Osteoporosis International

https://doi.org/10.1007/s00198-022-06584-8

REVIEW

Comparison of various treatment modalities for the management

of bone marrow edema syndrome/transient osteoporosis in men
and non‑pregnant women: a systematic review
Konstantinos Paraskevopoulos1   · Anthimos Keskinis2 · Ioannis S. Vasios2 · Konstantinos G. Makiev2 ·
Konstantinos Tilkeridis2 · Georgios I. Drosos2 · Athanasios N. Ververidis2

Received: 1 August 2022 / Accepted: 20 October 2022

© International Osteoporosis Foundation and Bone Health and Osteoporosis Foundation 2022

Abstract
Summary  Transient osteoporosis (TO) or bone marrow edema syndrome (BMES) is a self-limited clinical condition, which
affects middle-aged men and women. It can be treated with miscellaneous conservative and surgical measures, which are
analyzed in this systematic review.
Introduction  BMES/TO is a transient clinical entity, which can be treated with various therapeutic modalities. The aim of
our study was to assess the efficacy of different therapeutic options for the alleviation of pain and reduction of bone marrow
edema (BME) in patients with BMES/TO, as well as to propose a therapeutic algorithm.
Methods  PubMed, Scopus, Cochrane, and Google Scholar were searched. Eligibility and extraction of studies were conducted
by two authors. Methodological quality assessment was carried out with the modified Delphi technique, Methodological
Index for Non-Randomized Studies (MINORS) criteria, and Cochrane Collaboration’s risk of bias tool. Outcomes that were
compared were time of pain resolution, VAS pain scores, and BME regression on magnetic resonance imaging (MRI).
Results  A total of 36 articles (880 patients) were included. Bisphosphonates had higher efficiency in less than 1-month
outcomes on pain resolution compared with core decompression (CD), while iloprost was more efficient at 1–3 months
compared with bisphosphonates and CD. At 3–6 months, all three of the aforementioned showed equal results on pain resolu-
tion, and at a period of 6–12 months, CD and extracorporeal shockwave therapy (ESWT) showed excellent results followed
by bisphosphonates and the conservative group (CG) consisting of non-steroidal anti-inflammatory drugs (NSAIDs) and/
or analgesics and/or restricted weight bearing. On MRI at 1–3 months, bisphosphonates, iloprost, and CD had relatively the
same outcomes on BME resolution, with the least promising being the CG. At 3–6 months, CD seemed to have achieved the
best results on the resolution of BME, followed by ESWT, CG, and bisphosphonates group. At 6–12 months, ESWT had the
best outcomes compared with the conservative, bisphosphonates, and iloprost groups.
Conclusion  BMES/TO has been treated with many non-standardized measures due to the low number of highly reliable
studies. Current literature shows promising results with regard to the reduction of the clinical course of BMES/TO, but fur-
ther large multicenter randomized controlled trials, as well as standardized radiological and clinical scores, are warranted
to acquire evidence-based recommendations on the therapeutic algorithm.

Keywords  Bone marrow edema syndrome · Transient osteoporosis · Bisphosphonates · Extracorporeal shockwave therapy ·
Iloprost · Hyperbaric oxygen therapy

Introduction

Bone marrow edema (BME) is a radiological term, which

describes common magnetic resonance imaging (MRI)
findings characterized by increased signal intensity on T2w
* Konstantinos Paraskevopoulos and fat-suppressed MRI sequences, and decreased signal
konspara1996@gmail.com intensity on T1w sequences [1, 2]. There are miscellaneous
Extended author information available on the last page of the article causes of BME such as ischemic, mechanical, and reactive

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[3]. Bone marrow edema syndrome (BMES) or transient
osteoporosis (TO) is a clinical entity, transient in nature
and of uncertain etiology, which is diagnosed on MRI and
is primarily manifested in the lower extremities, with the
hip joint being the most frequently affected joint [4, 5]. It
mainly presents in middle-aged men but can be manifested
in non-pregnant and pregnant women in the last trimester of
gestation as well [6, 7]. The clinical features of the syndrome
include acute onset of pain accompanied with reduction of
range of motion, absence of the previous history of trauma,
normal radiographs (later osteopenia may arise), and non-
specific laboratory findings, as well as BME on MRI [8,
9]. Although BMES/TO progressively resolves within 3
to 9 months without any intervention, the principal aim of
the treatment is to decrease its clinical course and alleviate
patients’ pain [10]. Various treatment regimens have been
proposed for this purpose including the administration of
pharmacological agents like non-steroidal anti-inflammatory
drugs (NSAIDs), bisphosphonates, prostacyclin analogs
(iloprost), monoclonal antibodies (denosumab), and the uti-
lization of non-pharmacological alternatives such as hyper-
baric oxygen therapy (HBOT) and extracorporeal shockwave
therapy (ESWT). Core decompression (CD) is the surgical
method of choice in the non-responsive specimens [2, 4,
11–13].
There is a lack of standardized guidelines with regard to
the available treatment options for BMES/TO. In the litera-
ture, the majority of the conducted studies are case series
and retrospective cohort studies, which are of low level of
evidence. If only there had been an established therapeutic
algorithm, patients would have been managed more prop-
erly, therefore, resuming their daily activities and returning
to work sooner. The purpose of this review was to system-
atically analyze and make comparisons of all the published
articles that assessed the efficacy of various therapeutic regi-
mens for the alleviation of pain and reduction of BME in
patients with BMES/TO, as well as to propose a therapeutic
algorithm.
Methods
This systematic review was conducted in accordance with
the Preferred Reporting Items for Systematic Reviews and
Meta-Analysis (PRISMA) [14]. The search parameters were
defined as follows:
• (P) Population: patients with BMES/TO
• (I) Intervention: administration of bisphosphonates, ilo-
prost, denosumab, HBOT, ESWT, non-specific treatment
(NSAIDs, analgesics, restriction of weight-bearing), and
CD
• (C) Comparison: among the different types of treatments
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• (O) Outcome: mean time of BME and pain resolution,
VAS pain scores
Inclusion/exclusion criteria
This systematic review contains articles reporting the multi-
ple types of treatment options for the management of BMES/
TO (bisphosphonates, iloprost, denosumab, HBOT, ESWT,
CD, and non-specific measures). Articles that were eligible
to be included were as follows:
1. Case series, retrospective comparative and non-compar-
ative studies, prospective comparative/non-comparative
studies, and randomized-controlled trials (RCTs)
2. Written in English
3. Include patients with BMES/TO diagnosed on MRI
4. Articles with adequate results (mean time of pain regres-
sion or resolution of BME on MRI and clinical scores)
Articles with the following features were excluded:
1. Articles written in languages other than English
2. Non-full text availability
3. Case reports, reviews, editorials, experimental trials,
animal studies, and letters to the editor
4. BME related to secondary causes (avascular necrosis,
trauma, ligamentous injury, bone bruise, severe osteo-
arthritis, osteochondral lesions, subchondral fracture/
microfracture, tumor, infection)
5. Juvenile BMES
6. Pregnancy
7. Regional migratory osteoporosis
Search strategies and data source
Two authors (K.P and A.K) did a thorough systematic search
of the literature on the 17th of February 2022, including
articles from four databases (PubMed, Scopus, Cochrane,
and Google Scholar). The following search strategy was
utilized to find any relevant articles: “bone marrow edema
syndrome” OR “bone marrow edema syndrome” OR “tran-
sient osteoporosis” OR “transient bone marrow edema” OR
“transient bone marrow edema.” Any discrepancy between
the authors with regard to the selection of retrieved studies
was resolved by a third author (GI.D).
Study selection and exclusion
Two independent authors (K.T and KG.M) conducted the
study selection and exclusion process. The detailed flow
chart is presented in (Fig. 1). The initial search yielded
1374 results. Duplicate removal was carried out with the
use of Mendeley Reference Manager, thus 795 remained for
Osteoporosis International

