M.D Elie Vesale

M.D Horace Roman

M.D Gaby Moawad

M.D Louise Benoit
email: louise.am.benoit@gmail.com

M.D Cyril Touboul

M.D Emile Darai

M.D Sofiane Bendifallah

VOIDING DYSFUNCTION AFTER COLORECTAL SURGERY FOR ENDOMETRIOSIS: A SYSTEMATIC REVIEW AND META-ANALYSIS

Keywords: Endometriosis, bowel involvement, meta-analysis, voiding dysfunction, gastrointestinal endometriosis

In this meta-analysis, we found that, rectal shaving causes less postoperative voiding dysfunction than discoid excision or segmental resection in colorectal surgery for endometriosis.

In this setting, the occurrence of postoperative voiding dysfunction ranges from 0-40% from one study to another [START_REF]Urinary functional disorders bound to deep endometriosis and to its treatment: review of the literature[END_REF] and is mainly due to iatrogenic injury of the pelvic anatomic nerves. Indeed, the bladder is innerved by the inferior hypogastric plexus originating for the superior hypogastric plexus (autonomous), the pelvic nerves (parasympathetic) and the hypogastric nerve (sympathetic). T ' innerved by the pudendal nerve (somatic). The inferior hypogastric plexus can be injured at two different locations during surgery for colo-rectal endometriosis: during the dissection of the utero-sacral ligaments (inferior hypogastric nerve) or during the opening of the pararectal space (hypogastric nerve). Although it may resolve spontaneously after one to three weeks, it can also persist for months, years or for a lifetime [START_REF] Bonneau | Incidence of pre-and postoperative urinary dysfunction associated with deep infiltrating endometriosis: relevance of urodynamic tests and therapeutic implications[END_REF]. Its occurrence has been reported to affect the quality of life in 20-30% of patients after DE surgery (3)(4) and there are few therapeutic options: mainly intermittent self-catheterization and neuromodulation [START_REF] Timoh | Contribution of sacral neuromodulation to manage persistent voiding dysfunction after surgery for deep infiltrating endometriosis with colorectal involvement: preliminary results[END_REF].

For colorectal endometriosis, three main surgical approaches have been reported (6) [START_REF] Donnez | Rectovaginal septum adenomyotic nodules: a series of 500 cases[END_REF]: (i) a radical procedure allowing the complete removal of the endometriosis location by segmental resection (8) [START_REF] Darwish | Surgical treatment of deep infiltrating rectal endometriosis: in favor of less aggressive surgery[END_REF], and conservative surgery based on (ii) discoid resection or (iii) rectal shaving. Currently, pelvic surgeons agree that a nerve-sparing (NS) technique reduces the risk of persistent urinary retention due to iatrogenic injury of the pelvic autonomic nerves compared with the conventional (non-NS) technique [START_REF] Timoh | Contribution of sacral neuromodulation to manage persistent voiding dysfunction after surgery for deep infiltrating endometriosis with colorectal involvement: preliminary results[END_REF]. However, despite the NS technique, colorectal endometriosis surgery is still associated with a high rate of voiding dysfunction.

Therefore, the purpose of this systematic review and meta-analysis was to assess the occurrence of voiding dysfunction after surgery for DE with colorectal involvement according to the surgical approach, i.e. rectal shaving, discoid excision or colorectal 95 segmental resection. The impact of NS techniques were also assessed.

96

Material and methods

We performed a systematic review and meta-analysis following the recommendations from the Cochrane Collaboration [START_REF]Cochrane handbook for systematic reviews of interventions[END_REF] and in accordance with the PRISMA (Preferred Reported Items for Systematic Reviews and Meta-analyses)

guidelines [START_REF] Liberati | The PRISMA statement for reporting systematic reviews and meta-analyses of studies that evaluate healthcare interventions: explanation and elaboration[END_REF] . The protocol was approved beforehand (International Prospective

Register of Systematic Reviews PROSPERO ID: 3528920).

Electronic search

The following databases were searched: PubMed, Clinical Trials.gov, Embase, Two reviewers (EV and SB) independently assessed the quality of each included study. In case of discrepancies a third reviewer was consulted (ED, HR). The percentages, odd ratios (ORs) and confidence intervals (CIs) of each study were obtained or calculated from existing data (12) [START_REF] Hozo | Estimating the mean and variance from the median, range, and the size of a sample[END_REF].

Outcome Measures

The primary outcome was the occurrence of postoperative voiding dysfunction. As the voiding dysfunction rate varies according to the definition, we decided to first analyze the risk of voiding dysfunction regardless its definition and then to take a closer look at the risk of self-catheterization lasting more than 1 month. Moreover, we analyzed the rate of voiding dysfunction according to the surgical management of the colorectum as this outcome varies greatly depending on conservative management or radical colorectal resection.

Risk of Bias

The risk of bias was assessed using clarity of the statements, the eligibility criteria, size of the population, ethical considerations, representativeness, response rate, data collection, objective, definition of the objective, and consistency between research question and data reported.

The quality of the included studies was evaluated with the Study Quality Assessment Tools [START_REF]Study Quality Assessment Tools[END_REF]. Studies were considered as "satisfactory" when at least 70% of 12-14 assessment criteria were met, "fair" when 50% were respected, and "poor" when fewer than 50% of the criteria were fulfilled.

Statistical Analysis

ORs and their CIs were derived from each study as the primary endpoint. Pooled response means, defined as the estimated overall mean difference (with 95% CI), were described using forest plots. For pooled response means, a p-value <0.05 was considered significant. If no observed events was reported by the study for a given outcome, a 0.001 integer continuity correction was determined.

