Substantial changes in worldwide healthcare policy and the practice of joint replacement result from research into the failure rates of and systemic effects of metal-on-metal hip replacements
Submitting InstitutionUniversity of Bristol
Unit of AssessmentClinical Medicine
Summary Impact TypeTechnological
Research Subject Area(s)
Engineering: Biomedical Engineering
Medical and Health Sciences: Clinical Sciences
Summary of the impact
Research into the field of metal-on-metal (MoM) arthroplasty (joint
replacement) conducted at the University of Bristol in conjunction with
the National Joint Registry of England and Wales (NJR) has led to a
fundamental change in the practice of arthroplasty around the world and in
the clinical follow up of patients. High failure rates have been
identified nationally in England and Wales for MoM total hip arthroplasty
and certain designs of resurfacing arthroplasty in work conducted by our
department. Deleterious systemic effects of wear debris produced by these
implants have also been identified by our research. The use of these
devices has declined from 14% of procedures in 2008 to less than 1% in
2012. Citing our research, national bodies including NICE (2014), the MHRA
(2011 & 2012), the UK Department of Health (2012), British Orthopaedic
Association (2011 & 2012), NJR (2012), British Hip Society (2011 &
2012) and the US Food and Drug Administration (FDA) (2013) have issued
guidance suggesting the restricted use of such devices or close
surveillance of patients in whom these devices have been implanted.
University of Bristol research concerning MoM arthroplasty has followed
three arms: epidemiology (led by Professor Blom), clinical (led by
Professor Blom and Dr Case) and basic science (led by Dr Case). Professor
Blom is an orthopaedic surgeon and Head of the group, Dr Case is a
Consultant Senior Lecturer; both have been employed at the University
throughout the period of the REF.
The University's research into the field
began in 1994 when we demonstrated widely-disseminated metal wear
particles from patients with hip implants post-mortem in the local
tissues, lymphatic system, liver, spleen and brain when compared to
controls without implants. This raised the possibility of long-term
deleterious effects in these patients from exposure to metals, as has been
highlighted by the recent concerns of the regulatory bodies in Europe and
the US (European Commission and FDA). Our follow-up study published in
1996 demonstrated an increase in chromosomal aberrations in local soft
tissues for patients with implants in situ when compared with those with
no implant in situ and clonal lymphocyte expansion in 2/21 of these
patients with more than 10 years follow-up. Further studies published
between 2001 and 2005 demonstrated increased levels of aneuploidy (three
fold) and chromosomal translocations (two-fold) in the peripheral blood
lymphocytes of patients with hip implants in situ. The level of damage
appeared to be influenced by the alloy used (titanium alloys leading to
aneuploidy but no translocations, cobalt-chrome (CoCr) leading to both and
stainless steel not leading to either). These effects were observed over
periods ranging from two years after implantation of a well-fixed device
to 11 years after implantation at revision for a loose device. Wear debris
collected from such loose implants were observed to cause the same types
of chromosomal aberrations in human cells in tissue culture. Recent
studies in 2009, 2010 and 2011 have shown that cobalt chrome nanoparticles
can cause chromosome damage in human cells including human embryonic stem
cells across a placental cell barrier and can cause DNA damage in a foetus
in vivo.[4,5] This raises the possibility of teratogenicity in the baby of
a woman with a hip replacement in situ. The work described in the period
2008-2011 has been led by the University of Bristol and conducted in
collaboration with a number of units including Professor Ingham at the
University of Leeds.
Allied to this basic science approach to researching direct cellular
effects of wear debris from total hip replacement, we have studied the
epidemiological evidence regarding MoM bearing surfaces in comparison with
the alternative bearing surfaces in use. We hold the contract for the
analysis of the NJR, the largest joint arthroplasty database in the world.
