PhD Eric O Verger
email: e.verger@ican-institute.org

MD Judith Aron-Wisnewsky

PhD Maria Carlota Dao
email: mc.dao@ican-institute.org

PhD Brandon D Kayser
email: b.kayser@ican-institute.org

MD Jean-Michel Oppert
email: jean-michel.oppert@psl.aphp.fr

MD Jean-Luc Bouillot
email: jl.bouillot@apr.aphp.fr

MD Adriana Torcivia
email: adriana.torcivia@psl.aphp.fr

MD Karine Clément
email: karine.clement@psl.aphp.fr

Prof Karine Clément

Micronutrient and Protein Deficiencies After Gastric Bypass and Sleeve Gastrectomy: a one-year Follow-up

Keywords: Bariatric surgery, Roux-en-Y Gastric Bypass, Sleeve gastrectomy, Protein Bariatric surgery, Roux-en-Y Gastric Bypass, Sleeve gastrectomy, Protein 23 deficiency, Multivitamin and mineral supplementation. 24

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.

INTRODUCTION 26

Among the few therapeutic tools to treat morbid obesity, bariatric surgery (BS) 27 appears to be the most effective strategy as demonstrated by its ability to obtain major and 28 sustainable weight loss along with significant improvement of obesity related-comorbidities 29 [1,2]. As a result, the number of interventions has dramatically risen worldwide, and Roux-30 en-Y Gastric Bypass (GBP) and Sleeve Gastrectomy (SG) represented respectively 47% and 31 28% of the 340,000 BS performed in 2011 [3]. Since 2008, SG has emerged to such an extent 32 that it has become the most common procedure in several countries, as is the case in France 33 [3]. Although the two surgical techniques and their mechanisms of action differ, they appear 34 to be equally safe and both induce significant weight loss post-surgery [4]. 35 GBP includes diet restriction as well as the bypass of the proximal part of the jejunum 36 involved in nutrient absorption whereas SG is less invasive and principally restricts the 37 volume of the stomach [5] (reviewer #2, comment #4). Therefore SG, compared to GBP, 38 might be viewed as less likely to exacerbate the risk of micronutrient deficiencies in obese 39 patients who are already prone to such deficiencies before surgery [6]. Nevertheless, some 40 studies have demonstrated a considerably higher prevalence of nutrient deficiencies after SG 41 [7][8][9][10][11]. Others, comparing GBP and SG, found quite similar prevalence after both procedures 42 [12][13][14][15][16]. Although study designs differed, these converging results highlight the importance 43 of daily multivitamin and mineral supplementation after both procedures, at least in the first 44 year for SG, in accordance with the latest US guidelines [17]. While the previously mentioned 45 studies evaluated nutrient deficiencies using serum biomarker concentrations, only very few 46 have evaluated food and nutrient intake after GBP and SG: Freeman et al. evaluated food 47 intake two to four years after surgery [18], Moizé et al. and Coupaye et al. evaluated the 48 overall macronutrient intake during one year after BS but did not quantify micronutrient 49 where appendicular FFM (or FM) was calculated as the sum of FFM (or FM) from both arms 75 and both legs. Basal metabolic rate (BMR) was assessed with indirect calorimetry (Deltatrac 76 II monitor, Datex Instrumentarium Corp., Helsinki, Finland) enabling the evaluation of 77 underreporting of dietary intake [23]. 78 79

Dietary data and nutrient intakes 80

At baseline, T3 and T12, patients completed three consecutive web-based 24h dietary 81 records as described elsewhere [24], including two weekdays and one day on the weekend 82 whenever possible. All foods and beverages consumed at breakfast, lunch, dinner and snacks 83 were recorded. Validated photographs enabled patients to estimate portion size for each 84 reported food and beverage item [25]. Patients were also asked to indicate multivitamin and 85 mineral supplements use, specifying the product name and amount, following the nutritional 86 deficiency prevention treatment prescribed for every patient at our center, as described in 87 [26]. This includes supplementation during two weeks before surgery of vitamin D (once 88 4×100,000 IU), thiamin (250 mg/day), and vitamin B-12 (250μg/day). Fifteen days post-GBP 89 and SG, multivitamin and mineral supplements including Azinc "Forme et vitalité"® (two 90 capsules per day, containing 800 μg vitamin A, 1.4mg thiamin, 200 µg folate, 1µg vitamin B-91 12, 120 mg vitamin C, 200 IU vitamin D, 8 mg iron and 15 mg zinc), iron (2×80 mg/ day), 92 vitamin D (800 IU/day), and calcium (1,000mg/day) were started and continued for the first 93 year in both BS procedures. Intake of nutrients derived from food were calculated using an 94 updated version of the French database CIQUAL 2008 [27] which included more than 3,400 95 different food items. Nutrient intakes from multivitamin and mineral supplements were 96 calculated using nutrient profile based on the product name. Ingested foods were categorized 97 into 4 main food groups when possible: (i) fruit and vegetables, (ii) starchy foods, (iii) dairy 98 products, and (iv) meat and fish. The food groups were defined according to the French 99 National Nutrition and Health Program [28] and expressed in servings per day based on 100 standard serving sizes [29]. 101 102

Nutrient adequacy of the diet 103

Nutrient intake adequacy for each patient was calculated using the PANDiet index 104 [30]. Briefly, probability of adequacy for each nutrient was calculated, ranging from 0 to 1, 105 where 1 represents a 100% probability that the usual intake is adequate (i.e. it satisfies the 106 requirement or is not excessive compared to a reference value). According to this definition, 107 the probabilities of adequacy were computed to obtain the Adequacy sub-score (the higher, 108 the better the intake satisfies the nutrient requirements) and the Moderation sub-score (the 109 higher, the less likely the intake is excessive). The PANDiet score is taken as the mean of the 110 Adequacy and Moderation sub-scores, and ranges from 0 to 100; the higher the score, the 111 better the nutrient adequacy of the diet. As reference values, we used French nutritional 112 recommendations for healthy adults or European Union values when specific 113 recommendations were lacking. 114 115

Biochemical analyses 116

Blood samples were collected after an overnight fast to measure biochemical 117 parameters using routine techniques as described [31]. Blood count and iron metabolism 118 markers (i.e. ferritin, iron, transferrin, and saturation coefficient) were assessed using routine 119 care method (nephelemetry (reviewer #1, comment #9), ferrozine colorimetry and 120 immunoturbidimetry respectively). Prealbumin was assessed by immunoturbidimetry. Serum 121 concentrations of 25(OH)-vitamin-D3 and parathyroid hormone (PTH) were measured by 122 chemiluminescent assay (310600 Liaison XL Diasorin and 11972103 Modular E 170 Roche, 123 respectively), vitamin B-12 and folate were assessed using immunoanalysis ECL sandwich, 124 and thiamin and vitamin B-6 were assessed using HPLC [6]. Vitamin and mineral deficiencies 125 were defined as a result below the lower normal value given by the manufacturer [32]. 126 Secondary hyperparathyroidism was defined as an elevated PTH, above the high normal 127 laboratory value. All measurements were conducted at baseline, T3, T6 and T12 (except for 128 25(OH)-vitamin-D3, PTH, thiamin, folate and vitamin B-12 at T3, and PTH at T6). 129 130

Statistical analyses 131

Continuous variables are presented as median and interquartile range (IQR) and 132 frequencies as percentages (reviewer #2, comment #2). Mann-Whitney and paired Wilcoxon 133 rank-sum tests were, respectively, used to compare continuous variables between surgical 134 groups and time-points. Chi-squared and McNemar tests were used to compare frequencies 135 between surgical groups and time-points, respectively. An overall α level of 5% was used for 136 statistical tests following Holm-Bonferroni correction. These analyses were conducted on 137 both the patients who completed T3 and T6, and on the patients who completed T3, T6 and 138 T12 (reviewer #1, comment #1). Since no significant difference was observed between two 139 groups of patients both at baseline, and during the follow-up at T3 and T6, outcomes are 140 merged when presented on tables and figures. All analyses were performed using Statistical 141 Analysis Systems statistical software package version 9.3 (SAS Institute, Cary, NC, SA) 142 (reviewer #2, comment #3). 143

144

RESULTS

145

Clinical characteristics 146

Fifty-two patients were included in this study (22 GBP and 30 SG). All of them 147 completed the first six months follow-up of this study (T3 and T6), and 33 completed the one 148 year follow-up (T3, T6 and T12; 14 GBP and 19 SG) (reviewer #1, comment #1). 149 Importantly, the two groups were similar at baseline regarding sex, age, corpulence and body 150 composition (Table 1). Likewise, the severity of obesity related-comorbidities was similar in 151 the two groups, except for glucose intolerance, which was significantly more prevalent in the 152 GBP group (Table 1). 153

As expected, BS induced significant weight loss in both surgical techniques, however 154 GBP led to a significantly greater weight loss at T6 and T12 compared to SG (Table 1). More 155 specifically, the total and appendicular FFM (in kg) significantly decreased at T3 and then 156 stabilized at T6 and T12 in the two groups, while the total and appendicular FM (in kg) 157 significantly decreased along the one year follow-up in the GBP group whereas it 158 significantly decreased until T6 and then stabilized from T6 to T12 in the SG group (Figure 159 1). As a result, body composition significantly improved as demonstrated by changes in the 160 percentage of FFM and FM (Table 1). GBP induced a significant improvement of obesity-161 related comorbidities (except for high blood pressure (HBP)), whereas SG only led to a 162 significant improvement of dyslipidemia at T6 and T12 (Table 1). 163 164

Food and macronutrient intakes 165

At baseline, no difference was observed for energy, food or macronutrient intakes 166 between the two groups (Table 2). The BMR values revealed that patients from both groups 167 underreported their caloric intake by 8%. 168

