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. 2023 Apr 27;13:6918. doi: 10.1038/s41598-023-34177-w

Serum cobalt and chromium concentration following total hip arthroplasty: a Bayesian network meta-analysis

Filippo Migliorini 1,2,✉, Marco Pilone 3,4, Andreas Bell 2, Ricarda Merfort 1, Riccardo Giorgino 4, Nicola Maffulli 3,5,6
PMCID: PMC10140036  PMID: 37106086

Abstract

The present systematic review investigated the concentration of chromium (Cr) and cobalt (Co) in serum in patients who have undergone total hip arthroplasty (THA). The first outcome of interest was to investigate the mean concentration in serum of Cr and Co using different material combinations and to verify whether their concentrations change significantly using different patterns of head and liner in THA. The second outcome of interest was to investigate whether the time elapsed from the index surgery to the follow-up, BMI, sex, and side exert an influence on the mean concentration of Cr and Co in serum in patients who have undergone THA. The following material combinations were investigated (head-liner): Ceramic-Co Cr (CoCr), CoCr-CoCr, CoCr-Polyethylene, CoCr high carbide-CoCr high carbide. Data from 2756 procedures were retrieved. The mean length of follow-up was 69.3 ± 47.7 months. The ANOVA test evidenced good comparability in age, length of follow-up, BMI, and sex (P > 0.1). In patients who have undergone THA, the mean concentration in the serum of Co ranged between 0.5 µg/L and 3.5 µg/L, and the mean concentration of Cr from 0.6 to 2.6 µg/L. The difference in the concentration of Co and Cr in serum is strictly related to the implant configuration, with the coupling CoCr-CoCr showing the highest and CoCr-Polyethylene showing the lowest concentration. Patient characteristics, BMI, sex, side and the time elapsed from the index surgery to the last follow-up did not exert a significant influence on the concentration of Co and Cr in serum in patients who have undergone total hip arthroplasty (THA).

Subject terms: Medical research, Signs and symptoms, Materials science

Introduction

Total hip arthroplasty (THA) is a common procedure for patients with hip osteoarthritis. THA is associated with a significant improvement in patient reported outcome measures (PROMs)1–3. The weight bearing on the mobile components (head and liner) of THA produce friction, wear, tear, and deformation, and consequently the release of metal elements4. Particles release in implants with metallic mobile components, especially chromium (Cr) and cobalt (Co), is a concern1,5. These particles might remain into the joint capsule or migrate to the periarticular tissues or to other body sites though the blood and lymphatic circulation. The concentrations of Co and Cr in patients who have undergone THA with Co-Cr components are detectable in their serum. Several studies have been conducted to assess the serum concentration of Co and Cr in patients with such mobile components4,6–10. However, variability in implant components may impair a proper estimation of the serum concentration. Whether different mobile component configurations in THA (Ceramic-CoCr, CoCr-CoCr, CoCr-Polyethylene) is associated with differences in serum concentrations of Co and Cr is unclear and evidence is missing. Moreover, whether patient demographic may influence the serum concentration of Co and Cr has not been systematically evaluated. Recently, Co-Cr alloys have been enhanced with high carbide alloy (Co-CrHC) additives to increase the stability of the metals, and therefore, reduce wear, tear, and deformation over the time11–13. However, whether Co-CrHC is associated with a lower concentration of Co and Cr is also unclear.

The present systematic review investigated the concentration of Co and Cr in the serum of patients who had undergone THA. The first outcome of interest was to investigate the mean serum concentration of Cr and Co in patients who have undergone THA using different material combinations, and to verify whether their concentrations change significantly using different head and liner coupling. The second outcome of interest was to investigate whether the time elapsed from the index surgery to the follow-up, BMI, sex, and side exert an influence in the mean concentration in serum of Cr and Co. The following material combinations were investigated (head- liner): Ceramic-CoCr, CoCr-CoCr, CoCr-Polyethylene, CoCrHC-CoCrHC. It was hypothesised that patient characteristics and the time elapsed from the index surgery to the last follow-up did not exert a significant influence on the concentration of Co and Cr in serum.

