REVIEW
Regenerative therapies increase survivorship of avascular necrosisof the femoral head: a systematic review and meta-analysis
Luca Andriolo1& Giulia Merli2 & Carlos Tobar3 & Sante Alessandro Altamura1 & Elizaveta Kon4,5
& Giuseppe Filardo2
Received: 2 August 2017 /Accepted: 18 January 2018 /Published online: 6 February 2018# SICOT aisbl 2018
AbstractPurpose The aim of this study was to document the available evidence on the use of regenerative techniques for the treatment offemoral head osteonecrosis (or avascular necrosis of femoral head, AVN) and to understand their benefit compared to coredecompression (CD) alone in avoiding failure and the need for total hip replacement (THR).Methods The search was conducted on three medical electronic databases according to PRISMA guidelines. The studiesreporting number and timing of failures were included in a meta-analysis calculating cumulative survivorship with a Kaplan-Mayer curve. Moreover, the results on failures in treatment groups reported in RCT were compared with those documented incontrol groups, in order to understand the benefit of biological therapies compared to CD for the treatment of AVN.Results Forty-eight studies were included in this systematic review, reporting results of different types of regenerative techniques:mesenchymal stem cell implantation in the osteonecrotic area, intra-arterial infiltration with mesenchymal stem cells, implanta-tion of bioactive molecules, or platelet-rich plasma. Overall, reported results were good, with a cumulative survivorship of 80%after ten year follow-up, and better results when regenerative treatments were combined to CD compared to CD alone (89.9% vs70.6%, p < 0.0001).Conclusion Regenerative therapies offer good clinical results for the treatment of AVN. The combination of CDwith regenerativetechniques provides a significant improvement in terms of survivorship over time compared with CD alone. Further studies areneeded to identify the best procedure and the most suitable patients to benefit from regenerative treatments for AVN.
Keywords Hip . Avascular necrosis of femoral head . Osteonecrosis . Regenerative therapies . Biological therapies . Coredecompression
Introduction
Osteonecrosis of the femoral head or avascular necrosis(AVN) is a pathologic process that most commonly affects
young adults in the third and fourth decades of their life. Itsincidence is increasing, and every year, 10,000 to 20,000 newcases are diagnosed in the USA [1].
AVN can follow traumatic or non-traumatic conditions.The cause of atraumatic osteonecrosis of the femoral head isbelieved to be multifactorial, in some cases associated withboth genetic predisposition and exposure to risk factors [2].These include, but are not limited to, corticosteroid use, alco-hol abuse, previous trauma, haemoglobinopathy, Gaucher’sdisease, and coagulopathies. The onset of AVN may also beidiopathic [3]. Regardless of the specific initiating event, fail-ure of perfusion may occur due to three mechanisms [2]: vas-cular interruption, vascular occlusion, and extravascular com-pression. Any of these leads to a decreased blood supply/ischaemia in the femoral head. After a variable period of is-chaemia, osteocyte, adipocyte, and haemopoietic marrow ne-crosis occurs, followed by a sequence of reactions and vari-able repair attempts [2]. Although remodeling cycle continues
* Giulia [email protected]
1 II Orthopaedic and Traumatologic Clinic, Rizzoli OrthopaedicInstitute, Bologna, Italy
2 Nano-Biotechnology Laboratory-NaBi, Research and InnovationTechnology Department, Bologna, Italy
3 Department of Orthopedics and Traumatology, Avansalud Clinic ofSantiago, Santiago, Chile
4 Humanitas University Department of Biomedical Sciences,Milan, Italy
5 Humanitas Clinical and Research Center, Milan, Italy
International Orthopaedics (2018) 42:1689–1704https://doi.org/10.1007/s00264-018-3787-0
in adjacent areas of bone with an intact blood supply andviable cells, bone resorption generally predominates, causingfurther weakening of subchondral bone, progressive collapseof subchondral trabeculae, and, ultimately, development ofosteoarthritis [4].
It is estimated that 5–12% of total hip replacements (THRs)each year are performed to treat this disease [1], but theiroutcome has been shown to be less satisfactory compared toother indications, primarily due to the limited lifetime anddurability of THR in such young patients [4, 5]. As a result,there is an increasing focus on the development of early inter-ventions for AVN, aimed at preserving the native articulationto avoid or at least delay THR [5]. Core decompression (CD)is currently the most widely accepted surgical treatment forearly-stage AVN [6]. The rationale of its use is to reduce ordecompress the intraosseous pressure in the femoral head,resulting from venous congestion and other pathways, in orderto promote vascular invasion and to facilitate regeneration ofthe necrotic tissue. However, the overall clinical success rateof CD has been shown to be only 63.5%, and the rate forsubsequent THR or hip salvage surgery is about 33% [7].For this reason, its use has been debated [4] and, with thescope of improving CD results, the use of different regenera-tive techniques has recently been proposed to address earlyAVN stages.
The aim of this study was to document the available evi-dence on regenerative techniques in AVN with a systematicreview, and to perform a meta-analysis of their results in pre-serving subchondral bone from collapse compared to CD,thereby avoiding failure and the need for THR.
Materials and methods
A systematic review of the literature was performed on bio-logic therapies for AVN. The search was conducted onJune 23, 2017, using the following parameters on three med-ical electronic databases (PubMed, Scopus, and the CochraneCollaboration): ((Stem cells) OR (bone marrow) OR (mesen-chymal bone marrow) OR (biological therapies) OR (regener-ative therapies)) AND ((femoral head surgery) OR (femoralhead decompression) OR (hip decompression)) AND((osteonecrosis) OR (necrosis) OR (bone marrow oedema)OR (bone marrow pathology)). The guidelines for PreferredReporting Items for Systematic Reviews and Meta-analysis(PRISMA) were used [8]. Screening process and analysiswere conducted separately by two independent observers(GM and SAA).
First, the articles were screened by title and abstract. Thefollowing inclusion criteria for relevant articles were usedduring this initial screening: clinical reports of any level ofevidence, written in English language, with no time limitation,on biological regenerative therapies used to treat patients
affected by hip AVN. Exclusion criteria were articles writtenin other languages, preclinical studies, reviews, or clinicalstudies analyzing non-biological techniques. In the secondstep, the full texts of the selected articles were screened, withfurther exclusions according to the previously describedcriteria. Furthermore, articles not reporting clinical outcomedata were excluded. Reference lists from the selected paperswere also screened. Relevant data (type of study, type of treat-ment, no. of patients, age of the patients, disease staging,aetiology, follow-up, results, complications, and failures) werethen extracted and collected in a unique database with consen-sus of the two observers to be analyzed for the purposes of thepresent manuscript.
The primary aim of this review was to document through aqualitative analysis the different types of biological therapiesapplied in the clinical practice to treat hip AVN. Secondarily,the results of these procedures were further analyzed quanti-tatively, aiming at understanding their clinical potential interms of survivorship and THR prevention compared to CD.To this aim, studies reporting number and timing of failureswere selected, and the cumulative survivorship was analyzedwith a Kaplan-Mayer analysis [9, 10]. Studies were includedin the Kaplan-Mayer analysis only if they reported, for everysingle failure, either the specific time of revision to THR, or atleast a failure time in an interval no longer than 2 years.Moreover, the results on failures in treatment groups reportedin randomized controlled trials (RCTs) were compared withthose documented in control groups, in order to understandthe benefit of biological therapies compared to CD for thetreatment of AVN.