After both GBP and SG, energy intake drastically decreased at T3 and slightly 169 increased at T12, although not reaching baseline intake levels (significant at all time points, 170 Table 2). These changes in energy intake were explained by a significant decrease in food 171 intake at T3 in the two surgical groups (non-significant for dairy products) and a tendency for 172 a modest increase in food intake at T12 (significant for starchy foods in the SG group, Table 173 2). Total protein intake drastically and significantly decreased at T3 in both groups, and a 174 majority of patients reported protein intake below the recommended value of 60 g/day (85.7% 175 after GBP and 79% after SG, Table 2). Afterwards, total protein intake slightly but 176 significantly increased at T12, although it remained below the baseline levels (Table 2). 177 Furthermore, 61% of the patients reported low dietary protein intake (64% and 58% 178 respectively for GBP and SG groups, Table 2) at T12. No significant changes in 179 macronutrient distribution (total fat, SFA, PUFA and total carbohydrates) were observed 180 during the follow-up in the two groups (T3 and T12, Table 2). Energy, food and 181 macronutrient intakes were not different between the two groups during the follow-up (T3 182 and T12, Table 2). 183 184

Nutrient adequacy of the diet 185

At baseline, neither the PANDiet scores nor the probabilities of nutrient adequacy 186 differed between the two groups (Table 3). Low probabilities of adequacy for protein were 187 observed in both groups compared to the French adult population [30]. 188

After both BS, the percentage of patients taking the prescribed systematic 189 multivitamin and mineral supplements significantly increased, from baseline to T3: 14% 190 versus 77% for GBP and 10% vs. 76.7% for SG, as expected from the recommendations 191 (Table 3). This high adherence was maintained at T12 with 86% and 68% respectively for 192 GBP and SG (Table 3). Due to the supplementation, the global nutrient adequacy of the diet 193 did not drop and rather stabilized along the follow-up (PANDiet score and Adequacy sub-194 score were not significantly different at all time points) and the probability of adequacy for 195 vitamin D was improved (Table 3). Of note, when the global nutrient adequacy of the diet was 196 calculated without taking into account the prescribed supplementation, we found that it 197 drastically decreased at T3 and barely increased at T12 (Supplemental Table 1). However, 198 since the prescribed supplementation neither contains protein, fiber nor phosphorus, lower 199 probabilities of adequacy for these nutrients were observed in both groups at T3 compared to 200 baseline (Table 3). Furthermore, although the probabilities of adequacy for these four 201 nutrients significantly increased at T12 in both groups compared to T3 due to the slight 202 increase in food intake, they remained below the baseline values (except for protein in the 203 GBP group, Table 3). 204 205

Nutritional deficiencies 206

At baseline, none of the metabolic and nutritional parameters were different between 207 the two groups (Table 4). As expected in severe obesity, 100% and 83% of the patients from 208 the GBP and SG groups, respectively, presented 25(OH)-vitamin-D3 deficiency as seen by 209 serum concentrations below 30 ng/ml (Table 4) with subsequent secondary 210 hyperparathyroidism in 50% of the subjects, showing major deficiency in this population. 211

After both BS, prealbumin concentration drastically and significantly decreased at T3 212 and further stabilized at T6 and T12 (Table 4). At T12, 38% of GBP patients and 52% of SG 213 patients presented mild protein depletion as shown by prealbumin concentration below the 214 normal range of 0.2 g/l and 21% of GBP patients and 16% of SG patients presented risk of 215 mild protein malnutrition as shown by albumin concentration below the normal value of 37 216 g/l (Table 4). Of note, two patients in the GBP group and one patient in the SG group 217 presented both mild protein depletion and risk of mild protein malnutrition (reviewer #1, 218 comments #5,6&7). After both BS, vitamin D supplementation enabled a significant increase 219 in 25(OH)-vitamin-D3 serum concentrations at T6, which stabilized at T12 (Table 4). 220 However, 50% and 21% of GBP and SG patients, respectively, still displayed secondary 221 hyperparathyroidism at T12 (Table 4). Since all patients were prescribed multivitamin and 222 mineral supplementation, we verified whether this supplementation might induce serum 223 concentrations of selected vitamins and minerals above the normal range at T12. In fact, there 224 were only a few such cases in the overall cohort: one with elevated serum thiamin (700 225 nmol/l) and one with high serum ferritin (740 µg/l) in the SG group, and one with elevated 226 vitamin B12 (580 pmol/l) in the GBP group. Importantly, all such elevations remained below 227 toxic levels. 228

229

DISCUSSION

230

To the best of our knowledge, this is the first study to assess the relationship between 231 food intake, nutrient adequacy of the diet and nutritional biological parameters systematically 232 measured before, three and twelve months after GBP and SG. In this study where the patients 233 had similar clinical characteristics at baseline (except for T2D prevalence), our main findings 234 are: (i) protein intake significantly decreases after both GBP and SG, inducing mild protein 235 depletion in more than a third of the patients one year after both surgical techniques (reviewer 236 #1, comments #5,6&7); (ii) even though patients after GBP experienced greater weight loss 237 than after SG, both types of surgery induced similar food restriction effects on the nutritional 238 adequacy of the diet and, (iii) systematic multivitamin and mineral supplementation after SG 239 seems to prevent these nutritional deficiencies, the same way as in GBP in the first year. 240 After one year, we observed that GBP led to significantly greater weight loss 241 compared to SG, in accordance with previous data from the literature, including a large 242 multicenter study [33,34]. Nevertheless, some controversy remains. Indeed other reports show 243 that changes in body weight were similar one year after both GBP and SG [15,19,35], 244 although these were smaller cohorts. We evaluated the evolution of body composition and 245 observed that, in both surgeries, total FFM decreased until three months and then stabilized, 246 whereas total FM displayed a continuous decrease during the follow-up. Our results are 247 consistent with previous reports showing changes in body composition following GBP [22] or 248 SG [START_REF] Bužga | Dietary intake and ghrelin and leptin changes after sleeve gastrectomy[END_REF] as measured by DXA. Our results are also concordant with the only study comparing 249 these outcomes after both sleeve and by-pass [19]. In that study, the continuous weight loss 250 during one year was due to the decrease of total FM, the total FFM being spared after four 251 months [19]. More importantly, we observed that appendicular FFM decreased until three 252 months and then stabilized, whereas appendicular FM continued to decrease throughout the 253 follow-up period in both models. Appendicular FFM represents a better surrogate of muscle 254 mass than total FFM [START_REF] Kim | Total-body skeletal muscle mass: estimation by a new dual-energy X-ray absorptiometry method[END_REF], and this is the first time that this outcome and its evolution have 255 been studied after SG. Interestingly, the change in appendicular FFM was similar in the two 256 surgical procedures. 257

After both BS, we observed that 61% of the patients reported daily protein 258 consumption under the recommended value of 60 g/day at T12 (64% for GBP and 58% for 259 SG). Our results are consistent with those of Andreu et al. and Moizé et al. who found that 260 respectively 37% and 46% of patients had a daily protein intake below 60 g/day one year after 261 BS [19,[START_REF] Andreu | Protein intake, body composition, and protein status following bariatric surgery[END_REF]. In accordance with those findings, we did not find any difference between GBP 262 and SG [START_REF] Andreu | Protein intake, body composition, and protein status following bariatric surgery[END_REF]. We report a prevalence of insufficient protein intake that is nearly 2-fold higher 263 than that reported by Moizé et al. (61% versus 37%), which is mostly attributable to the 264 systematic protein supplementation prescribed by these authors to all of their patients [START_REF] Andreu | Protein intake, body composition, and protein status following bariatric surgery[END_REF]. 265

One objective of recommending a minimal protein intake of 60 g/day after both GBP and SG 266 is to mitigate post-surgical FFM loss in the first months [17]. Indeed, Moizé et al. 267 demonstrated that patients with insufficient protein intake during the follow-up lost more 268 FFM in both SG and GBP than patients with sufficient protein intake [19]. Because skeletal 269 muscle is the primary site of insulin-stimulated glucose disposal during euglycemia [START_REF] Defronzo | The effect of insulin on the disposal of intravenous glucose. Results from indirect calorimetry and hepatic and femoral venous catheterization[END_REF], loss 270 of FFM might contribute to the development of insulin resistance and should be avoided in 271 order to maintain the beneficial metabolic outcomes. An important goal of future long-term 272 follow-up studies will be to determine whether insufficient protein intake following BS might 273 result in loss of muscular strength. Furthermore, longer-term weight stabilization (and regain) 274 should also be assessed in link with the quantity of protein intake. 275

After both BS, we also observed that prealbumin concentration significantly 276 decreased, resulting in more than a third of patients exhibiting mild protein depletion 277 (reviewer #1, comments #5,6&7). Our results are in line with the few studies that reported 278 changes in prealbumin concentration after GBP or SG. All studies found lower values at T12 279 after GBP compared to baseline [15,[START_REF] Coupaye | Nutritional consequences of adjustable gastric banding and gastric bypass: a 1-year prospective study[END_REF][START_REF] Sallé | Zinc deficiency: a frequent and underestimated complication after bariatric surgery[END_REF]. Results with SG are more heterogeneous, with 280 reports showing both lower [START_REF] Friedrich | Laparoscopic sleeve gastrectomy compared to a multidisciplinary weight loss program for obesity--effects on body composition and protein status[END_REF] or no change in prealbumin concentrations [15,[START_REF] Sallé | Zinc deficiency: a frequent and underestimated complication after bariatric surgery[END_REF]. Of note, 281

Moizé et al. reported that 14% of GBP and 16% of SG patients experienced abnormalities in 282 prealbumin concentrations at T12 after BS [14]. As mentioned above, this difference may be 283 due to the systematic prescription of protein supplement in the Hospital Clinic of Barcelona 284 [19,[START_REF] Andreu | Protein intake, body composition, and protein status following bariatric surgery[END_REF]. Adequate protein intake after BS is of utmost importance to prevent the patients from 285 experiencing hair loss, poor wound healing and adverse effects such as infections after skin 286 repair surgery and ultimatelybut rarelyprotein-calorie malnutrition [START_REF] Agha-Mohammadi | Nutritional deficiency of post-bariatric surgery body contouring patients: what every plastic surgeon should know[END_REF][START_REF] Faria | Dietary protein intake and bariatric surgery patients: a review[END_REF] (reviewer #1, 287 comments #5,6&7). 288

