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Bone & Joint Research
Vol. 13, Issue 11 | Pages 682 - 693
26 Nov 2024
Wahl P Heuberger R Pascucci A Imwinkelried T Fürstner M Icken N Schläppi M Pourzal R Gautier E

Aims

Highly cross-linked polyethylene (HXLPE) greatly reduces wear in total hip arthroplasty, compared to conventional polyethylene (CPE). Cross-linking is commonly achieved by irradiation. This study aimed to compare the degree of cross-linking and in vitro wear rates across a cohort of retrieved and unused polyethylene cups/liners from various brands.

Methods

Polyethylene acetabular cups/liners were collected at one centre from 1 April 2021 to 30 April 2022. The trans-vinylene index (TVI) and oxidation index (OI) were determined by Fourier-transform infrared spectrometry. Wear was measured using a pin-on-disk test.


Orthopaedic Proceedings
Vol. 106-B, Issue SUPP_16 | Pages 62 - 62
19 Aug 2024
Devane PA Horne JG Chu A
Full Access

We present minimum 20 year results of a randomized, prospective double blinded trial (RCT) of cross-linked versus conventional polyethylene (PE), using a computer assisted method of PE wear measurement. After Ethics Committee approval, 122 patients were enrolled into an RCT comparing Enduron (non cross-linked PE) and highly cross-linked Marathon PE (DePuy, Leeds, UK). Other than the PE liners, identical components were used, a Duraloc 300 metal shell with one screw, a 28mm CoCr femoral head and a cemented Charnley Elite femoral stem. All patients were followed with anteroposterior (A∼P) and lateral radiographs at 3 days, 6 weeks, 3 months, 6 months, 1, 2, 3, 4, 5, 10 and 20 years. PE wear was measured with PolyMig, which has a phantom validated accuracy of ± 0.09mm. At minimum 20 year follow-up, 47 patients had died, 5 of which had been revised prior to their death. Another 32 patients were revised and alive, leaving 43 patients unrevised and alive (15 Enduron, 28 Marathon). No patients were lost to follow-up, but 2 were not able to be radiographed (dementia), leaving 41 patients (15 Enduron, 26 Marathon) available for PE wear measurement. After the bedding-in period, Enduron liners had a wear rate of 0.182 mm/year, and Marathon liners had a wear rate of 0.028 mm/year. At 20 years follow-up, 37 patients had required revision. Patients with conventional PE had three times the revision rate (28/37) of those who received XLPE (9/37). This is the longest term RCT showing substantially improved clinical and radiological results when XLPE is used as the bearing surface


Aims

The aim of this study was to compare the migration of the femoral component, five years postoperatively, between patients with a highly cross-linked polyethylene (HXLPE) insert and those with a conventional polyethylene (PE) insert in an uncemented Triathlon fixed insert cruciate-retaining total knee arthroplasty (TKA). Secondary aims included clinical outcomes and patient-reported outcome measures (PROMs). We have previously reported the migration and outcome of the tibial components in these patients.

Methods

A double-blinded randomized controlled trial was conducted including 96 TKAs. The migration of the femoral component was measured with radiostereometry (RSA) at three and six months and one, two, and five years postoperatively. PROMs were collected preoperatively and at all periods of follow-up.


Bone & Joint Open
Vol. 5, Issue 6 | Pages 514 - 523
24 Jun 2024
Fishley W Nandra R Carluke I Partington PF Reed MR Kramer DJ Wilson MJ Hubble MJW Howell JR Whitehouse SL Petheram TG Kassam AM

Aims

In metal-on-metal (MoM) hip arthroplasties and resurfacings, mechanically induced corrosion can lead to elevated serum metal ions, a local inflammatory response, and formation of pseudotumours, ultimately requiring revision. The size and diametral clearance of anatomical (ADM) and modular (MDM) dual-mobility polyethylene bearings match those of Birmingham hip MoM components. If the acetabular component is satisfactorily positioned, well integrated into the bone, and has no surface damage, this presents the opportunity for revision with exchange of the metal head for ADM/MDM polyethylene bearings without removal of the acetabular component.

Methods

Between 2012 and 2020, across two centres, 94 patients underwent revision of Birmingham MoM hip arthroplasties or resurfacings. Mean age was 65.5 years (33 to 87). In 53 patients (56.4%), the acetabular component was retained and dual-mobility bearings were used (DM); in 41 (43.6%) the acetabulum was revised (AR). Patients underwent follow-up of minimum two-years (mean 4.6 (2.1 to 8.5) years).


