Low Dose Radiation Therapy Induces Long-Lasting Reduction of Pain and Immune Modulations in the Peripheral Blood – Interim Analysis of the IMMO-LDRT01 Trial

Donaubauer, Anna-Jasmina; Becker, Ina; Weissmann, Thomas; Fröhlich, Birgitta M.; Muñoz, Luis; Gryc, Thomas; Denzler, Manuel; Ott, Oliver J.; Fietkau, Rainer; Gaipl, Udo S.; Frey, Benjamin

doi:10.3389/fimmu.2021.740742

Cited by 11 publications

(10 citation statements)

References 41 publications

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“…As different phenotypes of the monocytes determine the ability of OC to differentiate, the question about a potential radiation induced modulation of osteoclastogenesis by changing the phenotype ( 65 ) could be subject for further studies. Interestingly, a decreased activation of monocytes has been shown after LD-RT in the interim analysis of our study ( 36 ).…”

Section: Discussionsupporting

confidence: 69%

“…We have reported in an interim analysis of this study that after local LD-RT, pain perception of the patients, evaluated with the VAS scale (1–10), significantly decreased over time, starting from a general pain level indicating medium to severe initial stages ( 36 ) and suggesting that inflammation might be involved in the course of the diseases ( 3 ). In addition to pain reduction, some immune cell types were modulated and their activation was downregulated ( 36 ).…”

Section: Introductionmentioning

confidence: 78%

“…In the frame of the IMMO-LDRT01 trial [details in ( 36 )], blood samples were taken at several time points before and after therapy from a subgroup of patients, mostly suffering from Calcaneodynia and Achillodynia and further analyzed. In our analysis, we focused on the ratio of subtypes of T cells that impact bone metabolism, i.e.…”

Section: Resultsmentioning

confidence: 99%

“…For details on the IMMO-LDRT01 trial (NCT02653079), see ( 36 ). Briefly, all patients enrolled were affected by chronic degenerative and inflammatory diseases.…”

Section: Methodsmentioning

confidence: 99%

“…According to their personal decision, all patients underwent in this study the 1 st and the 2 nd series. The pain perception of the patients, evaluated with the VAS scale (1–10), showed a significant decrease over time, starting from a general pain level of 6.5 and dropping to 3.8 ( 36 ). This mean pain level indicates advanced stages, suggesting that inflammation might be involved in the course of the treated diseases.…”

Section: Methodsmentioning

confidence: 99%

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Modulation of Differentiation and Bone Resorbing Activity of Human (Pre-) Osteoclasts After X-Ray Exposure

et al. 2022

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Low-dose radiotherapy (LD-RT) is a local treatment option for patients with chronic degenerative and inflammatory diseases, in particular musculoskeletal diseases. Despite reported analgesic and anti-inflammatory effects, cellular and molecular mechanisms related to osteoimmunological effects are still elusive. Here we test the hypothesis that X-irradiation inhibits the differentiation of precursor osteoclasts into mature osteoclasts (mOC) and their bone resorbing activity. Circulating monocytes from healthy donors were isolated and irradiated after attachment with single or fractionated X-ray doses, comparable to an LD-RT treatment scheme. Then monocytes underwent ex vivo differentiation into OC during cultivation up to 21 days, under conditions mimicking the physiological microenvironment of OC on bone. After irradiation, apoptotic frequencies were low, but the total number of OC precursors and mOC decreased up to the end of the cultivation period. On top, we observed an impairment of terminal differentiation, i.e. a smaller fraction of mOC, reduced resorbing activity on bone, and release of collagen fragments. We further analyzed the effect of X-irradiation on multinucleation, resulting from the fusion of precursor OC, which occurs late during OC differentiation. At 21 days after exposure, the observation of smaller cellular areas and a reduced number of nuclei per mOC suggest an impaired fusion of OC precursors to form mOC. Before, at 14 days, the nuclear translocation of Nuclear Factor Of Activated T Cells 1 (NFATc1), a master regulator of osteoclast differentiation and fusion, was decreased. In first results, obtained in the frame of a longitudinal LD-RT study, we previously reported a pain-relieving effect in patients. However, in a subgroup of patients suffering from Calcaneodynia or Achillodynia, we did not observe a consistent decrease of established blood markers for resorption and formation of bone, or modified T cell subtypes involved in regulating these processes. To assess the relevance of changes in bone metabolism for other diseases treated with LD-RT will be subject of further studies. Taken together, we observed that in vitro X-irradiation of monocytes results in an inhibition of the differentiation into bone-resorbing OC and a concomitant reduction of resorbing activity. The detected reduced NFATc1 signaling could be one underlying mechanism.