Although SG merely restricts the volume of the stomach without intestinal 289 malabsorption [5], it also leads to an accelerated gastric emptying (reviewer #2, comment #4). 290 Subsequently faster gastrointestinal passage might promote nutrient deficiencies [START_REF] Melissas | Sleeve Gastrectomy -A "Food Limiting[END_REF], as 291 observed in a recent study with increased faecal excretion of fatty acids [46], resulting in a 292 state of moderate malabsorption. Furthermore, SG decreases gastric intrinsic factor and 293 gastric acid production, two factors involved in vitamin B-12 and iron absorption. Because 294 most of our patients took the prescribed daily multivitamin and mineral supplements one year 295 after both GBP and SG, few patients experienced nutritional abnormalities (except for 296 25(OH)-vitamin-D3) and there was no difference between the two surgical groups. Our 297 results were consistent with previous data from the literature [14,15]. Conversely, others 298 reported a higher risk of vitamin B-12 and 25(OH)-vitamin-D3 deficiencies after GBP 299 compared to SG [12]. It should be noted that in these three studies, patients undergoing GBP 300 or SG were instructed to take multivitamin and mineral supplements on a daily basis after BS. 301

Another point to take into account, is the risk of developing undesirably high levels of 302 micronutrient concentrations due to the systematic supplementation as was previously 303 reported after SG [7,8,11]. Herein, we only identified one patient with serum thiamin and 304 another with serum ferritin above normal range. Nevertheless, it should be noted that the risk 305 of excessive levels in those studies were mostly observed for vitamin A and B-6, which we 306 did not assess. Altogether, these data highlight the importance to prescribe daily multivitamin 307 and mineral supplements after both GBP and SG at least in the first year, but also to monitor 308 the adherence of the patients to their supplementation. 309 At baseline, the higher prevalence of glucose intolerance in patients undergoing GBP 310 reflects the process of selection for different BS techniques, where GBP is the first choice for 311 patients with T2D or glucose intolerance since it demonstrated its superiority over SG to 312 improve glycemic status post-surgery [35]. We also observed that neither GBP nor SG 313 enabled a significant improvement of HBP in terms of overall prevalence. Nevertheless, both 314 the number of patients treated and the number of treatments per patients tended to decrease 315 after both surgeries, suggesting slight improvement of HBP in this cohort of obese patients 316 with many comorbidities. Nevertheless our data are in accordance with previous studies, 317 which indicated that HBP may not be the best resolved comorbidity after surgery [47,48] 318

(reviewer #1, comment #4). 319
One of the main strengths of our study is the use of a validated web-based method of 320 dietary assessment which allowed us to provide detailed quantification of the food and 321 nutrient intake for each patient [24]. This method allows us to assess the use of multivitamin 322 and mineral supplements and measure adherence of the patients to the supplementation. 323 Although the interventions were not randomized in our study, our participants had 324 comparable clinical characteristics at baseline (except for T2D) and were provided the same 325 systematic supplementation regardless of the surgical procedure. The main limitation 326 concerns the relative small number of patients, especially in the group who completed the one 327 year follow-up (reviewer #1, comment #1). This may have prevented us from detecting 328 changes between FFM loss and low protein intake after both procedures. Future studies with 329 longer follow-up periods and larger sample size are needed to determine how poor dietary 330 habits and nutritional deficiencies correlate with weight maintenance at longer term and with 331 the improvement or resolution of obesity related co-morbidities. We intend to follow this 332 cohort in the second year of their surgery to assess their evolution in terms of nutritional risks 333 and body composition (reviewer #2, comment #7). 334

In conclusion, we observed similar food restriction effects on the nutritional adequacy 335 of the diet in the first year post GBP and SG surgery. We also observed comparable 336 consequences in terms of bioclinical evolution and micronutrient serum concentrations. 337 Altogether, our results advocate for a cautious monitoring of protein intake and a systematic 338 multivitamin and mineral supplementation after both GPB and SGat least in the first year 339 for SG. 340 <12 g/dl N(%) 2 ( 9) 0 (0) 1 ( 5) 1 ( 7) 0 (0) 1 (3) 0 (0) 1 ( 5)

TABLES

Ferritin (μg/l) <30 μg/l N(%)

3 ( 14) 0 (0) 1 ( 5) 1 ( 7) 3 ( 10)

1 (3) 1 (3) 1 (5)
Iron (μmol/l) <9 μmol/l N (%) 4 ( 18) 0 (0) 0 (0) 0 (0) 2 ( 7) 2 ( 7) 0 (0) 1 ( 5)

Transferrin (g/l) >3.1 g/l N(%) Transferrin saturation coefficient (%) 0.21 (0.16-0.26) 0.22 (0.17-0.24) 0.25 (0.19-0.32) 0.24 (0.19-0. Background: Roux-en-Y gastric bypass (GBP) and sleeve gastrectomy (SG) have increased 2 dramatically, potentially increasing the prevalence of nutritional deficiencies. The aim of this 3 study was to analyze the effects of food restriction during the first year after bariatric surgery 4 (BS) on nutritional parameters. 5

3 (14) 2 (9) 2 (9) 1 (7) 3 (10) 0 (0) 1 (3) 0 (0

25(OH)-vitamin-D3 (ng

Methods: 22 and 30 obese patients undergoing GBP and SG were prospectively followed at 6 baseline and three, six and twelve months after BS (N=14 and N=19 at T12). We evaluated 7 food intake and nutrient adequacy (T0, T3, T12), as well as serum vitamins and minerals 8 concentration (T0, T3, T6, T12). 9

Results: At baseline, GBP and SG patients had similar clinical characteristics, food intake, 10 nutrient adequacy and serum concentration. The drastic energy and food reduction led to very 11 low probabilities of adequacy for nutrients similar in both models (T3, T12). Serum analysis 12 demonstrated a continuous decrease in prealbumin during the follow-up, indicating mild 13 protein depletion in 37% and 38% of GBP patients and 57% and 52% of SG patients, 14 respectively at T3 and T12. Conversely, despite the low probabilities of adequacy observed at 15 T3 and T12, systematic multivitamin and mineral supplementation after GBP and SG 16 prevented most nutritional deficiencies. 17

Conclusion: GBP and SG have comparable effects in terms of energy and food restriction, 18

and subsequent risk of micronutrient and protein deficiencies in the first year post BS. Such 19 results advocate for a cautious monitoring of protein intake after GPB and SG and a 20 systematic multivitamin and mineral supplementation in the first year after SG. 21

INTRODUCTION 26

Among the few therapeutic tools to treat morbid obesity, bariatric surgery (BS) 27 appears to be the most effective strategy as demonstrated by its ability to obtain major and 28 sustainable weight loss along with significant improvement of obesity related-comorbidities 29 [1,2]. As a result, the number of interventions has dramatically risen worldwide, and Roux-30 en-Y Gastric Bypass (GBP) and Sleeve Gastrectomy (SG) represented respectively 47% and 31 28% of the 340,000 BS performed in 2011 [3]. Since 2008, SG has emerged to such an extent 32 that it has become the most common procedure in several countries, as is the case in France 33 [3]. Although the two surgical techniques and their mechanisms of action differ, they appear 34 to be equally safe and both induce significant weight loss post-surgery [4]. 35 GBP includes diet restriction as well as the bypass of the proximal part of the jejunum 36 involved in nutrient absorption whereas SG is less invasive and principally restricts the 37 volume of the stomach [5]. Therefore SG, compared to GBP, might be viewed as less likely to 38 exacerbate the risk of micronutrient deficiencies in obese patients who are already prone to 39 such deficiencies before surgery [6]. Nevertheless, some studies have demonstrated a 40 considerably higher prevalence of nutrient deficiencies after SG [7][8][9][10][11]. Others, comparing 41 GBP and SG, found quite similar prevalence after both procedures [12][13][14][15][16]. Although study 42 designs differed, these converging results highlight the importance of daily multivitamin and 43 mineral supplementation after both procedures, at least in the first year for SG, in accordance 44 with the latest US guidelines [17]. While the previously mentioned studies evaluated nutrient 45 deficiencies using serum biomarker concentrations, only very few have evaluated food and 46 nutrient intake after GBP and SG: Freeman et al. evaluated food intake two to four years after 47 surgery [18], Moizé et al. and Coupaye et al. evaluated the overall macronutrient intake 48 during one year after BS but did not quantify micronutrient intake [15,19], and Moizé et al. 49 evaluated macronutrient and some selected mineral intake during five years after BS [14]. 50

Therefore, we aimed to analyze food restriction effects on the nutritional adequacy of 51 the diet, on macro and micronutrient intake evolution as well as their consequences in terms 52 of bioclinical evolution and micronutrient serum level during one year after both GBP and 53

SG. 54 (BMR) was assessed with indirect calorimetry (Deltatrac II monitor, Datex Instrumentarium 75

Corp., Helsinki, Finland) enabling the evaluation of underreporting of dietary intake [23]. 76 77

Dietary data and nutrient intakes 78

At baseline, T3 and T12, patients completed three consecutive web-based 24h dietary 79 records as described elsewhere [24], including two weekdays and one day on the weekend 80 whenever possible. All foods and beverages consumed at breakfast, lunch, dinner and snacks 81 were recorded. Validated photographs enabled patients to estimate portion size for each 82 reported food and beverage item [25]. Patients were also asked to indicate multivitamin and 83 mineral supplements use, specifying the product name and amount, following the nutritional 84 deficiency prevention treatment prescribed for every patient at our center, as described in 85 [26]. This includes supplementation during two weeks before surgery of vitamin D (once 86 4×100,000 IU), thiamin (250 mg/day), and vitamin B-12 (250μg/day). Fifteen days post-GBP 87 and SG, multivitamin and mineral supplements including Azinc "Forme et vitalité"® (two 88 capsules per day, containing 800 μg vitamin A, 1.4mg thiamin, 200 µg folate, 1µg vitamin B-89 12, 120 mg vitamin C, 200 IU vitamin D, 8 mg iron and 15 mg zinc), iron (2×80 mg/ day), 90 vitamin D (800 IU/day), and calcium (1,000mg/day) were started and continued for the first 91 year in both BS procedures. Intake of nutrients derived from food were calculated using an 92 updated version of the French database CIQUAL 2008 [27] which included more than 3,400 93 different food items. Nutrient intakes from multivitamin and mineral supplements were 94 calculated using nutrient profile based on the product name. Ingested foods were categorized 95 into 4 main food groups when possible: (i) fruit and vegetables, (ii) starchy foods, (iii) dairy 96 products, and (iv) meat and fish. The food groups were defined according to the French 97 National Nutrition and Health Program [28] and expressed in servings per day based on 98 standard serving sizes [29]. 99 100

