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We investigated whether the drug denosumab modulates the inflammatory response after total hip arthroplasty in a randomized controlled trial. Significantly increased expression of RANKL was found in patients treated with denosumab. This could provide an explanation for the rebound effect with rapid loss of BMD seen after discontinuation of denosumab treatment.

PURPOSE: To evaluate whether denosumab, a human monoclonal antibody directed against receptor activator of nuclear factor kappa-B ligand (RANKL), modulates the inflammatory response after cementless total hip arthroplasty (THA) in patients with osteoarthritis of the hip.

METHODS: Sixty-four patients operated with cementless THA were randomized to two doses of 60-mg denosumab or placebo 1-3 days and 6 months postoperatively. Serum samples were analyzed by a multiplex extension assay detecting 92 inflammation-related proteins. Bone turnover markers were assessed. Proteins were analyzed using linear mixed effect models. Validation of conspicuous findings was performed with ELISA.

RESULTS: Two proteins were significantly affected by denosumab treatment: RANKL and tumor necrosis factor receptor super family member 9 (TNFRSF9). Serum levels of RANKL were more than twice as high in the denosumab than in the placebo group 3 months after surgery (ratio 2.10, p<0.001). Six and 12 months after surgery, the expression of RANKL was still elevated in the denosumab-treated group (ratios 1.50, p < 0.001; 1.47, p =0.002). The expression of TNFRSF9 was lower in the denosumab group at 3 months (ratio 0.68, p<0.001). In the denosumab group, concentrations of bone turnover markers were substantially reduced after 3 months, remained suppressed after 6 and 12 months, but increased above baseline at 24 months after surgery.

CONCLUSION: Two subcutaneous denosumab injections 6 months apart increase RANKL and depress TNFRSF9 after THA. This provides a possible explanation for the rebound effect on bone turnover markers as well as bone mineral density (BMD) upon withdrawal of denosumab. None of the other measured markers of inflammation was influenced by denosumab treatment.

Background: Denosumab preserves periprosthetic bone mineral density (pBMD) around uncemented total hip arthroplasty (THA) components. This exploratory analysis of a previously published randomized controlled trial (RCT) aimed to assess the medium-term effects of denosumab and to investigate the impact of any rebound phenomenon after treatment cessation.

Methods: 64 non-osteoporotic patients undergoing uncemented THA were enrolled in a randomized, double-blind, placebo-controlled phase-2 trial and received either 2 doses of denosumab or placebo. The primary outcome was pBMD at 12 months, measured by dual-energy X-ray absorptiometry (DEXA). At a mean follow-up of 5.6 years (range 4.3–7.3), 54 patients remained for clinical assessment, DEXA, and plain radiography. The study was registered on ClinicalTrials.gov (NCT01630941).

Results: No differences in pBMD in the acetabular Digas zones or femoral Gruen zones were found between groups. The estimated mean difference in the sum of all Digas zones was 0.042 g/cm² (95% CI -0.31 to 0.35; p = 0.81), and for the sum of all Gruen zones -0.06 g/cm² (95% CI -0.55 to 0.43; p = 0.80). No statistically significant differences were observed in patient-reported outcome measures or the incidence of heterotopic ossification (HO). A gradual decline in pBMD was evident but not associated with any adverse events.

Conclusion: At 5 years, the adjusted between-group difference and its 95% confidence interval suggested no clinically relevant persistent effect of denosumab.  Short-term treatment with denosumab can thus not be recommended to preserve periprosthetic bone after THA. Whether longer treatment duration or a sequential post-denosumab regimen could influence long-term periprosthetic bone preservation remains unknown and warrants further investigation.

Background 

Several studies using positron emission tomography (PET) show highly elevated periprosthetic bone uptake of fluorine-18 sodium fluoride (¹⁸F-fluoride), suggestive of implant loosening after arthroplasty. Focus so far has been on qualitative but not on quantitative assessment. There is also a lack of intraoperative confirmation of preoperative ¹⁸F-fluoride PET findings. Although the method seems to have acceptable accuracy and high sensitivity, an attempt to improve the specificity and an overall validation of the method appear warranted.

Questions/purposes 

(1) Is there a difference in ¹⁸F-fluoride uptake around loose versus well-fixed THA and TKA components? (2) Can ¹⁸F-fluoride uptake measures provide a threshold that differentiates loose from well-fixed implants undergoing revision for a variety of septic and aseptic indications? (3) In a population restricted to THA and TKA undergoing revision for aseptic indications, can measurement of ¹⁸F-fluoride uptake still distinguish loose from well-fixed components? (4) What is the interrater reliability of measuring ¹⁸F-fluoride uptake?

