The Egyptian Rheumatologist 41 (2019) 183–187

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The Egyptian Rheumatologist

journal homepage: www.elsevier.com/locate/ejr

Original Article

Therapeutic efficacy of intra-articular injection of platelet–rich plasma

and ozone therapy in patients with primary knee osteoarthritis
Nahla M. Gaballa a, Yassir A. Mohammed a, Lamiaa M. Kamel b, Heba M. Mahgoub a,⇑
a
Rheumatology and Rehabilitation Department, Faculty of Medicine, Zagazig University, Egypt
b
Clinical Pathology Department, Faculty of Medicine, Zagazig University, Egypt

a r t i c l e i n f o a b s t r a c t

Article history: Background: Platelet-rich plasma (PRP) and ozone therapy have been proposed as therapeutically effi-
Received 16 July 2018 cient agents for the management of pain in knee osteoarthritis (KOA).
Accepted 17 July 2018 Aim of the work: To reveal the efficiency of intra-articular injection of PRP and ozone therapy in the treat-
Available online 23 July 2018
ment of patients with primary KOA compared to a basic rehabilitation program.
Patients and methods: 60 patients with KOA were randomly classified into 3 groups (20 patients each);
Keywords: group I received intra-articular PRP injection, group II received ozone and group III performed a rehabil-
Platelet-rich plasma
itation program. All patients were assessed by visual analogue scale (VAS), Western Ontario and
Ozone
Knee
McMaster Universities Osteoarthritis Index (WOMAC) and 6-min walk test at baseline and after 1 and
Osteoarthritis 3 months.
WOMAC Results: The patients mean age was 55 ± 4.5 years and were 46 females: 14 males (F:M 29:3). The age and
gender were comparable among the 3 groups. There was high significant difference between PRP and
others 2 groups as regard VAS after 1 and 3 months treatment (p < 0.001) while there was insignificant
difference between groups II and III after one month from treatment; but there was significant difference
between them at three months. After treatment regarding WOMAC score there was a significant differ-
ence between studied groups after 1 and 3 months of treatment (p < 0.05) while there was an insignifi-
cant difference between groups regarding 6 min–walk test after 1 and 3 months.
Conclusion: The use of autologous PRP is an efficient treatment of KOA and resulted in better outcomes
than ozone therapy up to 3 months.
Publishing services provided by Elsevier B.V. on behalf of Egyptian Society of Rheumatic Diseases. This is
an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

1. Introduction treatment with infiltrative substances such as steroids and hya-

Osteoarthritis (OA) is a degenerative joint disease, characterized
by articular cartilage degradation which can affect many joints in
the body, but is especially frequent in weight bearing joints such
as the knee and hip [1]. In Egyptian patients with OA many factor
have been implicated in the disease pathogenesis [2–7].
Complementary health approaches in combination with conven-
tional medicines for the treatment of knee OA (KOA) have been
considered especially in young, less educated and rural-based
patients [8]. As part of the overall management of patients with
OA it is crucial to use a therapeutic strategy including rehabilita-
tion programs in addition to non-steroidal anti-inflammatory
drugs, analgesics, chondro-protective agents and intra-articular
Peer review under responsibility of Egyptian Society of Rheumatic Diseases.
⇑ Corresponding author at: Rheumatology and Rehabilitation Department,
Medical Administration for Students Affairs, Zagazig University, Egypt.
E-mail address: hmahgoub90@gmail.com (H.M. Mahgoub).
luronic acid [9]. In Egyptian KOA patients, glucosamine/chon-
droitin sulfate improved knee pain, stiffness and function and
was considered beneficial as a symptomatic treatment and not as
a cartilage sparing drug in the management of the disease [10].
Conservative treatments have been described to increase the
quality of life of patients particularly in the early phases, when
the pathophysiology of the disease does not change [11].
Platelet-rich plasma (PRP) has been suggested for the management
of KOA pain [12]. The autologous nature of PRP is one of its main
advantages because this averts any immune reaction or blood
transmission disease. The suggested use of this therapy in KOA
patients has been increasing in the last few years [13].
Ozone therapy is an approach proving to have therapeutically
efficiency with analgesic effect by activating cellular metabolism;
regulating the membrane capacity and making fluids run normally
in the inflamed tissues. The anti-inflammatory and anti-oxidant
effects help immunomodulation by activating immune-competent
cells and it protects against the endothelial dysfunction [14].

https://doi.org/10.1016/j.ejr.2018.07.005
1110-1164/Publishing services provided by Elsevier B.V. on behalf of Egyptian Society of Rheumatic Diseases.
This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
184 N.M. Gaballa et al. / The Egyptian Rheumatologist 41 (2019) 183–187

