Dose dependent effects of extracorporeal shockwave therapy on pain and function in osteonecrosis of femoral head: A systematic review

Abstract

Purpose

To investigate the effectiveness of different dosages of extracorporeal shockwave therapy (ESWT) on pain, function and radiographic outcomes in patients with osteonecrosis of femoral head (ONFH).

Procedure

The PRISMA (Preferred Reporting Items for Systematic Reviews and Meta Analysis) guidelines were followed to conduct this review. The systematic literature search was done by using six different electronic databases include MEDLINE (assessed by Pubmed) CENTRAL (Cochrane Library Central Register of Controlled Trials), Web of Science, PEDro (Physiotherapy Evidence Database), Scopus and Science Direct. Retrospective and prospective cohort studies; case control study, randomized clinical trials were included. Screening conducted by two independent authors along with inclusion and exclusion criteria of included studies. The methodological quality assessment for cohort studies and randomized clinical trials was done by using Structured Effectiveness Quality Evaluation Scale (SEQES) and Newcastle-Ottawa Scale for case control study.

Result

Total 1410 articles were found from various databases. After duplicates removed 450 articles remained. Followed by title and abstract screening 53 articles eligible for full text reading, out of them 13 articles met the inclusion criteria and included in this review.

Conclusion

High energy flux densities of ESWT found to be more effective followed by low and moderate energy flux densities in earlier course of the disease compared to later stages in terms of pain relief, functional improvement and disease progression. Due to high variability among study design, ESWT dosages, patient characteristics and considering the paucity of well conducted studies, the present study cannot be conclusive.

1. Introduction

Osteonecrosis of femoral head (ONFH) is a type of clinical condition that is characterized by ischemic necrosis of the head of femur because of its poor blood supply.¹ Commonly seen in young and middle aged individuals (30–50 years). In a recent retrospective cohort study the prevalence of ONFH in north Indian steroid administrated patient population is about 37.3 % followed by 20.1 % for alcoholics and 15.3 % for trauma patients.²

Multiple factors associated with ONFH like trauma, corticosteroid use, alcoholism, smoking, coagulation disorders, HIV (human immunodeficiency virus) infection and other rare disorders such as hyperlipidemia, dysbarism. Vascular endothelial damage and microvascular thrombosis occurs, ultimately slow down the blood perfusion to femoral head, increased intraosseous pressure leads to venous stasis. Results in, necrosis of femoral head occurs that leads to pain, collapse of subchondral bone, loss of hip function and arthritis in young adults.³

ONFH can be treated surgically and conservatively. Surgical treatment includes joint preservation techniques like vascularized bone grafting, total hip replacements, hip osteotomies and core decompression. Core decompression is the gold standard for femoral head preservation useful in early stages, but with unsatisfactory results in later stages of the disease. Post operative complication rates are higher in surgically treated patients.¹ Non surgical treatments includes life style changes like weight control, drug therapy, hyperbaric oxygen therapy, biophysical modalities like extracorporeal shockwave therapy (ESWT)⁴ and pulsed electromagnetic field therapy (PEMF).⁵ ESWT and PEMF have similar anti-inflammatory, analgesic, chondroprotective, tissue regenerative, osteogenic and angiogenic effects in early stages of ONFH.^5,6

ESWT received much attention because there is a convincing evidence which shows that ESWT is effective in treating ONFH with no severe complications and fewer side effects such as pain, swelling and minor hematoma in early as well as later stages of disease which resolves on its own^7,8

ESWT produce acoustic pressure waves which are converted to mechanical energy and act at the molecular, cellular and tissue level to produce biological changes in bone and soft tissues.⁹ It is widely used to treat various musculoskeletal, bone and cartilage related disorders.¹⁰

Numerous studies reviewed the effect of shockwave therapy on pain and function in ONFH patients but dosage were heterogeneous.11, 12, 13 A recent systematic review conducted by Zhang et al. evaluate the effect of ESWT on pain, function and radiographs¹⁴ but the effect of particular dose on these outcomes is still not known.

Therefore, the purpose of this systematic review is to summarize the available literature exploring how different doses of ESWT will affect the clinical and radiographic outcomes in patients with ONFH.