Results
The database search identified 713 records, and the abstractswere screened and selected according to the inclusion/exclusion criteria. As shown in Fig. 1, a total of 66 full-textarticles were assessed for eligibility. Eighteen articles did notfulfill the criteria and were further excluded, leading to a totalof 48 studies used for the qualitative analysis (a detaileddescription of these studies is reported in Table 1). As shownin Fig. 2, two thirds were published in the last four years,showing an increment in the interest on this surgical approach,whereas only 16 articles had been published in the previous11 years. Overall, the evaluation of evidence level showedeight RCTs, two prospective comparative studies, seven ret-rospective comparative studies, 28 case series, and three casereports.
The biologic therapies analyzed in the included studieswere heterogeneous, often applied in different combinations,mostly associated with the use of classic procedures (like CDor drilling), and sometimes associated bone substitutes (detailsof the specific procedures applied in each study are reported in
1690 International Orthopaedics (SICOT) (2018) 42:1689–1704
Table 1). From a biologic point of view, four different types oftreatment could be distinguished:
1. Stem cells applied in the osteonecrotic area: bonemarrow-derived MSCs, mostly as bone marrow concen-trate (BMC) [11–40], more rarely cultured [41–45] orsimply as bone marrow aspirates [46, 47], adipose-tissue-derived MSCs [48], or allogeneic human umbilicalcord-derived MSCs [49].
2. Intra-arterial injection of stem cells: the types of stem cellsused with this approach were peripheral blood MSC mo-bilized by G-CSF [50], allogeneic human umbilical cord-derived MSCs [51], bone marrow-derived MSCs [52], orthe combination of the last two methods [53].
3. Bioactive molecules: recombinant human bone morpho-genetic protein: rhBMP-2 [12, 54], rhBMP-7 [47, 55],partially purified human BMP [56], or rhFGF-2 [57].
4. Platelet-rich plasma: either used with bone graft [58],BMC [24], or adipose-tissue derived MSCs andhyaluronic acid [48].
The included studies also involved the use of different bonesubstitutes: autografts [21, 23, 25, 29, 54, 55, 58] (includingalso vascularized bone grafts [41–43]), allografts [28], xeno-grafts [47], synthetic bone grafts, and scaffolds [27, 31, 34, 38,
45, 47, 57]. Metal constructs were also applied to reinforcebone architecture [42, 49, 50]. Some studies also combinedpharmacological treatments, like intravenous iloprost [11] ororal bisphosphonates [13], hyaluronic acid [48], or physicaltherapy with low-intensity pulsed ultrasound [14].
These studies reported the results of AVN treatment in2645 hips of 1988 patients. The populations included in theselected studies were very heterogeneous in terms of age,etiology, and AVN stage. Age presented a wide range: whilemean age was around 35–45 years, patients ranged from chil-dren and teenagers to seniors. Only two studies analyzed spe-cifically young populations, affected by sickle cell disease inone case [22] and by AVN after femoral neck fractures in theother [12]. Etiology included steroid therapy (847 hips), alco-hol (515 hips), sickle cell disease (446 hips), idiopathic (364hips), trauma (121 hips), chemotherapy (8 hips), smoke (13hips), immunosuppressive therapy (29 hips), HIV (10 hips),lupus (23 hips), pregnancy (1 hips), Cushing disease (1 hips),Caisson disease (11 hips), hepatitis C (3 hips), or other notspecified etiologies (25 hips). AVN stage was evaluated withdifferent systems: Association Research Circulation Osseous(ARCO) classification in 19 articles [11, 12, 15, 16, 19, 27, 29,33, 35, 38, 39, 42–44, 50, 51, 53, 54], Ficat classification in 14articles [13, 17, 20, 23–25, 28, 38, 46, 47, 49, 52, 55, 58],Japanese Orthopaedic Association (JOA) classification in 5
Fig. 1 PRISMA flowchart of thesystematic literature review
International Orthopaedics (SICOT) (2018) 42:1689–1704 1691
Table1
Detaileddescriptionof
the48
studiesselected
inthesystem
aticreview
Author
Levelof
evidence
Patient/
hip
treated
Age
(years)
Staging
Etio
logy
Technique
Follo
w-up
Conclusions
Com
plications/notes
Pilgeet
al.
Ortho
Rev
2016
LevelII
Prospective
comparative
study
20/20
Control
group:
10 Treatment
group:
10
38.4 (1
5–58)
ARCO2:
12ARCO3:
6ARCO4:
2
Steroid:
5Chemotherapy:6
Idiopathic:8
Smoke:1
Control
group:
CD+iloprostiv.
Treatmentg
roup:
CDcombinedwith
BMC+iloprostiv.
30.6
months
(4–69)
Anim
provem
entinclinicalscores
was
show
nin
treatm
entg
roup,but
notin
controlg
roup.
2patientsintreatm
entgroup
and4
incontrol
groupweretreatedwith
THR.
Noseriousadversereactionto
iloprostinfusion.
3patientshadflushsymptom
sand2patients
complainedofamild
headache
during
infusion.
Chenet
al.
Molecular
Medicine
Reports
2016
LevelIV
Caseseries
9/9
41.1 (2
8–51)
ARCOII:
5ARCO
IIIa:4
Steroid:
6Alcohol:2
Idiopathic:1
Intra-arterialinjectionof
hUC-M
SCs
24months
Intra-arterialinfusion
ofhU
C-M
SCsprom
ote
therepairandregenerationin
thecondition
ofbone
necrosis.
Nospecificcomplication.
Injected
cells:5
–10×10
6cells/m
l.
Gao
etal.
Nature
Scientific
Report
2016
LevelIV
Caseseries
51/51
16.3 (1
1.4–-
18.1)
ARCOI:3
ARCOII:
21ARCOIII:
27
Femoralneck
fractures
CD+im
plantationof
BMCandrhBMP-2
6.8years
The
combinationof
CD+im
plantationof
BMC
andrhBMP-2provided
benefi-
cialeffectsfor
hips
affected
byearly-
tomiddle-stage
osteonecrosisafterfemoral
neck
fracturesin
childrenandadolescent.1
pa-
tient
required
THR.
9/51
hips
show
edradiologicalcollapseof
thef
emoralhead
ornarrow
ingofthehipjointspace.
Gianakoset
al.
HSS
Journal
2016
LevelIII
Retrospective
comparative
study
49/62
Control
group:
40 Treatment
group:
22
Control
group:
43Treatment
group:
38
Control
group:
FicatI:3
FicatIIa:
25FicatIIb:1
Treatment
group:
FicatI:1
FicatIIa:
13FicatIIb:6
Control
group:
Steroid:
20Idiopathic:1
5Anticoagulation:
4Traum
a:1
Treatmentg
roup:
Steroid:
8Idiopathic:1
2Anticoagulation:
2
Control
group:
Bisphosphonatetherapyalone
Treatmentg
roup:
Bisphosphonatetherapyin
combinationwith
CDandBMC
Control:
25.3
months
Treatment:
22.7
months
Thisstudydemonstratesno
significantd
ifferencein
clinicaloutcom
esbetweenthe
twotreatm
entg
roups.
Treatmentw
ithbisphosphonate+CD+BMC
show
asimilarchance
ofprogressingin
AVN
comparedto
hips
treatedwith
bisphosphonatealone.
21/40hips
incontrolg
roup
and
5/22
hips
intreatm
ent
grouprequired
aTHR.
Mishimaet
al.
Eur
JOrthop
Surg
Traum
atol
2016
LevelIV
Caseseries
14/22
40(20–58)
JOAB:2
JOAC1:
10JO
AC2:
10
Steroids:1
5hips
Traum
a:3hips
Alcohol:2
hips
Idiopathic:2
hips
CDwith
BMCandLIPUS
26months
(24–30)
BMCplus
LIPUSofferasafeand
effectivetreatmento
fAVN.
Progression
ofcollapsein
8/22
hips,but
none
required
THR.
