Effect of repeated intra-articular administration of collagen as a treatment for knee osteoarthritis: a case report

Abstract

Intra-articular injections aimed at correcting underlying pathophysiological processes and providing pain relief are essential for managing knee osteoarthritis (KOA). Collagen, the primary component of articular cartilage, has a long half-life, making it a promising candidate for intra-articular injections with a low risk of serious side effects. The first of the two cases in this report involved a woman in her early 70s with a 6-year history of persistent left knee pain. The second case involved a woman in her mid-50 s with a >7-year history of right knee pain. Both patients received hyaluronic acid injections every 6 months, totaling 10 injections over 5 years. They were diagnosed with Kellgren–Lawrence grade 2 KOA. The patients received two 3-mL intra-articular injections of 6% collagen, administered at baseline and 6 months later. Improvements in clinical outcomes, including visual analog scale scores and Western Ontario and McMaster Universities Osteoarthritis Index scores, were observed and maintained in both patients, with no side effects reported. In summary, when collagen injections were administered to these two patients with KOA, clinical improvements lasted approximately 6 months, and repeated treatments demonstrated efficacy and safety similar to the initial course.

Introduction

Osteoarthritis (OA) is a debilitating musculoskeletal disorder primarily characterized by the destruction of articular cartilage, leading to inflammation, severe pain, and functional limitations as the damage extends to the bones and ligaments of the affected joints. ¹ Degenerative knee OA (KOA) is increasingly prevalent with aging and is a growing global concern because of the aging of the population. It often manifests as a significant source of individual functional disability.^2,3 Among the various types of OA, KOA has the highest prevalence, with treatment options including non-pharmacological, pharmacological (oral medications and injections), and surgical interventions.^4–6 Among pharmacological interventions, the most commonly used intra-articular injections are corticosteroids and hyaluronic acid (HA). ⁷ HA injections, known for their lubricating properties, increase the viscosity of synovial fluid, enhancing lubrication and cushioning effects to reduce joint pain. Currently, a widely used treatment method for early-stage cartilage damage involves intra-articular injections of HA products.^8,9 HA products have anti-inflammatory and chondroprotective properties. ¹⁰ However, the long-term efficacy of HA is still debated, and there is a lack of solid evidence supporting its effectiveness. ¹¹ Even the most widely used intra-articular HA injections remain controversial in terms of their superiority over a placebo, leading the American Academy of Orthopedic Surgeons to not recommend their routine use. ¹²

Therefore, intra-articular injections that target the underlying pathophysiological processes while providing pain relief are necessary. ¹³ Collagen, the main component of articular cartilage, possesses a strong triple-helix structure and has a longer half-life than corticosteroids or HA, making it a promising alternative candidate for intra-articular injections with a lower risk of serious side effects.^14,15 The triple-helix structure and low antigenicity of atelocollagen ensure its biocompatibility and safety in medical applications. Therefore, it has been used in various fields of tissue reconstruction and medical treatment.^16,17 Collagen also plays a role in cartilage protection by replenishing the lamina splendens. ¹⁸ While several studies have reported the efficacy of collagen injections for KOA, there are few reports on the effectiveness and safety of repeat administrations.^13,19,20 Therefore, this case report aims to present the changes in patient-reported outcome measures (PROMs) and safety in two patients with KOA who received intra-articular collagen injections multiple times at 6-month intervals.

Case presentation

Patient 1

A woman in her early 70 s presented to the outpatient clinic with a 6-year history of persistent left knee pain. She was 151 cm tall, weighed 61 kg, and had a body mass index of 26.8 kg/m². The patient’s medical history included diabetes and high blood pressure, both of which were being managed with medication. She had been a homemaker for 40 years and maintained a regular walking routine of more than three times per week, walking for approximately 2 hours per session for >20 years. Clinical examination revealed medial joint line tenderness and a knee joint range of motion of 0 to 135 degrees. Knee X-ray imaging confirmed findings consistent with Kellgren–Lawrence (KL) grade 2 OA (Table 1). Radiological imaging of the knee demonstrated joint space narrowing, subchondral sclerosis, and osteophytes along the edge of the knee joint (Figure 1).

Table 1.

Patients’ characteristics in both cases.

