sex and risk of hip implant failure
TRANSCRIPT
Sex and Risk of Hip Implant Failure: assessing the role of sex‐associated biomarkers
Lisa Torosyan, MD, PhDDivision of Epidemiology, OSB/CDRH
CDRH Health of Women (HoW) Program Launch June 25, 2013
Copyright ©
2012 American Medical Association. All rights reserved.
Sex and Risk of Hip Implant Failure:
Assessing Total Hip Arthroplasty Outcomes in the United States. Inacio et al. JAMA Intern Med. 2013;173(6):435-441.
Figure. Kaplan-Meier survival plot of primary total hip arthroplasty survival by sex. Log rank P
=
.005. Shaded areas: 95% CIs.
• Kaiser Permanente
Total Joint
Replacement Registry: ‐
35
140 operations ‐
46 medical centers ‐
319 surgeons
• Revision rates at
median follow‐up
of 3 years:
F 2.3%
M 1.9%
• When controlling for
potential confounders,
RR for women:
1.23 to 1.30
Gender‐dependent
reasons for revision:
•Aseptic revision:
F 0.57 M 0.44
•Aseptic loosening:
F 8.1% M 14.7%
Sex and Risk of Hip Implant Failure:
Assessing Total Hip Arthroplasty Outcomes in the United States. Inacio et al. JAMA Intern Med. 2013;173(6):435-441.
More evidence on the sex‐dependent factors underlying MoM
THA failure
Various sex ratio in THA patients with aseptic loosening: Prosthesis? Patient demographics? 35,140 THAs:
F 8.1% vs.
M 14.7% P = .006 (Inacio et al 2013)1589 THAs: F 4.3% vs.
M 1.1% P = .0006 (Latteier et al 2011) 2049 THAs: F 3.8% vs.
M 0.9% P = .002 (Berend et al 2012)
Risk factors for aseptic loosening following THA MacInnes et al., Recent Advances in Arthroplasty, published online Jan 2012
• Patients vary in their
osteolytic response to
particulate wear debris
• In‐vitro macrophage
responsiveness to particulate
debris varies between
individuals
• PBMCs taken from patients
with a susceptibility to
osteolysis exhibit greater
cytokine responses
• Genetically‐determined
susceptibility and variable
responsiveness to THA AE
GNAS1 as a sex‐related candidate biomarker for aseptic loosening
• TT‐FEMALES: longer time to aseptic loosening compared to TC+CC (P = 0.022)
• CC‐MALES: longer time to loosening than TC and TT carriers (P = 0.018, P = 0.023), and
>11‐fold lower risk of loosening, HR 0.088 (95% CI: 0.02–0.50; P =0.006)
Gene Allele (MA)
Population MAF (95% CI)
White/ Caucasian MAF (95% CI)
White Hispanic MAF (95% CI)
Black African American MAF (95% CI)
Asian Hmong MAF (95% CI)
American Indian MAF (95% CI)
P value
GNAS C(T) 0.480 0.475-0.485
0.477 0.472-0.482
0.575 0.527-0.623
0.700 0.610-0.790
0.606 0.536-0.676
0.545 0.492-0.598 <0.0001
rs7121 20q13.3 GNASGeneID: 2778
Obesity, Cancer, ASEPTIC LOOSENING ?
GNAS1 rs7121:sex and ethnicity associations
Cross et al. BMC Genet 2010
1000 Genome project, Ensemble:
Caucasians – T allele; Asians – C allele
GNAS1 as an example of putative sex/ethnicity‐related genetic
biomarkers for THA AE
Epidemiologic evidence:
A higher rate for revision due to aseptic loosening was found in
female THA patients
predominantly of Caucasian/European descent.
Genetic evidence:
GNAS1 rs7121 was identified as an independent factor determining
time to early
loosening following THA
Synthesis of epidemiologic and genetic evidence on GNAS1 rs7121 could provide
explanation for the higher risk of aseptic loosening in female THA patients in the
US:
A majority of THA patients are of European/Caucasian descent and, therefore, are expected
to carry the C‐allele associated with more favorable prognosis only in male THA patients;
Only patients of Asian, Hispanic, and especially African descent
are expected to carry the
T‐allele which was associated with more favorable prognosis in female THA patients.
