Quentin Griseti

Christophe Jacquet

Pierre Sautet

Matthew P Abdel

Sébastien Parratte

Matthieu Ollivier

Jean-Noël Argenson

J-N Argenson

Antimicrobial properties of antibiotic-loaded implants

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.

Results

For MSSA and MRSA, no inhibitory effect was found in the control group, and antibioticloaded smooth titanium alloy beads showed a short inhibitory effect until day 2. For MSSA, both tantalum and 3D porous titanium beads showed significantly larger mean Zois than cement beads (all p < 0.01) each day until day 7 for tantalum and until day 3 for 3D porous titanium. After six days, antibiotic-loaded cement had significantly larger mean ZOIs than the 3D porous titanium (p = 0.027), but no significant difference was found with tantalum (p = 0.082). For MRSA, both tantalum and 3D porous titanium beads had significantly larger mean Zois than antibiotic-loaded cement each day until day 6 for tantalum (all p < 0.01) and until day 3 for 3D porous titanium (all p < 0.04). Antibiotic-loaded cement had significantly larger mean ZOIs than tantalum and 3D porous titanium from day 7 to 9 (all p < 0.042). conclusion These results show that porous metal implants can deliver local antibiotics over slightly varying time frames based on in vitro analysis. introduction prosthetic joint infection (pJi) remains the main cause of failure in primary and revision total knee arthroplasty (tKa). [START_REF] Parvizi | Proceedings of the International Consensus on periprosthetic joint infection[END_REF][START_REF] Parvizi | International consensus group on periprosthetic joint infection. Definition of periprosthetic joint infection[END_REF] local delivery of antibiotics, mainly using antibiotic-loaded bone cement, [START_REF] Bishop | Vancomycin elution, activity and impact on mechanical properties when added to orthopedic bone cement[END_REF] is commonly used in the management of pJi. over the past decade, tantalum [START_REF] Jenkins | Minimum five-year outcomes with porous tantalum acetabular cup and augment construct in complex revision total hip arthroplasty[END_REF][START_REF] Flecher | Use of porous tantalum components in Paprosky two and three acetabular revision. A minimum five-year follow-up of fifty one hips[END_REF] and porous titanium [START_REF] Denehy | Metaphyseal Fixation Using Highly Porous Cones in Revision Total Knee Arthroplasty: Minimum Two Year Follow Up Study[END_REF][START_REF] Sultan | Cementless 3D printed highly porous titanium-coated baseplate total knee arthroplasty: survivorship and outcomes at 2year minimum follow-up[END_REF] have been successfully used as metaphyseal devices to address bone loss and improve biological fixation at revision tKa. as their use involves a decrease in the amount of antibiotic-loaded cement required at the surgical site, previous authors have investigated the antimicrobial properties of intrinsic [START_REF] Schildhauer | Bacterial adherence to tantalum versus commonly used orthopedic metallic implant materials[END_REF][START_REF] Tokarski | Is tantalum protective against infection in revision total hip arthroplasty?[END_REF] and/or artificially created antibiotic-loaded porous materials. [START_REF] Sautet | Antibiotic-loaded tantalum may serve as an antimicrobial delivery agent[END_REF][START_REF] Sautet | Vancomycin elution kinetics from porous tantalum metal[END_REF] in two previous studies we have shown that tantalum does not have any intrinsic antimicrobial properties but is able to deliver vancomycin in both liquid and solid environments. [START_REF] Sautet | Antibiotic-loaded tantalum may serve as an antimicrobial delivery agent[END_REF][START_REF] Sautet | Vancomycin elution kinetics from porous tantalum metal[END_REF] To date, no study has examined the antimicrobial properties of antibiotic-loaded 3d-printed porous titanium (3dt) and compared it with bone cement. the aim of this study was to compare the ability of tantalum, 3dt, antibiotic-loaded cement, and smooth titanium alloy to inhibit staphylococci in an in vitro environment, based on the evaluation of the zone of inhibition (Zoi) and the duration of antibacterial activity. The hypothesis was that there would be no significant difference in the inhibition of methicillin-sensitive (mssa) or methicillin-resistant Staphylococcus aureus (mrsa) between the two groups.

Methods

in order to study the antibacterial properties of various alloys, ten 3d-printed porous titanium (tritanium; stryker, mahwah, new Jersey, usa) cylinders (1 cm 3 , 4 g mean pore size 400 to 500 μm porosity of 55% to 65%), ten trabecular metal (Tantalum; Zimmer-biomet, Warsaw, indiana, usa) cylinders (1 cm 3 , 4 g mean pore size 400 μm to 500 μm, porosity 75% to 80%) and ten smooth titanium alloy (ti-6al-4v eli alloy; medtronic, dublin, ireland) cylinders (1 cm 3 , 4 g) were supplied by the manufacturers. as we aimed to reproduce 'clinical implants', all cylinders were created using the same protocol as those used to design augments, sleeves, or cones used at arthroplasty. all cylinders were sterilized by the manufacturers and shipped in individual packages.

ten antibiotic-loaded cement cylinders measuring 1 cm 3 (palacos; Heraeus Kulzer GmbH, Wehrheim, Germany) were constructed as a control group. the preparation of the cylinders was standardized using identical sterile moulds, filled with sterilized and prepackaged cement. in particular, one 40 g batch of polymethylmethacrylate (pmma) was used to which 1 g of vancomycin powder was added. cement and vancomycin were mixed using a dedicated vacuum (Palamix; Heraeus Kulzer GmbH, Wehrheim, Germany) and following the recommendations of the supplier; 20 ml of liquid monomer was then added and mixed for 60 seconds. While still doughy, loaded cement preparations were used to fill dedicated moulds and create ten 1 cm 3 beads. soaking solutions were prepared by dissolving and diluting the antibiotics as follows: 1 g of vancomycin (sandoz; Holzkirchen, Germany) in 20 ml of sterile water (pH 5.5, osmolarity 0 mosmol/l) for injection (cdm lavoisier, paris, france), resulting in a concentration of 50 mg/ml. then, each cylinder was soaked in an individual beaker with antibiotic solution for one hour at room temperature. samples were tested for mssa and mrsa inhibition using a medium diffusion bioassay as previously described. [START_REF] Sautet | Antibiotic-loaded tantalum may serve as an antimicrobial delivery agent[END_REF][START_REF] Sautet | Vancomycin elution kinetics from porous tantalum metal[END_REF] each specimen (metal and cement cylinders) was placed using sterile forceps on an agar plate inoculated with either mssa or mrsa, and then incubated at 37 °c for 24 hours. each cylinder was withdrawn daily and put on a new agar plate to simulate a new bacterial agents' attack. this step was repeated each day until no antibiotic activity was found. all manipulations were performed under a hood. each day, the antibiotic Zoi was recorded with diameters measured in millimetres using a digital vernier caliper and with an automated computed evaluation (scan 1200-interscience, saint-nom-la-bretèche, france), to assess intra-and interobserver reproducibility. the diameter of the porous tantalum and cement cylinders was subtracted from the total Zoi (figure 1). in order to assess reproducibility the measurements of the Zois were repeated twice by the same observer (intraobserver) and compared with automatic measurement (interobserver). High-definition photographs of each sample were made every day. The intraclass correlation coefficients (ICCs) indicated a nearly perfect intra-and interobserver reproducibility for the measurement of ZOI (ICC 0.96 IC 95% [0.93 to 1] and ICC 0.98 IC 95% [0.96 to 1], respectively). Statistical analysis. Parameters of interest were expressed as mean and SD. Differences between groups were evaluated using a non-parametric (Wilcoxon signed-rank) test due to our sample size. based on previously reported Zois of antibioticloaded cement, our sample size was sufficient to distinguish differences > 3 mm with an expected standard deviation of 2 mm and a statistical power > 90%. 12

Results

For MSSA and MRSA, no inhibitory effect was found in antibiotic-loaded smooth titanium alloy, having a short inhibitory effect until day 2 only. for mssa, both tantalum and 3dt beads had statistically significantly larger mean ZOIs than cement beads (all p < 0.01) each day until day 7 for tantalum and until day 3 for 3dt (figure 2). After six days, antibiotic-loaded cement had a larger mean ZOI than 3DT (p = 0.027), but no significant difference was found with tantalum (p = 0.082) until no inhibitory effect occurred at day 12 (table i and figure 3).

for mrsa, both tantalum and 3dt beads had statistically significantly larger mean ZOIs than antibiotic-loaded cement each day until day 6 for tantalum (all p < 0.01) and until day 3 for 3DT (all p < 0.04) (figure 2). antibiotic-loaded cement had larger mean Zois than tantalum and 3dt between day 7 and 9 (all p < 0.04) but not after nine days, until no inhibitory effect occurred at day 12 (table ii and figure 4).

Discussion

The hypothesis of our study was confirmed. First, porous implants can deliver antibiotics to a surgical site; secondly, this ability provided tantalum implants with an antibacterial potential equivalent to that of antibiotic-loaded cement in the treatment of mssa; thirdly, for both tantalum and 3dt this antibacterial potential was substantial but less than that of antibiotic-loaded cement in the treatment MRSA; and finally, tantalum-loaded cylinders inhibited staphylococcal adhesion for a longer period than 3d-printed and antibiotic-loaded porous titanium implants. since porous metal implants are increasingly being used at revision tHa and tKa, local antibiotics delivered using the simple soaking process described in this study might play a role in mitigating the risk of pJi. However, an advantage of local antibiotics is that they can be administered at much higher concentrations than is achievable parenterally, without the associated systemic toxicity. [START_REF] Bishop | Vancomycin elution, activity and impact on mechanical properties when added to orthopedic bone cement[END_REF][START_REF] Chen | Antibiotic-loaded bone cement and periprosthetic joint infection[END_REF][START_REF] Hanssen | Local antibiotic delivery systems: where are we and where are we going?[END_REF][START_REF] Valle | Effective bactericidal activity of tobramycin and vancomycin eluted from acrylic bone cement[END_REF] antibiotics may also be delivered in this way into avascular areas which are inaccessible using parenteral antibiotics. [START_REF] Hanssen | Practical applications of antibiotic-loaded bone cement for treatment of infected joint replacements[END_REF][START_REF] Cierny | Infected tibial nonunions (1981-1995). The evolution of change[END_REF] these data allow us to believe that future antibiotic-loaded porous constructs will help surgeons decrease the rates of infection and reinfection in revision tKa. [START_REF] Kokko | A retrieval analysis perspective on revision for infection[END_REF] this study has limitations. the in vitro model of the in vivo release of antibiotics from porous tantalum and antibioticloaded cement only approximated to the behavior of vancomycin released into synovial fluid. The diffusion medium does not fully represent the complex in vivo environment and we only evaluated the antimicrobial properties of vancomycinsoaked porous implants on nearby staphylococci. thus, we cannot draw conclusions about a more distant effect or about local antibiotic pharmacokinetics. secondly, we were unable to determine the exact concentration of vancomycin on the cylinders before they were placed on the agar plates. We assumed that each cylinder was soaked in an identical solution containing the same amount of vancomycin (50 mg/ml). thirdly, the process described in this study is an off-label use of both porous implants and vancomycin powder. We did not investigate the potential deleterious effects of the integration of vancomycin implants on bone ingrowth. further study focusing on the ideal timing of the soaking period is needed to evaluate the concentration/dose effect of a more clinically relevant length of time (five to 15 minutes).