Orthopaedic Proceedings
Vol. 106-B, Issue SUPP_8 | Pages 9 - 9
10 May 2024
Owen D
Full Access

Background. Increasing evidence suggests a link between the bearing surface used in total hip arthroplasty (THA) and the occurrence of infection. It is postulated that polyethylene has immunomodulatory effects and may influence bacterial function and survival, thereby impacting the development of periprosthetic joint infection (PJI). This study aimed to investigate the association between polyethylene type and revision surgery for PJI in THA using data from the Australian Orthopaedic Association National Joint Replacement Registry (AOANJRR). We hypothesized that the use of XLPE would demonstrate a statistically significant reduction in revision rates due to PJI compared to N-XLPE. Methods. Data from the Australian Orthopaedic Association National Joint Replacement Registry (AOANJRR) spanning September 1, 1999, to December 31, 2021, were used to compare the infection revision rates between THA using N-XLPE and XLPE. We calculated the Cumulative Percentage Revision rate (CPR) and Hazard Ratio (HR) while controlling for factors like age, sex, body mass index (BMI), American Society of Anesthesiologists’ (ASA) grade, and head size. Results. From the total 361,083 primary THAs, 26,827 used N-XLPE and 334,256 used XLPE. Excluding data from the first 6 months post-surgery, 220 revisions occurred in the N-XLPE group and 1,055 in the XLPE group for PJI. The HR for infection revision was significantly higher in N-XLPE compared to XLPE, at 1.64 (95% CI, 1.41–1.90, p<0.001). Conclusions. This analysis provides evidence of an association between N-XLPE and revision for infection in THA. We suspect that polyethylene wear particles contribute to the susceptibility of THA to PJI, resulting in a significantly higher risk of revision for infection in N-XLPE hips compared to those with XLPE. Level of Evidence. Therapeutic Level III


Bone & Joint 360
Vol. 12, Issue 6 | Pages 17 - 20
1 Dec 2023

The December 2023 Hip & Pelvis Roundup360 looks at: Early hip fracture surgery is safe for patients on direct oral anticoagulants; Time to return to work by occupational class after total hip or knee arthroplasty; Is there a consensus on air travel following hip and knee arthroplasty?; Predicting whether patients will achieve minimal clinically important differences following hip or knee arthroplasty; High-dose dual-antibiotic-loaded cement for hip hemiarthroplasty in the UK (WHiTE 8): a randomized controlled trial; Vitamin E – a positive thing in your poly?; Hydroxapatite-coated femoral stems: is there a difference in fixation?


Bone & Joint Open
Vol. 4, Issue 11 | Pages 839 - 845
6 Nov 2023
Callary SA Sharma DK D’Apollonio TM Campbell DG

Aims. Radiostereometric analysis (RSA) is the most accurate radiological method to measure in vivo wear of highly cross-linked polyethylene (XLPE) acetabular components. We have previously reported very low wear rates for a sequentially irradiated and annealed X3 XLPE liner (Stryker Orthopaedics, USA) when used in conjunction with a 32 mm femoral heads at ten-year follow-up. Only two studies have reported the long-term wear rate of X3 liners used in conjunction with larger heads using plain radiographs which have poor sensitivity. The aim of this study was to measure the ten-year wear of thin X3 XLPE liners against larger 36 or 40 mm articulations with RSA. Methods. We prospectively reviewed 19 patients who underwent primary cementless THA with the XLPE acetabular liner (X3) and a 36 or 40 mm femoral head with a resultant liner thickness of at least 5.8 mm. RSA radiographs at one week, six months, and one, two, five, and ten years postoperatively and femoral head penetration within the acetabular component were measured with UmRSA software. Of the initial 19 patients, 12 were available at the ten-year time point. Results. The median proximal, 2D, and 3D wear rates calculated between one and ten years were all less than 0.005 mm/year, with no patient recording a proximal wear rate of more than 0.021 mm/year. Importantly, there was no increase in the wear rate between five and ten years. Conclusion. The very low wear rate of X3 XLPE liners with larger articulations remains encouraging for the future clinical performance of this material. Cite this article: Bone Jt Open 2023;4(11):839–845


