https://sportaerztezeitung.com/author/shakibaei-mehdi/?mab_v3=14263 Sportmedizin für Ärzte, Therapeuten & Trainer Tue, 06 Jun 2023 10:01:52 +0000 de hourly 1 https://wordpress.org/?v=7.0.4 https://sportaerztezeitung.com/wp-content/uploads/2021/08/cropped-s_icon_square@2x-32x32.png https://sportaerztezeitung.com/author/shakibaei-mehdi/?mab_v3=14263 32 32 https://sportaerztezeitung.com/rubriken/therapie/14263/phytopharmaceuticals-and-extracorporeal-shock-wave-therapy-for-tendinopathy/ Thu, 08 Jun 2023 08:00:34 +0000 https://sportaerztezeitung.com/?p=14263 In simplified terms, the initial phase of tendinopathy treatment focusing on reducing pain and inflammation must be followed by a second phase to promote effective tendon regeneration. It is now well-known that extracorporeal shock wave therapy (ESWT), corticosteroids, non-steroidal anti-inflammatory drugs (NSAIDs) and certain phytopharmaceuticals (in this specific case, bromelain, curcumin and boswellic acid) are safe and effective in the initial phase (the list is representative but not exhaustive).

Far less well-known, on the other hand, are the (positive and negative) effects of these treatments and drugs in the second phase, which is particularly crucial for combination therapy.

Inflammatory processes in tendon tissue

Tendinopathies are tendon problems that arise due to degeneration and secon­dary inflammation and are steadily becoming more common, particularly in sports medicine. To date, up to 50 % of the diagnoses requiring treatment in sports medicine involve tendinopathy [1, 2]. This is due to both continuous overuse and mechanical stress on the tissue in sports activities and to inappropriate loading in daily life; however, rare adverse drug reactions are also known to be triggers. Moreover, lifestyle factors such as poor diet and lack of exercise may also be substantially involved in inflammatory processes in tendon tissue [3 – 5]. These usually manifest as pain and restricted movement and considerably reduce the quality of life of the affected subjects [6, 7]. To counteract these circumstances as rapidly as possible, NSAIDs and corticosteroids are currently still widely used internatio­nally to inhibit central pro-inflammatory mediators and thereby suppress inflammatory responses and alleviate both pain and swelling [8, 9]. This invol­ves the targeting of molecules such as MAP (mitogen-activated protein) kinases and NF-κB (nuclear factor kappa B), which play a major role in inflammatory processes and act as switches that can be turned on or off, either inducing or stopping inflammatory cascades. Consequently, this also influences the expression of other molecules involved in signaling pathways such as COX-2 (cyclooxygenase-2) and MMPs (matrix metalloproteinases) [9 – 13].

However, although these drugs provide temporary relief, they are also known to have many undesirable effects. In fact, these drugs may not only cause long term damage to other organ systems [14 –16] but can actually block tendon regeneration, which is the opposite of what is desired when treating tendinopathies [17 – 21]. Studies have shown that particularly corticosteroids (e.g., dexame­thasone) und NSAIDs (e.g., celecoxib), still the standard treatment for tendino­pathy in many countries, downregulate not only inflammatory molecules but also the gene expression of the transcription factor scleraxis. The latter can be considered as a marker gene for the vitality of tenocytes (i.e., the characteristic cells of the tendons and ligaments responsible for the development and remodeling of the extracellular matrix (ECM)), as it induces tenocytes not only to form new ECM but also to synthesize collagen I and tendon-specific proteoglycans, the primary components of the ECM [13, 21 – 23]. This explains why a drug-­induced decrease in the gene expression of scleraxis also contributes to a marked reduction in the regenerative capacity of tendon tissue, which is hugely important particularly for athletes. At the same time, the decrease in collagen formation in combination with pain-relie­ving drugs also increases the risk of tendon tears, as pain is suppressed but with a concomitant loss of tissue flexibility and function [24, 25]. This highlights the need for alternative treatment methods that can be used to support regeneration, i.e., the formation of tendon tissue. Various studies have demonstrated precisely these properties in various phyto­pharma­ceuticals such as bromelain, curcumin and boswellic acid. Their modu­lating effect allows these phytopharmaceuticals to interrupt inflammatory cascades and simultaneously stimulate anabolic processes in tendon cells, e.g., by increasing the expression of scleraxis und matrix-specific proteins (Tables 1 + 2) [2, 26 – 42].

