The Open Orthopaedics Journal




ISSN: 1874-3250 ― Volume 14, 2020

Biomarkers in Arthroplasty: A Systematic Review



Marty T Mertens 1, Jasvinder A Singh*, 1, 2, 3, 4
1 Rheumatology Section, Medicine Service, Minneapolis, MN, USA
2 Center for Chronic Disease Outcomes Research at the VA Medical Center, Minneapolis, MN, USA
3 Division of Rheumatology, Department of Medicine, University of Minnesota, Minneapolis, MN, USA
4 Departments of Health Sciences Research and Orthopedics, Mayo Clinic School of Medicine, Rochester, MN, USA

Abstract

We performed a systematic review of all MEDLINE-published studies of biomarkers in arthroplasty. Thirty studies met the inclusion criteria; majority evaluated biomarkers for osteolysis, aseptic prosthetic loosening, and prosthetic infections. Four studies reported an elevated Cross-linked N-telopeptides of type I collagen (urine or serum) in patients with osteolysis or aseptic prosthetic loosening when compared to appropriate controls. Two or more studies each found elevated C-reactive protein, erythrocyte sedimentation rate, and interleukin-6 in patients with infected prosthetic joints compared to controls. Most other biomarkers were either examined by single studies or had inconsistent or insignificant associations with outcomes. We conclude that the majority of the biomarkers currently lack the evidence to be considered as biomarkers for arthroplasty outcomes. Further studies are needed.

Keywords: Biomarkers, arthroplasty, systematic review.


Article Information


Identifiers and Pagination:

Year: 2011
Volume: 5
First Page: 92
Last Page: 105
Publisher Id: TOORTHJ-5-92
DOI: 10.2174/1874325001105010092

Article History:

Received Date: 9/10/2009
Revision Received Date: 4/4/2010
Acceptance Date: 7/7/2010
Electronic publication date: 16/3/2011
Collection year: 2011

© Mertens and Singh; Licensee Bentham Open.

open-access license: This is an open access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/3.0/) which permits unrestricted, non-commercial use, distribution, and reproduction in any medium, provided the work is properly cited.


* Address correspondence to this author at the University of Alabama, Faculty Office Tower 805B, 510 20th Street S, Birmingham, AL 35294, USA; Tel: 205-934-8158; Fax: 205-966-9685; E-mail: jasvinder.md@gmail.com





INTRODUCTION

Total hip and knee arthroplasty (THA and TKA) represent a major advance in the treatment of refractory hip/knee joint pain. TKA and THA are performed very commonly and are projected to increase dramatically in numbers in the next two decades [1Kurtz S, Ong K, Lau E, Mowat F, Halpern M. Projections of primary and revision hip and knee arthroplasty in the united states from 2005 to 2030 J Bone Joint Surg Am 2007; 89: 780-5.]. Increasing longevity, earlier age at arthroplasty, and excellent pain and functional outcomes with these procedures are cited as reasons for the increasing incidence of these procedures. A number of patients, however, have suboptimal outcomes. Complications may include refractory pain, peri-prosthesis osteolysis with aseptic loosening, heterotopic ossification, and infection, which may result in a failed arthroplasty. Evaluation for complications of arthroplasty are primarily clinical, with few prognostic or diagnostic tests easily available that allow early identification of this subgroup of patients with suboptimal outcomes.

Biomarkers are objective indicators of biologic processes, pathologic processes or pharmaceutical responses to therapeutic interventions [2Waqqas s. Biomarkers Definitions Working Group. Biomarkers and surrogate endpoints: Preferred definitions and conceptual framework Clin Pharmacol Ther 2001; 69: 89-95.]. A number of studies have assessed the prognostic and diagnostic utility of biomarkers in improving evaluation of outcomes following arthroplasty. The purpose of this systematic review is to summarize the data from the literature regarding biomarkers for arthroplasty outcomes. We specifically evaluated if there are any valid biomarkers for osteolysis or loosening of the prosthesis, prosthetic infections, pain/stiffness following arthroplasty, or other complications following arthroplasty.

METHODS

Study Design

All English language studies investigating biomarkers for various clinical outcomes of arthroplasty in humans were included in this review. Exclusion criteria included case reports, meta-analyses, and reviews. Studies that evaluated short term post-operative changes in biomarkers, biomarker changes related to medical therapies following arthroplasty, thromboembolic outcomes, and studies limited to pathology only were excluded as they were felt to be beyond the scope of this review.

Search Methods for Identification of Studies

A Cochrane librarian searched the MEDLINE electronic bibliographic database up to July 2008 using the MeSH terms “arthroplasty”, “replacement” and “biomarkers” and similar terms. The reference lists of identified publications were reviewed to identify any additional studies (Appendix 1 and 2).

Data Collection

Two reviewers (MM and JS) independently applied inclusion/exclusion criteria to all potential studies and extracted data and outcomes using a standardized form. Any disagreements were resolved by discussion between the two reviewers, referring to a third party if necessary. Review authors were not blinded to any features of studies, since unblinding has minimal impact on selection bias [3Berlin JA. Does blinding of readers affect the results of meta-analyses? University of pennsylvania meta-analysis blinding study group Lancet 1997; 350: 185-6.].