Statistical heterogeneity among the studies was assessed using C ' Q the I 2 index. A I 2 <50% or p-values of <0.1 signified that there was no significant heterogeneity. If no heterogeneity was observed, the fixed-effects model was adopted. In case of heterogeneity, the random-effects model was used for pooled estimates. If I 2 > 50% (high heterogeneity), subgroup analyses were carried out when possible. If sufficient data were available, a predefined subgroup analyses for the primary outcome was undertaken.

All statistical analysis was performed on Review Manager (RevMan, IOS, version (5.3),

Copenhagen: The Nordic Cochrane Centre, The Cochrane Collaboration, 2011). For the comparison of the nerve sparing techniques, the number of patients and percentages are presented. Comparison was performed using Fisher's exact test (qualitative variable) and p< 0.05 was considered statistically significant. For this analysis, statistical analysis was performed using R 3.6.0 software (http://lib.stat.cmu.edu/R/CRAN/).

Results

Study selection

A total of 201 studies fulfilling our electronic search criteria were identified. After screening by title and abstract and removing duplicate papers, 148 full text articles were assessed. Of these, one systemic review was excluded. From the 147 remaining papers, 79

were excluded and among the 68 remaining papers, 17 were not eligible for the review (Figure 1). Among the 51 papers included in the review, 38 were not included in the metaanalysis because these studies did not compare different surgical techniques. The final result for the descriptive analysis included a total of 51 studies, 13 articles for the global metaanalysis (regardless of the definition) and five articles for the meta-analysis of selfcatheterization > 1 month (Table 1).

Study characteristics -Descriptive analysis

Twenty-four prospective studies were identified; two randomized controlled trials, one case control study and 24 retrospective studies with a total 5962 patients undergoing surgery for DE involving the colorectum. 3).

Postoperative voiding dysfunction regardless of the definition

When analyzing the occurrence of postoperative voiding dysfunction regardless of the definition, rectal shaving was statistically less associated with postoperative voiding dysfunction than segmental colorectal resection (OR 0.34, 95% CI 0.18-0.63, I 2 = 0%, p=0.0006) (Figure 2). This difference was no longer significant when comparing discoid excision and segmental colorectal resection (OR 0.74, 95% CI 0.32-1.69, I 2 = 29%, p=0.47) (Figure 2). Rectal shaving resulted in less voiding dysfunction than discoid excision (OR 0.22, 95% CI 0.09-0.51, I 2 = 0%, p=0.0004) (Figure 2).

Postoperative voiding dysfunction defined as self-catheterization > 21 days

Rectal shaving was associated with a lower risk of prolonged self-catheterization (i.e. lasting for more than 21 days) compared with segmental colorectal resection (OR 0.3, 95% CI 0.14-0.66, I 2 = 0%, p=0.003) (Figure 3). This outcome was no longer significant when comparing discoid excision and segmental colorectal resection (OR 0.72, 95% CI 0.4-1.31, I 2 = 63%, p=0.28) (Figure 3). As no studies included both shaving and discoid excision and defined voiding dysfunction as self-catheterization time >21 days, no comparison was evaluable for these techniques.

Postoperative voiding dysfunction according to conservative versus radical surgery

A comparison between conservative surgery (i.e. rectal shaving and discoid excision) and radical surgery (i.e. segmental colorectal resection) demonstrated that conservative strategy had a lower risk of postoperative voiding dysfunction (Risk Difference -0.04, 95% CI -0.07; -0.02, I 2 = 23%, p=0.001). (Figure 4)

Nerve-sparing technique

Twenty-six studies including 3120 patients (1402 conservative and 1718 radical surgeries) clearly reported an NS technique while 25 studies including 2843 patients (1001 conservative and 1842 radical surgeries) did not specifically mention an NS technique (Table 2).

Sixty-two (4.4%) and 18 (1.8%) patients, respectively, had postoperative voiding dysfunction after conservative surgery with an NS and with a non-NS technique (p=0.03). For radical surgery, 222 (12.9%) patients and 208 (11.3%) patients had postoperative voiding dysfunction after an NS and a non-NS technique, respectively (p=0.15).

Duration of postoperative self-catheterization

The mean time of self-catheterization could not be estimated for each group as not all the studies reported the exact catheterization time.

Discussion

We report a systematic review and meta-analysis focusing on the occurrence of voiding dysfunction after surgery for deep endometriosis (DE) with colorectal involvement comparing three surgical approaches. The estimated overall rate of voiding dysfunction was 7.6% with a prevalence of 2.4%, 7.5% and 10.1% after rectal shaving, discoid excision and segmental colorectal resection, respectively. Self-catheterization > 1 month mainly occurred after segmental colorectal resection (13.6%). Evaluating urinary function preoperatively is therefore of paramount importance in digestive endometriosis.

The assessment of voiding dysfunction before and after colorectal resection for endometriosis surgery is a major issue in daily practice. However, the current evidence- Interestingly, this difference was no longer significant when comparing discoid excision and segmental resection, although considerable heterogeneity was observed between the studies (OR 0.74, 95% CI 0.32-1.69, I 2 = 29%, p=0.47). Self-catheterization >1 month occurred in 13.6% of the patients and almost only after segmental colorectal resection.

Considering this definition, we observed that the risk was significantly lower after rectal shaving compared to segmental resection (OR 0.3, 95% CI 0.14-0.66, I 2 = 0%, p=0.003).

The difference was not significant when discoid resection was compared to segmental In the current review, 26 studies clearly mentioned an NS technique compared to 25 studies where it was unclear whether this technique was used. In contrast to De Resende J .' w, we found no difference in postoperative voiding dysfunction according to the use of an NS technique. However, the interpretation of these results is compromised because: i) the studies did not aim to compare the techniques; ii) a study which does not mention an NS technique does not necessarily exclude NS surgery; iii) surgery with NS are usually more invasive procedures with a high extent of resection; iv)

there is a lack of objective and uniform criteria to define postoperative voiding dysfunction and; v) surgical skills may have improved over time.

