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Symptomatic (Pain and Inflammation) and Disease-Modifying Effect (Minimal Joint Space) of Intra-articular Ozone (O2-O3) in Osteoarthritis of the Knee: a Clinical Case

  • Marcos Edgar Fernández-CuadrosEmail author
  • Olga Susana Pérez-Moro
  • María Jesús Albaladejo-Florín
  • Sandra Álava-Rabasa
Medicine
  • 51 Downloads
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Abstract

The objective of the clinical case is to report the symptomatic effect and, for the first time, the disease-modifying effect of ozone in a patient with osteoarthritis of the knee. A 67-year-old woman has been infiltrated with ozone 1 time/week for 4 weeks, using an oxygen-ozone volume of 20 ml, at a 20-µg/ml concentration. Another cycle of ozone treatment was boosted at 6 months follow-up. Clinical outcomes such as pain, function, and quality of life were measured by the Western Ontario and McMaster University Index for Osteoarthritis (WOMAC) scale. Biochemical markers of inflammation such as C-reactive protein (CRP), erythrocyte sedimentation rate (ESR), and uric acid were performed at the beginning and at the end of ozone (O2-O3) treatment protocol. Radiological outcome was evaluated as the change in minimal joint space at the medial compartment of joint space, at the beginning and at 12 months follow-up in both knees. In the first and second ozone cycles, clinical (pain, function, rigidity) and biochemical variables (CRP, ESR, uric acid) improved in our case report. Minimal joint space at medial compartment improved in both knees after 12 months follow-up. Intra-articular ozone (O2-O3) has shown a symptomatic effect and especially a disease-modifying effect in a patient with knee osteoarthritis, improving pain, function, and rigidity; decreasing inflammation biomarkers (CRP, ESR, and uric acid); and increasing the joint space of the medial component evidenced radiologically. The structural effect is reported for the first time in literature. No adverse effects have been observed after intra-articular ozone infiltrations.

Keywords

Knee osteoarthritis Biomarkers Ozone therapy Pain 

Introduction

Osteoarthritis is the most prevalent joint disease. It affects almost 4 million people and originates 50% of the total disabilities in Spain. Arthrosis affects the quality of life (QoL) of the people who suffer from it, in the physical, emotional, and social aspects. The economic impact is such that the direct cost of osteoarthritis in Spain is 4738 million euros/year and represents 0.5% of the gross domestic product [1].

Osteoarthritis has no cure and its etiology is multifactorial. The treatment objectives in the short term are to improve pain, function, and quality of life, and in the long term, it is to delay/reverse joint destruction. Conservative treatment includes hygienic dietary measures, analgesics, NSAIDs, chondroitin sulfate/glucosamine, and infiltrations (corticosteroids, hyaluronic acid, PRP). The definitive surgical treatment includes total replacement arthroplasty, which has a success rate of 95% at 10 years, although this technique is not free of risks and complications [2]. Controversy exists regarding the symptomatic and disease-modifying effect of conservative treatments, such as chondroitin sulfate/glucosamine [3, 4].

Risk factors for osteoarthritis include obesity, trauma, biomechanical factors, and chronic inflammation [1, 5]. Several studies and years of experience have shown that ozone (O2-O3) is able to modulate inflammation and pain in patients with osteoarthritis of the knee [5]. In addition, ozone (O2-O3) has anabolic effects that could modify the natural history of the disease in patients with osteoarthritis of the knee [5].

For the management of knee osteoarthritis, it is necessary to use biomarkers for the diagnosis, monitoring, and progression of the disease. These biomarkers should evaluate clinical (pain, stiffness, function), biochemical (C-reactive protein, erythrocyte sedimentation rate, uric acid, interleukins), and radiological (minimal femorotibial joint space) results [6, 7].

Nowadays, there are no studies reported in the literature that demonstrate that ozone (O2-O3) has a structural effect on osteoarthritis of the knee [1, 5], although it has proven its effect on the symptoms of osteoarthritis, whether pain or inflammation [6, 7, 8].