We, however, think that this method is robust. it has been validated in one of our previous studies. [START_REF] Sautet | Antibiotic-loaded tantalum may serve as an antimicrobial delivery agent[END_REF] all measurements were done using manual and automated methods to enhance the precision of our data collection. as most of the methodological part of the study follows the previously validated protocol, we did not include control cylinders. We have previously shown that tantalum has no intrinsic properties which inhibit bacterial adhesion. [START_REF] Sautet | Antibiotic-loaded tantalum may serve as an antimicrobial delivery agent[END_REF] Han et al [START_REF] Han | Porous titanium scaffolds with self-assembled micro/ nano-hierarchical structure for dual functions of bone regeneration and anti-infection[END_REF] were the first to investigate the microarchitectural advantages of a porous metal alloy, using chitosan-coated bovine serum albumin nanoparticles and oxidized alginate in a layer-by-layer manner fixed on porous titanium scaffolds. They showed that the nanostructures of their specimens were able to deliver growth factors and antibacterial agents (vancomycin) in a liquid environment. their methods are promising even if the engineering and manufacturing of specimens may not easily be used clinically. following this initial discovery of the properties of a porous alloy a few authors have investigated the antimicrobial properties of antibiotic-loaded implants. chang et al [START_REF] Chang | In vitro activities of daptomycin-, vancomycin-, and teicoplanin-loaded polymethylmethacrylate against methicillin-susceptible, methicillin-resistant, and vancomycin-intermediate strains of Staphylococcus aureus[END_REF] described an in vitro study of antibiotic-loaded cement prepared from 1 g of vancomycin per 40 g of pmma for inhibition of MSSA. They reported a two-day antibacterial effect, but their protocol was based on dilution bioassay. using the same analysis yuenyongviwat et al [START_REF] Yuenyongviwat | Inhibitory effects of vancomycin and fosfomycin on methicillin-resistant Staphylococcus aureus from antibiotic-impregnated articulating cement spacers[END_REF] reported inhibitory effects of vancomycin-loaded cement on mrsa adhesion for four weeks. These results contrast with our maximal 12-day inhibition for antibiotic-loaded cement. first, the concentrations of vancomycin in the three protocols were different (4 g vancomycin for one articulating spacer vs 1 g for all our cylinders). We thought that only a drop of antibiotic could inhibit bacteria on as small a surface as an agar plate. We preferred to use a solid loaded implant that could be used to treat staphylococci on a solid medium, day after day. We believe that this protocol permits closer estimations of in vivo conditions.

We estimated, with a method similar to this study protocol, antimicrobial properties of tantalum cylinders and antibioticloaded cement [START_REF] Sautet | Antibiotic-loaded tantalum may serve as an antimicrobial delivery agent[END_REF] . We found that porous tantalum cylinders inhibited mssa for up to 12 days, whereas cement cylinders inhibited mssa for nine days. porous tantalum cylinders had statistically significantly larger mean ZOIs than the antibioticloaded cement each day until day 11. these results are similar to those in this further study for the first ten days. Antibioticloaded cement cylinders, however, inhibited mssa adhesion for a longer period in this study. We think that this difference might be explained by the method which we used in this study to mix vancomycin with cement in a dedicated vacuum. recently, Gergely et al [START_REF] Gergely | Towards the optimization of the preparation procedures of PMMA bone cement[END_REF] highlighted the advantages in terms of antibiotic and cement distribution in the final product using vacuumed cement preparation. as such, the equal distribution of antibiotics in all cylinders might have positively affected the duration of antimicrobial inhibition described in this study.

Finally, if porous implants exhibited antibacterial properties similar to those of antibiotic-loaded cement when treating mssa, vancomycin-loaded cement allowed longer antimicrobial potential than tantalum and 3dt when treating mrsa. This three-day difference might be clinically detrimental and an additional study should be conducted using a higher soaking concentration and/or different antibiotics.

in conclusion, we found that porous metal implants can deliver local antibiotics over slightly varying time frames based on in vitro analysis. antibiotic-loaded tantalum and 3dt constructs showed superior antimicrobial properties when compared with smooth titanium alloy. future goals include impregnating porous metals with antibiotics for intraoperative use during revision tKa.

Fig. 2 a

 2 Fig. 2 a) Zone of inhibition (ZOI) analysis (Day 7) regarding vancomycinloaded specimens and methicillin-resistant Staphylococcus aureus. b) ZOI analysis (Day 7) regarding vancomycin-loaded specimens and methicillin-sensitive S. aureus. 3DT, 3D-printed porous titanium; ALBC, Antibiotic-loaded bone cement.

Fig. 1 Measurement

 1 Fig. 1 Measurement of the zone of inhibition. The calculation is based on the following equation: ZOI = Raw ZOI (blue circle) -specimen's diameter (green circle).

Table i .

 i Mean ZOI (mm) measured every day on a new agar plate inoculated with methicillin-sensitive Staphylococcus aureus.

	Material	J1	J2	J3	J4	J5	J6	J7	J8	J9	J10	J11	J12
	Tantalum (SD)	32.6 (1.47) 23.8 (0.69) 22.62	17.02	16.50	11.88	9.56 (7.21) 6.14 (6.63) 0	0	0	0
				(2.95)	(5.31)	(3.14)	(7.58)
	3DT (SD)	32.94	22.7 (2.08) 17.04	11.7 (1.92) 10.9 (2.15) 1.96	1.18 (2.63) 0	0	0	0	0
		(5.29)		(2.21)			(4.38)
	STA (SD)	30.3 (4.52) 0)	0	0	0	0	0	0	0	0	0	0
	ALBC (SD)	20.33 (0.8) 14.92	14.04	10.98	10.4 (3.24) 14.46	8.66 (6.12) 4.64 (4.24) 4.2 (6.6) 1.02 (2.28) 1.74 (3.89) 1.20 (2.68)
			(2.38)	(4.92)	(1.12)		(5.72)
	*DT, 3D-printed porous titanium; ALBC, Antibiotic-loaded bone cement; STA, smooth titanium alloy.
			Fig. 3
	Zone of inhibition analysis regarding methicillin-sensitive
	Staphylococcus aureus adhesion. 3DT, 3D-printed porous titanium;
	ALBC, Antibiotic-loaded bone cement; STA, smooth titanium alloy.

Zone of inhibition analysis relating to methicillin-resistant Staphylococcus aureus adhesion. 3DT, 3D-printed porous titanium; ALBC, Antibiotic-loaded bone cement; STA, smooth titanium alloy.


Ragna C Jonker

W A H Loes

Bart C H Van Beers

H Van Der Wal

Sebastien Charles Vogely

René M Parratte

Rudolf W Castelein

Poolman

Loes W A H Van Beers

Bart C H Van Der Wal

H Charles Vogely

Sebastien Parratte

René M Castelein

Rudolf W Poolman

Can dual mobility cups prevent dislocation without increasing revision rates in primary total hip arthroplasty? A systematic review

Keywords:

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

Introduction

Total hip arthroplasty (THA) for end-stage osteoarthritis of the hip is one of the most successful orthopedic surgical procedures. It treats pain, improves function and thereby increases quality-oflife [START_REF] March | Outcomes after hip or knee replacement surgery for osteoarthritis. A prospective cohort study comparing patients' quality of life before and after surgery with age-related population norms[END_REF]. However, dislocation is the leading cause for early revision surgery after THA [START_REF] Bozic | The epidemiology of revision total hip arthroplasty in the United States[END_REF]. Most dislocations occur during the first year after surgery, of which approximately half within the first three months after surgery [START_REF] Hailer | The risk of revision due to dislocation after total hip arthroplasty depends on surgical approach, femoral head size, sex, and primary diagnosis[END_REF][START_REF] Meek | Epidemiology of dislocation after total hip arthroplasty[END_REF][START_REF] Phillips | Incidence rates of dislocation, pulmonary embolism, and deep infection during the first six months after elective total hip replacement[END_REF]. Hip dislocation is a major problem that results in reduced functioning and a deterioration in quality-of-life [START_REF] Enocson | Quality of life after dislocation of hip arthroplasty: a prospective cohort study on 319 patients with femoral neck fractures with a one-year follow-up[END_REF]. After a first dislocation, there is an increased chance that the THA will re-dislocate again, with rates reported up to 60% [START_REF] Martinot | Course of dislocated posterior hip arthroplasty: a continuous 232-patient series at a mean 10 years' follow up (range, 1-22 years)[END_REF][START_REF] Kotwal | Outcome of treatment for dislocation after primary total hip replacement[END_REF][START_REF] Yuan | Dislocation after total hip arthroplasty[END_REF]. In addition to the negative consequences for a patient, dislocations also increase healthcare costs. For an uncomplicated single dislocation, these costs were estimated at 19% of total hospital costs, when revision surgery was required these costs increased up to 148% [START_REF] Abdel | The functional and financial impact of isolated and recurrent dislocation after total hip arthroplasty[END_REF][START_REF] Sanchez-Sotelo | Hospital cost of dislocation after primary total hip arthroplasty[END_REF].