Methods

Eligibility criteria

All the clinical trials investigating the concentration (µg/L) of Cr and/ or Co in serum in patients who have undergone THA were considered. Only studies which clearly stated the composition of head and/ or liner components were eligible. Reviews, opinions, letters, editorials were not considered. In vitro, computational, biomechanics, and animal studies were not eligible. Prospective studies level I to II of evidence, according to Oxford Centre of Evidence-Based Medicine14, were considered. Given the authors language abilities, articles in English, German, Italian, French and Spanish were eligible. Missing data on the mean serum concentration (µg/L) of Cr and Co warranted the exclusion from the present study.

Search strategy

This study compiles with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses: the 2020 PRISMA checklist15. The PICOTD algorithm was preliminary pointed out:

  • P (Problem): end-stage OA;

  • I (Intervention): THA;

  • C (Comparison): Ceramic-CoCr, CoCr-CoCr, CoCr-Polyethylene, CoCrHC-CoCrHC;

  • (Outcomes): concentration in serum;

  • T (Time): minimum 24 months follow-up;

  • D (Design): clinical trial.

In December 2022, the following databases were accessed: PubMed, Web of Science, Google Scholar, Embase. No time constrain was set for the search. The following matrix of keywords were used in each database to accomplish the search using the Boolean operator AND/OR: THA AND (OR hip OR arthroplasty OR replacement OR prosthesis) AND (serum OR blood OR plasma) AND (CoCr OR Cr Co OR Cr OR Co OR metal OR steel OR high carbide). No additional filters were used in the databases search.

Selection and data collection

Two authors (F. M. and R.M.) separately performed selection and data collection. The full-text of the studies which matched the topic of interest were accessed. If the full-text was not, the article was excluded. The references of the full-text articles were screened by hand by the reviewers for inclusion. In case of disagreements, a third author (N.M.) took the final decision.

Data extraction

Two authors (F.M. and R.M.) independently performed data extraction in a Microsoft Office Excel spreadsheet (version 16, Microsoft Corporation, Redmond, USA). The following generalities were retrieved: first author, year, length of the follow-up, and journal of publication. The following data at baseline were collected: number of patients, women, side, mean age, and mean BMI (Kg/m2). Data concerning the mean serum concentration (µg/L) of Cr and Co were extracted at last follow-up.

Assessment of the risk of bias

The risk of bias was evaluated in accordance with the guidelines in the Cochrane Handbook for Systematic Reviews of Interventions16. Two reviewers (R.G. and A.B.) evaluated the risk of bias of the extracted studies independently using the risk of bias of the software Review Manager 5.3 (The Nordic Cochrane Collaboration, Copenhagen). The following endpoints were evaluated: selection, detection, performance, attrition, reporting, and other bias. Disagreements were solved by a third author (N.M.).

Synthesis methods

The statistical analyses were performed by the main author (F.M.) following the recommendations of the Cochrane Handbook for Systematic Reviews of Interventions17. For descriptive statistics, mean and standard deviation were used. To evaluate baseline comparability of patient demographic, the SPSS software was used. The analysis of variance (ANOVA) was performed assuming that values of P > 0.05 indicated comparability. The STATA/MP software (Stata Corporation, College Station, Texas, USA) was used for the network meta-analysis. The analyses were performed through the STATA routine for Bayesian hierarchical random-effects model. Continuous variables were analysed through the inverse variance method with standardized mean difference (SMD) effect measure. The confidence interval was set at 0.95. Heterogeneity was assessed using χ2 and Higgins-I2 tests. If χ2 > 0.05, no statistically significant heterogeneity was found. A fixed model effect was used. If χ2 < 0.05 and Higgins-I2 > 60% high heterogeneity was found and a random model effect was used for analysis. A multiple linear model regression analysis through the Pearson Product-Moment Correlation Coefficient (r) was used. The Cauchy–Schwarz formula was used for inequality: + 1 is considered as positive linear correlation, while and − 1 a negative one. Values of 0.1 <| r |< 0.3, 0.3 <| r |< 0.5, and | r |> 0.5 were considered to have weak, moderate, and strong correlation, respectively. The overall significance was assessed through the χ2 test, with values of P < 0.05 considered statistically significant.