From each study, we extracted the following data – (1) study population, (2) methods and details of any interventions, (3) type of arthroplasty and implant, knee vs hip vs other, cemented vs noncemented, primary vs revision, and (4) types of biomarkers evaluated. Outcome data were extracted, where possible, as raw numbers, plus any summary measures where standard deviations or confidence intervals were given. If no raw results were available, specific outcomes were described in detail.

RESULTS

Eligible Studies

A total of 105 articles met initial criteria from the initial MEDLINE search completed in June 2007. The search was updated in July 2008 and a total of 149 articles were identified (Fig. 1). A total of 30 studies met inclusion/exclusion criteria, 26 from the original search and four additional studies from the reference lists of these studies.

Fig. (1)

Summary of screening of eligible studies.



Osteolysis

A total of five studies evaluated biomarkers for osteolysis following knee or hip arthroplasty (summarized in Table 1). Most comparisons were made to populations with arthroplasty with no osteolysis and to healthy controls without arthroplasty.

Table 1

Summary of screening of eligible studies.




Collagen telopeptides:

Three studies evaluated collagen telopeptides as biomarkers for osteolysis following hip arthroplasty. Antoniou et al. [4Antoniou J, Huk O, Zukor D, et al. Collagen crosslinked n-telopeptides as markers for evaluating particulate osteolysis: A preliminary study J Orthop Res 2000; 18: 64-7.] reported significantly higher urinary cross-linked N-telopeptides of type-T collagen in patients with osteolysis following hip arthropathy compared to controls. von Schewelov et al. [5von Schewelov T, Carlsson A, Dahlberg L, von Schewelov T, Carlsson A, Dahlberg L. Cross-linked n-telopeptide of type i collagen (ntx) in urine as a predictor of periprosthetic osteolysis J Orthop Res 2006; 24: 1342-8.] found a near significant increase in urinary cross-linked N-telopeptide in the osteolysis versus non-osteolysis group (p=0.06), which became significant after adjusting for age, gender, and time after surgery. Arabmotlagh et al. [6Arabmotlagh M, Sabljic R, Rittmeister M, Arabmotlagh M, Sabljic R, Rittmeister M. Changes of the biochemical markers of bone turnover and periprosthetic bone remodeling after cemented hip arthroplasty J Arthroplasty 2006; 21: 129-34.] found serum C-terminal telopeptides of type I collagen 3 weeks post-operatively to be significantly correlated with bone loss one year after hip arthroplasty.

Interleukin-1β (IL-1β) and Tumor Necrosis Factor-alpha (TNF-α):

Neither of the two studies that evaluated serum IL-1 β or TNF-α as a biomarker for osteolysis following hip arthroplasty found a significant difference between patients with osteolysis compared to controls [7Fiorito S, Magrini L, Goalard C, Fiorito S, Magrini L, Goalard C. Pro-inflammatory and anti-inflammatory circulating cytokines and periprosthetic osteolysis J Bone Joint Surg Br 2003; 85: 1202-6., 8Hernigou P, Intrator L, Bahrami T, Bensussan A, Farcet JP. Interleukin-6 in the blood of patients with total hip arthroplasty without loosening Clin Orthop Relat Res 1999; 147-54.].

IL-6:

Two studies [7Fiorito S, Magrini L, Goalard C, Fiorito S, Magrini L, Goalard C. Pro-inflammatory and anti-inflammatory circulating cytokines and periprosthetic osteolysis J Bone Joint Surg Br 2003; 85: 1202-6., 8Hernigou P, Intrator L, Bahrami T, Bensussan A, Farcet JP. Interleukin-6 in the blood of patients with total hip arthroplasty without loosening Clin Orthop Relat Res 1999; 147-54.] evaluated IL-6 as a biomarker for osteolysis following hip arthroplasty. Hernigou et al. [8Hernigou P, Intrator L, Bahrami T, Bensussan A, Farcet JP. Interleukin-6 in the blood of patients with total hip arthroplasty without loosening Clin Orthop Relat Res 1999; 147-54.] reported significantly higher IL-6 levels in patients with osteolysis compared to controls, while, in contrast, Fiorto et al. [7Fiorito S, Magrini L, Goalard C, Fiorito S, Magrini L, Goalard C. Pro-inflammatory and anti-inflammatory circulating cytokines and periprosthetic osteolysis J Bone Joint Surg Br 2003; 85: 1202-6.] did not find a significant difference in IL-6 levels with similar comparison groups.

Other:

Biomarkers evaluated by single studies included bone alkaline phosphatase (bone ALP) and osteocalcin [6Arabmotlagh M, Sabljic R, Rittmeister M, Arabmotlagh M, Sabljic R, Rittmeister M. Changes of the biochemical markers of bone turnover and periprosthetic bone remodeling after cemented hip arthroplasty J Arthroplasty 2006; 21: 129-34.]; IL-11, transforming growth factor-beta (TGF- β), matrix metalloproteinase-1 (MMP-1) and prostaglandin E-2 (PGE-2) [7Fiorito S, Magrini L, Goalard C, Fiorito S, Magrini L, Goalard C. Pro-inflammatory and anti-inflammatory circulating cytokines and periprosthetic osteolysis J Bone Joint Surg Br 2003; 85: 1202-6.]; and C-reactive protein (CRP) [8Hernigou P, Intrator L, Bahrami T, Bensussan A, Farcet JP. Interleukin-6 in the blood of patients with total hip arthroplasty without loosening Clin Orthop Relat Res 1999; 147-54.]. Only IL-11 was significantly lower in patients with osteolysis when compared to healthy controls and those without osteolysis.

