Conservative treatment of spontaneous osteonecrosis of the knee in the early stage: Pulsed electromagnetic fields therapy

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European Journal of Radiology 82 (2013) 530– 537

Contents lists available at SciVerse ScienceDirect

European Journal of Radiology

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onservative treatment of spontaneous osteonecrosis of the knee inhe early stage: Pulsed electromagnetic fields therapy

.M. Marcheggiani Mucciolib,∗, A. Grassib, S. Setti c, G. Filardob, L. Zambellid,. Bonanzingab, E. Rimondia, M. Busaccaa, S. Zaffagninib

Isituto Ortopedico Rizzoli, University of Bologna, Radiology Dept. Via Pupilli, 1 40136 Bologna (BO), ItalyIsituto Ortopedico Rizzoli, University of Bologna, III Orthopaedic and Traumatologic Clinic and Biomechanics Laboratory Via di Barbiano, 1/10, 40136ologna (BO), ItalyIGEA SpA, Clinical Biophysics, Via Parmenide, 10/A, 41012 Carpi (MO), ItalyVilla Igea Viale Antonio Gramsci, 42, 47122 Forlì (FC), Italy

r t i c l e i n f o

rticle history:eceived 15 August 2012eceived in revised form 5 November 2012ccepted 8 November 2012

eywords:pontaneous osteronecrosisneeonservative treatmentulsed electromagnetic fields therapy

a b s t r a c t

Background: Hypothesis: pulsed electromagnetic fields treatment might improve symptoms in the earlystage of spontaneous osteonecrosis of the knee.Methods: Twenty-eight patients (19M/9F, age 49.8 ± 16.4 years) suffering from symptomatic (pain)Koshino stage I spontaneous osteonecrosis of the knee, confirmed by magnetic resonance imaging (MRI)were treated with local pulsed electromagnetic fields therapy (6 h daily for 90 days). Clinical evaluation:baseline, 6- and 24-month follow-up by VAS for pain, knee society score (KSS), Tegner and EQ-5D scales.MRI evaluation: baseline and 6-month follow-up, measuring bone marrow lesion’s areas and gradingthese lesions by WORMS score. Failures: patients undergoing knee arthroplasty.Results: Pain significantly reduced at 6 months (from 73.2 ± 20.7 to 29.6 ± 21.3, p < 0.0001), whichremained almost unchanged at final follow-up (27.0 ± 25.1). KSS significantly increased in first 6 months(from 34.0 ± 13.3 to 76.1 ± 15.9, p < 0.0001) and was slightly reduced at final follow-up (72.5 ± 13.5,p = 0.0044). Tegner median level increased from baseline to 6-month follow-up (1(1–1) and 3(3–4),respectively, p < 0.0001) and remained stable. EQ-5D improved significantly throughout the 24 months(0.32 ± 0.33, baseline; 0.74 ± 0.23, 6-month follow-up (p < 0.0001); 0.86 ± 0.15, 24-month follow-up(p = 0.0071)). MRI evaluation: significant reduction of total WORMS mean score (p < 0.0001) and meanfemoral bone marrow lesion’s area (p < 0.05). This area reduction was present in 85% and was corre-lated to WORMS grading both for femur, tibia and total joint (p < 0.05). Four failures (14.3%) at 24-month

follow-up.Conclusions: Pulsed electromagnetic fields stimulation significantly reduced knee pain and necrosis areain Koshino stage I spontaneous osteonecrosis of the knee already in the first 6 months, preserving 86%of knees from prosthetic surgery at 24-month follow-up. No correlation was found between MRI andclinical scores.Level of evidence: Level IV; case series.

. Introduction

Since the first description by Ahlback et al. [1], osteonecro-is (ON) of the knee has been widely investigated and classified,

nd three entities have been identified: secondary ON, post-rthroscopic ON and spontaneous ON of the knee (SONK). Each type

∗ Corresponding author at: Istituto Ortopedico Rizzoli, University of Bologna,iomechanics Laboratory, Via di Barbiano, 1/10, 40136 (BO), Italy.el.: +39 051 6366507; fax: +39 051 583789.