Resende et al [START_REF] De Resende | Risk of urinary retention after nerve-sparing surgery for deep infiltrating endometriosis: A systematic review and meta-analysis[END_REF] could not detect significant benefits of NS compared with conventional non-NS surgery in terms of relative risk (RR) of urinary retention at discharge.

Nevertheless, they found a statistically significant advantage of NS with respect to RR of persistent urinary retention by the need for self-catheterization for 3 months or more even if no clear criteria (e.g., minimum residual volume) was presented to define the need for self-catheterization after surgery. Although several NS techniques have been reported for delayed functional complications (e.g. urinary retention, constipation, and sexual dysfunction) due to autosomal nerve damage of the bowel, they have not been 100%

successful [START_REF] Landi | Laparoscopic nerve-sparing complete excision of deep endometriosis: is it feasible?[END_REF]. The surgeon should consider both of these complications when choosing the most appropriate surgical procedure and provide information on functional outcomes to patients treated for colorectal endometriosis [START_REF] Roman | Delayed functional outcomes associated with surgical management of deep rectovaginal endometriosis with rectal involvement: giving patients an informed choice[END_REF]. Indeed, identifying and sparing the pelvic nerves should be standard practice in 2020 as it is accepted that the more nerves are preserved, the fewer sexual, rectal and bladder disorders you cause [START_REF] Uccella | Functional outcomes of nerve-sparing laparoscopic eradication of deep infiltrating endometriosis: a prospective analysis using validated questionnaires[END_REF].

The strengths of this review include the use of an exhaustive search strategy applied to five different databases. In addition, it seems to be the first to report the risk of postoperative voiding dysfunction comparing three surgical approaches for DE with colorectal involvement. Methodological limitations such as differences between criteria used for defining the voiding dysfunction may limit the quality of the available evidence.

Furthermore, the absence of taking preoperative voiding dysfunction into account should be mentioned as a limitation. However, most of the articles included in this review lacked data on preoperative voiding dysfunction and we were thus unable to know if the postoperative dysfunction was due to operative damage. In addition, the heterogeneity between some studies may limit the accuracy and the validity of the results. Finally, for the sake of completeness, some comparisons, in particular that of NS procedures, may be rough estimates rather than accurate comparisons because of the lack of studies comparing NS and classical surgery in the context of colorectal resection for DE.

Conclusion

Conclusion:

  Colorectal surgery for endometriosis has a significant impact on urinary function regardless of the technique. However, rectal shaving causes less postoperative voiding dysfunction than discoid excision or segmental resection. Introduction Deep endometriosis (DE) surgery can involve the . It can induce voiding dysfunction, especially in the context of bowel resection (segmental, discoid resection or shaving).

  based literature is marked by a major weakness due to the lack of consensus in the definition used. For instance, voiding dysfunction may correspond to a variety of clinical conditions such as urinary retention, bladder atonia, incomplete urinary bladder emptying requiring intermittent catheterization after postoperative day 7 or with a post-voiding bladder volume of more than 100ml[START_REF] Jayot | Comparison of Laparoscopic Discoid Resection and Segmental Resection for Colorectal Endometriosis Using a Propensity Score Matching Analysis[END_REF](2)[START_REF] Daraï | Randomized trial of laparoscopically assisted versus open colorectal resection for endometriosis: morbidity, symptoms, quality of life, and fertility[END_REF]. Likewise, some authors define the duration of voiding dysfunction as transient when self-catheterization lasts under 30 days (2) or up to 6 weeks, while others extend this definition to 6 months (33)[START_REF] De Resende | Risk of urinary retention after nerve-sparing surgery for deep infiltrating endometriosis: A systematic review and meta-analysis[END_REF]. All these definitions which should be reporting the same outcome render interpretation and comparison of clinical data somewhat difficult and heterogeneous. Moreover, few reports distinguish preoperative from de novo voiding dysfunction which can occur in 7.8% of their patients with colorectal endometriosis.To overcome such a limitation, we decided to present the results considering (i) the voiding dysfunction whatever the definition used (tables 2,3,4), (ii) the voiding dysfunction based on the definition of self-catheterization > 1 month, and also (iii) the use of an NS technique.Regardless of the definition, rectal shaving appears to result in a lower risk of voiding dysfunction than discoid excision (OR 0.22, 95% CI 0.09-0.51, I 2 = 0%, p=0.0004) and segmental colorectal resection (OR 0.34, 95% CI 0.18-0.63, I 2 = 0%, p= 0.0006).

Figure 1 :Figure 2 . 1 . 1 .Figure 3 . 2 . 1 .Figure 4 .

 12113214 Figure 1: Flow chart of the eligibility of studies for inclusion in the meta-analysis

Figure 1 :

 1 Figure 1: Eligibility of studies for inclusion in the meta-analysis

  In this setting, Ballester et al. conducted a comparative study between a group of patients with DE and a control group[START_REF] Ballester | Urinary dysfunction after colorectal resection for endometriosis: results of a prospective randomized trial comparing laparoscopy to open surgery[END_REF] based on a validated questionnaire (International Prostate Symptom Score). They showed a significantly higher incidence of preoperative voiding dysfunction in the DE group.Several authors hypothesized[START_REF]Urinary functional and urodynamic preoperative evaluation of patients with deep pelvic surgical endometriosis: about 12 cases[END_REF] the need of systematic preoperative urodynamic investigation in the context of DE as the rate of preoperative voiding dysfunction can be more than 25%. However, identification of patients who might benefit from preoperative urodynamic testing remain debatable. The majority of published studies in the current systematic review did not include preoperative assessment of lower urinary tract dysfunction therefore we were unable to refine the assessment of voiding dysfunction rates. Moreover, Bonneau et al reported that half of their patients with preoperative voiding dysfunction had normal urodynamic test values[START_REF] Bonneau | Incidence of pre-and postoperative urinary dysfunction associated with deep infiltrating endometriosis: relevance of urodynamic tests and therapeutic implications[END_REF].