The Bone & Joint Journal
Vol. 105-B, Issue 10 | Pages 1052 - 1059
1 Oct 2023
El-Sahoury JAN Kjærgaard K Ovesen O Hofbauer C Overgaard S Ding M

Aims. The primary outcome was investigating differences in wear, as measured by femoral head penetration, between cross-linked vitamin E-diffused polyethylene (vE-PE) and cross-linked polyethylene (XLPE) acetabular component liners and between 32 and 36 mm head sizes at the ten-year follow-up. Secondary outcomes included acetabular component migration and patient-reported outcome measures (PROMs) such as the EuroQol five-dimension questionnaire, 36-Item Short-Form Health Survey, Harris Hip Score, and University of California, Los Angeles Activity Scale (UCLA). Methods. A single-blinded, multi-arm, 2 × 2 factorial randomized controlled trial was undertaken. Patients were recruited between May 2009 and April 2011. Radiostereometric analyses (RSAs) were performed from baseline to ten years. Of the 220 eligible patients, 116 underwent randomization, and 82 remained at the ten-year follow-up. Eligible patients were randomized into one of four interventions: vE-PE acetabular liner with either 32 or 36 mm femoral head, and XLPE acetabular liner with either 32 or 36 mm femoral head. Parameters were otherwise identical except for acetabular liner material and femoral head size. Results. A total of 116 patients participated, of whom 77 were male. The median ages of the vE-PE 32 mm and 36 mm groups were 65 (interquartile range (IQR) 57 to 67) and 63 years (IQR 56 to 66), respectively, and of the XLPE 32 mm and 36 mm groups were 64 (IQR 58 to 66) and 61 years (IQR 54 to 66), respectively. Mean total head penetration was significantly lower into vE-PE acetabular liner groups than into XLPE acetabular liner groups (-0.219 mm (95% confidence interval -0.348 to -0.090); p = 0.001). There were no differences in wear according to head size, acetabular component migration, or PROMs, except for UCLA. There were no cases of aseptic loosening or failures requiring revision at long-term follow-up. Conclusion. Significantly lower wear was observed in vE-PE acetabular liners than in XLPE acetabular liners. No difference in wear was observed between different head size or PROMs except for the UCLA at ten years. Cite this article: Bone Joint J 2023;105-B(10):1052–1059


Bone & Joint Research
Vol. 12, Issue 9 | Pages 571 - 579
20 Sep 2023
Navacchia A Pagkalos J Davis ET

Aims

The aim of this study was to identify the optimal lip position for total hip arthroplasties (THAs) using a lipped liner. There is a lack of consensus on the optimal position, with substantial variability in surgeon practice.

Methods

A model of a THA was developed using a 20° lipped liner. Kinematic analyses included a physiological range of motion (ROM) analysis and a provocative dislocation manoeuvre analysis. ROM prior to impingement was calculated and, in impingement scenarios, the travel distance prior to dislocation was assessed. The combinations analyzed included nine cup positions (inclination 30-40-50°, anteversion 5-15-25°), three stem positions (anteversion 0-15-30°), and five lip orientations (right hip 7 to 11 o’clock).


Bone & Joint 360
Vol. 12, Issue 4 | Pages 44 - 46
1 Aug 2023
Burden EG Whitehouse MR Evans JT


Orthopaedic Proceedings
Vol. 105-B, Issue SUPP_11 | Pages 20 - 20
7 Jun 2023
Navacchia A Pagkalos J Davis E
Full Access

