Low-Dose Radiotherapy for Painful Knee Osteoarthritis

Low-dose radiotherapy (LDRT) has been used in several European countries for painful degenerative musculoskeletal disorders, including knee osteoarthritis. Clinical studies have reported improvements in pain and function after LDRT, although findings from controlled trials have been heterogeneous and uncertainty remains regarding the magnitude of the treatment-specific effect. This study is designed to prospectively characterize clinical changes following a standardized LDRT regimen in patients with painful primary knee osteoarthritis treated across multiple centers.

This is a prospective, multicenter, interdisciplinary, open-label, non-randomized, single-group interventional study. A total of 283 participants aged 60 years or older with symptomatic primary knee osteoarthritis will be enrolled. Each participant will contribute one index knee; in participants with bilateral knee osteoarthritis, the more painful knee will be designated as the index knee.

All participants will receive one continuous course of LDRT consisting of six fractions of 0.5 Gy, for a total dose of 3.0 Gy. Fractions will be administered twice weekly on nonconsecutive days over approximately 3 weeks. Treatment will be planned using computed tomography and delivered using a standardized technique across participating centers. No second protocol-scheduled radiotherapy course will be administered before completion of the Day 90 assessment.

Participants will be evaluated before treatment and at approximately 45 and 90 days after the last radiotherapy fraction. The primary analysis will assess the change from baseline to Day 90 in average pain intensity in the index knee during the previous 7 days, measured using an 11-point Numerical Rating Scale. Additional assessments will evaluate pain, stiffness, physical function, health-related quality of life, global patient assessment, clinically relevant pain response, analgesic treatment, co-interventions, treatment adherence, and adverse events.

Because the study has no concurrent control or sham-treatment group, observed changes after treatment cannot be attributed exclusively to radiotherapy. The study is intended to estimate within-participant longitudinal changes after a standardized LDRT intervention and to describe clinical response and safety in routine multicenter practice. Potential contributions from the natural course of osteoarthritis, regression to the mean, participant expectations, and concomitant treatments will be considered when interpreting the results.

• Low-Dose Radiotherapy (LDRT) (Radiation): Low-dose radiotherapy will be delivered to the index knee as six fractions of 0.5 Gy each, for a total prescribed dose of 3.0 Gy. Fractions will be administered twice weekly on nonconsecutive days over approximately 3 weeks. Treatment will be planned using computed tomography simulation. The clinical target volume will include the relevant femoral and tibial articular and subchondral surfaces, joint capsule, synovium, and periarticular tissues. A nominal 5-mm planning target volume margin will be applied. Treatment will be delivered using opposed anteroposterior and posteroanterior fields with 6-MV photons.

Primary outcomes

• Change From Baseline in Average Index-Knee Pain Intensity at Day 90 [Baseline and Day 90 (90 ± 14 days after the last radiotherapy fraction)]: Average pain intensity in the index knee during the previous 7 days will be assessed using an 11-point Numerical Rating Scale (NRS) ranging from 0 (no pain) to 10 (worst imaginable pain). Change will be calculated as baseline NRS minus Day 90 NRS. Positive values indicate improvement, zero indicates no change, and negative values indicate worsening.

