent (bisphosphonate, denosumab, raloxifene, or menopausal hormone replacement therapy), a bone resorption marker (serum CTX) can be assayed 3 to 12 months after treatment initiation depending on the drug. Pharmacological effectiveness results in serum CTX levels that are at least within the normal range for non-menopausal women. If the serum CTX levels remain high, treatment adherence and modalities should be reviewed with the patient. If appropriate, a treatment change should be considered. However, an important point is that CTX assays are interpretable only if performed in the morning after an overnight fast. Furthermore, in patients with a history of fracture, the assay must be performed at least 6 months after the event (Grade B).

Treatment safety

For methodological reasons, extension studies of phase III randomized controlled trials supply only a low level of evidence regarding antifracture efficacy. However, they show that prolonged therapy is safe both overall and for bone tissue. During bisphosphonate therapy for up to 10 years, the incidence of gastrointestinal and other adverse events was not higher than in the placebo group during the randomized controlled phases.

Exposure to bisphosphonates or denosumab is among the risk factors for osteonecrosis of the jaw. In patients with osteoporosis, the incidence of osteonecrosis of the jaw is extremely low and similar to that in the general population (see section 5 on follow-up). Thus, the ASBMR task force reported an incidence of 0.001% to 0.01% patient-years (100).

Bisphosphonate or denosumab therapy is also one of the risk factors for atypical femoral fractures. With bisphosphonates, the risk is very low, with an estimate of 3. Patients should be informed of the risk of rare adverse events such as uveitis.

Denosumab is associated with a risk of hypocalcemia, particularly in patients with vitamin D deficiency or kidney failure. An evaluation must be conducted to ensure that the bone fragility requiring denosumab therapy is not a complication of chronic kidney disease. In this situation, a serum calcium assay should be performed before each denosumab injection.

Treatment duration 7.1. Theoretical treatment duration

The duration of osteoporosis drug therapy depends on age, the BMD treatment response, bone and overall tolerance of the drug, and occurrence of fractures during treatment (consensus of experts). The antifracture efficacy of available osteoporosis drugs was proven in randomized controlled trials lasting 3 to 5 years, or 18 months for teriparatide (Grade A).

Studies have assessed the effects of longer treatment durations: 10 years for alendronate (104-105), 7 years for risedronate (106), 8 years for raloxifene (107), 9 years for zoledronic acid (108), and 10 years for denosumab (109). As these studies had no control group, their results cannot establish long-term efficacy. However, they provide valuable data on long-term osseous and extraosseous treatment safety. An evaluation is recommended 2 years after treatment discontinuation. The interval between subsequent evaluations depends on the type of treatment. The carry-over effect on BMD after treatment discontinuation is more prolonged with zoledronic acid and alendronate than with the other drugs. No carry-over effect exists with denosumab; instead, a rebound bone resorption effect with loss of some of the BMD gains occurs at treatment discontinuation.

Course of action in clinical practice

Treatment sequences

Several treatment sequences have been validated. BMD values decrease after the recommended 18-month-long course of teriparatide therapy. Consequently, teriparatide therapy should be followed immediately by treatment with an antiresorptive agent (bisphosphonate or denosumab) (110-112). Similarly, denosumab discontinuation is followed by bone loss with an increase in the risk of multiple vertebral fractures. There is some evidence that bisphosphonates may prevent bone loss after denosumab discontinuation.

Therefore, oral or injectable bisphosphonate therapy should be given for 6 to 12 months when denosumab is stopped (113-114) (consensus of experts).

The oral bisphosphonate-denosumab sequence produces a larger BMD increase than does prolonged bisphosphonate therapy (115-117). In contrast, taking zoledronic acid after

  selection of first-line osteoporosis medications and treatment sequences. Keywords: Osteoporosis. Menopause. Fracture. Recommendations. Bone absorptiometry. FRAX.

A c c e p t e d M a n u s c r i p t 6 Gynécologie

 6 Médicale, Groupe d'Étude de la Ménopause et du Vieillissement hormonal, Groupe de Recherche et d'Information sur les Ostéoporoses (GRIO), Société Française de Chirurgie Orthopédique, Société Française d'Endocrinologie, Société Française de Gériatrie et de Gérontologie, and Société Française de Rhumatologie (SFR).

A c c e p t e d M a n u

  s c r i p t to the general population occurs chiefly among patients younger than 70 years of age[START_REF] Leblanc | Hip fracture and increased short-term but not long-term mortality in healthy older women[END_REF].

A c c e p t e d M a n u s c r i p t 9 disease.

 9 The risk/benefit ratio should be evaluated carefully in the event of comorbidities and the treatment options and administration modalities should be discussed with the patient.

A c c e p t e d M a n u s c r i p t 11 strongly

 11 with the fracture risk in cohort studies overall, is used in the FRAX tool, and can serve to monitor treatment effects.3.1.2.2. Relation between a low T-score and the fracture risk

A c c e p t e d M a n u s c r i p t 12 Numerous

 12 factors increase the risk of falls (Table1). Routinely evaluating and managing risk factors for falls in elderly patients would raise major challenges. Therefore, HAS guidelines, together with guidelines issued in the UK and US in 2010[AW3] and recommendations by other scientific societies, support the use of simple tests and questions as screening tools for elderly patients. In practice, a history of falling, particularly within the last 3-6 months and regardless of the circumstances, or a fear of falling that restricts selfsufficiency should prompt an evaluation for causes of balance impairment, if needed during a specialized geriatric visit. In doubtful cases, dynamic balance impairments responsible for an up-and-go time above 14 seconds or static balance impairments with a single-leg stance time below[AW4] 5 seconds and/or instability during the sternal push test indicate a need for an etiological workup and an appropriate management strategy[START_REF]British geriatrics Society clinical practice guideline : prevention of falls in older persons[END_REF][START_REF] Blain | A Comprehensive Fracture Prevention Strategy in Older Adults : The European Union Geriatric Medicine Society (EUGMS) Statement[END_REF].