	NS surgery for DE with colorectal involvement has been shown to decrease the
	incidence of urinary side effects (44)(45). De Resende Junior et al. recently conducted a
	meta-analysis (41) including four studies that strictly compared NS and non-NS techniques
	resection although a high heterogeneity among studies was observed (OR 0.72, 95% CI (33)(46)(47)(48). The authors found a common OR of 0.19 [95%CI: 0.03-1.17; (I
	0.4-1.31, I 2 = 63%, P=0.28). The most frequent type of surgery was segmental resection 21⁄450.20%; P1⁄40.09)] the need of self-catheterization at discharge in the NS group
	compared to the conventional non-NS technique.

(61.3% of patients) since this technique was most historical surgical technics and can be proposed no matter the lesion size, the circumference involved and the presence of multifocal lesions.

Colorectal endometriosis is a source of urinary dysfunction in itself due to infiltration of the hypogastric plexus. Urinary function should thus be systematically evaluated preoperatively to distinguish preexisting from de novo voiding dysfunction subsequent to surgery (17)(42)

[START_REF] Ballester | Urinary dysfunction after colorectal resection for endometriosis: results of a prospective randomized trial comparing laparoscopy to open surgery[END_REF]

. Considering the high heterogeneity of the rates of voiding dysfunction reported in the various studies (ranging from 0 to 40%) (Table

1

), future studies should include evaluation of preoperative urinary symptoms by urodynamic testing and electrophysiology exam to determine whether intraoperative nerve damage of the pelvic plexus is the cause.

Table 1 :

 1 Bowel surgery for DE has a significant impact on urinary function regardless of the technique and patients should be clearly informed pre-operatively. Rectal shaving causes Studies reporting voiding dysfunction rate after colorectal surgery for deep endometriosis

	less postoperative voiding dysfunction than discoid excision or segmental resection. It is
	therefore essential to detect preoperative urinary symptoms and to define a high-risk group
	for which urodynamic testing could be helpful. Moreover, a consensual definition of
	postoperative voiding dysfunction as well as the indication for self-catheterization should be
	used to develop a predictive tool which would be useful when counseling patients and to
	determine clinical trial eligibility.

Table 2 :

 2 Nerve sparing versus non-nerve sparing technique in colorectal surgery for deep endometriosis

Table 1 : Studies reporting voiding dysfunction rate after colorectal surgery for deep endometriosis

 1

	NC= non-concerned	NR= non-reported

*Studies reporting at least two groups of colorectal surgery.

NC= non-concerned

Table 2 : Nerve sparing versus non-nerve sparing technique in colo-rectal surgery for deep endometriosis

 2

Disclosure statement: The authors declare that they have no conflicts of interest and nothing to disclose.

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Pouilles Jean-Michel

Anna Gosset

Breteau Alice

Trémollieres Florence

TBS in Early Postmenopausal Women with Severe Vertebral Osteoporosis

Keywords: idiopathic osteoporosis, DXA, TBS, Abbreviations : BMD, bone mineral density, DXA, dual X-ray absorptiometry, FN, femoral neck, HR-pQCT, high-resolution peripheral quantitative computed tomography, LS, lumbar spine, µCT, micro-computed tomography, QCT, quantitative computed tomography, TBS, trabecular bone score

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 agematched 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.