Effects of phytopharmaceuticals

Bromelain, the main ingredient in Wobenzym®, is an enzyme extracted from pineapples that has long been used in traditional medicine to alleviate pain and swelling [43 – 46]. This effect is primarily due to the decrease in stress markers, such as the MDA (malondialdehyde) level, in tenocytes and the resulting interruption of inflammatory processes [46]. In terms of the regene­rative effect of bromelain, it has also been shown that the enzyme stimulates particularly tenocyte formation, i.e., new tendon tissue develops, thus supporting the healing of injuries [2, 32]. It has not yet been addressed in the lite­rature whether bromelain also acts directly on the gene expression of scleraxis.

Similar effects in tendon tissue have also been achieved with the use of curcumin. As one of the many components of curcumin root, curcumin has gained particular significance in recent years as a herbal anti-inflammatory agent [47 – 50]. This effect is based on the capacity of curcumin to target various signaling pathways involved in inflammatory processes. Modulation of the ­inflammatory marker NF-κB can be considered as one of the primary targets of curcumin. With the inhibition of NF-κB, all pro-inflammatory cascades and end molecules such as COX-2 and MMPs regulated by NF-κB are also turned off, resulting in the inhibition of inflammation at various molecular levels [35, 42]. It is, however, the marked ana­bolic effect of curcumin that is crucial for the regeneration process in tendino­pathy [35 – 40, 42]. Specifically, it has been shown that curcumin strongly upregulates the expression of collagen, thereby boosting collagen synthesis [35, 39]. It has also been demonstrated that curcumin can prevent the calcification that commonly occurs after a tendon injury with chronic inflammation by downregulating osteogenesis, i.e., the formation of bone, locally at the injury site and simultaneously stimulating teno­genesis, i.e., the formation of new tendon cells [40]. Apart from curcumin, Calebin A (a further bioactive component of the curcumin root) is also gaining increasing prominence due to its anti-­inflammatory mode of action [51, 52]. In a recently conducted study we showed that Calebin A is able not only to inhibit inflammatory cascades, such as the NF-κB signaling pathway and its pro-­inflammatory end products, but also to upregulate scleraxis in tendon cells, which is highly relevant particularly for tendon tissue regeneration [26]. The multi-modulatory effect of Calebin A becomes even more clear if one consi­ders that a functional connection between NF-κB and scleraxis has also been demonstrated [26]. The anti-inflammatory and regeneration-promoting effect of Calebin A illustrates its potential at different levels in the treatment of tendinopathy.

Boswellic acid, an extract from the gum resin of the Boswellia tree, has also been successfully used in many studies as an ­anti-inflammatory and pain-relieving ­active substance for musculoskeletal symptoms [27, 53 – 55]. Its particular potential lies in inhibiting pro-inflammatory processes and messenger substances that play a crucial role in the pathogenesis of tendinopathy. The crucial factor here is especially that the molecules that contribute to matrix degradation (MMPs, COX-2) are also turned off [27, 28, 56]. This prevents the further degradation of particularly collagen and other important components of the ECM, thus interrupting the loss of tendon cells at the pathology site and maintaining their vitality. Furthermore, the formation of ECM is necessary to ensure the formation of new tenocytes, as the ECM is essential for their inte­grity at many levels [35, 57 – 59]. Rapid pain relief and less restricted movement have also been reported in a clinical study involving the administration of a combination of boswellic acid and curcumin extracts to patients with tendon symptoms [29, 30, 60]. Moreover, this phytopharmaceutical combination (curcumin and boswellic acid) has been shown to be more effective compared to celecoxib in the treatment of patients with osteoarthritis, which further supports the findings regarding the modu­latory and anabolic properties of phyto­pharmaceuticals at the molecular level [61]. As in case of bromelain it has not yet been addressed in the literature whether boswellic acid also acts directly on the gene expression of scleraxis.