Fig.1  Diagnostic and therapeu-

Records identified through
tic algorithm for the manage- database searching: Additional records
ment of BMES/TO Pubmed: 504 identified through other
sources

Identification
Scopus: 652
Google scholar: 200 (n=0)
Cochrane database: 18
(n=1374)

Records after duplicates removed

(n=795)

Screening Records
Records screened by
title and abstract excluded
(n=795) (n=730)
Eligibility

Full-text articles Exclusion reasons (n=29)

assessed for eligibility 1. Other language (n=7)
(n=65) 2. Case reports (n=4)
3. No full-text available (n=5)
4. Osteoporosis (n=2)
5. Insufficient results (n=9)
6. Other causes of BME (n=1)
7. No MRI diagnosis (n=1)
Included

0 Studies included in the

review (n=36)

further screening. After a meticulous analysis of the articles’
titles and abstracts, 730 articles were excluded. Therefore,
65 full-text articles were left for eligibility assessment, and
29 were excluded with referred reasons. Finally, 36 articles
were included in this systematic review (Fig. 1).
Outcomes of interest
Three independent authors (K.P, A.K, and IS.V) screened
the included articles and extracted the following demo-
graphic data and generalities: year of article publica-
tion, study design, patients’ number, age, gender, joints
involved, treatment protocols, and mean onset of symp-
toms. For each study, relevant information regarding the
outcomes of treatment protocols was retrieved, includ-
ing mean time of pain resolution and radiological BME
area regression, clinical and functional scores, as well as
adverse events or complications of each intervention. Spe-
cifically, the clinical and functional scores were: Visual
Analogic Score (VAS) for pain, Western Ontario and
McMaster Universities Arthritis Index (WOMAC), Har-
ris Hip Score (HHS), 36 short form survey health (SF-
36), Mazur Ankle Score, Weber Ankle Score, Larson Knee
Score, Efficacy Verbal Score (EVS), Knee Society Score
(KSS), and American Orthopaedic Foot and Ankle Society
Score (AOFAS). Demographic, clinical, and radiological
data that could not be extracted independently for each
treatment option in the studies describing more than one
therapy were not included. Weeks and days were converted
into months in order to calculate the average periods
considering a week and a day are equivalent to 0.25 and
0.033 months, respectively.
Methodological quality assessment
In our systematic review, two independent authors (K.P and
A.K) performed the quality assessment section and any disa-
greement between them was solved by a third author (GI.D).
The level of evidence of each included study was noted using
the Wright et al. criteria [15]. A modified Delphi technique
developed by Moga et al. including 18 points was applied to
evaluate the case series. Studies that scored 13 and greater
were considered as high quality, 7–12 as moderate quality,
and 0–6 as low quality [16]. Non-comparative and compara-
tive studies were assessed using the 12-point Methodologi-
cal Index for Non-Randomized Studies (MINORS) criteria

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[17]. The risk of potential biases in the RCTs was appraised
with the Cochrane Collaboration’s risk of bias tool [18].
Results
Study characteristics and demographic data
This systematic review comprises 36 articles, including 19
case series [7, 11, 19–35], 5 retrospective comparative stud-
ies [36–40], 6 prospective cohort studies [41–46], 3 pro-
spective non-randomized comparative studies [47–49], and
3 RCTs [50–52] describing 7 different treatment modalities
for the management of BMES/TO. Publication years ranged
from 1993 to 2021. In total, 880 patients were included,
504 (60%) males and 331 (40%) females with a mean age
of 50.81 years. Mean onset of symptoms was 2.7 months.
Total number of bones affected from various joints was 473
in the hip joint, 276 in the knee joint, and 218 in the foot and
ankle joint. The aforementioned data regarding each treat-
ment group were given separately in detail in (Tables 1, 2,
3, 4, 5, and 6).
Methodological quality assessment
According to Wright et al., our systematic review included
19 level IV [7, 11, 19–35], 5 level III [36–40], 9 level II
[41–49], and 3 level I [50–52] studies. Six studies [7, 20,
24, 32, 33, 35] were deemed as high quality, 11 [11, 19, 21,
23, 25–29, 31, 34] as moderate quality, and 2 [22, 30] as low
quality according to modified Delphi technique by Moga
et al. According to MINORS checklist, comparative studies
[36–40, 47–49] had a mean of 14,75 (range from 11 to 20)
out of 24 points, and non-comparative studies [41–46] had
a mean of 10,66 (range 9 to 12) out of 16 points. A total of
3 RCT’s [50–52] were assessed according to our Cochrane
Collaboration’s risk of bias tool, which evaluated 7 param-
eters including the random sequence generation, allocation
concealment, blinding of participants and personnel, analy-
sis intention (blinding of outcome assessment), incomplete
outcome data, selective reporting (selection of the reported
results), and other types of bias not considered previously
(e.g., design bias, contamination bias).
Comparison of pain resolution
In studies with a follow-up of less than 1 month, 19/19
(100%) in the bisphosphonates group [7] and 16/29
(55%) in the CD group [29, 31)] were free of pain. Within
1–3 months of follow-up, pain resolution was reported in
62/71 (87%) in the bisphosphonates group [19, 24, 47],
23/23 (100%) in the iloprost group [41, 48], and 47/48
(98%) in the CD group [44, 48]. When follow-up was
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Osteoporosis International
3–6 months, regression was noticed in 12/12 (100%) in the
bisphosphonates group [23], 4/4 (100%) in the CD group
[26], and 59/59 (100%) in the conservative group (CG)
consisting of NSAIDs and/or analgesics and/or restricted
weight bearing [27, 30]. Finally, within the period of
6–12 months of follow-up, pain subsided in 20/20 (100%) in
the ESWT group [40], 70/77 (91%) in the bisphosphonates
group [20–22, 47], 18/18 (100%) in the CD group [45], and
45/61 (74%) in the CG [25, 26, 28, 29, 37]. More details are
displayed in (Tables 1, 2, 3, 4, 5, and 6).
Comparison of MRI outcomes
Seventy-two percent (72%) of the included studies had the
initial purpose to analyze both pre- and post-intervention
MRI outcomes, with a total of 564 patients. Out of them,
530 (94%) had pre- and post-intervention MRI results, and
34 patients (6%) were lost on follow-up.
In studies with 1–3 months of follow-up, 45/51 (88%) in
the bisphosphonates group [7, 19, 20, 24], 40/46 (87%) in
the CD group [31, 44, 48, 52], 38/44 (86%) in the iloprost
group [34, 41, 48], and 16/31 (52%) in the CG [30, 51] had
complete resolution of BME. From 3 to 6 months of follow-
up, BME disappeared in 33/40 (83%) in the ESWT group
[40, 50], 28/93 (30%) in the bisphosphonates group [7, 42,
50], 64/68 (94%) in the CD group [26, 40, 48], and 26/66
(39%) in the CG [27, 49]. Lastly, from 6 to 12 months of
follow-up, BME regressed in 54/54 (100%) in the ESWT
group [32, 50], 20/26 (77%) in the bisphosphonates group
[37, 50], 3/7 (43%) in the iloprost group [36], and 18/25
(72%) in the CG [28]. Further information is demonstrated
in (Tables 1, 2, 3, 4, 5, and 6).
Comparison of VAS pain scores
Mean VAS pain scores at clinical presentation were 7.79 in
the ESWT group [32, 33, 38, 40, 49, 50], 7.26 in the bispho-
sphonates group [24, 36, 42, 43, 47, 50], 7.94 in the CG [25,
38, 49], and 8.29 in the CD group [29, 40]. In studies with
a follow-up of less than 1 month, mean VAS scores were
3.90 in the CD group [29, 40] and 2.11 in the bisphospho-
nates group [7]. From 1 to 3 months of follow-up, mean VAS
scores were 2.26 in the ESWT group [29, 33, 40], 6.54 in the
CG [38], and 3.24 in the bisphosphonates group [7, 24, 36,
42, 43, 47, 50]. From 3 to 6 months of follow-up, mean VAS
scores dropped to 1.51 in the ESWT group [38, 49], 3.76 in
the CG [38, 49], and 1.92 in the bisphosphonates group [36,
42, 43, 47]. From 6 to 12 months of follow-up, mean VAS
scores were 3.84 in the ESWT group [40] and 1.16 in the
bisphosphonates group [36, 47]. Over 12 months of follow-
up, mean VAS scores were 0.85 in the ESWT group [33, 49]
and 4.64 in the CG [25, 49]. In-depth analysis is presented
in (Tables 1, 2, 3, 4, 5, and 6) and in (Figs.2, 3).
 Table 1  Summarize of studies containing Bisphosphonates
Authors Study design N Joints Treatment Mean age (y) Gender Mean onset MRI results Pain resolution Clinical scores Adverse events
protocol of symp-
toms