2. Method

2.1 Protocol and Registration: This Systematic review was registered in International Prospective Register of Systematic Reviews (PROSPERO) with registration number: CRD42021265947. Preferred reporting items for systematic Review and Meta- Analysis (PRISMA) guidelines were followed for this systematic review.¹⁵ (Fig. 1).

Fig. 1.

PRISMA flowchart showing identification and selection of trials for the systematic reviews.

2.1. Eligibility criteria

Studies included only the patients having ONFH with ARCO stage I to IV. Treated by ESWT at various doses. Patients of age ≥18 years irrespective of their gender. Follow up of the treatment should be ≥ 6 months. English language studies including retrospective and prospective cohort studies; case control study and randomized clinical trials (RCTs) were included. Comparator would be any invasive or non invasive treatment.

2.2. Search strategy

Electronic databases including PubMed, Scopus, Web of Science, CENTRAL (Cochrane Library Central Register of Controlled Trials), PEDro and Science Direct. With no time limitation and last search was performed on November 2021. The following search terms were used: Avascular necrosis, Extracorporeal shockwave therapy, ESWT, Femoral head, Ischemic necrosis, Osteonecrosis of femoral head.

2.3. Quality assessment

Screening was conducted by two independent researchers along with inclusion and exclusion process of included studies. Any disagreement was resolved by discussion and consensus. Structured Effectiveness Quality Evaluation Scale (SEQES) was used for cohort and randomized clinical trials. It consists of 24 items and each item was scored if criteria were met. (score 2 = criterion fully met, score 1 = criterion partially met and 0 = criterion not met). Total score of 40–50 represent as high quality study, 30–39 as moderate quality study, score of 20–29 as a low-quality study, score below 20 as a very-low-quality study. Newcastle-Ottawa Scale was also used for one case control study in which score of <4 was considered as poor, score of 5–6 as fair and score of >7 as good.¹⁶

2.4. Data extraction

Data was extracted by the principal author on the basis of characteristics of the included trials (author's name, year of trial conduction, design and follow up period), participants (number of participants, age, gender, ARCO stage, intervention (type of ESWT, frequency, energy density/intensity, duration), outcome (pain measured by any of the following (no limitations) like VAS, NPRS, Healing (x-ray, CT scan MRI), function measured by any of the following like HHS, HOOS, WOMAC). Two reviewers worked independently and any conflicts were resolved through dialogue.

2.5. Study selection

Two authors independently executed the process of search and selection of studies. All records of different databases were exported to Zotero and duplicates were removed. Title, abstract and keywords screened for each relevant study and inapplicable studies were excluded. Full text of the remaining articles was retrieved and assessed according to the eligibility criteria.

3. Results

3.1. Literature search

Fig. 1 shows the flow diagram of our search strategy according to PRISMA guidelines. Total 1410 articles identified from various databases. After duplicates removed, 450 articles remained. Followed by title and abstract screening 53 articles eligible for full text reading out of them 40 articles excluded with some reasons. Therefore 13 articles met the inclusion and exclusion criteria that finally included in this review. Out of which 8 articles were cohort studies, 4 randomized clinical trial and 1 case control study. VAS and HHS are common outcome measures used to assess pain and function at baseline and after the treatment. Other outcome measures were radiographs and MRI for the assessment of disease progression.

3.2. Study characteristics

Characteristics of included studies are mentioned in Table 1. Studies included 442 patients diagnosed with ONFH of ARCO stage from I to IV age from 18 to 79 years with 574 number of total hips and follow up ranged from 6 months to 130.6 months and all were treated with ESWT of various doses. EFDs of included studies ranges from 0.12 mJ/mm2 to 0.62 mJ/mm2 that is from moderate to high level and shockwave impulses range from 1000 to 6000. In this trial we categorize the EFD as low: <0.28 mJ/mm2, moderate: 0.28–0.6 mJ/mm2 and high: >0.6 mJ/mm2.

Table 1.

Study characteristics.

