Osseointegration reduces aseptic loosening of primary distal femoral implants in pediatric and adolescent osteosarcoma patients: a retrospective clinical and radiographic study

The challenge of distal femoral replacement (DFR) longevity remains a priority for orthopaedic oncologists as the overall survival and activity level of young patients with osteosarcoma continues to improve. This study hypothesized that increased extracortical osseointegration at the bone-implant shoulder (i.e., where the metal implant shaft abuts the femur) will improve stress transfer adjacent to the implant, as evidenced by reduced cortical bone loss, radiolucent line progression and implant failure in young patients (< 20 years) following DFR surgery. Twenty-nine patients of mean age 13.09 ± 0.56 years received a primary DFR. The clinical outcome of 11 CPS®, 10 GMRS®, 5 Stanmore® and 3 Repiphysis® implants was evaluated over a mean follow-up period of 4.25 ± 0.55 years. The osseous response to a bone-implant shoulder composed of either a hydroxyapatite-coated grooved ingrowth collar (Stanmore®), a porous metal coating (GMRS®) or a polished metal surface (Repiphysis®) was quantified radiographically. All (100.0%) of the Stanmore® implants, 90.0% of GMRS®, 81.8% of CPS® and 33.3% of the Repiphysis® implants survived. Significantly increased extracortical bone and osseointegration were measured adjacent to the Stanmore® bone-implant shoulder when compared with the GMRS® and Repiphysis® implants (p < 0.0001 in both cases). Significantly decreased cortical loss was identified in the Stanmore® group (p = 0.005, GMRS® and p < 0.0001, Repiphysis®) and at 3 years, the progression of radiolucent lines adjacent to the intramedullarly stem was reduced when compared with the GMRS® and Repiphysis® implants (p = 0.012 and 0.026, respectively). Implants designed to augment osseointegration at the bone-implant shoulder may be critical in reducing short- (≤ 2 years) to mid- (≤ 5 years) term aseptic loosening in this vulnerable DFR patient group. Further longer-term studies are required to confirm these preliminary findings.


Introduction
Osteosarcoma is a primary malignancy of bone that most commonly impacts the distal femur, predominantly affecting those between the ages of 10 and 14 and those over the age of 65 years [1].Neoadjuvant chemotherapy combined with tumor resection is accepted as the treatment of choice [2].Replacement of the distal femur with a mega endoprosthesis after wide tumor resection offers the benefits of same-day weight bearing, faster rehabilitation, and early walking [3].Long-term 10-and 15-year survival rates following total knee replacement surgery are reported to range between 90.9 and 95.4% [4].In contrast, Haijie et al. [5] recently reported that the mean 5-, 10-, 15-and 20-year implant survival rate of a distal femoral replacement (DFR) in adults was 78.3, 70.1, 61.6 and 38.3%, respectively.The identifiable risk factors are younger age, an increased level of bone resection and increased time of follow-up, which places the pediatric population at particularly high risk [6].Implant infection and aseptic loosening (ASL) of the intramedullary stem remain the recognized major causes of failure [7][8][9].At the tissue level, ASL begins with localized cortical bone loss at the bone-shoulder implant junction, (i.e., where the metal implant shaft abuts the femur) [10].With time, this cortical bone loss is accompanied by the progression of radiolucent lines between the cement-bone interface adjacent to the intramedullary stem, eventually leading to ASL and implant failure [10].Concerns for successful longterm (i.e., > 10 years) fixation stimulated modifications in implant materials and design and to date several are in use, each with varying features targeted to reduce bone loss and ASL.Modern designs incorporate a bone ingrowth collar at the bone-implant shoulder with the goal of encouraging extracortical bone-implant osseointegration.This is reported to reduce disadvantageous high stresses within the stem fixation and protect the implant against ASL and surgical revision [11][12][13][14].Typically, bone does not directly adhere to a polished metal surface and varying types of ingrowth surfaces including fibermetal, porous metal coatings and more recently a hydroxyapatite (HA) coating have been assessed clinically [10,[14][15][16][17][18][19].Other prosthetic advancements include Biomet's Compress Compliant Pre-Stress (CPS®) technology (ZimmerBiomet Inc, Warsaw, IN, USA), designed to apply beneficial dynamic compressive loads to the bone cortex at the shoulder.This may eliminate ASL and is secured to bone without reliance on an intramedullary stem [20][21][22][23][24].
The aim of this study was to retrospectively review the clinical outcome of primary DFRs in young patients (< 20 years) in the short-(≤ 2 years) and mid-(≤ 5 years) term.All patients had received either a Stanmore® implant, a CPS® implant, the Stryker Global Modular Replacement System (GMRS®, Stryker, Mahwah NJ, USA) or a Repiphysis® implant (Repiphysis Limb Salvage System; Wright Medical Technology, Arlington, TN, USA).This study also aimed to evaluate the effect of an implant shoulder composed of a HA-coated grooved ingrowth collar (Stanmore®), a plasma sprayed porous titanium coating (GMRS®) or a polished metal surface (Repiphysis®) on the level of osseointegration and incidence and progression of radiolucent lines adjacent to the intramedullary stem fixation.Our hypothesis was that increased extracortical osseointegration at the boneimplant shoulder will improve stress transfer adjacent to the stem, as evidenced by reduced cortical bone loss, radiolucent line progression and implant failure.