The aim of the clinical case is to verify the symptomatic and disease-modifying effect of ozone (O2-O3) through clinical, biochemical, and radiological improvement in a patient with osteoarthritis of the knee.

Case Report

We present the clinical case of a South-American-origin 67-year-old woman. On medical history, she suffered hypertension controlled with captopril. On symptoms, the patient stated she presented 6 months ago bilateral knee pain, of mechanical type, with morning stiffness and difficulty climbing and descending stairs and slopes. This pain has been progressively increasing (graded 7/10 on visual analog scale), which has forced her to use analgesics (acetaminophen 1 g) as needed. The family doctor referred her to rehabilitation in her area, where the patient has performed bilateral quadricep strengthening, analgesic TENS (transcutaneous electrical nerve stimulation), and pulsed electromagnetic fields. The patient has been transferred to the Rehabilitation Service of Hospital Santa Cristina, because after 2 months of rehabilitation treatment, the patient denies any improvement. Summarizing, the interventions carried out before referral were conservative, including management of pain by analgesics (acetaminophen), physical exercises, TENS, and pulsed electromagnetic fields.

On physical examination, the patient presented pain in both medial compartments, crepitus at knee flexion, positive bilateral Zohlen maneuver, and preserved joint mobility. On radiological evaluation, radiography showed sclerosis and bilateral marginal osteophytes, with a decrease in the most marked medial space in the right knee compared with the left knee (Kellgren–Lawrence 3° grade in the right knee, Kellgren–Lawrence 2° grade in the left knee). Clinical signs and symptoms and radiological evaluation confirmed bilateral knee osteoarthritis, as stated by the criteria of the ACR (American College of Rheumatology) and by Kellgren–Lawrence radiographic scale [7].

The intervention carried out consisted of intra-articular ozone (O2-O3) infiltrations 1 time/week for 4 weeks, 20 cc at a concentration of 20 μg/ml. The results of the intervention (after treatment) include patient reporting clinical improvement in terms of pain, function, and rigidity. In addition, CRP (C-reactive protein), ESR (erythrocyte sedimentation rate), and uric acid were requested as biomarkers of inflammation at the beginning and end of treatment (1 cycle), and those biomarkers also improved after ozone (O2-O3) intervention (Table 1).
Table 1

Evaluation of the clinical (pain, stiffness, and function), biochemical (CRP, ESR, uric acid), and radiological variables at the beginning and at the end of treatment cycles (ozone therapy)

Variable

Before

After

Cycle of treatment

Clinical

VAS (0–10)

7

3

First cycle

WOMAC pain (0–20)

14

6

First cycle

WOMAC rigidity (0–8)

4

2

First cycle

WOMAC function (0–68)

50

28

First cycle

Biochemical

CRP (mg/ml)

0.3

0.2

First cycle

ESR (mm/h)

18

9

First cycle

Uric acid (mg/ml)

6.8

5.9

First cycle

Clinical

VAS (0–10)

9

6

Second cycle

WOMAC pain (0–20)

18

12

Second cycle

WOMAC rigidity (0–8)

4

40

Second cycle

WOMAC function (0–68)

50

0.2

Second cycle

Biochemical

CRP (mg/ml)

0.3

0.2

Second cycle

ESR (mm/h)

17

10

Second cycle

Uric acid (mg/ml)

6

5.8

Second cycle

Radiological

Medial compartment right knee (mm)

2.9

4.6

12 months follow-up

Medial compartment left knee (mm)

3.4

4.0

12 months follow-up

VAS visual analog scale, WOMAC Western Ontario and McMaster Index for Osteoarthritis, CRP C-reactive protein, ESR erythrocyte sedimentation rate

Six months after the treatment, the patient was reviewed, and she reported clinical worsening, so it was decided to restart the second treatment cycle; after which, clinical and laboratory improvement was again observed (Table 1).