The study objective was to compare the efficiency of intra-
articular injection of PRP and ozone therapy in the treatment of
patients with primary KOA compared to a basic rehabilitation
program.
2. Patients and methods
This study included 60 KOA patients randomly selected from
the Rheumatology and Rehabilitation Department, Zagazig Univer-
sity Hospitals, during the period of April 2017 till March 2018. All
patients fulfilled 2016 ACR revised criteria for early diagnosis of
KOA [15]. Exclusion criteria included patients with systemic or
metabolic diseases, on immunosuppressive or anticoagulant treat-
ment, with history of previous invasive procedure or intra-articular
steroid injection to the knee during the preceding 12 months. The
study was approved by the ethics committee of Zagazig University
in accordance to the Declaration of Helsinki. All patients gave their
informed consent prior to their inclusion in the study.
They were randomly classified into 3 equal groups according to
their treatment; group I (PRP group) received 2 intra-articular PRP
injection in the symptomatizing KOA (one every two weeks), group
II (ozone group) received a weekly intra-articular ozone injection
for 4 successive weeks and group III (Rehabilitation group)
received a basic rehabilitation program including infrared (IR),
trans cutaneous electric nerve stimulation (TENS), quadriceps
muscle strengthening exercises (quadriceps setting and straight
leg raise), hamstring stretch and gluteus strengthening at a fre-
quency of 3 sessions/week for 1 month (considered as a control
group).
At the first visit, all patients were subjected to full history tak-
ing, general and complete knee joint examination. The severity of
pain was assessed by the visual analogue scale (VAS) [16]. Patients
were asked to complete Western Ontario and McMaster Universi-
ties Osteoarthritis Index (WOMAC) in order to evaluate the func-
tion of the affected knee [17]. Plain x-ray of the affected knee
(anteroposterior and lateral views) was done for grading of KOA
according to the Kellgren–Lawrence (KL) grading system [18].
The 6-min walk test in meters was also recorded.
PRP preparation: 15 ml. of total blood was collected under asep-
tic conditions and centrifuged at 1800 rpm for 15 min to separate
erythrocyte and then at 3500 rpm for 10 min to concentrate
platelets.
Ozone therapy: It was generated using the medical ozone Hyper
Medozon device. Special attention was paid to an accurate control
of the ozone supply concentrations and of the right quantity given
to the patients in due time. A catalyzer which neutralizes (absorbs)
the additional ozone after 10 s allows the production of a stable
concentration of 25 lg/ml [19].
Rehabilitation program was 3 sessions/week for 4 successive
weeks and consisted of infrared (IR), transcutaneous electric nerve
stimulation (TENS), quadriceps muscle strengthening exercises
(quadriceps setting and straight leg raise), hamstring stretch and
gluteus strengthening.
All patients were re-evaluated by physical examination, assess-
ment of VAS for pain, WOMAC score and 6-min test at the end of
treatment (1 month) and after 3 months.
Statistical analysis: Collected data were analyzed by statistical
package for social sciences version 13 (SPSS Inc., Chicago, USA).
Data were shown as a mean ± standard deviation. For parametric
data, Student t-test was used to compare the means of two groups.
Non-parametric data were analyzed by the Mann–Whitney U and
Kruskal–Wallis tests to compare 2 and 3 groups, respectively.
Chi-square test was used to compare categorical data. Spearman’s
correlation coefficient and regression tests were performed.
p-values were considered significant if <0.05.
3. Results
The patients mean age was 55 ± 4.5 years and were 46 females:
14 males (F:M 3.3:1). Group I (PRP) included 5 males and 15
females with a mean age of 53.6 ± 4.6 years (47–64 years) and
disease duration of 5.4 ± 3.2 years (1–12 years). Group II (ozone)
included 4 males and 16 females with a mean age of
56.3 ± 4.4 years (48–64 years) and disease duration of 5.9 ± 3.5 ye
ars (1–14 years) while group III (rehabilitation) included 5 males
and 15 females with a mean age of 55.3 ± 4.2 years (49–64 years)

Table 1
Comparison of visual analogue scale of pain, functional status and 6 min walking for the studied groups before, after 1 and 3 months treatment in patients with primary knee
osteoarthritis.

Parameters Primary KOA patients (n = 60)