Methods
Between 2000 and 2020, 30 patients underwent primary DFR limb salvage surgery within the Nemours Children's Health system at hospitals based in Orlando, Pensacola and Jacksonville in Florida, and at the Nemours/Alfred I. duPont Hospital for Children in Wilmington, Delaware, USA.This study received ethical board approval from the Nemours Office of Human Subjects Protection (IRB# 1,351,573).Our study was retrospective and as such, written informed consent was not required.Data were retrieved from the EPIC electronic medical record system.Surgery was performed by one of six orthopaedic surgeons, and all patients were treated following a biopsy-proven diagnosis of high-grade osteosarcoma.Patients who received a DFR for the reconstruction of a metastatic lesion or in a revision procedure were excluded.One patient was excluded as the DFR was a revision, leaving 29 patients (Figs. 1 and 2).
All patients received neoadjuvant and adjuvant multidrug combination chemotherapy in accordance with the Children's Oncology Group AOST 0331 study (Supplementary Table S1).Patients received cisplatin, doxorubicin and methotrexate (MAP) and during DFR surgery, chemotherapeutic efficacy was determined according to changes in tumor size.Those patients with no or limited tumor regression at the time of surgery were categorized as non-responders and their chemotherapeutic treatment was modified accordingly.Although the targeted clinical function of each DFR was equivalent, the type of implant design used was selected based on the surgeon's preference.The implant design variables are presented in Table 1, and implant removal and clinical complications were assessed in accordance with the Henderson Classification system of endoprosthetic failure [25] (Table 2).

Radiographic analysis
Radiographic analysis was performed by examining both antero-posterior (AP) and medio-lateral (ML) radiographs taken of each surviving patient throughout the length of the follow-up period.In total, 99 radiographs were analyzed with a mean of 6 (range, 1-18) radiographs per patient.The number of radiographs available varied according to length of follow-up, frequency of follow-up imaging, and availability of radiographs.Analysis included determination of, (1) extracortical bone growth over the bone-implant junction, (2) osseointegration at the boneimplant shoulder, (3) cortical bone loss at the shoulder of the prosthesis, and (4) radiolucent line (RL) progression adjacent to the cemented stem fixation (Fig. 3a and b).As the CPS® device does not feature a cemented stem, these implants were not included in the radiographic analysis.Radiographic images taken immediately post-operation were used to measure the most proximal point on the greater trochanter down to the most distal point of the patellar surface, and %bone resection was calculated.