Nutrient adequacy of the diet 101

Nutrient intake adequacy for each patient was calculated using the PANDiet index 102 [30]. Briefly, probability of adequacy for each nutrient was calculated, ranging from 0 to 1, 103 where 1 represents a 100% probability that the usual intake is adequate (i.e. it satisfies the 104 requirement or is not excessive compared to a reference value). According to this definition, 105 the probabilities of adequacy were computed to obtain the Adequacy sub-score (the higher, 106 the better the intake satisfies the nutrient requirements) and the Moderation sub-score (the 107 higher, the less likely the intake is excessive). The PANDiet score is taken as the mean of the 108 Adequacy and Moderation sub-scores, and ranges from 0 to 100; the higher the score, the 109 better the nutrient adequacy of the diet. As reference values, we used French nutritional 110 recommendations for healthy adults or European Union values when specific 111 recommendations were lacking. 112 113

Biochemical analyses 114

Blood samples were collected after an overnight fast to measure biochemical 115 parameters using routine techniques as described [31]. Blood count and iron metabolism 116 markers (i.e. ferritin, iron, transferrin, and saturation coefficient) were assessed using routine 117 care method (nephelemetry, ferrozine colorimetry and immunoturbidimetry respectively). 118

Prealbumin was assessed by immunoturbidimetry. Serum concentrations of 25(OH)-vitamin-119 D3 and parathyroid hormone (PTH) were measured by chemiluminescent assay (310600 120

Liaison XL Diasorin and 11972103 Modular E 170 Roche, respectively), vitamin B-12 and 121 folate were assessed using immunoanalysis ECL sandwich, and thiamin and vitamin B-6 were 122 assessed using HPLC [6]. Vitamin and mineral deficiencies were defined as a result below the 123 lower normal value given by the manufacturer [32]. Secondary hyperparathyroidism was 124 defined as an elevated PTH, above the high normal laboratory value. All measurements were 125 conducted at baseline, T3, T6 and T12 (except for 25(OH)-vitamin-D3, PTH, thiamin, folate 126 and vitamin B-12 at T3, and PTH at T6). 127 128

Statistical analyses 129

Continuous variables are presented as median and interquartile range (IQR) and 130 frequencies as percentages. Mann-Whitney and paired Wilcoxon rank-sum tests were, 131 respectively, used to compare continuous variables between surgical groups and time-points. 132

Chi-squared and McNemar tests were used to compare frequencies between surgical groups 133 and time-points, respectively. An overall α level of 5% was used for statistical tests following 134 Holm-Bonferroni correction. These analyses were conducted on both the patients who 135 completed T3 and T6, and on the patients who completed T3, T6 and T12. Since no 136 significant difference was observed between two groups of patients both at baseline, and 137 during the follow-up at T3 and T6, outcomes are merged when presented on tables and 138 figures. All analyses were performed using Statistical Analysis Systems statistical software 139 package version 9.3 (SAS Institute, Cary, NC, SA). 140 141

RESULTS

142

Clinical characteristics 143

Fifty-two patients were included in this study (22 GBP and 30 SG). All of them 144 completed the first six months follow-up of this study (T3 and T6), and 33 completed the one 145 year follow-up (T3, T6 and T12; 14 GBP and 19 SG). Importantly, the two groups were 146 similar at baseline regarding sex, age, corpulence and body composition (Table 1). Likewise, 147 the severity of obesity related-comorbidities was similar in the two groups, except for glucose 148 intolerance, which was significantly more prevalent in the GBP group (Table 1). 149

As expected, BS induced significant weight loss in both surgical techniques, however 150 GBP led to a significantly greater weight loss at T6 and T12 compared to SG (Table 1). More 151 specifically, the total and appendicular FFM (in kg) significantly decreased at T3 and then 152 stabilized at T6 and T12 in the two groups, while the total and appendicular FM (in kg) 153 significantly decreased along the one year follow-up in the GBP group whereas it 154 significantly decreased until T6 and then stabilized from T6 to T12 in the SG group (Figure 155 1). As a result, body composition significantly improved as demonstrated by changes in the 156 percentage of FFM and FM (Table 1). GBP induced a significant improvement of obesity-157 related comorbidities (except for high blood pressure (HBP)), whereas SG only led to a 158 significant improvement of dyslipidemia at T6 and T12 (Table 1). 159 160

Food and macronutrient intakes 161

At baseline, no difference was observed for energy, food or macronutrient intakes 162 between the two groups (Table 2). The BMR values revealed that patients from both groups 163 underreported their caloric intake by 8%. 164

After both GBP and SG, energy intake drastically decreased at T3 and slightly 165 increased at T12, although not reaching baseline intake levels (significant at all time points, 166 Table 2). These changes in energy intake were explained by a significant decrease in food 167 intake at T3 in the two surgical groups (non-significant for dairy products) and a tendency for 168 a modest increase in food intake at T12 (significant for starchy foods in the SG group, Table 169 2). Total protein intake drastically and significantly decreased at T3 in both groups, and a 170 majority of patients reported protein intake below the recommended value of 60 g/day (85.7% 171 after GBP and 79% after SG, Table 2). Afterwards, total protein intake slightly but 172 significantly increased at T12, although it remained below the baseline levels (Table 2). 173 Furthermore, 61% of the patients reported low dietary protein intake (64% and 58% 174 respectively for GBP and SG groups, Table 2) at T12. No significant changes in 175 macronutrient distribution (total fat, SFA, PUFA and total carbohydrates) were observed 176 during the follow-up in the two groups (T3 and T12, Table 2). Energy, food and 177 macronutrient intakes were not different between the two groups during the follow-up (T3 178 and T12, Table 2). 179 180

Nutrient adequacy of the diet 181

At baseline, neither the PANDiet scores nor the probabilities of nutrient adequacy 182 differed between the two groups (Table 3). Low probabilities of adequacy for protein were 183 observed in both groups compared to the French adult population [30]. 184

After both BS, the percentage of patients taking the prescribed systematic 185 multivitamin and mineral supplements significantly increased, from baseline to T3: 14% 186 versus 77% for GBP and 10% vs. 76.7% for SG, as expected from the recommendations 187 (Table 3). This high adherence was maintained at T12 with 86% and 68% respectively for 188 GBP and SG (Table 3). Due to the supplementation, the global nutrient adequacy of the diet 189 did not drop and rather stabilized along the follow-up (PANDiet score and Adequacy sub-190 score were not significantly different at all time points) and the probability of adequacy for 191 vitamin D was improved (Table 3). Of note, when the global nutrient adequacy of the diet was 192 calculated without taking into account the prescribed supplementation, we found that it 193 drastically decreased at T3 and barely increased at T12 (Supplemental Table 1). However, 194 since the prescribed supplementation neither contains protein, fiber nor phosphorus, lower 195 probabilities of adequacy for these nutrients were observed in both groups at T3 compared to 196 baseline (Table 3). Furthermore, although the probabilities of adequacy for these four 197 nutrients significantly increased at T12 in both groups compared to T3 due to the slight 198 increase in food intake, they remained below the baseline values (except for protein in the 199 GBP group, Table 3). 200

224

DISCUSSION

225

To the best of our knowledge, this is the first study to assess the relationship between 226 food intake, nutrient adequacy of the diet and nutritional biological parameters systematically 227 measured before, three and twelve months after GBP and SG. In this study where the patients 228 had similar clinical characteristics at baseline (except for T2D prevalence), our main findings 229 are: (i) protein intake significantly decreases after both GBP and SG, inducing mild protein 230 depletion in more than a third of the patients one year after both surgical techniques; (ii) even 231 though patients after GBP experienced greater weight loss than after SG, both types of 232 surgery induced similar food restriction effects on the nutritional adequacy of the diet and, 233 (iii) systematic multivitamin and mineral supplementation after SG seems to prevent these 234 nutritional deficiencies, the same way as in GBP in the first year. 235

After one year, we observed that GBP led to significantly greater weight loss 236 compared to SG, in accordance with previous data from the literature, including a large 237 multicenter study [33,34]. Nevertheless, some controversy remains. Indeed other reports show 238 that changes in body weight were similar one year after both GBP and SG [15,19,35], 239 although these were smaller cohorts. We evaluated the evolution of body composition and 240 observed that, in both surgeries, total FFM decreased until three months and then stabilized, 241 whereas total FM displayed a continuous decrease during the follow-up. Our results are 242 consistent with previous reports showing changes in body composition following GBP [22] or 243 SG [START_REF] Bužga | Dietary intake and ghrelin and leptin changes after sleeve gastrectomy[END_REF] as measured by DXA. Our results are also concordant with the only study comparing 244 these outcomes after both sleeve and by-pass [19]. In that study, the continuous weight loss 245 during one year was due to the decrease of total FM, the total FFM being spared after four 246 months [19]. More importantly, we observed that appendicular FFM decreased until three 247 months and then stabilized, whereas appendicular FM continued to decrease throughout the 248 follow-up period in both models. Appendicular FFM represents a better surrogate of muscle 249 mass than total FFM [START_REF] Kim | Total-body skeletal muscle mass: estimation by a new dual-energy X-ray absorptiometry method[END_REF], and this is the first time that this outcome and its evolution have 250 been studied after SG. Interestingly, the change in appendicular FFM was similar in the two 251 surgical procedures. 252

After both BS, we observed that 61% of the patients reported daily protein 253 consumption under the recommended value of 60 g/day at T12 (64% for GBP and 58% for 254 SG). Our results are consistent with those of Andreu et al. and Moizé et al. who found that 255 respectively 37% and 46% of patients had a daily protein intake below 60 g/day one year after 256 BS [19,[START_REF] Andreu | Protein intake, body composition, and protein status following bariatric surgery[END_REF]. In accordance with those findings, we did not find any difference between GBP 257 and SG [START_REF] Andreu | Protein intake, body composition, and protein status following bariatric surgery[END_REF]. We report a prevalence of insufficient protein intake that is nearly 2-fold higher 258 than that reported by Moizé et al. (61% versus 37%), which is mostly attributable to the 259 systematic protein supplementation prescribed by these authors to all of their patients [START_REF] Andreu | Protein intake, body composition, and protein status following bariatric surgery[END_REF]. 260

