Over the Therapeutic Benefit of Extracorporeal Shockwave Therapy in Orthopaedic Patients

Shockwaves can be defi ned as transient pressure oscillations which propagate in three dimensions and offer an increased pressure in a very short period of time. Biological effects of shockwave therapy have been proven to stimulate the release of angiogenic growth factors, and contribute to the improvement of blood supply which leads to the repair of bone and soft tissue. The role of ESWT in the treatment of chronic calcifying tendinitis of the rotator cuff has been evaluated in many studies. ESWT has been gaining attention as an alternative option to surgical excision of calcifi cation or when other conservative options have not proven effi cient. The main purpose for using ESWT in heel spur is to increase the local blood supply by inducing neovascularisation. This action influences the inflammatory process and furthermore stimulates the local metabolism. Also, shockwaves have been proposed as a possible treatment in early phases of femoral head necrosis in adults. In case of patellar tendinopathy in vitro studies have shown biological effects, while clinical effects remain unclear. Data suggests that ESWT associated with other physical modalities achieve realiable clinical importance of pain reduction in lateral epycondylitis. However there is still a lack of standardisation and a consensus is needed regarding frequency and intensity.


REVIEW
It has been observed that ESWT can lead to the development of histological changes in the applied area, the eff ects being partially dose dependent.Focal infi ltration of the infl ammation occurs at the skin level, and focal necrosis of the muscle fi ber associated with infl ammatory reaction has been observed,but with complete disappearence in time 16,17 .Also, osteoneogenesis has been observed depending on dose in case of high energy application, but with no eff ect in case of low energy application [18][19][20] .Due to those changes, induced by the physical and biological properties of shockwaves, the present review proposes the analysis of ESWT impact in diff erent musculoskeletal disorders.

MATERIAL AND METHODS
A systematic review was conducted with the purpose of collecting potentially eligible publications, accessing the electronic databases available PubMed, Embase, and Cochrane library using the following terms: shock wave/shockwave, ESWT, plantar fasciitis, lateral epicondylitis, calcifying tendinitis, shoulder, avascular necrosis, tendinopathy, insertional.Th e searches were limited to articles in English.Additional studies were searched using the reference list of the chosen articles.

RESULTS AND DISCUSSIONS
Th e assessment of search results evidenced a signifi cant amount of eligible studies, but also a variation in application methodology and number of sessions.Th e role of ESWT in treatment of chronic calcifying tendinitis of the rotator cuff has been evaluated in many studies [21][22][23][24][25][26][27] .Calcifying tendinitis is a frequent condition in orthopaedic and rehabilitation practice and represents a well documented cause for shoulder pain.It is characterised by the deposit of calcium hydroxyapatite crystals inside rotator cuff tendons 28,29 .ESWT has been gaining attention as an alternative option to surgical excision of calcifi cation or when other conservative options have not proven effi cient.Some studies have suggested the use of ESWT in athletes with refractory tenditinis as a preintervention therapy before arthroscopic surgery.Favorable results have also been observed for treatment of superior lateral brachial cutaneous nerve compression syndrome (SLBCN).Pan et al. observe an allevation of pain intesity and an improvement of shoulder joint function in patients with SLBCN compared to the control group which received homone injection 31

