Abstract
Background: Aseptic loosening is the most frequent cause of implant failure in total hip arthroplasty. While a direct link between aseptic loosening and periprosthetic bone loss remains elusive, there is plentiful evidence for a close association with early implant migration. The present trial was primarily designed to evaluate whether a single infusion of 4 mg of zoledronic acid prevented early implant migration in patients with osteonecrosis of the femoral head.
Methods: Fifty patients were consecutively enrolled to receive either zoledronic acid or saline solution after cementless total hip arthroplasty. Radiographs, biochemical parameters of bone turnover, and the Harris hip-rating score were determined preoperatively and at each follow-up examination at seven weeks, six months, one year, and yearly thereafter. The median follow-up period was 2.8 years.
Results: We found a significant subsidence of the stem of up to a mean (and standard deviation) of -1.2 ± 0.6 mm at two years within the control group, and the cups had a mean medialization of 0.6 ± 1.0 mm and a mean cranialization of 0.6 ± 0.8 mm (p < 0.001). Treatment with zoledronic acid effectively minimized the migration of the cups in both the transverse and the vertical direction (mean, 0.15 ± 0.6 mm and 0.06 ± 0.6 mm, respectively; p < 0.05), while only a trend to decreased subsidence of the stem was detected. Finally, the Harris hip score rapidly increased over time in both treatment groups, although this increase was significantly more pronounced in the zoledronate-treated group than in the control group (analysis of variance, p = 0.008).
Conclusions: A single infusion of zoledronic acid shows promise in improving initial fixation of a cementless implant, which may improve the clinical outcome of total hip arthroplasty in patients with osteonecrosis of the femoral head.
Level of Evidence: Therapeutic Level I. See Instructions to Authors for a complete description of levels of evidence.
Aseptic loosening is by far the most frequent cause of implant failure and remains a major concern in total joint replacement1. In general, loosening is associated with periprosthetic bone resorption adjacent to the implant surface, and several causes including mechanical factors, such as the implant design and materials, stress transfer (stress-shielding), and micromotion2-4, as well as biological factors, such as tissue necrosis, bone-remodeling, disuse osteoporosis, and the host response to wear debris5-8, have been discussed. Many authors have focused on periprosthetic bone loss during the early postoperative phase after cementless total hip arthroplasty and the development of osteolysis9,10. Despite the beneficial effect of bisphosphonates in maintaining and improving periprosthetic bone quality11,12, there is still no direct evidence that improvement in bone density will also improve implant function or will even decrease the risk of revision surgery. In contrast, the lack of initial fixation and insufficient primary stability has been considered by Mjöberg13 to result in increased migration and, finally, in loosening of the implants. Indeed, many studies have confirmed that accelerated early migration is strongly associated with a higher rate of aseptic loosening in mid-term and long-term follow-up14-17.
There are some conflicting reports regarding the outcome of total hip arthroplasty in patients with osteonecrosis of the femoral head, with most of the reports indicating that total hip arthroplasty is less durable in these patients. While cementless components seem to provide better results in these patients than do cemented implants, the outcome still appears to be inferior for both the femoral and the acetabular components compared with that reported for patients with osteoarthritis18-23. Recently, Radl et al. found that the rate of aseptic loosening with the need for revision surgery during six years of follow-up was higher for patients with osteonecrosis than for those with osteoarthritis, and it was significantly (p < 0.001) associated with a more pronounced subsidence determined by the EBRA-digital method (Einzel-Bild-Roentgen-Analysis single-image radiographic analysis) at two years24.
Although the beneficial effects of bisphosphonates on periprosthetic bone mass and bone strength are well established, little is known about their effects on implant migration. This, however, is an important issue, because successful prevention of early implant migration with bisphosphonates may improve the survival rate of total hip replacements. The aim of this study was to evaluate the safety, practicability, and efficacy of a single dose of 4 mg of zoledronic acid after total hip arthroplasty to prevent early migration of the femoral and acetabular components in patients with osteonecrosis of the femoral head.