Loosening

A total of 14 studies evaluated biomarkers for loosening of the prosthesis following knee or hip arthroplasty compared to healthy controls or patients with non-loosened prostheses (summarized in Table 2). Nine studies evaluated serum biomarkers and five, synovial fluid biomarkers.

Table 2

Summary of Biomarkers for Loosening of Prosthesis




Serum Biomarkers

Collagen Telopeptides:

Five studies evaluated various collagen peptides as a biomarker for prosthetic loosening. Serum levels of a C-terminal propeptide of type I procollagen (PICP) were not significantly different between clinically loosened hip prosthetic joints and controls [9Schneider U, Breusch SJ, Termath S, et al. Increased urinary crosslink levels in aseptic loosening of total hip arthroplasty J Arthroplasty 1998; 13: 687-92.] or between unfixed vs fixed knee protheses [10Li MG, Thorsen K, Nilsson KG, Li MG, Thorsen K, Nilsson KG. Increased bone turnover as reflected by biochemical markers in patients with potentially unstable fixation of the tibial component Arch Orthop Trauma Surg 2004; 124: 404-9.]. However, Savarino et al. [11Savarino L, Granchi D, Cenni E, et al. Systemic cross-linked n-terminal telopeptide and procollagen i c-terminal extension peptide as markers of bone turnover after total hip arthroplasty J Bone Joint Surg Br 2005; 87: 571-6.] demonstrated a significantly lower PICP concentrations in loosened hip prostheses compared to stable hip implants. Serum N-terminal propeptide of type I procollagen (PINP) levels did not differ between patients with hip prostheis loosening and controls [12Wilkinson JM, Hamer AJ, Rogers A, et al. Bone mineral density and biochemical markers of bone turnover in aseptic loosening after total hip arthroplasty J Orthop Res 2003; 21: 691-.].

Savarino et al. [11Savarino L, Granchi D, Cenni E, et al. Systemic cross-linked n-terminal telopeptide and procollagen i c-terminal extension peptide as markers of bone turnover after total hip arthroplasty J Bone Joint Surg Br 2005; 87: 571-6.] reported significantly higher serum cross-linked N-terminal telopeptide (NTx) levels in loosened hip protheses compared to controls. Li et al. [10Li MG, Thorsen K, Nilsson KG, Li MG, Thorsen K, Nilsson KG. Increased bone turnover as reflected by biochemical markers in patients with potentially unstable fixation of the tibial component Arch Orthop Trauma Surg 2004; 124: 404-9.] found significantly higher levels of serum cross-linked C-terminal telopeptides (ICTP) in unfixed knee arthroplasties when compared to fixed joints. Conversely, Wilkinson et al. [12Wilkinson JM, Hamer AJ, Rogers A, et al. Bone mineral density and biochemical markers of bone turnover in aseptic loosening after total hip arthroplasty J Orthop Res 2003; 21: 691-.] found no difference in ICTP levels between patients with loosened hip prostheses and controls. Moreschini et al. [13Moreschini O, Fiorito S, Magrini L, et al. Markers of connective tissue activation in aseptic hip prosthetic loosening J Arthroplasty 1997; 12: 695-703.] found no significant difference in type III procollagen peptide levels in patients with loosened hip prostheses when compared to controls with osteoarthritis.

Schneider et al. [9Schneider U, Breusch SJ, Termath S, et al. Increased urinary crosslink levels in aseptic loosening of total hip arthroplasty J Arthroplasty 1998; 13: 687-92.] and Wilkinson et al. [12Wilkinson JM, Hamer AJ, Rogers A, et al. Bone mineral density and biochemical markers of bone turnover in aseptic loosening after total hip arthroplasty J Orthop Res 2003; 21: 691-.] both found significantly increased levels of urinary crosslinked N-telopeptides of type I collagen in patients with loosened hip arthroplasty when compared to stable prostheses.

TNF-α:

Two studies [14Granchi D, Verri E, Ciapetti G, et al. Bone-resorbing cytokines in serum of patients with aseptic loosening of hip prostheses J Bone Joint Surg Br 1998; 80: 912-7., 15Hundric-Haspl Z, Pecina M, Haspl M, et al. Plasma cytokines as markers of aseptic prosthesis loosening Clin Orthop 2006; 453: 299-304.] evaluated TNF-α as a biomarker for loosening of arthroplasty. Hundri-Haspl et al. [15Hundric-Haspl Z, Pecina M, Haspl M, et al. Plasma cytokines as markers of aseptic prosthesis loosening Clin Orthop 2006; 453: 299-304.] noted significant increase in TNF-α values in patients with loosened knee and hip arthroplasty when compared to controls, while Granchi et al. [14Granchi D, Verri E, Ciapetti G, et al. Bone-resorbing cytokines in serum of patients with aseptic loosening of hip prostheses J Bone Joint Surg Br 1998; 80: 912-7.] found no difference in TNF-α levels in similar comparison groups.