To address the problem of dislocation, Gilles Bousquet developed the dual mobility (DM) cup in France in the 1970s [START_REF] Batailler | The evolution of outcomes and indications for the dual-mobility cup: a systematic review[END_REF]. This design is a combination of the low friction arthroplasty by Sir John Charnley [START_REF] Charnley | The long-term results of low-friction arthroplasty of the hip performed as a primary intervention[END_REF] and a large diameter head by Mac Kee [START_REF] Burroughs | Range of motion and stability in total hip arthroplasty with 28-, 32-, 38-, and 44-mm femoral head sizes: an in vitro study[END_REF]. The DM cup consists of two articulations between three different components; a metallic acetabular shell, a mobile polyethylene liner and a femoral head. The mobile liner articulates both with the acetabular shell and the femoral head. This should provide more stability and biomechanically reduce the risk of dislocation [START_REF] Bouchet | Posterior approach and dislocation rate: a 213 total hip replacements case-control study comparing the dual mobility cup with a conventional 28-mm metal head/polyethylene prosthesis[END_REF][START_REF] Boyer | Primary total hip arthroplasty with dual mobility socket to prevent dislocation: a 22-year follow-up of 240 hips[END_REF][START_REF] Philippot | The use of a dualarticulation acetabular cup system to prevent dislocation after primary total hip arthroplasty: analysis of 384 cases at a mean follow-up of 15 years[END_REF]. Dislocation rates reported for the DM cup range from 0 to 3.6% [START_REF] Boyer | Primary total hip arthroplasty with dual mobility socket to prevent dislocation: a 22-year follow-up of 240 hips[END_REF][START_REF] Philippot | The use of a dualarticulation acetabular cup system to prevent dislocation after primary total hip arthroplasty: analysis of 384 cases at a mean follow-up of 15 years[END_REF][START_REF] Caton | A comparative and retrospective study of three hundred and twenty primary Charnley type hip replacements with a minimum follow up of ten years to assess wether a dual mobility cup has a decreased dislocation risk[END_REF][START_REF] Darrith | Outcomes of dual mobility components in total hip arthroplasty: a systematic review of the literature[END_REF][START_REF] Fresard | Seven-year results of a press-fit, hydroxyapatite-coated double mobility acetabular component in patients aged 65 years or older[END_REF][START_REF] Prudhon | Dual mobility cup: dislocation rate and survivorship at ten years of follow-up[END_REF], which seems slightly lower than the 0.5 to 6% reported for the standard, unipolar (UP) cups [START_REF] Bourne | The dislocating hip: what to do, what to do[END_REF][START_REF] Dargel | Dislocation following total hip replacement[END_REF][START_REF] Jolles | Posterior versus lateral surgical approach for total hip arthroplasty in adults with osteoarthritis[END_REF][START_REF] Lachiewicz | Low early and late dislocation rates with 36-and 40-mm heads in patients at high risk for dislocation hip[END_REF][START_REF] Malkani | Early-and late-term dislocation risk after primary hip arthroplasty in the medicare population[END_REF]. Also, the use of DM cups for revision surgery in patients with recurrent dislocation has shown promising results [START_REF] Hailer | The risk of revision due to dislocation after total hip arthroplasty depends on surgical approach, femoral head size, sex, and primary diagnosis[END_REF][START_REF] Langlais | Dual mobility cemented cups have low dislocation rates in THA revisions[END_REF][START_REF] Philippot | Prevention of dislocation in total hip revision surgery using a dual mobility design[END_REF]. Internationally, DM cups are used widely for revision surgery [START_REF] Guyen | Use of a dual mobility socket to manage total hip arthroplasty instability[END_REF][START_REF] Simian | Dual mobility cup in revision total hip arthroplasty: dislocation rate and survival after 5 years[END_REF][START_REF] Vasukutty | The double-mobility acetabular component in revision total hip replacement: the United Kingdom experience[END_REF] and as primary THA in patients at high risk for dislocation [START_REF] Vasukutty | A double mobility acetabular implant for primary hip arthroplasty in patients at high risk of dislocation[END_REF][START_REF] Hernigou | Dual-mobility or constrained liners are more effective than preoperative bariatric surgery in prevention of THA dislocation[END_REF]. In France, DM cups are used in an estimated 30% of all primary THAs [START_REF] Epinette | Cost-effectiveness model comparing dual-mobility to fixed-bearing designs for total hip replacement in France[END_REF]. In the Netherlands, DM cups are mostly used in case of specific patient characteristics, such as cognitive impairment, neuromuscular diseases or as a standard procedure for revision surgeries due to recurrent dislocations [START_REF] Bloemheuvel | Dual mobility cups in primary total hip arthroplasties: trend over time in use, patient characteristics, and mid-term revision in 3,038 cases in the Dutch Arthroplasty Register (2007-2016)[END_REF]. These characteristics might negatively affect the risk for dislocation and revision surgery compared to the general THA population. Potential disadvantages of DM cups are known to include; increased liner wear [START_REF] Gaudin | Equivalent wear performance of dual mobility bearing compared with standard bearing in total hip arthroplasty: in vitro study[END_REF], loosening [START_REF] Philippot | Intraprosthetic dislocation: a specific complication of the dual-mobility system hip[END_REF][START_REF] Farizon | Results with a cementless alumina-coated cup with dual mobility. A twelve-year follow-up study[END_REF] and intra prosthetic dislocation (IPD) [START_REF] Philippot | Intraprosthetic dislocation: a specific complication of the dual-mobility system hip[END_REF][START_REF] Fabry | Intra-prosthetic dislocation of dual-mobility cups after total hip arthroplasty: potential causes from a clinical and biomechanical perspective[END_REF]. These disadvantages may result in revision surgery at longer follow-up. However, when used for revision surgery, there seems to be a significantly lower re-revision rate for the DM cup at 5 years of follow-up [START_REF] Bloemheuvel | Lower 5-year cup re-revision rate for dual mobility cups compared with unipolar cups: report of 15,922 cup revision cases in the Dutch Arthroplasty Register (2007-2016)[END_REF]. Higher implant costs in several countries compared with many conventional UP cup implants [START_REF] Mendenhall | Orthopedic Network News Editorial[END_REF] are of topic, but a systematic review of Rudy et al. [START_REF] Rudy | Cost-effectiveness of dual mobility and a value-based algorithm of utilization[END_REF] states that DM cups are cost-effective.

Despite the increased and, in some countries, extensively use of DM cups, high quality evidence of their effectiveness is lacking [START_REF] Darrith | Outcomes of dual mobility components in total hip arthroplasty: a systematic review of the literature[END_REF]. There are a few well-conducted literature reviews, but the level of evidence of the included studies is moderate to low and the rates of revision were not specifically investigated. These studies did not make a distinction between case-control and registry studies, which is important because dislocations resolved by closed reduction will be missed in registry studies with revision as endpoint. Some of these reviews report on outcomes of the DM cup in revision surgery [START_REF] Levin | Modern dual-mobility cups in revision total hip arthroplasty: a systematic review and meta-analysis[END_REF][START_REF] Faldini | How to prevent dislocation after revision total hip arthroplasty: a systematic review of the risk factors and a focus on treatment options[END_REF], or included patients with femoral neck fractures [START_REF] Romagnoli | The efficacy of dual-mobility cup in preventing dislocation after total hip arthroplasty: a systematic review and meta-analysis of comparative studies[END_REF]. There are also reviews that did not make a direct comparison between the DM cup and UP cup [START_REF] Batailler | The evolution of outcomes and indications for the dual-mobility cup: a systematic review[END_REF][START_REF] Darrith | Outcomes of dual mobility components in total hip arthroplasty: a systematic review of the literature[END_REF][START_REF] Levin | Modern dual-mobility cups in revision total hip arthroplasty: a systematic review and meta-analysis[END_REF][START_REF] Faldini | How to prevent dislocation after revision total hip arthroplasty: a systematic review of the risk factors and a focus on treatment options[END_REF][START_REF] Romagnoli | The efficacy of dual-mobility cup in preventing dislocation after total hip arthroplasty: a systematic review and meta-analysis of comparative studies[END_REF][START_REF] Pituckanotai | Risk of revision and dislocation in single, dual mobility and large femoral head total hip arthroplasty: systematic review and network meta-analysis[END_REF][START_REF] Reina | Dual-mobility constructs in primary and revision total hip arthroplasty: a systematic review of comparative studies[END_REF][START_REF] Martino | Dislocation following total hip arthroplasty using dual mobility acetabular components a systematic review[END_REF][START_REF] Martino | Early intraprosthetic dislocation in dual-mobility implants: a systematic review[END_REF], particularly regarding the rate of revision. Therefore, the aim of this study was to perform a systematic review of the literature to investigate whether there is a difference in the rate of dislocations and revisions after primary THA for degenerative diagnoses, between a DM cup or a UP cup.

Methods

Search strategy and selection criteria

We performed a systematic review of literature in order to identify articles reporting ondislocation rates in both DM cups and UP cups for patients undergoing primary THA. We conducted a literature search of the PubMed, Embase and Cochrane databases in July 2019. To improve the search quality, a medical librarian assisted in the literature search. The search terms in PubMed for [Title/Abstract] were (((dual OR double) AND mobility) OR mobile bearing OR tripolar) AND hip. In Embase the search included: 1. dual mobility OR double mobility OR tripolar OR mobile bearing / 2. dislocat* / 3. hip / 4: 1 + 2 + 3. In Cochrane we searched for: (((dual OR double) AND mobility) OR tripolar OR mobile bearing) AND dislocat* AND hip (in title, abstract & keywords).

Inclusion criteria for our review were:

• Patients receiving a primary THA, due to a degenerative diagnosis (e.g. osteoarthritis, necrosis of the femoral head, rheumatoid arthritis, dysplasia) • DM cup used as an intervention • UP cup used as a control • Dislocation and/or revision described as outcome There was no selection in time period. Studies published in English or French were eligible for inclusion in this review. To gain reliable results on dislocation rates, we set a minimum follow-up period of 6 months. Exclusion criteria included the use of the DM cup in revision or trauma surgery primarily and reports of the same patient cohorts in different journals.

Two authors (RJ and LvB) performed all data screening and data extraction, using the mentioned selection criteria. Both reviewers screened the full-text articles of the papers found eligible in the first round. In case of different opinions, consensus was reached by discussion between both reviewers. Included articles were divided into two groups; case-control studies and registry studies.

Methodological quality assessment

We used Methodological Index for Non-randomized Studies (MINORS) to assess methodological quality [START_REF] Slim | Methodological Index for non-randomized studies(MINORS): development and validation of a new instrument[END_REF]. This validation index was developed to determine the quality of observational and non-randomized studies. Two investigators (RJ and LvB) independently assessed the quality of each study, scoring the 12-item scale. In case of discussion, a third investigator (NW) was consulted. An item was scored as '0 when not reported, '1 when it was inadequately reported, and '2 when it was adequately reported, with a maximum and ideal score of 24 for comparative studies. This systematic review conforms with the PRISMA guidelines [START_REF] Moher | Preferred reporting items for systematic review and meta-analysis protocols (PRISMA-P) 2015 statement[END_REF] and was registered at Prospero (registry number CRD42018091921).

Statistics

For descriptive statistics, we used totals, means and medians. Statistical analyses were performed using SPSS version 21. A test for normality was performed. With normally distributed data, an independent t-test was performed and the 95% confidence interval (CI) was given. In case of no normality, a Mann-Whitney-U test was used and the interquartile range (IQR) was given. A p value < 0.05 was considered significant.