SUMMARYDespite the enormous success of THA, patients face a number of
potential complications, many of them sex‐dependent.
Further studies on discovery of molecular signatures associated with unfavorable outcomes can clarify the reasons for variable individual
susceptibility to THA AE.
Biomarker‐based noninvasive diagnostic tests can enable early detection and therapeutic management of undesired THA outcomes in
sex‐, age‐, and ethnicity‐stratified patient subpopulations.
Copyright ©
2012 American Medical Association. All rights reserved.
F vs. M:
•Women patients with THA were older
than men
•The race‐related gender difference
was found only in THA patients of Asian
decent:
F 4.1% vs.
M 2.7%
The following diagnoses were more
frequent in female THA patients:
•Osteoarthritis, the major underlying
cause fro THA•Rheumatoid arthritis•Dysplasia
Sex and Risk of Hip Implant Failure:
Assessing Total Hip Arthroplasty Outcomes in the United States. JAMA Intern Med. 2013;173(6):435-441.
F vs.
M: •smaller femoral heads•more metal on XLPE
implants •less MoM bearings•more frequent use of
hybrid rather than
cementless fixation
Even after statistically
controlling for head
sizes, women had a
15% higher risk of
revision.
Sex and Risk of Hip Implant Failure:
Assessing Total Hip Arthroplasty Outcomes in the United States. JAMA Intern Med. 2013;173(6):435-441.
Copyright ©
2012 American Medical Association. All rights reserved.
• 1589 primary MoM THA in 1363
patients, follow‐up ‐
60 months• Complications observed more frequently in women:
• cup revision (8.2% vs. 2.7%; P = .0000);• aseptic loosening (4.3% vs. 1.1%; P = .0006), similar to the analysis of 2049
THAs by Berend 2012: (3.8% vs. 0.9%, P = .002); and
• failure for metal‐bearing complications (2.2% vs. 0.6%; P = .0126).
Additional sex‐related differences:•Smaller cups and heads in women compared to men, but no significant difference in
size between failures and non‐failures in women.•A higher inclination angle in women compared to men, but no significant difference in
the inclination angle in failures vs. non‐failures in women.•Higher inclination angles in male failures due to metal complications, and a failure
increase with an inclination angle >45° only in men. •The need for further investigation of sex‐specific factors in THA failure
• The failure of MOM implants was almost twice as high for women than men, which is consistent with data from the England and Wales registries (5.1% vs 3.7% at 5 years) and from a smaller US study (8.2% vs 2.7% at 2 years, Latteier
et al, 2011).• NJR of England and Wales: higher occurrence of implant
failure in women with MoM implants after adjusting for age and femoral head size (Smith et al. Lancet 2012).
• Data on the risks and benefits of THA devices for women and men could allow better informed choices for the more
than 300
000 US patients undergoing THA annually, thus reducing the need for revision surgery and its concomitant
risk of myocardial infarction
Cross et al. BMC Genet. 2010; 11: 51.
Population based allele frequencies of disease associated polymorphisms in
the Personalized Medicine Research Project
• The allele frequencies for a panel of disease‐ associated 51 polymorphisms were determined
within the entire Personalized Medicine Research Project population based cohort.
• Differences in allele frequencies between self reported race, region of origin, and sex were
determined.• One of the three genes that exhibited sex
differences was GNAS.• GNAS was associated with different responses to
hip arthroplasty.