Combination of ESWT & phytopharmaceuticals

The effectiveness of ESWT in the treatment of tendinopathy has also been demonstrated at the highest level of evidence in a variety of studies (both clinical and in basic research) conducted by members of our group (e.g., [62, 63]). As with phytopharmaceuticals, the use of ESWT has been shown to contribute to tendon regene­ration, by substantially enhancing the expression of tendon-­specific molecules such as scleraxis, thereby inducing an anabolic effect in the tissue [64]. Based on the similar effects of ESWT and phytopharmaceuticals, an initial study (on tendinopathy of the Achilles tendon) in which ESWT was combined with bromelain actually showed a synergistic effect of the two treatments, with bromelain enhancing the mode of action of ESWT [33]. A similar outcome was also achieved in a further study in which boswellic acid and curcumin extracts were administered concomitantly in the treatment of various tendinopathies (Achilles tendon, tennis elbow, supraspinatus tendon) with ESWT. Improved and more rapid regeneration with a consequent reduction in NSAID intake was also reported in this study compared to the control group, who only received treatment with ESWT [60].

Conclusion

In summary, due to its enhancement of anabolic effects, combination therapy involving the use of both ESWT and phytopharmaceuticals such as bromelain, curcumin and boswellia is a promising perspective, the full potential of which is currently only just beginning to be understood and realized in sports medi­cine. Due in particular to their low or even zero toxicity and the associated absence of undesirable effects, even with long-term use, phytopharmaceuticals are potentially a promising adjunct to ESWT and provide new approaches for the treatment of tendinopathy. It is therefore all the more important to verify the data discussed here also in Germany and the EU and to draw appropriate conclusions for the future treatment of tendinopathy.

Conflict of interests: in December 2021 and August 2022 the Department of Anatomy II at LMU ­Munich received grants from Electro Medical Systems (Nyon, Switzerland) to fund basic research into extracorporeal shock wave therapy.

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]]> https://sportaerztezeitung.com/rubriken/therapie/12118/phytopharmaka-und-extrakorporale-stosswellen-bei-tendinopathien/ Tue, 16 Aug 2022 08:00:03 +0000 https://sportaerztezeitung.com/?p=12118 Grob vereinfacht dargestellt muss bei der Therapie von Tendinopathien einer ersten Phase der Bekämpfung von Entzündung und Schmerz eine zweite Phase der effektiven Sehnenregeneration folgen. Es ist mittlerweile weithin bekannt, dass extrakorporale Stoßwellentherapie (ESWT), Kortikosteroide, nicht-steroidale anti-inflammatorische Medikamente (NSAIDs) und bestimmte Phytopharmaka (hier konkret: Bromelain, Curcumin und Weihrauch) gut und effektiv in der ersten Phase wirken (die genannte Liste ist repräsentativ, aber nicht vollständig). 

Viel weniger bekannt dagegen sind die (positiven und negativen) Wirkungen der genannten Therapieformen und Medikamente in der zweiten Phase, was insbesondere für Kombinationstherapien von entscheidender Bedeutung ist.

Entzündungsgeschehen im Sehnengewebe

Tendinopathien sind degenerative und sekundär entzündliche Sehnenleiden, deren Inzidenzen insbesondere im sportmedizinischen Bereich stetig steigen. Mittlerweile entfallen auf Tendino­­pa­thien bis zu 50 % der behandlungsbedürftigen Diagnosen in der Sportmedizin [1, 2]. Ursächlich hierfür sind sowohl permanente Überbeanspruchung und mechanischer Stress des Gewebes bei sportlicher Betätigung als auch Fehlbelastungen im Alltag; aber auch seltene Nebenwirkungen von Medikamenten sind als Auslöser bekannt. Darüber hinaus können auch Lifestyle-Faktoren, wie eine schlechte Ernährungsweise oder mangelnde Bewegung maßgeblich zum Entzündungsgeschehen im Sehnengewebe beitragen [3 – 5], welche sich meist durch Schmerzen und Bewegungseinschränkungen bemerkbar machen und die Lebensqualität der Betroffenen maßgeblich herabsetzen [6, 7]. Um diesen Umständen möglichst schnell entgegenzuwirken, werden aktuell international immer noch weit verbreitet NSAIDs und Kortikosteroide eingesetzt, die hemmend auf zentrale pro-inflammatorische Mediatoren wirken, wodurch Entzündungsreaktionen unterdrückt und sowohl Schmerz als auch Schwellung gelindert werden [8, 9]. Die moleku­laren Targets sind dabei Moleküle wie beispielsweise MAP-(Mitogen-activated protein) Kinasen oder NF-κB (Nuclear Factor kappa B), die als Hauptakteure im entzündlichen Geschehen fungieren und wie Schalter an- oder ausgeschaltet werden können, wodurch Entzündungskaskaden entweder induziert oder gestoppt werden. Infolgedessen wird auch die Expression von weiteren, im Signalweg involvierten Molekülen wie beispielsweise COX-2 (Cyclooxygenase-2) oder MMPs (Matrixmetalloproteinasen) beeinflusst [9 – 13].

