Autophagy: A Culprit in Aseptic Implant Loosening?
This post comes from Fred Nelson, MD, an orthopaedic surgeon in the Department of Orthopedics at Henry Ford Hospital and a clinical associate professor at Wayne State Medical School. Some of Dr. Nelson’s tips go out weekly to more than 3,000 members of the Orthopaedic Research Society (ORS), and all are distributed to more than 30 orthopaedic residency programs. Those not sent to the ORS are periodically reposted in OrthoBuzz with the permission of Dr. Nelson.
Periprosthetic membranes are fibrous granulomatous tissues composed of wear debris and numerous cell types, including fibroblasts, macrophages, osteoclasts (OCs), osteoblasts (OBs), osteocytes (OSTs), mesenchymal stem cells (MSCs), synovial cells, endothelial cells, and, rarely, lymphocytes. Macrophages ingest wear debris, resulting in the production of proinflammatory factors such as tumor necrosis factor (TNF); interleukin (IL)-1, IL-6, IL-17; macrophage colony-stimulating factor (M-CSF); and reactive oxygen species. In addition, macrophages can differentiate into OCs, which can induce the fibroblast cytokines that contribute to bone resorption.
Autophagy is the basic catabolic mechanism that degrades/recycles unnecessary or dysfunctional cellular components through the action of lysosomes. The breakdown of cellular components promotes cellular survival during stress, such as starvation, by maintaining cellular energy levels. In most instances, autophagy does not lead to cell death. Although the products of autophagy are typically recycled intracellularly, they may also be secreted.
Autophagy is also important for the differentiation of OBs, OSTs, and OCs. In addition, autophagy is involved in OB mineralization, and autophagy proteins are required for OC bone resorption. Autophagy appears to be triggered by wear debris in OCs, OBs, and macrophages, where the process promotes the secretion of proinflammatory proteins associated with the development of aseptic loosening. Autophagy can also be involved in the secretion of proteins such as chemokine (C-C motif) ligand 2 (CCL2) and leukemia inhibitory factor (LIF), which were both overexpressed in aseptic loosening in a rat model.
Autophagy inhibition has been shown to decrease osteolysis severity in animal models. For example, 3-methyladenine inhibition of the autophagy response to TiAl6V4 particles improved bone microarchitecture in a murine calvaria resorption model. Although autophagy will probably not be the final answer for prosthetic loosening, it is an avenue that should prompt future research into new therapeutic approaches.
Reference
Camuzard O, Breuil V, Carle GF, Pierrefite-Carle V. Autophagy Involvement in Aseptic Loosening of Arthroplasty Components. J Bone Joint Surg Am. 2019 Mar 6;101(5):466-472. doi: 10.2106/JBJS.18.00479. PMID: 30845042
Preventing Acetabular Component Migration in Revision THA
Revision total hip arthroplasty (THA) is a challenging procedure for many reasons, not the least of which is the risk of aseptic loosening leading to re-revision, especially in patients with severe acetabular defects. Acetabular components made of porous tantalum have a developed a good reputation for lower rates of re-revision, relative to components made of other materials. In the November 21, 2018 issue of The Journal of Bone & Joint Surgery, Solomon et al. bolster the evidence base regarding the success of porous tantalum acetabular components in revision THA.
The authors conducted a single-center prospective cohort study that used radiostereometric analysis (RSA) to accurately measure acetabular component migration in 55 revision THAs that involved a porous tantalum acetabular component. Over a mean follow-up of 4 years, 48 of the 55 components migrated <1 mm, the threshold that, based on previous findings in the literature, the authors defined as predicting later loosening. Five of the 7 components that exceeded the threshold were re-revised for loosening related to patient symptoms.
The RSA data for the 5 components that required re-revision revealed large proximal translations and sagittal rotations that increased over time until re-revision, although the RSA readings revealed that the majority of the migration occurred in the first 6 weeks. Among the components that did not exceed the 1 mm threshold for migration at 2 years, none have been subsequently re-revised for loosening.
The authors also analyzed fixation methods in this cohort. They found that, at 2 years, the median proximal translation of components that used inferior screw fixation was significantly lower than that of components without inferior screw fixation. The take-home messages from this study seem to be as follows:
- Porous tantalum acetabular components really do perform well in revision THA.
