Phytopharmaceuticals and extracorporeal shock wave therapy for tendinopathy

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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Autoren

Univ.-Prof. Dr. Mehdi Shakibaei

Lehrstuhl Anatomie I der LMU München, ist einer der weltweit führenden Experten auf dem Gebiet der Grundlagenforschung zur Entzündungsmodulation des muskuloskelettalen Systems mittels Phytopharmaka.

Univ.-Prof. Dr. med. Christoph Schmitz

ist Inhaber des Lehrstuhls II der Anatomischen Anstalt der Ludwig-Maximilians Universität München und wissenschaftlicher Beirat der sportärztezeitung.

Anna-Lena Müller

ist wissenschaftliche Mitarbeiterin in der Arbeitsgruppe von Prof. Mehdi Shakibaei am Lehrstuhl Anatomie I der LMU München und forscht intensiv auf dem Gebiet von Tendinopathien in Kombination mit Phytopharmaka.

Aranka Brockmüller

ist Ärztin und Doktorandin in der Arbeitsgruppe von Prof. Mehdi Shakibaei am Lehrstuhl Anatomie I der LMU München und forscht auf dem Gebiet der Entzündungsmodulation durch Phytopharmaka.