Agarwala (2019) Case series (IV) 19 Hip/19 single 5 mg i.v 42.1 17 M 4w 16/19 CR (12w) 19/19 CR preVAS none
zoledronic 2F 3/19 PR (12w) (2.8w) 7.16/2.11 (2w)
acid/daily p.o 3/19 CR (6 m) /0.74 (4w) /0
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500 mg Ca and (6w)

400 IU vitD/
analgesics
as required/
weight-bearing
as tolerated
Baier (2013) Retrospective 10 Knee/6 (FC/6) i.v ibandronate 34.6 N/A N/A 2/6 CR (12 m) N/A preVAS 5.6/2.6 self-limiting flu-
comparative Ankle/2 6 mg once m 3/6 PR (12 m) (3 m) /1.5 like/3
study (III) (talus/2) for 3 m/RWB/ 1/NR (12 m) (12 m)
Foot/2 (navic/2) analgesics on preWOMAC
demand 50.5/27.5
(3 m) /20.8
(12 m)
PC preSF-36
24.3/66.1
(3 m) /80.9
(12 m)
MC preSF-36
56.5/79.2
(3 m) /84.0
(12 m)
Bartl (2012) Prospective 30 Knee/15 i.v ibandronate 41 23 M 3.2 m 30/30 PR (6 m) 23/30 CR (3 m) preVAS knee flu-like/3 muscu-
comparative Ankle/15 6 mg in 100 ml 7F 27/30 CR 8.5/4.5 (1 m) loskeletal pain/1
study (II) sodium chlo- (12 m) /1.6 (6 m) /1.2
ride in 30 min (12 m)
once m for preVAS ankle
3 m/analgesics 8.2/4.1 (1 m)
(21 patients) /1.9 (6 m) /0.9
(12 m)
preMazur ankle
51/88 (6 m)
/91 (12 m)
preLarson knee
54/86 (6 m)
/89 (12 m)

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Table 1  (continued)
Authors Study design N Joints Treatment Mean age (y) Gender Mean onset MRI results Pain resolution Clinical scores Adverse events
protocol of symp-

13
toms

Evangelatos Case series (IV) 9 Hip/9 single i.v zole- 53.9 7 M 2 m 9/9 CR (3 m) 9/9 CR (1.1 m) N/A APR which is
(2020) dronic acid 2F flu-like (44.4%)
5 mg/daily p.o lasts for 72 h
1000 mg Ca
and 800 IU
vitD/RWB 1 m
Flores-Robles Case series (IV) 17 Ankle/9 single i.v zole- 53.9 8 M 4.4 m 5/8 CR (3 m) 15/17 PR (3 m) N/A none
(2017) Hip/5 dronic acid 9F 3/8 PR (3 m) 13/17 CR
Foot/2 5 mg (12 m)
Knee/1
Gao (2015) RCT (I) 20 Knee/20 alendronate 45.1 9 M 3.8w 5/20 CR (6 m) N/A preVAS 6.1/4.9 none
70 mg p.o 11F 8/20 PR (6 m) (1 m) /2.8
weekly/ 18/20 CR (3 m)
alprostadil (12 m) preWOMAC
10 μg ivgtt 20/20 CR 56.9/38.7
daily/ PWB (18 m) (1 m) /27.8
6w/analgesics (3 m) /24.6
on demand, (6 m) /20.9
restriction (12 m)
from impact
sports
Kotwal (2019) Case series (IV) 7 N/A RWB/bisphos- N/A N/A 2 m N/A 7/7 CR (9.5 m) N/A N/A
phonates
Ringe (2005) Prospective 12 Hip/7 Single i.v 44 5 M 7w N/A 7/12 CR (6 m) preVAS 8.4/4.8 none
cohort study Foot/2 (calc/2) ibandronate of 7F 5/12 PR (6 m) 1 m) /1.8 (3 m)
(II) Other/3 4 mg/ Second /0.5 (6 m)
i.v of 2 mg
(3 patients)-
optional after
3 m and daily
calcium 1 g
and vitD
800 IU sup-
plements (12
patients)/
analgesics (9
patients)
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 Table 1  (continued)
Authors Study design N Joints Treatment Mean age (y) Gender Mean onset MRI results Pain resolution Clinical scores Adverse events
protocol of symp-
toms