Introduction

Postmenopausal osteoporosis is the most common form of osteoporosis that affects approximately 40% of aging women [START_REF] Florence | Osteoporosis prevention, diagnosis and therapy[END_REF]. A decline in ovarian function is the primary contributor to osteoporosis in postmenopausal women. Estrogen deficiency causes an increase in bone remodeling which leads to accelerated bone loss and alterations in the microarchitecture of bone. Therefore, the subsequent increase in the incidence of fragility fractures with aging is the consequence of low bone mass and microarchitecture defects as well extra-osseous factors (such as falls) [START_REF] Florence | Osteoporosis prevention, diagnosis and therapy[END_REF]. In the absence of a fragility fracture, osteoporosis is defined as a T-score value below 2.5 standard deviations from the young adult mean [START_REF] Kanis | The diagnosis of osteoporosis[END_REF]. The discovery of a very low BMD (T-score ≤ -3) at the beginning of menopause is a rare event that calls for the elimination of all causes of secondary osteoporosis in the first instance [START_REF] Ferrari | Osteoporosis in young adults: pathophysiology, diagnosis, and management[END_REF]. In the absence of any identifiable cause, it raises the question of its pathophysiology and consequence on the subsequent risk of fracture. In any event, and regardless of the underlying cause of low bone mass, it is logical to consider the risk of fracture to be particularly high in women who already have severe osteoporosis at the beginning of menopause [START_REF] Sowers | Amount of bone loss in relation to time around the final menstrual period and follicle-stimulating hormone staging of the transmenopause[END_REF]. Even though no prospective study has been conducted in this specific subset of women with very low BMD, several studies have demonstrated the value of BMD measured by DXA at the time of menopause to predict the risk of fragility fractures over 20 years [START_REF] Florence | Osteoporosis prevention, diagnosis and therapy[END_REF]. Moreover, the gradient of risk for hip fracture is higher in women at a young age than at an older age and for the lowest BMD values [START_REF] Johnell | Predictive value of BMD for hip and other fractures[END_REF]. Previous studies conducted in premenopausal women with fragility fractures and/or low BMD have also reported deteriorations in both cortical and trabecular microarchitecture [START_REF] Misof | Bone material properties in premenopausal women with idiopathic osteoporosis[END_REF]. Such deterioration has been noted both at the distal radius and the tibia by high-resolution peripheral computed tomography (HRpQCT) and at the central skeleton by quantitative computed tomography (QCT) [START_REF] Chevalley | Fracture history of healthy premenopausal women is associated with a reduction of cortical microstructural components at the distal radius[END_REF][START_REF] Liu | Individual trabeculae segmentation (ITS)-based morphological analysis of high-resolution peripheral quantitative computed tomography images detects abnormal trabecular plate and rod microarchitecture in premenopausal women with idiopathic osteoporosis[END_REF]. A severe deficit in areal and volumetric BMD has also been observed [START_REF] Cohen | Central QCT reveals lower volumetric BMD and stiffness in premenopausal women with idiopathic osteoporosis, regardless of fracture history[END_REF]. It is important to note that women with low BMD who had never experienced a fracture were as severely affected as those with low BMD and fragility fractures. While BMD is routinely measured by DXA, the assessment of bone microarchitecture requires the use of invasive techniques (bone biopsies) or research tools such as HR-pQCT which is not available in routine clinical practice. Trabecular bone score (TBS) is a bone texture measurement that quantifies variations in pixel grey level from lumbar spine DXA images [START_REF] Shevroja | Use of Trabecular Bone Score (TBS) as a complementary approach to dual-energy X-ray absorptiometry (DXA) for fracture risk assessment in clinical practice[END_REF]. Significant correlations have been reported between TBS and 3D trabecular bone structure parameters assessed by micro-computed tomography (µCT) in bone biopsies of the iliac crest [START_REF] Muschitz | TBS reflects trabecular microarchitecture in premenopausal women and men with idiopathic osteoporosis and low-traumatic fractures[END_REF]. Strong positive associations between TBS, trabecular number and bone volume fraction [START_REF] Muschitz | TBS reflects trabecular microarchitecture in premenopausal women and men with idiopathic osteoporosis and low-traumatic fractures[END_REF] have been found. Therefore, TBS was suggested as a surrogate technique to assess cancellous bone microarchitecture as well as an additional tool to determine trabecular bone properties. Even though there is a correlation between TBS and BMD values such as approximately 10 to 25% of TBS variance is explained by BMD [START_REF] Shevroja | Use of Trabecular Bone Score (TBS) as a complementary approach to dual-energy X-ray absorptiometry (DXA) for fracture risk assessment in clinical practice[END_REF], several cross-sectional and prospective studies have also shown that TBS is an independent predictor of the risk of fracture in patients with osteoporosis or other bone fragility-related conditions [START_REF] Shevroja | Use of Trabecular Bone Score (TBS) as a complementary approach to dual-energy X-ray absorptiometry (DXA) for fracture risk assessment in clinical practice[END_REF][START_REF] Mccloskey | A meta-analysis of Trabecular Bone Score in fracture risk prediction and its relationship to FRAX[END_REF]. Therefore, the goal of this cross-sectional study was to evaluate the properties of trabecular bone using TBS in postmenopausal women with severe vertebral osteoporosis at the beginning of menopause. By comparing the association between TBS and BMD values, our aim was to formulate hypotheses on the pathophysiology of osteoporosis in this population. Accordingly, if TBS is decreased to a greater extent than lumbar spine BMD, this would indicate that rapid bone loss is the major contributor to vertebral osteoporosis in this population. It is indeed likely that the impact of bone loss would degrade bone quality more rapidly than bone mineral density. On the other hand, if a strong correlation is found between TBS and lumbar spine BMD, this would suggest that osteoporosis is rather related to a low peak bone mass than to further degradation. Therefore, we compared TBS values between early postmenopausal women with severe idiopathic vertebral osteoporosis and healthy control women who were matched either for age or vertebral BMD.

Subjects and methods

Study population:

Among the postmenopausal women who attended our outpatient menopause clinic over the last 10 years, we identified all early postmenopausal women whose DXA measurement had shown severe vertebral osteoporosis defined as a vertebral T-score ≤ -3. According to the inclusion criteria described below, 105 women ("cases", group 1) for whom the duration of menopause was less than 5 years were selected: Two control groups were also selected from the women who attended our menopause clinic during the same period of time:

-Group 2: 105 healthy women with normal vertebral BMD matched for age and years since menopause; -Group 3: 105 otherwise healthy older osteoporotic women (duration of menopause of more than 10 years) who were matched for vertebral BMD.

All cases and controls had been referred to our menopause clinic by their general practitioner or gynecologist for evaluation of the consequences of postmenopausal estrogen deficiency on metabolism and bone. They were evaluated through the same standard procedure as already described elsewhere [START_REF] Ribot | Assessment of the risk of postmenopausal osteoporosis using clinical factors[END_REF][START_REF] Tremollieres | Fracture Risk Prediction Using BMD and Clinical Risk Factors in Early Postmenopausal Women: Sensitivity of the WHO FRAX Tool[END_REF] including a personal interview, a medical examination, a fasting blood sample with particular focus on secondary causes of osteoporosis (when needed) and bone densitometry measurements. To be included, all the women had to have experienced natural menopause (not the consequence of oophorectomy or chemotherapy/radiotherapy) after the age of 45 years. Participants were excluded if they had a history of or presented with conditions that affect bone metabolism including endocrinopathies (hypogonadism or a prior history of hypoestrogenic amenorrhea for more than 3 months, hyperthyroidism, glucocorticoid excess, type 1 or type 2 diabetes mellitus, primary hyperparathyroidism or prolactinoma), anorexia nervosa, bulimia, celiac disease or other gastrointestinal malabsorption syndromes, inflammatory or autoimmune diseases (rheumatoid arthritis, connective tissue diseases), renal dysfunction, hypercalciuria or any history of malignancy (except for dermatological cancers). Women who had taken glucocorticoids, anticonvulsants, chemotherapy and/or any anti-osteoporotic drugs (estrogens, bisphosphonates, raloxifene, denosumab, teriparatide) for more than 3 months were also excluded. Treatment with calcium and/or vitamin D was allowed. In addition, women with DXA measurements that were not evaluable due to degenerative spinal changes or artifacts were not selected.