Injected
cells:2
.91×10
7cells/m
l.
Yan
etal.
Current
Orthopedic
Practice
2016
LevelIII
Retrospective
comparative
study
86/86
Control
group:
42 Treatment
group:
44
Control
group:
37.2
Treatment
group:
39.6
Control
group:
ARCOI:2
ARCOII:
40Treatment
group:
ARCOI:3
ARCOII:
41
Control
group:
Steroid:
29Alcohol:1
3Treatmentg
roup:
Steroid:
28Alcohol:1
6
Control
group:
CDalone
Treatmentg
roup:
CD+BMCim
plantation
26.3
months
BMCtransplantationinadditionto
CDrelives
articular
pain
anddelaytheprogression
ofearlyAVN.
4hipin
controlg
roup
and1in
treatm
entg
roup
underw
ent
THR.
Nocomplications
wereobserved.
Injected
cells:3
.76×10
7cells/m
l.
Pepke
etal.
Orthopedic
Reviews
2016
LevelI
Randomized
controlled
clinicaltrial
24/25
Control
group:
14
Control
group:
44.5
ARCOII:
25Chemotherapy:2
Immunosuppressive
therapy:
4
Control
group:
CDalone
Treatmentg
roup:
CD+BMCim
plantation
24months
Nosignificantb
enefitfrom
the
additionalinjectionof
BMC
intheshortterm.
Injected
cells:118.9×10
6cells/m
l.
1692 International Orthopaedics (SICOT) (2018) 42:1689–1704
Tab
le1
(contin
ued)
Author
Levelof
evidence
Patient/
hip
treated
Age
(years)
Staging
Etio
logy
Technique
Follo
w-up
Conclusions
Com
plications/notes
Treatment
group:
11
Treatment
group:
44.3
6/14
incontrolg
roup
and4/11
intreatm
entg
roup
underwent
THR.
Samyet
al.
Indian
JOrthop
2016
LevelIV
Caseseries
30/40
36.7 (2
0–48)
FicatIIb:
16FicatIII:
24
Steroid:1
5Idiopatic:2
0Traum
a:5
Drilling
ofnecroticarea
andfilledwith
acompositeof
bone
graftm
ixed
with
PRP
41.4
months
(36–50)
The
useof
bone
graftm
ixed
with
PRPim
provethereparable
capacity
ofnecroticarea.
4hips
underwentT
HR.
Nocomplications
wereobserved.
Cruz-Pardos
etal.
Hip
Int
2016
LevelIII
Retrospective
comparative
study
45/60
Control
group:
19 Treatment
group:
41
Control
group:
36.7 (2
0–68)
Treatment
group:
42.6 (2
3–70)
Control
group:
FicatI:5
FicatII:11
Treatment
group:
FicatI:8
FicatII:33
Control
group:
Steroid:6
Alcohol:5
Idiopathic:6
Anticoagulation:
1Other:1
Treatmentg
roup:
Steroid:1
4Alcohol:3
Idiopathic:1
2HIV:8
Control
group:
CDalone
Treatmentg
roup:
CDcombinedwith
BMCgraftinginto
thecore
tract
45months
(24–171)
Nosignificantradiologicand
clinicaldifferences
betweenoutcom
eof
CDplus
BMCandCDalone.
10/19hips
incontrolg
roup
and
22/41in
treatm
ent
grouprequired
aTHR.
Kurodaet
al.
IntO
rthop
2015
LevelIV
Caseseries
10/10
39.8
(29–53)
JOA
Stage1:
1Stage2:
9Ty
peA:1
Type
B:1
Type
C1:
1Ty
peC2:
7
Steroid:1
8Alcohol:6
CDwith
singlelocaladm
inistrationof
800μg
ofrhFGF-2-im
pregnatedgelatin
hydrogel
12months
Stageprogressionandcollapsedid
noto
ccur
innine
cases,with
significant
improvem
ento
fclinical
scores
byoneyear
postoperatively.
Com
putedtomographyconfirmed
bone
regeneration
inthefemoralheads.
Onlyonecase
offemoralhead
collapserequiringTHR.
1adverseeventrelated
tosurgery(headache
dueto
spinalanesthesia).
Persiani
etal.
ActaOrthop
Belg
2015
LevelIV
Caseseries
29/31
34 (26–53)
Steinberg
I:11
Steinberg
II:1
6Steinberg
III:2
Steinberg
IV:2
Steroid:1
8Alcohol:6
Idiopathic:7
CD+BMCim
plantation
37months
(23–-
48months)
25hips
show
edreliefof
symptom
sandresolutionof
the
osteonecrosisatmagnetic
resonanceim
aging.The
progressionof
thedisease
occurred
in6hips
(2Stage
II,2StageIIIand2StageIV
),which
required
THR.
Thistechniqueiseffectivein
delaying
THRin
earlystages.
Nocomplicationwas
observed.
Gao
etal.
JNanom
ater
2015
LevelIV
Caseseries
12/12
–FicatII:12
–Im
plantationof
noveln
anoscaledC
Drod+
umbilicalcord
MSC
12months
Thiscombinedtreatm
entp
rovides
significantimprovem
ents
ofHHSwithoutfailuresin
the
firsty
earof
f-up,
suggestingthatiseffectivefor
thetreatm
ento
fearlyAVN
Progressionof
thediseaseonly
inonecase
at18
mf-up.
Nocomplicationwas
observed.
Aoyam
aet
al.
ArchPh
ysMed
Rehabil
2015
LevelIV
Caseseries
10/10
31.7
(20–48)
JOAIIIA
:6
JOAIIIB:
4
Steroid:4
Idiopathic:6
Culturedbone-m
arrowderivedMSC
transplantation
augm
entedby
vascularized
bone
grafting
12months
Culturedbone-m
arrowderived
MSC
transplantationin
individualswith
AVNprovides
significantimprovem
ents
onexternalrotation,extensor
andabductor
musclestrength,
andphysicalfunction,without
THR.
Noseriouscomplicationwerenoted.
Intenserehabilitationprogram.
International Orthopaedics (SICOT) (2018) 42:1689–1704 1693
Tab
le1
(contin
ued)
Author
Levelof
evidence
Patient/
hip
treated
Age
(years)
Staging
Etio
logy
Technique
Follo
w-up
Conclusions
Com
plications/notes
Tabatabaee
etal.
JArthroplasty
2015
LevelI
Randomized
controlled
clinicaltrial
18/28
Control
group:
14 Treatment
group:
14
29.08 (18–56)
Control
group:
26.8
Treatment
group:
31
ARCOI:5
ARCOII:
16ARCOIII:
7
Steroid:1
9Idiopathic:9
Control
group:
CDalone
Com
binationtreatm
entg
roup:
CD+BMCim
plantation
24months
BMCinjectionwith
CDcouldbe
aneffectivetherapyforthe
earlystages
ofAVN,w
ithscore
improvem
ent.
Nofailuresandbetterradiological
results
comparedto
control
group.
Noseriouscomplicationwerenotedin
both
theclinicalgroups.
Daltroet
al.
Stem
CellR
esTher
2015
LevelIV
Caseseries
89/89
33 (18–55)
Ficat0
:20
FicatI:3
1FicatIIA
:16
FicatIIB:
22
SickleCellD
isease
Injectionof
BMCthroughapercutaneous
approach
inthecenterof
theosteonecrotic
area
37.3
months
(12–-
60months)
Injectionof
BMCprovides
significantimprovem
ento
fHHS
scorein
allO
NHFstages,as
wellasreducespain,
ameliorates
quality
ofdaily
activities,and
preventsthe
progressionof
thediseases
withoutany
conversion
toTHR.