Results

Study selection

The initial search identified 702 articles, of which, after screening for title, abstract and full-text, a total of eight articles met our inclusion criteria and were eligible for inclusion in this systematic review [START_REF] Bouchet | Posterior approach and dislocation rate: a 213 total hip replacements case-control study comparing the dual mobility cup with a conventional 28-mm metal head/polyethylene prosthesis[END_REF][START_REF] Caton | A comparative and retrospective study of three hundred and twenty primary Charnley type hip replacements with a minimum follow up of ten years to assess wether a dual mobility cup has a decreased dislocation risk[END_REF][START_REF] Bloemheuvel | Dual mobility cups in primary total hip arthroplasties: trend over time in use, patient characteristics, and mid-term revision in 3,038 cases in the Dutch Arthroplasty Register (2007-2016)[END_REF][START_REF] Epinette | Clinical outcomes. survivorship and adverse events with mobilebearings versus fixed-bearings in hip arthroplasty-A prospective comparative cohort study of 143 ADM versus 130 Trident cups at 2 to 6-year follow-up[END_REF][START_REF] Homma | Benefit and risk in short term after total hip arthroplasty by direct anterior approach combined with dual mobility cup[END_REF][START_REF] Rowan | Dual-mobility vs fixed-bearing total hip arthroplasty in patients under 55 years of age: a single-institution, matched-cohort analysis[END_REF][START_REF] Tarasevicius | Short-term outcome after total hip arthroplasty using dual-mobility cup: report from Lithuanian Arthroplasty Register[END_REF][START_REF] Kreipke | Dual mobility cups: effect on risk of revision of primary total hip arthroplasty due to osteoarthritis[END_REF] (Fig. 1).

Study characteristics and methodological quality assessment

The eight articles we included were published between 2011 and 2019, with a reported surgery period from 1995 to 2016. Five of the included articles were case-control studies of which three were single surgeon reports published by French authors [START_REF] Bouchet | Posterior approach and dislocation rate: a 213 total hip replacements case-control study comparing the dual mobility cup with a conventional 28-mm metal head/polyethylene prosthesis[END_REF][START_REF] Caton | A comparative and retrospective study of three hundred and twenty primary Charnley type hip replacements with a minimum follow up of ten years to assess wether a dual mobility cup has a decreased dislocation risk[END_REF][START_REF] Epinette | Clinical outcomes. survivorship and adverse events with mobilebearings versus fixed-bearings in hip arthroplasty-A prospective comparative cohort study of 143 ADM versus 130 Trident cups at 2 to 6-year follow-up[END_REF]. The two other case-control studies were single center studies from Japan [START_REF] Homma | Benefit and risk in short term after total hip arthroplasty by direct anterior approach combined with dual mobility cup[END_REF] and the United States of America [START_REF] Rowan | Dual-mobility vs fixed-bearing total hip arthroplasty in patients under 55 years of age: a single-institution, matched-cohort analysis[END_REF]. We included three registry studies reporting on dislocation of the DM cup [START_REF] Bloemheuvel | Dual mobility cups in primary total hip arthroplasties: trend over time in use, patient characteristics, and mid-term revision in 3,038 cases in the Dutch Arthroplasty Register (2007-2016)[END_REF][START_REF] Tarasevicius | Short-term outcome after total hip arthroplasty using dual-mobility cup: report from Lithuanian Arthroplasty Register[END_REF][START_REF] Kreipke | Dual mobility cups: effect on risk of revision of primary total hip arthroplasty due to osteoarthritis[END_REF]. Head size differed from 22.2 mm to ≥ 38 mm 2).

No meta-analysis was performed, because there was too much dissimilarity in the methodology of the studies, resulting in clinical and methodological heterogeneity.

Case-control studies: dislocation and revision rates

A total of 1.198 hips were included, of which 549 were DM cups and 649 were UP cups (Table 3). Mean age at surgery was 68.2 years for the DM cups and 65.9 years for the UP cups. Follow-up differed from a minimum of 6 months up to 10 years. Only one dislocation was reported for the DM cup group (0.2%), in contrast to 46 reported dislocations for the UP cup group (7.1%) (p = 0.009, IQR = 0.00-7.00). The overall revision rate was nine (1.6%) in the DM group and 39 (6.0%) in the UP group (p = 0.046, CI = -16.93-5.73). All cause revisions reported in the DM group were for aseptic loosening (cup; n = 1, stem; n = 3, total; n = 4), periprosthetic fracture (n = 4) and groin pain (n = 1). All cause revisions for the UP group were for instability (n = 30), aseptic loosening (cup; n = 2, stem; n = 3, both; n = 1, total; n = 6), infection (n = 2) and periprosthetic fracture (n = 1). Overall cup revision rate (aseptic cup loosening, dislocation and groin pain) for the DM cup was two (0.4%) and 33 (5.1%) for the UP cup (p = 0.081, IQR = 0.00-3.25).

Registry studies: revision for dislocation and overall revision rates

A total of 223.297 hips were included, of which 5.935 were DM cups and 217.362 were UP cups (Table 4). Mean age at surgery was 71.4 years for the DM cups and 69.1 years for the UP cups. The median follow-up time differed from 2.5 to 3.2 years. The overall revision rate was 161 (2.7%) in the DM group and 3.332 (1.5%) in the UP group (p = 0.275, IQR = 41.00-866.25). There were 14 revisions for dislocation reported in the DM cup group (8.7%) and 1.093 reported in the UP cup group (32.8%) (p = 0.050, IQR = 3.50-293.25).

Discussion

Dislocation remains one of the most common complications of THA. Risk factors for dislocation can be patient-related, procedurerelated or implant-related. Because patient related factors cannot be changed, investigation on procedure-related or implant-related factors have been a topic of research. This systematic review presents an overview of literature comparing the results of dislocation and revision rates between two principally different types of acetabular components for primary THA; the DM cup and the UP cup. Key findings of this systematic review are a lower rate of dislocation and lower rate of revision surgery for dislocation in DM cups, when used in primary THA, based on level 3 quality of evidence.

The case-control studies of this systematic review, reported only one [START_REF] Caton | A comparative and retrospective study of three hundred and twenty primary Charnley type hip replacements with a minimum follow up of ten years to assess wether a dual mobility cup has a decreased dislocation risk[END_REF] dislocation (0.2%) for the DM cup and 46 dislocations (7.1%) for the UP cup. Although research has shown that the use of a larger femoral heads may provide more stability and thereby reduce the risk of dislocation [START_REF] Burroughs | Range of motion and stability in total hip arthroplasty with 28-, 32-, 38-, and 44-mm femoral head sizes: an in vitro study[END_REF][START_REF] Sikes | Instability after total hip arthroplasty. Treatment with large femoral heads vs constrained liners[END_REF][START_REF] Howie | Large femoral heads decrease the incidence of dislocation after total hip arthroplasty: a randomized controlled trial[END_REF][START_REF] Berry | Effect of femoral head diameter and operative approach on risk of dislocation after primary total hip arthroplasty[END_REF], three out of five case-control studies used heads of 28 mm or smaller for the UP cup [START_REF] Bouchet | Posterior approach and dislocation rate: a 213 total hip replacements case-control study comparing the dual mobility cup with a conventional 28-mm metal head/polyethylene prosthesis[END_REF][START_REF] Caton | A comparative and retrospective study of three hundred and twenty primary Charnley type hip replacements with a minimum follow up of ten years to assess wether a dual mobility cup has a decreased dislocation risk[END_REF][START_REF] Epinette | Clinical outcomes. survivorship and adverse events with mobilebearings versus fixed-bearings in hip arthroplasty-A prospective comparative cohort study of 143 ADM versus 130 Trident cups at 2 to 6-year follow-up[END_REF]. Caton et al. [START_REF] Caton | A comparative and retrospective study of three hundred and twenty primary Charnley type hip replacements with a minimum follow up of ten years to assess wether a dual mobility cup has a decreased dislocation risk[END_REF] in particular reported a high rate of dislocation (12.1%) with the use of small size 22.2 mm heads in this group, operated with a posterolateral approach. In contrast, Homma et al. [START_REF] Homma | Benefit and risk in short term after total hip arthroplasty by direct anterior approach combined with dual mobility cup[END_REF], reported only on one dislocation in their UP group, using 32 mm (n = 46) and 36 mm (n = 14) heads and a direct anterior approach. Despite their great benefits on stability and range-of-motion, a potential disadvantage of a large femoral head in combination with a thin polyethylene liner may be the increased risk of liner fracture [START_REF] Moore | Early failure of a cross-linked polyethylene acetabular liner. A case report[END_REF] and wear [START_REF] Johnson | Short-term wear evaluation of thin acetabular liners on 36-mm femoral heads[END_REF]. However, specifically in newer, highly crosslinked polyethylene DM liners, no implications of high failure rates due to wear have been reported [START_REF] Adam | Dual articulation retentive acetabular liners and wear: surface analysis of 40 retrieved polyethylene implants[END_REF][START_REF] Loving | Wear performance evaluation of a contemporary dual mobility hip bearing using multiple hip simulator testing conditions[END_REF][START_REF] Netter | Effect of microseparation and third-body particles on dual-mobility crosslinked hip liner wear[END_REF]. Another factor that could have contributed to the low rate of dislocation reported by Homma et al. [START_REF] Homma | Benefit and risk in short term after total hip arthroplasty by direct anterior approach combined with dual mobility cup[END_REF], may be the direct anterior approach. Although, various studies have shown benefits of the direct anterior approach on dislocation rate [START_REF] Sheth | Anterior and anterolateral approaches for THA are associated with lower dislocation risk without higher revision risk[END_REF][START_REF] Tsukada | Lower dislocation rate following total hip arthroplasty via direct anterior approach than via posterior approach: five-year-average follow-up results[END_REF], a systematic review of Higgens et al. [START_REF] Higgins | Anterior vs. posterior approach for total hip arthroplasty, a systematic review and meta-analysis[END_REF] did not confirm any clear superiority on dislocation compared to the well known posterior approach.

Rates of revision surgery in the case-control studies also seem to be considerably lower in the DM cup group; 1.6% versus 6.0%. In the UP cup group, 30 out of 39 (76.9%) revisions were performed for recurrent instability. Despite the fact that this large share may probably be due to a selection bias for articles reporting on dislocation rates, other studies confirm that instability in UP cups is one of the most common reasons for revision surgery [START_REF] Bozic | The epidemiology of revision total hip arthroplasty in the United States[END_REF][START_REF] Hailer | The risk of revision due to dislocation after total hip arthroplasty depends on surgical approach, femoral head size, sex, and primary diagnosis[END_REF].

In contrast to the case-control studies, the registry studies showed higher rates of revision surgery for the DM cup. Whereas dislocation (32.8%) is the leading reason for revision of UP cups, infection (29.8%) seems to be a common reason for revision of DM cups. Literature on the relation between DM cups and revision for infection is not consistent and based on observational data [START_REF] Reina | Infection as a cause of primary total hip arthroplasty revision and its predictive factors[END_REF][START_REF] Prudhon | Is dual mobility associated with an increased risk of revision for infection? Matched cohort of 231 cases of dual-mobility cups and 231 fixed cups[END_REF].