Study	M/F Age Y No of patients (N)	Outcoms	Key Findings	ESWT characteristics	Effect size
Vulpiani et al., 2010 (Prospective cohort study)	23/13 49.3 (11.9) 52.7 (14.6) 45.9 (14.1) N = 36	VAS HHS X ray/MRI (Follow up: 24 months)	Pain and HHS scores improved significantly (p < 0.05) in stage I patients at all follow up periods. While stage II and III patients improved at 3rd and 4th follow up. No changes observed in lesion size in stage I and II	EFD: 0.50 mJ/mm2 SW: 2400	0.54 1.23 NR
Lee et al., 2015 (Retrospective cohort study)	n1 = 9/7 n2 = 4/4 47.8 N = 24	VAS HHS X ray/MRI (Follow up: 27 months)	Both VAS and HHS score improved significantly (p < 0.001) in group 1 (stage I and II). No improvement (p = 0.280) was seen in group 2 (stage III).Radiographs also showed improvement	EFD: 27 kV SW: 6000	0.82 0.52 NR
Ludwig et al., 2001 (Prospective cohort study)	12/10 54.9 ± 12.3 N = 22	VAS HHS MRI (Follow up: 12 months)	VAS and HHS scores improved significantly (p < 0.001) after 1 year of treatment with ESWT. On MRI 4 patients showed complete healing, lesion size decrease in 6 patients and no change in 4 patients	EFD: 25mJ/mm2 SW: 4000	5.6 4.46 NR
Wang et al., 2009 (Prospective cohort study)	n1 = 2/13 n2 = 21/3 n1 = 32.33 ± 8.97 n2 = 36.47 ± 8.95 N = 39	VAS HHS X ray/MRI (%) (Follow up: 12 months)	No significant changes was observed for VAS, HHS and MRI (p = 0.467,p = 0.194 and p = 0.226) between both the groups as ESWT was equally effective in SLE and non SLE ONFH patients.	EFD: 0.62 mJ/mm2 SW: 1500	0.02 0.24 0.14
Wang et al., 2007 (Prospective cohort study)	n1 = 20/5 n2 = 13/10 n1 = 38.6 ± 12.6 n2 = 35.7 ± 4.7 N = 48	VAS HHS MRI/Xray (%) (Follow up: 24 months)	No significant changes was observed for VAS and HHS (p = 0.400 and 0.313) between groups. Xray and MRI showed decrease in lesion size but not significant (p = 0.146). This showed ESWT is effective with or without alendronate	EFD: 0.62 mJ/mm2 SW: 6000 (1500 X 4)	0.079 0.15 NR

Study	M/F Age Y No of patients (N)	Outcomes	Key Findings	ESWT characteristics	Effect size
Wang et al., 2016 (Randomized clinical trial)	32/10 41.8 ± 9.1 N = 33	VAS HHS X ray (%): MRI (%) Serum biomarkers (Follow up: 31.4 ± 7.5 months)	Pain and HSS improved significantly (p < 0.05) in high dosage group compared to low dosage group after 6 months of treatment. Significant changes observed (p < 0.05) in serum biomarkers in high dose group. No significant changes (p > 0.05) observed in x ray and MRI	EFD: 0.510 mJ/mm2 SW:2000,4000 and 6000	0.25 0.092 0.096 0.40
Wang et al., 2005 (Randomized clinical trial)	n1 = 20/3 n2 = 23/2 19–63 N = 48	VAS HHS X ray/MRI (%) Follow up: 24 months)	ESWT group has better pain and HHS score (p < 0.001) at each time interval compared to surgical group. Compared to surgical group lesion size in ESWT group significantly decrease at all time points (p < 0.001,0.003,0.040)	EFD: 0.62 mJ/mm2 SW: 6000 (500 X 4)	0.62; 0.4 1.3; 0.46 0.46
Chen et al., 2009 (Randomized clinical trial)	14/3 42.9 ± 9.3 N = 17	VAS HHS MRI (%) (Follow up: 18 months)	Both ESWT and THA showed significant improvement in pain and HHS score (p < 0.001). However ESWT was more effective. Lesion size decreased after treated with ESWT but not significant (p = 0.466)	EFD: 0.62 mJ/mm2 6000 (1500 X 4)	2.3 1.94 NR
Ding et al., 2019 (Retrospective cohort study)	n1 = 36/10 n2 = 37/6 n1 = 50.02 ± 1.34 n2 = 49.69 ± 1.23 N = 56	VAS HHS X ray/MRI cm3 (Follow up: 22 months)	VAS and HHS significantly improved after treatment (p < 0.001) within the groups. No statistical significant difference found between the groups (p > 0,05).On MRI statistical significant difference observed necrosis volume (p < 0.05)	EFD: 0.16–0.22 mJ/mm2 SW: 1500 to 2000	0.03 0.44 0.66