A c c e p t e d M a n u s c r i p t 13 recommendations

 13 set forth below (consensus of experts) are based on national validation and calibration studies[START_REF] Briot | update of French guidelines for the pharmacological treatment of postmenopausal osteoporosis[END_REF][START_REF] Briot | FRAX®: prediction of major osteoporotic fractures in women from the general population : the OPUS study[END_REF][START_REF] Sornay-Rendu | The FRAX tool in French women : How well does it describe the real incidence of fracture in the OFELY cohort?[END_REF][START_REF] Trémollieres | Fracture risk prediction using BMD and clinical risk factors in early postmenopausal women. Sensitivity of the WHO FRAX tool[END_REF][START_REF] Couris | FRAX® probabilities and risk of major osteoporotic fracture in France[END_REF] and on international recommendations (NOF, NOS, NOGG).

  A c c e p t e d M a n u s c r i p t 15 nonpharmacological components. The efficacy of available osteoporosis medications in preventing fractures was proven in populations with osteoporosis diagnosed based on BMD criteria or on a history of fracture (Tables

4 . 1 .M a n u s c r i p t 16 4

 4116 recommendations set forth here consider both the first treatment course and subsequent treatments. Box 3 gives examples of treatment recommendations for various clinical situations. Osteoporosis medications 4.1.1. Recommendations for fracture patients A c c e p t e d .1.1.1. Severe fractureDXA should be performed before making treatment decisions if allowed by the medical situation (Grade A). Osteoporosis drug therapy is recommended in patients of all ages after a severe fragility fracture (hip, vertebra, distal femur, proximal humerus, pelvis, proximal tibia)

A c c e p t e d M a n u

  s c r i p t comorbidities and, more specifically, memory impairments; poor adherence; and polypharmacy (consensus of experts). 4.1.1.2. Non-severe fractures (wrist and other sites) DXA should be performed before making treatment decisions (Grade A). Given the correlation between declining BMD values and rising fracture risk, the treatment indications depend on the T-score (consensus of experts). These indications are reported in Fig. 2 (29-31). Treatment is recommended if the T-score is ≤-2 at the lumbar spine and/or hip. If the Tscore is >-2 and <-1, it may be best to seek advice from a bone disease specialist and to use fracture prediction tools (FRAX ® , TBS, and bone turnover markers). If the T-score is >-1, treatment is not recommended (consensus of experts). When osteoporosis drug therapy is indicated, the following drugs may be used (in alphabetical order): alendronate, 70 mg/week or 10 mg/day; risedronate, 35 mg/week or 75 mg on 2 consecutive days once a month or 5 mg/day; zoledronate, 5 mg as a single intravenous infusion per year; denosumab, 60 mg subcutaneously every 6 months (reimbursed only when used after a bisphosphonate); raloxifene, 60 mg/day; and menopausal hormone replacement therapy in women aged 50 to 60 years of age who have menopausal symptoms. Raloxifene should be reserved for patients at only moderate risk for non-vertebral fractures (Grade A), i.e., who are younger than 70 years of age and have none of the following risk factors: femoral T-score -3, high risk of falls, and history of non-vertebral fracture. Menopausal hormone replacement therapy is indicated in postmenopausal women who have menopausal symptoms and are younger than 60 years of age, as proof of efficacy exists only for the early postmenopausal period. The treatment duration should be determined based on the menopausal symptoms and on a discussion of the risk/benefit ratio with the patient.

A c c e p t e d M a n u s c r i p t

  Patients without menopausal symptoms may be given hormone replacement therapy if they fail to tolerate or to respond to other osteoporosis drugs. In patients receiving dosages lower than those recommended for bone protection, repeat DXA should be performed 2 to 3 years after treatment initiation (Grade A). If the BMD values are still low, an osteoporosis drug can be added to the hormone replacement regimen.

  Given the correlation between declining BMD values and rising fracture risk, the treatment indications depend on the T-score (consensus of experts). These indications are reported in fig.2[START_REF] Fujiwara | Fracture prediction from bone mineral density in Japanese men and women[END_REF][START_REF] Sornay-Rendu | Identification of osteopenic women at high risk of fracture : the OFELY study[END_REF][START_REF] Johnell | Predictive value of BMD for hip and other fractures[END_REF]. Treatment is recommended if the T-score is ≤-3 at the lumbar spine and/or hip. If the T-score is >-3 et ≤-2, it may be best to seek advice from a bone disease specialist and to use fracture prediction tools (FRAX ® , TBS, and bone turnover markers). If the T-score is >-2, treatment is not recommended (consensus of experts).