We have previously reported on the improved all-cause revision and improved revision for instability risk in lipped liner THAs using the NJR dataset. These findings corroborate studies from the Australian (AOANJRR) and New Zealand (NZOA) joint registries. The optimal orientation of the lip in THAs utilising a lipped liner remains unclear to many surgeons. The aim of this study was to identify impingement-free optimal liner orientations whilst considering femoral stem version, cup inclination and cup version. A cementless THA kinematic model was developed using a 20 degree XLPE liner. Physiological ROM and provocative dislocation manoeuvre analyses were performed. A total of 9 cup positions were analysed (inclination 30–40–50 degrees, anteversion 5-15-25 degrees) and combined with 3 stem positions (anteversion 0-15-30 degrees) and 5 lip orientations (right hip 11 to 7 o'clock). Some lip orientation/component position combinations lead to impingement within the physiological ROM range. Using a lipped liner increases the femoral head travel distance prior to dislocation when impingement occurs in the plane of the lip. In THAs with a cup inclination of 30 and 40 degrees, inferior lip orientations (7–8 o'clock for a right hip) performed best. Superior lip orientation performed best with a cup inclination of 50 degrees. Femoral stem version has a significant effect on the range of movement prior to impingement and hence the preferred lip orientation. The optimal orientation of the lip in lipped liner THA is dependent on the position of both the acetabular and femoral components. In the common component orientation combination of stem anteversion 15, cup inclination 40 and cup anteversion 15, the optimal lip orientation was postero-inferiorly (8 o'clock for a right hip). Preventing impingement during physiological ROM is possible with appropriate lip liner orientation


Orthopaedic Proceedings
Vol. 105-B, Issue SUPP_8 | Pages 27 - 27
11 Apr 2023
Puente Reyna A Schwiesau J Altermann B Grupp T
Full Access

The purpose of the study was to compare the mechanical properties, oxidation and wear resistance of a vitamin E blended and moderately crosslinked polyethylene for total knee arthroplasty (MXE) in comparison with clinically established polyethylene materials. The following polyethylene materials were tested: CPE (30 kGy e-beam sterilized), XLPE (75 kGy gamma crosslinked @ 100°C), ViXLPE (0.1 % vitamin E blended, 80 kGy e-beam crosslinked @ 100°C), and MXE (0.1 % vitamin E blended polyethylene, 30 kGy gamma sterilized). For the different tests, the polyethylene materials were either unaged or artificially aged for two or six weeks according to ASTM F2003-02. The oxidation index was measured based on ASTM F2102 at a 1 mm depth. Small punch testing was performed based on ASTM F2977. Mechanical properties were measured on unaged materials according to ASTM D638. Wear simulation was performed on a load controlled 3 + 1 station knee wear simulator (EndoLab GmbH, Thansau, Germany) capable of reproducing loads and movement of highly demanding activities (HDA) as well as ISO 14243-1 load profiles. The load profiles were applied for 5 million cycles (mc) or delamination of the polyethylene components. Medium size AS e.motion. ®. PS Pro (Aesculap AG, Tuttlingen, Germany) femoral and tibial components with a ZrN-multilayer surface, as well as Columbus. ®. CR cobalt-chrome alloy femoral and tibial components were tested. Particle analysis was performed on the serum samples of the ISO 14243-1 wear simulations based on ISO 17853:2011 and ASTM F1877. The analysis of the mechanical properties show that moderately crosslinked polyethylene (MXE) might be a superior material for total knee arthroplasty applications [Schwiesau et al. 2021]. The addition of vitamin E in a moderately crosslinked polyethylene prevented its oxidation, kept its mechanical characteristics, and maintained a low wear, even under a HDA knee wear simulation


Bone & Joint 360
Vol. 12, Issue 2 | Pages 45 - 46
1 Apr 2023
Evans JT Whitehouse MR


Orthopaedic Proceedings
Vol. 105-B, Issue SUPP_3 | Pages 21 - 21
23 Feb 2023
Sandow M Page R Hatton A Peng Y
Full Access

The 2021 Australian Orthopaedic Association National Joint Replacement Registry report indicated that total shoulder replacement using both mid head (TMH) length humeral components and reverse arthroplasty (RTSA) had a lower revision rate than stemmed humeral components in anatomical total shoulder arthroplasty (aTSA) - for all prosthesis types and diagnoses. The aim of this study was to assess the impact of component variables in the various primary total arthroplasty alternatives for osteoarthritis in the shoulder. Data from a large national arthroplasty registry were analysed for the period April 2004 to December 2020. The study population included all primary aTSA, RTSA, and TMH shoulder arthroplasty procedures undertaken for osteoarthritis (OA) using either cross-linked polyethylene (XLPE) or non-cross-linked polyethylene (non XLPE). Due to the previously documented and reported higher revision rate compared to other anatomical total shoulder replacement options, those using a cementless metal backed glenoid components were excluded. The rate of revision was determined by Kaplan-Meir estimates, with comparisons by Cox proportional hazard models. Reasons for revision were also assessed. For a primary diagnosis of OA, aTSA with a cemented XLPE glenoid component had the lowest revision rate with a 12-year cumulative revision rate of 4.7%, compared to aTSA with cemented non-XLPE glenoid component of 8.7%, and RTSA of 6.8%. The revision rate for TMH was lower than aTSA with cemented non-XLPE, but was similar to the other implants at the same length of follow-up. The reason for revision for cemented aTSR was most commonly component loosening, not rotator cuff deficiency. Long stem humeral components matched with XLPE in aTSA achieve a lower revision rate compared to shorter stems, long stems with conventional polyethylene, and RTSA when used to treat shoulder OA. In all these cohorts, loosening, not rotator cuff failure was the most common diagnosis for revision