mean ± SD, median (range)
Treat Before After 1 After 3 p-
ment groups (n = 20 each) treatment months months value
VAS PRP 6.8 ± 1.1 3.1 ± 1.1 3.5 ± 0.9 <0.0003
7 (5–9) 3 (1–5) 3 (2–5)
Ozone therapy 6.9 ± 1.2 4.6 ± 1.4 6.2 ± 1.8 <0.0002
7 (5–9) 4.5 (2–7) 6.5 (3–9)
Rehabilitation 7.2 ± 0.95 5.3 ± 1.3 7±1 <0.0001
7 (5–9) 5 (3–7) 7 (5–9)
p-value 0.5 <0.0002 <0.0003
WOMAC PRP 49 ± 7.5 21.3 ± 8 23 ± 8.5 <0.0004
47 (40–64) 20.5 (11–39) 24 (13–42)
Ozone therapy 52 ± 6.8 34.5 ± 7 48 ± 7 <0.0002
51.5 (44–64) 34 (25–55) 49 (36–58)
Rehabilitation 52 ± 5.5 45 ± 6 53.2 ± 7.4 <0.0001
54 (44–64) 46 (38–58) 56 (36–66)
p-value 0.18 <0.0001 <0.0002
6 min walk PRP 183.5 ± 64 236 ± 53.6 231.5 ± 67.3 0.001
170 (80–300) 235 (160–320) 220 (150–350)
Ozone therapy 201 ± 64 231 ± 57.4 212 ± 64 <0.0002
190 (80–300) 225 (150–350) 200 (100–320)
Rehabilitation 211 ± 61.3 241.5 ± 56.9 210 ± 56 0.052
200 (100–300) 250 (140–350) 200 (130–300)
p-value 0.38 0.8 0.5

KOA: knee osteoarthritis, PRP: platelet-rich plasma, VAS: visual analog scale, WOMAC: Western Ontario and McMaster Universities Osteoarthritis Index. Bold values are
signficant at p < 0.05.
 N.M. Gaballa et al. / The Egyptian Rheumatologist 41 (2019) 183–187 185

Table 2
Comparison of visual analogue scale of pain, functional status and 6 min walking for the studied groups before, after 1 and 3 months treatment in patients with primary knee
osteoarthritis.

Parameters mean ± SD Treatment groups in KOA patients (n = 20 each)

PRP Ozone Rehabilitation
M (n = 5) F (n = 15) p M (n = 4) F (n = 16) p M (n = 5) F (n = 15) P
VAS
At start 6.2 ± 1.3 7 ± 0.96 0.12 7.8 ± 0.9 6.7 ± 1.2 0.12 7. ± 1.6 7.3 ± 0.7 0.73
After 1 mo 2.6 ± 0.89 3.3 ± 1.1 0.23 5 ± 0.8 4.4 ± 1.5 0.48 6.4 ± 1.3 4.9 ± 1.2 0.03
After 3 mo 3.4 ± 0.89 3.5 ± 0.9 0.88 6.3 ± 0.9 6.1 ± 1.9 0.9 7 ± 1.4 7.1 ± 0.9 0.9
WOMAC
At start 43.4 ± 4.6 51 ± 7.4 0.02 56.7 ± 5 51 ± 6.9 0.13 53 ± 4.6 51.9 ± 5.9 0.65
After 1 mo 22 ± 10.4 21.1 ± 7.5 0.93 35.7 ± 4.6 34 ± 7.5 0.7 44 ± 3.7 45.5 ± 6.7 0.63
After 3 mo 23.6 ± 8.5 22.9 ± 8.8 0.8 54 ± 4.3 46 ± 7 0.06 56 ± 1.6 52.2 ± 8.3 0.08
6-min walk
At start 160 ± 70 191 ± 63 0.36 225 ± 68 195. ± 64 0.43 214 ± 62 210 ± 63 0.9
After 1 mo 186 ± 29.7 252.7 ± 49.6 0.01 247.5 ± 61 227 ± 57.6 0.53 198 ± 41.4 256 ± 54.7 0.045
After 3 mo 170 ± 30.8 252 ± 63.8 0.014 217 ± 53.8 211 ± 68 0.85 214 ± 62 208.7 ± 56 0.86

KOA: knee osteoarthritis, PRP: platelet-rich plasma, VAS: visual analog scale, WOMAC: Western Ontario and McMaster Universities Osteoarthritis Index. Bold values are
significant at p < 0.05.

Table 3
Correlations of the Kellgren-Lawrence (KL) radiologic grading with the studied parameters in the 3 groups at baseline, after 1 and 3 months treatment in patients with primary
knee osteoarthritis.

Parameters r (p) KL grade in KOA patients (n = 60) study groups

PRP (n = 20) Ozone therapy (n = 20) Rehabilitation (n = 20)
Disease duration (years) 0.84 (0.0001) 0.67 (0.001) 0.1 (0.6)
Body mass index 0.58 (0.008) 0.2 (0.4) 0.028 (0.9)
VAS at start 0.47 (0.038) 0.6 (0.006) 0.53 (0.016)
after 1 mo 0.08 (0.75) 0.45 (0.049) 0.14 (0.56)
after 3 mo 0.44 (0.051) 0.42 (0.065) 0.62 (0.004)
WOMAC at start 0.76 (0.0001) 0.2 (0.35) 0.33 (0.16)
after 1 mo 0.75 (0.0001) 0.33 (0.16) 0.03 (0.9)
after 3 mo 0.7 (0.0001) 0.45 (0.049) 0.06 (0.82)
6 min walk at start 0.42 (0.065) 0.02 (0.9) 0.009 (0.97)
after 1 mo 0.61 (0.005) 0.07 (0.76) 0.25 (0.29)
after 3 mo 0.65 (0.002) 0.3 (0.2) 0.009 (0.97)