IL-1β:

Three studies [13Moreschini O, Fiorito S, Magrini L, et al. Markers of connective tissue activation in aseptic hip prosthetic loosening J Arthroplasty 1997; 12: 695-703.-15Hundric-Haspl Z, Pecina M, Haspl M, et al. Plasma cytokines as markers of aseptic prosthesis loosening Clin Orthop 2006; 453: 299-304.] evaluated serum IL-1β as a biomarker for arthroplasty loosening. Hundri-Haspl et al. [15Hundric-Haspl Z, Pecina M, Haspl M, et al. Plasma cytokines as markers of aseptic prosthesis loosening Clin Orthop 2006; 453: 299-304.] noted significant increase in IL-1β in patients with loosened knee and hip arthroplasty when compared to controls. Granchi et al. [14Granchi D, Verri E, Ciapetti G, et al. Bone-resorbing cytokines in serum of patients with aseptic loosening of hip prostheses J Bone Joint Surg Br 1998; 80: 912-7.] did not find a difference in IL-1β when comparing loosened hip arthroplasty to healthy controls. However, on subgroup analysis, they found a significant increase in IL-1β in patients with loosened titaniumaluminium-vanadium (TiAIV) cemented hip prostheses in comparison to healthy controls as well as loosened cobalt-chromium (CrCoMo) hip implants (cemented and uncemented) and uncemented TiAIV implants. Moreschini et al. [13Moreschini O, Fiorito S, Magrini L, et al. Markers of connective tissue activation in aseptic hip prosthetic loosening J Arthroplasty 1997; 12: 695-703.] reported detectable IL-1β in 4 of 9 patients with loosened hip implants compared to only 1 of 13 patients with fixed hip implant and 0 of 13 patients with OA prior to arthroplasty, though no statistical analysis was performed.

IL-6:

Two studies [14Granchi D, Verri E, Ciapetti G, et al. Bone-resorbing cytokines in serum of patients with aseptic loosening of hip prostheses J Bone Joint Surg Br 1998; 80: 912-7., 16Streich NA, Breusch SJ, Schneider U, Streich NA, Breusch SJ, Schneider U. Serum levels of interleukin 6 (il-6), granulocyte-macrophage colony-stimulating factor (gm-csf) and elastase in aseptic prosthetic loosening Int Orthop 2003; 27: 267-71.] found no significant differences in IL-6 levels in patients with loosened hip arthroplasty compared to controls.

Granulocyte-macrophage colony stimulating factor (GM-CSF):

Streich et al. [16Streich NA, Breusch SJ, Schneider U, Streich NA, Breusch SJ, Schneider U. Serum levels of interleukin 6 (il-6), granulocyte-macrophage colony-stimulating factor (gm-csf) and elastase in aseptic prosthetic loosening Int Orthop 2003; 27: 267-71.] demonstrated detectible levels of GM-CSF in only 1 of 23 patients with loosened hip arthroplasty and in 0 of 23 of fixed hip implant patients. Granchi et al. [14Granchi D, Verri E, Ciapetti G, et al. Bone-resorbing cytokines in serum of patients with aseptic loosening of hip prostheses J Bone Joint Surg Br 1998; 80: 912-7.] reported significantly higher levels of GM-CSF in patients with a loosened hip arthroplasty when compared to healthy controls. This significant increase was demonstrated in all subgroups (cemented/uncemented TiAIV implants, cemented CrCoMo implants) except loosened uncemented CrCoMo implants which were similar to controls.

Osteocalcin:

Schneider et al. [9Schneider U, Breusch SJ, Termath S, et al. Increased urinary crosslink levels in aseptic loosening of total hip arthroplasty J Arthroplasty 1998; 13: 687-92.] reported significantly higher osteocalcin levels in loosened versus stable prostheses, while Wilkinson et al. [12Wilkinson JM, Hamer AJ, Rogers A, et al. Bone mineral density and biochemical markers of bone turnover in aseptic loosening after total hip arthroplasty J Orthop Res 2003; 21: 691-.] found no difference with the same comparison. Li et al. [10Li MG, Thorsen K, Nilsson KG, Li MG, Thorsen K, Nilsson KG. Increased bone turnover as reflected by biochemical markers in patients with potentially unstable fixation of the tibial component Arch Orthop Trauma Surg 2004; 124: 404-9.] found significantly higher osteocalcin levels in patients with potentially unstable knee prostheses compared to patients with stable implants at 12 months, but no differences were noted at 24 months.

Bone alkaline phosphatase (ALP):

Bone-specific ALP levels were similar in patients with and without loosening of hip prosthesis in two studies [9Schneider U, Breusch SJ, Termath S, et al. Increased urinary crosslink levels in aseptic loosening of total hip arthroplasty J Arthroplasty 1998; 13: 687-92., 12Wilkinson JM, Hamer AJ, Rogers A, et al. Bone mineral density and biochemical markers of bone turnover in aseptic loosening after total hip arthroplasty J Orthop Res 2003; 21: 691-.].

Urine deoxypyridinoline:

Schneider et al. [9Schneider U, Breusch SJ, Termath S, et al. Increased urinary crosslink levels in aseptic loosening of total hip arthroplasty J Arthroplasty 1998; 13: 687-92.] found significantly higher urine deoxypyridinonline levels in patients with loosened hip implants compared to stable implants, while Wilkinson et al. [12Wilkinson JM, Hamer AJ, Rogers A, et al. Bone mineral density and biochemical markers of bone turnover in aseptic loosening after total hip arthroplasty J Orthop Res 2003; 21: 691-.] reported no significant difference in similar comparison groups.