Nocomplications
wereobserved
during
orafterthetreatm
ent.
Injected
cells:9
.7×10
8cells.
BMCderivedfrom
SCDpatientsmaintain
theability
ofosteogenicdifferentiation.
Mao
etal.
JBoneMiner
Res
2015
LevelI
Randomized
controlled
clinicaltrial
55/89
Control
group:
25/41
Treatment
group:
30/48
35.3 (1
8–65)
Control
group:
36.1
Treatment
group:
34.6
ARCOI:
18ARCOII:
52ARCO
IIIA
:19
Steroid:3
1Alcohol:3
2Idiopathic:2
6
Control
group:
Biomechanicalsupportto
thesubchondralb
one
(poroustantalum
rodim
plantation)
Com
binationtreatm
entg
roup:
Biomechanicalsupport+Intra-arterially
injectionof
peripheralbloodMSC
mobilized
byG-CSF
36months
Com
binationtreatm
entp
rovides
superior
results
regardingclinicaloutcom
esuch
aspain,function,
activity,and
motioncompared
tobiom
echanical
supportalone.
3hips
underw
entT
HRintreatment
group,compared
to9in
controlg
roup.
Nocomplicationwas
observed.
Injected
cells:2
.47×10
8which
contained
1.71
±0.7×10
6CD34
+cells.
Zhaoet
al.
Biomed
Res
Int
2015
LevelIV
Caseseries
24/31
33.21
(23–45)
ARCO
IIIc:1
9ARCOIV:
12
Idiopathic:4
Steroid:1
4Alcohol:4
Traum
a:2
Culturedbone-m
arrowderivedMSC
transplan-
tation
associated
with
porous
tantalum
rodim
plan-
tation
combinedwith
vascularized
iliac
grafting
64.4
months
(26–-
78months)
The
treatm
entp
rovides
improvem
entsof
HHSscore
inallO
NHFstages.
THRrequired
in5/31
joints.
Nocomplicationwas
observed
inboth
treatmentg
roups.
Injected
cells:2
06cells/m
l.
Wanget
al.
Eur
Orthop
Surg
Traum
atol
2014
LevelIV
Caseseries
15/20
35 (23–58)
ARCO
IIB:1
0ARCO
IIC:6
ARCO
IIIA
:3ARCO
IIIB:1
Steroid:4
Alcohol:4
Idiopathic:1
2
BMCmixed
with
corticalandcancellous
bone
(harvested
from
theipsilateralcrest)were
impacted
into
theexcavatedarea
24months
(9–-
36months)
The
treatm
entp
rovidesan
overall
successof
80%,their
HHShadsignificant
improvem
entand
thisnew
methodwas
bestforearly-stage
smalllesions.
4clinicalfailures,butn
oTHR.
Nocomplicationsuch
asinfection,femoral
neck
fracturewereseen
during
operation
andpostoperation.
Caiet
al.
Transplant
Proc
2014
LevelIV
Caseseries
30/49
41.6
(19–63)
ARCOII:
24ARCOIII:
25
Steroid:1
2Alcohol:9
Idiopathic:9
Intra-arterially
injectionof
allogeneichuman
umbilicalcord-derived
MSC
sandBMC
16.9
months
(12–21)
The
treatm
entp
rovide
significant
therapeutic
effects
inAVN,w
ithoutconversions
toTHR.
Nocomplicationwas
observed.
Sunet
al.
PLoS
One
2014
LevelIII
Retrospective
comparative
study
42/72
Control
group:
39 Treatment
group:
33
30.9 (2
2–54)
Control
grou-
p:30.7
Treatment
group:
31.1
Control:
ARCO
IIb:
6ARCO
IIc:18
ARCO
IIIa:1
9Treatment:
Amajority
ofthe
patients
hadahistoryof
SARS
andweretreated
with
high-dosecortico-
steroids.
Control
group:
Standard
background
therapy(impacted
bone
grafting)
Treatmentg
roup:
Standard
background
therapy+rhBMP-2
6.1years
(5–7.7
years)
The
useof
rhBMP-2
couldbe
use-
fultoim
proves
the
speedandquality
ofthebone
repairbutthisstudy
lacksof
statisticaldifference.
The
survivalrateof
thefemoralhead
was
71.8%
and81.8%
incontrol
Postoperativecomplications:
3ectopicossificationin
(2in
bone
grafting+
rhBMP2
and1in
bone
graftinggroup);
4lateralfem
oralcutaneousnervelesion
(both
2hips
inthe2groups).
Excellent
andgood
results
inselected
patients
(ARCOII).
1694 International Orthopaedics (SICOT) (2018) 42:1689–1704
Tab
le1
(contin
ued)
Author
Levelof
evidence
Patient/
hip
treated
Age
(years)
Staging
Etio
logy
Technique
Follo
w-up
Conclusions
Com
plications/notes
ARCO
IIb:
4ARCO
IIc:21
ARCO
IIIa:11
andtreatm
entg
roup,respec-
tively.
Aoyam
aet
al.
TissueEng
PartBRev
2014
LevelIV
Caseseries
10/10
31.7
(20–48)
ARCO
3A:
6pt.
ARCO
3B:
4pt.
Steinberg
3:6
Steinberg
4:4
Steroid:4
Idiopathic:6
Culturedbone-m
arrowderived
MSC
+vascularized
iliac
bone
graft
24months
Thisprocedureissafeandno
conversion
toTHRwas
registered,with
clinical
improvem
entand
food
bone
regeneration.
Frequentcom
plications:increasein
creatine
phosphokinaseandC-reactiveprotein,anem
ia,
hippain,decreaseinalbuminandtotalp
rotein,
complications
atthewounded
area,w
ound
pain,
andfever.
Injected
cells:1
.2×10
8cells.
Novaiset
al.
JPediatr
Orthop
2014
LevelIV
Retrospectivecase
series
11/14
12.7 (9
.7–1-
8)
Steinberg
1B:1
Steinberg
1C:3
Steinberg
2C:1
Steinberg
3C:1
Steinberg
4A:1
Steinberg
4B:2
Steinberg
4C:5
SickleCellD
isease
MultipleepiphysealdrillingandBMC
implantation
25months
(12–-
47months)
Thistreatm
entprovidesstatistically
significant
improvem
entinhippainand
motion.
2patientsfailedrequiringfurther
surgeries.
Nocomplicationwas
observed.
Maet
al.
Stem
CellR
esTher
2014
LevelI
Randomized
controlled
clinicaltrial
39/49
Control
group:
18/24
Treatment
group:
21/25
35(18–55)
Control
group:
34.8
Treatment
group:35.6
FicatI:7
FicatII:32
FicatIII:
10
Steroid:2
6Alcohol:7
Idiopathic:1
2
Control
group:
CD+autologous
bone
graft
Treatmentg
roup:
CD+autologous
bone
graftw
ithBMC
24months
Implantationof
theautologous
BMCgrafting
combinedwith
CDiseffective
topreventfurther
progressionfortheearlystages
ofAVN.
Conversionto
THRwas
required
in4patientsin
controlg
roup
and2patientsin
treatm
entg
roup.
Nocomplicationwas
observed.
The
stageof
AVNmight
affecttheoutcom
e,whileetiologicalfactorsdo
not.
Chotivichit
etal.
JMed
Assoc
Thai
2014
LevelIV
Retrospectivecase
series
32/34
31.9 (1
4–54)
FicatII:21
FicatIII:
13
Steroid:2
6SLE:9
Idiopathic:5
CDwith
bone
marrowaspirateinjection
24.6
months
stageII
27.8
months
stageIII
CD+injectionof
bone
marrow
aspirateprovides
only
fairresults
instageIIandIII,
with
4THRin
stage
IIand5THRin
stageIII.
