Researchers who found patients with metal-containing joint replacements had significantly higher concentrations of cobalt in their cerebrospinal fluid (CSF) than patients without arthroplasties said this could be relevant to the future manufacturing of orthopaedic implants.
Although CSF in both groups carried this and other metals, the increase in cobalt levels may be of clinical importance, said Anastasia Rakow, MD, of Charité-Universitätsmedizin Berlin in Germany, and colleagues in the 204-person study.
“In view of the known neurotoxic potential of especially cobalt, but also of titanium and niobium,” the group wrote in JAMA Network Open, “it will be important to determine whether these increased levels correlate with objective measures of neurotoxic effects.”
They added that such studies may be particularly relevant in patients with new-onset or deterioration of pre-existing neurological or psychiatric disorders after arthroplasty, and generally, in manufacturing orthopaedic implants of the future.
Shedding of metal molecules from medical devices has long been a concern, particularly for so-called metal-on-metal hip implants, reports MedPage Today. As Rakow and colleagues explained, metal leakage has been shown “to negatively impact bone and soft tissues surrounding” implanted devices.
“Worries about systemic effects have more recently been growing, with case reports and series linking systemic arthroprosthetic cobalt exposure to significant cardiac, thyroid, and/or neurological dysfunction, for example.”
Cobalt is particularly toxic, but other metals commonly used in arthroplasty devices – titanium, niobium, chromium, aluminium, and others – may also be damaging to neural tissues.
While metal levels in blood and serum are known to be increased in people with implanted devices, the extent to which they may cross the blood-brain barrier, and what adverse effects may result, are less well understood.
“Studies on structural changes in the brain as a function of bloodstream exposure to cobalt and chromium released from arthroplasty implants show contradictory results,” Rakow’s group observed.
Samples
The researchers obtained whole blood, serum, and CSF samples from 102 arthroplasty patients and the same number of age- and sex-matched patients without such implants. For those with arthroplasties, the median time since implant was just under 10 years.
Mean current age was 72 for arthroplasty patients and 67 for controls, and 58% of both groups were women.
One-third of the implant group had more than one device. Almost exactly half the group had knee replacement, 49% had hip implants, and the rest had shoulder arthroplasties.
Median levels of certain metals in whole blood were as follows for arthroplasty patients versus controls (all μg/L):
• Cobalt: 0.27 patients, 0.16 controls
• Chromium: o.47 patients, 0.42 controls
• Titanium: 8.05 patients, 7.15 controls
• Niobium: 0.02 patients, 0.01 controls
• Zirconium: 0.05 patients, 0.03 controls
In CSF, however, only cobalt appeared to be significantly more plentiful among arthroplasty patients than in controls (median 0.03 vs 0.02 μg/L), the researchers indicated.
More detailed analyses, however, suggested that other metals could also be a concern. For example, patients with at least one cobalt-chromium-molybdenum device showed significantly higher CSF levels of both cobalt and chromium than did controls.
Another finding suggested that excessive wear or device failure might be responsible for increased CSF cobalt: participants reporting pain in the implanted joint had higher cobalt levels relative to controls. “This significant difference was not observed in patients with a pain-free index joint,” Rakow and colleagues noted.
One limitation to the study was that more than one-third of both implant patients and controls also had non-arthroplasty metallic implants, such as dentures and cardiovascular stents and pacemakers; some 15% had metal piercings as well, and about 6% reported occupational exposures.
These sources may account for the detectable metal levels in controls' fluids, potentially confounding the results.
Also, the arthroplasty group was older on average than controls, and the cross-sectional study design precluded any tracking of
patients over time.
Study details
Metal concentrations in blood and cerebrospinal fluid of patients with arthroplasty implants
Anastasia Rakow, Alexander Kowski, Sascha Treskatsch et al.
Published in JAMA Network Open on 28 March 2025
Abstract
Importance
Arthroprosthetic metal exposure has been linked to neurological dysfunction, but evidence of central nervous system exposure is largely missing.
Objective
To compare levels of all arthroplasty-relevant metals in cerebrospinal fluid (CSF), whole blood, and serum of patients with and without large joint replacement.
Design, Setting, and Participants
The NeuroWear pilot study was a single-site hospital-based cross-sectional study conducted between April 2018 and November 2019. Laboratory personnel and investigators were blinded to group allocation. Patients presenting for elective surgery under spinal anaesthesia and patients scheduled for lumbar puncture at a university medical centre were eligible for inclusion. Patients aged 18 years and older with at least one large joint replacement in situ (103 case participants) and age- and sex-matched arthroplasty-naive patients (108 control participants) were recruited. One case and 6 control participants were excluded. Each case participant was matched with 1 control participant to achieve equal self-reported sex and a minimal age difference. The data analyses were performed between May 2023 and February 2024.
Exposure
Presence of large joint replacement.
Main Outcomes and Measures
CSF, whole blood, and serum levels of aluminium, cobalt, chromium, molybdenum, nickel, niobium, tantalum, titanium, vanadium, and zirconium were quantified.
Results
A total of 204 patients (118 [58%] women and 86 [42%] men; median [range] age 69.4 [21.3-93.1] years) were included for metal analyses. In CSF, median (range) cobalt levels were significantly higher in the implant group (0.03 [0.01-0.64] μg/L) compared with the control group (0.02 [0.01-0.19] μg/L). Cobalt levels in CSF were significantly correlated with cobalt levels in serum (r = 0.72; 95% CI, 0.53-0.85) and whole blood (r = 0.82; 95% CI, 0.62-0.92). Significantly higher whole blood median (range) levels of cobalt (implant: 0.27 [0.07-24.10] μg/L; control: 0.16 [0.08-0.99] μg/L), chromium (implant: 0.47 [0.24-4.76] μg/L; control: 0.42 [0.21-1.52] μg/L), titanium (implant: 8.05 [1.14-37.20] μg/L; control: 7.15 [1.80-20.70] μg/L), niobium (implant: 0.02 [0.01-1.14] μg/L; control: 0.01 [0.01-0.11] μg/L), and zirconium (implant: 0.05 [0.01-39.90] μg/L; control: 0.03 [0.01-1.95] μg/L) were detected. Patients with an implant were found to have significantly higher median (range) CSF metal levels for titanium (implant: 0.75 [0.12-1.40] μg/L; control: 0.57 [0.13-1.10] μg/L), niobium (implant: 0.02 [0.01-0.16] μg/L; control: 0.01 [0.01-0.03] μg/L), and zirconium (implant: 0.05 [0.01-0.44] μg/L; control: 0.04 [0.01-0.28] μg/L) if those metal levels were elevated in serum. Patients with cobalt-chromium-molybdenum implant components exhibited significantly higher median (range) chromium levels in CSF than control participants (implant: 0.31 [0.02-2.05] μg/L; control: 0.23 [0.02-1.10] μg/L).
Conclusions and Relevance
In this cross-sectional study, chronic exposure to arthroplasty implants was associated with corresponding metal accumulation in blood and CSF. Arthroprosthetic cobalt, chromium, titanium, niobium, and zirconium seemed to cross neural barriers and accumulate in CSF. Correlation analyses suggested cobalt-specific transport mechanisms across neural barriers. In view of the neurotoxic effects of cobalt, subsequent studies are needed to determine whether CSF metal concentrations correlate with objective measures of neurotoxic effects and whether this may be of relevance, particularly in patients with new-onset or rapid deterioration of neurological conditions following arthroplasty.
MedPage Today article – Metal concentrations in blood and cerebrospinal fluid of patients with arthroplasty implants (Open access)
https://www.medpagetoday.com/orthopedics/orthopedics/114877
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