E-mail address: [email protected] (G.M. Marcheggiani Muccioli).

720-048X/$ – see front matter © 2012 Elsevier Ireland Ltd. All rights reserved.ttp://dx.doi.org/10.1016/j.ejrad.2012.11.011

© 2012 Elsevier Ireland Ltd. All rights reserved.

of knee ON presents with different epidemiology, pathogenesis andalso treatment [2].

The most controversial entity is SONK. It is defined as a sponta-neous disorder (without any recognized etiology), usually affectingthe medial femoral condyle (MFC), and generally occurs in patientsolder than 55 years of age with no associated risk factors for ON.The incidence of SONK is 3.4% in persons aged >50 years and 9.4%in persons aged >65 years who presented with symptoms in themedial meniscus [3]. The origin of SONK is not clear as it seems

to be related both to compromised microcirculation of the sub-condral bone and microfractures of a traumatic nature [4]. Thedisease manifests itself clinically with pain, exacerbated by load,and reduced joint range of motion. By magnetic resonance imaging

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MRI) it appears as an area of high signal intensity on T2-weightedmages usually of the medial femoral condyle (MFC), associated to

focal and low-signal finding in the subchondral bone of the epi-hysis on T1-weighted images in later stages [5]. The propensityf SONK to affect the MFC may be explained by local difference oflood supply to anatomic regions of the knee.

There is disagreement on which MRI signal changes constitutearly SONK and which ones suggest bone marrow edema (BME),

common finding usually associated with transient osteoporo-is or trauma [5,6]. These inconsistencies have led to controversynd disagreement on how this condition should be managed. Ini-ial nonsurgical management should be attempted, as the naturalistory of small and midsized lesions is favorable [2]. Proposedreatments are protected weight bearing, restriction of activity andonsteroidal anti-inflammatory drugs (NSAIDs). The use of pulsedlectromagnetic fields (PEMFs) was recently proposed as treatmentf ON in the femoral head [7] and as a possible new approacho reduce knee osteoarthritis (OA) progression [8]. PEMFs stim-lation is a local, safe, and noninvasive treatment for enhancingndogenous bone repair [9]. Thanks to the beneficial effects onhe subchondral bone [10] and ability to reduce inflammatory pro-esses at the knee [7] it seems to be an interesting option for thereatment of SONK.

The purpose of this study was to report the clinical and MRI out-omes of PEMFs therapy for the conservative management of SONKn the early stage and above all to check if there was a correlationetween them. The primary end-point analyzed was symptomspain) reduction at the 6-month follow-up. Secondary end-pointsnalyzed were MRI SONK area reduction at the 6-month follow-p and symptoms (pain) reduction at the 24-month follow-up.

mprovement in knee function and the avoidance of knee replace-ent surgery were also investigated.

. Materials and methods

Between 2008 and 2010, 30 consecutive patients were enrolledith clinical and radiological diagnosis of Koshino stage I SONK

no radiographic abnormalities) [11], considered eligible for PEMFsherapy. More specifically, inclusion criteria were:

. middle-aged or elderly patient (age >45 years);

. presence of symptomatic, acute and progressive pain, associ-ated with non-traumatic bone marrow lesion (BML), defined as abone marrow edema (high-intensity signal area on T2-weightedimages) without a crescent area (low-intensity signal subchon-dral area on T1-weighted images);

. no abnormalities on antero-posterior knee radiography;

. no ligamentous knee laxity.

xclusion criteria were:

. previous knee surgery or presence of total hip replacement onaffected or contralateral limb;

. varus or valgus knee deformity exceeding 10◦;

. body mass index (BMI) > 30 kg/m2;

. presence of at least one of the following conditions: infection,knee trauma, rheumatoid arthritis, autoimmune diseases, sys-temic diseases, tumors, use of steroids, alcoholism or nicotineabuse, systemic lupus erythematous, coagulopathies, tumors,chemotherapy and radiation, Cushing’s Syndrome, diabetes,familiar thrombophilia, liver and renal diseases.