A second revision was made at 6 months of the second cycle, which corresponded to 12 months since the beginning of the first infiltration, and the patient reported maintaining clinical improvement. An anterior–posterior radiograph of the knees was then requested bilaterally, which showed an increase in the minimum joint space in the medial compartment, in both knees (Table 1, Figs. 1 and 2), confirming that ozone (O2-O3) has produced an structural change on both degenerated knees.
Fig. 1

X-ray of the right knee at the beginning and end of treatment (12 months of follow-up) shows improvement in the medial compartment (0.29 to 0.46 mm). An anabolic structural change in medial compartment has been observed after ozone (O2-O3) intervention

Fig. 2

X-ray of the left knee at the beginning and end of treatment (12 months of follow-up) shows improvement in the medial compartment (0.34 to 0.40 mm). An anabolic structural change in medial compartment has been observed after ozone (O2-O3) intervention

After second cycle of treatment, the patient was discharged, due to clinical, biochemical, and radiological improvement; however, it will be reviewed every 6 months, to assess the repetition of ozone infiltrations (O2-O3), if necessary.

On tolerability and side effect analysis, no adverse effects have been reported in the patient, except for an occasional episode of pain during the infiltration, pain that disappeared between 10 and 15 min.

Discussion

The clinical case has demonstrated the effectiveness of ozone (O2-O3) in osteoarthritis of the knee, modifying for the first time clinical, biochemical, and radiological biomarkers. This clinical case confirms the symptomatic and disease-modifying effect of intra-articular ozone therapy in a patient with knee osteoarthritis.

For the first time, the structural change of ozone (O2-O3) on knee osteoarthritis was confirmed radiologically, which would have a direct implication on the management of knee osteoarthritis and demonstrates that ozone (O2-O3) could modify the progression of the natural history of the disease.

Osteoarthritis of the knee is the most common cause of pain and disability in Western societies, as in Spain [2]. It is so prevalent that 50% of people between 60 and 75 years have some radiological sign, and 80% of people over 80 have clinical and radiological signs [1, 2].

Osteoarthritis commonly affects middle-aged people. In younger groups, it affects both sexes equally, but after 50 years more women are affected, as it was in our clinical case (67-year-old woman) [1, 2, 5].

The healthy knee is composed of articular cartilage, subchondral bone, synovial tissue, and joint capsule. In osteoarthritis of the knee, there is destruction of the articular cartilage with narrowing of the joint space, sclerosis of subchondral bone, and formation of osteophytes and subchondral cysts [1, 2, 5] as in our clinical case.

Today there is no treatment for osteoarthritis, so the management objectives are to reduce symptoms (pain, stiffness, dysfunction) and to decrease/slow down joint wear and tear [1, 2]. This fact has great scientific relevance, because it demonstrates for the first time that ozone (O2-O3) has a symptomatic and disease-modifying effect (as has been clearly demonstrated in this clinical case) which could modify the paradigm of treatment for the management of knee osteoarthritis.

Recently, osteoarthritis has been associated with low-grade chronic inflammation, as it is believed that chronic oxidative damage is involved in the changes and progression of knee osteoarthritis. According to authors such as Atias et al., Weinstein et al., and Borreli et al., chronic oxidative stress plays such an important role in osteoarthritis of the knee, and the future of treatment will depend on the suppression of oxidative damage without damaging the antioxidant defense mechanisms of the organism [2]. In this sense, it would be of great therapeutic value to act on the modulation and regulation of inflammation to reduce the progression of osteoarthritis. In addition, the future treatment of osteoarthritis should aim to reduce cartilage destruction and promote joint repair. Therefore, the main objective in the management of osteoarthritis should be to act on a large number of proinflammatory cytokines produced in the affected joint [2].