Study	M/F Age Y No of patients (N)	Outcomes	Key Findings	ESWT characteristics	Effect size
Han et al., 2016 (Case control)	24/6 64.9 ± 6.4 N = 19	VAS HHS HOOS WOMAC (Follow up: 6 months)	Two different low EFD used between the groups. All outcomes improved (p < 0.05) after treating with low EFD. Improves function and relieves pain.	EFD: 0.12 mJ/mm2 0.32 mJ/mm2 SW: 1000	0.12 0.05 0.72 0.04 NR
Algarini et al., 2018 (Retrospective cohort study)	9/12 37.5 ± 4.8 N = 21	VAS HHS MRI (%) (Follow up: 5 ± 3.5 Y)	Pain and functional outcomes improved after treating with ESWT (p < 0.001). Lesion size decreased after treatment but not significant (p > 0.235)	EFD: 26 kV SW: 3000 to 4000	0.72 1.12 0.96
Xie et al., 2018 (Retrospective cohort study)	23/8 41.2 N = 31′	VAS HHS MRI (Follow up: 130.6 months)	At final follow up both pain and function improved significantly (p < 0.001) more in stage I compared to stage II and III. Lesion size improved in all stage I followed by stage II and III	EFD: 26 kV SW:1000	0.61 0.62 NR
Wang et al., 2012 (Retrospective cohort study)	NR NR N = 48	VAS HHS X ray/MRI (%) (Follow up: 8 to 9 Y)	After long term use ESWT was more effective than core decompression (p < 0.001). Lesion size and BME decreased without significant change (p > 0.05) favors ESWT	EFD: 0.474 mJ/mm2 SW:6000	2.71 2.2 1.15

Note (s): F: Female; M: Male; Y: Years, VAS: Visual Analogue Scale; HHS: Harris Hip Score; HOOS: Hip dysfunction and Osteoarthritis Outcome Score; WOMAC: Western Ontario and McMaster University Osteoarthritis Index; MRI: Magnetic Resonance Imaging; NR: Not Reported; N: no. of patients; SW: Shock Waves; ESWT: Extracorporeal shockwave therapy; EFD: Energy flux density.

3.3. Quality assessment

Majority of the selected studies graded as moderate quality i.e., out of 8 cohort studies 7 were of moderate quality and 1 of low quality. All 4 RCTs were of moderate quality. One case control study graded as poor quality. Table: 2, Table: 3 shows the quality assessment of included studies.

Table: 2.

Quality appraisal of included studies using Structured Effectiveness QualityEvaluation Scale (SEQES.).