IL-2 receptor:

Two studies [14Granchi D, Verri E, Ciapetti G, et al. Bone-resorbing cytokines in serum of patients with aseptic loosening of hip prostheses J Bone Joint Surg Br 1998; 80: 912-7., 16Streich NA, Breusch SJ, Schneider U, Streich NA, Breusch SJ, Schneider U. Serum levels of interleukin 6 (il-6), granulocyte-macrophage colony-stimulating factor (gm-csf) and elastase in aseptic prosthetic loosening Int Orthop 2003; 27: 267-71.] found no significant differences in IL-2 receptor concentrations in patients with prosthesis loosening compared to controls.

Other:

The evidence for each of the following was based on single studies. Significantly higher levels of osteoprotegerin (OPG) and RANKL [17Granchi D, Pellacani A, Spina M, et al. Serum levels of osteoprotegerin and receptor activator of nuclear factor-kappab ligand as markers of periprosthetic osteolysis J Bone Joint Surg Am 2006; 88: 1501-9.], hyaluronic acid [13Moreschini O, Fiorito S, Magrini L, et al. Markers of connective tissue activation in aseptic hip prosthetic loosening J Arthroplasty 1997; 12: 695-703.], urine pyridinoline [9Schneider U, Breusch SJ, Termath S, et al. Increased urinary crosslink levels in aseptic loosening of total hip arthroplasty J Arthroplasty 1998; 13: 687-92.] and IL-8 [15Hundric-Haspl Z, Pecina M, Haspl M, et al. Plasma cytokines as markers of aseptic prosthesis loosening Clin Orthop 2006; 453: 299-304.] were found in patients with loosened hip implants compared to their respective controls. Elastase levels were not significantly different between patients with loosened implant and controls [16Streich NA, Breusch SJ, Schneider U, Streich NA, Breusch SJ, Schneider U. Serum levels of interleukin 6 (il-6), granulocyte-macrophage colony-stimulating factor (gm-csf) and elastase in aseptic prosthetic loosening Int Orthop 2003; 27: 267-71.].

Synovial Biomarkers

Four studies evaluated various biomarkers in synovial fluid as a marker for loosening of the prosthetic joint when compared to controls.

IL-1β:

Nivbrant et al. [18Nivbrant B, Karlsson K, Karrholm J. Cytokine levels in synovial fluid from hips with well-functioning or loose prostheses J Bone Joint Surg Br 1999; 81: 163-6.] found significantly higher synovial IL-1β in loosened hip implants compared to osteoarthritis patients, but were similar to patients with fixed hip prostheses. Similarly, Kovacik et al. [19Kovacik MW, Gradisar IA Jr, Haprian JJ, et al. Osteolytic indicators found in total knee arthroplasty synovial fluid aspirates Clin Orthop 2000; 186-94.] reported significantly higher synovial IL-1β levels in patients with loosened knee prostheses compared to osteoarthritis patients.

Other:

Nivbrant et al. [18Nivbrant B, Karlsson K, Karrholm J. Cytokine levels in synovial fluid from hips with well-functioning or loose prostheses J Bone Joint Surg Br 1999; 81: 163-6.] demonstrated significantly higher synovial TNF-α levels in loosened prosthetic hip joints when compared to OA patients, though not when compared to fixed hip implants. Synovial IL-6 levels were similar between all of these groups, though too few observations were available for comparisons. Kawasaki et al. [20Kawasaki M, Hasegawa Y, Kondo S, et al. Concentration and localization of ykl-40 in hip joint diseases J Rheumatol 2001; 28: 341-5.] noted significantly higher YKL-40 levels, a growth factor for chondrocytes and fibroblasts, in failed hip implants when compared to OA patients, though these levels were similar to patients with osteonecrosis of the hip. Other biomarkers found to be significantly elevated in loosened prostheses when compared to OA patients in single studies were TNF-related activation protein (TRAP) concentrations [19Kovacik MW, Gradisar IA Jr, Haprian JJ, et al. Osteolytic indicators found in total knee arthroplasty synovial fluid aspirates Clin Orthop 2000; 186-94.], IL-8 [21Sypniewska G, Lis K, Bilinski PJ, Sypniewska G, Lis K, Bilinski PJ. Bone turnover markers and cytokines in joint fluid: Analyses in 10 patients with loose hip prosthesis and 39 with coxarthrosis Acta Orthop Scand 2002; 73: 518-22.], and IL-10 [21Sypniewska G, Lis K, Bilinski PJ, Sypniewska G, Lis K, Bilinski PJ. Bone turnover markers and cytokines in joint fluid: Analyses in 10 patients with loose hip prosthesis and 39 with coxarthrosis Acta Orthop Scand 2002; 73: 518-22.]. Lower concentrations of osteocalcin, B-crosslaps, and bone ALP were also noted in loosened hip prostheses when compared to OA patients in a single study [21Sypniewska G, Lis K, Bilinski PJ, Sypniewska G, Lis K, Bilinski PJ. Bone turnover markers and cytokines in joint fluid: Analyses in 10 patients with loose hip prosthesis and 39 with coxarthrosis Acta Orthop Scand 2002; 73: 518-22.]. IL-1α concentrations were similar in both groups [21Sypniewska G, Lis K, Bilinski PJ, Sypniewska G, Lis K, Bilinski PJ. Bone turnover markers and cytokines in joint fluid: Analyses in 10 patients with loose hip prosthesis and 39 with coxarthrosis Acta Orthop Scand 2002; 73: 518-22.].