Secondary outcomes

• Change From Baseline in Average Index-Knee Pain Intensity at Day 45 [Baseline and Day 45 (45 ± 7 days after the last radiotherapy fraction)]: Average pain intensity in the index knee during the previous 7 days will be assessed using an 11-point Numerical Rating Scale (NRS) ranging from 0 (no pain) to 10 (worst imaginable pain). Change will be calculated as baseline NRS minus Day 45 NRS. Positive values indicate improvement, zero indicates no change, and negative values indicate worsening.
• Change From Baseline in WOMAC Pain Subscale Score [Baseline, Day 45 (45 ± 7 days after the last radiotherapy fraction), and Day 90 (90 ± 14 days after the last radiotherapy fraction)]: The WOMAC pain subscale consists of 5 items, each scored from 0 to 4, yielding a total score from 0 to 20. Higher scores indicate greater pain. Change from baseline will be assessed at Day 45 and Day 90.
• Change From Baseline in WOMAC Stiffness Subscale Score [Baseline, Day 45 (45 ± 7 days after the last radiotherapy fraction), and Day 90 (90 ± 14 days after the last radiotherapy fraction)]: The WOMAC stiffness subscale consists of 2 items, each scored from 0 to 4, yielding a total score from 0 to 8. Higher scores indicate greater stiffness. Change from baseline will be assessed at Day 45 and Day 90.
• Change From Baseline in WOMAC Physical Function Subscale Score [Baseline, Day 45 (45 ± 7 days after the last radiotherapy fraction), and Day 90 (90 ± 14 days after the last radiotherapy fraction)]: The WOMAC physical function subscale consists of 17 items, each scored from 0 to 4, yielding a total score from 0 to 68. Higher scores indicate greater functional limitation. Change from baseline will be assessed at Day 45 and Day 90.
• Change From Baseline in KOOS-PS Score [Baseline, Day 45 (45 ± 7 days after the last radiotherapy fraction), and Day 90 (90 ± 14 days after the last radiotherapy fraction)]: The 7-item Knee injury and Osteoarthritis Outcome Score-Physical Function Shortform (KOOS-PS) will be used to assess physical function. The raw score will be transformed to a 0-to-100 Rasch-based score, where 0 indicates no difficulty and 100 indicates extreme difficulty. Change from baseline will be assessed at Day 45 and Day 90.
• Change From Baseline in EQ-5D-3L Health Utility Index [Baseline, Day 45 (45 ± 7 days after the last radiotherapy fraction), and Day 90 (90 ± 14 days after the last radiotherapy fraction)]: Health-related quality of life will be assessed using the Spanish EQ-5D-3L. The health utility index will be calculated from the five dimensions using the Spanish value set. Higher index values indicate better health status. Change from baseline will be assessed at Day 45 and Day 90.
• Change From Baseline in EQ VAS Score [Baseline, Day 45 (45 ± 7 days after the last radiotherapy fraction), and Day 90 (90 ± 14 days after the last radiotherapy fraction)]: Overall health status will be assessed using the EQ Visual Analogue Scale (EQ VAS), ranging from 0 to 100, where 0 represents the worst imaginable health state and 100 represents the best imaginable health state. Change from baseline will be assessed at Day 45 and Day 90.
• Change From Baseline in Patient Global Assessment of the Index Knee [Baseline, Day 45 (45 ± 7 days after the last radiotherapy fraction), and Day 90 (90 ± 14 days after the last radiotherapy fraction)]: Patient Global Assessment (PGA) will evaluate the overall impact of index-knee osteoarthritis during the previous 7 days using a 0-to-100 scale. Participants will answer: "Considering all the ways in which the osteoarthritis of your index knee affects you, how would you rate your knee during the past 7 days?" A score of 0 indicates very well/no impact and 100 indicates very poorly/maximum impact. Change from baseline will be assessed at Day 45 and Day 90.
• Proportion of Participants With at Least a 30% Reduction in NRS Pain Intensity [Day 45 (45 ± 7 days after the last radiotherapy fraction) and Day 90 (90 ± 14 days after the last radiotherapy fraction)]: A pain responder will be defined as a participant with at least a 30% reduction from baseline in average index-knee pain intensity measured using the 0-to-10 Numerical Rating Scale (NRS). Percentage reduction will be calculated as \[(baseline NRS - follow-up NRS) / baseline NRS\] × 100. The proportion of participants meeting this criterion will be assessed at Day 45 and Day 90.
• Proportion of Participants With at Least a 50% Reduction in NRS Pain Intensity [Day 45 (45 ± 7 days after the last radiotherapy fraction) and Day 90 (90 ± 14 days after the last radiotherapy fraction)]: A pain responder will be defined as a participant with at least a 50% reduction from baseline in average index-knee pain intensity measured using the 0-to-10 Numerical Rating Scale (NRS). Percentage reduction will be calculated as \[(baseline NRS - follow-up NRS) / baseline NRS\] × 100. The proportion of participants meeting this criterion will be assessed at Day 45 and Day 90.
• Proportion of Participants Meeting OMERACT-OARSI Responder Criteria [Day 45 (45 ± 7 days after the last radiotherapy fraction) and Day 90 (90 ± 14 days after the last radiotherapy fraction)]: Participants will be classified as OMERACT-OARSI responders if they meet either of the following criteria: (1) high improvement in pain or physical function, defined as an improvement of at least 50% and an absolute improvement of at least 20 points on a 0-to-100 scale; or (2) improvement in at least 2 of 3 domains-pain, physical function, and Patient Global Assessment-defined as an improvement of at least 20% and an absolute improvement of at least 10 points on a 0-to-100 scale. The proportion of responders will be assessed at Day 45 and Day 90.
• Participants With Changes in Analgesic Treatment or Rescue Medication Use [From baseline through Day 90 (90 ± 14 days after the last radiotherapy fraction)]: Changes in analgesic treatment for index-knee osteoarthritis will be recorded throughout follow-up, including initiation, discontinuation, or dose modification of analgesic medication and use of rescue medication. The proportion of participants with at least one change in analgesic treatment or rescue medication use will be summarized through Day 90.
• Participants Receiving an Index-Knee Co-intervention During Follow-up [From baseline through Day 90 (90 ± 14 days after the last radiotherapy fraction)]: Index-knee co-interventions during follow-up will be recorded, including intra-articular corticosteroid or hyaluronic acid injections, radiofrequency procedures, other interventional procedures, or surgery. The proportion of participants receiving at least one such co-intervention will be summarized through Day 90.
• Proportion of Participants Completing the Planned Radiotherapy Course [From the first radiotherapy fraction through completion of the planned course (approximately 3 weeks)]: Treatment completion will be defined as receipt of all six planned radiotherapy fractions of 0.5 Gy each, corresponding to a total prescribed dose of 3.0 Gy to the index knee. The proportion of participants completing the planned radiotherapy course will be summarized.
• Incidence and Severity of Adverse Events [From the first radiotherapy fraction through Day 90 (90 ± 14 days after the last radiotherapy fraction)]: Adverse events occurring from the first radiotherapy fraction through Day 90 will be recorded and graded according to the Common Terminology Criteria for Adverse Events (CTCAE), version 5.0. For each event, the event term, severity grade, onset and resolution dates, relationship to radiotherapy, actions taken, treatment required, and outcome will be documented. The incidence and severity of adverse events will be summarized.

