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 Merligiuliamerli85@gmail.com

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

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Patient/

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Age

(years)

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Etio

logy

Technique

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II:8

6Steinberg

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IV:3

2

Steroid:3

1Alcohol:5

6Idiopathic:1

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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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