Table 3.

Clinical trials with radon application from year 2000 on.

First Author Year of Publication	Trial Design	Patient Number Indication	Dose	Type of Exposure Frequency Duration	Endpoints and Timepoints	Most Important Findings	Ref.
Franke et al., 2000	Prospective; blinded; randomized	60 patients RA	Radon group: 1.3 kBq/L, 1.6 g/L CO2 Placebo group: 1.6 g/L CO2	Bath 20 min 15 times 4 weeks T = 35 °C Additional: Physiotherapy Occupational therapy Galvanic bathes (3/week) Classic massage	Endpoints: Pain intensity (VAS) Keitel functional Test (KFI) Arthritis Impact Measurement (AIMS) Timepoints: Before and directly after therapy, as well as, 3 and 6 months after therapy.	Pain intensity decreased in both groups, radon treatment results in a significant and longer lasting benefit from pain relief; KFI more in radon group; AIMS score was significantly increased in radon treated patients up to 6 months; KFI score shows a not significant benefit in radon treated patients	[98]
Van Tubergen et al., 2001	Prospective; different treatment groups at different places.	120 patients AS (40 spa with radon, 40 spa w/o radon 40 physical therapy at home)	Radon group: 0.536 WLM Placebo group: Thermal water + sauna Hydrotherapy Bathing Sports	Gallery/ inhalation Each 1 h 16 times 3 weeks T = 38–41 °C Additional: Physical exercise Postural correction therapy	Endpoints: BASFI Well-being VAS Pain intensity VAS Morning stiffness Timepoints: Before therapy After therapy week 4, 16, 28, and 40	Primary goals borderline significant; pooled index of change shows highly significant differences as well as long-lasting effects of radon compared to conventional treatment	[105]
Yamaoka et al., 2004	Prospective	15 people (putative healthy individuals)	Radon group: 2080 Bq/m3 Sauna Group: 54 Bq/m3 Control Group: 54 Bq/m3	Inhalation 40 min 5 times TRadon = 36 °C TSauna = 48 °C TControl = 36 °C	Endpoints: SOD AOC lipid metabolism CD4/CD8 immune cells vasoactive substances diabetes-associated markers Timepoints: Blood draw before and at 2 h after each treatment. In addition, 5 and 10 days after treatment.	Significant increase in SOD as well as decrease of lipid metabolism and cholesterol at 10 days for radon and sauna group; radon enhances T cell activity significantly, while sauna has similar effects, only significant at 10 days after treatment; radon enhances the CD4 T cell amount significantly after treatment, while CD8 T cells were decreased, respectively; radon group shows significantly more endorphin and a reduced vasopression	[112]
Yamaoka et al., 2004	Prospective	20 patients OA	Radon group: 2080 Bq/m3 non-controlled	Inhalation 40 min each Every 2 days T = 42 °C	Endpoints: SOD, catalase, lipid peroxide, total cholesterol, GSH, β-endorphin, ACTH, uric acid, ANP, and vasopressin levels in blood Timepoints: Before therapy, 2 h, 2, 4 and 6 weeks after therapy	SOD activity is significantly and long-lasting increased; Catalase activity is significantly increased after 4 and 6 weeks; T cells of CD4 type are increased, while CD8 T cells are decreased from 2 to 4 weeks after therapy; β-endorphin and anti-ANP levels were significantly and long-lasting increased after therapy; Vasopressin was significantly and long-lasting decreased; Cholesterol and lipid peroxide levels were significantly and long-lasting decreased	[113]
Shehata et al., 2006	Retrospective	83 patients AS (radon treatment) 10 patients AS (conv. Treatment) 10 patients LBP	Radon group: ~4.5 nCi/l Placebo groups: Convent. Therapy	Gallery/ inhalation 1 h each T = 38–41 °C 9–12 times 3–4 weeks Additional: Physiotherapy Hydrotherapy Massage Exercises	Endpoint: TGF-β (total and active form) Timepoint: Before, during and after the treatment (~0, 2 and 4 weeks)-	Total TGF-β level increased significantly in radon exposed patients compared to conventional treated patients or LBP controls; active TGF-β increased strongly and significantly in radon exposed patients compared to conventional treated patients or LBP controls; therapy responders show an inverse correlation with CRP concentration	[107]