A c c e p t e d M a n u s c r i p t 19 Preventing

 19 falls and their consequences is crucial in elderly and/or frail patients. The implementation of appropriate fall prevention measures has been reported to decrease falls in elderly patients who are at high risk for falls and who live at home[START_REF] Gillespie | Interventions for preventing falls in older people living in the community[END_REF].Fall prevention measures include exercises to improve balance, vitamin D supplementation if serum 25-OHvitamin D levels are low, decreasing the use of medications that impair alertness or induce postural hypotension, eliminating environmental hazards, improving vision, and providing appropriate treatment for lower limb pain. The assessment of risk factors for falls in individual patients and the provision of appropriate management requires collaboration among the networks involved in fracture care and in geriatric care, rehabilitation departments, and geriatric teams. Participation in physical activity programs that include specific balance exercises is key to successful fall prevention. Also needed are muscle strengthening exercises; work on coordination and stamina; and activities to increase joint motion range, particularly at the ankle (79). These exercises have been proven effective in decreasing the risk of falls and of complicated falls (Grade A). Patients older than 65 years of age should be advised to engage in moderate-to-high intensity exercises at least twice a week, preferably on nonconsecutive days, with 8 to 12 repeats of 8 to 10 exercises (updated recommendations by the French national health and nutrition program [PNNS, Programme National Nutrition Santé-Révisions des repères relatifs à l'activité physique et à la sédentarité 2016] (www.anses.fr).Many barriers to engaging in physical activities have been reported. Patients often feel that their age or health problems make exercising difficult. However, these two factors indicate a strong need for exercise. Patients should be encouraged and supported in their efforts to develop an exercise routine. No specific exercise duration is recommended, but each exercise should be repeated until a further repeat would be difficult to perform without help.

A c c e p t e d M a n u s c r i p t 20 Both

 20 the quality and the intensity of the physical activity are important. That increasing the level of physical activity and participating in exercise programs act synergistically to decrease the fall risk and, in some studies, the fracture risk should be clearly explained to elderly patients and their carers. (Grade B)[START_REF] El-Khoury | The effect of fall prevention exercise programmes on fall induced injuries in community dwelling older adults : systematic review and metaanalysis of randomised controlled trials[END_REF][START_REF] El-Khoury | Effectiveness of two year balance training programme on prevention of fall induced injuries in at risk women aged 75-85 living in community : Ossébo randomised controlled trial[END_REF][START_REF] Gill | Effect of structured physical activity on prevention of serious fall injuries in adults aged 70-89 : randomized clinical trial (LIFE Study)[END_REF].

A c c e p t e d M a n u s c r i p t 21 deficiency

 21 due to comorbidities, malabsorption, difficulty achieving therapeutic goals, or initial profound vitamin D deficiency defined as serum 25-OH-vitamin D <10 ng/mL).

A c c e p t e d M a n u s c r i p t 22 Patients

 22 must receive clinical follow-up (consensus of experts). Fractures must be recorded and evaluations performed to detect new risk factors and/or diseases associated with osteoporosis. Patients should be asked about falls, and their risk factors for falls should be assessed. Treatment adherence should receive careful attention. Finally, adverse drug effects should be sought. Vertebral fractures are responsible for loss of height. Consequently, height should be measured once a year in patients with osteoporosis. A reduction in height is a nonspecific sign of vertebral disease (90-92).As with all treatments for chronic disease, osteoporosis medications are effective only when taken as ordered. Several studies have established that poor treatment adherence is associated with decreased effectiveness (93). Treatment adherence monitoring is therefore a crucial component of the clinical follow-up. In addition, in the oldest patients, adherence to fall prevention measures should be assessed.Patients receiving treatment for postmenopausal osteoporosis should be informed about the very low risk of osteonecrosis of the jaw and of atypical femoral fractures associated with bisphosphonates and denosumab. Dental care should be provided as needed before treatment initiation. If the patient receives regular care from a dentist and is not scheduled for a dental extraction or other invasive dental procedure in the short term, antiresorptive treatment can be started. An evaluation by a dentist is recommended for patients who do not see a dentist regularly. If the short-term fracture risk is high, for instance after a severe fracture, the dental evaluation should not delay the initiation of osteoporosis therapy. The recommendations for oral care during treatment are the same as in the general population, i.e., a dentist visit at least once a year. Dental extractions can be performed if needed, with antibiotic therapy.Bisphosphonate or denosumab therapy for osteoporosis does not contraindicate dental implant surgery. (http://afssaps.sante.fr/htm/10/filltrpsc/lp071203.htm) (www.sscmfco.fr). These

A c c e p t e d M a n u s c r i p t 23 recommendations

 23 do not apply to patients taking bisphosphonate or denosumab therapy for osteolytic tumors.

A c c e p t e d M a n u s c r i p t 24 5. 2 . 2 .

 2422 BMD target in patients with postmenopausal osteoporosisSetting a BMD target may change current practice regarding the duration of the first treatment course. At present, the duration is determined in advance based on efficacy data from placebo-controlled trials. Recommended durations are thus 18 months with teriparatide, 3 years with zoledronic acid and denosumab, and 5 years with other drugs. At the end of these periods, the decision to stop or continue the treatment is determined based on the residual fracture risk.

A c c e p t e d M a n u s c r i p t 25 5. 4 .

 254 Spinal radiographs or vertebral fracture assessmentRadiographs or VFA to detect vertebral fractures are indicated in postmenopausal women during osteoporosis drug therapy who report spinal pain and/or whose height as measured prospectively decreases by at least 2 cm (90) (consensus of experts).

2 to 50 cases

 50 /100 000 patient-years by the ASBMR task force (101). The risk decreases after treatment discontinuation. Concomitant risk factors such as specific femoral and knee geometry features may be present. The diagnosis should be considered when a patient reports persistent pain in the groin or thigh. These data do not challenge the favorable risk/benefit ratio in patients at risk for osteoporotic fractures (101-102).

A c c e p t e d M a n u s c r i p t 26 The

 26 body of evidence in the literature indicates that the risk of cancer is not increased in patients exposed to bisphosphonates (103). Furthermore, data suggest an anti-tumor effect of antiresorptive drugs (oral and injectable bisphosphonates and denosumab) in patients with breast cancer.