Prosthetic Infections

A total of seven studies evaluated biomarkers for infection of the prosthesis following knee or hip arthroplasty (summarized in Table 3). Three studies, Rafiq et al. [22Rafiq M, Worthington T, Tebbs SE, et al. Serological detection of gram-positive bacterial infection around prostheses J Bone Joint Surg Br 2000; 82: 1156-61.], Galdbert et al. [23Galdbart JO, Allignet J, Tung HS, et al. Screening for staphylococcus epidermidis markers discriminating between skin-flora strains and those responsible for infections of joint prostheses J Infect Dis 2000; 182: 351-5.], and Frank et al. [24Frank KL, Hanssen AD, Patel R, Frank KL, Hanssen AD, Patel R. Icaa is not a useful diagnostic marker for prosthetic joint infection J Clin Microbiol 2004; 42: 4846-9.] evaluated markers for specific infections of prosthetic joints and four studies evaluated diagnostic biomarkers for prosthetic infections.

Table 3

Summary of Biomarkers for Infected Prostheses




C-reactive protein (CRP) and Erythrocyte sedimentation rate (ESR):

Three separate studies [25Di Cesare PE, Chang E, Preston CF, et al. Serum interleukin-6 as a marker of periprosthetic infection following total hip and knee arthroplasty J Bone Joint Surg Am 2005; 87: 1921-7.-27Nilsdotter-Augustinsson A, Briheim G, Herder A, et al. Inflammatory response in 85 patients with loosened hip prostheses: A prospective study comparing inflammatory markers in patients with aseptic and septic prosthetic loosening Acta Orthop 2007; 78: 629-39.] each found significantly higher CRP and ESR levels in patients infected prosthetic joints compared to aseptic revisions. Spangehl et al. [28Spangehl MJ, Masri BA, O'Connell JX, Duncan CP. Prospective analysis of preoperative and intraoperative investigations for the diagnosis of infection at the sites of two hundred and two revision total hip arthroplasties J Bone Joint Surg Am 1999; 81: 672-83.] prospectively analyzed patients undergoing hip revisions and noted a sensitivity of 0.96 and specificity of 0.92 for CRP levels >10 mg/L for infected versus aseptic revisions. For ESR>30, the respective sensitivity was 0.82 and specificity, 0.85.

IL-6:

Two studies [25Di Cesare PE, Chang E, Preston CF, et al. Serum interleukin-6 as a marker of periprosthetic infection following total hip and knee arthroplasty J Bone Joint Surg Am 2005; 87: 1921-7., 26Bottner F, Wegner A, Winkelmann W, et al. Interleukin-6, procalcitonin and tnf-alpha: Markers of periprosthetic infection following total joint replacement J Bone Joint Surg Br 2007; 89: 94-.] each noted significantly higher levels of serum IL-6 in infected prosthetic joints when compared to aseptic joints undergoing revision arthroplasty.

Other cytokines:

Bottner et al. [26Bottner F, Wegner A, Winkelmann W, et al. Interleukin-6, procalcitonin and tnf-alpha: Markers of periprosthetic infection following total joint replacement J Bone Joint Surg Br 2007; 89: 94-.] noted elevated levels of serum TNF-α and procalcitonin in patients with infected prosthetic joints compared to aseptic prosthetic revisions.

Synovial fluid markers:

Nilsdotter et al. [27Nilsdotter-Augustinsson A, Briheim G, Herder A, et al. Inflammatory response in 85 patients with loosened hip prostheses: A prospective study comparing inflammatory markers in patients with aseptic and septic prosthetic loosening Acta Orthop 2007; 78: 629-39.] noted significantly higher synovial fluid concentrations of TNF-α, IL-1β, and IL-6 in those with infected prosthetic hip joints when compared to aseptic controls.

Bacterial markers:

Galdbert et al. [23Galdbart JO, Allignet J, Tung HS, et al. Screening for staphylococcus epidermidis markers discriminating between skin-flora strains and those responsible for infections of joint prostheses J Infect Dis 2000; 182: 351-5.] evaluated bacterial genes from Staphylococcus epidermidis strains cultured from prosthetic infections as compared to S. epidermidis strains from skin flora of healthy controls. They found significantly greater frequency of biofilm production and the ica A operon in infected prostheses. In contrast, Frank et al. [24Frank KL, Hanssen AD, Patel R, Frank KL, Hanssen AD, Patel R. Icaa is not a useful diagnostic marker for prosthetic joint infection J Clin Microbiol 2004; 42: 4846-9.] found no difference in frequency of the ica A operon in coagulase-negative staph species cultured from prosthetic infections in comparison to strains obtained from prosthetic joints without evidence of infection.

Rafiq et al. [22Rafiq M, Worthington T, Tebbs SE, et al. Serological detection of gram-positive bacterial infection around prostheses J Bone Joint Surg Br 2000; 82: 1156-61.] reported significantly elevated titers of IgG to cellular lipoteichoic acid in patients with prosthetic joint infections as compared to patients with osteoarthritis or closed fractures. IgM titers were similar between these groups.