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Section: Discussionsupporting

confidence: 69%

Section: Introductionmentioning

confidence: 78%

Section: Resultsmentioning

confidence: 99%

“…For details on the IMMO-LDRT01 trial (NCT02653079), see ( 36 ). Briefly, all patients enrolled were affected by chronic degenerative and inflammatory diseases.…”

Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

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Modulation of Differentiation and Bone Resorbing Activity of Human (Pre-) Osteoclasts After X-Ray Exposure

et al. 2022

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Low-dose radiotherapy of osteoarthritis: from biological findings to clinical effects—challenges for future studies

et al. 2023

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Osteoarthritis (OA) is one of the most common and socioeconomically relevant diseases, with rising incidence and prevalence especially with regard to an ageing population in the Western world. Over the decades, the scientific perception of OA has shifted from a simple degeneration of cartilage and bone to a multifactorial disease involving various cell types and immunomodulatory factors. Despite a wide range of conventional treatment modalities available, a significant proportion of patients remain treatment refractory. Low-dose radiotherapy (LDRT) has been used for decades in the treatment of patients with inflammatory and/or degenerative diseases and has proven a viable option even in cohorts of patients with a rather poor prognosis. While its justification mainly derives from a vast body of empirical evidence, prospective randomized trials have until now failed to prove the effectiveness of LDRT. Nevertheless, over the decades, adaptions of LDRT treatment modalities have evolved using lower dosages with establishment of different treatment schedules for which definitive clinical proof is still pending. Preclinical research has revealed that the immune system is modulated by LDRT and very recently osteoimmunological mechanisms have been described. Future studies and investigations further elucidating the underlying mechanisms are an essential key to clarify the optimal patient stratification and treatment procedure, considering the patients’ inflammatory status, age, and sex. The present review aims not only to present clinical and preclinical knowledge about the mechanistic and beneficial effects of LDRT, but also to emphasize topics that will need to be addressed in future studies. Further, a concise overview of the current status of the underlying radiobiological knowledge of LDRT for clinicians is given, while seeking to stimulate further translational research.

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ArthroRad trial: randomized multicenter single-blinded trial on the effect of low-dose radiotherapy for painful osteoarthritis—final results after 12-month follow-up

Niewald,

Moumeniahangar,

Müller

et al. 2023

Strahlenther Onkol

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Objective Updated report about the randomized comparison of the effect of radiotherapy on painful osteoarthritis (OA) applying a standard dose vs. a very low dose regime after a follow-up of 1 year. Patients and methods Patients presenting with OA of the hand/finger and knee joints were included. After randomization (every joint region was randomized separately) the following protocols were applied: (a) standard arm: total dose 3.0 Gy, single fractions of 0.5 Gy twice a week; (b) experimental arm: total dose 0.3 Gy, single fractions of 0.05 Gy twice a week. The dosage was blinded for the patients. For evaluation the scores after 1‑year visual analog scale (VAS), Knee Injury and Osteoarthritis Outcome Score–Short Form (KOOS-PS), Short Form Score for the Assessment and Quantification of Chronic Rheumatic Affections of the Hands (SF-SACRAH) and 12-item Short-Form Health Survey (SF-12) were used (for further details: see [1]). Results The standard dose was applied to 77 hands and 33 knees, the experimental dose was given to 81 hands and 30 knees. After 12 months, the data of 128 hands and 45 knees were available for evaluation. Even after this long time, we observed a favorable response of pain to radiotherapy in both trial arms; however, there were no reasonable statistically significant differences between both arms concerning pain, functional, and quality of life scores. Side effects did not occur. The only prognostic factor was the pain level before radiotherapy. Conclusions We found a favorable pain relief and a limited response in the functional and quality of life scores in both treatment arms. The possible effect of low doses such as 0.3 Gy on pain is widely unknown.

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Low Dose Radiation Therapy Induces Long-Lasting Reduction of Pain and Immune Modulations in the Peripheral Blood – Interim Analysis of the IMMO-LDRT01 Trial

Cited by 11 publications

References 41 publications

Modulation of Differentiation and Bone Resorbing Activity of Human (Pre-) Osteoclasts After X-Ray Exposure

Modulation of Differentiation and Bone Resorbing Activity of Human (Pre-) Osteoclasts After X-Ray Exposure

Low-dose radiotherapy of osteoarthritis: from biological findings to clinical effects—challenges for future studies

ArthroRad trial: randomized multicenter single-blinded trial on the effect of low-dose radiotherapy for painful osteoarthritis—final results after 12-month follow-up

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