Franke et al., 2007	Prospective; blinded; randomized	134 patients RA (67 patients per group)	Radon group: 1.1 kBq/L, 1.3 g/L CO2 Placebo group: 1.6 g/L CO2	Baths 20 min 15 times 3 weeks T = 35 °C Additional: Physiotherapy Occupational therapy Galvanic bathes (3/week) Swedish massage	Endpoints: pain intensity, pain frequency, morning stiffness, functional capacity (all VAS), Drug intake Timepoints: Before and after last treatment, 3, 6, 9, and 12 months after treatment	Drug intake was significantly reduced from month 9 on; both groups had treatment effects, most not significant; repeated measurement ANCOVA revealed significant and long-lasting enhanced quality of life due to fewer limitations induced by pain	[99]
Moder et al., 2010	Prospective	33 AS patients	Radon group: ~4.5 nCi/L non-controlled	Gallery/ inhalation 90 min each 10 times 3 weeks 37–40.5 °C	Endpoints: Disease activity, BASDAI. BASFI, BASMI serum concentration of RANKL, OPG, TNFα, TGF-β, IL-17, IL-6 Timepoints: Before and after therapy (3 weeks)	Disease-associated scores BASDAI. BASFI, BASMI decreased significantly after therapy; serum conc. of TGF-β1, IL-6, TNF-α, RANKL, OPG, as well as OPG/RANKL ratio was significantly increased; active form of TGF-β, IL-6, TNFα.	[106]
Franke et al., 2013 (IMuRa Trial)	Prospective; blinded; randomized; multicentric	652 Patients BP 437 pts. OA 230 pts. RA 98 pts. AS 39 pts. Multi 146 pts.	Radon group (332 patients) Radon bathes according to specific center (with or without CO2) or Radon Speleotherapy Control group: (320 patients) Placebo bathes according to specific center (either tap water or non-radon-containing fountain, with or without CO2)	Bath 20 min 12 times 3–4 weeks T = 36–38 °C	Endpoints: Pain intensity (VAS) Pain Questionnaire Functional capacity (FFbH) Western Ontario questionnaire (WOMAC) Health assessment questionnaire (HAQ) BASFI Drug intake Timepoints: Before and after last treatment, 3, 6, and 9 month after treatment	Radon treatment leading to significant and long-lasting relieve of self-assessed pain (VAS); OA and BP patients have the strongest and most lasting benefit from radon treatment, while OA patients seem to additionally have an enhanced quality of living up to 6 months after treatment	[76]
Dischereit et al., 2014 (Article in german)	Prospective	24 patients RA 24 patients OA	Radon group 44 kBq/m3 non-controlled	Gallery/ inhalation 60 min each 12 times 3 weeks T = 37.5–41 °C	Endpoints: Pain intensity and duration Disease activity and functional score (BASDAI; BAS-G) Serum levels of RANKL, OPG, and TNF-α Timepoints: Directly before and after therapy, as well as 3 months after therapy	Pain was relieved after therapy and after 3 months in AS patients and after 3 months in OA patients; BASDAI was reduced significantly, and long-lasting in AS patients; TNF-α level was decreased in both groups, significantly in OA; RANKL level was significantly decreased in both groups, OPG increased only in AS; RANKL/OPG ratio decreased only AS significantly	[108]
Winklmayr et al., 2015	Prospective; blinded; randomized	64 healthy individuals Married partners	Radon group 412–900 Bq/L, Placebo: thermal water	Bath 20 min 5 times + 3 times brush up T = 36–39 °C Additional: Mountain hiking 3–4 h daily	Endpoints: Serum conc. OPG, RANKL, OPG/RANKL ratio Timepoints: Day 0, 6, 60, and 63 and 6 months after last treatment	Treatment benefits were seen in both groups in OPG, RANKL, and OPG/RANKL ratio; detected borderline significant trend towards bigger effect in Radon treated group	[114]
Lange et al., 2016 and 2012	Prospective	25 patients RA 24 patients OA	Radon group 4.5 nCi/l non-controlled	Gallery/ inhalation 60 min each 12 times 3 weeks T = 37.5–41 °C	Endpoints: serum conc. RANKL, OPG, TNF-α, and ACPA Timepoints: Directly before and after therapy	The serum conc. of TNFα and RANKL levels decreased in both groups; only in RA patients, OPG level increased, leading to a decreased RANKL/OPG ratio; ACPA titers decreased only in RA patients	[115,116]