The study was approved by the local ethics committee.

Interview:

All the women completed a standardized computer-assisted questionnaire, described extensively elsewhere [START_REF] Ribot | Assessment of the risk of postmenopausal osteoporosis using clinical factors[END_REF], and this was recorded by the same trained research nurse. The following clinical and historical data were extracted for each woman: age, weight, height, body mass index (kg/m 2 ), reproductive history, risk factors for osteoporosis, self-reported personal and family history of low-trauma fracture after 40 years and medications. A family history of fracture was considered positive if a parent or sibling had a typical fragility fracture including hip, vertebral, humeral or wrist fracture. Information on smoking habits and alcohol consumption were also obtained. Current smoking was defined as consumption of more than 10 cigarettes per day for more than 1 year at the time of the survey.

Medical examination:

Each woman underwent a medical examination whereby all recorded data were validated and completed when necessary. Height (cm) and weight (kg) were measured with an automatic scale and body mass index (kg/m²) was calculated.

Bone mineral density measurement: For all the women, lumbar spine and femoral neck bone mineral densities (BMDs, g/cm²) were measured by an IOF-ISCD certified technician using a single DXA scanner (GE Lunar iDXA, GE Healthcare, Madison, WI -software version 14.10). T-scores (SD from young normal) for each measurement site were calculated using the Lunar normative database for France for age 25-35 as previously published (n = 110, mean spine BMD=1.18 ± 0.12 g/cm²; mean FN= 0.990 ± 0.12) [START_REF] Ribot | Assessment of the risk of postmenopausal osteoporosis using clinical factors[END_REF].

Vertebral Fracture assessment: All women in groups 1 and 3 had vertebral fracture assessment (VFA) of the thoracolumbar spine (T4-L5) by DXA scans. Confirmatory X-ray radiographs were performed whenever a vertebral abnormality that could indicate a fracture was found.

Results

Clinical characteristics of the women:

The mean age of cases was 53.1 ± 2.6 years with a mean duration of menopause of 2.4 years. Cases were significantly (p<0.05) smaller and thinner and had a history of more fractures than age-matched controls (23% vs 3.8% (p < 0.05)). There was no significant difference in fractures between the cases and the older BMD-matched controls (23 % vs 27 %) (Table 1). In the group 1 women, fractures involved ribs (n=8), vertebrae (n=8), wrist (n=5), proximal humerus (n=2) and other minor bone sites (n=7). Six patients had more than 1 fracture. In group 3, the distribution of fractures was as follows: ribs n= 6, vertebrae n= 8, wrist n=8, proximal humerus n=1 and other n=5. Four patients had more than 1 fracture. Moreover, a family history of non-hip fractures was more frequently reported in the group 1 women than in the women in both control groups (p<0.05). The percentage of smokers was also higher among the women in group 1 than among those in the 2 control groups (p <0.05) (table 1).

Bone mineral density and TBS values:

Mean lumbar spine (LS) and femoral neck (FN) BMD values (and T-scores) were significantly lower in the cases than in the age-matched non osteoporotic women (group 2) (0.770 ± 0.05 g/cm 2 vs 1.106 ± 0.11 g/cm 2 ; p < 0.001 and 0.700 ± 0.07 g/cm 2 vs 0.872 ± 0.12 g/cm 2 ; p < 0.001, respectively). Differences in BMD between the cases and the age-matched women remained significant (p<0.0001) after controlling for weight and height (and BMI).

There was no significant difference in mean LS and FN BMDs (and T-scores) between the cases and the older osteoporotic women (BMD-matched control group, group 3) (table 2). Mean TBS values were significantly different within the 3 groups (p < 0.001). The mean TBS value was significantly lower in the cases than in the age-matched women (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). Adjustment for height did not modify the results in covariance analyses. On the other hand, after adjustment for vertebral BMD (p<0.0001), there was no longer a difference in mean TBS values between the cases and the age-matched controls while it remained significantly higher in the cases than in the older osteoporotic controls (table 2). However the difference in mean TBS values was no longer significant between the cases and the older osteoporotic controls after adjustment for age (1.23 vs 1.23).

A femoral neck T-score below -2.5 was found in 46 out of 105 women in group 1. However, there was no significant difference in mean TBS values (1.23 ± 0.06 vs 1.24 ± 0.07, p=0.67) or lumbar spine BMD (0.763 ± 0.06 g/cm 2 vs 0.774 ± 0.04 g/cm 2 , p= 0.29) between those with and those without femoral neck osteoporosis in this group. There was also no difference in mean BMD and TBS values between women who reported a history of fragility fractures and those who did not, neither in group 1 nor in group 3 (data not shown).

Predictors of TBS values:

In univariate analysis, a significant correlation (p<0.05) was found between TBS and lumbar spine, and femoral neck BMD, age, years since menopause, and height (no association with weight, parental history of fracture or parity). TBS was negatively and independently associated with age (r=-0.31; p<0.0001) and height (r=-0.20; p<0.001) in a multivariate analysis including age, vertebral and femoral neck BMD, height and weight (R²=0.60; p<0.0001) (table 3). The regression slopes between TBS and vertebral BMD values were not significantly different within the 3 groups although there was a trend toward a greater correlation between TBS and lumbar spine BMD values in the healthy control group than in the other 2 osteoporotic groups (group 1: r= 0.34 vs group 2: r =0.53 (p=0.21) and in group 1 vs group 3: r =0.34 (p=0.99)) (figure 1).