Author Year/Scale items	Algarini et al., 2018	Xie et al., 2018	Wang et al., 2012	Wang et al., 2016	Wang et al., 2005	Wang et al., 2009	Wang et al., 2007.	Ding et al., 2019	Vulpiani et al., 2012	Lee et al., 2015	Ludwig et al., 2001	Chen et al., 2009.	Han et al., 2016
1	2	2	2	2	2	2	2	2	2	2	2	2	2
2	0	0	2	2	2	1	2	1	0	1	0	2	1
3	2	2	2	2	2	2	2	2	2	2	2	2	2
4	2	2	2	1	2	2	2	1	2	2	1	2	2
5	0	0	2	2	2	1	2	1	0	1	0	1	1
6	0	0	1	2	1	0	1	0	0	1	0	0	0
7	0	0	0	0	1	1	1	0	0	0	0	0	0
8	0	0	0	1	1	1	0	0	0	0	0	0	0
9	1	1	2	0	0	0	1	0	0	0	0	0	0
10	0	0	0	0	0	0	0	0	2	2	1	1	2
11	2	2	2	2	2	2	2	2	2	2	2	1	2
12	2	2	2	2	1	2	1	2	2	2	2	2	1
13	1	2	1	1	1	1	1	1	1	1	1	1	1
14	1	1	0	0	0	0	0	0	0	0	0	0	0
15	0	0	2	2	2	1	2	1	0	1	0	1	1
16	0	0	1	1	1	1	1	1	1	1	1	1	2
17	1	1	1	1	1	1	1	1	1	1	1	1	2
18	1	1	2	1	2	2	2	2	2	2	2	2	2
18	2	2	2	2	2	2	2	2	2	2	1	1	2
19	2	2	2	2	2	2	2	2	2	2	2	2	2
20	2	2	2	2	2	1	1	2	2	1	2	2	2
21	2	2	2	2	2	2	2	2	2	1	2	2	2
22	2	2	2	1	2	2	2	2	2	2	2	2	0
23	1	1	1	1	1	1	1	0	0	0	0	0	0
24	2	2	2	2	2	2	1	2	2	2	2	2	2
Total	37	29	37	34	36	32	34	28	29	32	26	30	31

Note: Each item scored if criteria met: 2 for best score for high quality,1 indicates fair quality, 0 indicates poor quality or unmet criteria. Cumulative score of each study, Total score of 40–50: high-quality study, Score of 30–39: moderate quality study, a score of 20–29 as a low-quality study, score below 20 as a very-low-quality study.

Table: 3.

New Castle Otawa Scale for quality assessment scale of case control study.

Author			Selection		Comparability of cases and controls		Exposure		Total score
	Adequate case definition	Representativeness of cases	Selection of controls	Definition of controls		Ascertainment of exposure	Same method of ascertainment	Non response rate
Han et al., 2016	1*	1*	–	–	–	–	1*	1*	4

Note(s): Each score represents if individual criterion within the subsection was fulfilled.

A study can be given a maximum of one star for each numbered item within the Selection and Exposure categories. A maximum of two stars can be given for Comparability.

Newcastle-Ottawa Quality Assessment Scale. Poor <4,Fair: 5–6, Good:>7.

3.4. Result of individual studies

3.4.1. Studies using low energy densities EFD<0.28 mJ/mm2

Ding et al. 21 investigated the clinical efficacy of individual extracorporeal shockwave therapy (IESWT) compared with conventional ESWT at low energy density of 0.16–0.22 mJ/mm2 at 1500–2000 impulses. Statistically significant difference was observed in healing rate (p < 0.05; effect size:0.66) and necrosis volume (p < 0.05) between groups after 18 months of follow up favoring IESWT compared to conventional ESWT.VAS and HHS score was improved after treatment (p < 0.001) within the groups but no statistical significant difference was observed between the groups (p > 0.05; effect size: 0.03,0.44).

Han et al.¹⁸ compared two low energy densities of 0.12 mJ/mm2 and 0.32 mJ/mm2 with 1000 shocks per session in 19 patients with 30 hips (ARCO stage I to III) and found significant improvement in pain and functional outcomes (p < 0.05, effect size:0.12, 0.05) after 6 months follow up.

Both studies showed significant improvement in pain and functional outcomes after treated with ESWT at different follow up periods and one study showed reduction in necrosis volume at low EFD used between 0.16 and 0.32 mJ/mm2.

3.4.2. Studies using moderate energy densities EFD: 0.28–0.6 mJ/mm2

Vulpiani et al.¹² included 36 patients with ONFH of ARCO stage I,II, III. All patients received four sessions of ESWT with moderate EFD of 0.50 mJ/mm2 at 2400 impulses at various follow up periods of 3,6,12 and 24 months. Early ARCO stage I patients obtained significant improvement in VAS and HHS (p < 0.05, effect size: 0.54, 1.23) at all follow ups. While ARCO stage II and III patients showed significant changes in VAS and HHS at 3rd and 4th follow up time periods. ARCO stage I and II lesion shows no changes on radiographs and MRI. ESWT found to be beneficial in stage I and II compared to stage III.