The patients were conservatively treated with self-administeredEMFs therapy for 6 h per day for 90 days. Treatment began within

days from diagnosis. The battery-operated device (I-ONE®, Igea

Fig. 1. Representation of the battery-operated pulsed electromagnetic fields ther-apy device, with the coil placed on the affected knee.

S.p.A., Carpi (MO), Italy) generated a peak magnetic field of 1.5 mT,at a frequency of 75 Hz and a duty-cycle of 10% (Fig. 1). The coilwas placed on the affected knee, avoiding direct contact with theskin. The device had a timer to monitor patient compliance to thetreatment. The patients were instructed to interrupt the treatmentin presence of adverse events, such as a burning sensation or skinirritation.

A full weight-bearing was allowed. Restriction of physical activ-ity was also recommended. Cycling and swimming were the onlysports activities allowed.

To control pain, which at the start of stimulation had beenpresent, nonsteroidal antiinflammatory drug (NSAID) therapy wasutilized for 21 ± 9 days (diclofenac 150 mg per day). None of thepatients were on bisphosphonates at the same time.

The study protocol was approved by the Institutional ReviewBoard of our Institute, and patients signed an informed consentbefore recruitment.

2.1. Clinical examination

All patients were clinically evaluated at baseline, and 6-monthand 24-month follow-up (mean 24.9 ± 0.9 months; range 24.0–25.9months) by two independent examiners blinded to the MRI status.

A visual analog scale (VAS) (a 100-mm horizontal line, wherethe left end represents no pain, and the right end maximum possi-ble or unbearable pain) was used to assess the degree of knee pain[12]. Follow-up evaluation included the knee society clinical rat-ing system (KSS) involving a clinical evaluation (that assesses pain,range of motion, stability, contracture in bending, active extensiondeficit, alignment) and a functional one (that examines autonomyin walking, climbing stairs, use of sticks or frames); both score val-ues ranged from 0 to 100; an excellent result scores between 85and 100, a good one between 70 and 84, a fair one between 60 and69 and poor result less than 60 [13]. The overall Tegner activitylevel [14] was also recorded. Data concerning physical and men-

tal health were collected through the European Quality of Life-5Dimensions (EQ-5D), a self-reported health state instrument foruse as a measure of health outcome [15].

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Fig. 2. Sub-division of knee joint according to WORMS grading. MF: medial femoral condyle; LF: lateral femoral condyle; the trochlear groove was considered part of MF. TheL a), cenS s. Thea ach t

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F (not represented in figure) and MF were divided into three regions: anterior (MF: subspinous non-articulating portion of the tibial plateau beneath the tibial spinenterior (MTa), central (MTc) and posterior (MTp). The subchondral component of e

All data regarding subsequent surgical treatments until 24onths after the treatment were recorded, in particular regarding

nicompartmental knee arthroplasty (UKA) and total knee arthro-lasty (TKA); those cases were considered as failures.

.2. Magnetic resonance imaging

MRI evaluation of the involved knee was carried out by a singlexperienced radiologist (X. X.) before and 6 months after the treat-ent with a 1.5-T unit (Signa, GE Medical Systems, Milwaukee,I, USA). The aim was to study the cancellous bone and the size

f the BML, not the cartilage, even if PD (proton density) sagittalnd PD coronal weighted sequences were performed for view-ng the thickness and signal intensity of the articular cartilage.he cancellous bone and the pre and post treatment size of theML were studied by T1-weighted spin-echo and fat-suppressed

ast spin-echo T2-weighted sequences collected in the sagittal,oronal, and axial planes, and STIR (short-tau inversion-recovery)equence in the sagittal plane. Parameters for the T1-weightedequence were 300–683/15 ms (TR/TE), for the T2-weighted fastpin-echo sequences they were 2200–5000/26–51 ms, with an echorain of 6–10 and for STIR sequences they were TR 6000–7000, TI100–135)/TE (25–40) with an echo train of 6–10. Fat suppressionas achieved with frequency-selective presaturation 90◦ pulse. Theeld of view was 14–16 cm, matrix 256–320–192, number of exci-ations 1–2, and slice thickness 3 mm (0.5–1 interslice gap).