Thistechniquedoes
notu
seconcentration
process.
Calorietal.
Injury
2014
LevelIV
Retrospectivecase
series
38/40
46.3 (2
1–73)
FicatI:7
FicatII:25
FicatIII:8
Posttraumatic:4
Steroid:7
Idiopathic:2
7
CDandim
plantationof
bone
marrowaspirate+
grow
thfactors(rhB
MP-7)+
scaffold
ofxenograft
bone
substitutewas
inserted
inside
thetunnel
ofthefemur
36months
CD+recombinant
morphogenetic
proteins
+bone
marrowaspirate+xenograft
bone
substitutedecrease
theincidenceof
fracturalstage
non-traumatic
osteonecrosisandtheprogres-
sion
ofAVNandpain.
5patientsunderwentT
HR.
4casesof
calcificationin
thesofttissuenearthe
surgeryaccess.
1subtrochantericfractureof
thefemur
1week
afterCD.
Martin
etal.
LevelIV
49/73
43FicatI:5
7Steroid:4
417
months
International Orthopaedics (SICOT) (2018) 42:1689–1704 1695
Tab
le1
(contin
ued)
Author
Levelof
evidence
Patient/
hip
treated
Age
(years)
Staging
Etio
logy
Technique
Follo
w-up
Conclusions
Com
plications/notes
CroatMed
J2013
Retrospectivecase
series
FicatII:16
Alcohol:1
0Idiopathic:9
Other:1
0
CDof
thefemoralhead
+adultB
MC+PR
Pare
injected
into
thearea
ofosteonecrosis
Thistreatm
entp
rovidesa
significantp
ainreliefin
86%
ofpatients,satisfactory
results
inpatients
with
earlystageAVNandcan
lead
tocomplete
resolutionofthenecroticlesion.
16hips
underw
entT
HR.
2postoperativetrochantericbursitisat
immediatef-up.
Mao
etal.
Bone
2013
LevelIV
Caseseries
62/78
36.3 (2
2–54)
FicatI:1
6FicatII:52
FicatIII:
10
Steroid:3
0Alcohol:2
7Idiopathic:9
Traum
a:12
Intra-arterialBMCviamedialcircumflex
femoralartery
4.8years
(1–5
years)
The
intra-arterialdeliveryof
autol-
ogousBMC
provides
reliefof
symptom
s,im
proves
hip
functionanddelays
thepro-
gression
ofthedisease.
Only6hips
requiringTHR.
Nocomplicationwas
observed.
The
clinicaloutcom
eisbetterwhenitisapplied
priorto
thecollapse.
Lim
etal.
Exp
Mol
Med
2013
LevelIII
Retrospective
comparative
study
128/190
Control
group:
31 Treatment
group:
159
Control
group:
34.4
Treatment
group:
36.3
FicatIIa:
56FicatIIb:
47FicatIII:
57
Steroid:5
4Alcohol:2
4Idiopathic:2
5Other:4
Control
group:
CD,curettage
andabone
graft
Treatmentg
roup:
MultipledrillingandBMC
87months
(8–-
134month-
s)
Com
parableoutcom
esbetween
multipledrilling+
BMCim
plantationandCD
techniques,w
itha
failurerateof
43%
and45.2%,
respectively,
after5years.
Injected
cells:1
.69×10
7cells.
Betterresults
inpatientswho
hadmorecells
transplanted.
Rastogi
etal.
Musculoskelet
Surg
2013
LevelI
Randomized
controlled
clinicaltrial
40/60
Control
group:
30Treatment
group:
30
Control
group:
33.0
Treatment
grou-
p:34.7
–Steroid:1
8Alcohol:8
Idiopathic:2
6Smoking:
8
Control
group:
CDandunprocessedbone
marrowinjection
Treatmentg
roup:
CD+BMCim
plantation
24months
Controlandtreatm
entgroup
show
ssignificant
differenceswhencompared
with
preoperative
scores,w
ithoutstatistically
significantinter-group
differencesin
clinicalscores.
3conversion
toTHRonly
inthe
grouptreatedwith
CD
andunprocessedbone
marrow
injection.
Nocomplications
werenotedin
both
groups.
Transplantedcells:1
.1×10
8cells.
Liu
etal.
ArchOrthop
Traum
aSu
rg2013
LevelIII
Retrospective
comparative
study
34/55
Control
group:
27 Treatment
group:
28
Control
group:
38.1
Treatment
group:
38.0
ARCO
IIb:
25ARCO
IIc:30
Steroid:1
9Alcohol:2
9Idiopathic:7
Control
group:
CDwith
implantationof
porous
nano-
hydroxylapatite/polyamide66
composite
bone
filler
Treatmentg
roup:
CDwith
implantationof
BMCwith
porous
nano-hydroxylapatite/polyam
ide66
compositebone
filler
Control:
24.9
Treatment:
26.7
CD+BMCtreatm
entp
rovides
betteroutcom
esrespecttoCDaloneindecrease
hippain,improve
hipfunction,preventing
collapseof
thefemoralhead,
with
4failures,comparedto5in
controlg
roup.
Aarvold
etal.
Surgeon
2013
LevelIV
Caseseries
4/5
36.25
FicatII:5
Steroid:3
Alcohol:1
Idiopathic:1
CD+im
pactionof
BMC/m
illed
allograft
(obtainedfrom
frozen
femoralheads)
construct
44months
Thistreatm
entshowsthepotential
ofBMC/allograft
constructsforthetreatm
ento
fearlystageAVN.
2hips
underwentT
HR.
Exvivo
analysis.
Kanget
al.
YonseiM
edJ
2013
LevelIV
Caseseries
52/61
43.80 (19–66)
ARCOI:5
ARCOII:
35ARCOIII:
18ARCOIV:
3
Steroid:6
Alcohol:1
6Idiopathic:2
2Traum
a:6
CDcombinedwith
auto
iliac
bone
graftand
implantationof
BMC
68months
(60–-
88months)
Overallclinicalresults
ofour
procedurewere
notsatisfactory,with
26hip
having
bador
failedclinicalresults,
particularly
inpatients
with
largelesions
Correlationbetweenoutcom
eandlesion
size.
Paket
al.
Pain
Physician
LevelIV
Casereport
234
and39
––
Injectionof
adiposetissue-derivedstem
cells
with
12months
The
injectionof
stem
cellmixture
demonstratethe
Injected
cells:1
6×10
6cells.
1696 International Orthopaedics (SICOT) (2018) 42:1689–1704
Tab
le1
(contin
ued)
Author
Levelof
evidence
Patient/
hip
treated
Age
(years)
Staging
Etio
logy
Technique
Follo
w-up
Conclusions
Com
plications/notes
2012
hyaluronicacid,P
RPandCaC
l2to
activate
PRP.ThenPR
P+Cacl2injectionevery
4weeks
presence
ofnewly
regenerated
tissuein
2severely
necroticfemoralheads.
Senet
al.
JArthroplasty
2012
LevelI
Randomized
controlled
clinicaltrial
40/51
Control
group:
25 Treatment
group:
26
–ARCOI,
IIMitchell
A:1
3Mitchell
B:1
3Mitchell
C:1
9Mitchell
D:1
Steroid:1
4Alcohol:6
Idiopathic:1
Pregnancy:1
Cushing
disease:1
Traum
a:17
Control
group:
CDalone
Treatmentg
roup:
CD+BMCim
plantation
24months
BMCinstillationcanresultin
betterclinicaloutcom
eand
hipsurvival,w
ithonly
1THRin
treatm
entg
roup
vs6in
controlg
roup.
Nocomplications
wereobserved.