- When indicated, inferior screw fixation lowers the risk of component migration.
- Early component migration is a good predictor of long-term component survivorship.
Activities that Patients—and their PTs—Should Avoid After THA
The adult joint-reconstruction community has made great strides in the last 2 decades in understanding what causes aseptic loosening of arthroplasty components. For example, revelations about polyethylene particulate debris has led to the production of highly cross-linked polyethylene, which in turn has lowered wear rates, decreased revision rates, and increased the survivorship of total hip implants (see related OrthoBuzz post). Still, polyethylene debris is only one factor that can lead to aseptic loosening. Another important, yet often overlooked, factor is friction between the impacted acetabular shell and the host bone.
In the October 3, 2018 issue of The Journal, Bergmann et al. report data that help us better understand the “friction factor” in aseptic loosening. The authors implanted specially designed, instrumented acetabular components that measured in vivo friction moments among nine patients while they engaged in >1,400 different activities. The authors found that 124 of those activities led to friction moments >4 Nm—which appears to be the upper limit for facilitating a firm union between the acetabular component and the native socket.
Movements such as muscle stretching in the lunge position, the breaststroke in swimming, 2-legged standing with muscles contracted, and a single-legged stance while moving the contralateral leg were among those that created the highest friction between the implant and the host bone—and that could impede bone ingrowth into the acetabular component and thus contribute to aseptic loosening. The study also highlights the importance of periodic unloading of the prosthetic joint to allow proper synovial lubrication, which helps minimize the effects of high-friction moments. The good news is that the vast majority of activities studied do not appear to result in friction forces above the 4 Nm threshold.
Although these data should be confirmed with other in-vivo instrumented prostheses (assuming there are more patients willing to receive acetabular components capable of delivering telemetric data), they provide practical insight into the real-world forces placed on total hip prostheses after implantation. Such information can be used to counsel patients regarding high-friction and sustained-loading activities to be avoided, and it can help physical therapists and surgeons tailor postoperative regimens that optimize patient recovery while minimizing the risk to implanted prostheses.
Marc Swiontkowski, MD
JBJS Editor-in-Chief
What’s New in Musculoskeletal Basic Science 2017
Every month, JBJS publishes a Specialty Update—a review of the most pertinent and impactful studies published in the orthopaedic literature during the previous year in 13 subspecialties. Click here for a collection of all OrthoBuzz Specialty Update summaries.
This month, Matthew J. Allen, VetMB, PhD, author of the December 6, 2017 Specialty Update on Musculoskeletal Basic Science, summarized the five most compelling findings from among the more than 60 noteworthy studies summarized in the article.
Cartilage Repair
–Deriving induced pluripotent stem cells (iPSCs) from peripheral blood cells1 rather than from dermal fibroblasts obviates the need for in vitro expansion. This method may also serve to boost interest in the use of commercial cell-based therapies with defined potency that are available off-the-shelf and don’t require separate cell-harvesting procedures.
–The FDA recommends that large-animal models be used to corroborate basic-science findings from small-animal models. Recent work has demonstrated the efficacy of insulin-like growth factor (IGF)-1 in supporting mechanically competent repair tissue following chondrocyte implantation in a pig model.2
Infection
–Infection, especially from organisms that have developed antimicrobial resistance and/or that produce biofilms, continues to pose a challenging problem for orthopaedic surgeons. To provide a more rational and stratified approach to managing these complex cases, Getzlaf et al. recommend the use of a multidisciplinary approach in which patient-specific information about individual microorganisms is combined with detailed understandings of the vulnerabilities of candidate bacterial species.3
Aseptic Loosening
–There is a resurgence of interest in the role of subclinical infection in the etiopathogenesis of aseptic loosening. At the same time, molecular diagnostic methods for microbial infection are moving forward.4 Such methods may serve to highlight the relevance of subclinical microbial contamination as a cause of aseptic loosening.
Cartilage Imaging
–While the goal of cartilage imaging is to develop tools that are fast, inexpensive, sensitive, accurate, and noninvasive, there is growing interest in the use of more direct, invasive techniques such as optical coherence tomography (OCT),5 which could be used in vivo at the time of surgery to analyze cartilage damage.