Another single expert radiologist (X. X.) retrospectively exam-ned all MRIs on the same MRI monitor in a blinded fashion, eval-ating BML areas on fat-suppressed fast spin-echo T2-weightedequences. The absence of subchondral focal low-intensity signalrea was evaluated on T1-weighted sequences. They were mea-ured and graded by whole-organ magnetic resonance imagingcore (WORMS) for marrow abnormality considering 15 differentegions (subdivided by anatomical landmarks) with the knee in fullxtension. The patella was divided into lateral facet (LP) and medialacet (MP). The patellar ridge was considered part of the MP. Theubchondral component of each patellar region extended the fullhickness of the bone to the opposite cortex. The femoral articu-ar surface was divided into medial (MF) and lateral (LF) condyles,

ith the trochlear groove considered as part of MF. The boundaryetween MF and LF was defined by a plane aligned with the lateral

all of the femoral notch (Fig. 2A). MF and LF were each divided into

hree regions: anterior (a): extending from the anterior-superiorsteochondral junction to the anterior margin of the anterior hornf the meniscus; central (c): extending from the anterior margin of

tral (MFc) and posterior (MFp). MT: medial tibial plateau; LT: lateral tibial plateau; LT (not represented in figure) and MT were also divided into three equal regions:

ibial region extended 2 cm beneath the articular surface.

the anterior horn of the meniscus to the posterior capsular attach-ment of the posterior horn of the meniscus; posterior (p): extendingfrom the posterior capsular attachment of the posterior horn ofthe meniscus to the posterior-superior osteochondral junction. Thesubchondral component of each femoral region extended perpen-dicularly from the articular surface to the level of an imaginary lineconnecting the anterior and posterior osteochondral junctions. Themedial tibial plateau (MT) and lateral tibial plateau (LT) were eachdivided into three equal regions: anterior (a), central (c) and poste-rior (p). Based on these subdivisions, the patellofemoral joint (PFJ)comprised regions MP, LP, MFa and LFa; the medial femoro-tibialjoint (MFTJ) comprised regions MFc, MFp, MTa, MTc and MTp; andthe lateral femoro-tibial joint (LFTJ) comprised regions LFc, LFp,LTa, LTc and LTp. The non-articulating portion of the tibial plateaubeneath the tibial spines was designated as the subspinous region(S). The subchondral component of each tibial region extended 2 cmbeneath the articular surface (Fig. 2B). BMLs were graded in eachof the 14 articular regions (excluding the non-articulating S region)from 0 to 3 based on the extent of regional involvement: 0 = none;1 = <25% of the region; 2 = 25–50% of the region; 3 = >50% of theregion. The maximum scores for MFTJ, LFTJ, PFJ, region S and theentire knee were 15, 15, 12, 3 and 45, respectively [16].

A quantitative measurement of BML areas was also performedby the same single expert radiologist (X. X.) using Osirix MD Soft-ware (Pixmeo Sarl) and expressed in mm2. This was obtained bymeasuring the area on the same sagittal slice used to calculate theWORMS grade. A single measurement was obtained for the medialfemoral (MF), lateral femoral (LF), medial tibial (MT) and lateraltibial (LT) regions on the sagittal view. An analogous measure-ment was performed on the coronal plane considering the sameregions (MF, LF, MT, LT) with the anatomical landmarks describedpreviously.

2.3. Statistical analysis

Statistical analysis was performed using Analyze-it-2.00(Analyze-it Software, Ltd., Leeds, UK).

A priori sample size definition of 4 patients was prospectivelyestimated for the paired Student’s t-test with a power of 90%, start-ing from the hypothesis of 3.2 of difference between pre-treatment

and 6 months FU mean values for VAS and a variance in mea-surements of 1.8 (referring to Kraenzlin et al. [17]). Consideringa high dropout rate in the long term, we decided to enroll 30patients.

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Table 1Demographic data.