Betteroutcom
ein
traumaticAVNthan
innon-
traumaticAVN.
Injected
cells:5
×10
8mononuclearcellto
keep
5×10
7CD34
+.
Civininietal.
IntO
rthop
2012
LevelIV
Caseseries
31/37
43.9 (2
4–56)
Steinberg
Ic:3
Steinberg
IIa:7
Steinberg
IIb:
11Steinberg
IIc:9
Steinberg
IIIa:7
Steroid:1
4Bonemarrow
transplantation:
4Alcohol:1
0SLE:1
Idiopathic:6
CD+injectionof
BMC+newcomposite
injectable
bone
substitute(PRO-D
ENSE
®)
20.6
months
(12–-
32months)
Significantimprovem
ento
ffunctionandsymptom
s.100%
radiologicalsuccessonly
inpatient
with
stageI.
Thistechniquewas
bestfor
early-stagelesions.
3jointsunderw
entT
HR.
Nocomplications
relatedto
theprocedurewere
seen
during
oraftertheoperation.
Zhaoet
al.
Bone
2012
LevelI
Randomized
controlled
clinicaltrial
93/97
Control
group:
44 Treatment
group:
53
33.1 (1
8–55)
ARCOIC:
5pt.
ARCO
IIA:
30pt.
ARCO
IIB:
46pt.
ARCO
IIC:
23pt
Steroid:2
4Alcohol:1
9Idiopathic:3
0Traum
a:20
Caisson
disease:11
Control
group:
CDalone
Treatmentg
roup:
CDwith
culturedbone-m
arrowderivedMSC
60months
Exvivo
expansionofbone-m
arrow
derivedMSC
and
implantationprovides
signifi-
cantlyim
provem
ento
fpain
andotherjointsym
ptom
sanddelayor
avoid
theprogressionofosteonecrosis
andtotalh
ipreplacem
ent.
2and10
patientsfailedintreatment
andcontrolg
roups,
respectively.
Nocomplications
wereobserved.
Implantedcells:2
×10
6cells.
Yoshiokaet
al.
IntO
rthop
2011
LevelIV
Caseseries
6/9
31.5 (1
6–52)
JOA1:
2JO
A2:
4JO
A3A
:1JO
A3B
:2
Corticosteroid-induced
AVNin
SLE
CD+BMCim
plantation
41months
(37–-
53months)
BMCtreatm
entp
rovidesa
significantimprovem
ent
ofpain
andfunction,with
1THR.
Implantedcells:5
.32×10
7cells/m
l.
Gangjietal.
Bone
2011
LevelI
Doubleblinded
controlled
clinicaltrial
19/24
Control
group:
11 Treatment
group:
13
Control
group:
45.7
Treatment
group:
42.2
ARCOI:4
ARCOII:
20
Steroid:2
0Alcohol:2
Idiopathic:2
Control
group:
CDalone
Treatmentg
roup:
CD+BMCim
plantation
60months
BMCim
plantationin
thenecrotic
lesion
provides
betterresults
inearlyONand
delayits
progression,
reducespain
anddecreasesthe
volumeof
necroticlesion.
2patientsfailedintreatmentgroup
and3in
controlg
roup.
Nocomplications
wereobserved.
Yam
asaki
etal.
JBoneJoint
Surg
2010
LevelIII
Retrospective
comparative
study
30/39
Control
group:
9 Treatment
group:
30
Control
group
49 Treatment
group
41
JOA1:
2JO
A2:
34JO
A3A
:3
Steroid:2
4Alcohol:1
0Idiopathic:5
Control
group:
Implantationof
cell-free
IP-CHAscaffold
into
thesiteof
osteonecrosis
Treatmentg
roup:
Transplantationof
BMC-seededIP-CHA
Control:
31months
Treatment:
29months
BMCtreatm
entp
rovide
aprogressionof
bone
repair,
acceleratesrevascularisation
alongthetransitionzone.
Thisstudydescribedtheapparent
effectivenessof
implantationof
BMCwith
IP-CHA.
Nointra-or
postoperativecomplications
wereobserved
ineithergroup.
International Orthopaedics (SICOT) (2018) 42:1689–1704 1697
Tab
le1
(contin
ued)
Author
Levelof
evidence
Patient/
hip
treated
Age
(years)
Staging
Etio
logy
Technique
Follo
w-up
Conclusions
Com
plications/notes
1THRin
treatm
entg
roup
vs.3
incontrolg
roup.
Wanget
al.
ArchOrthop
Traum
aSu
rg2010
LevelIV
Caseseries
45/59
37.5 (1
6–56)
ARCOI:2
ARCO
IIA:7
ARCO
IIB:1
3ARCO
IIC:2
8ARCO
IIIA
:9
Steroid:2
9Alcohol:2
2Idiopathic:8
CD+BMCim
plantation
27.6
months
(12–-
40months)
CD+BMCsignificantly
improved
thejointp
ain,
delayedthejointreplacement
anditisindicated
forthetreatm
ento
fstageIand
IIof
AVN.
7patientsunderwentT
HR.
Nocomplications
wereseen
during
oraftertheoperation.
Worstoutcom
eforsteroid-inducedAVN.
Hernigouet
al.
Indian
JOrthop
2009
LevelIV
Caseseries
342/534
39(16–61)
Steinberg
Ior
IISteroid:1
02Alcohol:1
50SCD:2
82
CD+BMCim
plantation
13years(8–18
y)Thistreatm
entp
rovide
acomplete
resolutionof
AVNin
69patients.
THRwas
necessaryin
94hips.
Injected
cells:2
4×10
3cells.
Patient
who
receivehigh
number
ofprogenitorcells
obtainsbetterresults.
Hendrichet
al.
OrthopRev
2009
LevelIV
Caseseries
37–
––
CD+BMCim
plantation
14months
(2-
-24months)
Goodresults
inAVNandsafety
wereproved.O
nly1
patient
needsTHR.
Nospecificcomplication.
Seyleret
al.
Clin
Orthop
RelatRes
2008
LevelIV
Caseseries
33/39
35(18–52)
FicatII:22
FicatIII:
17
Steroid:1
2hips
Alcohol:8
hips
SLE:7
hips
Tobacco:
4hips
HepatitisC:3
hips
HIV:2
hips
Other:3
CDwith
nonvascularizedbone
grafting
procedures
+OP-1(BMP7)
36months
(24–-
50months)
Significantimprovem
ento
fmean
HHS.13failures.
Thisisan
effectiveandsafe
procedure.
Yam
asaki
etal.
Med
SciM
onit
2008
LevelIV
Casereport
2/4
Case1:
18Case2:
40ARCOII:
2ARCOIII:
2
Alcool:2
Idiopathic:2
Transplantationof
BMCintotheaffected
area
ofonehip(lefth
ip)usingIP-CHAin
two
patients,
whiletheotherhipwas
simultaneously
treatedwith
transtrochantericrotationalosteotomy
22months
Transplantationof
BMCmay
provideabeneficial
treatm
entfor
bone
repairin
the
condition
ofON.
Nofailureswereseen
inthissm
all
sample.
1.9×10
9bone-m
arrow
mononuclearcellin
case
1and2.7×10
9in
case
2.Noprogressionof
collapse.
Kaw
ateet
al.
ArtifOrgans
2006
LevelIV
Casereport
3/4
28(25–30)
Steinberg
Case1:
4ACase2:
bil
4CCase3:4C
Steroid:4
Culturedbone-m
arrowderivedMSC
transplan-
tation
with
b-TCPceramics
34months
(27–-
48months)
The
MSCs/b-TCPtransplantation
provides
asignificantscleroticchange
atthebeginning.