Allerdings sind bei der Einnahme dieser Medikamente, trotz kurzfristiger Erleichterung der Beschwerden, viele unerwünschte Nebenwirkungen bekannt, sodass nicht nur häufig andere Organsysteme Langzeitschäden davontragen [14 – 16], sondern auch eine Regene­ration des Sehnengewebes ausbleibt, welche für eine effektive und vor allem nachhaltige Therapie aber unerlässlich ist [17 – 21]. Studien haben gezeigt, dass insbesondere Kortikosteroide (z. B. Dexamethason) und NSAIDs (z. B. Celecoxib), die in vielen Ländern nach wie vor als Standardtherapie bei Tendinopathien eingesetzt werden, nicht nur Entzündungsmoleküle herunterregulieren, sondern auch die Genexpression des Transkriptionsfaktors Skleraxis. Dieser kann als Markergen für die Vitalität von Tenozyten (also den  charakteristischen Zellen der Sehnen und Bänder, welche für den Auf- und Umbau der extrazellulären Matrix (EZM) verantwortlich sind) betrachtet werden, da er nicht nur die Neubildung dieser, sondern auch die Synthese von Kollagen I und sehnenspezifischen Proteoglykanen als Hauptbestandteile der EZM durch die Tenozyten veranlasst [13, 21 – 23]. Somit wird deutlich, dass eine medikamenteninduzierte reduzierte Genexpression von Skleraxis auch zu einer stark verminderten Regenerationsfähigkeit von Sehnengewebe beiträgt, was insbesondere für Athleten von immenser Bedeutung ist. Gleichzeitig wird durch die verminderte Kollagen-Bildung in Kombination mit schmerzlindernden Medikamenten das Risiko für eine Sehnenruptur erhöht, da Schmerzen unter­drückt werden, das Gewebe jedoch an Flexibilität und Funktion verliert [24, 25]. Dies verdeutlicht die Notwendigkeit von alternativen Behandlungsmethoden, die unterstützend bei der Regeneration, d. h. beim Aufbau von Sehnen­gewebe, wirken und im Rahmen einer Kombinationstherapie eingesetzt werden können. Bei verschiedenen Phytopharmaka, wie z. B. Bromelain, Kurkuma und Weihrauch, wurden genau diese Eigenschaften in diversen Studien gezeigt. Durch ihre modulierende Wirkung sind diese Phytopharmaka im Stande, entzünd­liche Kaskaden zu unterbrechen und zeitgleich anabole Prozesse, z. B. durch die erhöhte Expression von Skleraxis und matrixspezifischen Proteinen, in Sehnenzellen zu stimulieren (Tabellen 1 + 2) [2, 26 – 42]. 

Effekte von Phytopharmaka

Bromelain, Hauptbestandteil des Präparats Wobenzym®, ist ein Enzym, das aus der Ananaspflanze gewonnen wird und in der traditionellen Medizin schon lange Anwendung als schmerz- und schwellungslindernder Wirkstoff findet [43 – 46]. Dieser Effekt resultiert insbesondere daraus, dass Stressmarker, wie beispielsweise die MDA (Malondial­dehyd)-Konzentration, in Tenozyten gesenkt und dadurch entzündliche Prozesse unterbrochen werden [46]. Bezüglich der regenerativen Wirkung von Bromelain konnte zudem nachgewiesen werden, dass vor allem die Neubildung von Tenozyten durch das Enzym angeregt wird, also neues Sehnengewebe entsteht und Verletzungen somit bei der Heilung unterstützt werden [2, 32]. Die Frage, ob Bromelain auch direkt auf die Genexpression von Skleraxis wirkt, wurde in der Literatur bisher noch nicht beantwortet.