Study Design and Subjects
The study was primarily designed to evaluate whether a single infusion of 4 mg of zoledronic acid can prevent early implant migration. Secondary objectives included assessments of biochemical parameters reflecting bone turnover and vitamin-D status, as well as evaluation of the clinical outcome with use of the Harris hip-rating system. The protocol developed by the investigators was accepted by the local ethics committee (No. 12-152ex01/02; ), and the study was performed without industrial sponsorship. The trial was conducted in accordance with the Declaration of Helsinki (World Medical Association; ), and all patients gave their written informed consent prior to the start of treatment.
Fifty patients were consecutively enrolled into the study from July 2002 to March 2005. The inclusion criterion was the diagnosis of end-stage osteonecrosis of the femoral head (stage-V and VI disease according to the Association Research Circulation Osseous grading system25) on the basis of clinical and radiographic findings, which was also confirmed by magnetic resonance imaging and/or histological examination of the resected femoral head in all patients. Exclusion criteria were any history of disorders known to severely affect bone and mineral metabolism, including Paget disease and severe osteoporosis; previous treatment with bisphosphonates, fluorides, or calcitonin within the previous two years; and childbearing potential in women. The associated conditions and main risk factors for osteonecrosis among the forty-nine patients enrolled in the study included alcohol abuse (eighteen patients; 37%), corticosteroid use (six; 12%), end-stage renal disease with dialysis (three; 6%), diabetes (two; 4%), and posttraumatic state (one; 2%). Eighteen patients (37%) had two or more risk factors, while nineteen patients (39%) had no apparent risk factors and the osteonecrosis was designated as idiopathic.
Surgery
Total hip replacement was performed with use of the Zweymüller Alloclassic total hip system with a cementless rectangular straight titanium stem without a collar and an Allofit cementless titanium-backed acetabular cup (Sulzer Orthopedics, Baar, Switzerland). All of the procedures were performed by experienced surgeons using a standardized anterolateral transgluteal approach. One patient needed revision surgery after repeated dislocations within a few weeks after total hip arthroplasty and was excluded (the control group included twenty-four patients). In three patients, an alternative cup system had to be implanted (two threaded cups and one Burch-Schneider ring), and their data were excluded from the end-point analyses. Seventeen of the remaining forty-six press-fit cups were additionally secured by one, two, or three titanium cancellous screws (seven of twenty-three patients in the zoledronic acid group and ten of twenty-three in the control group). All of the patients routinely received perioperative antibiotics. Postoperatively, all patients were limited to partial weight-bearing (50% of body weight) and received antithrombotic prophylaxis with low-molecular-weight heparin for six weeks. Subsequently, the patients were permitted to advance to full weight-bearing as tolerated, and a rehabilitation program was begun.
Randomization
One day after surgery, the patients were randomly assigned to receive an intravenous infusion of 4 mg of either zoledronic acid or placebo (saline solution) in a double-blind fashion. The randomization and consecutive preparation of the study medications were performed by a pharmacist, were labeled with the study number of the subject, and were supplied to the study personnel to ensure blinding of patients, investigators, and the site personnel. All infusions were 20 mL in volume and were infused over a period of fifteen minutes. All patients were instructed to begin supplementary intake of calcium and vitamin D (1000 mg and 400 IU per day, respectively).
End Points and Monitoring
The primary end point of the study was a change in implant migration in patients receiving zoledronic acid compared with the control group during a minimum follow-up of two years, with intervals at seven weeks, six months, one year, and yearly thereafter. A total of 576 standardized, plain radiographs of the hip were analyzed with the EBRA-digital software (University of Innsbruck, Innsbruck, Austria), which has been demonstrated to be an accurate method to analyze clinically relevant migration of the femoral and acetabular components after total hip arthroplasty17,26-30. All measurements were performed independently by two investigators who were fully blinded to randomization (C.S. and G.F.); radiographs in the upper 20% of interobserver variance in subsidence were measured additionally by a third investigator (R.R.), and mean values were used for analysis.