A c c e p t e d M a n u s c r i p t 27 Treatment

 27 discontinuation after the first drug course can be considered in patients meeting the following criteria (consensus of experts): no fracture during treatment; no new risk factors; no BMD decrease >0.03 g/cm 2 at the spine or hip; and, in patients with a history of severe fracture, a femoral T-score ≥-2.5 or -2. Considering each specific situation is not feasible, and these recommendations should be adapted to each individual patient.

A c c e p t e d M a n u s c r i p t 28 oralu s c r i p t 40 Box 1 :

 28401 bisphosphonates does not result in BMD values above those obtained with prolonged oral bisphosphonates (118). Disclosure of interest: BRIOT K: Occasional interventions as an expert or speaker for Amgen, MSD, Lilly, and Pfizer ROUX C: Occasional interventions for ALEXION, AMGEN, PFIZER, and UCB; and clinical trial research contracts for ULTRAGENYX THOMAS T: Occasional interventions for Amgen, Chugaï, Expanscience, Gilead, HAC-Pharma, LCA, MSD, Novartis, Pfizer, Thuasne, UCB, Abbvie, BMS, Lilly, TEVA, and Medac BLAIN H: Occasional interventions as an expert or speaker for Lilly and Expanscience BUCHON D: No conflicts of interest CHAPURLAT R: Occasional interventions as an expert or speaker for Amgen, UCB, Radius, and Lilly F DEBIAIS: Occasional interventions as an expert or speaker for Amgen, Expanscience, Lilly, MSD, Novartis, Roche, and Servier FERON JM: Occasional interventions as an expert or speaker for Amgen et Lilly GAUVAIN JB: No conflicts of interest GUGGENBUHL P: Occasional interventions as a speaker and invitations to symposia for AMGEN, Lilly, and NOVARTIS LEGRAND E: Occasional interventions as an expert or speaker for Amgen and Lilly LEHR-DRYLEWICZ AM: No conflicts of interest Criteria for reimbursement of dual-energy X-ray absorptiometry (DXA) in France (Journal Officiel, June 30, 2006: Décision du 29 juin 2006 de l'Union nationale des caisses d'assurance maladie relative à la liste des actes et prestations pris en charge par l'assurance maladie) First DXA In the general population, regardless of age and gender 1. Evidence of osteoporosis: vertebral fracture confirmed radiologically (vertebral body deformity) with no evidence of trauma or tumor; previous nonvertebral fracture without significant trauma (at sites other than the skull, fingers, toes, and cervical spine) 2. Disease or treatment known to induce osteoporosis: systemic glucocorticoid therapy prescribed for at least 3 months in a daily dosage >7.5 mg of prednisone-equivalent; if possible, DXA should be performed at treatment initiation 3. Documented history of a disease or treatment known to induce osteoporosis: prolonged hypogonadism (including bilateral orchiectomy or prolonged anti-androgen therapy with a Gn-Rh analog), uncontrolled hyperthyroidism, hypercorticism, primary hyperparathyroidism, and osteogenesis imperfectaAdditional criteria (vs. the general population) in postmenopausal women (including those taking hormone replacement therapy in doses below the values recommended for bone protection):1. History of hip fracture without significant trauma in a first-degree relative 2. Body mass index <19 kg/m² 3. Menopause before 40 years of age, for whatever reason 4. History of glucocorticoid therapy for at least 3 consecutive months in a daily dosage >7.5 mg prednisone equivalent.Second DXA:-Discontinuation of osteoporosis drug therapy in a postmenopausal woman, except if the drug is stopped prematurely because of adverse events -In postmenopausal women with no history of fracture, when the first DXA showed normal BMD values or osteopenia and no osteoporosis therapy was given, DXA can be repeated 3 to 5 years later.

A c c e p t e d M a n u s c r i p t 41 Table 1 :A c c e p t e d M a n u s c r i p t 42 Box 2 :

 411422 Risk factors for falls in the home (stairs, rugs) -use or failure to use walking aids -fall hazards out of doors (uneven sidewalks, slippery surfaces) -cane used inappropriately or not at all Socioeconomic factors: education, income, living conditions, social integration Risk factors for fractures risk of osteoporotic fractures independently from bone mineral density

3. Evaluation of the fracture risk and treatment decisions

	Decisions about offering osteoporosis treatment are guided by the existence, type, and
	date of previous fractures; patient age; risk factors for falls; bone mineral density (BMD)

  confounders such as renal function or a recent fracture. No markers are available for predicting DXA results. In contrast, bone turnover markers can predict bone loss. Combining several markers and/or combining markers and risk factors might improve the prediction of

bone fragility. No marker associated with an increased fracture risk was reproducibly identified in published studies. However, combining markers and BMD measurement may improve predictive performance. According to recommendations recently issued by experts, there is insufficient evidence that bone turnover markers help to predict the fracture risk in clinical practice (57). thus, routine bone turnover marker assays are not recommended for this purpose but may help specialists decide whether osteoporosis therapy is in order in difficult cases. Furthermore, marker assays are useful for monitoring the effects of anti-resorptive treatments.