Because DM cups are regularly used in frail patients at risk for dislocation, this risk of infection and overall increased rate of revision surgery in DM cups is probably due to confounding for patient characteristics and co-morbidities. Patient characteristics reported by Bloemheuvel et al. [START_REF] Bloemheuvel | Dual mobility cups in primary total hip arthroplasties: trend over time in use, patient characteristics, and mid-term revision in 3,038 cases in the Dutch Arthroplasty Register (2007-2016)[END_REF] confirm this suspicion, with an ASA-score of three and four in 31% in the DM cup group, compared to only 13% in the UP cup group. The DM cup is becoming increasingly utilized worldwide. It is regularly selected in revision surgery to treat instability [START_REF] Guyen | Use of a dual mobility socket to manage total hip arthroplasty instability[END_REF][START_REF] Simian | Dual mobility cup in revision total hip arthroplasty: dislocation rate and survival after 5 years[END_REF][START_REF] Vasukutty | The double-mobility acetabular component in revision total hip replacement: the United Kingdom experience[END_REF] and at present often used as primary THA in patients at high risk for dislocation [START_REF] Vasukutty | A double mobility acetabular implant for primary hip arthroplasty in patients at high risk of dislocation[END_REF][START_REF] Hernigou | Dual-mobility or constrained liners are more effective than preoperative bariatric surgery in prevention of THA dislocation[END_REF][START_REF] Fessy | What are the risk factors for dislocation in primary total hip arthroplasty? A multicenter casecontrol study of 128 unstable and 438 stable hips[END_REF]. Since the DM cup was already developed in the 1970s, many long-term results of case series with DM cups in primary THA have been published [START_REF] Boyer | Primary total hip arthroplasty with dual mobility socket to prevent dislocation: a 22-year follow-up of 240 hips[END_REF][START_REF] Philippot | The use of a dualarticulation acetabular cup system to prevent dislocation after primary total hip arthroplasty: analysis of 384 cases at a mean follow-up of 15 years[END_REF][START_REF] Fresard | Seven-year results of a press-fit, hydroxyapatite-coated double mobility acetabular component in patients aged 65 years or older[END_REF][START_REF] Prudhon | Dual mobility cup: dislocation rate and survivorship at ten years of follow-up[END_REF][START_REF] Farizon | Results with a cementless alumina-coated cup with dual mobility. A twelve-year follow-up study[END_REF][START_REF] Philippot | Survival of cementless dual mobility socket with a mean 17 years follow-up[END_REF]. To our knowledge, there are only a few other systematic reviews reporting on the DM cup [START_REF] Batailler | The evolution of outcomes and indications for the dual-mobility cup: a systematic review[END_REF][START_REF] Darrith | Outcomes of dual mobility components in total hip arthroplasty: a systematic review of the literature[END_REF][START_REF] Rudy | Cost-effectiveness of dual mobility and a value-based algorithm of utilization[END_REF][START_REF] Levin | Modern dual-mobility cups in revision total hip arthroplasty: a systematic review and meta-analysis[END_REF][START_REF] Faldini | How to prevent dislocation after revision total hip arthroplasty: a systematic review of the risk factors and a focus on treatment options[END_REF][START_REF] Romagnoli | The efficacy of dual-mobility cup in preventing dislocation after total hip arthroplasty: a systematic review and meta-analysis of comparative studies[END_REF][START_REF] Pituckanotai | Risk of revision and dislocation in single, dual mobility and large femoral head total hip arthroplasty: systematic review and network meta-analysis[END_REF][START_REF] Reina | Dual-mobility constructs in primary and revision total hip arthroplasty: a systematic review of comparative studies[END_REF][START_REF] Martino | Dislocation following total hip arthroplasty using dual mobility acetabular components a systematic review[END_REF][START_REF] Martino | Early intraprosthetic dislocation in dual-mobility implants: a systematic review[END_REF]. A network meta-analysis of four different bearings was performed by Pituckanotai et al. [START_REF] Pituckanotai | Risk of revision and dislocation in single, dual mobility and large femoral head total hip arthroplasty: systematic review and network meta-analysis[END_REF] in which all preoperative diagnoses were included for both primary THA and revision surgery. Batailler et al. [START_REF] Batailler | The evolution of outcomes and indications for the dual-mobility cup: a systematic review[END_REF], Martino et al. [START_REF] Martino | Dislocation following total hip arthroplasty using dual mobility acetabular components a systematic review[END_REF], Darrith et al. [START_REF] Darrith | Outcomes of dual mobility components in total hip arthroplasty: a systematic review of the literature[END_REF] Rudy et al. [START_REF] Rudy | Cost-effectiveness of dual mobility and a value-based algorithm of utilization[END_REF] Reina et al. [START_REF] Reina | Dual-mobility constructs in primary and revision total hip arthroplasty: a systematic review of comparative studies[END_REF] and Levin et al. [START_REF] Levin | Modern dual-mobility cups in revision total hip arthroplasty: a systematic review and meta-analysis[END_REF] reported on outcomes of the DM cup in primary THA and revision surgery. However, no direct comparison between the primary THA with both DM cup and UP cup was made. Faldini et al. [START_REF] Faldini | How to prevent dislocation after revision total hip arthroplasty: a systematic review of the risk factors and a focus on treatment options[END_REF] only reported on revisions. Romagnoli et al. [START_REF] Romagnoli | The efficacy of dual-mobility cup in preventing dislocation after total hip arthroplasty: a systematic review and meta-analysis of comparative studies[END_REF] included patients with femoral neck fractures and revision surgery. De Martino et al. [START_REF] Martino | Dislocation following total hip arthroplasty using dual mobility acetabular components a systematic review[END_REF] excluded French language articles. De Martino et al. [START_REF] Martino | Early intraprosthetic dislocation in dual-mobility implants: a systematic review[END_REF] only reported on patients with early IPD.

There are some limitations applying to this study. Only eight articles met our inclusion criteria for comparing results of the DM cup to the UP cup. Although, the DM cup was already developed in France in the 1970s, we did not find any French comparative studies before 2011. Looking at the results of the MINORS-criteria, ranging from 11 to 16 points, the methodological quality of the included articles may be rated as medium to low depending on the cut-off points [START_REF] Grisar | Autogenous transalveolar transplantation of maxillary canines: a systematic review and meta-analysis[END_REF][START_REF] De Boer | Cancer survivors and unemployment: a meta-analysis and meta-regression[END_REF]. Furthermore, we need to make two substantive remarks on the included studies. First, we must note that 24 stem revisions in the study of Rowan et al. [START_REF] Rowan | Dual-mobility vs fixed-bearing total hip arthroplasty in patients under 55 years of age: a single-institution, matched-cohort analysis[END_REF] were excluded (Table 3), because of a specific stem-type complication. This specific stem was only used in the DM group and because of the potential risk of fretting and corrosion at the modular neck junction, voluntarily recalled by its own manufacturer [START_REF] Meftah | Early corrosion-related failure of the Rejuvenate modular total hip replacement[END_REF][START_REF] Nawabi | Comprehensive analysis of a recalled modular total hip system and recommendations for management[END_REF]. Secondary, we must note that there may be a selection bias by differences in population selection of the registry studies. Bloemheuvel et al. [START_REF] Bloemheuvel | Dual mobility cups in primary total hip arthroplasties: trend over time in use, patient characteristics, and mid-term revision in 3,038 cases in the Dutch Arthroplasty Register (2007-2016)[END_REF] reported on their entire study population, whereas Tarasevicius et al. [START_REF] Tarasevicius | Short-term outcome after total hip arthroplasty using dual-mobility cup: report from Lithuanian Arthroplasty Register[END_REF] chose an implant selected control group and Kreipke et al. [START_REF] Kreipke | Dual mobility cups: effect on risk of revision of primary total hip arthroplasty due to osteoarthritis[END_REF] a sex, age, component fixation and year of surgery matched control group. Results of this systematic review suggests lower rates of dislocation and lower rates of revision for dislocation in favor of the DM cups. However, because included studies were of medium to low methodological quality, no clear conclusion on the use of DM cups for primary THA can be drawn. Therefore, level 1 studies (randomized controlled trials) should be conducted to confirm the results of the current literature.

Conclusion

This systematic review assed dislocation and revision rates of DM cups compared to UP cups in primary THA for degenerative diagnosis in five case-control studies and three registry studies. The case-control studies reported overall lower rates of dislocation and revision for DM cups. However, this finding is not confirmed in the registry studies, which may be due to biased, patient specific indication, for using DM cups. Though rates of revision for dislocation in DM cups seem considerably lower in the registry studies. Further research is necessary to evaluate the possible advantages using a DM cup in patients with hip osteoarthritis.

Disclosure of interest

The authors declare that they have no competing interest. The research department of the OLVG received grant from Link and Lima, unrelated to this work.

Funding

Fig. 1 .

