In modern medicine, combination therapies are playing an increasingly important role. They combine different therapeutic modalities in a targeted manner to achieve additive and syner­gistic effects. Across many medical specialties, exercise training delivers powerful systemic effects that perfectly complement pharmacolog­ical, device-based and psychosocial treatment appro­aches. This article outlines the scientific foun­da­tions, advantages and methodological challenges of these concepts. What becomes clear is that combination therapies often represent complex interventions where success hinges on the seamless coordination of all elements.

In modern medicine, integrative treatment approaches are increasingly taking centre stage, as isolated single interventions give way to compre­hensive, interdisciplinary treatment approaches. Combination therapy is a key principle in this field. It combines various therapeutic approaches in a targeted manner to achieve additive and synergistic effects that can exceed the efficacy of individual measures. Exercise training in particular plays a significant role in this context, as it acts systemically on numerous pathomechanisms and – also due to technological advances – can now be integrated into virtually all specialist disciplines (cf. Issue X).

Combination therapy does not simply mean applying several therapies alongside one another. While indi­vidual interventions target specific pathomechanisms in isolation and parallel prescriptions often proceed without proper coordination, combination therapy delivers a strategically coordinated interaction between different therapeutic measures. With this approach, various therapeutic modalities are coor­dinated with regard to their timing, mechanisms of action, dosage and objectives, so that they reinforce each other both functionally and biologically.

Exercise training plays a key role in these concepts, as it works both systemically and specifically: it influ­ences muscle power, cardiovascular perfor­mance, neuroplastic processes, immune functions, psycho­logical stability, as well as numerous cellular and molecular regulatory systems.

Combination therapies are in many cases complex interventions in the strict scientific sense. According to the UK Medical Research Council (MRC) frame­works, complex interventions are characterised by several interacting components. These include not only the therapeutic procedures themselves, but also contex­tual factors such as the professional groups involved, organisational processes, patient participa­tion, adhe­rence and setting conditions. The effectiveness of these interventions comes not simply from their individual components, but critical­ly from how these components interact (Craig et al., 2008; Skivington et al., 2021).

Complex interventions present unique metho­dological challenges when it comes to their development, evaluation and implementation. Tradi­tional rando­mised controlled trials (RCTs) are often insufficient to fully capture the complex causal rela­tionships. In addition, Process Evaluations, Realist Evaluations, Cluster-RCTs and Mixed-Methods approaches are increasingly being employed to system­atically examine both effectiveness and mechanisms of action, context dependencies and implementation factors (Hawe et al., 2004; Peters et al., 2013). Exercise as a component of such complex combination therapies cannot therefore be considered in isolation, but must always be embedded within the overall therapeutic process and tailored to the context and patient needs.

Intradialytic training: exercise during haemodialysis
CKD patients undergoing haemodialysis frequently suffer from cardiovascular deconditioning, sarco­penia and fatigue. Intradialytic training (IDT) utilises dialysis time for therapeutic exercise sessions at the dialysis station, frequently using cycle ergometers or motor-assisted movement exercisers, such as the THERA-Trainer bemo.

Meta-analyses show significant improvements in maximal oxygen uptake, reduction of inflamma­tory markers (e.g. CRP, TNF-α), vascular elasticity as well as quality of life (Zhang et al., 2019; Heiwe & Jacobson, 2011). IDT is a complex intervention, requiring both medical-technical implementation and interprofessional coordination between nephrol­ogists, nursing staff and physiotherapy. At the same time, the therapy must be adapted to the individual health condition of the patient.

An outstanding example of Dialysis Training Therapy (DiaTT) is documented in the study of the same name, DiaTT (cf. Issue X). A large-scale, multicentre, cluster-randomised randomised trial on the effect of exercise during dialysis.

Orthopaedics: bone healing with shockwave therapy and training
In pseudarthrosis, the effectiveness of combined Extracorporeal Shockwave Therapy (ESWT) with functional movement training is particularly evident. Whilst ESWT stimulates angiogenic and osteogenic healing processes (e.g. VEGF, BMP-2), mechanical loading activates bone-adapting signalling pathways via mechanotransduction. Studies show higher healing rates and shorter consolidation times with a combined approach (Schaden et al., 2015; Wang et al., 2020).

This too is a complex intervention, as the treatment must be dosed individually for each patient, contin­uously adjusted throughout the healing process, and coordinated in an interdisciplinary manner. (See also Article X in this issue)

Neurological rehabilitation: electrostimulation combined with exercise
In neurorehabilitation – for example following stroke – functional electrical stimulation (FES) and active movement training are mutually beneficial. Electro­stimulation activates peripheral nerves and muscles, while exercise promotes neuroplastic reor­ganisation. Numerous studies demonstrate improved mobility, muscle power and functional independence with combined application (Howlett et al., 2015; de Sousa et al., 2016).

Since neurological deficits, motivation and cognitive resources vary greatly, adaptive therapy plans are essential, which further increase the complexity of the intervention.

Cardiology: exercise as an integrative component of heart failure therapy
The treatment of heart failure also follows a clear multimodal principle today. Medications such as ACE inhibitors, beta-blockers and SGLT2 inhibitors improve cardiac functions, whilst movement training optimises peripheral perfusion, muscle metabolism and exercise tolerance (McDonagh et al., 2021; Taylor et al., 2019). Exercise is firmly established as part of standard therapy in the current ESC guidelines.

The interdisciplinary coordination of medication dosages, training intensity, monitoring and patient education clearly illustrates the complex nature of this intervention.

Oncological rehabilitation: exercise complements systemic tumour therapies
Exercise reduces therapy-related side effects such as fatigue, polyneuropathies and depressive symptoms, but may also directly influence tumour progression through immunological and inflammatory effects (Campbell et al., 2019; Koelwyn et al., 2017). Many oncological guidelines therefore recommend the structured integration of exercise training during active tumour treatment.

Here, too, the challenge lies in dynamically tailoring exercise to treatment phases, side effects and each patient’s individual resources – a classic example of a complex therapeutic intervention.

Intensive care: early mobilisation under ventilation
In intensive care medicine, early mobilisation of venti­lated patients has proven to be an effective strategy for reducing immobilisation complications such as ICU-acquired weakness, delirium and prolo­nged ventilation times (Schweickert et al., 2009). The implementation of such programmes requires interdis­ciplinary coordination among intensive care specialists, physiotherapists, nursing staff, occupational therapists and family members – demonstrating, once again, the complex interplay of multiple components.

Conclusion: understanding complexity, harnessing synergies
Combination therapies are not merely a sequence of individual measures, but highly complex interven­tions in which therapeutic elements, patient factors and contextual conditions interact dynamically. In particular, exercise therapy plays a key role in these multimodal concepts – as a systemic, functional and psychological efficacy enhancer with proven additional benefit.

The development and successful implementation of such complex therapy concepts requires precise plan­ning, interdisciplinary collaboration, high therapy adherence, patient-centred indivi­dualisation and continuous monitoring.

Innovative care centres are increasingly integrating these principles into their core structure, creating healing environments – spaces thoughtfully designed both architecturally and organisationally to enhance healing processes and seamlessly integrate complex interventions into everyday clinical practice.

A key component in this approach is the use of cutting-edge medical technology: Technological assistance systems and smart movement exercisers are increasingly being used to support individual therapy goals safely, in measured doses and in an appropriate context – from acute care settings and early rehabilitation to aftercare. These solutions deliver precise control, progress tracking and adap­tation within the overall framework, creating new opportunities for the practical delivery of evidence-based combination therapies.