Extracortical bone formation and osseointegration
Similar to our previous studies [10,14], the bone-implant shoulder was divided into four quadrants (antero-posterior and medio-lateral) and the presence of extracortical bone growth scored as 0 where no extracortical growth was observed, and 1 when bone growth was observed in any 1 of the 4 quadrants.Similarly, evidence of radiographic osseointegration was also scored, where the presence of a radiolucent line separating the bony pedicle from the implant surface in any 1 of the 4 quadrants deemed the collar non-osseointegrated (score of 0).When radiographic osseointegration was present, the collar was given a score of 1.
Fig. 1 Antero-posterior (a) and medio-lateral (b) radiographs of each of the endoprosthetic designs investigated.Fifteen (51.7%) male and 14 (48.3%)female patients at a mean (and standard error of the mean) age of 13.09 ± 0.56 years (range 7.9-18.9years) were followed up for a mean of 4.25 ± 0.55 years (range 0.04-10.5 years).Thirteen implants were inserted into the left femur and 16 into the right.Of those implants fixed using an intramedullary stem, all were cemented in place

Cortical bone loss
Cortical bone loss was defined as the clear separation of bone (> 1 mm) from the shoulder of the implant.If a gap of > 1 mm was observed, a score of 1 was given, while no cortical bone loss at the interface was given a score of 0.

Radiolucent line score
The progression of a radiolucent line at the bone-cement interface adjacent to the stem was quantified from serial radiographs.Each antero-posterior and medio-lateral radiograph were divided into 12 equidistant zones (Fig. 3c) [10].A score of zero indicated that no radiolucent lines were observed.A score of 1 was given when a radiolucent Tumor progression Recurrence or progression of tumor with contamination of endoprosthesis line was observed in 1 zone and a maximal score of 24 indicated a loose stem fixation surrounded by radiolucent lines along the entire length, in both antero-posterior and medio-lateral planes.The progression of these lines was measured over the follow-up period.

Statistics
Implant survival was determined using a Kaplan-Meier analysis starting from the date of the original surgery with an end point of failure for any reason.Endoprosthetic failure was defined as the need for complete revision of the cemented component and conversion to a different prosthesis.Removal of the implant due to disease progression and amputation was not included as a cause of implant failure.Replacement of mechanically worn parts (e.g., bushings for the hinge knee replacement) was counted as complications and not as implant failures.The parameters of implant type, sex, age, %bone resection, implant lengthening, and length of follow-up were correlated with implant complications and the need for revision surgery using the Spearman's rank correlation coefficient.Differences in the prevalence of complications were assessed using the Chi-square test.
A Mann-Whitney U test was used to compare radiographic scores between groups.The distribution of data obtained did not present as skewed and no clear outliers were identified.Therefore mean ± standard error values are presented.All analyses were performed using IBM SPSS software (v25.0,SPSS, Illinois, USA) where p values < 0.05 were considered significant.

Patient survival
A total of 7 patients died (75.9% survival) (Table 3) where 3 of the 7 deaths showed poor response to chemotherapy at the time of surgical tumor resection.Local recurrence occurred in 3 patients (10.3%), and an amputation was performed in 2 patients 0.97 and 2.31 years post-surgery.The third patient was converted to a total femoral implant at 10 years of follow-up.

Implant removal
Kaplan-Meier analysis showed an implant survivorship of 100.0% in the Stanmore® group, 90.0% in the GMRS®, 81.8% in the CPS®, and 33.3% in the Repiphysis® group over the follow-up period (Fig. 4).When all implant types were combined, overall implant survival was 82.8%.A total of 5 implants (17.2%) were revised (Fig. 5 and Table 4).
A trend of increased implant revision in male patients was observed (71.4%, p = 0.058).The use of the extendable Stanmore® prosthesis was favored in the younger age group (14.8%,FU 4.85 years ± 1.19 (range, 1.14-7.32years); p = 0.025), whereas the GMRS® implant was most commonly used in older patients (30.0%,FU 3.61 years ± 1.04 (range, 0.04-10 years); p = 0.043).Our previous study showed that the administration of chemotherapy significantly increased the incidence of aseptic loosening adjacent to the DFR intramedullary stem [26].In this study, no significant differences in the total dose of MAP given per patient were found when compared between each of the implant groups, suggesting any changes in the bone response observed, may not be due to variations in the chemotherapy regimen given (Supplementary Table S2).