Ähnliche Effekte in Sehnengewebe konnten auch durch die Anwendung von Kurkuma erzielt werden. Insbesondere Curcumin als eine von vielen Kom­ponenten der Kurkumawurzel, hat in den letzten Jahren als pflanzlicher Entzündungshemmer an großer Bedeutung gewonnen [47 – 50]. Diese Wirkung beruht darauf, dass Curcumin die Fähigkeit besitzt, verschiedene Signalwege, die im Entzündungsgeschehen involviert sind, parallel anzugreifen. Dabei kann u. a. die Modulation des Entzündungsmarkers NF-κB als ein Hauptangriffsziel von Curcumin betrachtet werden. Mit der Inhibition von NF-κB werden gleichzeitig sämtliche pro-inflammatorische Kaskaden und Endmoleküle wie COX-2 oder MMPs, die von NF-κB reguliert werden, ausgeschaltet, sodass sich die Entzündungshemmung auf verschiedenen molekularen Ebenen bemerkbar macht [35, 42]. Ausschlaggebend für den Regenerationsprozess bei Tendinopathien ist jedoch die stark anabole Wirkung von Curcumin [35 – 40, 42]. Konkret konnte gezeigt werden, dass durch Curcumin die Expression von Kollagen stark hochreguliert und somit die Kollagensynthese angekurbelt wird [35, 39]. Außerdem konnte nachgewiesen werden, dass Curcumin eine nach einer Sehnenverletzung mit chronischer Entzündung die häufig eintretende Kalzifikation verhindern kann, indem die Osteogenese, also Knochenbildung, an der Verletzungsstelle lokal herunterreguliert und die Tenogenese, d. h. die Neubildung von Sehnenzellen, gleichzeitig stimuliert wird [40]. Neben Curcumin gewinnt auch Calebin A (ein weiterer bioaktiver Bestandteil der Kurkumawurzel) durch seine ebenfalls anti-entzündliche Wirkungsweise zunehmend an Bedeutung [51, 52]. In einer kürzlich durchgeführten Studie konnten wir in unserer Arbeitsgruppe zeigen, dass Calebin A nicht nur imstande ist, entzündliche Kaskaden wie den NF-κB-Signalweg und dessen entzündungsfördernde Endprodukte zu hemmen, sondern auch Skleraxis in Sehnenzellen hochzuregulieren, was insbesondere für die Regeneration von Sehnengewebe von großer Relevanz ist [26]. Dieser multi-modulatorische Effekt von Calebin A wird in Anbetracht dessen, dass zudem eine funktionelle Verbindung zwischen NF-κB und Skleraxis nachgewiesen werden konnte, noch deutlicher [26]. Der Effekt von Calebin A in der Entzündungshemmung mit gleichzeitiger Regenerationsförderung zeigt dessen mehrstufiges Potenzial bei der Behandlung von Tendinopathien.