FRAX probability of fracture:

The probabilities of fracture as calculated by the FRAX algorithm were significantly higher in the 2 osteoporotic groups (group 1 and 3) than in the healthy control group (p<0.05 to 0.01) (table 2). After adjusting for TBS values, the FRAX score was slightly higher in both osteoporotic groups but not in the healthy control group (table 2).

Discussion

In this study, we found that postmenopausal women with severe vertebral osteoporosis (as defined by a lumbar spine T-score ≤ -3) at the beginning of menopause had significantly lower TBS values than age-matched healthy postmenopausal women. However, it was significantly higher in the cases than in the older osteoporotic women who were matched for vertebral BMD. Nevertheless, this difference was no longer significant when age (or years since menopause) was taken into account. This could indicate that women with severe vertebral osteoporosis at the beginning of menopause have trabecular bone microarchitecture that is proportional to their vertebral BMD. Therefore, low bone mass could be more the consequence of a low peak bone mass than of subsequent degradation. This contrasts with the findings in older osteoporotic women where it is more likely that the greater decrease in mean TBS value reflects further deterioration of bone microarchitecture, probably related to postmenopausal bone loss (and/or aging). However, it could be noted that even though there was no significant difference in the regression slopes between TBS and vertebral BMD values within the 3 groups, there was a trend towards a greater difference between the 2 osteoporotic groups and the healthy control group than between the 2 osteoporotic groups. This could indicate that the dependency of TBS on vertebral BMD is weaker in women with severe vertebral osteoporosis at the beginning of menopause than in healthy age-matched controls. Therefore, this suggests that in group 1, additional alterations in bone microarchitecture cannot be completely excluded.

To our knowledge there is no study in early postmenopausal women with severe vertebral osteoporosis. A few studies are available on premenopausal women with idiopathic osteoporosis (with or without fractures). In these studies, data similar to ours, such as smaller size, lower BMI and a family history of osteoporosis were found in these women [START_REF] Ferrari | Osteoporosis in young adults: pathophysiology, diagnosis, and management[END_REF][START_REF] Donaldson | Spinal bone texture assessed by trabecular bone score in adolescent girls with anorexia nervosa[END_REF][START_REF] Cohen | Bone microarchitecture and stiffness in premenopausal women with idiopathic osteoporosis[END_REF][START_REF] Galusca | Constitutional thinness: unusual human phenotype of low bone quality[END_REF]. Microstructural deficits in both the central and peripheral skeleton assessed by different computed tomography techniques as well as by finite element analysis were often reported [START_REF] Misof | Bone material properties in premenopausal women with idiopathic osteoporosis[END_REF][START_REF] Liu | Individual trabeculae segmentation (ITS)-based morphological analysis of high-resolution peripheral quantitative computed tomography images detects abnormal trabecular plate and rod microarchitecture in premenopausal women with idiopathic osteoporosis[END_REF][START_REF] Donaldson | Spinal bone texture assessed by trabecular bone score in adolescent girls with anorexia nervosa[END_REF]. This contrasts with our study in which there was no significant difference in TBS values between early postmenopausal women with and without severe vertebral osteoporosis after adjustment for vertebral BMD. TBS is a bone texture parameter which is related to bone microarchitecture and proposed as a surrogate marker for the assessment of trabecular bone properties [START_REF] Muschitz | TBS reflects trabecular microarchitecture in premenopausal women and men with idiopathic osteoporosis and low-traumatic fractures[END_REF]. Our study is consistent with previous studies [START_REF] Liu | Individual trabeculae segmentation (ITS)-based morphological analysis of high-resolution peripheral quantitative computed tomography images detects abnormal trabecular plate and rod microarchitecture in premenopausal women with idiopathic osteoporosis[END_REF][START_REF] Cohen | Central QCT reveals lower volumetric BMD and stiffness in premenopausal women with idiopathic osteoporosis, regardless of fracture history[END_REF][START_REF] Shevroja | Use of Trabecular Bone Score (TBS) as a complementary approach to dual-energy X-ray absorptiometry (DXA) for fracture risk assessment in clinical practice[END_REF][START_REF] Muschitz | TBS reflects trabecular microarchitecture in premenopausal women and men with idiopathic osteoporosis and low-traumatic fractures[END_REF][START_REF] Mccloskey | A meta-analysis of Trabecular Bone Score in fracture risk prediction and its relationship to FRAX[END_REF][START_REF] Ribot | Assessment of the risk of postmenopausal osteoporosis using clinical factors[END_REF][START_REF] Tremollieres | Fracture Risk Prediction Using BMD and Clinical Risk Factors in Early Postmenopausal Women: Sensitivity of the WHO FRAX Tool[END_REF][START_REF] Donaldson | Spinal bone texture assessed by trabecular bone score in adolescent girls with anorexia nervosa[END_REF][START_REF] Cohen | Bone microarchitecture and stiffness in premenopausal women with idiopathic osteoporosis[END_REF][START_REF] Galusca | Constitutional thinness: unusual human phenotype of low bone quality[END_REF][START_REF] Leslie | Clinical factors associated with Trabecular Bone Score[END_REF][START_REF] Looker | Trabecular bone scores and lumbar spine bone mineral density of US adults: comparison of relationships with demographic and body size variables[END_REF][START_REF] Kim | The correlation between bone mineral density/trabecular bone score and body mass index, height, and weight[END_REF] in that we found a negative correlation between TBS, age and height and a positive correlation with lumbar spine and femoral neck BMD. Since TBS is derived from DXA images of the lumbar spine, it is not surprising that vertebral BMD contributed more to TBS variance than femoral neck BMD [START_REF] Shevroja | Use of Trabecular Bone Score (TBS) as a complementary approach to dual-energy X-ray absorptiometry (DXA) for fracture risk assessment in clinical practice[END_REF]. In addition, in our study there was no difference in mean TBS values in group 1 women with and without femoral neck T-scores below -2.5. Several studies conducted in postmenopausal women with osteoporosis [START_REF] Shevroja | Use of Trabecular Bone Score (TBS) as a complementary approach to dual-energy X-ray absorptiometry (DXA) for fracture risk assessment in clinical practice[END_REF][START_REF] Muschitz | TBS reflects trabecular microarchitecture in premenopausal women and men with idiopathic osteoporosis and low-traumatic fractures[END_REF][START_REF] Mccloskey | A meta-analysis of Trabecular Bone Score in fracture risk prediction and its relationship to FRAX[END_REF] as well as in patients with secondary osteoporosis [START_REF] Leslie | TBS (trabecular bone score) and diabetesrelated fracture risk[END_REF][START_REF] Peris | Idiopathic osteoporosis in premenopausal women. Clinical characteristics and bone remodelling abnormalities[END_REF] have shown that TBS is a predictor of the risk of fracture independently, at least in part, of BMD. As expected, because of the low BMD and the history of a higher fracture rate, the 10 year-risk of major osteoporotic fracture calculated by the FRAX tool was significantly higher in the cases than in the age-matched controls. It remained significantly lower than in the group of older women as one of the major determinants of FRAX score is age as well as decreased femoral BMD and a history of fracture. After adjustment for TBS, mean FRAX values were only slightly higher in the two osteoporotic groups but not in the healthy postmenopausal control group. These factors could indicate that the additional value of TBS in predicting the risk of fracture is relatively negligible in postmenopausal women with severe osteoporosis. It is of note that at present, there is no guideline to recommend the assessment of TBS to predict the risk of fracture in postmenopausal women with a very low vertebral T-score. This study has several strengths and limitations. It concerns a relatively large number of women with very low vertebral BMD at the beginning of menopause, which is unusual. Although data were collected over a 10-year period, all the women were selected at the same facility through the same selection process. We were particularly careful in matching cases with women in the 2 control groups for either age or vertebral BMD. Since several diseases have various impacts on cortical or trabecular bone which can affect the TBS value in different ways, we eliminated all women with a secondary cause of osteoporosis to obtain the most homogeneous population possible. The main limitation of our study is related to its cross-sectional nature which does not allow us to assess the risk of fracture. Only through a longitudinal follow-up would it be possible to evaluate the real risk of fracture over time, although effective anti-fracture therapy is more likely to be warranted in this population. In addition, TBS does not allow direct measurement of bone micro-architecture and our results would need to be confirmed by a benchmark technique such as HRpQCT. Our working hypothesis that TBS could help to clarify the underlying mechanisms of osteoporosis in this population also remains quite theoretical and further studies are required. Finally, our results were obtained in a specific population of early postmenopausal women with severe vertebral osteoporosis and may not apply to women with other causes of osteoporosis.