Complications, lengthening and %bone resection
Sixteen of 29 patients (55.2%) were re-admitted during the follow-up period and clinical complications were identified in 83.3% of patients.A trend was seen where the incidence of complications increased as the length of follow-up increased (p = 0.057).All 5 of the Stanmore® prostheses were lengthened in addition to 2 Repiphysis® and 1 CPS® implant.The mean number of lengthening sessions was 10.9 ± 3.1 (range, 4-28) and the mean lengthening amount was 56.2 ± 20.3 mm (range, 17-175 mm).Percentage bone resection varied between groups (Table 5).
No other significant correlations were found.

Qualitative analysis: CPS® implant
Radiographic analysis of all patients with a CPS® implant showed stable bone-implant fixation with no evidence of aseptic failure.Bone hypertrophy at the implant shoulder was observed in all patients in the years following surgery, with hypertrophy also seen associated with the pins in some patients (Fig. 10).

Discussion
Bone tumors in children are rare and prior to the use of effective chemotherapy, and overall patient survival rates were reported to be 15-20% at 2 years following surgical resection and/or radiotherapy [27,28].This study demonstrated a patient survival rate of 75.9% over a mean follow-up of 4.25 years.Although patient survival is highly dependent on the stage of osteosarcoma at diagnosis, our result is similar to other recent studies who report contemporary 5-year patient survival rates ranging between 60 and 78% in pediatric patients following limb-salvage and MAP treatment [2,[29][30][31].Thus, the challenges of DFR longevity remain a priority as overall survival and activity levels continues to improve; however, surgery is challenging in growing children and problems can result in loss of joint function, high-level amputation, and systemic sequelae for the patient [32].Aseptic loosening in young and physically active patients who place high demands on their prosthesis is a major concern [33].A study by Unwin et al. [6] reported a 67.4% probability of a Stanmore® DFR survival at 10 years with a significantly higher risk of ASL (13.6%) in patients < 20 years of age.Further, this study also identified that patients < 20 years of age and with > 60% of bone resection, having the poorest prognosis.Although massive bone tumor implants are widely used, the rate of post-surgical complications remains five to ten times higher than rates reported following routine joint arthroplasties [34,35].Studies show early (~ 6 month) complications that require revision, as well as the early formation, and progression of radiolucent lines adjacent to the intramedullary stem; an indicator of aseptic loosening and pending implant failure [10,14,26,36].In this study, an encouraging overall implant survival rate of 82.8% was found and the incidence of ASL that required revision was 10.3%.No correlation between %bone resection and implant failure was seen although mean levels were less than 60%.
To determine load distribution within the intramedullary fixation in adults, a clinical study by Taylor et al. [37] added strain gauges and telemetric instrumentation to a massive implant.At 100 weeks post-surgery, 60% of the applied load was directed through the cemented stem fixation when compared with 25% in the more immediate post-op period.These findings suggested a progressive mechanical cause of ASL and led to the concept that osseointegration at the shoulder offered more beneficial load distributions.As such, the Stanmore® and CPS® implants were designed to maximize osseous growth at the shoulder, and in this study, none of these implants failed due to ASL.Hydroxyapatite is classified as a bioactive, osseoconductive and osseoinductive material and bone is able to chemically bond with it providing increased interfacial and mechanical coupling, to superior levels when compared with a polished titanium implant surface [38,39].Our results showed significantly increased extracortical bone growth and osseointegration to the HA collar in the Stanmore® group when compared with both the GMRS® and Repiphysis® implants.Significantly reduced cortical loss and the progression of radiolucent lines was also evident in Stanmore-given patients over the follow-up period.These results are similar to other studies that investigated osseointegration and ASL [10,13,14].This study demonstrated poor performance of the Repiphysis® design where 2 of the 3 implants inserted were revised.Results are similar to other studies that report high rates of ASL as well as mechanical failure in young patients [40][41][42][43][44].
Two recent studies also reported a 100% implant survival rate of the Stanmore® implant in pediatric patients and both demonstrated overall poor survival (79.2% at 2 years and 21% at 5 years) of the Phenix-Rephiphysis® implant at a mean follow-up of 6.2 years [45] and 32% survival at 6 years [46].Infection of massive endoprostheses ranges between 8 and 40% [47,48] with CPS® implant infection reported as 14% over a 20-year follow-up [49].In this study, none of the DFR implants were revised due to infection and 3 patients were successfully treated for implant-associated infection.Two of these 3 patients had received a CPS® implant; however, this group of patients also experienced significantly higher %bone resection levels and the increased tissue exposed during surgery may account for the infections observed.Two CPS® implants failed due to fracture of the titanium traction bar.In both patients the implants appeared radiographically well fixed.Traction bar fracture has been reported in the same location in other studies [50,51]; however, the reason for fracture remains unclear.Nevertheless, our results indicate that the CPS® implant continues to be a reliable option for distal femoral limb salvage surgery and the absence of ASL is encouraging.Finally, multidrug chemotherapy impairs bone growth and causes early radiological signs of loosening in DFRs [26].No significant differences were found when the total dose and length of treatment was compared between implant groups.
Our study had several limitations.First, osteosarcoma is rare, and as such, the study is limited by its small sample size as well as loss of follow-up as patients transitioned out of the hospital system and into adult care.Furthermore, the cohort of patients presented individual differences in their activity levels, which would impact prosthetic survival.Because this study was a retrospective study, both antero-posterior and medio-lateral radiographs were not always available for review and this reduced the number of patients followed-up beyond 6 years post-operatively.Finally, a limitation was the study did not account for additional implant design variables including expandable versus non-expandable implants, and variations in the size of the intramedullary stem length and diameter.These parameters also likely impacted the bone response measured across designs.
In conclusion, chemotherapy and limb-salvage surgery yield good oncologic outcomes.As evidenced by an increased osseointegration score, and significantly reduced cortical bone loss, radiolucent line score, and 100.0%implant survival in the Stanmore® group, results from this study suggest that implant designs modified to augment osseointegration at the bone-implant shoulder may be critical in reducing the initiation and development of ASL in this vulnerable patient group.While the limitations of this study do not allow us to conclude that extracortical bone growth and osseointegration is directly responsible for a lower incidence of ASL, our results do confirm the unique ability of the HA collar on the Stanmore® implant to increase radiographic bone-implant contact at the implant shoulder, and in contrast to the other three designs investigated.Nevertheless, our results align with previous studies in adults that show the Stanmore® HA collar is critical to increasing osseointegration where the metal implant shaft abuts the femur, and this resulted in a significant, and subsequent reduction in aseptic loosening and DFR failure [10,14].Next steps involve investigating a larger pediatric cohort over a longer follow-up period to support these preliminary findings.