	Patient 1	Patient 2
Age, years	Early 70s	Mid-50 s
Sex	Female	Female
Body mass index, kg/m2	26.8	23.6
Underlying disease	Diabetes and hypertension	Hypertension
Duration of knee pain	6 years	7 years
Kellgren–Lawrence grade	Grade 2	Grade 2
WOMAC baseline scores
Pain	10	8
Stiffness	4	5
Function	22	18

WOMAC, Western Ontario and McMaster Universities Arthritis Index.

Figure 1.

Radiological imaging of the knee demonstrating joint space narrowing, subchondral sclerosis, and osteophytes along the edge of the knee joint.

The patient received intra-articular injections of atelocollagen (CartiZol; Sewon Cellontech, Seoul, Korea) at baseline and again at 6 months. Each injection had a volume of 3 mL and contained 180 mg of 6% atelocollagen. Prior to the intervention, the patient’s visual analog scale (VAS) scores were assessed using a Likert scale ranging from 0 to 10, with a resting VAS score of 3, a walking VAS score of 5, and a nighttime VAS score of 3. The Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) scores, a validated and reliable disease-specific questionnaire for KOA, were also evaluated. The score ranges for each item are 0 to 20 for pain, 0 to 8 for stiffness, 0 to 68 for function, and 0 to 96 for the total score. The patient’s initial WOMAC scores were 10 for pain, 4 for stiffness, 22 for function, and 36 for the total score.

At the 6-month follow-up, the patient’s VAS scores improved to a resting score of 1, walking score of 2, and nighttime score of 1. Her WOMAC scores also improved to 5 for pain, 2 for stiffness, 16 for function, and 23 for the total score. A second collagen injection was administered at the 6-month time point. Upon subsequent evaluation 6 months after the second injection, the patient’s VAS scores were 0 during resting, 2 while walking, and 1 at nighttime. Her WOMAC scores were 4 for pain, 3 for stiffness, 17 for function, and 24 for the total score (Table 2). The patient reported mild discomfort in the knee for 3 to 4 days after the initial injection, followed by symptom improvement. No signs of knee swelling or infection were observed during the 1-year observation period. The patient received no additional treatments, including physical therapy or therapeutic exercises, during the follow-up period.

Table 2.

VAS and WOMAC scores.

	VAS Resting	VAS Walking	VAS Nighttime	WOMAC Total	WOMAC Pain	WOMAC Stiffness	WOMAC Function
Patient 1
Baseline	3	5	3	36	10	4	22
6 months	1	2	1	23	5	2	16
12 months	0	2	1	24	4	3	17
Patient 2
Baseline	1	6	2	31	8	5	18
6 months	1	3	0	19	4	1	14
12 months	0	3	0	21	4	2	15

VAS, visual analog scale; WOMAC, Western Ontario and McMaster Universities Arthritis Index.

Patient 2

A woman in her mid-50 s presented with right knee pain persisting for more than 7 years. She worked as a department store counter clerk, engaging in activities that required standing for >10 hours a day for >10 years. Additionally, she participated in recreational activities, specifically hiking, approximately once every 2 weeks for >15 years. The patient had a history of hypertension and exhibited medial joint line tenderness. Her knee joint range of motion was 0 to 130 degrees, with pain worsening upon extensive knee flexion and a clicking sound noted during joint movement. The patient had previously received HA injections every 6 months, totaling 10 injections over 5 years. While initially effective, the HA injections provided diminishing relief after 3 years.

Radiographic examination revealed findings consistent with KL grade 2 KOA, including subchondral sclerosis, bony spurs, and a suspected loss of medial knee joint space (Figure 2). The patient received two administrations of 3-mL intra-articular injections of 6% atelocollagen at 6-month intervals. At baseline, she had a VAS score of 1 at rest, 6 while walking, and 2 at nighttime, while her WOMAC scores were 8 for pain, 5 for stiffness, 18 for function, and 31 for the total score (Table 1).

Figure 2.

Radiographic examination revealed findings consistent with Kellgren–Lawrence grade 2 osteoarthritis with subchondral sclerosis, bony spurs, and suspected loss of the medial knee joint space.

At the 6-month follow-up post-collagen injection, her VAS scores were 1 at rest, 3 while walking, and 0 at nighttime, with her WOMAC scores improving to 4 for pain, 1 for stiffness, 14 for function, and 19 for the total score. A second collagen injection was administered 6 months after the first. Six months later, her VAS scores were 0 at rest, 3 while walking, and 0 at nighttime, with WOMAC scores of 4 for pain, 2 for stiffness, 15 for function, and 21 for the total score (Table 2).