Ethical approval

This study complies with ethical standards.

Results

Study selection

The initial databases research resulted in 3477 articles. Of them 867 were excluded as they were duplicates. A further 2579 articles were excluded as they did not match the eligibility criteria: not reporting data on the concentration in Co and/ or Cr in serum (N = 1733), study design (N = 385), not focusing on THA (N = 329), poor level of evidence (N = 84), not clearly reported the composition of head and/ or liner (N = 45), language limitations (N = 3). A further eight studies were excluded as they did not report quantitative data under the outcomes of interests. Finally, 23 studies were included: 15 nonRCTs and 8 RCTs. The results of the literature search are shown in Fig. 1.

Figure 1.

Figure 1

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PRISMA flow chart of the literature search.

Risk of bias assessment

The risk of bias tool of the Cochrane Collaboration was used to evaluate the risk of bias. Given the prospective nature of the included studies, the overall risk of selection bias was low to moderate. Most studies did not perform assessor blinging or gave no information on it. Therefore, the risk of detection bias was moderate to high. The overall risk of attrition and reporting biases were both low to moderate, and the risk of other bias was moderate. Concluding, the overall quality of the methodological assessment was low to moderate (Fig. 2).

Figure 2.

Figure 2

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Cochrane risk of bias tool.

Study characteristics and results of individual studies

Data from 2756 THAs were retrieved. Of them, 53% (1461 of 2756) were performed on women. The mean length of the follow-up was 69.3 ± 47.7 months. The mean age was 59.9 ± 8.6 years and the mean BMI was 28.2 ± 1.9 kg/m2. The ANOVA test evidenced good comparability in age, follow-up, BMI and sex of the patient demographic (P > 0.1). The generalities of the included studies are shown in Table 1, and the patient demographic of each group is shown in Table 2.

Table 1.

Generalities and patient baseline of the included studies.