One objective of recommending a minimal protein intake of 60 g/day after both GBP and SG 261 is to mitigate post-surgical FFM loss in the first months [17]. Indeed, Moizé et al. 262 demonstrated that patients with insufficient protein intake during the follow-up lost more 263 FFM in both SG and GBP than patients with sufficient protein intake [19]. Because skeletal 264 muscle is the primary site of insulin-stimulated glucose disposal during euglycemia [START_REF] Defronzo | The effect of insulin on the disposal of intravenous glucose. Results from indirect calorimetry and hepatic and femoral venous catheterization[END_REF], loss 265 of FFM might contribute to the development of insulin resistance and should be avoided in 266 order to maintain the beneficial metabolic outcomes. An important goal of future long-term 267 follow-up studies will be to determine whether insufficient protein intake following BS might 268 result in loss of muscular strength. Furthermore, longer-term weight stabilization (and regain) 269 should also be assessed in link with the quantity of protein intake. 270

After both BS, we also observed that prealbumin concentration significantly 271 decreased, resulting in more than a third of patients exhibiting mild protein depletion. Our 272 results are in line with the few studies that reported changes in prealbumin concentration after 273 it should be noted that the risk of excessive levels in those studies were mostly observed for 299 vitamin A and B-6, which we did not assess. Altogether, these data highlight the importance 300 to prescribe daily multivitamin and mineral supplements after both GBP and SG at least in the 301 first year, but also to monitor the adherence of the patients to their supplementation. 302 At baseline, the higher prevalence of glucose intolerance in patients undergoing GBP 303 reflects the process of selection for different BS techniques, where GBP is the first choice for 304 patients with T2D or glucose intolerance since it demonstrated its superiority over SG to 305 improve glycemic status post-surgery [35]. We also observed that neither GBP nor SG 306 enabled a significant improvement of HBP in terms of overall prevalence. Nevertheless, both 307 the number of patients treated and the number of treatments per patients tended to decrease 308 after both surgeries, suggesting slight improvement of HBP in this cohort of obese patients 309 with many comorbidities. Nevertheless our data are in accordance with previous studies, 310 which indicated that HBP may not be the best resolved comorbidity after surgery [47,48]. 311 One of the main strengths of our study is the use of a validated web-based method of 312 dietary assessment which allowed us to provide detailed quantification of the food and 313 nutrient intake for each patient [24]. This method allows us to assess the use of multivitamin 314 and mineral supplements and measure adherence of the patients to the supplementation. 315 Although the interventions were not randomized in our study, our participants had 316 comparable clinical characteristics at baseline (except for T2D) and were provided the same 317 systematic supplementation regardless of the surgical procedure. The main limitation 318 concerns the relative small number of patients, especially in the group who completed the one 319 year follow-up. This may have prevented us from detecting changes between FFM loss and 320 low protein intake after both procedures. Future studies with longer follow-up periods and 321 larger sample size are needed to determine how poor dietary habits and nutritional 322 deficiencies correlate with weight maintenance at longer term and with the improvement or 323 resolution of obesity related co-morbidities. We intend to follow this cohort in the second 324 year of their surgery to assess their evolution in terms of nutritional risks and body 325 composition. 326

In conclusion, we observed similar food restriction effects on the nutritional adequacy 327 of the diet in the first year post GBP and SG surgery. We also observed comparable 328 consequences in terms of bioclinical evolution and micronutrient serum concentrations. 329 Altogether, our results advocate for a cautious monitoring of protein intake and a systematic 330 multivitamin and mineral supplementation after both GPB and SGat least in the first year 331 for SG. 332 TABLE 2. Energy, food and macronutrient intakes according to the surgical models at baseline, 3 months and 12 months 1 .

  36. Bužga M, Zavadilová V, Holéczy P, et al. Dietary intake and ghrelin and leptin changes after sleeve gastrectomy. Videosurgery Miniinvasive Tech. 2014 Dec;9(4):554-61. 37. Kim J, Wang Z, Heymsfield SB, et al. Total-body skeletal muscle mass: estimation by a new dual-energy X-ray absorptiometry method. Am J Clin Nutr. 2002 Aug 1;76(2):378-83. 38. Andreu A, Moizé V, Rodríguez L, et al. Protein intake, body composition, and protein status following bariatric surgery. Obes Surg. 2010 Nov;20(11):1509-15. 39. DeFronzo RA, Jacot E, Jequier E, et al. The effect of insulin on the disposal of intravenous glucose. Results from indirect calorimetry and hepatic and femoral venous catheterization. Diabetes. 1981 Dec;30(12):1000-7. 40. Coupaye M, Puchaux K, Bogard C, et al. Nutritional consequences of adjustable gastric banding and gastric bypass: a 1-year prospective study. Obes Surg. 2009 Jan;19(1):56-65. 41. Sallé A, Demarsy D, Poirier AL, et al. Zinc deficiency: a frequent and underestimated complication after bariatric surgery. Obes Surg. 2010 Dec;20(12):1660-70. 42. Friedrich AE, Damms-Machado A, Meile T, et al. Laparoscopic sleeve gastrectomy compared to a multidisciplinary weight loss program for obesity--effects on body composition and protein status. Obes Surg. 2013 Dec;23(12):1957-65. 43. Agha-Mohammadi S, Hurwitz DJ. Nutritional deficiency of post-bariatric surgery body contouring patients: what every plastic surgeon should know. Plast Reconstr Surg. 2008 Aug;122(2):604-13. 44. Faria SL, Faria OP, Buffington C, de Almeida Cardeal M, Ito MK. Dietary protein intake and bariatric surgery patients: a review. Obes Surg. 2011 Nov;21(11):1798-805. 45. Melissas J, Daskalakis M, Koukouraki S, et al. Sleeve Gastrectomy -A "Food Limiting" Operation. Obes Surg. 2008 Jul 29;18(10):1251-6.

  14.0 (10.0-16.0) 13.0 (12.0-17.0) 15.0 (13.0-18.0) 15.0 (12.0-18.0) 15.0 (12.0-22.0) 16.0 (14.0-19.0) 17.0 (13.0-19.0) 16.5 (130-19.0)

)

  33.0-37.0) a 39.0 (36.0-41.0) b 38.0 (36.0-41.0) b 39.0 (37.0-40.0) b 37.0 (35.0-39.0) a 40.0 (37.0-42.0) b 40.0 (38.0-42.0) b 41.0 (38.0-42.0) b <37 g/l N(%)

FIGURE 1 .

 1 FIGURE 1.Changes in body composition in the GBP and SG groups at baseline (T0) and along the follow-up (T3, T6 and T12).

FIGURE 1 .

 1 FIGURE 1.Changes in body composition in the GBP and SG groups at baseline (T0) and along the follow-up (T3, T6 and T12).

Figure 1

 1 Figure 1 Click here to download Figure: Figure1.tif

TABLE 1 .

 1 Anthropometric parameters and clinical characteristics according the surgical models at baseline, 3 months, 6 months and 12 months 1 .(HBP) is defined as a systolic blood pressure >140 mmHg and/or a diastolic blood pressure > 90mmHg or patients with an anti-hypertensive treatment; obstructive sleep apnea (OSA) is defined as an Index Apnea Hypopnea >5/hour with or without treatment.)

	GBP

TABLE 2 .

 2 Energy, food and macronutrient intakes according to the surgical models at baseline, 3 months and 12 months 1 .

	GBP

1

Labeled medians or percentages without a common letter differ between time-points for each surgical model, as tested by paired pairwise post hoc comparisons with Holm-Bonferroni correction or paired McNemar test.

TABLE 3 .

 3 Multivitamin and mineral supplementation, PANDiet scores and probabilities of nutrient adequacy according to the surgical models at baseline, 3 months and 12 months1

	GBP

TABLE 4 .

 4 Metabolic and nutritional parameters according the surgical models at baseline, 3 months, 6 months and 12 months1

	GBP

1

  Labeled medians or percentages without a common letter differ between time-points for each surgical model, as tested by paired pairwise post hoc comparisons with Holm-Bonferroni correction or paired McNemar test.

			GBP			SG
		Baseline	3 months	12 months	Baseline	3 months	12 months
		n=22	n=22	n=14	n=30	n=30	n=19
	Energy and food intakes
	Energy intake, kcal/d	2005 (1539-2266) c 711 (615-1006) a	1226 (8133-1559) b	1658 (1445-2395) c 833 (539-1108) a	1078 (793-1354) b
	BMR, kcal/d	2179 (2005-2409) c 1770 (1702-2072) b 1653 (1480-1791) a	1959 (1853-2218) c 1742 (1593-1894) b 1686 (1565-1963) a
	Fruit and vegetables, serving/d	4.8 (3.2-7.0) b	2.2 (0.8-3.2) a	2.1 (1.5-3.9) ab	3.0 (1.6-4.3) b	1.5 (0.8-2.1) a	1.4 (1.0-2.6) ab
	Starchy foods, serving/d	2.8 (2.1-3.7) b	0.7 (0.3-1.2) a	1.1 (0.8-1.6) a	2.6 (2.1-3.3) c	0.7 (0.3-1.1) a	1.2 (0.7-1.7) b
	Dairy products, serving/d	2.1 (1.3-3.1)	1.7 (0.5-2.6)	2.1 (0.8-2.5)	1.6 (1.0-2.4)	1.4 (0.6-1.9)	1.2 (0.7-1.7)
	Meat and fish, serving/d	1.4 (1.0-2.6) b	0.8 (0.6-1.1) a	0.7 (0.4-1.6) ab	1.6 (1.1-2.5) b	0.9 (0.6-1.4) a	1.0 (0.7-1.8) ab
	Macronutrient intakes
	Protein, g/d

TABLE 3 .

 3 Multivitamin and mineral supplementation, PANDiet scores and probabilities of nutrient adequacy according to the surgical models at baseline, 3 months and 12 months1

	GBP

TABLE 1 .