 1 Fig. 1. Flowchart of study selection procedure.

Table 1

 1 Study characteristics of included studies.

	Author	Year	Country	Type of study	Surgery period	Pre-operative diagnoses	Approach	Implant head size
	Bouchet et al. [15]		France	Retrospective case-control,	DM: 2005-2007	DM: osteoarthritis (n = 95), trauma (n = 4),	Posterolateral	DM: not specified
				single center, One surgeon	UP: 2003-2005	osteonecrosis (n = 3), other (n = 3)		UP: 28 mm
						UP: osteoarthritis (n = 100), osteonecrosis
						(n = 8)
	Caton et al. [18]		France	Retrospective case-control,	04/2000-09/2002	DM: osteoarthritis (n = 95), osteonecrosis	Posterolateral	DM: 22.2 mm
				one surgeon		(n = 6), fracture (n = 4)		UP: 22.2 mm
						UP: osteoarthritis (n = 209), osteonecrosis
						(n = 2), rheumatoid arthritis (n = 4)
	Epinette et al. [52]		France	Prospective comparative	02/2007-12/2011	DM: osteoarthritis (n = 134), osteonecrosis	Posterolateral	DM: 28 mm
				cohort study. One surgeon		(n = 7), other (n = 2)		UP: 28 mm
						UP: osteoarthritis (n = 111), osteonecrosis
						(n = 12), other (n = 7)
	Homma et al. [53]		Japan	Retrospect case-control,	DM: ?/2013-01/2015	DM: osteoarthritis (n = 41), osteonecrosis	Direct anterior	DM: not specified
				single centre. Age matched	UP: 10/2011-?/2013	(n = 3), fracture (n = 14), other (n = 2)		UP: 32 mm (n = 46)
				control group		UP: osteoarthritis (n = 55), osteonecrosis (n = 2),		and 36 mm (n = 14)
						fracture (n = 3)
	Rowan et al. [54]		United States of	Retrospective matched	DM: 12/2011-12/2013		Posterolateral	DM: 22.2 mm
			America	case-control, single center	UP: 02/2007-06/2014			(n = 9) and 28 mm
								(n = 127)
								UP: 28 mm (n = 13),
								32 mm (n = 90) and
								36 mm (n = 33)
	Tarasevicius et al. [55]		Lithuania	Retrospective registry	01/2011-12/2014	DM: osteoarthritis (n = 371), fracture (n = 138),	DM: posterolateral (n = 573)	DM: not specified
				study of the Lithuanian		rheumatoid arthritis (n = 4), hip dysplasia	and anterolateral (n = 47)	UP: 28 mm
				Arthroplasty Register		(n = 16), post-traumatic osteoarthritis (n = 22),	UP: posterolateral (n = 2.074)
				(LAR). DM systems		osteonecrosis (n = 40), other (n = 29)	and anterolateral (n = 96)
				compared to the Exeter		UP: osteoarthritis (n = 1.614), fracture (n = 365),
				cemented system		rheumatoid arthritis (n = 6), hip dysplasia
						(n = 38), post-traumatic osteoarthritis (n = 50),
						osteonecrosis (n = 88), other (n = 9)
	Kreipke et al. [56]		Denmark	Retrospective registry	1995-2013	DM: all osteoarthritis	DM: posterolateral (n = 2.162)	DM: not specified
				study of the Nordic		UP: all osteoarthritis	and anterolateral or other	UP: 28 mm, 32 mm
				Arthroplasty Register			(n = 115)	or 36 mm (not
				Association (NARA).			UP: posterolateral (n = 1.905)	specified)
				Matched cohort			and anterolateral or other
							(n = 372)
	Bloemheuvel et al. [35]		Netherlands	Retrospective registry	2007-2016	DM: osteoarthritis (n = 1.688), fracture	DM: posterolateral (n = 2.607),	DM: 22-28 mm
				study of the Dutch		(n = 424), late posttraumatic (n = 406), other	anterior (n = 96), anterolateral	(not specified)
				Arthroplasty Register		(n = 476)	(n = 41), direct lateral (n = 254),	(n = 2.784)
				(LROI)		UP: osteoarthritis (n = 185.062), fracture	other (n = 9)	UP: 22-28 mm
						(n = 7.065), late posttraumatic (n = 4.415),	UP: posterolateral	(n = 66.703), 32 mm
						Other (n = 14.163)	(n = 128.275), anterior	(n = 93.619), 36 mm
							(n = 21.102), anterolateral	(n = 4.002),
							(n = 15.801), direct lateral	≥ 38 mm (n = 1.452)
							(n = 44.249), other (n = 706)

DM: osteoarthritis (n = 106), dysplasia (n = 11), osteonecrosis (n = 10), inflammatory arthritis (n = 3), trauma (n = 3), other (n = 3) UP: osteoarthritis (n = 111), dysplasia (n = 11), osteonecrosis (n = 9), inflammatory arthritis (n = 4), trauma (n = 1) DM = dual mobility, UP = unipolar.

Table 2

 2 Quality assessment of non-randomised studies, using MINORS[START_REF] Slim | Methodological Index for non-randomized studies(MINORS): development and validation of a new instrument[END_REF] criteria. Quality evaluation criteria* Bouchet 2011 Caton 2014 Epinette 2015 Homma 2016 Rowan 2017 Tarasevicius 2017 Kreipke 2019 Bloemheuvel 2019 The items are scored 0 (not reported), 1 (reported but inadequate) or 2 (reported and adequate). The global ideal score being 16 for non-comparative studies and 24 for comparative studies.

	Clearly stated aim	2	2	1	2	2	2	2	2
	Inclusion of consecutive	2	2	0	1	1	2	2	2
	patients
	Prospective collection of data	0	0	1	0	0	1	0	0
	Endpoints appropriate to the	2	2	1	2	2	2	2	2
	study aim
	Unbiased assessment of the	0	0	0	0	0	0	0	0
	study endpoint
	Appropriate follow-up period 2	2	2	1	2	1	2	2
	Loss to follow-up less than 5% 0	1	2	0	0	0	0	0
	Prospective calculation of the	0	0	0	0	0	0	0	0
	study size
	Adequate control group	2	2	2	2	2	2	2	2
	Contemporary groups	1	2	2	1	1	2	2	2
	Baseline equivalence	1	1	1	1	1	1	1	1
	Adequate statistical analysis	2	2	1	1	2	2	2	2
	Total	14	16	13	11	13	15	15	15

for the UP cup and was 22.2 mm, 28 mm or not specified for the DM cup (Table

1

). Implants used for the DM cup were; Novea by Serf, Quattro by Lepine, Avantage by Biomet, ADM and MDM by Stryker, Stafit by Zimmer, Saturne by Amplitude, Polarcup by Smith & Nephew, Selexys DS by Mathys and Gyros-cup by Depuy. The mean MINORS score for the assessment of methodological quality was 14 points (58% of ideal score), ranging from 11 to 16 (Table

Table 3

 3 Results of included case-control studies.

	Author	Total	DM cup (n) UP cup (n) Mean age	Mean age	Gender DM	Gender UP	Follow-up	Follow-up	Dislocations	Dislocations	Total	Total	Cup	Cup
		operated			DM cup	UP cup	cup (M/F)	cup (M/F)	DM cup	UP cup	DM cup (n)		UP cup (n)	revisions	revisions	revisions	revisions
		hips (n)			(years)	(years)								DM cup (n)	UP cup (n)	DM cup (n)	UP cup (n)
	Bouchet et al. [15] 213	105	108	76.6	74.2	45/60	52/56	Mean 28 months	Mean 52 months	0		5	0	1	0	1
	Caton et al. [18]	320	105	215	78	70.8	42/63	91/124	Minimum 10 years Minimum 10 years 1	26	2	26	1	23
	Epinette et al. [52] 273	143	130	70.6	65.5	49/87	53/72	Maximum 4.45 years Maximum 6.71 years 0		7	4	9	1	7
	Homma et al. [53] 120	60	60	75.6	74	12/46	7/50	Minimum 6 months Minimum 6 months 0		1	0	1	0	0
	Rowan et al. [54] 272	136	136	48.5	48.4	43/74	48/79	Median 3.2 years	Median 3.4 years	0		7	3 a	2	0	2
	DM = dual mobility, UP = unipolar, M = male, F = female.

a 24 recalled modular femoral stems were excluded because of a specific stem-type complication.

Table 4

 4 Results of included registry studies.

	Author	Total	DM cup (n)	UP cup (n)	Mean age	Mean age	Gender DM	Gender UP	Follow-up	Follow-up	Revisions	Revisions	Total	Total
		operated			DM cup	UP cup	cup (M/F)	cup (M/F)	DM cup	UP cup	for	for	revisions	revisions
		hips (n)			(years)	(years)					dislocation	dislocation	DM cup (n)	UP cup (n)
											DM cup (n)	UP cup (n)
	Tarasevicius et al. [55]	2.790	620	2.170	63.2	68	237/383	787/1.383	Median 2.5 years	Median 2.5 years 4	52	14	86
	Kreipke et al. [56]	4.554	2.277	2.277	75.5	75.5	896/1.381	914/1.363	Median 2.99 years Median 3.2 years 2	24	97	72
	Bloemheuvel et al. [35] 215.953	3.038	212.915	70	69	1.104/1.934 70.144/14.771 Median 3 years	Median 3 years	8	1.017	50	3.174
	DM = dual mobility, UP = unipolar, M = male, F = female.

  Authors Ragna C. Jonker, Bart C.H. van der Wal, H. Charles Vogely, Sebastien Parratte, René M. Castelein and Rudolf W. Poolman did not receive any financing for this study. This systematic review was part of a grant application for a project towards dislocation in total hip arthroplasty. Part of this grant application was to perform a systematic review on this topic. This grant has been approved by the Van Rens Foundation and provides in salary costs for author Loes W.A.H. van Beers. No further funding was received for conducting this systematic review. Ragna C. Jonker; conceptualization and design of the study, methodology, data screening, data extraction, analysis descriptive data, writing and editing original draft. Loes W.A.H. van Beers; conceptualization and design of the study, methodology, data screening, check extracted data, statistical tests, reviewing and editing manuscript. Ragna C. Jonker and Loes W.A.H. van Beers contributed equally to this manuscript and join a first authorship. Bart C.H. van der Wal and Rudolf W. Poolman; conceptualization and design of the study, supervision, validation and reviewing the manuscript. H. Charles Vogely, Sebastien Parratte and René M. Castelein; supervision and validation of the manuscript.

	Author's contribution

Acknowledgement

We would like to thank the medical librarian that helped with the literature search: B. Berenschot (OLVG, Amsterdam). We also would like to thank Dr. N. Willigenburg (OLVG, Amsterdam) for helping with the assessment of the methodological quality.


Christophe Jacquet

Pierre Laumonerie

Sally Liarno

Ahmad Faizan

Akash Sharma

Louis Dagneaux

Matthieu Ollivier
email: ollivier.matthieu@yahoo.fr

Contralateral preoperative templating of lower limbs' mechanical angles is a reasonable option

Keywords: Mechanical axis, Lower limb, Asymmetry, Contralateral templating

Introduction

Preoperative templating is often used prior to total knee arthroplasty (TKA) and knee osteotomies [START_REF] Arnal-Burró | Three dimensional-printed patient-specific cutting guides for femoral varization osteotomy: do it yourself[END_REF][START_REF] Jaffry | Unicompartmental knee arthroplasties: robot vs. patient specific instrumentation[END_REF][START_REF] Munier | Can three-dimensional patient-specific cutting guides be used to achieve optimal correction for high tibial osteotomy? Pilot study[END_REF][START_REF] Pérez-Mañanes | 3D surgical printing cutting guides for open-wedge high tibial osteotomy: do it yourself[END_REF][START_REF] Stone | Functional outcomes and accuracy of patient-specific instruments for total knee arthroplasty[END_REF][START_REF] Thienpont | Total knee arthroplasty with patient-specific instruments improves function and restores limb alignment in patients with extra-articular deformity[END_REF] to plan the required surgery and correction. In cases where the femur or tibia exhibits abnormal mechanical angulation due to degenerative changes or fracture; side-to-side comparison of human joint anatomy appears to be common practice in the evaluation of surgical methods [START_REF] Anderson | Instrumented evaluation of knee laxity: a comparison of five arthrometers[END_REF][START_REF] Dargel | Side differences in the anatomy of human knee joints[END_REF][START_REF] Maderbacher | Assessing joint line positions by means of the contralateral knee: a new approach for planning knee revision surgery?[END_REF][START_REF] Mochizuki | Sex differences in femoral deformity determined using three-dimensional assessment for osteoarthritic knees[END_REF][START_REF] Schenk | Is the contralateral tibia a reliable template for reconstruction: a three-dimensional anatomy cadaveric study[END_REF][START_REF] Thienpont | Bone morphotypes of the varus and valgus knee[END_REF]. However, this approach assumes asymmetry of a subject's knee geometry from one side to the other to be negligible [START_REF] Eckstein | Side differences of knee joint cartilage volume, thickness, and surface area, and correlation with lower limb dominance-an MRI-based study[END_REF]. Limited data are available on the morphometric side differences of human knee joint dimensions, and more importantly the published results seem to be contradictory. Therefore, the validity of anatomic side-to-side comparisons might be questioned for their use in surgical practice [START_REF] Dargel | Side differences in the anatomy of human knee joints[END_REF][START_REF] Eckstein | Side differences of knee joint cartilage volume, thickness, and surface area, and correlation with lower limb dominance-an MRI-based study[END_REF][START_REF] Teitz | Symmetry of the femoral notch width index[END_REF].