To update the 2012 recommendations on pharmacotherapy for postmenopausal osteoporosisadvocated by the French National Authority for Health (

Ferring, Lilly, Meda, Medtronic, MSD, Novartis, Roche diagnostics, and UCB Members of the literature review task force Sauveur Bendavid (primary-care physician, Paris) Véronique Breuil (rheumatologist, Nice) Laure Chapuis (rheumatologist, xxx) Marie Flori (primary-care physician, xxx) Rose Marie Javier (rheumatologist, Strasbourg) Patrice Lopes (gynecologist, xxx) Brigitte Letombe (gynecologist, xxx) Philippe Merloz (orthopedic surgeon, xxx) Yves Rolland (geriatrician, xxx)


Marion Taleb

Nicolas Nardi

Alexis Arnaud

Nathalie Costet

Pierre-Yves Donnio

Charlotte Engrand

Edouard Habonimana

Eric Wodey

Pierre Tattevin
email: pierre.tattevin@chu-rennes.fr

Simplification of

come

ABSTRACT

Acute appendicitis in children requires early surgery, and a short course of antibiotics active on Enterobacteriaceae and anaerobes. Although aminoglycoside-containing 3-drug regimen have been used successfully for decades, simpler regimens with similar efficacy are increasingly used. We aimed to evaluate the impact of a switch from the combination of cefotaxime, metronidazole, and gentamicin (regimen 1), to piperacillin-tazobactam (regimen 2), as first-line regimen for complicated acute appendicitis in children. We enrolled 171 children, with a median age of 10 years [interquartile range, 6-13], treated with regimen 1 (n=80, April 2011-March 2013), or regimen 2 (n=91, April 2013-March 2015), after surgery for complicated acute appendicitis. The two groups were comparable, except for surgical approach (through laparoscopy in 46% of children before antibacterial regimen switch, versus 88% thereafter, P<0.001). Post-operative complications and durations of hospital stay were similar. Deviations from antibacterial treatment protocol decreased from 37% (29/80) to 14% (13/91, P<0.001), with a dramatic reduction of antibacterial treatment duration, from a median of 15 days [START_REF] Guillet-Caruba | Bacteriologic epidemiology and empirical treatment of pediatric complicated appendicitis[END_REF][START_REF] Dumont | The Microbiology of Community-acquired Peritonitis in Children[END_REF][START_REF] St Peter | Single daily dosing ceftriaxone and metronidazole vs standard triple antibiotic regimen for perforated appendicitis in children: a prospective randomized trial[END_REF][START_REF] Fishman | Perforated appendicitis: prospective outcome analysis for 150 children[END_REF][START_REF] Willis | Improvements in Antimicrobial Prescribing and Outcomes in Pediatric Complicated Appendicitis[END_REF], to 5 days [START_REF] Nadler | Monotherapy versus multi-drug therapy for the treatment of perforated appendicitis in children[END_REF][START_REF] Goldin | Aminoglycoside-based triple-antibiotic therapy versus monotherapy for children with ruptured appendicitis[END_REF][START_REF] Singer | The Third International Consensus Definitions for Sepsis and Septic Shock (Sepsis-3)[END_REF][START_REF] Schmitt | Bacterial studies of complicated appendicitis over a 20-year period and their impact on empirical antibiotic treatment[END_REF], P<0.001. Post-operative intra-abdominal abscess developed in 32 children (18.7%). Female gender (OR 2.76; 95% confidence interval [1.18-6.48], P=0.02) and sepsis or septic shock on admission (OR = 4.72 [1.12-19.97], P=0.035) were independently associated with post-operative intra-abdominal abscess, but not antibacterial regimen. This study shows that simplication of first-line antibacterial regimen for complicated appendicitis in children was associated with reduced protocol deviation, reduced duration of antiobiotics, and similar outcomes in terms of post-operative complications, and duration of hospital stay.

Keywords : piperacillin-tazobactam; aminoglycoside; appendicitis; protocol; adherence; antimicrobial stewardship

Introduction

Acute appendicitis is a common surgical condition that affects 0.3-0.4% of children, with a peak incidence between 8 and 13 years. Most common complications include perforation, peritonitis, and abscess, found in 25-39% of cases [START_REF] Meier | Perforated appendicitis in children: is there a best treatment?[END_REF]. Treatment of acute appendicitis usually relies on early surgery (appendectomy, and management of complications when necessary), and a short course of antibiotics (4-7 days) [START_REF] Lee | Antibiotics and appendicitis in the pediatric population: an American Pediatric Surgical Association Outcomes and Clinical Trials Committee systematic review[END_REF], although highly selected patients with a well circumscribed focus of infection may be cured by antimicrobial therapy alone [START_REF] Solomkin | Diagnosis and management of complicated intra-abdominal infection in adults and children: guidelines by the Surgical Infection Society and the Infectious Diseases Society of America[END_REF].

Aminoglycoside-containing 3-drug regimen have been used successfully for decades to treat complicated intra-abdominal infections in children, although simpler regimens, such as broadspectrum betalactam-betalactamase inhibitor combination, are of similar efficacy [START_REF] Solomkin | Diagnosis and management of complicated intra-abdominal infection in adults and children: guidelines by the Surgical Infection Society and the Infectious Diseases Society of America[END_REF][START_REF] Nadler | The Surgical Infection Society guidelines on antimicrobial therapy for children with appendicitis[END_REF][START_REF] Nadler | Monotherapy versus multi-drug therapy for the treatment of perforated appendicitis in children[END_REF][START_REF] Goldin | Aminoglycoside-based triple-antibiotic therapy versus monotherapy for children with ruptured appendicitis[END_REF].