Wang et al. (2012)¹⁹ compared the long term effects (8–9 years) of ESWT with core decompression and found significant difference in VAS and HHS at various follow ups favoring ESWT group than surgical group (p < 0.001, effect size: 2.7,2.1). ESWT group received 6000 impulses 0.474 mJ/mm2 of moderate EFD in single session. Also reported a significant decrease in lesion size and BME in ESWT group compared to surgical group (p < 0.05, effect size: 1.15).

Wang et al. (2016)²⁰ randomly divide 33 patients with 42 hips into 3 groups in which they received EFD of 24 kV (0.510 mJ/mm2) as low (2000), medium (4000) and high (6000) shockwave impulse doses. VAS score significantly reduced in high dose group compared to low and medium dosage groups at 6, 12 and 24 months after treatment (p = 0.037, 0.013 and <0.001, effect size:0.12). HHS score (p = 0.017, effect size:0.05) and BME (bone marrow edema) on MRI (p = 0.039) improved after 6 months in high dose group. Serum biomarkers after 1 month of treatment significantly reduced (p < 0.05).No changes was seen on imaging studies in any group (p > 0.05).

3.4.3. Studies using high energy density of above 0.6 mJ/mm2

Wang. (2005)²¹ randomly divide ONFH patients (stage I to III) to compare ESWT with core decompression and bone grafting. ESWT group received 6000 impulses at EFD of 0.62mJ/mm2. Evaluated at 1, 3, 6 and 24 months. Mean VAS and HHS score in ESWT group was significantly better at each time interval (p < 0.001; effect size: 0.62 and1.3) compared to surgical group.

In 2009 Wang et al.²² further evaluates the effectiveness of ESWT in systemic lupus erytheomatous (SLE) patients with ONFH compared with non-SLE ONFH patients. Both groups received 6000 impulses at 0.62mJ/mm2 EFD and followed up at 1, 3, 6 and 12 months. No significant difference was found between groups in VAS (p = 0.467; effect size: 0.02) and HHS (p = 0.194; effect size: 0.24). MRI and radiograph studies showed significant changes (p = 0.014; 0.033) within groups but found no significant difference (p = 0.226) between groups. SLE patients respond to ESWT in the same way as non-SLE ONFH patients.

Chen et al.²³ evaluated 17 patients with bilateral ONFH treated with total hip arthroplasty using press fit model fixed without using bone cement in one hip (stage III and IV ONFH) and ESWT in other hip (stage I,II and III ONFH). Patients received 6000 impulses at 0.62mJ/mm2 EFD. Both THA and ESWT showed significant improvement in VAS and HHS scores but favoring ESWT (p < 0.001; Effect size: 2.3 and 1.94).Radiograph and MRI showed significant reduction (p = 0.031) in BME and decrease in lesion size (p = 0.466) on ESWT side after treatment.

Wang et al.²⁴ performed a random allocation of 48 ONFH patients (stage I, II and III). Group A treated with ESWT alone with 6000 impulses at 0.62mJ/mm2 EFD, applied on femoral head. Group B received ESWT with 70 mg oral alendronate per week for 1 year. Followed up at 1, 3, 6 and 12 months. Post treatment both groups showed significant improvement in VAS and HHS (p < 0.001; Effect size: 0.079 and 0.15). Between groups no statistical difference was found (p = 0.40, 0.313). Lesion size and BME decreased after treatment without significant difference between groups (p > 0.05). To sum up, ESWT is effective with or without oral alendronate.

The prospective cohort study by Xie et al. (2018)¹³ evaluates the long term effect of ESWT on 31 patients with ONFH (stage I to III). Patients treated with 4000 impulses at 26 kV EFD. Mean follow up was 130.6 months. At final follow up VAS and HHS significantly improved (p < 0.001; Effect size: 0.61and 0.62). MRI showed more improvement in lesion size, in stage I followed by stage II and least improvement in stage III. Though, ESWT in its long term use found more effective in early stages of disease.