Mean St. Dev. Range

Age at treatment (years) 54.1 ±9.6 (45.9–74.2)Age at final follow-up (years) 56.7 ±9.8 (48.1–76.3)Final follow-up (month) 24.9 ±0.9 (24.0–25.9)BMI at treatment (kg/cm2) 26.0 ±3.9 (20.8–35.3)Sex: male/female 19 (67.8%)/9 (32.2%)Knee involved: right/left 16 (57.1%)/12 (42.9%)

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lation between WORMS grading and area size measured on thesagittal plane both at pre-treatment status and follow-up evalu-ation (Fig. 6).

Table 2WORMS scores.

Region Pre-treatment 6-month follow-up p-Value

Grade Grade

MFTJ MFc 2 (0–3) 0 (0–1) p = 0.0009MFp 1 (0–3) 0 (0–0) p = 0.0005MTa 0 (0–0) 0 (0–0) p = 0.0231MTc 0 (0–0) 0 (0–0) p = 0.0231MTp 0 (0–1) 0 (0–0) n.s.Total MFTJ 5 (2–7) 2 (0–2) p = 0.0001

LFTJ LFc 0 (0–3) 0 (0–0) p = 0.0030LFp 0 (0–2) 0 (0–0) p = 0.0083LTa 0 (0–0) 0 (0–0) n.s.LTc 0 (0–0) 0 (0–0) p = 0.1048LTp 0 (0–0) 0 (0–0) p = 0.2342Total LFTJ 1 (0–6) 0 (0–0) p = 0.0021

PFJ MFa 2 (0–3) 0 (0–1) p = 0.0003MP 0 (0–0) 0 (0–0) n.s.LFa 0 (0–1) 0 (0–0) p = 0.0049LP 0 (0–1) 0 (0–0) p = 0.0047Total PFJ 2 (1–4) 0 (0–1) p = 0.0002

Joint Total 11 (5–14) 3 (0–4) p < 0.0001

All values are reported as median (inter quartile range). MFTJ: medial femoral-tibial joint; LFTJ: lateral femoral-tibial joint; PFJ: patello-femoral joint; MFc: central

ge, BMI, follow-up are reported as mean, standard deviation and range. BMI: bodyass index.

Statistical comparison between the pre-treatment and follow-p parametric scores (VAS for pain, KSS and EQ-5D) was performedsing Student’s t-test. The population study was tested for nor-al distribution before the t-test was applied. For differences

etween time points in the Tegner level and WORMS score theon-parametric Wilcoxon test was used.

Correlation between the WORMS score and BML areas was ana-yzed by the Spearman rho test. On the sagittal view, the MF area

as matched with the sum of WORMS MFa, MFc and MFp regions,he LF area with the sum of LFa, LFc and LFp regions, the MT areaith the sum of MTa, MTc and MTP regions, the LT area with the

um of LTa, LTc and LTp regions.The level of significance was set at p < 0.05. Results are expressed

sing mean values ± standard deviation (SD) for parametric valuesnd median (inter-quartile range) for non-parametric ones.

. Results

Thirty consecutive patients suffering from SONK were recruitedor the study (Table 1).

Twenty-eight patients (93%) were available at the final follow-p (2 patients were in good condition, without pain, but theyefused to perform the final control for personal reasons: theyere considered lost to follow-up). Patient compliance to the ther-

py was satisfactory, and the average of daily treatment time withEMFs therapy was 6 ± 1 h for 90 ± 3 days. No side effects wereecorded and no patient discontinued the treatment.

.1. Clinical findings

The mean pain value at the baseline was 73.2 ± 20.7; it wasignificantly reduced to 29.6 ± 21.3 at the 6-month follow-upp < 0.0001) and remained similar at the 24-month follow-up27.0 ± 25.1) (n.s.). Pain reduction was found in 75% of patients.

The mean KSS at baseline was 34.0 ± 13.3 and was significantlyncreased to 76.1 ± 15.9 at the 6-month follow-up (p < 0.0001).t the 24-month follow-up the KSS score was slightly reduced

o 72.5 ± 13.5 but still significantly higher than before treatmentp = 0.0044). The distribution of KSS results (classified as excellent00–80, good 79–70, fair 69–60, poor <60) was summarized inig. 3.

