Sir,
We read this paper with interest. This is an exhaustive review of a
large
number of relevant papers on the subject. However, one of the main aims of
the article was to "introduce a framework for the risk assessment of
orthopaedic implants" which can only be achieved through balanced
argument and consultation with specialists in the appropriate field. We
have
sought opinions from experts in the field of genotoxicology to help us
understand the clinical importance of the seemingly alarming findings of
increased DNA damage in patients with metal-on-metal (MOM) hip
replacements.
The review cites four papers,1-4 all from Bristol, that support the
view that
DNA damage is associated with metal levels following hip replacements,
either loose metal on polyethylene (MOP) or MOM. However,
genotoxicologists highlight methodological weaknesses in these papers. In
addition, the review omits the views of two papers, one from Austria5 and
one from Italy,6 that challenge this view. We would like to redress the
bias
presented in the review of this important field.
The authors have published three papers1,3,4 that used Fluorescent
In-Situ
Hybridisation (FISH) to examine chromosomal abnormalities in white blood
cells from patients with hip prostheses. They used probes for chromosomes.1,2 However, as chromosomal damage occurs at random, analysis of
only 3 out of our 23 paired chromosomes may underestimate the true
frequency of chromosomal abnormalities. This may explain why the data is
inconsistent in these three papers. Bias may have been minimised through
the analysis of 300 metaphase preparations per sample, a substantial
number that would have been labour intensive. The data in these three
papers were displayed with average values, with no indication of the
results
obtained for individual patients, which makes it difficult to see if there
were
any outliers or correlations with the levels of ions in the patient's
circulation.
Additionally, there were very few patients with MOM implants in the paper
by
Doherty3 (one Ring and one Mckee-Farrar) and the paper by Daley1 (seven MOM hips).
The authors have also published two papers1,2 where an in vitro
analysis
was performed by exposing cells to wear debris, using the micronuclei (Mn)
and comet assays to measure outcome. These are robust assays, but in some
instances the number of cells and patients analysed was low – for example,
only 50 cells and six patient samples in one paper,2 and four patients in another.1 Additionally, the Mn assay was never taken one step further to
determine if the micronuclei were the result of whole chromosome loss or
fragmentation. However, these studies did indicate that the level of
chromosome damage was elevated following exposure to the wear debris,
which does emphasise the need for further study.
The paper by Masse et al6 was not quoted in this review and yet it
is a well
conducted and important paper that challenges the viewpoint of the
authors.
It was a longitudinal study of a substantial number of patients in two
cohorts
of patients with hip replacements, MOP (n=30) and MOM (n=30). They carried
out a Mn assay on lymphocytes isolated from patient blood samples.
However, only 1000 binucleate cells were examined in the Mn assay and only
40 metaphases for Sister Chromatid Exchange (SCE), which on the whole are rather low and brings the
robustness of the techniques into question. Additionally,
genotoxicologists
normally compare each patient with the average control data, whereas in this
study all the patient data were averaged, preventing the finding of
significant
abnormalities on an individual basis. Therefore, the existence of DNA
damage cannot be ruled out. We also notice that the level of Co and Cr in
this patient cohort is lower than others have reported, which may have an
effect on the frequency of DNA damage found.
The paper by Pilger5 entitled, "Urinary 8-hydroxydeoxyguanosine and
sister
chromatid exchanges in patients with total hip replacements" was quoted by
the review, but only in the context of metal levels following hip replacement.
In
fact, this study reports the results, in 46 patients with MOM hip
replacements, of: 1) urinary levels of 8-hydroxydeoxyguanosine (8-OHdG), a
marker of oxidative DNA damage; 2) the frequency of sister chromatid
exchanges in lymphocytes, a marker of DNA damage; and 3) blood
concentrations of chromium or cobalt. They concluded that "the levels of
urinary 8-OHdG and the frequencies of SCE in patients with total hip
replacements did not depend on their levels of Cr or Co in blood and
urine.
Although in some cases high amounts of metal release have been
determined, our data do not indicate a higher risk of genotoxic effects in
these patients. The increase in 8-OHdG in patients with implants 3–4 yr
old
might point to signs of wear that are associated with enhanced oxidative
processes."
Genotoxicologists usually approach the problem of agents causing DNA
damage with a basic screening test, before in-depth cytogenetic assays
such
as FISH. This appears to have been overlooked with regard to the analysis
of
DNA damage following MOM hip replacements. Quantifying the level of
micronuclei in blood from a large number of cells from a large number of
patients with metal-on-metal hip joints would be the screening test of
choice
by genotoxicologists. The results of these can then be used to determine
if
the Mn that arise are a consequence of aneuploidy or clastogenic events
(chromosome breakage). Following this, more in-depth analysis can be
undertaken such as FISH. If future genotoxic studies use the FISH
analysis
then they will need to examine all the chromosomes of at least 30 patients
in
the metaphases of at least 300 metaphases per patient. This is a labour
intensive task.
A. HART, MA, FRCSG(Orth),
Clinical Senior Lecturer and Honorary Consultant Orthopaedic
Surgeon,
Imperial College and Charing Cross Hospital,
London, UK.
J. SKINNER, FRCS(Orth)
Consultant Orthopaedic Surgeon,
Royal National Orthopaedic Hospital,
London, UK.
S. DOAK, PhD,
RCUK Fellow in Nanomedicine,
School of Medicine,
University of Wales Swansea,
Swansea, UK.
1. Daley B, Doherty AT, Fairman B, Case CP. Wear debris
from hip
or knee replacements causes chromosomal damage in human cells in tissue
culture. J Bone Joint Surg [Br] 2004;86-B:598-606.
2. Davies AP, Sood A, Lewis AC, et al. Metal-specific differences in levels of DNA damage caused by synovial fluid recovered at revision arthroplasty. J Bone Joint
Surg [Br] 2005;87-B:1439-44.
3. Doherty AT, Howell RT, Ellis LA, et al. Increased chromosome translocations and
aneuploidy in peripheral blood lymphocytes of patients having revision
arthroplasty of the hip. J Bone Joint Surg [Br] 2001;83-B:1075-81.
4. Ladon D, Doherty A, Newson R, et al. Changes in metal levels and chromosome aberrations in
the peripheral blood of patients after metal-on-metal hip arthroplasty. J
Arthroplasty 2004;19(Suppl 3):78-83.
5. Pilger A, Schaffer A, Rudiger HW, Osterode W. Urinary 8-hydroxydeoxyguanosine and sister chromatid exchanges in patients with
total hip replacements. J Toxicol Environ Health A 2002;65:655-64.
6. Masse A, Bosetti M, Buratti C, et al. Ion release and chromosomal damage from total hip
prostheses with metal-on-metal articulation. J Biomed Mater Res B Appl
Biomater 2003;67:750-7.
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