Singh (2016) Retrospective 11 N/A Single i.v infu- N/A N/A 22w N/A 11/11 CR (12w) N/A N/A
comparative sion of 5 mg
study (III) zoledronic acid
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(9 patients) /w
oral dose of
alendronate (2
patients)
Trevisan (2016) Case series (IV) 23 Hip/13 (acet/1) PWB/bisphos- 48.4 15 M 2.8 m N/A 23/23 CR N/A N/A
Knee/6 (LTP/1, phonates until 8F (7.1 m)
MFC/2, symptoms
LFC/1, subsided
MTP/1)
Ankle/2
(talus/2)
Foot/2
Vaishya (2017) Case series (IV) 12 Hip/14 PWB (crutches) 41 11 M 3.2 m N/A 12/12 CR N/A N/A
/NSAIDs/bis- 1F (17.1w)
phosphonates/
Ca/VitD
Varenna (2002) Case series (IV) 16 Hip/16 3 i.v infusions/ 38.3 13 M 8w 15/15 CR (3 m) 14/16 CR (2 m) preWOMAC arthralgias and
one every 3F 2/16 PR (2 m) functional fever/9
3d over 4 h 16/16 CR (3 m) 64.5/7 (1 m)
of 45 mg of preVAS 7.15/0.4
pamidronate (1 m)
in 500 mL of EVS (efficacy
isotonic saline verbal score):
solution signific improv
(n = 4) /excel
(n = 5) /asymp
(n = 7) (1 m)

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Table 1  (continued)
Authors Study design N Joints Treatment Mean age (y) Gender Mean onset MRI results Pain resolution Clinical scores Adverse events
protocol of symp-

13
toms

Vasiliadis Prospective 54 Knee/32 i.v zole- 52.7 19 M N/A 20/54 CR (6 m) N/A preVAS fever, myalgia/4
(2021) cohort study (MFC/11, dronic acid 35F 7.22/5.12(3 m)
(II) LFC/6, 5 mg/100 ml /2.34 (6 m)
MTC/14, fluid/ PWB for
LTC/1) 1 m and then
Hip/9 (neck/5, as tolerated
head/4)
Ankle/11
(talus/10,
fibular malleo-
lus/1)
Foot/2 (cunei/1,
meta/1)
OVERALL 240 Hip/92 46.27 127 M 2.6 m 45/51 CR 3 m 19/19 CR 0.7 m mean preVAS
Knee/80 85F 28/93 CR 6 m 9/9 CR 7.26 (N161)
Foot and 20/26 CR 12 m 1.1 m mean VAS
ankle/49 20/20 CR 18 m 14/16 CR (0.5 m) 2.11
6/27 PR 3 2 m (N19)
m38/50 PR 39/46 CR mean VAS (1 m)
6 m 3 m 3.17 (N97)
3/6 PR 12 m 12/12 CR mean VAS
4.43 m (1.5 m) 0.00
23/23 CR (N19)
7.1 m mean VAS (3 m)
7/7 CR 3.95 (N96)
9.5 m mean VAS (6 m)
40/47 CR 1.92 (N96)
12 m mean VAS
2/16 PR 2 m (12 m) 1.16
15/17 PR (N40)
3 m
5/12 PR 6 m

RCT​randomized controlled trial, N patients, MFC medial femoral condyle, LFC lateral femoral condyle, LTP lateral tibial plateau, MTP medial tibial plateau, FC femoral condyle, acet acetabu-
lar, navic navicular,calc calcaneus, cunei cuneiform, meta metatarsal, NSAIDs non-steroidal anti-inflammatory drugs, PWB partial weight-bearing, RWB restricted weight-bearing, Ca calcium
supplements, w weeks,d days, y years, m months, N/A not available, M male, F female, CR complete resolution, PR partial resolution, NR non-responders, BME bone marrow edema, p.o per os,
i.v intravenous, vitD vitamin D
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 Table 2  Summarize of studies containing Extracorporeal shockwave therapy
Authors Study design N Joints Treatment protocol Mean age(y) Gender Mean onset MRI results Pain resolution Clinical scores Complications
of symp-
toms

Zhang (2020) Case series (IV) 34 Hip/34 3 sessions (10d 39.4 23 M N/A 34/34 CR N/A preVAS 6.14 5 subcutaneous
each/interval 11F (12 m) preHHS 72.25 congestion
20–30d). Each points (disap-
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session 4–5 peared within

treatment points 1 w)
(each treatment
point 500 shocks/
total 2500–4000
shots/flux energy
density 0.50 mJ/
mm2)
Vitalli (2018) Retrospective 28 Knee/28 1 cycle, 3 sessions 61.64 10 M N/A preEA 784.82 N/A preKSSclinical pain during
comparative (MFC/28) once a w for 3 18F ­mm2 54.64/70.89 therapy
study (III) w/4000 shots of postEA 178.66 (1 m) /85.89
high energy/ EFD ­mm2 (4 m) (4 m)
of 0.55 mJ/mm2 preKSS-
functional
48.21/75.89
(1 m) /87.86
(4 m)
preVAS
8.14/4.11
(1 m) /1.54
(4 m)
Sansone (2017) Prospective 55 Knee/55 1 session every 3 w 59.8 22 M 6.9w preEA 759.98 N/A preWOMAC none
comparative (MFC/27, for 9 w/2000 shots 33F ­mm2 53.55/87.43
study (II) MTP/28) of high-energy/ postEA (3 m) /88.39 ()
EFD ranging from 88.38mm2 /88.27 (18 m)
0.22 to 0.43 mJ/ (6 m) preVAS
mm2/Hz = 4 7.84/1.58
(3 m) /1.49
(6 m)
/0.9(18 m)
Gao (2015) RCT (I) 20 Knee/20 2 sessions/high- 41.6 11 M 2.9w 13/20 CR (6 m) N/A preVAS 6.7/2.6 transient soft tis-
energy ESWT/ 9F 7/20 PR (6 m) (1 m) /1.1 sue swelling or
levels 3–4/EFD 20/20 CR (3 m) minor bruising
of > 0.44 mJ/ (12 m) preWOMAC
mm2/3000–4000 54.3/26.6
impulses/Hz = 2–3 (1 m) /10.9
(3 m) /9.8
(6 m) /9.7
(12 m)

13


Table 2  (continued)
Authors Study design N Joints Treatment protocol Mean age(y) Gender Mean onset MRI results Pain resolution Clinical scores Complications
of symp-