The median Tegner activity scale increased from 1(1–1) at base-ine to 3(3–4) at the 6-month follow-up (p < 0.0001) and remainedtable at the 24-month follow-up (n.s.), even if it did not reach theevel prior to symptom onset (4; 3–5) (p < 0.0001).

The mean EQ-5D score improved significantly form 0.32 ± 0.33t baseline to 0.74 ± 0.23 at the 6-month follow-up (p < 0.0001) andurther improved to 0.86 ± 0.15 at the final follow-up (p = 0.0071).

Although no restrictions had been given regarding weight-earing, 4 of 28 patients (15%) spent a period (1–2 months) without

oading the joint because of pain.Four of the 28 patients (14.3%) required a knee arthroplasty (2

KA and 2 TKA) within 24 months of the end of PEMFs therapyecause persistant pain and symptoms and radiographic findings of

Fig. 3. Distribution of knee society score (KSS) results at baseline, 6-months and 24-months follow-up. Excellent results were considered as KSS ranging 80–100, good79–70, fair 69–60 and poor <60.

late-stage disease. At the 24-month follow-up 85.7% of the treatedknees were preserved.

3.2. Magnetic resonance imaging findings

Higher values of WORMS score and wider BML areas wererecorded in the femoral medial compartment. MRI evaluationshowed a significant reduction in total WORMS score from pre-treatment evaluation to 6-month follow-up (p < 0.0001), especiallyregarding medial compartment (p = 0.0001) (Table 2). The WORMSscore decreased in 85.7% of patients. The quantitative study of theareas showed a significant reduction of BML areas for lesions affect-ing the femur (Figs. 4 and 5) in 89.5% of patients in the sagittal plane(73% of total area reduction, p < 0.0001) and in 78.5% of patients inthe coronal plane (63% of total area reduction, p = 0.0014 (Table 3)).Correlation analysis (Table 4) showed a significant positive corre-

medial femoral; MFp: posterior medial femoral; MTa: anterior medial tibial; MTc:central medial tibial; MTp: posterior medial tibial; LFc: central lateral femoral; LFp:posterior lateral femoral; LTa: anterior lateral tibial; LTc: central lateral tibial; LTp:posterior lateral tibial; MFa: anterior medial femoral; MP: medial patellar; LFa:anterior lateral femoral; LP: lateral patellar; n.s.: not significant.

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ig. 4. The fat-suppressed fast spin-echo T2-weighted MRI images showed the rednd C) to 6-months follow-up (B and D), both on coronal (A and B) and sagittal (C a

No correlation was found between MRI findings and clinicalcores.

. Discussion

Various treatment options have been proposed for the manage-ent of SONK, ranging from non-operative and pharmacological

reatment to joint preserving operative procedures and joint

rthroplasty. However, as the disease is relatively rare, a validatedreatment algorithm has yet to be developed.

As the lesion size and stage increases, most authors reportedlow progression to degenerative arthritis, affecting the efficacy of

able 3one marrow lesion area size.

Region Pre-treatmentArea (mm2)

Coronal viewMedial Femur 848 ± 696

Tibia 127 ± 303

Total MFTJ 972 ± 696

Lateral Femur 478 ± 787

Tibia 17 ± 55

Total LFTJ 495 ± 785

Joint Total 1467 ± 945

Sagittal viewMedial Femur 638 ± 602

Tibia 134 ± 333

Total MFTJ 771 ± 586

Lateral Femur 432 ± 619

Tibia 52 ± 177

Total LFTJ 484 ± 616

Joint Total 1256 ± 846

ll values are reported as mean ± standard deviation. MFTJ: medial femoral-tibial joint; L

of the hyper-intense signal of the subchondral bone from pre-treatment status (Aplane.

conservative treatment. Koshino [11] proposed SONK classificationbased on radiographic findings, describing a stage I (no radiographicevidence of osteonecrosis), stage II (a radiolucent subchondral ovallesion or flattening of the convexity of the condyle), stage III (expan-sion of the radiolucent area surrounded by a sclerotic halo anda calcified plate) and stage IV (secondary osteoarthritic changes).Aglietti et al. [18] proposed an area of subchondral lesion of 5 cm2

measured on antero-posterior radiography as a cut-off value pre-

dicting unfavorable prognosis and high risk of developing arthritis.As the range of treatment is wide, with no option being clearly supe-rior to another, it is reasonable to start with conservative treatmentin the case of stage I SONK. PEMFs treatment has been described as