• Areas of agreement SNPs overexpressed in patients with aseptic loosening and
periprosthetic osteolysis:– GNAS1– TNF‐238 A allele; TNF‐α
promoter (‐308G→A) transition– IL6‐174 G allele, IL6 (‐597) and (‐572)– MMP‐1‐promoting gene, C/C genotype for the MMP1, MT1‐MMP, MMP‐2– TGFB1 signal sequence (29T→C) transitions– A/A genotype for the OPG‐163, and MBL
He et al. International Orthopaedics (SICOT) (2013) 37:1025–1031
• Despite the enormous success rates of hip arthroplasty, patients face a number of potential
complications• Osteolysis and subsequent aseptic joint loosening is
the most common reason for joint revision• 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,
especially AL.– Plasma level of multiple biomarkers in THA patients with
prosthetic AL were elevated compared to healthy controls and .
• 57 German Caucasian patients with revision for aseptic loosening
after THA• T393C polymorphism in GNAS1, the gene coding for the stimulatory
Gas subunit, a ubiquitous AMP‐
dependent G‐protein contributing to bone physiology
• Gas/cAMP pathways are involved in:– parathyroid hormone‐mediated osteoblastogenesis;– bone disorders such as McCune‐Albright syndrome, Albright hereditary osteodystrophy, and
functional defects of osteoblasts;
– IL6 activation in osteoblasts, macrophages and osteoclasts. • FEMALES: median time to aseptic loosening was not significantly associated with single T393C genotypes,
but it was longer in TT carriers compared to TC+CC genotypes (P = 0.022).
• MALES: the CC carriers had longer time to loosening than TC and TT carriers (P = 0.018, P = 0.023), and the
CC genotype showed a more than 11‐fold lower risk of loosening, with a hazard ratio of 0.088 (95% CI:
0.02–0.50; P =0.006).
• Compared with T393 homozygous males (reference group), heterozygous patients had a 6.25‐fold lower
risk with a hazard ratio of 0.160 (95% CI: 0.04–0.71; P =0.016).
• T393C polymorphism may have gender‐dependent effects on the aseptic loosening after THA. More
favorable prognosis is suggested for males with CC‐genotype and females with TT‐genotype.
The C‐allele of the GNAS genetic variance (rs7121) could have co‐modifying effect on the obesity and aseptic loosening in female patients with THA
Hahn S, Frey UH, Siffert W, Tan S, Mann K, Janssen OE. The CC genotype of
the GNAS T393C polymorphism is associated with obesity and insulin
resistance in women with polycystic ovary syndrome.
Eur J Endocrinol.
2006,
155:763‐70.
•Case control study of 278 German women with poly cystic ovary syndrome
and 820 controls.
•The C allele of the GNAS1 polymorphism T393C (rs7121) was associated with
a higher mean body weight, a higher BMI and a higher indices of insulin
resistance compared to women without a C allele.
Individual susceptibility to periprosthetic osteolysis is associated with altered
patterns of innate immune gene expression in response to pro‐inflammatory
stimuli. Gordon et al. J Orthop Res.
2010;28(9):1127‐35. (UK)
See also Gordon’s publications on SNP analysis in hip arthroplasty
(Gordon et al. 2008, ref.61, from MacInnes’
Risk factors for asept loos., not found)
Abstract Susceptibility to osteolysis after total hip arthroplasty (THA) varies between individuals. We
examined whether patients susceptible to osteolysis (group I, n = 34 subjects) after cemented Charnley
THA have quantitatively different innate immune responses to pro‐inflammatory stimuli versus patients
without this susceptibility (group II, n = 28 subjects) at a mean of 14 years after primary surgery.
Extracted peripheral blood mononuclear cells were stimulated for
3 h using endotoxin (LPS, 100
ng/mL), endotoxin‐stripped titanium particles (Ti) or endotoxin‐stripped particles with adherent LPS
added‐back (TI + LPS). Subjects returned 1 week later and the experimental protocol was repeated.