Research on 434,560 primary hip replacements, of which 31,932 were
resurfacings, demonstrated that the failure rates of hip replacement were
higher for resurfacing than for conventional metal-on-polyethylene (MoP)
hip replacement at five years. Failure rates were much higher in women
and in smaller bearing sizes for resurfacing (predicted five-year failure
rates for women by head size: 8.3% (95% confidence interval 7.2-9.7) with
a 42mm head, 6.1% (5.3-7.0) with a 46mm head and 1.5% (0.8-2.6) with a
28mm MoP hip replacement). In men with resurfacings, higher failure rates
were observed with smaller joint heads (4.1% (3.3-4.9) with a 46mm head,
2.6% (2.2-3.1) with a 54mm head and 1.9% (1.5-2.4) with a MoP hip
replacement), while rates of failure were similar between larger
resurfacings and total hip replacement, only 23% of men had these size
implants put in. When total hip replacements with different bearing
surfaces were analysed, higher failure rates were observed in larger
bearing MoM total hip replacements when compared to the alternatives.
Whilst this failure rate increased as head size increased, the opposite
pattern was seen in ceramic-on-ceramic total hip replacements. In
response to a request from the MHRA, we analysed the risk of developing
specific and all cancers after metal hip replacement with MoM bearing
surfaces and found no increase in cancers up to 7 years after surgery
compared with the general population and alternative bearings.
References to the research
 Case CP, Langkamer VG, James C, Palmer MR, Kemp AJ, Heap PF, et al.
Widespread dissemination of metal debris from implants. J Bone Joint Surg
Br. 1994 Sep;76(5):701-12. PMID: 8083255
 Case CP, Langkamer VG, Howell RT, Webb J, Standen G, Palmer M, et al.
Preliminary observations on possible premalignant changes in bone marrow
adjacent to worn total hip arthroplasty implants. Clin Orthop Relat Res.
1996 Aug;(329 Suppl):S269-79. PMID: 8769341
 Davies AP, Sood A, Lewis AC, Newson R, Learmonth ID, Case CP.
Metal-specific differences in levels of DNA damage caused by synovial
fluid recovered at revision arthroplasty. J Bone Joint Surg Br. 2005
Oct;87(10):1439-44. PMID: 16189324
 Bhabra G, Sood A, Fisher B, Cartwright L, Saunders M, Evans WH, et
al. Nanoparticles can cause DNA damage across a cellular barrier. Nat
Nanotechnol. 2009 Dec;4(12):876-83. DOI: 10.1038/nnano.2009.313.
 Sood A, Salih S, Roh D, Lacharme-Lora L, Parry M, Hardiman B, et al.
Signalling of DNA damage and cytokines across cell barriers exposed to
nanoparticles depends on barrier thickness. Nat Nanotechnol. 2011
Dec;6(12):824-33. DOI: 10.1038/nnano.2011.188.
 Smith AJ, Dieppe PA, Howard PW, Blom AW, National Joint Registry for
England and Wales. Failure rates of metal-on-metal hip resurfacings:
analysis of data from the National Joint Registry for England and Wales.
Lancet. 2012 Nov 17;380(9855):1759-66. DOI: 10.1016/S0140-6736(12)60989-1
 Smith AJ, Dieppe PA, Vernon K, Porter M, Blom AW, National Joint
Registry of England and Wales. Failure rates of stemmed metal-on-metal hip
replacements: analysis of data from the National Joint Registry of England
and Wales. Lancet. 2012 Mar 31;379(9822):1199-204. DOI:
 Smith AJ, Dieppe PA, Porter M, Blom AW, National Joint Registry of
England and Wales. Risk of cancer in first seven years after
metal-on-metal hip replacement compared with other bearings and general
population: linkage study between the National Joint Registry of England
and Wales and hospital episode statistics. BMJ. 2012;344:e2383. DOI:
Recent Grants Pertaining to this Work:
 Medical Research Council, Research Grant. Biological consequences of
exposure to prosthetic nanoparticles. PI: Prof Ingham, University of
Leeds; Co-applicant: Dr Case. Dates: 1/6/2008-31/5/2011. Amount: £434,000
 Arthritis Research UK Project Grant. Is there systemic genotoxicity
after hip replacement using resurfacing arthroplasty? PI: Dr Case. Dates:
08/10/2009 - 05/2011. Amount: £100,124
 Furlong Foundation. Could physiologically relevant orthopaedic ions
cause indirect DNA and chromosome damage to human embryonic stem cells
across a trophoblast cell barrier? PI: Dr Case. Dates: 1/1/2011-2014.