Patients were evaluated clinically with use of subjective and objective information based on the Harris hip-rating system at each follow-up examination, and the total score was used for analysis. Clinical evaluation of adverse events and laboratory measurements, including serum chemistry, urine analysis, and hematological studies, was performed as indicated. A transient increase of >0.5°C in peripheral body temperature within twenty-four hours after the infusion of the study medication was designated as an "influenza-like" symptom. Laboratory analyses also included biochemical markers of bone turnover, which were measured from serum-separated fasting blood samples. Three patients with end-stage renal failure requiring hemodialysis were excluded from the analysis of bone-turnover markers (all received zoledronic acid); all other patients showed normal renal function (serum urea, serum creatinine, and creatinine clearance). Serum C-terminal telopeptides of collagen type I (ICTP [Orion Diagnostica Oy, Espoo, Finland] and CrossLaps [Nordic Bioscience Diagnostics, Herlev, Denmark]) were evaluated to assess the rate of bone resorption, and serum osteocalcin levels (CIS Bio International, Gif-sur-Yvette CEDEX, France) were evaluated to assess the rate of bone formation. Serum levels of 25-hydroxyvitamin D (Immunodiagnostic Systems, Boldon, England) were also determined.
Statistical Methods
Prior to the study, the total sample size was calculated as the number of patients needed to detect a difference in implant migration of 0.5 mm/yr within a minimum follow-up of two years, with a significance level of 0.05 and a power of 80%.
All patients finished the two-year follow-up; patients with missing data at three years (nine of twenty-five in the zoledronic acid group and eleven of twenty-four in the control group) were analyzed primarily with the last observation carried forward. The analyses were repeated with use of only the available data, and essentially the same results were produced (data not shown). Continuous variables are expressed as the mean with the 95% confidence interval unless otherwise stated; score variables are expressed as the median and range. The primary analysis for changes in implant migration and biochemical markers of bone turnover was performed by the analysis of variance on ranks for repeated measures to test the interaction between treatments over time. Additionally, analysis of covariance was performed to account for covariates observed following randomization. The effect within each variable was tested by the Friedman repeated-measures analysis of variance. Since these comparisons were performed for informational purposes only, no corrections for multiple comparisons were applied. Between-group comparisons of continuous variables at each time point were analyzed with use of the Mann-Whitney U test, and within-group comparisons between time points and baseline values were performed with use of the Wilcoxon signed-rank test. Categorical data were analyzed with use of the chi-square test and Fisher exact test as appropriate. All tests were two-tailed, with use of a critical value of p < 0.05.
Source of Funding
The trial was designed and performed as an academic investigation without any external or industrial funding sources.
Characteristics of Patients
The baseline characteristics of the patients and the characteristics of the implants used in total hip arthroplasty are summarized in Table I. No significant differences were found between the randomization groups.
Migration of the Implants
Within the placebo group, distal migration of the stem (subsidence) significantly increased up to a mean (and standard deviation) of -1.2 ± 0.6 mm and -1.3 ± 0.7 mm at two and three years, respectively, after total hip arthroplasty without reaching a plateau phase (p < 0.001). A similar migration pattern, less but nearly curvilinear, was also found for the acetabular components, with an average transverse migration (medialization) of 0.6 ± 1.0 mm and an average vertical migration (cranialization) of 0.6 ± 0.8 mm at two years in the control group (p < 0.001). The progress during follow-up is shown in Figure 1.
Efficacy for Primary End Point
Migration of the cups was effectively minimized within the zoledronic acid group; at two years, the mean transverse migration was 0.15 ± 0.6 mm and the mean vertical migration was 0.06 ± 0.6 mm, which is a significant difference compared with the migration pattern in the control group (p < 0.05). As shown in Figure 1, C and D, the efficacy of zoledronic acid to significantly minimize cup migration compared with the controls started at seven weeks for transverse migration and at six months for vertical migration (p < 0.05) and increased during the follow-up period. There were no significant differences in changes of inclination angle at any time point during follow-up (p > 0.05) (Fig. 1, B).