Lange et al., 2017					Endpoints: Pain VAS FFbH questionnaire ESR Serum CRP, RANKL, OPG, TNF-α, IL-10, and ACPA Timepoints: Directly before and after therapy, as well as 3 months after therapy	RA patients have significant immediate and lasting effect in pain relief, while health status (FFbH) is increasing; OA patients have significantly lasting pain relief effect; serum concentration of IL-10 is significantly increased directly after treatment in RA patients	[117]
Rühle et al., 2017 (RAD-ON01)	Prospective Blinded Randomized	100 patients with musculoskeletal disorders 50 patients per group Ambulant patients	Radon group 1200 Bq/L, Radon water only group); Radon/CO2 group 600 Bq/L and 1 g/l CO2; Radon-CO2-group Covered bath-tube	Bath 20 min each 9 times 3 weeks T = 35 °C	Endpoints: Immune modulation via DIoB [100] method Pain relief (VAS and questionnaire) Pain sensitivity (dolorimetry, pressure point measurement) Timepoints: Directly before as well as 6, 12, and 30 weeks after therapy	Long-lasting and significant pain reduction until end of observation period in whole trial population; significant and long-lasting increase in T cells and monocytes; significant temporarily increase of dendritic cells and regulatory T cells; significant and long-lasting reduction of the expression of the activation marker CD69 on T, B, and NK cells	[104]
Cucu et al., 2017 (RAD-ON01)					Endpoints: Amount of regulatory T cells Serum markers of bone and lipid metabolism	significant and long-lasting decrease of collagen fragments (CTX-I) and reduced levels of visfatin. Both factors are correlating significantly with pain intensity (VAS); regulatory T cells increase significantly and long-lasting after treatment	[102]
Rühle et al., 2018 (RAD-ON01)					Endpoints: Pain relief (VAS and questionnaire) Pain sensitivity (dolorimetry, pressure point measurement) Blood pressure Antioxidative capacity (AOC) Superoxiddismutase (SOD)	Long-lasting and significant pain reduction until the end of the observation period in whole trial population, Radon CO2 bathes show a trend to be less effective (n.s.); lowered blood pressure in both groups, nightly measured systolic and diastolic blood pressure significantly decreased in Radon/CO2 treated patients; SD-VLF decreased significantly after radon therapy; SOD2 reduced significantly 6 weeks after treatment and increased significantly long-lasting	[103]
Kullmann et al., 2018 (RAD-ON01)					Endpoints: Detection of inflammatory and anti-inflammatory cytokines in serum of patients.	No significant effects found for TNFα, IL-1β, IFNγ, IL-18, IL-1Ra, IL-10 concentration in serum of the patients; TGF-β concentration was significantly increased after treatment and significantly correlates with pain sensitivity; IL-18 level corresponds with lowered pain perception	[101]

Abbreviations: ACPA: anti-citrullinated peptide antibodies; ACTH: adrenocorticotropic hormone; ACTH: Adrenocorticotropine; AIMS: arthritis impact measurement score; ANP: atrial natriuretic polypeptide; AOC: Antioxidative Capacity; AS: ankylosing spondylitis; BAG-G: Bath Ankylosing Spondylitis Patient Global Score; BALF: bronchioalvelolar lavage fluid; BASDAI: Bath Ankylosing Spondylitis Disease Activity Index; BASFI: Bath Ankylosing Spondylitis Functional Index; BASMI: Bath Ankylosing Spondylitis Metrology Index; BP: Back Pain; CD: cluster of differentiation; CO₂: carbon dioxide; CRP: c-reactive protein; CTX: Cross Laps; FFbH: Funktions Fragebogen Hannover (Functional Capacity); GSH: Glutathione; HAQ: Health assessment questionnaire; IFN: interferon; IL: interleukin; KFI: Keitel functional index; LBP: lower back pain; OA: Osteoarthritis; OPG: osteoprotegerin; RA: rheumatoid arthritis; RANKL: receptor activator of NFkB Ligand; SOD: superoxide dismutase; TGF: transforming growth factor; TNF: tumor necrosis factor; VAS: Visual Analog Scale; WOMAC: Western Ontario questionnaire. Bold letters highlight the trial groups, additional treatments, trial endpoints, and timepoints of investigation.