The principal aim of this study was to evaluate the degree of asymmetry of the left and right knee joints with a particular emphasis placed on the mechanical parameters used in surgical preoperative planning. A secondary aim was to determine the effect of differing patient demographics on the degree of asymmetry present.

It was hypothesized that there will be no significant differences (as defined as < 2%) in morphometric dimensions between the right and left knees. Hence, the results of this research protocol will support the concept of obtaining reference data from the contralateral uninjured knee in orthopaedic practice, regardless of patients' demographic and morphological specificity.

Materials and methods

A CT scan-based modelling and analysis system composed of scans of over 15,000 bone segments was used for this study (SOMA, Stryker, Mahwah, New Jersey [START_REF] Schmidt | Stryker orthopaedic modeling and analytics (SOMA): a review[END_REF]). Using this system, the pelvis, bilateral femora, bilateral tibiae and patellae of 233 normal patients (102 males and 131 females, mean age 61.2 ± 15.4 years, mean BMI 24.9 ± 4.4 kg/m 2 ) representing a range of ethnicities (Caucasian, Asian and African American) were examined (Table 1). CT scan selection was done after radiographic inspection to rule out bone and joint anomalies, specimens with substantial arthritis, bone deformities or evidence of previous surgery. The demographic parameters evaluated in our analysis included age, gender, height, weight, body mass index (BMI) and ethnicity.

The non-weight-bearing hip-knee-ankle angle (nwHKA), lateral distal femoral angle (LDFA), medial proximal tibial angle (MPTA), posterior distal femoral angle (PDFA) and the global posterior plateau tibial angle (PPTA) were then calculated for each patient and each knee. All measurements were constructed using algorithm-calculated constructions on the corresponding bone which were then mapped to each chosen bone from the database. This resulted in reproducible and consistent constructs for each specimen [START_REF] Laumonerie | Which factors influence proximal femoral asymmetry?[END_REF]. Previous accuracy and reproducibility analysis estimated that this system allows automated measurement of upper femur anatomy with a margin of error < 2 mm and < 1° [START_REF] Banerjee | Innovations in hip arthroplasty threedimensional modeling and analytical technology (SOMA)[END_REF].

The nwHKA axes were defined from the knee centre to the femoral head centre and ankle centre, respectively. The mechanical axes were then projected onto the coronal plane and the angle between both axes determined. The distal femoral axis was then created from the most distal points on the medial femoral condyle and lateral femoral condyle. The lateral angle between the distal femoral axis and the mechanical axis in the coronal plane was then determined as the LDFA. The proximal tibial plane was then created by fitting over 35 points on the medial and lateral tibial compartments. The intersection of the proximal tibial plane and the coronal plane defined the frontal tibial axis. The medial angle between the coronal tibial axis and the tibial mechanical axis in the coronal plane was then determined as the MPTA. The intersection of the proximal tibial plane and the sagittal plane defined the sagittal tibial axis. The posterior angle between the sagittal tibial axis and the tibial mechanical axis in the sagittal plane was determined as the PPTA. Lastly, the axis connecting the anterior and posterior points, where the femoral condyles meet the metaphysis, was defined as the sagittal femoral axis. The posterior angle between the sagittal femoral axis and the femoral mechanical axis in the sagittal plane was defined as the PDFA (Fig. 1).

Side-to-side absolute differences (AD) were obtained by subtracting the result of the smaller value (left or right) from the result of the larger. Percent absolute asymmetry was determined using the following documented method: Percent asymmetry = (maximum*minimum)/(average of maximum and minimum) [START_REF] Schmidt | Stryker orthopaedic modeling and analytics (SOMA): a review[END_REF]. This variable was used to define the magnitude of asymmetry, and we defined as "substantial asymmetry" side-to-side difference > 2% [START_REF] Laumonerie | Which factors influence proximal femoral asymmetry?[END_REF].

To perform this study, an anonymized database was explored following a local ethic committee approval of the research protocol.

Statistical analysis

Means and standard deviations were determined for each of the measurements made for the population as a whole and for various subpopulations, based on gender and ethnicity. Normal (Gaussian) distributions of the absolute differences and percent asymmetry between pairs of femora were determined. Univariate analysis was performed using t tests. Pearson's coefficients were calculated to examine the correlations among absolute differences, specimen demographic data and femoral measurements. Multiple linear regression models were developed to establish the determinants for each of the variables that defined a difference between the left and right. For each model, variables with a p value less than 0.1 were kept in the final model. Sample size was calculated based on the estimated MPTA measurement (MPTA = 87 ± 3° [START_REF] Thienpont | Bone morphotypes of the varus and valgus knee[END_REF]) for a required level of statistical significance of α = 0.05, and a power of 1β = 0.9; 48 lower limb pairs would be required in each group or subgroups to detect > 2% asymmetry between knees. A trained statistician (MO) performed statistical analysis using SPSS software (Version 22; SPSS Inc, Chicago, IL, USA). All calculations were based on twotailed tests.

Results

Based on anatomical analysis of the 233 lower limb pairs, we found a mean nwHKA 180 ± 2.5°, mean LDFA 85.7 ± 2.1°, mean MPTA 85.8 ± 2.1°, mean PDFA 87.1 ± 1.9° and mean PPTA 84.2 ± 2.6°. No significant difference (all p > 0.05) was found between the left and right knee anatomy if symmetry was estimated upon mean differences (Table 2) and a high degree of correlation (all R 2 > 0.7) was found between the left and right measurements for all parameters of interest (Table 3).

These results did not find any substantial asymmetry (percentage of asymmetry > 2%) for all the anatomical parameters analysed: PPTA (mean AD = 1.4 ± 1.1°; mean As % = 1±0.6; n.s), PDFA (AD = 0.9 ± 0.7°; As % = 1.1 ± 0.8; n.s), LDFA (AD = 1.2 ± 0.9°; As % = 1.4 ± 1.1; n.s), MPTA (AD = 1.1 ± 0.9; As % = 1.3 ± 1.1; n.s), nwHKA (AD = 1.5 ± 1.2; As % = 0.8 ± 0.7; n.s) (Table 4).

Gender and ethnicity were not associated with a significantly higher AD asymmetry on univariate and multivariate analysis of all parameters (Table 5). We found a weak relationship between MPTA AD and age (p = 0.003) (Table 5). A significant correlation was also found between MPTA and nwHKA AD and BMI (respectively, p = 0.01 and p = 0.02). The same significant correlation was observed between MPTA and nwHKA AD and weight (p = 0.01, p = 0.03 respectively), when height only correlated with MPTA AD (p = 0.04) (Table 5).

Discussion

The key finding of the current study is that there is no substantial asymmetry between the two lower limbs regarding the anatomical parameters analysed. These results support obtaining morphometric reference data from the contralateral uninjured side in the evaluation of unilateral knee pathologies.

Only few studies have evaluated side-to-side differences of anatomic structures of the knee joint in an attempt to support the use of side-to-side comparisons. Eckstein et al. [START_REF] Eckstein | Side differences of knee joint cartilage volume, thickness, and surface area, and correlation with lower limb dominance-an MRI-based study[END_REF] proposed that the articular surface area, the volume, as well as the local thickness of cartilage in human knee joints were comparable between the right and left knees using magnetic resonance imaging. Based on their results, the authors supported obtaining reference data from the noninvolved side to estimate cartilage loss in unilateral osteoarthritis. In a recent study, Dargel et al. [START_REF] Dargel | Side differences in the anatomy of human knee joints[END_REF] studied 20 pairs of human cadaver knees. The coronal alignment, the morphometry of the articulating osseous structures of the femorotibial joint, the cruciate ligaments and the menisci were measured using established measurement methods and standard radiographs. This study has shown that for the femoral dimensions, there was a significant difference between the right and left knees in the anatomical lateral distal femoral angle (LDFA), with left knees (80.3 ± 2.2°) displaying more valgus alignment than right knees (82.1 ± 2.4°, p = 0.022). Any other morphometric data on the femoral dimensions showed no significant differences. In the tibial dimensions, there was a significant correlation between the right and left knees in the width of the tibial plateau (r = 0.966, p\0.001) and the depth of the medial (r = 0.887, p < 0.001) and lateral (r = 0.821, p < 0.001) tibial condyles. But, their measurements were based only on plain radiographic evaluation of a small sample for the coronal limb alignment, and we feel that our study using CT scan of 233 patients would be more relevant to clinical practice [START_REF] Arnal-Burró | Three dimensional-printed patient-specific cutting guides for femoral varization osteotomy: do it yourself[END_REF][START_REF] Munier | Can three-dimensional patient-specific cutting guides be used to achieve optimal correction for high tibial osteotomy? Pilot study[END_REF][START_REF] Pérez-Mañanes | 3D surgical printing cutting guides for open-wedge high tibial osteotomy: do it yourself[END_REF]. In another cadaveric study, Schenk et al. [START_REF] Schenk | Is the contralateral tibia a reliable template for reconstruction: a three-dimensional anatomy cadaveric study[END_REF] demonstrated small side differences in torsion between the left and right tibia, although these side differences in the coronal and sagittal plane were negligible. The present study confirms those conclusions and demonstrates no substantial side-to-side differences with regard to the set CT scan anatomical parameters used.