Fig. 3 a
Fig. 3 a An antero-posterior radiograph of a GMRS® implant showing cortical bone loss at the at the shoulder of the implant with a clear radiolucent line separating the implant surface from extracortical bone (a non-osseointegrated implant).b An antero-posterior radiograph of a Stanmore® implant showing bone in direct contact with the implant surface (an osseointegrated implant), with no cortical bone loss at the shoulder.c An antero-posterior radiograph showing

Fig. 4 Fig. 5
Fig. 4 Kaplan-Meier survival analysis of the DFRs with respect to implant manufacturer and implant fixation failure for any reason.The Kaplan-Meier estimate computes implant survival over time taking into account variabilities associated with individual patients.For each time interval, implant survival probability was calculated as the number of patients and implants surviving divided by the number

Fig. 10 a
Fig. 10 a A radiograph of a CPS® implant taken immediately post-surgery.b The same patient 2 years post-operation showing cortical hypertrophy at the implant shoulder (arrow) in the antero-posterior and c medio-lateral aspect.No cortical bone loss > 1 mm was evident, and no extracortical bone growth was observed in any of the patients

Table 1
A description of the features of each of the implant designs investigated, highlighting the differences in ingrowth surface parameters at the bone implant shoulder

Table 4
Endoprosthetic failure and complications over the follow-up period Data are presented using the Henderson Classification criterion.Additionally, 3 patients (10.3%) were identified with complications due to infection and all were readmitted to hospital for treatment.Infections necessitating surgical management through washout, incision and drainage or removal and replacement of parts occurred in 2 patients and aseptic wound dehiscence in a further 2 patients (6.9%).Prolonged pain that was non-responsive to physical therapy or non-steroidal anti-inflammatory medication was seen in 8 patients.Four patients were noted to have pain associated with leg-length discrepancies and three underwent a contralateral epiphysiodesis procedure