The Bone & Joint Journal
Vol. 105-B, Issue 1 | Pages 29 - 34
1 Jan 2023
Fransen BL Bengoa FJ Neufeld ME Sheridan GA Garbuz DS Howard LC

Aims

Several short- and mid-term studies have shown minimal liner wear of highly cross-linked polyethylene (HXLPE) in total hip arthroplasty (THA), but the safety of using thinner HXLPE liners to maximize femoral head size remains uncertain. The objective of this study was to analyze clinical survival and radiological wear rates of patients with HXLPE liners, a 36 mm femoral head, and a small acetabular component with a minimum of ten years’ follow-up.

Methods

We retrospectively identified 55 patients who underwent primary THA performed at a single centre, using HXLPE liners with 36 mm cobalt-chrome heads in acetabular components with an outer diameter of 52 mm or smaller. Patient demographic details, implant details, death, and all-cause revisions were recorded. Cox regression and Kaplan-Meier survival was used to determine all-cause and liner-specific revision. Of these 55 patients, 22 had a minimum radiological follow-up of seven years and were assessed radiologically for linear and volumetric wear.


The Bone & Joint Journal
Vol. 104-B, Issue 7 | Pages 833 - 843
1 Jul 2022
Kayani B Baawa-Ameyaw J Fontalis A Tahmassebi J Wardle N Middleton R Stephen A Hutchinson J Haddad FS

Aims. This study reports the ten-year wear rates, incidence of osteolysis, clinical outcomes, and complications of a multicentre randomized controlled trial comparing oxidized zirconium (OxZr) versus cobalt-chrome (CoCr) femoral heads with ultra-high molecular weight polyethylene (UHMWPE) and highly cross-linked polyethylene (XLPE) liners in total hip arthroplasty (THA). Methods. Patients undergoing primary THA were recruited from four institutions and prospectively allocated to the following treatment groups: Group A, CoCr femoral head with XLPE liner; Group B, OxZr femoral head with XLPE liner; and Group C, OxZr femoral head with UHMWPE liner. All study patients and assessors recording outcomes were blinded to the treatment groups. The outcomes of 262 study patients were analyzed at ten years’ follow-up. Results. Patients in Group C were associated with increased mean liner wear rates compared to patients in Group A (0.133 mm/yr (SD 0.21) vs 0.031 mm/yr (SD 0.07), respectively; p < 0.001) and Group B (0.133 mm/yr (SD 0.21) vs 0.022 mm/yr (SD 0.05), respectively; p < 0.001) at ten years’ follow-up. Patients in Group C were also associated with increased risk of osteolysis and aseptic loosening requiring revision surgery, compared with patients in Group A (7/133 vs 0/133, respectively; p = 0.007) and Group B (7/133 vs 0/135, respectively; p = 0.007). There was a non-statistically significant trend towards increased mean liner wear rates in Group A compared with Group B (0.031 mm/yr (SD 0.07) vs 0.022 mm/yr (SD 0.05), respectively; p = 0.128). All three groups were statistically comparable preoperatively and at ten years’ follow-up when measuring normalized Western Ontario and McMaster Universities Osteoarthritis Index (p = 0.410), 36-Item Short Form Health Survey (p = 0.465 mental, p = 0.713 physical), and pain scale scores (p = 0.451). Conclusion. The use of UHMWPE was associated with progressively increased annual liner wear rates after THA compared to XLPE. At ten years’ follow-up, the group receiving UHMWPE demonstrated an increased incidence of osteolysis and aseptic loosening requiring revision surgery compared to XLPE. Femoral heads composed of OxZr were associated with trend towards reduced wear rates compared to CoCr, but this did not reach statistical significance and did not translate to any differences in osteolysis, functional outcomes, or revision surgery between the two femoral head components. Cite this article: Bone Joint J 2022;104-B(7):833–843


The Bone & Joint Journal
Vol. 104-B, Issue 7 | Pages 801 - 810
1 Jul 2022
Krull P Steinbrück A Grimberg AW Melsheimer O Morlock M Perka C

Aims

Registry studies on modified acetabular polyethylene (PE) liner designs are limited. We investigated the influence of standard and modified PE acetabular liner designs on the revision rate for mechanical complications in primary cementless total hip arthroplasty (THA).