OTHER OUTCOMES

Pain/Stiffness

Hall et al. [29Hall GM, Peerbhoy D, Shenkin A, et al. Relationship of the functional recovery after hip arthroplasty to the neuroendocrine and inflammatory responses. [see comment] Br J Anaesth 2001; 87: 537-42.] found a significant correlation between peak CRP levels post-operatively and pain at time of discharge as well as between peak IL-6 levels post-operatively and time to be able to ambulate 10 and 25m following hip arthroplasty. No significant correlations were found between CRP or IL-6 levels post-operatively to 1 and 6 month Western Ontario and McMaster universities osteoarthritis index (WOMAC) values, a measure of arthritis-related disability.

Wozniak et al. [30Wozniak W, Markuszewski J, Wierusz-Kozlowska M, et al. Neutrophils are active in total joint implant loosening Acta Orthop Scand 2004; 75: 549-3.] prospectively found significantly higher nitrous oxide (NO) production from stimulated peripheral neutrophils 2 months and 2-3 years post-operatively in patients with pain compared to patients without pain following primary knee or hip arthroplasty.

Heterotopic Ossification

Wilkinson et al. [31Wilkinson JM, Stockley I, Hamer AJ, et al. Biochemical markers of bone turnover and development of heterotopic ossification after total hip arthroplasty J Orthop Res 2003; 21: 529-34.] noted significantly greater levels of C-telopeptide of type-I collagen, osteocalcin, and N-terminal propeptide of type-I procollagen in patients who developed heterotopic ossification at 26 weeks when compared to those without ossification. No differences were noted in bone ALP, urinary cross-linked N-telopeptide of type-I collagen, and urinary free deoxypridinoline.

Polyethyelene Wear

Messieh et al. [32Messieh M, Messieh M. Synovial fluid levels of lactate dehydrogenase in patients with total knee arthroplasty J Arthroplasty 1996; 11: 484-6.] noted a significant correlation between synovial lactate dehydrogenase (LDH) levels and polyethylene wear in eleven patients undergoing revision knee arthroplasty.

Hospital Outcomes

Ackland et al. [33Ackland GL, Scollay JM, Parks RW, et al. Pre-operative high sensitivity c-reactive protein and postoperative outcome in patients undergoing elective orthopaedic surgery Anaesthesia 2007; 62: 888-94.] prospectively noted patients with a preoperative CRP >3mg/L had a significantly longer mean hospital stay as compared to those with CRP <3 mg/L (7.5 vs 6.0 days, respectively) following knee or hip arthroplasty.

DISCUSSION

This systematic review of biomarkers in arthroplasty summarized the findings from 30 studies of clinical outcomes following knee and/or hip arthroplasty. Despite the enormous success rates of knee and hip arthroplasties, patients may face a number of potential complications post-operatively and during long-term follow-up, including periprosthetic osteolysis, implant loosening, and joint infections. Diagnostic and prognostic biomarkers have the potential to provide an early, accurate, and noninvasive diagnosis of these undesired outcomes as well as help design interventions to prevent some of these complications.

The most frequently studied arthroplasty outcomes with regards to biomarkers were osteolysis and prosthesis loosening. Osteolysis and subsequent aseptic joint loosening is the most common reason for joint revision in hip arthroplasty in the United States.

In our review of the published literature, only cross-linked Ntelopeptides of type I collagen (NTX-1) (serum or urine) was significantly associated with loosening/osteolysis, in more than two studies with appropriate controls (without loosening/osteolysis and/or healthy controls) [4Antoniou J, Huk O, Zukor D, et al. Collagen crosslinked n-telopeptides as markers for evaluating particulate osteolysis: A preliminary study J Orthop Res 2000; 18: 64-7., 9Schneider U, Breusch SJ, Termath S, et al. Increased urinary crosslink levels in aseptic loosening of total hip arthroplasty J Arthroplasty 1998; 13: 687-92., 11Savarino L, Granchi D, Cenni E, et al. Systemic cross-linked n-terminal telopeptide and procollagen i c-terminal extension peptide as markers of bone turnover after total hip arthroplasty J Bone Joint Surg Br 2005; 87: 571-6., 12Wilkinson JM, Hamer AJ, Rogers A, et al. Bone mineral density and biochemical markers of bone turnover in aseptic loosening after total hip arthroplasty J Orthop Res 2003; 21: 691-.]. Von Schewelov et al. found an insignificant difference between NTX-1 levels in patients with presence of osteolysis when compared to controls (p = 0.06), though became significant after adjustment for age, gender, and time after surgery.