 1 PANDiet scores and probabilities of nutrient adequacy according to the surgical models at baseline, 3 months and 12 months (calculated from foods only)1

	SUPPLEMENTAL DATA
	SUPPLEMENTAL GBP

Labeled medians or percentages without a common letter differ between time-points for each surgical model, as tested by paired pairwise post hoc comparisons with Holm-Bonferroni correction or paired McNemar test. *Represents significant differences between GBP and SG. Glucose intolerance is defined as either fasting hyperglycemia (1g/l ≤G< 1.26g/l) or 6%≤HBA1c<6.5%); dyslipidemia is defined as a patient with treatment (statin or fibrate) or hypertriglyceridemia ≥1.5g/l or hypoHDL<0.5g/l for women and hypoHDL<0.4g/l for men; High blood pressure

Labeled medians or percentages without a common letter differ between time-points for each surgical model, as tested by paired pairwise post hoc comparisons with Holm-Bonferroni correction or paired McNemar test.

Labeled medians without a common letter differ between time-points for each surgical model, as tested by paired pairwise post hoc comparisons with Holm-Bonferroni correction.

This project is supported by the « Contrat de Recherche Clinique » from Health ministry (CRC Fibrota P100503 -IDRCB 2011-A00759-32, recorded on clinical trial website (NCT: NCT01655017), as well as by the European Union's Seventh Framework Programme for research, technological development and demonstration under grant agreement HEALTH-F4-2012-305312 (Metacardis) and the National Agency of Research (Investissement D'Avenir, ANR-10-IAHU-05). JAW received a grant from Institut Appert and from Nestlé research. The authors declare that they have no conflict of interest. The authors wish to thank Ms Agathe Arlotti for the coordination of programs on bariatric surgery (BARICAN program), Ms Valentine Lemoine for her help in the follow-up of the patients and Dr Florence Marchelli who contributed to clinical and biological database constitution. This project is supported by the « Contrat de Recherche Clinique » from Health ministry (CRC Fibrota P100503 -IDRCB 2011-A00759-32, recorded on clinical trial website (NCT: NCT01655017), as well as by the European Union's Seventh Framework Programme for research, technological development and demonstration under grant agreement HEALTH-F4-2012-305312 (Metacardis) and the National Agency of Research (Investissement D'Avenir, ANR-10-IAHU-05). JAW received a grant from Institut Appert and from Nestlé research. The authors declare that they have no conflict of interest. The authors wish to thank Ms Agathe Arlotti for the coordination of programs on bariatric surgery (BARICAN program), Ms Valentine Lemoine for her help in the follow-up of the patients and Dr Florence Marchelli who contributed to clinical and biological database constitution.

<140 pmol/l N(%) 1 (5) / 1 (5) 0 (0) 1 (3) / 0 (0) 0 (0) 1 Labeled medians or percentages without a common letter differ between time-points for each surgical model, as tested by paired pairwise post hoc comparisons with Holm-Bonferroni correction or paired McNemar test. Normal ranges are as follows: hemoglobin [12][13][14][15][16][17] g/dl; ferritin µg/l; iron [9][10][11][12][13][14][15][16][17][18][19][20][21][22][23][24][25][26][27] μmol/l; transferrin [1.7-3.1] g/l; total iron binding capacity

MATERIAL AND METHODS

56

Patients 57

Obese candidates for either GBP or SG according to the international bariatric surgery 58 guidelines [20] (i.e. body mass index (BMI) ≥40kg/m², or ≥35kg/m² with at least one severe 59 obesity-related comorbidity) were treated in the Obesity Unit of Pitié-Salpetrière Hospital, 60 Institute of Cardio-metabolism and Nutrition, ICAN, Paris, France. Patients determined the 61 choice of technique, and advised by a multidisciplinary panel, from the hospital based on 62 medical history, level of corpulence and obesity-related comorbidity. Weight stable patients 63 were enrolled consecutively in this prospective non-randomized study from January 2012. 64 Hotel-Dieu hospital ethics committee approved the clinical protocol (number P100503 -65 IDRCB 2011-A00759-32) which was recorded on clinical trial website (NCT: 66 NCT01655017). Subjects gave their written informed consent prior to the study inclusion. 67 Medical history and clinical evaluation were obtained at baseline and during the 68 follow-up at three (T3), six (T6) and twelve months (T12) as described elsewhere [21]. 69 Anthropometric parameters were estimated by whole-body fan-beam DXA scanning (Hologic 70 Discovery W, software v12.6, 2; Hologic, Bedford, MA), as previously described [22]. 71

Variables from DXA used in the analyses were total and appendicular fat free mass (FFM, in 72 kg), and total and appendicular fat mass (FM, in kg), where appendicular FFM (or FM) was 73 calculated as the sum of FFM (or FM) from both arms and both legs. Basal metabolic rate 74 Conflict of interest. The authors declare that they have no conflict of interest. <12 g/dl N(%) 2 ( 9) 0 (0) 1 ( 5) 1 ( 7) 0 (0) 1 (3) 0 (0) 1 ( 5)

TABLES

Ferritin (μg/l) <30 μg/l N(%) 3 ( 14) 0 (0) 1 ( 5) 1 ( 7) 3 ( 10 <9 μmol/l N (%) 4 ( 18) 0 (0) 0 (0) 0 (0) 2 ( 7) 2 ( 7) 0 (0) 1 ( 5)

Transferrin (g/l) >3.1 g/l N(%) 3 ( 14) 2 ( 9) 2 ( 9) 1 ( 7) 3 ( 10 >80 µmol/l N(%) 1 ( 5) 2 ( 9) 1 ( 5) 1 ( 7) 2 ( 7) 0 (0) 1 (3) 0 (0)

Transferrin saturation coefficient (%) 0.21 (0.16-0.26) 0.22 (0.17-0.24) 0.25 (0.19-0.32) 0.24 (0.19-0.

Prealbumin (g/l) Vitamin D 0.00 (0.00-0.10) b 0.00 (0.00-0.00) a 0.00 (0.00-0.02) ab 0.02 (0.00-0.30) 0.00 (0.00-0.08) 0.15 (0.00-0.44) Vitamin E 0.29 (0.08-0.89) c 0.00 (0.00-0.00) a 0.00 (0.00-0.03) b 0.18 (0.02-0.44) b 0.00 (0.00-0.01) a 0.13 (0.00-0.39) b Calcium 0.87 (0.07-0.97) b 0.28 (0.00-0.77) a 0.49 (0.07-0.86) a 0.82 (0.43-0.97) b 0.06 (0.00-0.35) a 0.08 (0.00-0.56) a Magnesium 0.00 (0.00-0.00) b 0.00 (0.00-0.00) a 0.00 (0.00-0.00) a 0.00 (0.00-0.00) b 0.00 (0.00-0.00) a 0.00 (0.00-0.00)


J H Salmon
email: jhsalmon@chu-reims.fr

A C Rat
email: ac.rat@chu-nancy.fr

J Sellam

M Michel
email: mmichel@chu-reims.fr

J P Eschard
email: jpeschard@chu-reims.fr

F Guillemin
email: francis.guillemin@chu-nancy.fr

D Jolly
email: djolly@chu-reims.fr

Fautrel

Bruno Pr

Economic impact of lower-limb osteoarthritis worldwide: A systematic review of cost-of-illness studies

Introduction

Many studies have explored the economic burden of rheumatic diseases, mainly inflammatory arthritides and musculoskeletal disorders such as back problems [START_REF] Badley | The economic burden of musculoskeletal disorders in Canada is similar to that for cancer, and may be higher[END_REF][START_REF] Fautrel | Cost of illness studies in rheumatic diseases[END_REF][START_REF] Smith | The global burden of other musculoskeletal disorders: estimates from the Global Burden of Disease 2010 study[END_REF]. OA is the most frequent or prevalent chronic joint disease and a major contributor to functional disability and loss of autonomy in older adults [START_REF] Felson | The incidence and natural history of knee osteoarthritis in the elderly. The Framingham Osteoarthritis Study[END_REF]. According to the World Health Organization in 2010, among 289 diseases, OA has become the 11 th leading cause of years lived with disability, an increase from 16th to 11th within only 10 years [START_REF] Vos | Years lived with disability (YLDs) for 1160 sequelae of 289 diseases and injuries 1990-2010: a systematic analysis for the Global Burden of Disease Study[END_REF]. Moreover, OA has become a research priority in the European Community (Horizon 2020 Framework Programme) (6).

For a long time, OA, corresponding to a whole-joint disease involving cartilage, subchondral bone and synovium, was considered only a consequence of aging [START_REF] Bijlsma | Osteoarthritis: an update with relevance for clinical practice[END_REF]. Hip and knee OA causes the greatest burden to the population in terms of pain, stiffness and disability, thereby leading to the need for prosthetic joint replacement for the most severe cases [START_REF] Litwic | Epidemiology and burden of osteoarthritis[END_REF]. The disease may have various personal, social and economic consequences for patients, their environment and society: reduced productivity or premature exit from the workplace, autonomy loss, need for help, as well as increased healthcare use and sometimes institutionalization [START_REF] Brooks | Impact of osteoarthritis on individuals and society: how much disability? Social consequences and health economic implications[END_REF].

OA prevalence is expected to increase because of several concomitant factors: population growth and aging due to increasing life expectancy, increased overweight and obesity prevalence, and lack of disease-modifying OA drugs able to modify the progression of the disease. Thus, the burden to society is expected to increase substantially, at least for hip or knee replacement surgery [START_REF] Nemes | Projections of total hip replacement in Sweden from 2013 to 2030[END_REF]. In addition, OA prevalence could result in increased cardiovascular morbidity as an indirect consequence of reduced physical activity and increased need for nursing home facilities for the elderly population [START_REF] Bähler | Multimorbidity, health care utilization and costs in an elderly community-dwelling population: a claims data based observational study[END_REF].

The economic consequences of OA need to be investigated, especially those related to hip and knee OA. The present study aimed to provide, via a systematic review of the literature, an

M A N U S C R I P T A C C E P T E D ACCEPTED MANUSCRIPT
overview of the economic consequences -overall costs as well as cost breakdown -of hip and knee OA worldwide.