Methods

We analyzed 151,096 primary cementless THAs from the German Arthroplasty Registry (EPRD) between November 2012 and November 2020. Cumulative incidence of revision for mechanical complications for standard and four modified PE liners (lipped, offset, angulated/offset, and angulated) was determined using competing risk analysis at one and seven years. Confounders were investigated with a Cox proportional-hazards model.


Orthopaedic Proceedings
Vol. 104-B, Issue SUPP_4 | Pages 18 - 18
1 Apr 2022
Kayani B Baawa J Fontalis A Tahmassebi J Wardle N Middleton R Hutchinson J Haddad FS
Full Access

This study reports the ten-year polyethylene liner wear rates, incidence of osteolysis, clinical outcomes and complications of a three-arm, multicentre randomised controlled trial comparing Cobalt-Chrome (CoCr) and Oxidised Zirconium (OxZr) femoral heads with ultra-high molecular weight polyethylene (UHMWPE) versus highly cross-linked polyethylene (XLPE) liners in total hip arthroplasty (THA). Patients undergoing THA from four institutions were prospectively randomised into three groups. Group A received a CoCr femoral head and XLPE liner; Group B received an OxZr femoral head and XLPE liner; and Group C received an OxZr femoral head and UHMWPE liner. Blinded observers recorded predefined outcomes in 262 study patients at regular intervals for ten years following THA. At ten years follow-up, increased linear wear rates were recorded in group C compared to group A (0.133 ± 0.21 mm/yr vs 0.031 ± 0.07 mm/yr respectively, p<0.001) and group B (0.133 ± 0.21 mm/yr vs 0.022 ± 0.05 mm/yr respectively, p<0.001). Patients in group C were associated with increased risk of osteolysis and aseptic loosening requiring revision surgery compared with group A (7/133 vs 0/133 respectively, p=0.007) and group B (7/133 vs 0/135 respectively, p=0.007). There was a non-significant trend towards increased liner wear rates in group A compared to group B (0.031 ± 0.07 mm/yr vs 0.022 ± 0.05 mm/yr respectively, p=0.128). All three groups were statistically comparable preoperatively and at ten years follow-up when measuring normalised Western Ontario and McMaster Universities Osteoarthritis Index(p=0.410), short-form-36 (p = 0.465 mental, p = 0.713 physical), and pain scale scores (p=0.451). The use of UHMWPE was associated with progressively increased annual liner wear rates after THA. At ten years follow-up, this translated to UHMWPE leading to an increased incidence of osteolysis and aseptic loosening requiring revision THA, compared with XLPE. Femoral heads composed of OxZr were associated with a non-significant trend towards reduced wear rates compared to CoCr, but this did not translate to any differences in osteolysis, functional outcomes, or revision surgery between the two treatments groups


Bone & Joint 360
Vol. 11, Issue 2 | Pages 15 - 18
1 Apr 2022


The Bone & Joint Journal
Vol. 104-B, Issue 2 | Pages 200 - 205
1 Feb 2022
Orita K Goto K Kuroda Y Kawai T Okuzu Y Matsuda S

Aims

The aim of this study was to evaluate the performance of first-generation annealed highly cross-linked polyethylene (HXLPE) in cementless total hip arthroplasty (THA).

Methods

We retrospectively evaluated 29 patients (35 hips) who underwent THA between December 2000 and February 2002. The survival rate was estimated using the Kaplan-Meier method. Hip joint function was evaluated using the Japanese Orthopaedic Association (JOA) score. Two-dimensional polyethylene wear was estimated using Martell’s Hip Analysis Suite. We calculated the wear rates between years 1 and 5, 5 and 10, 10 and 15, and 15 and final follow-up.