Assays for mRNA induction for interleukin (IL)‐1alpha, IL‐1beta, IL‐1Ra, IL‐6, IL‐10, IL‐18, and tumor
necrosis factor (TNF) were made using quantitative real‐time PCR. Although baseline levels of mRNA
expression were slightly lower in group I, inducibility of mRNA expression was markedly greater in
group I versus group II for all cytokines in response to LPS or Ti + LPS, and for IL‐1alpha in response to Ti
(P < 0.05). LPS or Ti + LPS stimulation also resulted in an increase in the IL‐1/IL‐1Ra mRNA ratio in group
I versus group II (P < 0.05). mRNA induction was highly reproducible between subject visits (r > 0.7, P <
0.001). Osteolysis‐susceptible patients show repeatable, quantitatively different patterns of innate
cytokine gene expression in response to pro‐inflammatory stimuli versus THA patients who do not
display this susceptibility. These innate immune differences may
contribute to the variation in
osteolysis‐susceptibility observed clinically between individuals.
Suggestion: development of in vitro diagnostic/prognostic test for early detection and monitoring of
the proinflammatory immune response based on cytokine production
in hip transplant patients
Risk factors for aseptic loosening following total hip arthroplasty (MacInnes et al., from a book:
Recent Advances in Arthroplasty, pp.275‐294, published online Jan 2012)
Risk factors for aseptic loosening following total hip arthroplasty (MacInnes et al., from a book:
Recent Advances in Arthroplasty, pp.275‐294, published online Jan 2012)
Biologic effects of implant debris,
as reviewed in
Hallab and Jacobs, 2009 • Immune reactivity depends on:
– the dose, i.e., the concentration of
phagocytosable
particles per tissue
volume, which can be characterized by the
size distribution and amount of debris;– the shape: elongated particles (fibers) are
generally more proinflammatory than
round particles; – the material: metal particles are more
proinflammatory than polymers in vivo.
• Although to produce an in vitro
inflammatory
response, particles need to be <10µm, i.e.,
phagocytosable,
both soluble and particulate
debris derived from Co‐Cr‐Mo alloy implants can
induce monocyte/macrophage activation and
secretion of proinflammatory cytokines (IL1beta,
TNFalpha, IL6, IL8) by upregulating NFkB and
activating inflammasome danger signaling.
• Identification of new pathways of implant debris‐
induced inflammatory reactions, such as
activation of inflammasome‐mediated “danger
signaling”, provides new targets for improved
implant performance and therapeutic
intervention.
NALP3=NLRP3=PYPAF1=CIAS1 and genetic autoinflammatory syndromes,
or
Why NALP3 can mediate unprovoked systemic inflammation
which involves CNS, skin and joint and bone tissues • This protein interacts with ASC, which contains a caspase
recruitment domain, and is a member of the NALP3
inflammasome complex. This complex functions as an upstream
activator of NF‐kappaB signaling, and it plays a role in the
regulation of inflammation, immunity, and apoptosis.
• Mutations in this gene are associated with the cryopyrin‐
associated periodic syndromes:
‐
familial cold autoinflammatory syndrome (FCAS),
‐
Muckle‐Wells syndrome (MWS),
‐
chronic infantile neurological
cutaneous and articular
(CINCA)
syndrome, and
‐
neonatal‐onset multisystem inflammatory disease (NOMID).
• NOMID/CINCA
(or Prieur‐Griscelli syndrome) causes
uncontrolled inflammation including severe arthritis
and
neurologic
damage which may lead to the hearing loss. Joint
signs (35‐65%) can lead to unpredictable anomalies of growth
cartilage and long bones epiphyses suggestive of a
pseudotumour. Biopsy of skin lesions shows a perivascular
inflammatory infiltrate including granulocytes.
• NOMID has been successfully treated with anakinra (IL1‐
receptor antagonist).
• Activated NLRP3 inflammasome in mouse model caused
inflammation and abnormal skeletal development including
accelerated bone resorption and increased osteoclastogenesis
(Bonar et al. PLoS One 2012).http://a248.e.akamai.net/7/248/432/20101213115940/www.msdlatinamerica.com/
ebooks/ArthritisAlliedConditions/files/3b147cc82a21e2ab889fd76b34f4c516.gif
NOMID/CINCA symptoms which are similar to various clinical features attributed to the
metallosis
in hip transplant patients