The coronavirus disease pandemic has left a significant effect on global health, with a growing number of patients experiencing long-term complications even after recovering from the acute infection [1]. One of the less recognized but serious complications is osteonecrosis of the hip, which has been increasingly reported in post-COVID-19 patients [2].

Osteonecrosis, similarly defined as avascular necrosis, occurs due to the disruption of blood supply to the bone, leading to the death of bone tissue and, consequently, joint collapse and chronic pain [3]. While the exact mechanisms linking COVID-19 to osteonecrosis are still under investigation, it is hypothesized that hypercoagulability, steroid use during treatment, and the direct effects of the virus on vascular endothelium may contribute to this condition [4,5].

Various musculoskeletal conditions have been treated with ozone treatment, which is recognized as a promising alternative technique due to its potent anti-inflammatory, immunomodulatory, and regenerative properties. Ozone can improve tissue oxygenation, enhance blood flow, and stimulate the release of growth factors that promote healing [6,7]. Specifically, prolozone therapy, which involves the intra-articular injection of ozone, was shown to provide pain relief and improve joint function by stimulating tissue repair and regeneration [8].

In recent years, rectal ozone insufflation, a method of delivering ozone gas is introduced into the body via the rectum, has also gained attention as an effective systemic treatment [9,10]. This technique offers the advantage of enhancing oxygen metabolism and reducing oxidative stress throughout the body, thereby promoting overall healing and recovery. When combined with intra-articular prolozone therapy, rectal ozone insufflation may offer a synergistic effect, providing both localized and systemic benefits in managing osteonecrosis [11,12].

Hence, we objected to assess safety and the effectiveness of combining rectal ozone insufflation with intra-articular prolozone therapy in the treatment after coronavirus disease hip osteonecrosis, with the goal of reducing pain, improving joint function, and delaying the need for surgical intervention.

Research Design and Participants

This prospective cohort research involved a total of 50 patients diagnosed with post- coronavirus disease hip osteonecrosis. The research has been accepted by the institutional review board, and written informed consent has been collected from all participants.

Inclusion and Exclusion Criteria:

Participants included in the research have been between 21 and 65 years old, with an average age of 37.3 years. Both women and men cases were included, comprising 54% males and 46% females. Eligible patients were required to have confirmed osteonecrosis of the hip diagnosed by imaging, and COVID-19 recovery was confirmed by RT-PCR. Patients with comorbidities were not excluded, as 74% of the participants had pre-existing health conditions. Patients with a history of core decompression (14%) were also included.

Treatment Protocol:

All patients underwent combined treatment with rectal ozone insufflation and intra-articular prolozone therapy. The treatment aimed to reduce pain, progress function of joint, and delay the need for operative procedure, such as total hip arthroplasty (THA). Rectal ozone insufflation (150 ml, 35 μg/mL of ozone-oxygen mixture) was scheduled as 2 times per week for 4 weeks, followed by 4 sessions once weekly. Protocol for intra-articular hip injection comprised of 6 weekly sessions of prolotherapy 10 ml dextrose 5%, combined with 10 ml 25 μg/mL of ozone-oxygen mixture.

COVID-19 Characteristics:

COVID-19-related data were collected for all participants. The mean duration of hospitalization was 1.5 days (range: 0–8 days), with a mean onset of symptoms at 87.7 days post-infection (range: 35–175 days). Of the patients, 10% had a history of ICU admission, and 20% received steroid therapy during their COVID-19 treatment.

Outcome Measures:

The 1ry result was improvement in joint function, assessed using the Harris Hip Score (HHS) and Ficat & Arlet classification for hip osteonecrosis. Secondary outcomes included changes in pain levels, assessed using the Visual Analog Scale (VAS). HHS, Ficat & Arlet scores, and VAS scores were recorded at baseline and at follow-up intervals of one week, two weeks, four weeks, three months, and six months post-procedure.

Figure 1: Ultrasound-guided intra-articular hip joint injection.

Statistical Analysis

Descriptive statistics, including means and ranges, were used to summarize continuous data such as weight, age, body mass index, and hospital stay duration. Categorical variables, such as sex and comorbidities, were reported as percentages. Recurrent measures ANOVA has been utilized to evaluate alterations in HHS, Ficat & Arlet scores, and VAS scores over time. A P-value of less than 0.05 has been represented statistically significant.