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

Methods

Research question and literature search

We performed a systematic search of articles in EMBASE, MEDLINE via PubMed, Scopus and Cochrane databases across the period from 1966 to December 2014. We used the Participants, Interventions, Comparisons and Outcomes (PICO) strategy for the research question as follows: population, OA; intervention, analysis of costs of illness; control, different treatments and no treatment OA; and outcome, direct and indirect costs [START_REF]Cochrane Linked Data (beta)[END_REF]. The algorithm used to search article titles, abstracts and key words in EMBASE, MEDLINE and Scopus was ("Osteoarthritis"[Mesh]) AND "Cost of Illness"[Mesh]), (Direct cost AND Osteoarthritis), (Indirect cost AND Osteoarthritis). To optimize our research, we used only one keyword, "osteoarthritis," in the search equation for the Cochrane database.

Article selection

The titles and abstracts of all articles identified were independently screened by 2 rheumatologists (JHS and MM) who used predefined criteria to identify relevant articles; disagreements were resolved by consensus. Articles without an abstract and those in non-English or -French languages were excluded (Figure 1). Abstracts were excluded if 1) OA was not the main subject, 2) no cost data were reported, 3) no primary data were reported (e.g., literature review), 4) data focused only on surgical procedures, and 5) the abstract was from a society meeting before 2012. The full texts of the remaining articles were then retrieved. We excluded articles that had insufficient, imprecise or incomplete data (e.g., indirect costs only, lack of direct cost breakdown).

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

Data extraction

Data extracted were the database (insurance-or clinic-based), sample size (population-based or worker sample) and country of the study; patient demographics (gender, occupation profile [i.e., workers only or not]); and disease characteristics (OA definition [i.e., self-reported or based on American College of Rheumatology (ACR) criteria [START_REF] Altman | The American College of Rheumatology criteria for the classification and reporting of osteoarthritis of the hip[END_REF][START_REF] Altman | Development of criteria for the classification and reporting of osteoarthritis. Classification of osteoarthritis of the knee. Diagnostic and Therapeutic Criteria Committee of the American Rheumatism Association[END_REF]], involved joints, clinical expression and symptom intensity, radiologic features and Kellgren & Lawrence stage).

Costs

All costs were extracted from articles that described assessing them from a payer or societal perspective. Direct costs included medical doctor (MD) visits; hospitalizations, including emergency room visits, imaging or biologic work-up; treatment costs that were drug-related or not; joint replacement surgery; and complementary and alternative medicine use (acupuncturist, herbalist, and osteopathy). In addition, non-medical costs (transport, auxiliary devices and temporary caregivers) were included when available. Indirect costs included all types of productivity loss: temporary or long-term sick leave as well as disability status. Total costs were the sum of direct and indirect costs. With incomplete data, the corresponding author of the article was contacted by email to collect additional relevant information.

Extracted or elicited costs were converted to an annual cost and to 2013 euros (€) by using the Consumer Price Index of the relevant countries and the 2013 Purchasing Power Parities (Organization for Economic Cooperation and Development, www.oecd.org) between these countries and the European Union average (15).

Statistics

Costs are presented as mean ± SD and 95% confidence interval (95% CI). Direct and indirect costs per patient per year were summarized separately across studies and countries. Average

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costs were weighted by study sample size and were used to calculate the overall mean annual costs induced by hip or knee OA.

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Results

Literature search

We obtained 98 article titles with abstracts through the meta-search, and 45 abstracts were selected. The assessment of full texts resulted in 32 articles selected for the review (Figure 1) .

Selected studies

The 32 articles were heterogeneous (Table 1). Data sources were national surveys (n=18), A total of 19 articles estimated the overall OA economic burden without separating OA subtypes (upper limb, lower-limb and spine): 9 reported on only lower-limb OA (knee and/or hip OA) and 4 on general OA, with most lower-limb OA (> 50% [START_REF] Lanes | Resource utilization and cost of care for rheumatoid arthritis and osteoarthritis in a managed care setting: the importance of drug and surgery costs[END_REF][START_REF] Xie | Direct and indirect costs of osteoarthritis in Singapore: a comparative study among multiethnic Asian patients with osteoarthritis[END_REF][START_REF] Gore | Clinical comorbidities, treatment patterns, and direct medical costs of patients with osteoarthritis in usual care: a retrospective claims database analysis[END_REF] and > 60% [START_REF] White | Direct and indirect costs of pain therapy for osteoarthritis in an insured population in the United States[END_REF]). Among these 13 latter articles, the mean age was reported in 9: mean 57 ± 9 years or median 65.8 years (IQR 56.9-69.2). All articles described symptomatic OA patients.

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Cost structure

Overall, 31 articles reported annual direct costs per patient with OA. The reported direct cost categories varied (Table 2). Only 16 articles reported indirect costs. Only 4 studies explicitly stated that the human capital approach had been used to estimate the indirect costs of OA [START_REF] Leardini | Direct and indirect costs of osteoarthritis of the knee[END_REF][START_REF] Salaru | SAT0452 Direct and Indirect Costs of Osteoarthritis the Republic of Moldova[END_REF][START_REF] Woo | Socioeconomic impact of osteoarthritis in Hong Kong: utilization of health and social services, and direct and indirect costs[END_REF][START_REF] Xie | Direct and indirect costs of osteoarthritis in Singapore: a comparative study among multiethnic Asian patients with osteoarthritis[END_REF][START_REF] Koopmanschap | Indirect costs in economic studies: confronting the confusion[END_REF]. Absenteeism was reported in 14 articles, and only 2 described absenteeism and presenteism according to the method of Lofland et al. [START_REF] Dibonaventura | Impact of self-rated osteoarthritis severity in an employed population: cross-sectional analysis of data from the national health and wellness survey[END_REF][START_REF] Dibonaventura M Dacosta | Evaluating the health and economic impact of osteoarthritis pain in the workforce: results from the National Health and Wellness Survey[END_REF][START_REF] Lofland | A review of health-related workplace productivity loss instruments[END_REF].

Cost estimates for all OA

The supplemental table provides a summary of mean annual direct costs per patient (in 2013 €). The annual total cost per patient varied from 0.3 to 19.5 k€/year, direct cost per patient from 0.2 to 15.3 k€/year and indirect cost per patient from 0.05 to 9.4 k€/year. The weighted average annual costs per patient were 0.35, 2.4 and 0.06 k€/year for total, direct and indirect costs, respectively. The study by Levy et al. represented a significant weight because of the number of patients (3,400,000) and was an outlier in terms of cost estimates [START_REF] Levy | Socioeconomic costs of osteoarthritis in France[END_REF], which were far lower than those of other studies. This justified a sensitivity analysis excluding this study to explore the stability of our cost estimates. Consequently, a specific sensitivity analysis was conducted with removal of this paper: the weighted average annual costs per patient were then 8.5, 6.7 and 5.4 k€/year for total, direct and indirect costs, respectively.

Cost estimates for hip and knee OA

Table 3 provides a summary of mean annual direct costs per patient (in 2013 €). After adjustment to 2013 €, annual total costs per patient varied from 0.7 to 12 k€/year, direct costs per patient from 0.5 to 10.9 k€/year and indirect costs per patient from 0.2 to 12.3 k€/year. The weighted average annual costs per patient were 11.1 k€/year, 9.5 k€/year and 4.4 k€/year

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for total, direct (Figure 2a) and indirect costs (Figure 2b), respectively. A sensitivity analysis was conducted because of the substantial weight of the study by Gore et al. (number of patients 112,951) [START_REF] Gore | Clinical comorbidities, treatment patterns, and direct medical costs of patients with osteoarthritis in usual care: a retrospective claims database analysis[END_REF]. The weighted average annual direct cost without the Gore et al. study decreased from 9.5 to 6.8 k€/year (Figure 2a). Direct costs varied according to consideration of surgery. In fact, the weighted average annual direct costs per patient in populations without surgery, with surgery or awaiting surgery were 6.7, 10.8 (3 k€/year without Gore et al.) and 7.4 k€/year, respectively. The impact of the design of the study on costs was important: the weighted average annual total cost per patient was 10 k€/year for hospital-based cohorts (direct cost 2.1 k€/year and indirect cost 5.5 k€/year); 12 k€ for administrative databases (direct cost 10.2 k€/year and indirect cost 4.2 k€/year) and 6.8 k€/year for national surveys (direct cost 6.2 k€/year and indirect cost 6.4 k€/year).

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Discussion

We performed a systematic review of the literature of the economic consequences -overall costs as well as cost breakdown (direct and indirect) -of hip and knee OA worldwide.

Depending on the database and the diagnosis, OA articles reported different cost estimates for the disease, with a multiplication factor of 22-fold (hip and knee OA) and between the lowest and highest estimate. We found a gradient depending on the continent: direct costs in North America were 6.7 k€/year for all OA and 10 k€/year for hip and knee OA.

In Europe, direct costs were 0.7 k€/year and 1 k€/year respectively. This situation can be explained by the higher frequency of obesity and related comorbidities in the United States than in European countries [START_REF] Ng | Global, regional, and national prevalence of overweight and obesity in children and adults during 1980-2013: a systematic analysis for the Global Burden of Disease Study 2013[END_REF]. This is the first systematic review of the literature to specifically focus on the costs of hip and knee OA, which are a major contributor to global disability-adjusted life years [START_REF] Vos | Years lived with disability (YLDs) for 1160 sequelae of 289 diseases and injuries 1990-2010: a systematic analysis for the Global Burden of Disease Study[END_REF]. Puig-Junoy J et al reported recent data on hip and knee osteoarthritis costs [START_REF] Puig-Junoy | Socio-economic costs of osteoarthritis: a systematic review of cost-of-illness studies[END_REF]. However, this paper was a literature review on the cost of osteoarthritis in general, as opposed to a focus on hip and knee osteoarthritis costs in our review. Moreover we have included four new articles [START_REF] Rolfson | Costs related to hip disease in patients eligible for total hip arthroplasty[END_REF][START_REF] Bertin | Annual Cost of Patients with Osteoarthritis of the Hip and Knee in France[END_REF][START_REF] Salaru | SAT0452 Direct and Indirect Costs of Osteoarthritis the Republic of Moldova[END_REF][START_REF] Lapsley | Living with osteoarthritis: patient expenditures, health status, and social impact[END_REF]. The burden to society is expected to be high (prevalence of 10% to 20%) because of the prevalence of symptomatic disease [START_REF] Guillemin | Prevalence of symptomatic hip and knee osteoarthritis: a two-phase population-based survey[END_REF][START_REF] Jordan | Prevalence of knee symptoms and radiographic and symptomatic knee osteoarthritis in African Americans and Caucasians: the Johnston County Osteoarthritis Project[END_REF][START_REF] Jordan | Prevalence of hip symptoms and radiographic and symptomatic hip osteoarthritis in African Americans and Caucasians: the Johnston County Osteoarthritis Project[END_REF][START_REF] Andrianakos | Prevalence of symptomatic knee, hand, and hip osteoarthritis in Greece. The ESORDIG study[END_REF][START_REF] Salaffi | MAPPING) study. Prevalence of musculoskeletal conditions in an Italian population sample: results of a regional community-based study. I. The MAPPING study[END_REF][START_REF] Grotle | Prevalence and burden of osteoarthritis: results from a population survey in Norway[END_REF](59). The costs induced could be as high as 408 to 817 billion €/year and 350 to 700 billion €/year for total and direct costs, respectively, in Europe (59).