Subsidence significantly increased over time up to an average of -0.91 ± 0.51 mm at two years in the zoledronic acid-treated group (p < 0.001); thus, only a trend to decreased migration was apparent compared with controls (p = 0.108) (Fig. 1, A). When subsidence was adjusted for age, the differences during follow-up between the groups increased to significance (p = 0.04), and when median age was introduced as a dividing line to compare implant migration in younger patients with that in older patients (mean age, 50.6 ± 8.9 years and 70.9 ± 6.6 years, respectively), subsidence was higher in the older patients than in the younger patients in both groups (mean, -1.3 ± 0.7 mm compared with -1.0 ± 0.4 mm in the controls, and —1.2 ± 0.5 mm compared with -0.6 ± 0.3 mm in the treated group at two years, respectively; p < 0.05). Other covariates including idiopathic compared with secondary osteonecrosis, body mass index, and sex did not appear to significantly affect the main outcome. Additionally, the migration analysis was repeated after excluding the patients with medical conditions with the potential to seriously affect bone quality, that is, renal dialysis (three patients in the zoledronic acid group) and the use of steroids (one patient in the control group and five in the zoledronic acid group), with essentially the same results (data not shown).
Efficacy for Secondary End Points
There was an acute increase in the bone-resorption markers in the control group, with a peak at seven weeks after surgery (p = 0.0001 for ICTP, and no significant difference for CrossLaps). Thereafter, resorption markers continuously decreased below baseline levels (p < 0.001 at two years for CrossLaps and ICTP) (Fig. 2, A and B). The level of the bone-formation-marker osteocalcin also significantly increased, but peaked at six months after surgery and remained significantly increased during a follow-up of two years compared with baseline values (p < 0.05) (Fig. 2, C). Within the zoledronic acid-treated group, the values of CrossLaps were significantly suppressed within seven weeks after surgery and remained depressed during the entire follow-up period (p < 0.001) (Fig. 2, A). This was significantly different from the changes found in the placebo-treated patients at any interval during follow-up (p < 0.001). Similarly, osteocalcin values were also significantly depressed in treated patients compared with controls after seven weeks (p < 0.05) (Fig. 2, C), but the differences never reached significance compared with baseline levels (p > 0.05). Although serum C-terminal telopeptide of collagen type I (ICTP) levels tended to be depressed in the zoledronic acid group within the first year, no significant difference compared with the control group was found at any time point during follow-up (Fig. 2, B). No significant difference was found in 25-hydroxyvitamin-D levels between the two groups and during follow-up within a pronounced variability (Fig. 2, D).
The mean Harris hip score was significantly lower in the zoledronic acid-treated group compared with the control group at the preoperative baseline (p < 0.05). These scores in both groups rapidly improved over time, but patients treated with zoledronic acid had significantly higher scores than controls at each follow-up interval (Table II).
In general, zoledronic acid was well tolerated and there were no serious adverse events. However, fourteen (56%) of the twenty-five patients receiving it had influenza-like symptoms with a mean increase in peripheral body temperature of up to 1.7°C that resolved within one to two days. Similar symptoms, however, were also found in three of twenty-four patients who received placebo only.
A single dose of 4 mg of zoledronic acid after total hip arthroplasty minimized migration of the acetabular component, but it did not significantly reduce subsidence of the stem in patients with osteonecrosis of the femoral head. The migration rate of the implants was measured as the primary end point of the study because there is very good evidence of a strong association between accelerated initial migration and subsequent failure of the total hip replacement components.
In our cohort, subsidence progressed continuously up to a mean of -1.2 ± 0.6 mm and — 1.3 ± 0.7 mm at two and three years, respectively, after total hip arthroplasty without reaching a plateau phase (Fig. 1, A). This is within a range that was previously identified with use of another cementless implant system, in which subsidence was significantly increased (p < 0.001) in patients with osteonecrosis of the femoral head compared with patients with osteoarthritis (a median of 1.5 mm compared with 0.6 mm at two years)24, and which was also associated with a significantly higher failure rate during the median follow-up of six years (p = 0.01). Several reasons for the poorer outcome in patients with osteonecrosis, including a higher mechanical loading of implants due to higher physical activity levels in younger or male patients, have been discussed31,32. Although subsidence tended to be decreased, zoledronic acid did not prevent distal migration of the stem, and it might be speculated that this difference could be a function of age or sex due to randomization bias rather than a real biological effect of the drug. However, we found a positive association between age and subsidence of the stem in both treatment groups, which may have diminished the beneficial effect of zoledronic acid in our cohort. An influence of age on subsidence is also supported by the covariance analysis, in which subsidence was significantly decreased in patients treated with zoledronic acid during follow-up after adjusting for age, while other covariates including sex did not appear to affect migration. In contrast, no such age-related differences were found for the migration of the cups, as only slight cup migration in both the transverse and the vertical direction occurred with zoledronic acid treatment (Fig. 1, C and D). These findings may reflect substantial differences in the mechanism of migration between the femoral and acetabular components, and this might be of relevance when antiresorptive treatment is considered in an effort to reduce the prevalence of subsequent prosthetic loosening.