The patient reported experiencing pain with a heavy sensation in the knee for 5 days following the initial injection, but no swelling was observed. After 5 days, the pain resolved, and her overall knee symptoms improved. Following the second injection, the patient experienced pain for 3 days, which gradually resolved, with improved knee symptoms being well-maintained. No side effects or complications, including knee joint infection, were observed during the 1-year observation period. During the follow-up period, no supplementary treatments, such as physical therapy or therapeutic exercises, were administered.

Written informed consent for all treatments was obtained from the patients. This study did not require ethics committee approval because it did not involve animal or human clinical trials. Informed consent for publication was not applicable because all patient details were de-identified. The reporting of this study conforms to the CARE guidelines. ²¹

Discussion

In this case report, collagen injections were administered twice at 6-month intervals to two patients with KOA experiencing knee joint pain. The patients were followed for 1 year, during which improvements in PROMs, including VAS and WOMAC scores, were confirmed in both patients. Additionally, no side effects were observed.

The demand for intra-articular injections remains high, and HA injections are frequently used in treatment. ²² However, among KOA treatments, the safety of repeated applications has only been well-established for HA injections. ²³ Clinical studies using HA injections have shown that adverse reactions do not increase with repeated administration. By contrast, corticosteroid injections should be used cautiously because of their potential to cause cartilage damage with repeated use. ¹² Therefore, a treatment option that meets the high demand for intra-articular injections and is safe for repeated use is needed. Type 1 atelocollagen developed for this purpose offers several advantages.^13,19,20 The lamina splendens is a protective layer of cartilage that provides lubrication to joint surfaces by maintaining osmotic pressure and reducing frictional resistance. ²⁴ When this layer of articular cartilage is damaged, cartilage wear accelerates, and shear resistance decreases. ²⁵ Atelocollagen supplementation from the outside coats the damaged lamina splendens and can contribute to articular cartilage regeneration by participating in tissue structure organization, guided tissue regeneration, cell vitalization, and growth factor release. ¹⁸

Several studies have compared the effects of collagen injections to HA. Furuzawa-Carballeda et al. ¹⁹ compared the clinical efficacy of multiple injections of polymerized collagen and HA. After 6 months, the collagen group exhibited significantly greater improvement in VAS scores than the HA group. Another study assessed the clinical efficacy of intra-articular collagen injections of porcine origin compared with HA, revealing significant improvements in the collagen group’s VAS scores from baseline after 6 months, although no significant difference was noted between the collagen and HA treatment groups. ²⁰ In a study by Lee et al. ¹³ involving 200 patients with KL grade ≤3 KOA, 101 patients received collagen injections and 99 received a saline control in a double-blind, randomized, controlled clinical trial. After 24 weeks, the collagen injection group exhibited statistically superior improvements in VAS pain scores compared with the control group. Improvements in the WOMAC and 36-item Short-Form Health Survey scores after 24 weeks of collagen injections also confirmed the enhanced effects. Regarding safety, there were no significant differences in adverse events between the test and control groups, and the adverse events in the test group were not directly related to the collagen injections. This suggests that collagen injections can be a viable alternative in knee intra-articular injections and are actively used in clinical settings.^13,19,20 A review by Tarantino et al. ²⁶ indicated intra-articular administration of collagen could be a viable therapeutic option for KOA. The use of type I collagen as an intra-articular treatment for KOA was shown to be both effective and safe, with minimal side effects. ²⁶ In the present study, patients who received collagen injections experienced clinical improvements, and their conditions remained stable during the follow-up period.

Although previous clinical studies have confirmed the effectiveness of a single 3-mL injection of collagen lasting 6 months, ¹³ there is a lack of domestic and international research on the safety and efficacy of repeated injections. The findings from the present cases suggest that repeated collagen injections may provide sustained relief from pain and improvement in function without significant safety concerns. These cases contribute to the growing body of evidence supporting the use of collagen for managing KOA.

Conclusion

Collagen injections administered to patients with KOA led to improvements in clinical factors for approximately 6 months, and repeated treatments (second courses) demonstrated efficacy and safety similar to those of the initial course. When collagen injections were administered, improvements in clinical symptoms lasted for up to 6 months, indicating that a 6-month interval is appropriate for repeat treatment. This technique is considered a viable intra-articular injection option for repeated use in clinical practice because it can be administered safely without any adverse reactions.