Author and year Design Head material Liner material Procedures Mean age Mean BMI Women (%)
Briggs et al. 20159 NonRCT CoCr Polyethylene 22 73 28.7 77%
Cocr CoCr 23 67 28.1 74%
Cadossi et al. 201618 NonRCT Ceramic CoCr 20 65.9 28.5 70%
CoCr CoCr 29 61.8 26 41%
Chen et al. 20168 NonRCT CoCrHC CoCrHC 25 36
CoCr Polyethylene 25 35.4
Dahlstrand et al. 201710 RCT CoCr CoCr 41 65 27 51%
CoCr Polyethylene 44 67 27 54%
Darrith et al. 202019 NonRCT CoCr CoCr 49 57.59 33.58 51%
Al2O3, CoCr CoCr, ceramic, polyethylene 26 58.65 33.72 50%
Engh et al. 201420 RCT CoCr Polyethylene 33 61.6 29.9 30%
CoCr CoCr 22 62.2 28.7 60%
CoCr CoCr 30 63.4 29.1 29%
CoCr CoCr 30 63.4 29.1 29%
Grübl et al. 200621 RCT Al2O3 Al2O3 15 58.2 28.2 53%
CoCr CoCr 13 66.8 28.2 77%
Al2O3 Al2O3 15 58.2 28.2 53%
CoCr CoCr 13 66.8 28.2 77%
Gustafson et al. 201422 RCT CoCr CoCr 19 64 26 53%
Al2O3, CoCr Polyethylene 25 64 27 72%
CoCr CoCr 19 64 26 53%
Al2O3, CoCr Polyethylene 25 64 27 72%
Higgins et al. 202023 RCT CoCr CoCr 87 65.2 37%
AMC/ZTA CoCr 92 65.2 37%
Malviya et al. 201124 RCT CoCr CoCr 50 63.9 28.6 62%
CoCr Polyethylene 50 64.9 29.4 54%
CoCr CoCr 50 63.9 28.6 62%
CoCr Polyethylene 50 64.9 29.4 54%
Martin et al. 201825 NonRCT AMC/ZTA AMZ/ZTA 42 60 26.4 14%
CoCr CoCr 40 54 30.6 55%
Moroni et al. 201226 NonRCT CoCr PCU 15 67 27.7 60%
CoCr CoCr 15 61 25.5 60%
CoCr PCU 15 67 27.7 60%
CoCr CoCr 15 61 25.5 60%
Nam et al. 201527 NonRCT CoCr Polyethylene 10 54.2 27.3 50%
Ceramic Polyethylene 15 45.1 26 80%
OxZr Polyethylene 11 43.5 30.3 36%
Pozzuoli et al. 202028 NonRCT CoCr CoCr 34 66.1 24.3 68%
Ceramic AMZ/ZTA 34 68.6 25.5 62%
Savarino et al. 200829 NonRCT CoCr CoCr 32 72 75%
Al2O3 Al2O3 16 54 56%
Control group Control group 47 43 21%
Savarino et al. 200230 NonRCT CoCr CoCr 26 48 54%
CoCr Polyethylene 15 64 80%
Control group Control group 22 56 59%
Control group Control group 22 43 36%
Savarino et al. 200829 NonRCT CoCr CoCr 32 72 75%
Al2O3 Al2O3 16 54 56%
Control group Control group 47 43 21%
Savarino et al. 200230 NonRCT CoCr CoCr 26 48 54%
CoCr Polyethylene 15 64 80%
Control group Control group 22 56 59%
Control group Control group 22 43 36%
Schouten et al. 201731 NonRCT AMC/ZTA CoCr 36 62 30 50%
CoCr CoCr 31 64 30 32%
Schouten et al. 201232 RCT AMC/ZTA CoCr 41 61.5 29 45%
CoCr CoCr 36 63.8 29 36%
AMC/ZTA CoCr 41 61.5 29 45%
CoCr CoCr 36 63.8 29 36%
Tiusanen et al. 201333 NonRCT CoCrHC CoCrHC 46 62 50%
CoCrHC Polyethylene 46 60 48%
CoCrHC CoCrHC 46 62 50%
CoCrHC Polyethylene 46 60 48%
White et al. 201634 NonRCT AMC/ZTA Polyethylene 370 60.6 27.5 43%
CoCr Polyethylene 313 74.2 27.2 60%
Zijlstra et al. 201435 RCT CoCr Polyethylene 32
CoCr CoCr 28
CoCr Polyethylene 32
CoCr CoCr 28
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RCT randomised controlled trial, Al2O3 Alumina oxide ceramic, AMC/ZTA Alumina matrix composite/Zirconia toughed alumina, OxZR Oxidized zirconium, PCU Polycarbidate Urethan, CoCR Co Cr, CoCRHC CoCr—high carbid.

Table 2.

Demographic of the patients of each group (CoCR: Co Cr; CoCRHC: CoCr—high carbid).

Materials (head-liner) THAs Mean age Mean BMI Women
Ceramic-CoCr 230 63.2 ± 2.2 29.1 ± 0.6 49%
CoCr-CoCr 981 62.3 ± 5.5 28.1 ± 2.1 52%
CoCr-polyethylene 811 63.0 ± 9.8 27.7 ± 2.4 57%
CoCrHC-CoCrHC 258 59.6 ± 11.0 28.0 ± 1.4 45%
Control group 232 50.4 ± 26.4 26.4 ± 3.8 35%
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Mean concentration of Co and Cr in serum

The mean concentration of Co in serum ranged between 0.5 µg/L and 3.5 µg/L. The mean concentration of Cr in serum ranged between 0.6 and 2.6 µg/L. The concentration of both materials according to the different head- liner compositions is shown in Table 3.

Table 3.

Mean concentration in serum of Co and Cr using different materials combination.

Materials Co (µg/L) Cr (µg/L)
Ceramic-CoCr 1.7 ± 1.0 1.3 ± 0.6
CoCr-CoCr 3.5 ± 5.1 2.6 ± 4.4
CoCr-Polyethylene 0.5 ± 0.5 0.6 ± 0.4
CoCrHC-CoCrHC 0.7 ± 1.1 1.1 ± 1.7
Control Group 0.3 ± 0.1 0.3 ± 0.2
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Chromium

The coupling CoCr-Polyethylene demonstrated the lowest concentration of Cr in serum, followed by CoChHC-CoChHC, and Ceramic-CoCr. The coupling CoCr-CoCr demonstrated the highest concentration of Cr in serum. The overall effect was significant (95% CI: 0.0781 to 0.1225, Fig. 3). All network comparisons are showed in Appendix A.