In conclusion, low TBS values were found in early postmenopausal women with severe vertebral osteoporosis even though they were almost entirely explained by a decrease in vertebral BMD. Although this requires confirmation by further studies, our results could indicate that low bone mass is rather the consequence of a low peak bone mass than of further bone degradation. In any event, it is unlikely that TBS provides additional information to BMD measurement in the evaluation of trabecular bone properties in this population.

Figure 1 :

 1 Figure 1: Correlation between TBS and lumbar spine BMD in the 3 groups. The regression slopes are not statistically different between the 3 groups.

  Spearman's rank correlation coefficient was used to analyze the correlations between TBS and clinical characteristics and BMDs. Multivariate logistic regression analyses were then performed to analyze the relation of the different clinical variables found to significantly affect TBS values

	FRAX score:
	We used the algorithm available at www.shef.ac.uk/FRAX to calculate individual FRAX
	values based on each woman's hip BMD measurement and clinical characteristics at
	baseline.
	Statistical analysis:
	Statistical analyses were performed using MedCalc (software version 18.11.3, Belgium). A p-
	value of 0.05 was set as the threshold for statistical significance.

Trabecular Bone Score (TBS) measurement Lumbar spine TBS was obtained using DXA scans at the same region of interest (L2-L4) using TBS Insight software (Version Medimaps, Bordeaux France) by a technician blinded to the patients' clinical outcome. For scans performed before January 2012, the DXA files were digitally exported to a specific TBS calculation workstation that uses the latest version of TBS software (courtesy Didier Hans, Center of Bone Diseases, Lausanne University Hospital Switzerland). One-way analysis of variance (ANOVA) was used to compare clinical characteristics, TBS, BMD values and biochemical parameters among the three groups (patients, age-matched and BMD-matched controls). Categorical variables were analyzed using the X² test. Analysis of covariance was used to calculate adjusted mean BMD and TBS after controlling for confounders.

Table 1 :

 1 Clinical characteristics of cases and matched controls

	Cases (group 1)	Age-matched	BMD-matched
	(n = 105)	controls (group 2)	controls (group 3)
		(n = 105)	(n= 105)

Table 2 :

 2 Comparison of BMD and TBS values between cases and controls * p <0.001 between groups 1 and 2 § p <0.05 between groups 1 and 3

	£ p <0.0001 between groups 1 and 3

Table 3 :

 3 Parameters independently associated with TBS in a multiple regression analysis (n=315)

	Independent variables	Coefficient	Standard Error	p	Partial R
	Years since menopause	-0.00376	0.000668	< 0.0001	-0.30
	Lumbar spine BMD	0.3834	0.0240	< 0.0001	0.67
	Height	-0.00237	0.000664	0.0004	-0.20
	* p<0.05 between cases and age-matched controls
	§ p<0.05 between cases and BMD-matched controls