**1. Introduction**

Total hip arthroplasty (THA) is one of the most successful orthopaedic procedures and has relieved pain and improved hip function in millions of patients worldwide. Despite the success of modern prosthetic designs and bearing surfaces, around 10% of THA prostheses still fail within 10 years1. Improvements in surgical technique and prosthesis design have decreased the incidence of deep sepsis, dislocation and fracture, however aseptic loosening, the clinical end point of osteolysis, remains the most frequent complication and in the UK accounts for 63% of all revision surgery (Table 1)2. Prosthesis loosening results in pain and disability, requiring revision surgery. Revision THA is associated with a 3 to 8-fold greater in-hospital mortality, poorer functional outcome, longer hospital stay, and higher cost than primary surgery1,3-5.

The problem of osteolysis has been recognized in Judet's acrylic hemiarthroplasty introduced in the 1940s. Prosthesis loosening complicating THA in the 1950's and 1960's was poorly understood and attributed to unconfirmed sepsis6 and prosthesis motion7. In the 1980's loosening was thought to be the result of "cement disease"8, arising due to a foreign body reaction to methyl methacrylate. When the development of cementless prostheses


Table 1. Summary of hip surgery data from 7th Annual Report National Joint Registry for England and Wales2

Risk Factors for Aseptic Loosening Following Total Hip Arthroplasty 277

the initiation of the biological response. The innate immune system is the body's first defense against foreign pathogens. Its ability to recognize and eliminate pathogens relies on pattern recognition receptors (PRR). PRRs are expressed by several cells in the monocyte cell lineage and include toll-like receptors (TLR) and the NOD-like receptors (NLR). These subfamilies evoke an inflammatory response either through the activation of transcription factors or through the formation of inflammasomes (Figure 1). Inflammasomes are large cytoplasmic complexes that activate inflammatory caspases required for the catalysis of pro-IL-1β and pro-IL-18 into their active forms18. Disorders of inflammasome signaling are

Fig. 1. Summary of pattern recognition receptors and their effector pathways. NALP = NACHT, LRR and PYD domain-containing proteins, IPAF = Ice protease activating factor, NAIP = neuronal apoptosis inhibitory protein, NOD = nucleotide-binding oligomerization

Caicedo et al found that metal implant debris stimulated an inflammatory response in macrophages through inflammasome signaling (Figure 2)19. Maitra found that UHMWPE wear particles are phagocytosed causing intracellular activation of NACHT, LRR and PYD domains-containing protein 3 (NLRP3) leading to inflammasome formation. In addition alkane polymers generated by UHMWPE activate TLRs through cell surface contact. This leads to the activation of transcription factors including NF-KB resulting in cytokine release20. St Pierre *et al* showed in a mouse model that titanium particles also induce an

domain proteins, CIITA = Major histocompatibility complex class-2 transactivator

inflammatory response through the activation of the NLRP3 inflammasome21.

associated with a number of auto-inflammatory conditions.

failed to eliminate this problem, wear at the bearing couple was subsequently identified as the main source of particulate debris giving rise to osteolysis.

Advances in prosthesis materials, design and surgical technique have improved the wear performance of prostheses, which will decrease the future incidence of osteolysis. However, an ageing population combined with younger more active patients now undergoing joint arthroplasty suggests that osteolysis and resulting prosthesis loosening will continue to be the major complication of THA.