6-month follow-upArea (mm2) D (delta) p-Value

238 ± 374 −71.9% p < 0.0001169 ± 366 +33.1% n.s.407 ± 447 −58.1% p = 0.0014119 ± 437 −75.0% p = 0.0485

16 ± 47 −8.3% n.s.135 ± 436 −72.7% p = 0.0471542 ± 535 −63.1% p = 0.0010

157 ± 256 −75.4% p = 0.0001116 ± 240 −13.0% n.s.265 ± 297 −65.6% p < 0.0001

26 ± 97 −93.9% p = 0.000826 ± 83 −49.3% n.s.52 ± 122 −89.3% p = 0.0004

317 ± 322 −74.8% p < 0.0001

FTJ: lateral femoral-tibial joint; n.s.: not significant.

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ig. 5. The absence of low-intensity signal subchondral crescent area on T1-weighnd at 6-months follow-up (B and D), both on coronal (A and B) and sagittal (C and

valid way to limit the progression of femoral head ON [7] and washown to reduce knee osteoarthritic lesion progression in guineaigs [8]. In fact, PEMFs treatment is reported to produce an anti-

nflammatory [19] and bone-healing effects [9,20], thus reducingroduction of free radicals and stimulating the osteogenic activityf osteoblasts [21].

The most important finding of the present study was thebility of PEMFs therapy to reduce pain significantly in 75% ofatients already at the 6-month follow-up. In 1982 Lotke et al.22] reported a resolution of symptoms in 88.9% of patients withtage I SONK treated with protected weight bearing and analgesic

rugs. Recently Kraenzlin et al. [17] reported that bisphosphonatereatment was able to produce a rapid improvement of clinicalymptoms and disability, with complete (53%) or partial (21%) res-lution of pain.

able 4orrelation analysis between WORMS score and bone marrow lesion area size.

Pre-treatment 6-month follow-up

p-Values r-Values p-Values r-Values

MF 0.0030 0.54 <0.0001 0.92MT <0.0001 0.90 <0.0001 0.00LF <0.0001 0.89 <0.0001 0.84LT <0.0001 0.68 <0.0001 0.78MFTJ <0.0001 0.75 <0.0001 0.82LFTJ <0.0001 0.88 0.0051 0.51TOT <0.0001 0.72 0.0007 0.60

ll values represent the correlation between the WORMS score and the area size ofhe same joint region; MF: medial femoral; MT: medial tibial; LF: lateral femoral;T: lateral tibial; MFTJ: medial femoral-tibial joint; LFTJ: lateral femoral-tibial joint;OT: total joint.

ages confirm the diagnosis of early SONK, both at pre-treatment status (A and C)ne.

PEMFs treatment was also effective in increasing knee functionwith good to excellent result in 75% of cases and in preserving 85.7%of knees affected by Koshino stage I SONK [11] from prostheticsurgery at 24 months’ follow-up without the need of protectedweight-bearing. As stage I-II SONK is characterized by subchon-dral fractures without areas of ON [23], the effect of PEMFs couldbe beneficial for the bone healing and resolution of bone marrowedema, thus reducing the symptoms and explaining the good-excellent result in 75% of patients reported in the present study.These results are comparable to those obtained by Massari et al. [7]by PEMFs stimulation in the treatment of ON of the femoral head:the treatment was able to preserve 80% of patients from total hipreplacement at 28 months mean follow-up.