Auch Weihrauch, ein Extrakt, der aus dem Gummiharz der Boswellia-Pflanze gewonnen wird, konnte schon mehrfach erfolgreich bei muskuloskelettalen Beschwerden als anti-entzündlicher und schmerzlindernder Wirkstoff angewendet werden [27, 53 – 55]. Dabei liegt das Potenzial von Weihrauch insbesondere darin, entzündungsfördernde Prozesse und Botenstoffe, die eine entscheidende Rolle in der Pathogenese von Tendinopathien spielen, zu hemmen. Ausschlaggebend ist dabei vor allem, dass auch Moleküle, die zur ­Matrixdegradation beitragen (MMPs, COX-2), ausgeschaltet werden [27, 28, 56]. Dadurch wird der weitere Abbau insbesondere von Kollagen und anderen wichtigen Bestandteilen der EZM verhindert, sodass der Verlust von Sehnenzellen an der Stelle der Pathologie unterbrochen und deren Vitalität erhalten werden kann. Zudem ist die Bildung von EZM notwendig, um die Neubildung von Tenozyten zu gewährleisten, da die EZM für deren Integrität auf viel­facher Ebene wesentlich ist [35, 57 – 59]. Außerdem konnte in einer klinischen Studie, in der eine Kombination aus Weihrauch und Kurkuma-Extrakten an Patienten mit Sehnen­beschwerden verabreicht wurde, eine schnelle Schmerzlinderung sowie eine verminderte Bewegungseinschränkung beobachtet werden [29, 30, 60]. Diese Phytopharmakakombination (Kur­­kuma und Weihrauch) erwies sich zudem in der Behandlung von Patienten mit Osteoarthritis als die effektivere Therapiemethode im Vergleich mit Celecoxib, was die Erkenntnisse der modulatorischen und anabolen Fähigkeiten von Phytopharmaka auf molekularer Ebene bestärkt [61]. Wie bei Bromelain wurde die Frage, ob Weihrauch auch direkt auf die Genexpression von Skleraxis wirkt, in der Literatur bisher noch nicht beantwortet.

Kombination ESWT & Phytopharmaka

Die Effektivität der ESWT bei der Behandlung von Tendinopathien wurde auch durch Mitglieder unserer Arbeitsgruppe in vielfältigen Studien (sowohl klinisch als auch in der Grundlagenforschung) auf höchstem Evidenz­niveau gezeigt (z. B. [62, 63]). Auch die Anwendung von ESWT kann, ähnlich wie Phytopharmaka, nachweislich zur Sehnenregeneration beitragen, indem die Expression von sehnenspezifischen Molekülen wie Skleraxis durch ESWT maßgeblich verstärkt wird, wodurch ein anaboler Effekt im Gewebe eintritt [64]. Basierend auf dem ähnlichen Effekt von ESWT und Phytopharmaka konnte in einer ersten Studie (bei Tendinopathie der Achillessehne), bei welcher  ESWT und Bromelain kombiniert wurden, tatsächlich eine synergistische Wirkung beider Therapien festgestellt und eine durch Bromelain verbesserte Wirkungsweise der ESWT erreicht werden [33]. Ein ähnliches Ergebnis wurde in einer weiteren Studie erzielt, in welcher Weihrauch und Kurkuma-Extrakte begleitend zur Behandlung verschiedener Tendinopathien (Achillessehne, Tennisellenbogen, Supraspinatussehne) mit ESWT verabreicht wurden. Auch hier wurde eine verbesserte und schnellere Regeneration und eine damit einhergehende verringerte Einnahme von NSAIDs im Vergleich zur Kontrollgruppe, die nur mit ESWT behandelt wurde, beobachtet [60].

Fazit

Zusammenfassend stellt eine Kombinationstherapie, bestehend aus der Anwendung von ESWT und Phytopharmaka wie Bromelain, Kurkuma oder Weihrauch, durch die Verstärkung anabolischer Effekte eine vielversprechende Perspektive dar, deren vollständiges Potenzial in der Sportmedizin bisher erst in Ansätzen verstanden und realisiert ist. Insbesondere aufgrund geringer oder sogar nicht vorhandener Toxizität und dem damit verbundenen Ausbleiben von unerwünschten Nebenwirkungen, selbst bei langfristiger Einnahme, können Phytopharmaka als eine vielversprechende Ergänzung zur ESWT dienen und eröffnen neue Therapieansätze in der Behandlung von Tendinopathien. Deshalb ist es umso wichtiger, die hier diskutierten Daten in randomisierten kontrollierten Studien auch in Deutschland und in der EU zu verifizieren und entsprechende Schlüsse für die Tendino­pathie-Behandlung der Zukunft zu ziehen.

Interessenkonflikt: im Dezember 2021 erhielt der Lehrstuhl Anatomie II der LMU eine Finanzspende der Firma Electro Medical Systems (Nyon, Schweiz) zur Förderung der Grundlagenforschung zur extrakorporalen Stoßwellentherapie.

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