13
toms

Gao (2015) Retrospective 20 Hip/28 (uni/12, EFD of 0.5 mJ/ 42.14 10 M N/A 20/20 CR (6 m) 20/20 CR preVAS transient soft tis-
comparative bil/8) mm2/3–4 levels/2 10F 10.16 m 8.3/3.84 sue swelling or
study (III) series of 3 treat- (10 m) minor bruising
ments/2000–3000 preHHS
impulses/alen- 45.23/86.86
dronate tb 70 mg (10 m)
p.o w for 14d and
alprostadil 10 μg
ivgqd for 14d/
PWB 4–6w post-
treatment
Cao (2021) Case series (IV) 20 Foot/20 The number of 46.20 6 M N/A preEA 132.13 N/A preVAS transient skin
(cunei/10, impacts per 14F ­mm2 7.75/2.40 erythema/2
calc/4, patient was 2000 postEA 41.46 (3 m) /0.7 (alleviated after
navic/3, times/the energy ­mm2 (38.25 m) 2 days)
meta/3) flow density was preAOFAS
0.18 mJ/mm2/ 62.10/82.80
the pressure was (3 m) /93.15
1.8–2.5 Pa/the (38.25 m)
frequency was
6–8 Hz/for 1 time/
week and a total
of 5 times in 1
course of treat-
ment
Agostino (2014) Prospective 20 Hip/20 2 sessions (48 h 43.23 12 M 4.2w preEA 981.9 N/A preHHS none
cohort study apart) /4000 shots 8F ­mm2 39.08/81.28
(II) at high-energy/ postEA (2 m) /91.76
EFD mean of 469.5mm2 (3 m) /95.06
0.5 mJ/mm2/PWB (2 m) (6 m) /95.55
for 30 d post- postEA 107.8 (15.52 m)
treatment ­mm2 (6 m)
Osteoporosis International
 Table 2  (continued)
Authors Study design N Joints Treatment protocol Mean age(y) Gender Mean onset MRI results Pain resolution Clinical scores Complications
of symp-
toms
OVERALL 197 Hip/82 49.84 94 M 1.39 m 33/40 CR 6 m 20/20 CR mean preVAS
Knee/103 103F 54/54 CR 12 m 10.16 m 7.79 (N143)
Foot and 7/20 PR 6 m mean VAS
Osteoporosis International

ankle/20 (1 m) 3.48

(N48)
mean VAS
(3 m) 1.65
(N95)
mean VAS
(4 m) 1.54
(N28)
mean VAS
(6 m) 1.49
(N55)
mean VAS
(10 m) 3.84
(N20)
mean VAS
(18 m) 0.9
(N55)
mean VAS
(38.25 m) 0.7
(N20)
mean preHHS
42.15 (N40)
mean HHS
(2 m) 81.28
(N20)
mean HHS
(3 m) 91.76
(N20)
mean HHS
(6 m) 95.06
(N20)
mean HHS
(10 m) 86.86
(N20)
mean HHS
(15.52 m)
95.55 (N20)

N patients, MFC femoral condyle, MTP medial tibial plateau, navic navicular, calc calcaneus, cunei cuneiform, meta metatarsal, bil bilateral, uni unilateral, PWB partial weight-bearing, w
weeks, d days,y; years, m months, N/A not available, M male, F female, CR complete resolution, PR partial resolution, EA edema area, ESWT extracorporeal shockwave therapy, EFD energetic
flux density

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Table 3  Summarize of studies containing Core decompression

Authors Study design N Joints Treatment Mean age (y) Gender Mean onset MRI results Pain resolution Clinical scores Adverse events
protocol of symp-

13
toms

Aigner (2005) Prospective 19 Hip/20 CD/RWB 6w 41 15 M 21w 14/20 CR (3 19/20 CR (6w) preHHS none
comparative 4F m) 53.7/95.1
study (II) 18/20 CR (6 m) (3 m)
2 AVN
Bashaireh Case series (IV) 10 Hip/10 CD/RWB 2w/ 43.7 10 M 50.4d N/A 1/10 CR (2d) preVAS 8.5/4.2 N/A
(2020) then 50% WB 6/10 CR (1w) (1d) /1.8 (2d) /
2–4w/ then 10/10 CR 0.5 (1w)
increasing (5.8w)
WB until full
WB after 4w
Berger (2006) Prospective 18 Knee/24 CD/PWB (1st d) 53.7 13 M 4w 12/12 CR (12w) 12/12 CR (6w) N/A N/A
cohort study (MFC/15, FWB within 4 5F
(II) LFC/7) to 6w
Calvo (2000) RCT (I) 6 Hip/7 N/A 39.3 6 M 1.7 m 6/6 CR (3 m) 6/6 CR (2 m) N/A none
Gao (2015) Retrospective 26 Hip/36 CD/crutches 4 43.36 14 M N/A 26/26 CR (6 m) 26/26 CR (12w) preVAS local hematoma/3
comparative to 6w 12F 8.21/5.93 (1d) and poor wound
study (III) preHHS healing/1
48,89/82.15
(1d)
Hofmann (1993) Case series (IV) 9 Hip/10 CD 44 9 M 4 m 8/8 CR (3 m) 9/9 CR (1w) preHHS N/A
48.2/98.8
(33 m)
Radke (2001) Case series (IV) 4 Ankle/3 (talus/3) CD 43.25 2 M 2.5 m N/A 4/4 CR (3.75 m) preWeber ankle none
Foot/1 2F 52/93 (4 m)
(cuboid/1)
Radke (2003) Prospective 18 Hip/22 CD 46.4 13 M 2.28 m 20/22 CR (6 m) 18/18 CR preHHS none
cohort study 5F 2 AVN (7.2 m) 37.2/89.45
(II) (1d)
Radke(2003) Retrospective 38 Hip/38 CD/PWB 6w 44 30 M N/A 2 AVN N/A preHHS N/A
comparative 8F 48.5/77.32
study (III) (1d)
OVERALL
Osteoporosis International
 Table 3  (continued)
Authors Study design N Joints Treatment Mean age (y) Gender Mean onset MRI results Pain resolution Clinical scores Adverse events
protocol of symp-
toms
OVERALL 148 Hip/143 44.74 112 M 2.76 m 40/46 CR 3 m 1/10 CR 2d mean preVAS
Knee/24 36F 64/68 CR 6 m 15/19 CR 8.29 (N36)
Foot and ankle/4 0.25 m mean VAS (1d)
Osteoporosis International

10/10 CR 5.44 (N36)

1.45 m mean VAS (2d)
31/32 CR 1.5 m 1.8 (N10)
6/6 CR 2 m mean VAS
4/4 CR 3.75 m (0.25 m) 0.5
18/18 CR 7.2 m (N10)
mean preHHS
38.34 (N110)
mean HHS (1d)
81.51 (N82)
mean HHS
(3 m) 95.1
(N19)
mean HHS
(33 m) 98.8
(N9)

RCT​ randomized controlled trial, N patients, MFC medial femoral condyle, LFC lateral femoral condyle, CD core decompression, ANA analgesics, NSAIDs non-steroidal anti-inflammato-
rydrugs, PWB partial weight-bearing, FWB full weight-bearing, RWB restricted weight-bearing, Ca calcium supplements, w weeks, d days, y years, m months, N/A not available, M male, F
female, CR complete resolution, AVN avascular necrosis

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Table 4  Summarize of studies containing conservative group

Authors Study design N Joints Treatment protocol Mean age (y) Gender Mean onset MRI results Pain resolution Clinical scores
of symp-