After1yearitcouldbe
noteda
revascularization,
probably
derivedfrom
the
vascularized
fibula.
Thisprocedureisnotindicated
forcaseswith
severepreoperativecollapse.
Nopatient
failed.
Lieberm
anet
al.
Clin
Orthop
RelatRes
2004
LevelIV
Caseseries
15/17
47(36–62)
FicatIIa:
15FicatIIb:1
FicatIII:1
Steroid:1
4Alcohol:4
CD+hB
MP
53months
(26–-
94months)
CD+Hum
anbone
morphogenetic
proteinprovide
reliefof
pain,delay
the
radiographicprogression.
3patientsunderwentT
HR.
Gangjietal.
JBoneJoint
Surg
2004
LevelII
Prospective
comparative
study
13/18
Control
Group:
8 Treatment
Group:
10
Control
Group:
48.8
Treatment
Group:
40.9
ARCOI:2
ARCOII:
16
Steroid:1
4Alcohol:2
Idiopathic:2
Control
group:
CDalone
Treatmentg
roup:
CD+BMCim
plantation
24months
CD+BMCprovidesignificant
decrease
inthelevel
ofpain,and
otherjoint
symptom
s.The
volume
ofnecroticlesionssignificantly
improveonly
intreatm
entg
roup.
1698 International Orthopaedics (SICOT) (2018) 42:1689–1704
articles [14, 32, 34, 41, 57], Steinberg classification in sevenarticles [18, 22, 31, 36, 40, 41, 45], and Mitchell classificationin one article [30]. Overall, lesions of different stages, fromearly-stage AVN to collapsed head, were treated. Finally, eval-uation time was also heterogeneous, with nine studiesreporting short-term (< 24 months follow-up), 32 medium-term (24–60 months), and seven long-term results (>60 months). The heterogeneity documented among studiesmay have influenced the results, as reported in some studiesshowing a better outcome for less severe and smaller lesions[21, 23, 29, 31, 40, 52, 54]. Other factors found to influencethe final outcome were the number of transplanted cells [25,36, 40] and etiology, with steroid-induced AVN showingpoorer results [31, 40, 46] and traumatic AVN achieving betterimprovement than non-traumatic AVN [30].
Clinical results are reported in detail in Table 1. In sum-mary, all 28 case series showed clinical score improve-ments, as well as good radiological and histological out-comes, with the only exceptions represented by the studyby Chotivichit et al. [46], who showed short-term diseaseprogression in 76% of the stage 2 and 69% of the stage 3AVN after the injection of bone marrow aspirate, and thestudy by Kang et al. [29], who reported negative results in26/61 hips at 68 months of follow-up.
Among comparative studies, seven were retrospectivecomparative studies [13, 15, 17, 25, 34, 54]: six missed tofind any significant difference between treatment and controlgroups, analyzing clinical scores, radiologic outcomes andfailures, and only one [27] reported significantly increasedclinical and radiological scores, with fewer failures. Two levelII prospective comparative studies [11, 39] were found in theliterature. The study of Pilge et al. [11] performed a match-pair subanalysis of a RCT, but the number of patients wasunderpowered to obtain any significant difference.Conversely, Ganji et al. [39], although dealing with a verysmall survey of 18 hips, reported a significant increase inscores among patients treated with BMC, whereas patientstreated only with CD did not significantly improve.Moreover, the failure rate of the treatment group was signif-icantly lower than the control group.
The eight RCTs confirmed overall favourable results forthe biological augmentation, with only two studies missingto find any significant difference. In detail, Pepke et al. [16]reported comparable clinical scores and failure rate, analyzingat two year’ follow-up 11 hips treated with CD and BMCimplantation against 14 hips treated with CD alone. Rastogiet al. [26] compared 30 hips treated with CD and unprocessedbone marrow with 30 hips treated with CD and BMC implan-tation, finding a significant difference in radiological score,but none in clinical scores. The other six RCTs [19, 23, 30,33, 44, 50] reported a higher improvement of clinical andradiological outcomes in the groups treated with biologicalaugmentation (four studies with BMC, one study withT
able1
(contin
ued)
Author
Levelof
evidence
Patient/
hip
treated
Age
(years)
Staging
Etio
logy
Technique
Follo
w-up
Conclusions
Com
plications/notes
2patientsunderwentT
HRin
controlg
roup,w
hereas
nopatient
failedin
treatm
ent
group.
Hernigouet
al.
Clin
Orthop
RelatRes
2002
LevelIV
Caseseries
116/189
31(16–61)
Steinberg
I:59
Steinberg
II:8
6Steinberg
III:12
Steinberg
IV:3
2
Steroid:3
1Alcohol:5
6Idiopathic:1
0SCD:6
4Organ
transplantation:
21Others:7
CD+BMCim
plantation
7years
(5–11years)
Patientswith
hips
instageIIIand
IVpreoperativelyhad
apoor
results
andprogressed
instages.
34patientsfailedandunderw
ent
THR.
Nospecificcomplication.
Higherrisk
tofailureforpatientswith
corticosteroid
treatm
entand
stageIII-IV.
Correlationbetweenthegreaternumberof
progenitorcellandsm
allerlesionswith
better
outcom
es.
AVNetiology
influences
theresults.
Injected
cells:2
5×10
3cells.
AVNavascularnecrosisof
thefemoralhead,CD
core
decompression,MSC
mesenchym
alstem
cell,
BMCbone
marrow
concentrate,ARCO
Associatio
nResearchCirculatio
nOsseous,JOAJapanese
OrthopedicAssociatio
n,SC
Dsickle
celldisease,
SLEsystem
iclupuserythematosus,TH
Rtotalhipreplacem
ent,IP-CHAinterconnected
porous
calcium
hydroxyapatite,
G-CSF
granulocyte-colony
stim
ulatingfactor,rhB
MPrecombinant
human
bone
morphogeneticprotein,b-TC
Pbeta-tricalcium
phosphate,hU
C-M
SCshuman
umbilicalcord-derived
MSCs,LIPUSlow-intensity
pulsed
ultrasound,
PRPplatelet-richPlasm
a,HHSHarrisHip
Score
International Orthopaedics (SICOT) (2018) 42:1689–1704 1699
cultured bone-marrow derivedMSC, and one study with intra-arterial injection of peripheral blood MSC).
The meta-analysis of failures with the Kaplan-Mayer anal-ysis among 1467 patients analyzed in 41 studies (excludingstudies not reporting the number or the time of failures)showed a total estimated cumulative survivorship of 89.1%at 24 months of follow-up, 81.9% at 60 months of follow-up,and 80% at 120 months of follow-up, confirming overall goodresults and durability for biological therapies (Fig. 3).
Finally, in order to make a comparative evaluation of ho-mogeneous treatment and control groups, a meta-analysis wasperformed including only level 1 RCT dealing with stem cellaugmentation [16, 19, 23, 26, 30, 33, 44, 50]. The total esti-mated cumulative survivorship for biological therapies andcontrol group was of 95.6 vs. 85.7% at 24 months of follow-up and 89.9 vs. 70.6% at 60 months of follow-up, with astatistically significant difference between the two curves(p < 0.0001, evaluated with the log rank method), showing
the benefit of regenerative therapies compared to CD to pro-vide longer lasting results for the treatment of AVN (Fig. 4).
Discussion
The main finding of this study is that regenerative therapiesoffer a higher survivorship over time compared to controlgroup for the treatment of AVN, as demonstrated by a level Imeta-analysis.