Methods 

This was a retrospective assessment of a diagnostic test, ¹⁸F-fluoride PET/CT, which was performed prior to revision surgery. We included 63 patients with 31 THAs and 32 TKAs. Sixty-five percent of patients were female, and the mean age at ¹⁸F-fluoride PET/CT was 66 years. The THA had different modes of fixation (cemented, cementless, and hybrid; 45%, 32%, and 23%, respectively), whereas all TKAs were cemented. Imaging was conducted using routine protocols 1 hour after tracer injection. The interobserver reproducibility was analyzed using Spearman rank correlations and Bland-Altman analyses. Two independent observers were trained separately by a nuclear physician to measure maximal periprosthetic standardized uptake values (SUV_max) for each arthroplasty component (n = 126). Findings at surgery (whether the components were well fixed or loose, as well as the presence or absence of infection) were used as a reference. Presence of periprosthetic joint infection was retrospectively determined based on the criteria suggested by the European Bone and Joint Infection Society (EBJIS): clinical features in combination with blood analysis, synovial fluid cytologic analysis, and microbiology test results. Receiver operating characteristic (ROC) curves were plotted to assess the area under the curve (AUC) for each investigated component separately, indicating suitable SUV_max thresholds that differentiate loose from well-fixed components. After excluding patients with confirmed or suspected PJI per the EBJIS criteria (n = 12), the above analysis was repeated for the remaining patients with aseptic loosening (n = 51).

Results 

We found higher ¹⁸F-fluoride uptake around loose versus well-fixed components in all but femoral TKA components (median [range] SUV_max for well-fixed versus loose THA cups 10 [7 to 30] versus 22 [6 to 64], difference of medians 12; p = 0.003; well-fixed versus loose TKA femoral components 14 [4 to 41] versus 19 [9 to 42], difference of medians 5; p = 0.38). We identified favorable ROC curves for all investigated components except femoral TKA components (THA cups AUC 0.81 [best threshold 13.9]; THA femoral stems AUC 0.9 [best threshold 17.3]; femoral TKA components AUC 0.6 [best threshold 14.3]; tibial TKA components AUC 0.83 [best threshold 15.8]). ¹⁸F-fluoride was even more accurate at diagnosing loosening when we limited the population to those patients believed not to have prosthetic joint infection (THA cups AUC 0.87 [best threshold 14.2]; THA femoral stems AUC 0.93 [best threshold 15.0]; femoral TKA components AUC 0.65 [best threshold 15.8]; tibial TKA components AUC 0.86 [best threshold 14.7]). We found strong interrater correlation when assessing SUV_max values, with Spearman ρ values ranging from 0.96 to 0.99 and Bland-Altman plots indicating excellent agreement between the two independent observers.

Conclusion 

Measuring SUV_max after ¹⁸F-fluoride PET/CT is a useful adjunct in the diagnostic evaluation for suspected implant loosening after THA and TKA. The method appears to be both accurate and reliable in diagnosing implant loosening for all components except femoral TKA components. In a real-world mixed population with both low-grade infection and aseptic loosening, the method seems to be fairly easy to learn and helpful to subspecialized arthroplasty clinicians. When infection can be ruled out, the method probably performs even better. Further prospective studies are warranted to explore the reason why femoral TKA component loosening was more difficult to ascertain using this novel technique.

Level of Evidence 

Level III, diagnostic study.

Aims: To compare the diagnostic accuracy of 18F-fluorodeoxyglucose (18F-FDG)- and 18F-fluoride-positron emission tomography/computed tomography (PET/CT) in detecting prosthetic joint infection (PJI). 

Methods: Eighty-eight patients with symptomatic total hip (THA, n = 45) or knee arthroplasties (TKA, n = 43) who underwent both 18F-FDG- and 18F-fluoride-PET/CT within 30 days, were retrospectively analysed. The standardised uptake values (SUVmax) were measured for each component. Infection status was determined according to EBJIS criteria and classified as “confirmed” or “likely” in 19/88 (21.6%) patients. Diagnostic accuracy was evaluated by measuring median SUVmax values with interquartile ranges (IQRs) and computing the area under the receiver operating characteristic (ROC) curve with 95% confidence intervals (CIs). Intraclass correlation coefficients (ICCs) were used to assess intra- and interobserver reliability

Results: 18F-FDG-PET/CT showed significantly higher SUVmax values around infected components compared to non-infected components, excluding THA cups: THA cups 3.9 (IQR 2.4–9.6) vs 2.9 (IQR 2.2–3.6; p = 0.66), THA stems 4.5 (IQR 3.3–5.9) vs 2.6 (IQR 2.0–3.6; p = 0.01), femoral TKA components 4.0 (IQR 2.8–5.8) vs 2.3 (IQR 1.6–2.9; p = 0.02), and tibial TKA components 5.5 (IQR 4.2–7.7) vs 2.6 (IQR 2.1–3.7; p < 0.001). For 18F-fluoride-PET/CT, significant differences were only detected in tibial TKA components. AUC values for 18F-FDG ranged from 0.91 (95% CI 0.81–1.00) for tibial TKA components to 0.55 (95% CI 0.27–0.83) for THA cups. Corresponding AUCs for 18F-fluoride were consistently lower. Intra-observer reliability was excellent for THA cups (ICC = 0.999), THA stems (0.983), and tibial TKA components (0.974), and fair for femoral TKA components (0.775).

Conclusion: 18F-FDG-PET/CT provided superior discrimination between infected and non-infected arthroplasty components compared to 18F-fluoride, achieving AUCs >0.76 for all sites except THA cups. Consequently, 18F-FDG is recommended as the tracer of choice in PET/CT imaging for suspected PJI.