Regarding MRI evaluation, in this study a significant reduc-tion of mean BML area was found using both the WORMS scoreand an original technique of measurement even at the 6-monthfollow-up. This area reduction was present in 85% of patients andis closely correlated to WORMS grading (p < 0.05). Lecouvet et al. [5]described resolution of bone marrow edema at short-term follow-up in 60% of patients with stage I-II SONK treated with functionaldischarge and non-steroid analgesics. Various authors have pro-posed different methods to quantify areas on MRI scans, developedfor bone marrow edema measurement, using digital or manualmeasurement, with different anatomical landmarks and diametersto detect the size of the lesions [24–27]. All of them had difficultyto quantify the 3D volume of the edema using 2D slices withoutrepeated measurement and complex computation. In this paper

the same MRI slices used to calculate the WORMS score were alsoused to quantify the area of BML in mm2 using a common MRImanager software. A significant correlation was found betweenWORMS score and the quantitative measurement for both total

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Fig. 6. Representation of correlation analysis between WORMS score and bone marrow lesion (BML) area. A positive correlation is found for lateral and medial compartments,b t; LFT

jiutatstncubisrantte

iitowco

a

oth at pre-treatment status and 6-months follow up. MTFJ: medial femo-tibial join

oint surface and all sub-regions, thus showing how analogous find-ngs can be obtained with the two different methods. The former,sing the metric system, appears to be more precise compared tohe four-grade WORMS score, which on the other hand has thedvantage of localizing the lesions more accurately, as it divideshe condyle in anterior, central and posterior sub-regions. Furthertudies should be performed in order to define whether size or loca-ion influence the prognosis of this disease. In fact, from this serieso significant correlation was found between MRI findings andlinical outcomes, both at baseline, 6-month and 24-month follow-ps, and no prognostic value could be attributed to the extent ofone marrow edema. This finding might be explained consider-

ng the early stage of SONK of the patients evaluated, where noubchondral ON lesions were described. In fact, Lecouvet et al. [5]eported the presence of subchondral areas of low signal intensitynd epiphyseal contour deformity, histologically representative ofecrotic and fragmented bone, as an important prognostic elemento detect early irreversible SONK. The same authors reported thathe extent of bone marrow edema was of no prognostic significanceither.

A cost analysis between various SONK’s conservative therapiess beyond the scope of this paper. Nevertheless, we are aware thatn this case series patients treated with PEMFs therapy did not sus-ained costs for braces, crutches, long term treatment with NSAIDsr bisphosphonate, thrombo-hembolic prophylaxes associated toeight bearing restriction. So, the cost of PEMFs therapy could be

omparable to that of classic conservative managements, although

nly a well designed study and cost analysis could clarify this issue.

This study has several limitations.The most important weakness of this study was the lack of

control group consisting of non-treated symptomatic patients.

J: lateral femoro-tibial joint; TOT: total joint.

The formation of such control group was not possible for ethicalreasons. In fact, it is unacceptable to refuse any treatment to a symp-tomatic patient. This does not allow the beneficial effects of PEMFsto be compared definitively. Although we are aware that a group ofpatients treated with weight-bearing restriction and NSAIDs couldbe a possible control group, it was not the aim of this work tocompare two different treatments but investigate the clinical andradiographic effects of PEMFs in early SONK.

Another limitation of this study was the fact that the adminis-tration of NSAIDs and patient-imposed weight-bearing restrictionmight confound the clinical outcomes, even if several authorsreported no influence of weight-bearing status on the progres-sion of hip ON [7,28]. Moreover the number of patients includedis rather small, even though it is similar to other case series; never-theless a significant reduction in clinical and radiological scores wasfound.

Lastly, the follow-up period may have been to short to detectprogression of lesions and to demonstrate treatment failure.

5. Conclusions

PEMFs stimulation can play a role in the conservative treatmentof early stage SONK. It was able to reduce knee pain significantly (in75% of cases) and necrosis area (in 85% of cases) already at the 6-month follow-up. No correlation was found between MRI findingsand clinical scores. This treatment increased knee function with

good-to-excellent KSS results in 75% of cases, thus preserving 86%of knees from prosthetic surgery at 24-month follow-up. Furthercontrolled studies are needed to investigate the long-term resultsof this therapy.

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G.M. Marcheggiani Muccioli et al. / Euro

onflict of interest

Stefania Setti is an Igea S.p.A. employ; the other authors have noonflict of interest.

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