Purpose: Osteoarthritis (OA) is the most common form of joint disease. Synovial inflammation plays an important role in OA pathophysiology. Currently, no disease modifying treatment is available and all approaches are symptomatic. However, non-surgical treatment options (e.g. education, analgesics and exercise therapy) have limited effects, while surgical options (e.g. total joint replacement) are not (yet) appropriate for many OA patients. In some countries, low-dose radiation therapy (LD-RT) is widely used as treatment for OA, while relatively unknown in others. Studies in vitro and in OA animal models have shown anti-inflammatory effects of LD-RT. However, systematic literature review has shown that high-level evidence for beneficial effects in clinical practice is lacking. Therefore, we set up two parallel prospective RCTs with the aim to assess the effect of LD-RT on clinical outcomes and inflammation in patients with hand or knee OA. Methods: Patients with hand OA (n = 56) or knee OA (n = 55) according to ACR-criteria, with a pain score ≥5 out of 10 and not responding to analgesics and exercise therapy were included in two double-blinded RCTs. Patients were randomly allocated 1:1 to the experimental (6x 1Gy LD-RT in two weeks) or sham (6x 0Gy in two weeks) intervention, stratified for pain score (<8 vs. ≥8). The primary outcome was the number of patients improving on pain and functioning, according to the OMERACT-OARSI responder criteria, 3 months post-intervention. Secondary outcomes were changes in inflammatory aspects assessed by ultrasound (US; both knee and hand) and MRI (knee only), as well as serum ESR and CRP levels. In hand OA, hand joints were scored semi-quantitatively (0–3) for US effusion, synovial thickening and power Doppler signal. In knee OA, we assessed the mean US effusion and synovial thickness (mm) from four locations, and the summed MRI effusion/synovitis (semi-quantitatively; 0–3) from four locations. Logistic and linear regression analyses were used to assess differences in dichotomous and continues outcomes, respectively. Analyses were adjusted for pain stratum. Results: Baseline characteristics are shown in Table 1. The proportion of responders over time is shown in Figure 1. After 3 months, in hand OA, there were 8 (29%) responders in the experimental group and 10 (36%) in the sham group (OR 0.69; 95%CI 0.22–2.17). In knee OA, there were 12 (44%) responders in the experimental group and 12 (43%) in the sham group (OR 1.09; 95%CI 0.37–3.19). In both hand and knee OA, no significant changes in clinical outcomes and inflammatory aspects were observed in both the experimental and sham group. Conclusions: We were unable to demonstrate a beneficial effect of LD-RT on pain and functioning in patients with hand or knee OA, nor on the underlying inflammatory OA processes. In light of absence of other high-level evidence, we advise against the use LD-RT as treatment for hand and knee OA. Dutch Trial Register: NTR4574Table 1Baseline characteristicsHandOAKnee OAExperimental (n = 28)Sham (n = 28)Experimental (n = 27)Sham (n = 28)Male/Female, n4/248/2012/1515/13Age (years)67(1)62(12)62 (9)68 (9)BMI (kg/m2)26 [24–27]29 [26–31]29 [25–30]26 [24–31]Symptom duration, <5 years, yes/no, n19/915/1316/1114/14Pain(0–100)#54(19)56(15)41(14)39(17)Functioning (0–100)#55(25)59(16)40(17)38(19)NRS pain (0–10)6.1(1.9)6.3(1.5)5.8(1.6)5.4(1.6)NRS stiffness(0–10)6.2(2.0)6.3(1.8)5.9(1.5)4.6(2.6)NRS PGA(0–10)5.3(2.2)5.9(1.7)5.6(2.2)4.6(2.3)ESR over upper limit yes/no, n5/235/2310/174/24CRP over upper limit yes/no, n3/259/195/227/21US effusion joint count (0–18), n6 [5–8]5 [3–8]NANAUS synovial thickening joint count (0–18), n3 [1–4]1 [1–3]NANAUS power Doppler signal joint count (0–18), n1 [0–2.5]1 [0–3]NANAUS effusion thickness (mm)NANA6 [4–8]5 [4–7]US synovial thickness (mm)NANA2 [1–3]2 [1–31]MRI effusion/synovitis (0–12)NANA5 [3–8]4 [2–7]Values are shown as mean (sd)or median [25%-75%]; lower scores indicate better health status; #: for hand OA the Australian/Canadian hand osteoarthritis index (AUSCAN) is used, for knee OA the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) is used; NRS: numeric rating scale; PGA: patient global assessment; ESR: erythrocyte sedimentation rate; CRP: C-reactive protein; US: ultrasound; MRI: magnetic resonance imaging; NA: not assessed. Open table in a new tab Values are shown as mean (sd)or median [25%-75%]; lower scores indicate better health status; #: for hand OA the Australian/Canadian hand osteoarthritis index (AUSCAN) is used, for knee OA the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) is used; NRS: numeric rating scale; PGA: patient global assessment; ESR: erythrocyte sedimentation rate; CRP: C-reactive protein; US: ultrasound; MRI: magnetic resonance imaging; NA: not assessed.