Sex: All, ages: 60 Years to any

Inclusion Criteria:

* Age 60 years or older.
* Clinical and radiographic diagnosis of primary knee osteoarthritis.
* Kellgren-Lawrence grade II or III osteoarthritis in the index knee.
* Pain in the index knee for at least 6 months.
* Baseline average index-knee pain intensity greater than 4 on a 0-to-10
* Numerical Rating Scale (NRS), referring to the previous 7 days.
* Persistent clinically relevant knee pain despite documented prior conservative management. Conservative management must include pharmacological treatment appropriate to the participant's clinical profile and therapeutic exercise and/or physiotherapy. If any of these measures were not undertaken because of contraindication, intolerance, or clinical inability, the reason must be documented.
* Radiograph of the index knee performed within 6 months before inclusion and adequate to confirm the diagnosis and Kellgren-Lawrence grade. A new radiograph will be obtained if no valid recent examination is available.
* Ability to understand the study procedures and reliably complete the required clinical assessments and questionnaires.
* Written informed consent to participate in the study.

Exclusion Criteria:

* Kellgren-Lawrence grade 0, I, or IV in the index knee.
* Knee prosthesis in the index knee.
* Previous radiotherapy involving the treatment region.
* Body mass index greater than 39 kg/m².
* Active connective tissue disease with clinically relevant skin or soft-tissue involvement in the treatment region, including active systemic lupus erythematosus or rheumatoid arthritis when considered clinically relevant for radiotherapy.
* Fibromyalgia or a psychiatric disorder that, in the investigator's judgment, would substantially compromise reliable assessment of pain or patient-reported outcomes.
* Inability to provide informed consent or to reliably complete the required study assessments.
* Intra-articular corticosteroid injection, intra-articular hyaluronic acid injection, or radiofrequency procedure involving the index knee within the 2 months before inclusion.

• Muller JA, Alsalloum J, Vordermark D, Delank S. KORT - Knee osteoarthrosis radiotherapy trial: Protocol for a multidisciplinary pathway and a planned sham-controlled phase III trial of low-dose radiotherapy in knee osteoarthritis. Osteoarthr Cartil Open. 2026 Feb 27;8(2):100764. doi: 10.1016/j.ocarto.2026.100764. eCollection 2026 Jun. PMID 41859527
• Fazilat-Panah D, Javadinia SA, Shabestani Monfared A, Attarian F, Babaei M, Yousefghahari B, Najafzadeh Sadati S, Ahmadi N, Fallah Tafti H. Effects of low dose rate radiotherapy on pain relief, performance score, and quality of life in patients with knee osteoarthritis; a double-blind sham-controlled randomized clinical trial. Int J Radiat Biol. 2025;101(5):541-548. doi: 10.1080/09553002.2025.2473975. Epub 2025 Mar 5. PMID 40043233
• Kim BH, Shin K, Kim MJ, Kim HJ, Ro DH, Wang JH, Lee DH, Kim DH, Sun J, Lee JH, Kim JY, Hong EH, Cho SJ, Han HS, Park W. Low-dose RaDiation therapy for patients with KNee osteoArthritis (LoRD-KNeA): a protocol for a sham-controlled randomised trial. BMJ Open. 2023 Feb 10;13(2):e069691. doi: 10.1136/bmjopen-2022-069691. PMID 36764712
• Mahler EAM, Minten MJ, Leseman-Hoogenboom MM, Poortmans PMP, Leer JWH, Boks SS, van den Hoogen FHJ, den Broeder AA, van den Ende CHM. Effectiveness of low-dose radiation therapy on symptoms in patients with knee osteoarthritis: a randomised, double-blinded, sham-controlled trial. Ann Rheum Dis. 2019 Jan;78(1):83-90. doi: 10.1136/annrheumdis-2018-214104. Epub 2018 Oct 26. PMID 30366945
• Niewald M, Muller LN, Hautmann MG, Dzierma Y, Melchior P, Graber S, Rube C, Fleckenstein J; working group "Benign diseases" of the DEGRO (German Society for Radiation Oncology). ArthroRad trial: multicentric prospective and randomized single-blinded trial on the effect of low-dose radiotherapy for painful osteoarthritis depending on the dose-results after 3 months' follow-up. Strahlenther Onkol. 2022 Apr;198(4):370-377. doi: 10.1007/s00066-021-01866-2. Epub 2021 Nov 1. PMID 34724085

• Enrique Barrós, MD, MSc, Study director, Universidad Rey Juan Carlos