Table 1: Distribution of General characteristics in the examined cases.

Post-COVID-19 complications, including hip osteonecrosis, have become a growing concern. Osteonecrosis occurs when blood flow to the bone is disrupted, causing tissue death and joint damage (13).

Ozone therapy has shown potential due to its anti-inflammatory and regenerative effects. Intra-articular prolozone, where ozone is injected directly into the joint, may help reduce pain and promote healing (14, 15). Additionally, rectal ozone insufflation offers systemic benefits, improving oxygen use and reducing stress on the body (16, 17). Combining these two approaches could provide a new, non-invasive way to treat post-COVID-19 hip osteonecrosis, offering relief and delaying the need for surgery.

In the current research, the average age of participants was 37.3 years, varying from 21 to 65 years. The mean weight was 82.7 kg, with a range of 62 to 105 kg, and the mean BMI was 27.6, ranging from 21 to 33. Of the participants, 54% were male and 46% were female, with approximately 74% having comorbidities.

In line with our outcomes, Fernández-Cuadros ME et al., (18) that aimed to assess the efficiency of rectal ozone (O₃) in coronavirus disease cases with severe pneumonia. They found that the patients' mean age was 66.5 ± 25.7 years, with a vary of 37 to 87 years. The ratio of males to females was one to one.

Similarly, our study was consistent with, Sozio E et al., (7), who evaluated the adjuvant function of oxygen/ozone treatment in mild to moderate SARS-CoV-2 pneumonia. They reported a mean age of 63.8 ± 13.2 years, with 55 males (59.8%) and a mean BMI of 27.0 ± 5.2.

In our study, regarding COVID-19 characteristics, the mean duration of hospitalization was 1.5 days, ranging from 0 to 8 days, and the mean onset of symptoms was 87.7 days, ranging from 35 to 175 days. Additionally, 10% of patients had a history of ICU admission, and 20% received steroid therapy.

Our study aligns with, Fernández-Cuadros ME et al., (18), who revealed that cases diagnosed with severe coronavirus disease pneumonia obtained standard pharmaceutical therapies (azithromycin, lopinavir/ritonavir, and hydroxychloroquine), corticosteroid treatment in a descending regimen, oxygen treatment, and monoclonal antibodies (anakinra (anti IL-1) in one case and tocilizumab (anti IL-6) in 2 cases), nevertheless continued to persisted with dyspnea, necessitating oxygen supply with a strong flow rate.

As well, our study was supported by, Sozio E et al., (24), who reported which the most frequent symptom at coronavirus disease onset was fever, occurring in 80 cases (87.0%). Steroids were used in 7 cases (7.6%). The length of hospital stay was 10 days, with a range of 6.5 to 13.5 days, and ICU admission occurred in 9 cases (9.8%).

Our findings indicate that hip osteonecrosis significantly improved after 6 months. The mean Ficat & Arlet score prior to the technique was 2.4 on the right side (vary: two to four) and 2.6 on the left side (vary: two to four). After 6 months, the mean Ficat & Arlet score decreased to 2.3 on the right side (vary: one to four) and 2.2 on the left side (vary: one to four). Of the patients, 44% had hip osteonecrosis on the left side, 30% had bilateral involvement, and 26% had it on the right side. Additionally, 14% had a history of core decompression.

These findings were consistent with those of Xin-You Gao MD et al., (19), who evaluated the radiographic and clinical results of ozone treatment for osteonecrosis of the femoral head (ONFH). They reported a significant reduction in bone marrow edema of the femoral head with ozone therapy than the control group (P-value less than 0.001). In their study, 13 of 49 hips (26.53%) in the control group suffered total hip arthroplasty, while only 6 of 58 hips (10.34%) in the ozone treatment group required hip arthroplasty through a thirty-month monitoring (P-value equal 0.041). Cumulative examination showed a lower rate of conversion to hip arthroplasty in the ozone treatment group (log-rank test; P-value equal 0.022).