In March 2013, a local multidisciplinary group of professionals involved in the care of children with appendicitis, including pediatric surgeon, anesthesiologist, microbiologist, and infectious diseases physician, modified the first-line antibacterial treatment of appendicitis for children in our institution, with two objectives: i) to decrease the complexity of workload for nurses, and rates of deviation from the previous protocol, i.e. the triple combination of cefotaxime, gentamicin, and metronidazole; ii) to reduce the rate of post-operative intraabdominal abscess, from a baseline range of 15-20% in 2008-2012. In April 2013, piperacillin-tazobactam became the first-line regimen for all children operated for complicated appendicitis, and was incorporated in the computerized system for drug prescription, with standard duration, intervals, and weight-based dose. In addition, a specific note against the use of oral switch beyond day five for children with favorable outcome was added in the protocol. The main objective of this study was to evaluate the impact of these protocol changes on the incidence of post-operative complications. Secondary objectives were the evaluation of protocol deviations, and the analysis of risk factors for post-operative intraabdominal abscess.

A C C E P T E D M

A N U S C R I P T 5

Materials and methods

Study design

We performed a retrospective, observational study of all children <18-year old who underwent surgery for complicated appendicitis from April 2011 to March 2015 in the Rennes university hospital, Western France. Cases were identified through the computerized database of the pediatric surgery department. Complicated appendicitis were defined as appendicitis that required surgery, associated with at least one of the followings, reported in the surgery report: i) abscess; ii) local peritonitis; iii) disseminated peritonitis. Data were collected from medical files by one investigator (MT), on a standardized questionnaire, including demographic information (age, weight, sex), comorbidities, septic shock or sepsis (according to 2016 definition [START_REF] Singer | The Third International Consensus Definitions for Sepsis and Septic Shock (Sepsis-3)[END_REF]), surgical approach, timing, doses, and duration of antibacterial treatment, post-operative complications, and length of hospital stay. The study was approved by our institutional review board.

Procedures

From April 2011 to March 2013 (former protocol group, G1), most children received intravenous cefotaxime (150 mg/kg/day), and intravenous metronidazole (35 mg/kg/day) for at least 5 days, associated with intravenous gentamicin (5 mg/kg/day), for the first 3 days.

From April 2013 to March 2015 (new protocol group, G2), most children received intravenous piperacillin-tazobactam, 250 mg/kg/day, for at least 5 days. Children with sepsis also received intravenous gentamicin (5 mg/kg/day), for the first 3 days. A switch to oral antibiotics (mostly amoxicillin-clavulanate) was left to the discretion of the surgeon before April 2013 (G1), while it was specifically not recommended thereafter (G2). Surgical treatment was performed by a senior surgeon, and included appendectomy, performed by

A C C E P T E D M A N U S C R I P T 6
laparoscopy or open surgery, at the discretion of the surgeon, associated with source control, whenever required. All children were re-evaluated one month after appendectomy.

Statistics

Continuous variables were expressed as median [quartile 1-quartile 3], and compared using Student t-test or Mann-Whitney U-test. Categorical variables were expressed as numbers (%), and compared using Chi 2 or Fisher exact tests. P<0.05 was considered statistically significant. For multivariate analysis of risk factors for intra-abdominal abscess, all variables with P<0.2 by univariate analysis were evaluated using a stepwise logistic regression model. Logistic regression analyses were performed using SPSS software, version 16.0.

Results

During the study period, 171 children operated for acute appendicitis fulfilled inclusion criteria: 80 from April 2011 to March 2013 (G1), and 91 from April 2013 to March 2015 (G2). Baseline characteristics and management were similar in both groups (Table 1), except for surgical technique, as appendectomy was performed through laparoscopy in 80% of children in G2, as compared to only 37% in G1 (P<0.0001). Incidence and characteristics of post-operative complications were also similar in both groups, as were durations of intravenous antibacterial treatment, and hospital stay. Of note, deviations from antibacterial treatment procedures were observed in 37% (29/80) of children in G1, as compared to 14% (13/91) in G2 (P<0.001). This improvement was mostly related to deviations regarding antibacterial treatment duration, that decreased from 33% (26/80), to 8% (7/91).

Consequently, the median duration of antibacterial treatment was dramatically reduced from a median of 15 days [START_REF] Guillet-Caruba | Bacteriologic epidemiology and empirical treatment of pediatric complicated appendicitis[END_REF][START_REF] Dumont | The Microbiology of Community-acquired Peritonitis in Children[END_REF][START_REF] St Peter | Single daily dosing ceftriaxone and metronidazole vs standard triple antibiotic regimen for perforated appendicitis in children: a prospective randomized trial[END_REF][START_REF] Fishman | Perforated appendicitis: prospective outcome analysis for 150 children[END_REF][START_REF] Willis | Improvements in Antimicrobial Prescribing and Outcomes in Pediatric Complicated Appendicitis[END_REF] in G1, to 5 days [START_REF] Nadler | Monotherapy versus multi-drug therapy for the treatment of perforated appendicitis in children[END_REF][START_REF] Goldin | Aminoglycoside-based triple-antibiotic therapy versus monotherapy for children with ruptured appendicitis[END_REF][START_REF] Singer | The Third International Consensus Definitions for Sepsis and Septic Shock (Sepsis-3)[END_REF][START_REF] Schmitt | Bacterial studies of complicated appendicitis over a 20-year period and their impact on empirical antibiotic treatment[END_REF] in G2, P<0.001.

A C C E P T E D M A N U S C R I P T 7

Post-operative intra-abdominal abscess developed in 32 children (18.7%). Bivariate and multivariate analysis of risk factors are presented in Table 2. Female gender (OR 2.76; 95% confidence interval [1.18-6.48], P=0.02) and sepsis or septic shock on admission (OR = 4.72 [1.12-19.97], P=0.035) were the two variables independently associated with an increased risk of post-operative intra-abdominal abscess.