BACKGROUND
Shockwaves can be defi ned as transient pressure oscillations which propagate in three dimensions and off er an increased pressure in a very short period of time, typically in a matter of a few nanoseconds 1,2 .Th eir main chracteristics are represented by positive (PØ) and negative (P-)peak pressure, rise time (Tr) and impulsed width (Tw).Th e principles of shockwave application refer to the propagation of waves through tissue such as water, gas or inside solid state bodies, pressure pulses acting directly or indirectly regardless of the generating source 3,4 .
Th e fi rst use of ESWT on the musculoskeletal system was made by Karpman et al. in an attempt to desintegrate the surrounding bone cement in patients scheduled for endoprosthesis replacement on the hip joint 5 .He was then followed by Valchanou et al. who applied shockwave therapy in pseudoarthrosis in the possibility of fragmenting the bone tissue 6 .It was further noticed an improvement in pain and functional levels from the application of ESWT for diff erent chronic insertion enthesiopathies.Analgaesic eff ect of ESWT was believed to be caused by overstimulation of the treated area which resulted in a reduction of signal transmission to the central nervous system.Although there weren't signifi cant prospective studies, the number of ESWT applications had an extensive grouth in the nineties decade, even surpassing the number of applications used in urology for lithotripsy [7][8][9] .
Th e main categories of shockwaves refer to focused shockwave therapy which involves single pressure pulses focused on a specifi c target and are generated in water inside the device, and radial shockwaves which are produced by acceleration of a projectile with the use of compressed air 10,11 .From a physical point of view the typical form of the shockwave is characterised by a very short ascent until the maximum pressure results from asymmetric attenuation when traveling through tissue 12 .Also, the biological eff ects of shockwave therapy tend to stimulate the release of angiogenic growth factors, and contribute to the improvement of blood supply which leads to the repair of bone and soft tissue 2,13 .Molecular eff ects of shockwaves have been observed in experimental models, especially regarding the release of substance P and prostaglandin E2 which can be responsible for the biological actions of ESWT.An indirect eff ect is the induction of cavitation, which is expressed as the appearence of gas fi lled bubbles in the presence of a negative pressure gradient 14,15 .
for rotator cuff tendinopathy on 86 patients and express a clinically relevant decrease of pain and higher Constant Murley scores compared to control group at baseline and follow-up period 32 .
Plantar heel pain represents one of the most frequently met disorders of the foot region, well documented in the literature, but without obtaining a uniform diagnosis, mostly because the background pathways are still unclear 33,34 .Today, the term ,,painful heel" is used by many authors, as well as ,,heel spur", although the condition is not always clearly evidenced by x rays.,,Fasciitis plantaris'' is a term that refers to an infl ammatory status of the plantar fascia in the proximity of the calcaneal insertion 35,36 .Main symptoms include pain, associated with decreased range of motion.A number of conservative treatments have been outlined, including physical therapy with low energy laser, ultrasound and iontophoresis associated with pharmacological treatment or steroid injections, but without clear evidence of their effi cacy [37][38][39][40] .
Th e main purpose for using ESWT is to increase the local blood supply by inducing neovascularisation.Th is action aff ects the infl ammatory process and furthermore stimulates the local metabolism.In a metaanalysis on 9 studies and 935 patients on the use of shockwave therapy in chronic plantar fasciitis, the authors observed that ESWT groups had higher improvement rates than placebo groups (OR 2.58, 95%, [CI] 1.97-3.39,2][43] . Another discussion regards the number of sessions that are needed for heel spur.Most protocols involve 4 to 5 sessions, but there are trials that evaluated the eff ect of a single session of ESWT in plantar fasciitis.Scheuer et al. performed an observational study on 284 patients (363 feet) that received ESWT and were required to complete a clinical questionnaire immediately after ESWT administration and after 19-77 weeks of follow-up.76% of patients from the group that was treated with only 1 session expressed satisfying pain relief.Although the authors suggested that a single session of ESWT could off er similar outcomes as multiple sessions, further data is needed to establish the suitable number of treatment sessions as well as the adequate energy fl ux density that is required to increase the eff ectiveness of the treatment 44 .
A systematic analysis by Roerdink et al. on the possible complications that can result from plantar application, reviewed 39 studies and 2697 heels and observed that no complications are to be expected until one year post treatment.However there isn't any reliable data on long term complications, therfore some precautions are recommended.Also, in some cases transient pain after application, swelling and throbbing sensation were reported 45 .
Shockwaves have been proposed as a possible treatment in early phases of femoral head necrosis in adults.From a morphopathological point of view, osteonecrotic lessions usually have similar patterns.Most frequently, it involves an undelying circulatory disorder, which is associated with bone cell destruction due to insuffi cient oxygen supply and malnutrition.Until now, no gold standard has been developed and treatment options are still in debate [46][47][48][49][50] .
Conservative approaches include only measures that are designed to reduce the symptomatology without interrupting the progress of the disease.Shockwaves are documented to stimulate bone regeneration, and it has been suggested that it may also induce specifi c signals for growth and maturation of the mesenchymal progenitors of the bone marrow.At the same time, shockwaves produce increased concentrations of free radicals [51][52][53][54][55] .A link has been detected between morphogenic proteins (BMP) and shockwave activity regarding bone regeneration.Literature data evidences that fact that ESWT can increase the expression of BMP in calus during fracture healing.However, precautions should be given, especially because in high doses it can create an imbalance in calcium homeostasis which can lead to tissue damage [56][57] .In some case reports Durst et al. express the development of humeral head osteonecrosis, 3 years after the administration of high energy ESWT for calcifi c tendinitis, while Liu et al report a case of humeral head osteonecrosis in 3 month after receiving ESWT.Although these are isolated cases, it has been suggested that a diminished diameter of the anterior humeral circumfl ex artery in these two cases could explain for the development of complications 58,59 .
In a systematic review by Zhang et al, with a total of 17 articles including 6 RCT, 2 cohorts, 9 open label trials and 2 case reports, the authors observed an improvement in motor function and pain relief in case of ESWT use for osteonecrosis of the femoral head.Although the imagistics evidenced a reduction of bone marrow edema, the evolution of bone necrosis could not be stopped after ESWT.Also, the association of other conservative treatments with shockwave therapy did not infl uence the fi nal eff ect 60 .However ESWT could off er some benefi t in case of hip endoprosthesis decision, granting better bone conditions for the surgeon and a higher bone mass density.and also a disconcorcance of the number of impulses that varied from 500 to 2500.Tibial anterior syndrome is often triggered by sudden load peaks and intensive running and consists of pain localised in the middel and lower third of the tibialis anterior, representing the third most common sports injury after achillodynia and stress fracture 75 .By some authors, ESWT is proven more eff ective than traditional conservative treatments including nonsteroidal anti-infl ammatory medication, standard physiotherapy program, kinetotherapy or, and the use of a knee strap 76 .
Analysis of ESWT outcomes for painful stump neuroma has been documented in the literature.Jung et al. randomize thirty patients with stump neuroma at the distal end of an amputation site into two groups.One group benefi ted from ESWT at the area of the neuroma site which was identifi ed using ultrasound guidance, and the second group benefi ted from transcutaneous electrical nerve stimulation and pharmacological treatment.Changes in McGill pain questionnaire were observed, but no signifi cant changes in size or pressure threshold.However, the study demonstrated that the application of ESWT could reduce the side eff ects generated through injection therapies and surgical treatments 77 .
Greater trochanteric pain syndrome (GTPS) represents a clinical condition which includes pain and tenderness around the greater trochanter area, which can radiate to the lateral side of the hip or thigh and is generally associated with trochanteric bursitis, but literature also suggests a degeneration process or a tearing of the gluteal tendons 78,79 .Conservative treatment consists of medication, rest, physical therapy or corticosteroid injections.Surgical treatment with the lengthening of iliotibial band and fascia is considered only in refractory cases 80 .Seo et al. investigate with the use of MRI the outcome of ESWT in GTPS patients and obtain succesuful rates of pain reduction over long term follow up 81 .
Other studies have tried to evaluate eff ectiveness of acupuncture compared to ESWT, resulting in favorable data for both treatments regarding pain relief.Also, the authors found no signifi cant improvement of DASH score and maximum grip strengh for both shockwave therapy and acupuncture.However the study had certain bias issues, including a relatively small sample of patients and also the fact that most enrolled patients reported to have applied massage therapy by themselves during the treatment period which could have lead to an underestimation of therapeutic eff ect in the stu-