In recent years, there has been a rise in the utilization of local ozone injections for managing degenerative and inflammatory illnesses associated with the musculoskeletal system. These injections activate the body's anti-oxidative and anti-inflammatory capabilities (21). The hip joint is treated with 10-15 cc of an oxygen-ozone mixture at a level of 15-25 microgram per milliliter on a weekly basis, even though that complete consensus hasn’t been reached regarding ozone dosages and concentrations (22). The therapy was started with anti-inflammatory and analgesic doses of ozone for joint effusion and pain induced by osteonecrosis in their patient report. (23).

Our study found that the Visual Analog Scale score significantly enhanced over the follow-up period. The mean Visual Analog Scale score prior to the technique was 7.6, ranging from 5 to 9. One week after the procedure, the mean Visual Analog Scale score reduced to 5.7 (range: 3 to 9). At two weeks, it further decreased to 4.7 (range: 3 to 8). By four weeks, the mean score was 3.5 (range: 2 to 7). At three months, the mean VAS score was 4.3 (range: 2 to 6), and at six months, it improved to 3.4 (range: 1 to 7).

Our results were in line with, Fernández-Cuadros ME et al., (18), who presented According to the preliminary findings of a small series of cases who were diagnosed with severe coronavirus disease pneumonia. Radiological, biochemical, and clinical improvement was observed following five sessions of rectal ozone therapy (one hundred milliliter of ozone at thirty-five micrograms per milliliter). No negative consequences reported following rectal insufflation except a sensation of bloating, and slight meteorism that subsided spontaneously.

Additionally, our findings were consistent with those of Xin-You Gao MD et al., (19), who reported a significant reduction in pain intensity in the two the control group and the ozone treatment group at each monitoring period point than baseline (all P-value less than 0.05). Nevertheless, the Visual Analog Scale scores for pain intensity in the ozone treatment group were statistically lesser than those in the control group (ninety-five percent confidence interval 1.0 to 2.3; P-value less than 0.001). At the final monitoring, while significant improvement was observed in the Visual Analog Scale scores, this improvement did not reach statistical significance for patients with Association Research Circulation Osseous (ARCO) stage one and two when than their scores before ozone treatment.

Moreover, our findings were aligning with, Seyam O et al., (20) who revealed that ozone treatment is utilized to relieve hip pain because of functional overload, pain induced by tendinitis, bursitis and 1ry or 2^nd coxarthrosis.

Furthermore, our study was concordance with a previous case report study conducted with YILDIZGÖREN MT et al., (23) demonstrated that the pain correlated with osteonecrosis decreased and the pain-free walking distance was improved by the weekly injection of intra-articular ozone for a period of five weeks. Based on the findings of this investigation, ozone can be regarded as an effective adjunctive therapy choice for cases who are suitable and suffer from hip pain as a result of osteonecrosis.

Our results showed a significant increase in the Hip Harris score throughout the follow-up period. The mean Hip Harris score before the procedure was 67.4, with a range of 61 to 78. At four weeks after the procedure, the mean score increased to 83.8 (range: 75 to 93). At three months, the mean score was 81.9 (range: 70 to 88), and at six months, it was 82.8 (range: 68 to 96).

Our results were concordance with, Xin-You Gao MD et al., (19), who reported a significant improvement in HHS at each monitoring period point than baseline in both the control and ozone treatment groups (all P-value less than 0.05). Nevertheless, the Harris Hip Score in the ozone therapy group was statistically greater than in the control group (ninety-five percent confidence interval -17.0 to -6.8; P-value less than 0.001). During the concluding monitoring, while a significant improvement was observed in HHS, this improvement did not reach statistical significance for cases with Association Research Circulation Osseous stage one and two than their scores before ozone therapy.

Ozone treatment is efficacious in treating hip osteonecrosis, a disorder where traditional medical treatments are often ineffective and the risk of operation on the hip is elevated. 14 Ozone treatment can assist in delaying the necessity for hip arthroplasty (23).

In conclusion, our study supports the effectiveness of combining rectal ozone insufflation with intra-articular prolozone therapy in managing post-COVID-19 hip osteonecrosis, demonstrating significant improvements in pain, joint function, and overall patient outcomes.

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