13
toms

Vitali (2018) Retrospective com- 28 Knee/28 (MFC/28) analgesics/ 60.98 9 M N/A 40% reduction of N/A preKSS clinical
parative study NSAIDs/RWB 19F BME (4 m) 50.54/59.29 (1 m)
(III) /62.32 (4 m)
preKSS functional
47.68/54.29 (1 m)
/58.04 (4 m)
preVAS 8.25/6.54
(1 m) /4.39 (4 m)
Sprinchorn (2011) Case series (IV) 6 Ankle/3 (talus/3) controlled ankle 60.83 1 M 3.5 m N/A 6/6 CR (7.5 m) preVAS 7.8/0.8
Foot/3 (cuboid/2, motion walker or 5F (13 m)
cunei/1) stiff-soled post-
operative shoe
Singh (2016) Retrospective com- 7 N/A pneumatic walking N/A N/A 22w N/A 7/18 CR (25.6w) N/A
parative study boot/RWB 8w 11/18 NR (8w)
(IV)
Sansone (2017) Prospective com- 31 Knee/31 (MFC/17, RWB/restriction of 61.1 10 M 6.2w 41% reduction of 0/31 CR (18 m) preWOMAC
parative study MTP/14) physical activity 21F BME (6 m) 4/31 51.93/62.39 (6 m)
(II) CR (6 m) 27/31 /63.56 (18 m)
PR (6 m) preVAS 7.70/4.76
(6 m) /4.52 (18 m)
Radke (2003) Retrospective com- 5 Hip/5 NSAIDs/RWB 44 4 M N/A 1 AVN N/A preHHS 38.6/80.6
parative study 1F (2–4y)
(III) postWOMAC 2.08
(2–4y)
Radke (2001) Case series (IV) 6 Ankle/5 (talus/5) analgesics/RWB 48 5 M 0.83 m N/A 6/6 (6.6 m) Weber ankle
Foot/1 (navic/1) 1F 95(3–9 m)
Holzer (2009) Case series (IV) 43 Hip/49 RSW/NSAIDs 45.6 37 M 6w 22/35 CR (3.4 m) 49/49 CR (14w) N/A
(rarely) 6F 12/35 PR (3.4 m)
1/35 NR (3.4 m)
30/31 CR (15 m)
1/31 PR (15 m)
Fernandez-Canton Case series (IV) 25 Ankle/26 (talus/16, NSAIDs/Ca/cal- 54 12 M 9.7 m 18/25 CR (12 m) 23/25 CR (12 m) N/A
(2003) fibula or tibia/10) citonin/physical 13F 5/25 PR (12 m) 25/25 CR (24 m)
Foot/72 (navic/16, therapy/rest/mas- 2/25 NR (12 m)
calc/13, sage alone or in
cuboid/15, combination
cunei/18, tar-
sal/10)
Osteoporosis International
 Table 4  (continued)

Authors Study design N Joints Treatment protocol Mean age (y) Gender Mean onset MRI results Pain resolution Clinical scores
of symp-
toms

Capone (2011) RCT (I) 21 Hip/21 PWB/analgesics or 45.9 17 M 1.9 m 6/21 CR (3 m) 21/21 CR (22.6 m) preWOMAC
NSAIDs 4F 8,7/17,2 (3 m)
Osteoporosis International

/22,6 (6 m) /25

(12 m)
Bashaireh (2020) Case series (IV) 5 Hip/5 analgesics/NSAIDs 35.6 4 M 92d N/A 3/5 CR (48.3w) N/A
1F 2/5 NR (48.3w)
Balakrishnan Case series (IV) 10 Hip/12 NSAIDs/restriction 41 10 M 4.7 m 10/10 CR (7.5w) 10/10 CR (5.8 m) N/A
(2003) of activities
OVERALL 187 Hip/92 64.21 109 M 3.39 m 10/10 CR 1.88 m 49/49 CR 3.5 m mean preVAS 7.94
Knee/59 71F 6/21 CR 3 m 10/10 CR 5.8 m (N65)
Foot and ankle/110 22/35 CR 7/18 CR 6.4 m mean VAS (1 m)
3.4 m 6/6 CR 6.6 m 6.54 (N28)
4/31 CR 6 m 6/6 CR 7.5 m mean VAS (4 m)
18/25 CR 26/30 CR 12 m 4.39 (N28)
30/31 CR 15 m 0/31 CR 18 m mean VAS (6 m) 0.8
12/35 PR 21/21 CR 22.6 m (N6)
3.4 m 25/25 CR 24 m mean VAS (13 m)
27/31 PR 6 m 4.76 (N31)
5/25 PR 12 m mean VAS (18 m)
1/31 PR 15 m 4.52 (N31)

RCT​;randomized controlled trial, N patients, MFC medial femoral condyle, MTP medial tibial plateau, navic navicular, calc calcaneus, cunei cuneiform, meta metatarsal, NSAIDs non-steroidal
anti-inflammatory drugs, PWB partial weight-bearing, RWB restricted weight-bearing, Ca calcium supplements, w weeks, d days, y years, m months, N/A not available, M male, F female, CR
complete resolution, PR partial resolution, NR non-responders, BME bone marrow edema, AVN avascular necrosis

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Table 5  Summarize of studies containing Iloprost

13
Authors Study design N Joints Treatment pro- Mean age (y) Gender Mean onset MRI results Pain resolution Clinical scores Complications
tocol of symp-
toms

Baier (2013) Retrospective 10 Knee/5 (FC/5), i.v iloprost 5–6 h 35.2 N/A N/A 3/7 CR (1y) 3/7 reduced pain preVAS 6.4/1.1 headache/2, flush-
comparative Ankle/3 on 5 consecu- PR (1y) immediately (3 m) /1.1 like symptoms/3,
study (III) (talus/3) Foot/2 tive d starting 1/7 NR (1y) (8/10) (12 m) facial rash/6,
(navic/2) dose 20 μg preWOMAC increasing pain
(day 1)/30 μg 53.6/13.4 (3 m) during infusion/4
for (day 2) /12.1 (12 m)
and 40 μg for preSF-36 physi-
the remaining cal 29/79.7
3 days (3 m) /80.9
(12 m)
preSF-36 mental
55.8/82.8 (3 m)
/86.1 (12 m)
Aigner (2005) Prospective 23 Ankle/12 5 i.v infu- 59.1 8 M N/A 15/21 CR (3 m) N/A N/A N/A
cohort study (talus/12) sions with 15F 3/21 PR (3 m)
(II) Foot/11 (cunei/4, 20 or 50 mg 3/21 NR (3 m)
meta/4, calc/2, iloprost/3w
navic/1) PWB
Aigner (2005) Prospective 17 Hip/18 5 infusions 20 μg 49 13 M 16w 17/17 CR (3 m) 17/17 CR (4w) preHHS 64.7/97 severe headache/1
comparative s iloprost over 4F (3 m) (discontinued
study (II) 6 h on 5 con- the therapy),
secutive d/3w patients/9: 8
RWB cases of mild
headache and
7 cases of mild
nausea
Aigner (2001) Case series(IV) 6 Ankle/6 (talus/6) 5 infusions 58.4 1 M 5.4 m 6/6 CR (3 m) 6/6 CR (5w) preMazur 58/91 patients/4:
of 50 μg of 5F (1 m) /93 (3 m) severe/1 and
iloprost given mild cases of
over 6 h on 5 headache/3,
consecutive d severe/2 and
mild cases of
nausea/2
OVERALL 56 Hip/18 51.69 22 M 4.36 m 38/44 CR 3 m 17/17 CR 1 m
Knee/5 24F 3/7 CR 12 m 6/6 CR 1.25 m
Foot and ankle/34 3/21 PR 3 m
3/7 PR 12 m