Figure 3.

Figure 3

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Forest plot of the comparison on Cr.

Cobalt

As expected, the control group and the coupling CoCr-CoCr demonstrated the lowest and the highest concentration of Cr in serum, respectively. After the control group, the coupling CoCr-Polyethylene demonstrated the lowest concentration of Cr in serum, followed by the coupling CoChHC-CoChHC, Ceramic-CoCr. The overall effect was significant (95% CI 0. 0.1345–0.1871, Fig. 4). All network comparisons are showed in Appendix B.

Figure 4.

Figure 4

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Forest plot of the comparison on Co.

Multiple linear regressions

There was evidence of a weak association between BMI and the concentration of Co in serum (r = 0.3; P = 0.03). The time elapsed from the index surgery to the last follow-up, sex, and side did not evidence any statistically significant association with the concentration of Co and Cr in serum (Table 4).

Table 4.

Multiple linear regressions.

Endpoint Co Cr
r P r P
Follow-up 0.1 0.9 0.1 0.9
BMI 0.3 0.03 0.2 0.2
Male/female 0.6 0.6 0.1 0.9
Right/left 0.3 0.3 0.2 0.2
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Discussion

According to the main findings of the present study, the mean concentration of Co in the serum of patients who have undergone THA ranged between 0.5 µg/L and 3.5 µg/L, and the mean concentration of Cr from 0.6 to 2.6 µg/L. The difference in the concentration of Co and Cr in serum is strictly related to the implant configuration, with the coupling CoCr-CoCr showing the highest and the coupling CoCr-Polyethylene showing the lowest concentration. These results confirm our hypothesis that patient characteristics and the time elapsed from the index surgery to the last follow-up did not exert any significant influence on the concentration of Co and Cr in serum in patients who have undergone THA.

Co exists in two forms: Co2+ and Co3+ and the absorption is mediated by the same receptor of Fe2+36,37. Co has an important role as a constituent of vitamin B 12 (hydroxocobalamin)38. Occupational exposure to Co typically happens in hard metal industry, with the inhalation of dust; in the construction industry, through skin contact with cement; in the e-waste recycling industry, from the release of Co from several electronic devices36,39,40. Co can be toxic for different organs due to the accumulation and the oxidative stress36. Co can cause a rapid and reversible decline of cardiac systolic function41. Co can cross the blood–brain barrier and cause peripheral and central nervous system deficit42. Hearing loss, optic nerve atrophy, cognitive decline, motor axonopathy, and sensitive symptoms have been documented43–45. Co inhalation is associated with the ‘hard metal lung disease’46. Skin contact provokes contact dermatitis and it is considered an occupational disease 47. The hematologic effect of Co is uncertain: some studies show an association between red blood cell count and haemoglobin levels and Co concentration48,49. Co decreases the iodine uptake by the thyroid resulting in gout and the development of hypothyroidism50. Exposure to Co, associated with tungsten carbide (WC–CO) can augment the risk of developing lung cancer51,52. The WC–CO nanoparticles generate ROS and promote cells proliferation and inflammation53.

Cr exists in different oxidation states from − 2 to + 654. Cr enters the cells through specific transporters, and it is reduced by glutathione reductase55. During this process, several reactive oxygen species can be formed, including ion superoxide and hydrogen peroxide55. Cr is excreted by the kidneys and through bile and hair in lower proportion56. Cr hazard has spread given its industrial usage57. Because of the heavy water contamination, urban areas are more at risk than rural areas 58. The established threshold of Cr in drinking water is 0.1 mg/l59. Inhalation of Cr can cause parenchymal pneumonia, asthma, wheezing and mucosal lung damage60,61. Gastrointestinal symptoms of Cr ingestion are bloody diarrhoea, abdominal pain, vomiting and ulceration62. High concentration of Cr can provoke hepatotoxicity, causing necrosis of liver cells and lymphocytes infiltration, leading to liver dysfunction55,63. Cr has toxic effects on the reproductive system64,65. Cr induces an increase in IGF-1 receptors, FOXO1 and an elevation in p53 expression level in kidney cells66. Chronic exposure can cause tubular necrosis and renal failure66. Contact dermatitis is common among workers in leather factories, and it is classified as an occupational disease67. Cr is an extremely sensitizing agent, both through inhalation and skin contact67,68. Cr is a genotoxic agent and is carcinogen69. Professional exposure can cause lung and sinonasal cancer70. It can also be related with gastrointestinal tract cancer71.