Serum cytokines, such as serum IL-1 β or TNF-α, that have been suspected to be associated with development of osteolysis and loosening [35Perry MJ, Ponsford FM, Mortuza FY, Learmonth ID, Atkins RM, Elson CJ. Osteolytic properties of the synovial-like tissue from aseptically failed joint prostheses Br J Rheumatol 1996; 35: 943-50.-38Waddell J, Pritzker KP, Boynton EL. Increased cytokine secretion in patients with failed implants compared with patients with primary implants Clin Orthop Relat Res 2005; 434: 170-6.] had inconsistent associations with loosened prostheses [14Granchi D, Verri E, Ciapetti G, et al. Bone-resorbing cytokines in serum of patients with aseptic loosening of hip prostheses J Bone Joint Surg Br 1998; 80: 912-7., 15Hundric-Haspl Z, Pecina M, Haspl M, et al. Plasma cytokines as markers of aseptic prosthesis loosening Clin Orthop 2006; 453: 299-304.] and no association with osteolysis [7Fiorito S, Magrini L, Goalard C, Fiorito S, Magrini L, Goalard C. Pro-inflammatory and anti-inflammatory circulating cytokines and periprosthetic osteolysis J Bone Joint Surg Br 2003; 85: 1202-6., 8Hernigou P, Intrator L, Bahrami T, Bensussan A, Farcet JP. Interleukin-6 in the blood of patients with total hip arthroplasty without loosening Clin Orthop Relat Res 1999; 147-54.]. We postulate that this may be due to lack of well-designed studies rather than lack of association. A significant immunological response occurs in the periprosthetic tissue in many patients with prosthetic loosening, and it has been thought that this inflammatory process may contribute to the development of osteolysis and aseptic loosening [35Perry MJ, Ponsford FM, Mortuza FY, Learmonth ID, Atkins RM, Elson CJ. Osteolytic properties of the synovial-like tissue from aseptically failed joint prostheses Br J Rheumatol 1996; 35: 943-50.-38Waddell J, Pritzker KP, Boynton EL. Increased cytokine secretion in patients with failed implants compared with patients with primary implants Clin Orthop Relat Res 2005; 434: 170-6.]. Other biomarkers for osteolysis or prosthesis loosening were either studied by single studies or had inconsistent or insignificant differences.

Prosthetic infections lead to significant morbidity, are difficult to diagnose, and may lead to significant disability. CRP and ESR, both of which are currently used clinically in the diagnosis and follow-up of patients with prosthetic joint infections, were consistently found to be significantly elevated in septic prosthetic joints as compared to aseptic joint revision controls in a number of studies [25Di Cesare PE, Chang E, Preston CF, et al. Serum interleukin-6 as a marker of periprosthetic infection following total hip and knee arthroplasty J Bone Joint Surg Am 2005; 87: 1921-7.-28Spangehl MJ, Masri BA, O'Connell JX, Duncan CP. Prospective analysis of preoperative and intraoperative investigations for the diagnosis of infection at the sites of two hundred and two revision total hip arthroplasties J Bone Joint Surg Am 1999; 81: 672-83.]. Interleukin-6 was consistently found to be elevated in septic prostheses as compared to aseptic revision controls [25Di Cesare PE, Chang E, Preston CF, et al. Serum interleukin-6 as a marker of periprosthetic infection following total hip and knee arthroplasty J Bone Joint Surg Am 2005; 87: 1921-7., 26Bottner F, Wegner A, Winkelmann W, et al. Interleukin-6, procalcitonin and tnf-alpha: Markers of periprosthetic infection following total joint replacement J Bone Joint Surg Br 2007; 89: 94-.].

A number of other arthroplasty outcomes included in this review, such as heterotopic ossification, pain following arthroplasty, post-operative hospital outcomes, and polyethylene wear, were evaluated only by one or two studies. Because of this, it is difficult to make adequate assessments for there potential use as biomarkers for these outcomes.

This review had a number of limitations, mostly related to limitations of the included studies. The large variability of the biomarkers measured in the included studies with only a few studies replicating the results for each biomarker in more than one study/population, limited our ability to draw conclusions for most biomarkers. The majority of the included studies were case control studies with small sample sizes, with half of the included studies containing <50 patients. A number of these studies measured multiple biomarkers at multiple outcomes, making them prone to type I error, i.e., finding a positive result just by chance. Well-designed studies of larger, welldefined cohorts are needed to improve our understanding of the utility of these biomarkers in predicting arthroplasty outcomes.

In conclusion, this review evaluated 30 studies that measured different biomarkers for knee and hip arthroplasty outcomes. While a few biomarkers – namely cross-linked N-telopeptides of type I collagen for prosthesis loosening or osteolysis and CRP, ESR, and IL-6 for infected prostheses – were found consistently significantly different from control groups in the included studies, most biomarkers lack the evidence to be considered adequate markers for the arthroplasty outcomes at the present time. However, this is an exciting area of research that has the potential to impact and improve arthroplasty outcomes. Further studies are necessary, likely with larger study populations and longer prospective follow-up, to determine which of these biomarkers will have clinical application in diagnosis and/or prognosis of arthroplasty outcomes.

GRANT SUPPORT

Supported by the NIH CTSA Award 1 KL2 RR024151-01 (Mayo Clinic Center for Clinical and Translational Research).

Acknowledgments

ACKNOWLEDGEMENTS

We thank Indy Rutks of the Cochrane Library group at the Minneapolis Veterans Affairs Medical center, Minneapolis for performing and updating the search.

Appendix 1

Search strategy for Systematic Review Performed in 2007 (Updated in July 2008)

Database: Ovid MEDLINE(R) <1950 to July Week 4 2007>

Search Strategy:

---------------------------------------------------------------------------

  1. Biological Markers/ or biomarkers.mp. (79469)
  2. exp Arthroplasty, Replacement, Knee/ or exp Arthroplasty, Replacement/ or exp Arthroplasty, Replacement, Hip/ or exp Arthroplasty/ or exp Arthroplasty, Replacement, Finger/ or exp Joint Prosthesis/ or arthroplasty.mp. (39802)
  3. 1 and 2 (125)
  4. limit 3 to english language (105)

Appendix 2

Summary of the Included Studies



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