N patients, FC femoral condyle, navic navicular, calc calcaneus, cunei cuneiform, meta metatarsal, PWB partial weight-bearing, RWB restricted weight-bearing, w weeks, d days, y years, m
months, N/A not available, M male, F female, CR complete resolution, PR partial resolution, NR non-responders
Osteoporosis International
 Table 6  Summarize of studies containing Hyperbaric oxygen therapy and Denosumab
Authors Study design N Joints Treatment protocol Mean age (y) Gender Mean onset MRI results Pain resolution Clinical scores Adverse events
of symp-
toms
Osteoporosis International

HBOT
Capone (2011) RCT (I) 20 Hip/20 5 daily sessions over 44.8 20 M 1.7 m 11/20 CR (3 m) 14/20 CR (3 m) preWOMAC barotrauma/2
four consecutive w 2F 20/20 CR (24 m) 8.4/23.3 (3 m) /25 migration/2
Pause of one m/ (6 m) /25 (12 m)
repeat (total of 40
sessions) breathing
100% oxygen/2.2
ATA in a mul-
tiplace pressure
chamber for 90 min
using a mask
breathing system
Guler (2015) Case series (IV) 18 Hip/18 RWB/diclofenac 38.6 12 M 6.1w 18/18 CR (8.3 m) 18/18 CR (3.9 m) preHHS 55.6/88.8 none
sodium (100 mg/d) 6F (3 m) /96.0 (6 m)
until the pain
free/risedronate
(150 mg/month)
for 6 m/HBOT was
applied at a dose
of 2.5 ATA at 2 h
per d for 30 d (30
session/60 h)/ace-
tylsalicylic acid was
given at a dose of
100 mg/d for 3 m
Denosumab
Rolvien (2017) Case series (IV) 14 Hip/8 single dose of subcu- 49 8 M 5.2 m 7/14 CR (3–6 m) N/A N/A none
(head/8) taneous denosumab 6F 6/14 PR (3–6 m)
Knee/5 60 mg /20.000 IE 1/14 NR (3–6 m)
(distal VitD weekly prior
femur/5) to the injection
Foot/1
(meta/1)

RCT​randomized controlled trial, N patients, meta metatarsal, HBOT hyperbaric oxygen therapy, RWB restricted weight-bearing, w weeks, d days, y years, m months, N/A not available, M male,
F female, CR complete resolution, PR partial resolution, NR non-responders, vitD vitamin D, ATA​atmosphere absolute

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 Osteoporosis International

a major population (pregnant women) was excluded. The

8.5
hip joint was the commonest affected joint (49%) followed
8 by the knee joint (28%) and the foot and ankle joint (23%).
7.5 According to our results, bisphosphonates had better short-
term (< 1 month) outcomes on pain resolution compared
7
with CD, while iloprost was more efficient at 1–3 months
6.5 compared with bisphosphonates and CD. In the long run at
ESWT Bisphosphonates Conservave CD
3–6 months, all three of the aforementioned showed equal
VAS pain score at clinical presentaon results on pain resolution, while at a period of 6–12 months,
CD and ESWT showed excellent results followed by bispho-
sphonates and then the CG. On MRI at 1–3 months, bisphos-
Fig. 2  Mean VAS pain score at clinical presentation
phonates, iloprost, and CD had relatively the same outcomes
on BME resolution, with the least promising being the CG.
7 At 3–6 months, CD seemed to have achieved the best results
6 on the resolution of BME, followed by ESWT, CG, and then
5 the bisphosphonates group. In the long-term at 612 months,
4 ESWT had the best outcomes compared with the conserva-
3 tive, bisphosphonates, and iloprost groups. The above are
2 observations rather than definitive statements because there
1 is a lack of statistical analysis.
0 Each treatment method has its own potential mechanism
ESWT Bisphosphonates Conservave CD
of action. Bisphosphonates have shown to bear anti-inflam-
<1 month 1-3 months 3-6 months 6-12 months >12 months matory properties, which along with the inhibition of osteo-
clastic activity and bone resorption are features contribut-
ing to the treatment of BMES/TO [7, 43, 47]. Iloprost, as
Fig. 3  Mean VAS pain score post-treatment
a synthetic PGI2 analog leads to vasodilatation, which in
turn causes the absorption of interstitial fluid, reducing the
Adverse events and complications pressure within the bone. It is claimed that iloprost may have
osteoblastic activity as well [53]. HBOT is another treat-
In the iloprost group, adverse events included mild-severe ment modality, which through the increase of oxygenation
headache (15 patients, 27%), flush-like symptoms (3 can induce bone metabolic activity, proliferation of collagen
patients, 5%), facial rash (6 patients, 11%), pain during infu- and fibroblast as well as new capillary formation. Its vaso-
sion (4 patients, 7%) and mild-severe nausea (11 patients, active component can promote the reduction of edema and
20%). In the ESWT group, therapy-related events were sub- the increase of microcirculation of the affected joint [51].
cutaneous congestion points (5 patients, 3%), pain during Additionally, extracorporeal shockwaves exert an angio-
therapy (28 patients, 14%), transient soft tissue swelling genic and trophic effects. The endothelial nitric oxide (NO)
or bruising (40 patients, 20%), and transient skin erythema synthesis provides the necessary NO (vasoactive effect).
(2 patients, 1%). In the CD group, complications included Furthermore, shockwaves’ actions result in osteoblast and
poor wound healing (1 patient, 1%) and local hematoma (3 periosteal cell activation, inducing osteogenic differentiation
patients, 2%). In the bisphosphonates group, adverse events of mesenchymal stem cells and increased production of bone
were flu-like symptoms (10 patients, 4%), musculoskeletal deposition markers. Lastly, it is involved in bone remodeling
pain (14 patients, 6%), and fever (13 patients, 5%). HBOT through the reduction of pro-osteoclastogenic factors [54].
was associated with barotrauma (2 patients, 5%). Denosumab binds to the RANKL preventing interaction
with RANK receptors on osteoclasts. It has a quicker effect
on reducing remodeling compared to bisphosphonates, but
Discussion unfortunately it has been used in the treatment of BMES/TO
in only one study [11].
The main findings of this systematic review concern the BMES/TO is strictly diagnosed on MRI. It is associated
outcomes of various pharmacological agents (bisphospho- with an extensive, diffuse area of BME and could be dif-
nates, iloprost, denosumab, NSAIDs), ESWT, HBOT, and ferentiated from other secondary causes of BME because in
surgical core decompression for the treatment of BMES/ BMES/TO the subchondral bone has no other morphological
TO. The condition was predominantly manifested in men changes, there is a lack of history of trauma and the clini-
(60%); the reason for the predominance of men was that cal course is benign, leading to complete resolution. In rare

