Arthrotomy‐based preclinical models of particle‐induced osteolysis: A systematic review

Abstract

We completed a systematic literature review of in vivo animal models that use arthrotomy-based methods to study particle-induced peri-implant osteolysis. The purpose of the review was to characterize the models developed to date, to determine the questions addressed, to assess scientific rigor and transparency and to identify gaps in knowledge. We probed three literature databases (Medline, Embase and Scopus) and found 77 manuscripts that fit the search parameters. In the most recent 10 years, researchers mainly used rat and mouse models, whereas in the previous 20 years large animal, canine and rabbit models were more common. The studies have demonstrated several pathophysiology pathways, including macrophage migration, particle phagocytosis, increased local production of cytokines and lysosomal enzymes, elevated bone resorption and suppressed bone formation. The effect of variation in particle characteristics and concentration received limited attention with somewhat mixed findings. Particle contamination by endotoxin was shown to exacerbate peri-implant osteolysis. The possibility of early diagnosis was demonstrated through imaging and biomarker approaches. Several studies showed that both local and systemic delivery of bisphosphonates inhibits the development of particle-induced osteolysis. Other methods of inhibiting osteolysis include the use of anabolic agents and altering the implant design. Few studies examined non-surgical rescue of loosened implants, with conflicting results with alendronate. We found that the manuscripts often lacked the methodological detail now advocated by the ARRIVE guidelines, suggesting that improvement in reporting would be useful to maximize rigor and transparency.

Discovery of biomarkers to identify peri‐implant osteolysis before radiographic diagnosis

“…Further, if patients at risk for subsequent osteolysis development could be identified at an early stage, this at-risk group could be designated for more intensive monitoring, in an effort to identify complications prior to substantial bone loss. Finally, although there are currently no validated treatment options for peri-implant osteolysis apart from revision surgery, several preclinical animal models have identified pharmacological agents able to prevent or reverse osteolysis if treatment is initiated early 11–13 . If biomarkers are validated, it is possible that they could motivate future pharmaceutical clinical trials by identifying patients either at risk for osteolysis or early in disease progression, for recruitment into such trials.…”

“…Finally, although there are currently no validated treatment options for peri-implant osteolysis apart from revision surgery, several preclinical animal models have identified pharmacological agents able to prevent or reverse osteolysis if treatment is initiated early. [11][12][13] If biomarkers are validated, it is possible that they could motivate future pharmaceutical clinical trials by identifying patients either at risk for osteolysis or early in disease progression, for recruitment into such trials. In addition, validated biomarkers can be used as a method to monitor response to any pharmacological intervention as they are more sensitive than radiographic studies.…”

“…Additionally, preclinical studies have shown that biological and pharmacological treatment strategies are able to prevent osteolysis progression if initiated early. [11][12][13] Unfortunately, clinical trials to test early intervention strategies are lacking. Bisphosphonates, when given late in disease progression, have been tested clinically without success.…”

Early Changes in Cement–Bone Fixation Using a Novel Rat Knee Replacement Model

“…Preclinical models used to investigate cement–bone interfaces to date have typically used a pre‐polymerized poly(methyl methacrylate) (PMMA) rod placed in the medullary cavity of long bones . There is also a large body of work investigating the effect of cement or polyethylene debris on bone osteolysis, alone, and in the presence of an implant . These approaches are useful to study the response of host bone to bulk PMMA or debris, but these preclinical models cannot recapitulate the cement–bone interdigitation found in knee replacements.…”

“…6,7 There is also a large body of work investigating the effect of cement or polyethylene debris on bone osteolysis, 8 alone, and in the presence of an implant. 6,7,9 These approaches are useful to study the response of host bone to bulk PMMA or debris, but these preclinical models cannot recapitulate the cement-bone interdigitation found in knee replacements. Knee replacement models have been developed for the mouse, 10 rat, 11,12 and rabbit, 13 but these were not specifically designed to explore cement-bone interdigitation.…”