Algarni and Moallem²⁵ conducted a retrospective cohort study in 21 patients with ONFH (stage I and II) of any etiology. 3000 to 4500 impulses delivered on affected area at 26 kV EFD. Average follow up was 5 years. After 8 months of treatment with ESWT the VAS and HHS score significantly improved (p < 0.001, Effect size:0.72; 1.12). Lesion size decreased on MRI but not statistically significant (p > 0.235, Effect size:0.96). BME reduced significantly (p < 0.003) at final follow up. In conclusion, ESWT helps in improving clinical outcomes in early staged disease.

Lee et al.²⁶ performed a comparative analysis in 24 patients based on ARCO staging group 1 (ARCO I and II) and group 2 (ARCO stage III). All patients received 6000 impulses at 27 kV energy density per session.VAS score improved in both groups (p < 0.001, effect size: 0.82) when compared with pre treatment verses final follow up of 24 months. HHS improved significantly in group 1 (p < 0.001, effect size: 0.52) but not in group 2 (p = 0.280). Author concludes that, ESWT improves VAS and HHS score at 24 month follow up, in early stage as well as in mid and later stages of disease.

Ludwig et al.²⁷ used very high energy density of 25.5 mJ/mm2 with 4000 impulses in 22 patients of ONFH (ARCO stage I-IV). Statistical significant difference was found in VAS score (p < 0,001; effect size: 5.6) and HHS score (p < 0,001,effect size: 4.46) after 1 year of treatment. MRI showed complete healing in 4 patients, significant decrease in lesion size area of 6 patients and no change in 4 patients. In conclusion, greater improvement after ESWT was observed through subjective and objective measures.

4. Discussion

This current systematic review evaluated the effectiveness of various doses of ESWT on pain, function and radiographic outcomes in patients with ONFH (ARCO stage I to IV) of any etiology and mainly focuses on the effect of particular dose (low, moderate and high) on the improvement of these outcomes. No previous systematic review examined the effect of various doses of ESWT on these outcomes.

EFDs of included studies range from 0.12 mJ/mm2 to 0.62 mJ/mm2. In this review, we categorize the trials on the basis of energy flux densities as low EFD<0.28 mJ/mm2; moderate EFD: 0.28–0.6 mJ/mm2 and high EFD>0.6 mJ/mm2. Result from individual studies directed us towards heterogeneity due to study design, dosage, treatment follow up and patient characteristics. But results are more towards improvement in outcomes after ESWT treatment.

To summarize the findings of included studies all three categories (low, moderate and high) of EFDs are effective in managing pain and function in early (stage I) and mid (stage II) stage of ONFH and it delays the further progression of disease shown by MR and radiographic findings compared to later stages (III and IV). It suggests that early detection of disease stage followed by its treatment is very important.

Previous systematic reviews and meta analysis^28,29 reviewed the effectiveness of ESWT on ONFH patients of different stages and etiologies found that ESWT improves pain perception, motor function and slow down the disease progression. Rapid pain reduction, functional and metabolic improvement was observed in BME syndrome patients of hip when received 4000 ESWT impulses at 0.4–0.6 mJ/mm2 EFD after 6 months.³⁰

Exact mechanism of action of varying energy densities of ESWT remains unknown but various experimental studies showed that high energy densities of ESWT significantly increase bone morphogenetic proteins, new cortical bone formation, improves bone mass and bone strength, up regulate cell proliferation, increase angiogenic mediators at tendon, bone-tendon interphase like VEGF, BMP2 RUNX2, osteogenetic gene expression in BMSCs, alkaline phosphatase and osteocalcin mRNA expressions. All these biological processes leads to tissue regeneration, wound healing, neovascularization, bone remodeling and anti inflammation which in turn improves subchondral bone remodeling and prevent femoral head collapse. A decrease in substance P release was also noted after shockwave therapy, associated with pain relief.^11,25,31, 32, 33

Whereas medium and low energy densities showed similar effects but they were less prevailing. This assumption has been supported with Rompe et al. which showed dose dependent effects on tendon and paratenon after ESWT treatment in animal model.^33,34

In accordance with previous literature this systematic review showed that, application of ESWT depends on disease stage. In this review only two studies^11,17 used low EFDs found to be more effective in earlier stage of ONFH. Whereas rest of the studies used moderate and high doses of ESWT which was effective in mid and later stages.