This systematic review allowed to document several regen-erative procedures. Biological therapies to address AVN wereintroduced in the clinical practice in the 1990s, aiming at im-proving the results of CD [6]. In particular, stem cell-basedtherapies have been used with the rationale of enhancing theeffect of core decompression by promoting bone formation inAVN [6]. Different factors may explain the effectiveness ofBMC [59, 60]: the presence of stem cells endowed with oste-ogenic properties, the secretion of angiogenic cytokines,resulting in increased angiogenesis and subsequent improve-ment in osteogenesis, as well as the presence of endothelialcell progenitors actively engaged in neoangiogenesis from thepre-existing capillaries and able to enhance the generation ofpericytes and vascular mural cells [6].
Aside from BMC, this systematic review documented sev-eral other regenerative techniques, proposed in the last20 years to improve AVN healing. These include implantationof other types of MSC (like adipose-tissue derived or alloge-neic human umbilical cord-derived MSCs) in theosteonecrotic area, intra-arterial injection of MSCs, implanta-tion of bioactive molecules (recombinant human bone mor-phogenetic protein or growth factors), and PRP. They wereused to treat extremely heterogeneous AVN conditions in het-erogeneous populat ions and, a t the moment , no
Fig. 2 Publishing trend of studies on regenerative treatments for AVN,with the corresponding levels of evidence
Years
11109876543210
100%
90%
80%
70%
60%
50%
40%
30%
20%
10%
0%
1700 International Orthopaedics (SICOT) (2018) 42:1689–1704
Fig. 3 Survivorship curve of 1467 patients treated with regenerative procedures
recommendation can be made on the most efficient treatmentor on the best indications [61]. Nevertheless, a meta-analysisof the survivorship curve among 1467 patients analyzed in 41studies showed an overall total estimated cumulative survivor-ship of 80% at 120 months of follow-up, confirming goodresults and durability for the biological augmentationapproach.
The interest in regenerative therapies for AVN is rising,with growing evidence provided by the increasing numberof published case series, RCT, reviews, and meta-analysis,with particular focus on results of cell-based therapies.Literature evidence has been analyzed in the past few years,with several authors supporting the overall benefit both interm of clinical and radiological outcomes.
In 2014, Li et al. [62] published a meta-analysis includingone RCT and one comparative study, reporting a significantimprovement in clinical outcomes, evaluated with the Harriship score (HHS). Later in the same year, Lau et al. [4] pub-lished a systematic review on five studies, including threeRCTs reporting better clinical results, and two reporting betterradiological results for CD and BMC compared to CD alone.In 2016, three meta-analyses were published on the use ofcell therapy combined with CD for the treatment of AVN.Clinical results were analyzed by Yuan et al. [63], who in-cluded one RCT and three comparative studies and found asignificant difference in HHS between treatment and controlgroups. They also demonstrated an improvement of radiolog-ical outcome, in terms of AVN progression, including sixarticles, two of which were RCT. This result was also con-firmed by Villa et al. [64] on two RCT, and by Papakostidiset al. [65], who included three RCTs and three comparativestudies to document a reduced rate of femoral head collapse.Finally, in a recent systematic review, Piuzzi et al. [66] in-cluded 11 comparative studies, 8 of which were RCTs. Theyconcluded that cell therapies led to a significant clinical
improvement in 7/11 comparative studies and a better radio-logical outcome in 8/11 studies.
While all the aforementioned literature reviews and analy-sis agree on an overall positive outcome in terms of symptom-atic relief and functional improvement, reflected in the differ-ent clinical scores, and of radiographic appearance of the fem-oral heads after regenerative treatments, only a weaker evi-dence supported possible benefits in terms of failures. Thereduction of the number of failures, defined as the need toundergo THR, can actually be considered the most importantgoal in this type of patients. In fact, the durability of THR is aconcern in such young patients, with a considerable risk forrevision arthroplasty during their lifetime. Therefore, the suc-cess of non-replacement procedures is of key importance bothfor patients’ quality of life and for the impact on the healthcare system and society.
Failures were analyzed in two systematic reviews, whichreported that the majority of the current literature found alower number of THR in patients treated with CD and celltherapy compared with patients treated with CD alone [4, 66].Meta-analysis articles, however, were not able to providestrong evidence to confirm these findings. In fact, Villa et al.[64] included in the analysis two RCTs and were not able tofind a significant difference. Similarly, Papakostidis et al. [65]performed a meta-analysis of failures on six comparative stud-ies, but they only found a tendency for cell therapy against CDalone. Only Yuan et al. [63] were able to demonstrate a sig-nificant decrease in failures in hips treated with both CD andBMC, but with the limits of a meta-analysis including threeretrospective comparative studies and therefore low study lev-el. This is not of secondary importance, since a direct correla-tion between low study quality and positive results has beendemonstrated in the literature [67].
The present study was able to document, for the first timewith methodologically strong level I analysis, that the use of
Years
6543210
100%
90%
80%
70%
60%
50%
40%
30%
20%
10%
0%
Fig. 4 Comparison between thesurvivorship curves of patientstreated with biological therapies(black line) vs. control group(gray line)
International Orthopaedics (SICOT) (2018) 42:1689–1704 1701
regenerative therapies can reduce the number of failures com-pared to CD alone. The Kaplan-Mayer method was used toperform a meta-analysis of eight level I RCTs in order tocalculate and compare the survivorship of control and treat-ment groups. At medium-term follow-up, 89.9% of hips treat-ed with CD and regenerative therapies survived, against70.6% of hips treated with CD alone.
This meta-analysis still presents some limitations. The firstone is represented by the heterogeneity of the populationsanalyzed, with heterogeneous lesion stages, etiologies, andpatient characteristics. Anyway, this limit is overtaken in thelevel I meta-analysis that represents a comparison betweencontrol and treatment groups which were homogeneous in-side the single RCT. However, residual heterogeneity amongthe whole populations does not allow to draw conclusionsabout patients who could get the maximum benefit from theprocedures. Another methodological limitation is the inclu-sion of a time interval for failures, which limits the value ofthe survivorship curve in studies with short follow-up; none-theless, this is not of primary matter for a treatment which isintended to last decades. Moreover, AVN was evaluated withdifferent systems, which introduces variability in the interpre-tation of the results. Finally, the included studies describedresults of different treatments (even though the meta-analysisfocused on RCT, all regarding stem cell-based therapies),which may have different success rates. In addition, there isa lack of homogeneity among control groups, sometimes cho-sen as CD alone, sometimes as CD plus not concentratedbone marrow aspirate. Indeed, at the present moment, theBMC approach itself lacks standardization with respect tothe quantitative and qualitative characterization of methodsfor cell harvest, cell processing, and cell transplantation/de-livery, as described in a recent review by Piuzzi et al. [68].Therefore, it is not possible to propose a regenerative therapyagainst the others, and neither there is evidence to understandif the ideal treatment could include more than one singletherapy, creating a biologic chamber using the Bdiamondconcept^ for bone healing [69]. Moreover, PEMF and hyper-baric oxygen therapy may represent suitable options for theearlier stages [70], and future studies should further exploretheir potential and treatment indication, alone or in combina-tion with the emerging regenerative options. However, thisanalysis still allowed to draw interesting conclusions on thepotential of biological treatments.
This systematic review documented a growing interest onregenerative therapies for the treatment of AVN. Overall, theyoffer good clinical results, with an overall survivorship rate of80% at ten years. The level I meta-analysis showed that thecombination of CD with regenerative techniques provides asignificant improvement in terms of survivorship over timecompared to CD alone. Further studies are needed to identifythe best procedure and the most suitable patients to benefitfrom regenerative treatments for AVN.
Acknowledgements The authors thank Elettra Pignotti for the assistancein the statistical analysis and Lucia Mancini for English editing.
Compliance with ethical standards
Conflict of interest The authors declare that they have no conflict ofinterest.
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