Discussion

The major findings of this study are as follows: i) the simplification of first-line antibacterial treatment for children with complicated appendicitis, from an aminoglycosidecontaining 3-drug regimen (cefotaxime-metronidazole-gentamicin), to a broad-spectrum betalactam-betalactamase inhibitor combination (piperacillin-tazobactam), was not associated with any significant change in terms of post-operative complications; ii) a specific recommendation against the use of oral switch after discharge for children with favorable outcome at day five post-surgery was associated with a dramatic decrease in the median duration of antibacterial treatment, from 15 days to 5 days (P<0.001), again with no measurable increase in the incidence of adverse events; iii) both changes were associated with a lower rate of deviations from our local protocol; iv) however, despite these achievements, we failed to reduce the rate of post-operative intra-abdominal abscess. Of note, female sex, and sepsis or septic shock, were the only independent predictor of intra-abdominal abscess in our study.

Major pathogens in complicated appendicitis are coliforms (Enterobacteriaceae, especially Escherichia coli), anaerobes (primarily Bacteroides fragilis), and Streptococcus sp., mostly milleri group streptococci [START_REF] Solomkin | Diagnosis and management of complicated intra-abdominal infection in adults and children: guidelines by the Surgical Infection Society and the Infectious Diseases Society of America[END_REF][START_REF] Schmitt | Bacterial studies of complicated appendicitis over a 20-year period and their impact on empirical antibiotic treatment[END_REF]. Pseudomonas aeruginosa has been identified in 5-19% of community-acquired appendicitis in children, but its pathogenicity has not been proven in this context, so that antibacterial regimens with no anti-pseudomonal activity (e.g.

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A N U S C R I P T 8 third-generation cephalosporin plus metronidazole) are among the most common first-line regimens for complicated appendicitis worldwide [START_REF] Meier | Perforated appendicitis in children: is there a best treatment?[END_REF][START_REF] Lee | Antibiotics and appendicitis in the pediatric population: an American Pediatric Surgical Association Outcomes and Clinical Trials Committee systematic review[END_REF][START_REF] Nadler | The Surgical Infection Society guidelines on antimicrobial therapy for children with appendicitis[END_REF][START_REF] Kronman | Extended-Versus Narrower-Spectrum Antibiotics for Appendicitis[END_REF][START_REF] Lelli | Historical changes in the postoperative treatment of appendicitis in children: impact on medical outcome[END_REF]. Intra-operative culture swabs are not routinely recommended for appendicitis, due to the complexity of microbiological patterns, and the limited impact on patients care, as final results with drug susceptibility testing become available by the time antibacterial treatment is no longer necessary [START_REF] Foo | Intra-operative culture swabs in acute appendicitis: a waste of resources[END_REF]. However, due to marked differences in susceptibility patterns between different communities and institutions, sentinel studies repeated over time with routine cultures and drug susceptibility testing are required to monitor the appropriateness of first-line regimens. If resistance to a regimen is present in >10% of isolates of a common intraabdominal pathogen in the community, use of that regimen should be avoided [START_REF] Solomkin | Diagnosis and management of complicated intra-abdominal infection in adults and children: guidelines by the Surgical Infection Society and the Infectious Diseases Society of America[END_REF]. Three recent French studies have examined the bacterial ecology of acute appendicitis in children [START_REF] Schmitt | Bacterial studies of complicated appendicitis over a 20-year period and their impact on empirical antibiotic treatment[END_REF][START_REF] Guillet-Caruba | Bacteriologic epidemiology and empirical treatment of pediatric complicated appendicitis[END_REF][START_REF] Dumont | The Microbiology of Community-acquired Peritonitis in Children[END_REF]: The majority of intraoperative specimens were polymicrobial (60-77%), and included E. coli (51-71%), streptococci (9-22%), strict anaerobes (mostly B. fragilis, 20-33%), and P. aeruginosa 6-19%. Piperacillin-tazobactam, active on 97% of isolates in a recent study from our area [START_REF] Guillet-Caruba | Bacteriologic epidemiology and empirical treatment of pediatric complicated appendicitis[END_REF], was thus selected as the preferred first-line regimen in our local protocol.

Although this broad-spectrum antibiotic certainly increases the risk of multidrug-resistance, and Clostridium difficile infection, there is no robust data to suggest that piperacillintazobactam has more impact on microbiota than the triple combination of cefotaxime, metronidazole, and gentamicin. In addition, as the implementation of the new protocol was associated with a dramatic reduction of total antibacterial treatment duration (i.e., from a median of 15 days [START_REF] Guillet-Caruba | Bacteriologic epidemiology and empirical treatment of pediatric complicated appendicitis[END_REF][START_REF] Dumont | The Microbiology of Community-acquired Peritonitis in Children[END_REF][START_REF] St Peter | Single daily dosing ceftriaxone and metronidazole vs standard triple antibiotic regimen for perforated appendicitis in children: a prospective randomized trial[END_REF][START_REF] Fishman | Perforated appendicitis: prospective outcome analysis for 150 children[END_REF][START_REF] Willis | Improvements in Antimicrobial Prescribing and Outcomes in Pediatric Complicated Appendicitis[END_REF], to a median of 5 days 15 [START_REF] Nadler | Monotherapy versus multi-drug therapy for the treatment of perforated appendicitis in children[END_REF][START_REF] Goldin | Aminoglycoside-based triple-antibiotic therapy versus monotherapy for children with ruptured appendicitis[END_REF][START_REF] Singer | The Third International Consensus Definitions for Sepsis and Septic Shock (Sepsis-3)[END_REF][START_REF] Schmitt | Bacterial studies of complicated appendicitis over a 20-year period and their impact on empirical antibiotic treatment[END_REF]), the overall impact on microbiota may have been reduced with the new protocol, although we have no data to support this.