Nowadays, various musculoskeletal, bone and cartilage related disorders are managed by ESWT non operatively in physiotherapy practice.^9,10 In most of the included studies, high dose of ESWT was used which can be taken as an advantage over operative treatments with minimum or no complications to treat effectively the early and mid stage ONFH patients as well as reduces the chances of surgery. However, only few studies in this review showed improvement in pain and function after treating with low and moderate doses of ESWT.

4.1. Limitations

First, to evaluate the effectiveness of a treatment RCTs are considered as gold standard, our search result only in 4 RCTs and rest of the studies are retrospective and prospective cohort studies. Second, limitation is that no meta-analysis was possible due to the high variability between study design, ESWT dosage used and patient characteristics. Third, the sample size and follow up of included studies is also varied.

4.2. Strength

Comprehensive literature search was performed from 6 major research databases. Future well designed RCTs addressing and comparing the effectiveness of low, moderate and high EFDs including shockwave impulses and frequency on pain, function and disease progression should be emphasized with long term follow ups and large sample size.

5. Conclusion

High intensity EFDs of ESWT found to be more effective in earlier course of disease compared to later stages in terms of pain relief, functional improvement and disease progression. Result of this systematic review also showed some improvement in outcome measures assessed after treatment with low and moderate EFD but the evidence is not enough to confirm these findings. Due to high variability among study design, ESWT dosages, patient characteristics and considering the paucity of well conducted studies, the present study cannot be conclusive. Therefore, further trials with good methodological quality are required to evaluate the effectiveness of low and moderate EFD should also come up.

Author contribution statement

Ali Abbas contributed in conceptualization, methodology, writing original draft Zainy Khan, Shabnam and Zubia Veqar, contributed in supervision, drafting and analysis of the manuscript.

Source of funding

None.

Declaration of competing interest

None.

Abbreviations

ONFH

Osteonecrosis of Femoral Head

ARCO

Association Research Circulation Osseous Classification

ESWT

Extracorporeal Shockwave Therapy

PEMF

Pulsed Electromagnetic Field

EFD

Energy Flux Density

NPRS

Numeric Pain rating scale

VAS

Visual Analogue Scale

WOMAC

Western Ontario and McMaster Universities Osteoarthritis Scale

HOOS

Hip Disability and Osteoarthritis Outcome Score

HHS

Haris Hip Score

VEGF

Vascular Endothelial Growth Factor

BMP2

Bone Morphogenetic Protein 2

RUNX2

Runt-related transcription factor 2

BMSCs

Bone Marrow Stromal Cells

Search strategy pubmed

A systematic literature search was performed on the databases: MEDLINE (assessed by PubMed), Web of Science, Scopus, Pedro, Science Direct and Cochrane Library. ((((extracorporeall) AND shockwave) AND therapy). ((extracorporeal) AND shockwave) AND therapy.

((extracorporeal) AND shockwave) AND therapy).

((extracorporeal shockwave) AND osteonecrosis) AND femoral head.

“shockwave” AND “therapy” AND “osteonecrosis” AND ″ femoral head".

(extracorporeal [Title] AND shockwave [Title] AND therapy [Title] AND osteonecrosis [Title].

Extracorporeal [Title] AND shockwave [Title] AND therapy [Title] AND osteonecrosis

Extracorporeal [Title] AND shockwave [Title] AND therapy AND osteonecrosis [Title] AND femur [Title].

Extracorporeal [Title] AND shockwave [Title] AND therapy [Title] AND avascular [Title] AND necrosis [Title].

Shockwave [Title] AND therapy [Title] AND osteonecrosis [Title].

Shockwave [Title] AND therapy AND avascular AND necrosis [Title] OR osteonecrosis [Title].

Shockwave [Title] AND therapy [Title] AND avascular [Title] AND necrosis [Title] AND healing [Title].

“shockwave therapy” AND “osteonecrosis”.

Extracorporeal shockwave therapy.

Osteonecrosis.

Femoral head.

#1 search: extracorporeal Shockwave Therapy* OR shockwave therapy*

#2 search: osteonecrosis* OR avascular necrosis* OR femoral head.

#3 search: ESWT* OR SWT*

#4 search: #1 AND #2 AND #3.