In a recent literature review, Fernández-Cuadros et al. stated that ozone (O2-O3) is able to modulate inflammation, acting on various inflammatory biomarkers, inhibiting proinflammatory cytokines, MMPS (minerometaloproteases), NO (nitric oxide), PgE2 (prostaglandin E2), and stimulating anti-inflammatory cytokines [1, 2]. In addition, Fernández-Cuadros has also reported that ozone (O2-O3) is capable of stimulating growth factors (TGF-1, IGF-1), chondrocytes, and stem cells [1, 2]. For these reasons, we believe that ozone (O2-O3) has a place in the management of osteoarthritis of the knee, which has been demonstrated in the presentation of the case report.

In our case report, ozone (O2-O3) has been able to reduce pain and stiffness, in addition to improving function and quality of life, evidenced by an improvement in the clinical scales VAS (visual analog scale) and WOMAC (Western Ontario and McMaster University Index for Osteoarthritis), with a duration of effect of 6 months. These results agree with what was previously reported by our study group [8]. The symptomatic effect of ozone (O2-O3) on knee osteoarthritis is demonstrated in our clinical case and endorsed by the clinical study of Fernández-Cuadros et al. [8].

In the patient of our study, ozone (O2-O3) has been able to decrease inflammatory markers such as CRP (from 0.3 to 0.2 mg%), ESR (from 18 to 9 mm/h), and uric acid (from 6.8 to 5.9 mg%), confirming that ozone (O2-O3) is able to modulate inflammation in patients with knee osteoarthritis, decreasing these markers of inflammation. This finding is related to the article recently published by Fernández-Cuadros et al. [6, 7].

After 1 year of follow-up and two treatment cycles, ozone (O2-O3) has been able to increase the minimum joint space of the medial compartment of both knees, as has been observed radiologically (from 2.9 to 4.6 mm in the right knee and from 3.4 to 4 mm in the left knee), reversing knee osteoarthritis in our patient. This finding confirms the disease-modifying effect of ozone (O2-O3) on osteoarthritis of the knee, findings that coincide with what was recently reported by Fernández-Cuadros et al. [9]. For the first time, this case report shows that ozone (O2-O3) is a drug capable of producing structural (anabolic) changes in knee osteoarthritis.

The use of intra-articular ozone (O2-O3) has proven to be a safe treatment, without adverse effects and capable of objectively improving clinical, laboratory, and radiological biomarkers, as it has been in the case of our patient with bilateral knee osteoarthritis. Therefore, we agree with Arias-Vazquez et al. and Nori-Zadehh et al. who, in two recent systematic reviews and meta-analyzes, believe that ozone (O2-O3) should be considered as a therapeutic alternative for the management of knee osteoarthritis [10, 11].

For the first time in the literature, an effective treatment of osteoarthritis is presented, capable of modifying the natural history of the disease, producing structural changes in the knee (evidenced radiologically) and reducing pain and inflammation (as evidenced by clinical scales and laboratory studies).

Conclusion

Intra-articular ozone has shown a symptomatic effect and specially a disease-modifying effect in a patient with knee osteoarthritis, improving pain, function, and rigidity; decreasing inflammation biomarkers (CRP, ESR, and uric acid); and increasing the joint space of the medial component evidenced radiologically. The structural effect is reported for the first time in literature. No adverse effects have been observed after intra-articular ozone infiltrations. The data reported in this study should be further corroborated in research with experimental designs in order to demonstrate the anabolic effect of ozone.

Notes

Acknowledgments

Saturnino Díaz Trujillo (librarian at the Hospital Universitario Santa Cristina) is acknowledged for the bibliographic search for the realization of this study. The assistants Aurelia Gómez Sierra and María del Carmen de la Riva Molina are also acknowledged for the logistical support on the realization of this study.

Compliance with Ethical Standards

Conflict of Interest

The authors declare that they have no conflict of interest.

Ethical Approval

The case report has been approved by the Ethical Committee of the Hospital.

Informed Consent

For the application of this treatment and publication of the case report, the patient signed an informed consent.

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© Springer Nature Switzerland AG 2019

Authors and Affiliations

  1. 1.Servicio de Medicina Física y RehabilitaciónHospital Universitario Santa CristinaMadridSpain

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