Mackert et al. (2017) study the eff ect of low energy
ESWT on metaphyseal fracture healing in osteoporotic rat models, and observe promising eff ects including an improvement of the biomechanical characteristics, enhanced callus quantity and quality and a modifi ed expression of bone specifi c transcription factors 61 .Th is could prove benefi cial, especially because osteoporotic fractures present a severely diminished bone quality, which often requires surgical fi xation.Nontheless, diminished bone mass density contributes to prolonged healing periods and increases the risk of instability and complication rates.Th erfore, ESWT could present as an alternative treatment option, with minimal sideeff ects compared to surgical or pharmacological modalities.
In case of epycondylitis humeri radialis or ,,tennis elbow", there are numerous conservative options that are proposed as main therapeutic option, surgical interventions being indicated only in a small number of refractory cases [62][63][64][65] .ESWT has been recommended as viable treatment option for these patients.However, a recent meta-analysis evidenced diff erences between the groups the received shockwave therapy and placebo group but not in a signifi cant manner.On the other side, the group that received ESWT along with other physical modalities reached a reliable clinical significance of pain reduction [66][67][68][69] .
ESWT role has been evaluated in sport pathologies such as patella syndrome and tibial anterior syndrome 70,71 .
Patella syndrome or ,,jumper's knee" represents a typical insertion tendinopathy, frequently caused by repetitive jumps.Th e syndrome is characterised by microruptures at the tendon to bone junction and is associated with fi brinoid necroses and mucoid degeneration 72 .Van der Worp et al. (2012) perform a systematic review in order to identify randomized controlled trials that studied the eff ectiveness of ESWT for patellar tendinopathy.It was observed from the analysis that in vitro studies show biological eff ects, while clinical eff ects remain unclear 73 .Th e confl icting data is however determined by multiple reasons.Th e fi rst reason is the absence of a gold standard for the diagnosis of a tendinopathy.Secondly, shockwaves are more eff ective in some stages of evolution compared to other stages, and lastly the eff ectiveness is infl uenced by the methodological aspects which include the number of pulses, intensity and focal depth.In a systematic review by Haake et al. 74 with the inclusion of 20 eligible studies, it was observed a variation of treatment sessions from 1 to 20 results were observed in the myocardial uptake within the stress myocardial scintigraphy.