Adverse reaction to metal debris (ARMD) was described after metal-on-metal (MOM) THA, caused by the corrosion of the head and neck component72. Metal particles induce a local inflammatory reaction that can provokes fibrosis and osteolysis36. ARMD includes different histological findings73. In metallosis, the activation of innate response induces the formation of a granuloma surrounding metal debris74. Aseptic lymphocytic vasculitis associated lesion is characterized by perivascular lymphocytic infiltration and lymphoid aggregates of B and T cells, similar to a type IV reaction75. Type I reaction is mediated by immunoglobulin76. Radiography is the first line investigation for the diagnosis although it is not sensitive (62–64%)73. Periprosthetic osteolysis or a radiodense joint effusion can be identified77–79. MRI is the most sensitive imaging to diagnose ARMD77. It can detect indirect signs such as wear-induced synovitis, and direct signs generated by magnetic field variation, produced by metal fragments80–82.

Our systematic review includes the most updated articles in the present literature. 8 RCT studies were included in this review. The other studies had an overall low-moderate risk of bias. This makes our conclusion very reliable. Our study did not examine only one type of implant, but it compared ions concentrations using different materials patterns. It allows the surgeon to have a comprehensive understanding of the risks of ions related diseases when a specific type of implant is chosen. To our knowledge, this is the first systematic review that examined the association between ions concentration and the patients’ characteristics. This is another step ahead for the personalised surgery.

The present study has limitations. Firstly, the retrospective nature of some studies included in our review. Patient selection was different among the included studies. Patients suffering from renal failure were not excluded in studies8,10,20,23–26,29,30. The predominant mechanism of Cr and Co excretion is glomerular filtration without reabsorption54,83. Renal failure can lead to an accumulation of the two ions and an increase in their toxicity, but no association was found between GFR and ion levels84,85. It is not clear whether renal failure is a contraindication for metal-on-metal implants, but in these patients, a strict follow-up is advised21,86,87. It could influence the ion concentration values. It was not used a standardised method for blood sample collection. Pre-operative data were not available in two studies19,28. Country, region, city closeness to the factory, pollution of the ground and even the season can influence ion levels in the blood serum88. The diameter of the femoral head implant was not well clarified among the included studies. It is shown that a femoral head diameter greater than 36 mm is correlated with ARMD33,89,90.

Conclusion

The mean concentration of Co in the serum of patients who have undergone THA ranged between 0.5 µg/L and 3.5 µg/L, and the mean concentration of Cr from 0.6 to 2.6 µg/L. The difference in the concentration of Co and Cr in serum is strictly related to the implant configuration, with the coupling CoCr-CoCr showing the highest and the coupling CoCr-Polyethylene showing the lowest concentration. Patient characteristics and the time elapsed from the index surgery to the last follow-up did not exert any significant influence on the concentration of Co and Cr in serum.

Supplementary Information

Supplementary Information. (35.3KB, docx)

Author contributions

F.M.: literature search, data extraction, conception and design, statistical analysis, writing; N.M.: supervision, revision; M.P.: writing; R.M.: literature search, data extraction. AB: risk of bias assessment; R.G.: risk of bias assessment. All authors have agreed to the final version to be published and agree to be accountable for all aspects of the work.

Funding

Open Access funding enabled and organized by Projekt DEAL.

Data availability

The datasets generated during and/or analysed during the current study are available throughout the manuscript.

Competing interests

The authors declare no competing interests.

Footnotes

Publisher's note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Supplementary Information

The online version contains supplementary material available at 10.1038/s41598-023-34177-w.

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Data Availability Statement

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