It has been hypothesized that systemically administrated bisphosphonates accumulate locally in freshly exposed bone mineral after drilling and reaming during the implantation of a hip prosthesis11 and may be retained in bone because they reattach after release by osteoclast resorption during the remodeling cycle. Such a recycling mechanism of an effective local amount of bisphosphonates is supported by our findings of a very pronounced and long-lasting effect of zoledronic acid. While absolute values of biochemical bone markers may be representative for the whole-body level of bone turnover, the relative changes during follow-up as shown in Figure 2 are likely rather to reflect the local response to surgery. A sufficient reduction in bone turnover may be crucial for implant fixation because it increases the lifespan of bone structural units, which may not only result in more complete mineralization33 but may also provide more unresorbed trabecular surface, which constitutes a critical prerequisite for a fast reactivation of osteoblasts and an accelerated development of new bone tissue34,35. This may also explain how the migration of uncemented cups, in which the anchorage in trabecular bone exposed by reaming the acetabular surface is of utmost importance, may be primarily determined by biological factors and is therefore highly responsive to zoledronic acid, while the initial fixation of the femoral components may substantially depend on other, nonbiological factors, including the mechanical microenvironment in the femur, which is known to be compromised in older patients because of an age-related loss of bone mass and quality. This concept is also supported by the findings of Onsten et al., who demonstrated that, in patients with rheumatoid arthritis who have highly increased bone turnover, the migration of the acetabular components was significantly accelerated (p < 0.04), while stem subsidence was not36.
Few studies targeting the potential of bisphosphonates in the prevention of prosthetic migration are currently available. Hilding and Aspenberg suggested in a double-blind study that six months of treatment with clodronate after total knee arthroplasty might reduce the risk of aseptic loosening, since initial fixation was increased at one year and migration was still significantly reduced (p = 0.02) at the time of the four-year follow-up37. In a randomized, double-blind trial of a hybrid-type total hip arthroplasty in patients with osteoarthritis, Wilkinson et al. found that a single dose of 90 mg of pamidronate significantly reduced femoral bone loss (p = 0.01) but did not affect pelvic bone mass, and cup migration even tended to be increased38. The reasons for the contradictory findings are unclear, but superior properties including the unique long-lasting effects of zoledronic acid may account for them39-41.
As expected, the Harris hip score rapidly increased to an overall excellent outcome after two years in both groups; notably, this was significantly more pronounced in patients treated with zoledronic acid (Table II). Since no difference in the functional outcome of total hip arthroplasty was apparent between the groups, pain and associated restrictions in daily activity, which are the major determinants in the Harris hip score, likely were responsible for the superior outcome in the zoledronic acid treatment group. Because the outcome was excellent in both groups, the clinical importance of this finding remains unclear and should be given more attention in subsequent trials, since this drug has also been shown to exert direct effects on the pathogenesis of bone pain42.
No patient was found to have impending implant loosening clinically or radiographically in our series, and it remains to be elucidated whether the beneficial effects of zoledronic acid will also reduce the rate of revision surgery in the long term. Nevertheless, the strengths of the present trial are the prospective, controlled, and double-blind study design in conjunction with independence from any industrial sponsorship, thus eliminating major confounding factors possibly biasing the outcome12. 
Note: The authors thank the administration of the Medical University of Graz and of the "Landeskrankenhaus Graz" for the opportunity to perform the study independent of any industrial sponsorship. They also thank Christa Barowitsch for performing the laboratory measurements, Barbara Primus and Marianne Leitner for randomization and preparation of the study medication, Silvia Ulz and Cornelia Wiedner for their support in the management of the follow-up visits, and Eugenia Lamont for critically reviewing the manuscript.
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