References
- Li Y, Liu T, Van Halm-Lutterodt N, Chen J, Su Q, Hai Y. Reprogramming of blood cells into induced pluripotent stem cells as a new cell source for cartilage repair. Stem Cell Res Ther.2016 Feb 17;7:31.
- Meppelink AM, Zhao X, Griffin DJ, Erali R, Gill TJ, Bonassar LJ, Redmond RW,Randolph MA. Hyaline articular matrix formed by dynamic self-regenerating cartilage and hydrogels. Tissue Eng Part A.2016 Jul;22(13-14):962-70. Epub 2016 Jul 7.
- Getzlaf MA, Lewallen EA, Kremers HM, Jones DL, Bonin CA, Dudakovic A,Thaler R, Cohen RC, Lewallen DG, van Wijnen AJ. Multi-disciplinary antimicrobial strategies for improving orthopaedic implants to prevent prosthetic joint infections in hip and knee. J Orthop Res.2016 Feb;34(2):177-86. Epub 2015 Dec 29.
- Palmer MP, Melton-Kreft R, Nistico L, Hiller NL, Kim LH, Altman GT, Altman DT, Sotereanos NG, Hu FZ, De Meo PJ, Ehrlich GD. Polymerase chain reaction-electrospray-time-of-flight mass spectrometry versus culture for bacterial detection in septic arthritis and osteoarthritis. Genet Test Mol Biomarkers.2016 Dec;20(12):721-31. Epub 2016 Oct 17.
- Novakofski KD, Pownder SL, Koff MF, Williams RM, Potter HG, Fortier LA. High-resolution methods for diagnosing cartilage damage in vivo. 2016 Jan;7(1):39-51.
Reverse TSA Components Are Durable, But Patient Outcomes Decline Over a Decade
Reverse total shoulder arthroplasty (RTSA) has yielded promising medium-term outcomes, but what about longer-term results? In the March 15, 2017 edition of The Journal, Bacle et al. look at patient outcomes, prosthetic survival, and complications after a mean follow up of 12.5 years.
The good-news finding from this study was that the overall prosthetic survival rate (using revision as the end point) was 93%, confirming the reliability of the Grammont-style prosthesis. Time, however, took its toll on other outcomes. For example, both mean and absolute Constant scores among the cohort decreased significantly compared with the scores at the medium-term follow up (a minimum of 2 years). The cumulative long-term complication rate was 29%, with 10 of the 47 complications occurring at a mean of 8.3 years. Seven of those 10 delayed complications were attributed to mechanical loosening.
The authors suggest that the deterioration of RTSA outcomes seen in this study “is probably related to patient aging coupled with bone erosion and/or deltoid impairment over time.” They conclude that long-term RTSA outcomes “may be impacted by both the etiology of the shoulder dysfunction and the time since implantation.”
For more peer-reviewed content related to RTSA from JBJS Essential Surgical Techniques, click on the following links:
- Patient-Matched Implementation for Reverse Total Shoulder Arthroplasty
- Glenoid Bone-Grafting in Revision to a Reverse Total Shoulder Arthroplasty: Surgical Technique
- Technique for Reverse Total Shoulder Arthroplasty for Primary Glenohumeral Osteoarthritis with a Biconcave Glenoid
What’s New in Hip Replacement
Every month, JBJS publishes a Specialty Update—a review of the most pertinent and impactful studies published in the orthopaedic literature during the previous year in 13 subspecialties. Click here for a collection of all OrthoBuzz Specialty Update summaries.
This month, James Ninomiya, MD, MS, lead author of the September 21, 2016 Specialty Update on Hip Replacement, selected the five most clinically compelling findings from among the nearly 70 studies summarized in the Specialty Update.
Bearing Survivorship
–A meta-analysis found no differences in short- and medium-term implant survivorship among the following three bearing combinations used in THA patients younger than 65 years of age: ceramic on ceramic, ceramic on highly cross-linked polyethylene, and metal on highly cross-linked polyethylene.1
Insight into Aseptic Loosening
–Pathogen-associated molecular patterns (“endotoxins”) on particulate wear debris may be partially responsible for aseptic loosening. An in vitro/in vivo study found that macrophages that did not express the pathogen-associated molecular pattern receptor called TIRAP/Mal had significantly diminished secretion of inflammatory proteins. Patients with a genetic polymorphism suppressing that receptor exhibited decreased osteolysis during in vivo experiments. This suggests that some patients may be genetically more prone to aseptic loosening.