Considerations of simplicity (low number of injections), and cost, are additional assets for this regimen [START_REF] St Peter | Single daily dosing ceftriaxone and metronidazole vs standard triple antibiotic regimen for perforated appendicitis in children: a prospective randomized trial[END_REF][START_REF] Fishman | Perforated appendicitis: prospective outcome analysis for 150 children[END_REF], in line with recent guidelines from the Surgical Infection Society [START_REF] Nadler | The Surgical Infection Society guidelines on antimicrobial therapy for children with appendicitis[END_REF], the American Pediatric Surgical Society [START_REF] Lee | Antibiotics and appendicitis in the pediatric population: an American Pediatric Surgical Association Outcomes and Clinical Trials Committee systematic review[END_REF], and the Infectious Diseases Society of America [START_REF] Solomkin | Diagnosis and management of complicated intra-abdominal infection in adults and children: guidelines by the Surgical Infection Society and the Infectious Diseases Society of America[END_REF].

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A N U S C R I P T 9 These latter guidelines advocated for the development of local clinical pathways to standardize the management of appendicitis, with compelling evidence that it improves both the process of care, and patient outcomes [START_REF] Solomkin | Diagnosis and management of complicated intra-abdominal infection in adults and children: guidelines by the Surgical Infection Society and the Infectious Diseases Society of America[END_REF]. Although our efforts to refine appendicitis pathway were successful regarding process of care, with better standardization (i.e. lower rate of protocol deviation), and a dramatic decrease of unnecessary use of antibiotics, we found no measureable impact on patients outcomes, with a rate of post-operative intra-abdominal abscess that remained within the baseline 15-20% range. Other studies on this issue were similarly 'half-successful', with significant improvement in antimicrobial prescribing, and/or better adherence to clinical practice guidelines, but no measurable impact on outcome [START_REF] Lee | Antibiotics and appendicitis in the pediatric population: an American Pediatric Surgical Association Outcomes and Clinical Trials Committee systematic review[END_REF][START_REF] Goldin | Aminoglycoside-based triple-antibiotic therapy versus monotherapy for children with ruptured appendicitis[END_REF][START_REF] Fishman | Perforated appendicitis: prospective outcome analysis for 150 children[END_REF][START_REF] Willis | Improvements in Antimicrobial Prescribing and Outcomes in Pediatric Complicated Appendicitis[END_REF].

This study has limitations: firstly, there are potential biases due to its observational, quasi-experimental design. Of note, surgical practices for appendicitis dramatically changed during the study period, with a gradual switch from open surgery to laparoscopy. However, rates of post-operative complications are similar with these two approaches [START_REF] Solomkin | Diagnosis and management of complicated intra-abdominal infection in adults and children: guidelines by the Surgical Infection Society and the Infectious Diseases Society of America[END_REF]. In addition, neither surgery type, nor study period, were associated with intra-abdominal abscess in our bivariate and multivariate analysis. Secondly, findings of this single-center study may not be generalizable to other context, especially in areas with different microbiological and resistance patterns. Thirdly, sample size was limited. However, this study adds another brick in the wall by demonstrating that the development of local protocol by a multidisciplinary team, with simple first-line regimen adapted to microbiological epidemiology, may improve the care of children with complicated appendicitis, and reduce the unnecessary use of antibiotics.

1 HIGHLIGHTS

 1 A switch from aminoglycoside-containing 3-drug regimen to piperacillin-tazobactam as the first-line treatment for complicated appendicitis in children allowed a dramatic reduction of protocols deviation, and antibacterial treatment duration  No impact was observed on outcomes (post-operative complications, duration of hospital stay)  Female gender and sepsis or septic shock on admission were the only variables independently associated with post-operative intra-abdominal abscess A C C E P T E D M A N U S C R I P T 3

  data are expressed as numbers (percentages). Quantitative data are expressed as medians [quartile 1-quartile 3]. *We used the 2016 definition for sepsis, i.e. life-threatening organ dysfunction caused by a dysregulated host response to infection.

Table 1 .

 1 Comparison of children operated for complicated appendicitis from April 2011 to March 2013 (group1, first-line antibacterial treatment cefotaxime-metronidazole-gentamicin), and from April 2013 to March 2015 (group 2, first-line antibacterial treatment piperacillin-

	tazobactam)
		Group 1 n=80	Group 2 n=91	P
	Age, years	9 [5-13]	10 [7-13]	0.503
	Female sex	35 (44)	36 (40)	0.579
	Weight, kg	32 [22-48]	34 [25-45]	0.834
	Baseline complications
	-Abscess	14 (17)	17 (19)	0.841
	-Localized peritonitis	27 (34)	34 (37)	0.623
	-Disseminated peritonitis	39 (49)	40 (44)	0.530
	Sepsis*/septic shock	5 (6)	7 (8)	0.712
	Surgery type
	-laparoscopy	37 (46)	80 (88)	<0.001
	-open appendicectomy	43 (54)	11 (12)	<0.001
	Time between admission and surgery, hours	8 [6-17]	8 [6-18]	0.674
	Time between first administration of antibiotic and surgery, hours	0 [0-9]	1 [0-6]	0.934
	Outcome
	Infectious complications	15 (19)
	-surgical site infections
	-intra-abdominal abscess
	Intravenous antibiotic duration, days
	Intravenous + oral antibiotic duration, days
	Hospital stay, days