CONCLUSIONS
Shockwave therapy can be indicated as an alternative treatment to surgical modalities or when other conservative methods have been proven insuffi cient.Further in vitro and placebo controlled studies are needed to establish the role of shockwaves in avascular necrosis of the femoral head.Low energy ESWT seems to bring a signifi cant improvement in pain levels and shoulder function and can contribute to the resorbtion of calcium deposits.Action mechanisms of ESWT need additional research, but accepted biological eff ects include an ingrowth of neovascularization and a stimulation of angiogenetic growth factors.
that refl ected a positive eff ect of manipulative massage on lateral epicondylitis 83 .Other indications of ESWT have been linked to treatment of skin lessions, some authors fi nding an in vitro bactericidal eff ect.Due to the fact that surface defects were involved, modifi cations of the shockwave head had to be made, in order for it not to be focused but planar to the treated area.Th e authors used low energy fl ow densities, with no anesthesia being necessary due to defocusing and the low energy fl ux.Encouraging results were obtained, with none of the patients experiencing a worsening of the wound, and a lessening of the infection was observed after the fi rst session 84 .Sho et al. perform a prospective study regarding eff ects of ESWT on burn patients with developed scar pain which included 40 patients with complete epithelization of open skin wounds that underwent skin grafting.Shockwave therapy was applied around the primary treatment site in accordance with the patients pain tolerarance with an energy fl ux density of 0.05 to 0.15 mJ/mm 2 and a number of 100 impulsescm 2 .Signifi cant diff erences were reporded regarding pain threshold, and Roles and Maudlsley scores compared to sham group after 3 sessions, off ering promising perspective over wound recovery 85 .

Abbreviations
Non orthopaedic indications refer to the benefi t of using ESWT as a treatment option for ischemic cardiomyopathy.Diff erent authors have studied in vitro and in vivo eff ects based on the fact that shockwaves can induce angiogenesis.Nishida et al. 86 apply ESWT on single donor human umbilical vein endothelial cells, and observe a signifi cant up-regulation of the mRNA expression of vascular endothelial growth factor and its receptors in vitro.Also, an increase of the regional myocardial blood fl ow was detected, the results suggesting a possible non-invasive therapeutic strategy for ischemic heart disease.Vainer et al. 87 evaluate the feasibility of ESWT in 33 patients with end-stage coronary artery disease with the application of 9 sessions of shockwave with ECG and echocardiography guidance.Th e assessment of patients included nitrate use, myocardial scintigraphy, and MRI.Th e results evidenced at 4 month follow-up a reduction of angina symptoms and nitrate use and an increase in exercise tolerance.Favorable