THA in Patients with RA
–A systematic review/meta-analysis of patients who were and were not taking a TNF-α inhibitor for rheumatoid arthritis prior to hip replacement found that those taking the drug had an increased risk of perioperative infection, with an odds ratio of 2.47.2 These results suggest that in order to decrease the risk of perioperative infections, it may be prudent to discontinue these drugs in advance of proposed joint replacement surgery.
Delaying THA for Femoral Head Osteonecrosis
–A systematic review/meta-analysis of patients with femoral head osteonecrosis concluded that injection of autologous bone marrow aspirate containing mesenchymal stem cells during core decompression was superior by a factor of 5 to core decompression alone in preventing collapse of the femoral head and delaying conversion to THA.3 This information may lead to new treatment paradigms for osteonecrosis.
Preventing Post-THA Dislocations
–A systematic review/meta-analysis that included more than 1,000 patients who underwent THA with a posterior or anterolateral approach found similar dislocation rates among those who were and were not given post-procedure restrictions in motion or activity.4 This suggests that the use of traditional hip precautions may not be necessary, and in fact may impede the rate of recovery following joint replacement surgery.
References
- Wyles CC, Jimenez-Almonte JH, Murad MH, Norambuena-Morales GA, Cabanela ME, Sierra RJ, TrousdaleRT. There are no differences in short- to mid-term survivorship among total hip-bearing surface options: a network meta-analysis. Clin Orthop Relat Res. 2015 Jun;473(6):2031-41. Epub 2014 Dec 17.
- Goodman SM, Menon I, Christos PJ, Smethurst R, Bykerk VP. Management of perioperative tumour necrosis factor α inhibitors in rheumatoid arthritis patients undergoing arthroplasty: a systematic review and meta-analysis. Rheumatology (Oxford). 2016 Mar;55(3):573-82. Epub 2015 Oct 7.
- Papakostidis C, Tosounidis TH, Jones E, Giannoudis PV. The role of “cell therapy” in osteonecrosis of the femoral head. A systematic review of the literature and meta-analysis of 7 studies. Acta Orthop. 2016 Feb;87(1):72-8. Epub 2015 Jul 29.
- Van der Weegen W, Kornuijt A, Das D. Do lifestyle restrictions and precautions prevent dislocation after total hip arthroplasty? A systematic review and meta-analysis of the literature. Clin Rehabil. 2016 Apr;30(4):329-39. Epub 2015 Mar 31.
Synovial Aspirates to Differentiate Septic vs Aseptic TKA Failures
When diagnosing loose components after total knee arthroplasty (TKA), orthopaedists often turn to synovial-fluid analysis to help them differentiate between septic and aseptic causes. But how useful are such analyses clinically? Although that was not the primary research question in the October 7, 2015 JBJS article by Chalmers et al., their findings shed light on the utility of synovial white blood-cell (WBC) counts in differentiating aseptic from septic loosening.
When the authors compared synovial-fluid characteristics among patients with periprosthetic infections to those among patients with various modes of aseptic failure (including extensor mechanism failure, component malposition, polyethylene wear, and periprosthetic fracture), they concluded that “to maximize the diagnostic accuracy of synovial aspiration, different [WBC] cutoffs may need to be employed depending on the clinical scenario and the alternative diagnosis being considered.”
For example, Chalmers et al. found that if there was radiographic evidence of component malposition at the same time a surgeon suspected periprosthetic infection, the optimal WBC cutoff would be 2104 cells/µL (sensitivity=95%; specificity=100%). But if a patient presented with a periprosthetic fracture and the surgeon suspected that the fracture may have occurred as a consequence of septic loosening, the optimal WBC cutoff would be 4697 cells/µL (sensitivity=89%; specificity=100%). Meanwhile, the current AAOS Clinical Practice Guideline cutoff for chronic periprosthetic infection is 1700 cells/µL.
The variability in these findings led the authors to conclude that “the optimal diagnosis of periprosthetic infection on the basis of synovial aspiration results may need to utilize different cutoff values depending on the alternative mode of failure being considered.”
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