 Medical Research Council, Research Grant. Dissecting mechanisms of
nanoparticle-mediated foetal toxicity. PI: Dr Case. Dates:
1/10/2011-1/10/2015. Amount: £82,000
 Medical Research Council, Research Grant. Use of nanoparticles to
deliver growth signals to the placenta. PI: Dr Case. Dates:
1/1/2013-1/1/2016. Amount: £590,168.68
 National Institute of Health Research Programme Grant. Improving
patients' experience and outcome of total joint replacement. PI: Prof
Blom. Dates: 2008-2011. Amount: £2,059,777
 Healthcare Quality Improvement
Partnership. Contract to run the National Joint Registry statistical
support and analysis programme. PI: Prof Blom. Dates: 2011-2014. Amount:
Details of the impact
Annually, over 1 million people worldwide undergo arthroplasty. The use
of metal-on-metal bearing surfaces increased rapidly until 2008/2009, when
it represented about 35% of hip replacements in the US and 20% of hip
replacements in the UK. Research from the University of Bristol first
raised concerns about the biological effects of these implants in 1994 and
went on to identify potential local and systemic problems culminating in
the largest epidemiological studies of these implants ever published,
which showed unequivocally that these implants fail at an unacceptably
high rate. These two Lancet publications drew the public's as well as the
regulatory bodies' attention to the problem, resulting in extensive
worldwide media coverage in print, radio and television, including BBC
national news, the cover of the Lancet and Radio 4's Today programme. The
University of Bristol research has led to the issuing of guidance from a
number of sources worldwide regarding the choice of implants for total hip
replacement and the follow-up regime of patients with implants at high
risk of failure in situ. The dramatic decrease in use of these prostheses,
consequent on our work, will save countless patients from unnecessary
suffering, complex revision surgery and vast cost in healthcare resources
and societal impact.
Chief Medical Officer guidance
On the 12 March 2012, in direct response to and quoting our Lancet
publication, the Chief Medical Officer and the Medical Director for NHS
England wrote to all Chief Executives of NHS Trusts, Strategic Health
Authorities and independent hospitals advising them on implant choice[a]
This advice, empowered by the research of the University of Bristol, has
contributed to a worldwide decline in the use of metal-on-metal hip
replacements and they now make up less than 1% of hip replacements
performed in England and Wales.[b] The worldwide trend followed the UK
lead in the use of these implants and the advice given by the Chief
Medical Officer directly cited the research of the University of Bristol.
Regulatory Body and Learned Society Advice: UK
Various bodies in the UK have issued advice regarding the long-term
systemic risks of exposure to metal wear products from Orthopaedic
implants and the risk of the early need for revision in metal-on-metal
bearings. Partly as a result of research from the University of Bristol,
the MHRA issued updated advice to surgeons that patients with
metal-on-metal hip replacements should be monitored annually for the life
of the hip replacement.[c,d] Similar guidance has been issued by both the
British Hip Society [e] and the British Orthopaedic Association.[f].
Accordingly, long-term annual follow-up, with monitoring of metal ion
levels and cross-sectional imaging as dictated by symptoms and individual
patient risk, is now standard practice in the UK. NICE has recently
circulated draft recommendations based on our publications. These
recommend against using metal-on-metal bearings. The definitive guidance
is due in 2014.
The European Commission has asked the Scientific Committee on Emerging
and Newly Identified Health Risks (SCENIHR) to assess the safety of
metal-on-metal joint replacements with a particular focus on hip implants.
Dr Case is an expert adviser. In the light of the above considerations,
SCENIHR is requested to provide a scientific opinion on the safety of
metal-on-metal joint replacements with a particular focus on hip
implants.[g] The Joint Research Centre scientific and policy report for
the European commission on hip replacements wrote in their conclusion
"Long term effects are still not fully assessed especially in terms of
carcinogenicity, genotoxicity and reproductive toxicity".[h] They quoted
210 papers, of which six were from the University of Bristol (the most
quoted research group).