The hypothesis regarding the symmetry of lower limb's mechanical angles has important consequences in clinical practice. The satisfactory results in the short and medium term of kinematic alignment in prosthetic knee surgery have led to the promotion of individual correction based on the patient's morphological characteristics [START_REF] Almaawi | The impact of mechanical and restricted kinematic alignment on knee anatomy in total knee arthroplasty[END_REF][START_REF] Hommel | Kinematic femoral alignment with gap balancing and patient-specific instrumentation in total knee arthroplasty: a randomized clinical trial[END_REF][START_REF] Howell | Accurate alignment and high function after kinematically aligned TKA performed with generic instruments[END_REF][START_REF] Maderbacher | Kinematic component alignment in total knee arthroplasty leads to better restoration of natural tibiofemoral kinematics compared to mechanic alignment[END_REF]. The philosophy of implants' positioning in kinematic alignment surgery is aimed to restore the lower limb axis to its original anatomy prior to bony and articular deformation [START_REF] Howell | Accurate alignment and high function after kinematically aligned TKA performed with generic instruments[END_REF]. It requires complete 3D preoperative templating to obtain the different values of the tibial, femoral and lower limb's axis [START_REF] Roland | Virtual axis finder: a new method to determine the two kinematic axes of rotation for the tibio-femoral joint[END_REF]. Thus, the use of the contralateral side may be necessary to restore this native alignment for peri-articular deformity associated with important bony or articular abnormalities such as malunion, wear or defects.

The same idea can be applied to lower limb axis correction during osteotomy surgery. Fürnstahl et al. [START_REF] Fürnstahl | Complex osteotomies of tibial plateau malunions using computer-assisted planning and patient-specific surgical guides[END_REF] proposed the "intact" contralateral anatomy as a reconstruction landmark to estimate preoperative deformity correction in complex osteotomies following tibial plateau fracture. In their study, they demonstrated the accuracy of this technique by using the contralateral tibia as a 3D reconstruction template. In all of the three cases, they did not observe a significant Table 4 Calculation of side-to-side absolute difference (AD) and percentage of asymmetry = (maximum minimum)/(average of maximum and minimum) (%As) "Substantial asymmetry" was defined as side-to-side difference > 2% (bold) nwHKA non-weight-bearing hip-knee-ankle angle, LDFA lateral distal femoral angle, MPTA medial proximal tibial angle, PDFA posterior distal femoral angle, PPTA posterior plateau tibial angle, n.s not significant Anatomical parameters Mean ± SD Range (min-max) p value Left PPTA (°) 83.9 ± 2.9 76-95. residual error of correction by comparing the preoperative planning with the 3D model of the postoperative tibia.

Victor et al. [START_REF] Victor | Virtual 3D planning and patient specific surgical guides for osteotomies around the knee: a feasibility and proof-of-concept study[END_REF] described the use of 3D planning for axis correction of misaligned lower limbs with both varus and valgus deformities. If the contralateral leg had a normal morphology and alignment, it served as the template to be matched by the operated limb after the osteotomy. The mean deviation between the planned wedge angle and the executed wedge angle was 0° (-1 to 1, SD 0.72) in the coronal plane and 0.3° (-0.9 to 3, SD 1.14) in the sagittal plan. They proposed that the contralateral tibia seemed to be a reliable reconstruction template for the 3D preoperative planning of complex corrective osteotomies of the tibia. Gender and the ethnicity were not associated with any absolute differences on univariate and multivariate analysis, confirming the use of contralateral templating as a valid option in male, female, Caucasian, Asian and African patients. With the number of knees available, we found asymmetry of MPTA and the nwHKA to positively correlate with BMI. We also found a significant correlation between the asymmetry of the MPTA and age. Older patients had more asymmetries regarding MPTA side-to-side measurement. However, these correlation values were very low and might only be statistically significant and not clinically relevant due to our statistical power in the entire cohort.

This study has several limitations. First due to the retrospective nature of our database evaluation, we were unable to evaluate information regarding patients' behaviour such as limb dominance and activity level, factors that could potentially correlate with asymmetry [START_REF] Cooper | Risk factors for the incidence and progression of radiographic knee osteoarthritis[END_REF][START_REF] Michaëlsson | Risk of severe knee and hip osteoarthritis in relation to level of physical exercise: a prospective cohort study of longdistance skiers in Sweden[END_REF]. We only included subjects without bony abnormalities and our population does not represent the majority of patients requiring operative knee treatment. The purpose of this study was to establish the baseline side-to-side lower limb asymmetry of healthy subjects, as intact bony and cartilage morphology is mandatory for the proposed contralateral templating. On the other hand, although patients with bony deformities or disease, previous surgery or surgical hardware were excluded, patients with minor osteoarthritic, dysplastic or traumatic changes may have been included in our cohort. Finally, although the restoration of lower limb anatomy and function is one of the goals of TKA or osteotomy surgery, based on the variation observed, we cannot conclude on potential clinical consequence related to asymmetrical bias in TKA/ osteotomy templating.

Despite these limitations, this study used 3D modelling and analytical technology to automate the data process and achieve a highly accurate degree of morphometric analyses. This is further supported by the results of the validation step, where a deviation of generally less than 2 mm and 1° was shown when compared with the mean of manually entered landmarks [START_REF] Banerjee | Innovations in hip arthroplasty threedimensional modeling and analytical technology (SOMA)[END_REF]. Another strength of this study is the number of pairs analysed (233), which is higher than the other studies analysing the side-to-side comparison of the knee geometry (20 in Dargel et al. [START_REF] Dargel | Side differences in the anatomy of human knee joints[END_REF], 15 in Eckstein et al. [START_REF] Eckstein | Side differences of knee joint cartilage volume, thickness, and surface area, and correlation with lower limb dominance-an MRI-based study[END_REF] and 51 in Schenk et al. [START_REF] Schenk | Is the contralateral tibia a reliable template for reconstruction: a three-dimensional anatomy cadaveric study[END_REF]). Those numbers allowed us to perform secondary analyses (effect of demographic and morphometric parameters on asymmetry) with adequate statistical power.

The data from this study confirm that contralateral templating is a valid option in cases where the femur or tibia exhibits abnormal mechanical angulation due to degenerative changes or fracture.

Conclusion

These data demonstrate that there is a non-statistically significant mechanical angle asymmetry between the two lower limbs. In cases where contralateral templating is used, such asymmetry will induce minimal (if any) clinical differences.

Fig. 1

 1 Fig. 1 Illustrations of our anatomical measurements. a nwHKA non-weight-bearing hip-knee-ankle angle; b MPTA medial proximal tibial angle; c LDFA lateral distal femoral angle; d PPTA posterior plateau tibial angle; e PDFA posterior distal femoral angle

Table 1 Demographic and anatomic parameters evaluated in our global series (left and right anatomic measurements are pooled together)

 1 BMI body mass index, nwHKA non-weight-bearing hip-knee-ankle angle, LDFA lateral distal femoral angle, MPTA medial proximal tibial angle, PDFA posterior distal femoral angle, PPTA posterior plateau tibial angle

	Demographic parameters	Mean ± SD	Range (min-max)
	Age (year)	61.2 ± 15.2	20-92
	Height (kg)	166.4 ± 8.7	141-194
	Weight (cm)	69.5 ± 14.9	44-128
	BMI (kg m -2 )	24.9 ± 4.4	16.5-51.4
	Anatomic parameters	Mean ± SD	Range (min-max)
	nwHKA (°)	180 ± 2.5	169.9-187.1
	LDFA (°)	85.7 ± 2.1	79.7-90.9
	MPTA (°)	85.8 ± 2.1	77.7-91.4
	PDFA (°)	87.1 ± 1.9	81.8-93.1
	PPTA (°)	84.2 ± 2.6	-2.7 to 14.2

Table 2

 2 Univariate analysis estimating difference of means left vs right nwHKA non-weight-bearing hip-knee-ankle angle, LDFA lateral distal femoral angle, MPTA medial proximal tibial angle, PDFA posterior distal femoral angle, PPTA posterior plateau tibial angle, n.s not significant

	Anatomical parameters	Difference of	95% Confi-	p value
		means	dence interval
		(right vs left)
	PPTA (°)	1.0	0.9-1.1	n.s
	PDFA (°)	0.9	0.8-1.0	n.s
	MPTA (°)	1.1	1.0-1.2	n.s
	LDFA (°)	1.2	1.0-1.3	n.s
	nwHKA (°)	1.5	1.3-1.6	n.s

Table 3

 3 Degree of correlation between the left and right measure-

	Variable by variable	Degree of cor-	95% CI	p value
		relation
	PPTA R vs PPTA L	0.80	[0.75-0.84]	< 0.01
	PDFA R vs PDFA L	0.85	[0.81-0.88]	< 0.01
	MPTA R vs MPTA L	0.80	[0.74-0.84]	< 0.01
	LDFA R vs LDFA L	0.74	[0.67-0.79]	< 0.01
	HKA R vs HKA L	0.75	[0.68-0.80]	< 0.01

ment for all parameters of interest nwHKA non-weight-bearing hip-knee-ankle angle, LDFA lateral distal femoral angle, MPTA medial proximal tibial angle, PDFA posterior distal femoral angle, PPTA posterior plateau tibial angle

Table 5

 5 Results of our multivariate analysis regarding asymmetry influencing factors; all p values calculated using multiple analysis of variance testing (MANOVA) R 2 correlation coefficient, AD absolute difference, BMI body mass index, nwHKA non-weight-bearing hip-knee-ankle angle, LDFA lateral distal femoral angle, MPTA medial proximal tibial angle, PDFA posterior distal femoral angle, PPTA posterior plateau tibial angle, n.s

			5
	AD	1.4 ± 1.1	0.0-13.7	n.s
	%As	1.0 ± 0.6	0.0-1.17
	Right PPTA (°)	83.6 ± 2.9	75.3-92.7
	Left PDFA (°)	87.4 ± 1.9	82.4-92.7
	AD	0.9 ± 0.7	0-3.6	n.s
	%As	1.0 ± 0.8	0-4.2
	Right PDFA (°)	87.2 ± 2	81.8-91.9
	Left LDFA (°)	85.9 ± 2	80.1-92.5
	AD	1.2 ± 0.9	0.0-4.4	n.s
	%As	1.4 ± 1.1	0.0-5.4
	Right LDFA (°)	85.5 ± 1.9	80.3-92.5
	Left MPTA (°)	85.9 ± 2.2	77.5-98.4
	AD	1.1 ± 0.9	0.0-14.5	n.s
	%As	1.3 ± 1.1	0.0-17.3
	Right MPTA (°)	85.9 ± 2.2	77.7-91.4
	Left nwHKA (°)	179.9 ± 2.6 169.9-190
	AD	1.5 ± 1.2	0.0-13.6	n.s
	%As	0.8 ± 0.7	0.0-7.7
	Right nwHKA (°)	180.2 ± 2.7 171.3-187.1

Funding No funding was needed for this study.

Compliance with ethical standards

Author contributions MO and PL designed the protocol. SL and FA made all CT measurements. MO and PL performed statistical analysis. CJ and LD wrote the initial draft. MO, LD and AS edited the different versions of the draft. CJ, PL, SL, FA, LD, MO and AS approved the submitted and final versions.

Conflict of interest CJ,AS, LD and PL have nothing to disclose. SL and FA are employees of Stryker. MO is an educational consultant for Stryker.

Ethical approval

The local ethics committee approved our study protocol prior to investigation.