Our review highlights the substantial heterogeneity in how the cost of OA has been estimated over the world during the last decades. Several sources of heterogeneity could be mentioned and taken into account when interpreting the results of this review. Variable definitions of hip and knee OA have been used -clinical, radiological or both [START_REF] Guillemin | Prevalence of symptomatic hip and knee osteoarthritis: a two-phase population-based survey[END_REF] Most studies included symptomatic OA patients and only 5 included patients with a diagnosis by radiographic criteria. OA diagnosis was based on ACR criteria [START_REF] Altman | The American College of Rheumatology criteria for the classification and reporting of osteoarthritis of the hip[END_REF][START_REF] Altman | Development of criteria for the classification and reporting of osteoarthritis. Classification of osteoarthritis of the knee. Diagnostic and Therapeutic Criteria Committee of the American Rheumatism Association[END_REF] or sometimes only on self-reported

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information, which is known to feature inadequate sensitivity or specificity as compared with clinical examination for ascertainment [START_REF] Peat | Clinical classification criteria for knee osteoarthritis: performance in the general population and primary care[END_REF]. Actually, from a public health perspective, a diagnosis based on both clinical and radiological features is recommended [START_REF] Guillemin | Prevalence of symptomatic hip and knee osteoarthritis: a two-phase population-based survey[END_REF]. In addition, some authors recently suggested separating OA by phenotypes, reflecting different risk factors, comorbidities and potentially pathogenic pathways [START_REF] Bijlsma | Osteoarthritis: an update with relevance for clinical practice[END_REF][START_REF] Courties | Metabolic stress-induced joint inflammation and osteoarthritis[END_REF]. Comorbidities such as obesity are closely related with lower-limb OA [START_REF] Richmond | Are joint injury, sport activity, physical activity, obesity, or occupational activities predictors for osteoarthritis? A systematic review[END_REF].

We could not assess this new "view" of OA because the reviewed articles did not provide enough details on medical history or comorbidities. However, integrating these phenotypic specificities in future epidemiological and economic analyses will be interesting; such phenotypes could have substantial impact on both functional outcome (health resource use) and loss of autonomy (due to comorbidities), thereby resulting in major differences in cost estimates [START_REF] White | Direct and indirect costs of pain therapy for osteoarthritis in an insured population in the United States[END_REF][START_REF] Berger | Patterns of pharmacotherapy and health care utilization and costs prior to total hip or total knee replacement in patients with osteoarthritis[END_REF][START_REF] Gore | Clinical comorbidities, treatment patterns, and direct medical costs of patients with osteoarthritis in usual care: a retrospective claims database analysis[END_REF].

As another source of heterogeneity, the patient selection method could have affected the results and led to selection bias or recruitment. Populations studied from administrative, hospital and national health survey databases could be substantially different, which questions the external validity of the results. In the same way, different countries or continents are represented by totally different health systems and cultural or genetic backgrounds, which may affect health resource use and productivity loss [START_REF] Xie | Direct and indirect costs of osteoarthritis in Singapore: a comparative study among multiethnic Asian patients with osteoarthritis[END_REF]. The characteristics of OA and the severity of structural damage contribute to the heterogeneity. However, these data are often difficult to assess.

Finally, although some methodological consensus has been reached to determine the reference case for economic assessment in rheumatic diseases [START_REF] Maetzel | Economic evaluation of programs or interventions in the management of rheumatoid arthritis: defining a consensus-based reference case[END_REF][START_REF] Hiligsmann | A reference case for economic evaluations in osteoarthritis: an expert consensus article from the European Society for Clinical and Economic Aspects of Osteoporosis and Osteoarthritis (ESCEO)[END_REF], we lack standardized methods for homogeneous estimates of the economic burden of such diseases. Some costs such as physiotherapy, emergency room visits, and complementary and alternative medicine use are not systematically included in direct cost estimates. Yet, the rates of use and expenditures for

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alternative therapies by adults with OA were high and can underestimate direct costs [START_REF] Ramsey | Use of alternative therapies by older adults with osteoarthritis[END_REF]. Only 4/13 articles of hip and knee OA included surgery in direct costs, even though joint surgery is considered an important cost driver in hip and knee OA (65) because of the costs of the procedure and the increasing use of knee and hip replacement in the recent and coming years [START_REF] Pabinger | Utilization rates of hip arthroplasty in OECD countries[END_REF][START_REF] Kurtz | Projections of primary and revision hip and knee arthroplasty in the United States from 2005 to 2030[END_REF]. This trend could result in a four-fold demand for knee arthroplasty in OECD countries by 2030 [START_REF] Pabinger | Utilization rates of knee-arthroplasty in OECD countries[END_REF]. There are substantial variations in total hip replacement and total knee replacement implant costs within and across hospitals. For example, the average implant cost per case ranged from $1797 to $12,093 for knee and from $2392 to $12,651 for hip [START_REF] Robinson | Variability in costs associated with total hip and knee replacement implants[END_REF].

These differences can be explained by socio-economic determinants and physician prescription patterns, with countries with higher medical expenditures and obesity prevalence having significantly higher utilization rates [START_REF] Pabinger | Utilization rates of knee-arthroplasty in OECD countries[END_REF]. Substantial costs associated with total joint replacement can be balanced by their expected benefits in the medium or long-term; however, their incremental cost effectiveness ratio varies greatly depending on the studies, ranging from $1026 to 28 100/QALY [START_REF] Nwachukwu | Current status of cost utility analyses in total joint arthroplasty: a systematic review[END_REF]. Out-of-pocket costs may be sometimes substantial [START_REF] Kotlarz | Insurer and out-of-pocket costs of osteoarthritis in the US: evidence from national survey data[END_REF][START_REF] Lapsley | Living with osteoarthritis: patient expenditures, health status, and social impact[END_REF]. In addition, costs incurred for caregivers may be included, but only one article provided estimated caregiver costs related to OA [START_REF] Gupta | The economic burden of disabling hip and knee osteoarthritis (OA) from the perspective of individuals living with this condition[END_REF]. Finally, the method commonly used to estimate indirect costs of OA was the human capital approach [START_REF] Leardini | Direct and indirect costs of osteoarthritis of the knee[END_REF][START_REF] Salaru | SAT0452 Direct and Indirect Costs of Osteoarthritis the Republic of Moldova[END_REF][START_REF] Woo | Socioeconomic impact of osteoarthritis in Hong Kong: utilization of health and social services, and direct and indirect costs[END_REF][START_REF] Xie | Direct and indirect costs of osteoarthritis in Singapore: a comparative study among multiethnic Asian patients with osteoarthritis[END_REF], which often maximizes indirect costs as compared with the friction cost method and induces larger variations in the magnitude of indirect costs estimated [START_REF] Xie | The need for standardization: a literature review of indirect costs of rheumatoid arthritis and osteoarthritis[END_REF]. All these elements contribute to the difficulty in providing a clear idea of the costs due to OA [START_REF] Berger | Patterns of pharmacotherapy and health care utilization and costs prior to total hip or total knee replacement in patients with osteoarthritis[END_REF][START_REF] Gore | Clinical comorbidities, treatment patterns, and direct medical costs of patients with osteoarthritis in usual care: a retrospective claims database analysis[END_REF].

Conclusions

Despite unstable estimates due to methodological issues in articles, this review confirmed that hip and knee OA induces substantial costs to society. With the aging of the population and the increasing prevalence of obesity in many developed countries, the economic burden of lower-

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ACCEPTED MANUSCRIPT limb OA could be even higher in the coming years [START_REF] Vos | Years lived with disability (YLDs) for 1160 sequelae of 289 diseases and injuries 1990-2010: a systematic analysis for the Global Burden of Disease Study[END_REF]. Hence, the disease is considered a public health problem and should be a research priority (6). Additional studies are needed to better assess the economic consequences of OA, especially with long-term studies, taking into account disease phenotypes and multimorbidity.

Authors' contributions:

The design of the study was conceived by JHS, BF, and DJ. Data collection, management and analysis were performed by JHS and BF. All authors participated in the interpretation of the results and manuscript writing. All have read and approved the final version of the manuscript for publication.

Funding: None

Conflict of interest: None

  insurance or administrative databases (n=8), convenience sample from hospital-based cohorts (n=5) or a randomized clinical trial (n=1). Sample sizes varied from 70 to 3,400,000. Seventeen studies focused on the presence of comorbidities in OA patients. Studies were conducted in North America (n=19), Europe (n=10), and Australasia (n=3). Periods of publication were 1995-2000 (n=5), 2000-2005 (n=6), 2005-2010 (n=8), and after 2010 (n=13). OA characteristics Most of the articles (n=27) included all types of OA patients, without restriction on age, gender or occupation; 5 focused on workers (< 65 years old). The diagnosis of OA was reported by the patient (n=8) or based on ACR criteria (n=24). In these latter articles, only 5 included radiographic data to assess OA severity based on Kellgren & Lawrence stage. The median patient follow-up was 12 months (interquartile range [IQR] 6-12).

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