US Food and Drug Administration
The FDA has issued guidance to patients who have received a
metal-on-metal implant. The advice and guidance issued in the UK as well
as similar guidance in Canada and Australia is cited in the report. The
FDA recommend follow-up every 1 to 2 years to check on the status of the
hip replacement and if any symptoms develop, the use of joint aspiration,
cross-sectional imaging and blood metal ion level testing to evaluate the
function of the joint. They further note that implants may have an effect
on general health, including hypersensitivity reactions, cardiomyopathy,
neurological and psychological changes, and renal and thyroid function
Other International Regulatory Bodies
Citing the research from the University of Bristol regarding the risk of
cancer following metal-on-metal joint replacement, as well as the
guidance issued by the MHRA, the Therapeutic Goods Administration (TGA) of
Australia has recommended a follow-up regime for patients with
metal-on-metal joint replacements that includes annual or more frequent
follow ups, the use of cross sectional imaging as well as plain
radiography and the measurement of blood metal ion levels routinely as
part of follow-up.[j] The TGA recommends revision surgery if there are any
symptoms, imaging abnormalities or where metal ion levels are rising.
Health Canada issued guidance in May 2012 advising annual follow-up of
patients and the use of cross-sectional imaging and blood metal ion level
analysis where there are any symptoms or physical examination
Sources to corroborate the impact
[a] Davies S, Keogh B. Metal on Metal Hip Replacements. Department of
Health; 2012 Mar. Major UK Directive citing the research described.
Available from: https://www.gov.uk/government/uploads/system/uploads/attachment_data/file/215116/dh_13
[b] NJR Steering Committee. National Joint Registry for England and
Wales: 9th Annual Report. njrcentre.org.uk. NJR Steering Committee; 2012.
Available from: http://www.njrcentre.org.uk/njrcentre/Reports,PublicationsandMinutes/Annualreports/tabid/86/Default.aspx.
Corroborates the major decline in use of metal-on-metal arthroplasty.
[c] MHRA Press Release. mhra.gov.uk. London: Medicines and Healthcare
Products Regulatory Agency; 2012. Available from: http://www.mhra.gov.uk/home/groups/comms-po/documents/news/con143785.pdf.
MHRA stipulation of need for annual monitoring.
[d] Metal-on-Metal Hip Implants [Internet]. Medicines and Healthcare
products Regulatory Agency. London; [cited 2013 Aug 19]. Available from: http://www.mhra.gov.uk/Safetyinformation/Generalsafetyinformationandadvice/Product-
metalhipimplants/. Stipulates need for annual monitoring of
[e] Large head metal-on-metal hip implants "should no longer be used,"
surgeons say [Internet]. Arthritis Research UK. 2012 [cited 2013 Aug 19].
Available from: http://www.arthritisresearchuk.org/news/general-news/2012/march/06-mar-large-head-
[f] Dias J. Metal on Metal Hip Replacements — The Facts [Internet].
British Orthopaedic Association. London; [cited 2013 Aug 19]. From: http://www.boa.ac.uk/PI/Pages/Metal-on-
Metal.aspx. Professional organisation stipulation for annual
[g] Scientific Committee on Emerging and Newly Identified Health Risks
Request for a scientific opinion on the safety of metal-on-metal joint
replacements with a particular focus on hip implants [Internet]. Brussels:
European Commission; 2013 Mar. Available from:
[h] Holzwarth U, Cotogno G. JRC Scientific and Policy Reports: Total Hip
Arthroplasty [Internet]. Luxembourg: European Commission; 2012 pp. 1-60.
Report No.: JRC72428. Available from: http://ihcp.jrc.ec.europa.eu/our_activities/public-health/hip-prostheses-new-jrc-report/.
European Union statement on metal-on-metal arthroplasty ([g] and [h]).
[i] Metal-on-Metal Hip Implants. fda.gov. Silver Spring: US Food and Drug
Administration; 2013. FDA statement on metal-on-metal arthroplasty.
Available from: http://www.fda.gov/MedicalDevices/ProductsandMedicalProcedures/ImplantsandProsthetics/
[j] Metal-on-Metal Hip Replacement [Internet]. Therapeutic Goods
Administration, Department of Health and Aging, Australian Government;
2012 Sep. Available from: http://www.tga.gov.au/hp/information-devices-mom-hip-implants.htm
[k] Metal-on-Metal Hip Implants — Information for Orthopaedic Surgeons
Regarding Patient Management Following Surgery [Internet]. Ottawa: Health
Canada, Government of Canada; 2012. Available from: http://www.healthycanadians.gc.ca/recall-alert-rappel-avis/hc-
sc/2012/14120a-eng.php. Australian [j] and Canadian [k] statements.