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Osteoporosis International
cases, it can migrate to adjacent joints, the so-called regional
migratory osteoporosis [3, 55].
Whether BMES/TO and avascular necrosis (AVN) are
distinct clinical entities remain uncertain [3]. The patho-
physiology of BMES/TO is still disputable, but it is thought
to be of ischemic etiology. The triggering point seems to be
a transient intraosseous thrombosis, which results in adipo-
cytes necrosis and reduction of hematopoietic cells. When
the blood circulation within the bone returns, the sequela is
reactive hyperemia accompanied with vasodilatation among
the necrotic adipocytes and increased perfusion, which leads
to the formation of BME [56]. BMES/TO should be mainly
differentiated from AVN. In AVN, the ischemic episode is
longer in duration, leading to bony necrosis. AVN can be
diagnosed on MRI with frequent findings including single
and double line signs (on T1w and T2w sequences, respec-
tively) as well as crescent sign [4, 56].
Precautions must be born in mind when using each of
the therapeutic methods due to their possible side effects.
With regard to iloprost, moderate to severe headaches and
flushes are among the commonest side effects, which can
be seen in approximately 70% of the patients and may con-
stitute the cause of incompliance to the therapy. Major side
effects are angina pectoris and arrhythmias. The medicine
can potentiate the effects of antihypertensive medications
and anticoagulants, thus they must be administered frugally
in such cases [53]. Bisphosphonates have minor upper gas-
trointestinal side effects, which include nausea, vomiting,
epigastric pain, and esophagitis. Intravenously administered
agents may increase the possibility of nephrotoxicity, as well
as acute phase response resembling influenza-like symptoms
(subsides in 2–3 days). Transient conjunctivitis is the most
frequent ocular side effect. Moreover, hypercalcemia, slight
increase in occurrence of atrial fibrillation in predisposed
patients, and rarely atypical femoral shaft fractures can hap-
pen [57]. HBOT may be associated with risk of barotrauma
(2%) and claustrophobia, while seldom severe complications
include progressive myopia, difficulty in breathing, and sei-
zures. Restrictive pulmonary disorders, pneumothorax, and
chemotherapy are absolute contraindications of HBOT [12,
58]. ESWT is an option that has a few side effects like local
erythema, swelling, and pain [55].
ESWT seems like an ideal alternative or adjuvant therapy
in combination with the conventional medicines, but a hand-
ful of studies have been conducted regarding its efficiency.
There have been a few treatment protocols in the literature,
but the most precise with the highest level of evidence is
that of Gao et al. in 20 patients suffering from BMES/TO
in the knee, in which the authors performed 2 sessions of
high-energy ESWT (once a week) adjusted at 3–4 levels at a
high energy flux density (EFD) of > 0.44 mJ/mm2 and with
3000–4000 impulses at a frequency of 2–3 Hz. The results
were favorable and the patients achieved a VAS pain score
of 2.6 in 1 month and 1.1 in 3 months post-treatment with
minor transient complications [50]. HBOT includes another
example of an alternative treatment but there is a scarcity
of studies. The most accurately and thoroughly performed
study was that of Capone et al. in 20 patients with BMES/TO
of the hip. The protocol was as follows: 5 daily sessions over
four consecutive weeks, pause of 1 month and then repeat
for a total of 40 sessions. Oxygen was 100% at 2.2 atmos-
phere absolute (ATA) in a multi-place pressure chamber for
90 min using a mask breathing system. Pain resolved in 14
patients in 3 months with minor complications [51]. There is
a reference of one study including 14 patients, utilizing the
anti-resorptive drug denosumab in the treatment of BMES/
TO. The protocol consisted of a single dose of subcutaneous
60 mg of denosumab. BME was completely resolved in 50%
and reduced in 43% of the patients, while VAS pain scores
decreased significantly [11].
There is a lack of standardized treatment protocol in the
literature with regard to BMES/TO. According to our sys-
tematic review results, we attempted to create a treatment
algorithm as a guidance to clinicians who encounter this
rare entity. When the diagnosis of BMES/TO is established,
the patient should be instructed to restrict weight-bearing of
the joint. Administration of NSAIDs for the pain can be pre-
scribed with or without the combination of bisphosphonates
(a single injection of 5 mg of zoledronic acid) or iloprost for
5 consecutive days (day 1-i.v. 20 μg over 5–6 h, day 2-i.v.
30 μg over 5–6 h, day 3–5-i.v. 40 μg over 5–6 h). HBOT or
ESWT can be used as adjuvant or in combination with the
aforementioned. Specifically, HBOT protocols vary from
15 to 90 sessions at 2.2–2.5 ATA with 90–120 mps, while
ESWT protocols include 1–9 sessions every 1–3 weeks for
3–9 weeks, 2000–4000 shots of high energy ESWT, EFD
of 0.22–0.55 mJ/mm2, 3–4 levels, and frequency of 2–4 Hz.
When a patient is not responding adequately, CD is advised
after 6–12 months of treatment with the above therapeu-
tic methods. CD is also recommended in patients who seek
faster remission of symptoms (achieved from 1 week to
7.2 months according to currently published studies) [26,
29, 31, 39, 40, 44, 45, 48, 52] (Fig. 2).
Our systematic review carries numerous limitations due
to the scarcity of high level of evidence studies. There is
significant heterogeneity with regard to the type of treat-
ment, joint involvement, onset and severity of symptoms,
and administration protocols. There is not a standard follow-
up period which leads to difficulty in the comparison and
synopsize of MRI, pain resolution, and VAS pain scores
among studies. VAS pain score is not an objective measure-
ment tool but a subjective one. Most of the studies compare
the outcomes of either iloprost, bisphosphonates, HBOT,
and ESWT with the CG, which leads to a lack of direct com-
parisons among studies. The number of patients treated with
each therapeutic option is not distributed equally among
13

studies. There is a lack of studies comparing the surgical
approach with the other options which leads to difficulty in
whether a patient is warranted for surgery due to failure of
the conservative approach.
Conclusion
BMES/TO has been treated with many non-standardized
measures due to the low number of highly reliable studies.
Current literature shows promising results with regard to the
reduction of the clinical course of BMES/TO, but further
large multicenter randomized controlled trials, as well as
standardized radiological and clinical scores, are warranted
to eventually acquire evidence-based recommendations on
the therapeutic algorithm.
Data availability  Available upon request.
Code availability  Not applicable.
Declarations  16. Moga C, Guo B, Schopflocher D, Harstall C (2012) Develop-
Conflict of interest  The authors declare no competing interests.
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 Osteoporosis International

Authors and Affiliations

Konstantinos Paraskevopoulos1   · Anthimos Keskinis2 · Ioannis S. Vasios2 · Konstantinos G. Makiev2 ·

Konstantinos Tilkeridis2 · Georgios I. Drosos2 · Athanasios N. Ververidis2

Anthimos Keskinis Athanasios N. Ververidis

anthimos13@hotmail.com anthimos13@hotmail.com
Ioannis S. Vasios 1
Medical Centre of Kato Nevrokopi, Department
giannisvasios@hotmail.gr
of Orthopaedic Surgery, University General Hospital
Konstantinos G. Makiev of Alexandroupolis, 68100 Alexandroupolis, Greece
costasmakiev@gmail.com 2
Department of Orthopaedic Surgery, Medical School,
Konstantinos Tilkeridis Democritus University of Thrace, University General
tilkerorth@icloud.com Hospital of Alexandroupolis, 68100 Alexandroupolis, Greece
Georgios I. Drosos
drosos@otenet.gr

13