KL: Kellgren Lawrence, KOA: knee osteoarthritis, PRP: platelet-rich plasma, VAS: visual analog scale, WOMAC: Western Ontario and McMaster Universities Osteoarthritis
Index. Bold values are signficant at p < 0.05.

and disease duration of 6.4 ± 3.3 years (1–14 years). There was no
significant difference between 3 groups as regard to age and sex.
The therapies in the 3 groups were safe with no reported compli-
cations such as infection or fever. Only minor adverse events were
detected such as mild pain at injected area and skin bruises. The KL
grading in the 3 groups was grade 1 in 6 (10%) patients, grade 2 in
32 (53.3%) and grade 3 in 22 (36.7%).
Comparison of VAS, WOMAC and 6 min walking for the studied
groups before treatment, at 1 and 3 months after treatment are
presented in table 1. On comparing the VAS, WOMAC and 6 min
test among the 3 groups after 1 and 3 months treatment there
was a significant difference between group I (PRP) with group II
(ozone) and group III (rehabilitation) as regard VAS at 1 and
3 months after treatment (p < 0.001) and between groups II and
III after 3 months (p < 0.03); there was a significant difference
among the studied groups after 1 and 3 months of treatment as
regards to WOMAC (p < 0.0001) and there was only a tendency
to improvement of walking 6 min test for all studied groups at
any time of treatment. On comparing the studied parameters as
regards to gender, in the PRP group there was a significant
difference in WOMAC before treatment (p = 0.02), and regarding
to 6- min test after 3 months (p = 0.014). Also, in the rehabilitation
group there was significant difference after 1 month as regards the
VAS (p = 0.03) and 6-min test (p < 0.045) (Table 2).
Correlations of the KL radiologic grading with the studied
parameters in the 3 groups at baseline, after 1 and 3 months are
presented in Table 3. In the PRP group, there was a significant
correlation between KL grades and WOMAC score at baseline and
follow up (r = 0.7, p < 0.0001); and with VAS only at baseline
(r = 0.47, p < 0.038), while inversely with the 6-min test after 1
and 3 months, (r = 0.61, p = 0.005) after 1 month, (r = 0.65,
p = 0.002) after 3 months. Multiple regression to predict a severe
radiology radiology grade in the PRP group showed that only the
disease duration was significant (p = 0.012) among other variables
including BMI, VAS and WOMAC at baseline.
4. Discussion
The present work aimed to compare the efficacy of intra-
articular injection of PRP and ozone therapy in the treatment of
KOA. There was a remarkable improvement in the VAS, WOMAC
and walking 6 min test in the PRP group after 1 and 3 months. This
was in agreement with the results of others [11,20,21] who found
that PRP resulted in a significantly better WOMAC score from 3 to
12 months post-injection. Another study [22] showed that the
evaluated parameters significantly improved at 24 months com-
pared with those at 12 months, but still better than those at base-
line. In another study on Egyptian KOA patients, Hassan et al. [23]
reported a highly significant improvement in VAS and functional
assessment scores after 6 months.
This reduction in pain is due to the capability of PRP to promote
the proliferation of chondrocytes, stimulate the production of syn-
ovial fluid and limit the inflammatory response [24]. It was
reported that intra-articular PRP injection is potent in degenerative
186 N.M. Gaballa et al. / The Egyptian Rheumatologist 41 (2019) 183–187
knees [25]. Therapy with PRP can potentially adjust the articular
inflammatory environment and the progression of OA due to the
presence of therapeutic concentrations of interleukin (IL-1ra) and
transforming growth factor (TGF-b) in PRP. Intra-articular infiltra-
tions with PRP could avert further degeneration of cartilage by
retarding OA progression in early stages of the disease [26].
There was a significant correlation between radiological grades
and WOMAC score at baseline and after treatment but as regard to
VAS only at the start, while 6- min test there was a negative signif-
icant correlation after 1 and 3 months. These results are in conso-
nance with those of Duymus et al. [19]. A meta-analysis
emphasized that PRP was effective in mild-moderate grades Chang
et al., [11]. PRP injections had a better response in those with low
grade OA [27]. It has been reported that better response rates are
evident in OA patients treated with PRP injections than in those
treated with hyaluronic acid [11,28]. Others reported a similar effi-
cacy [27,29] in elderly patients with advanced KOA who received
PRP in association with HA injection and showed pain relief and
functional improvement. The follow-up standard weight-bearing
x-ray images of knees also confirmed the improvement and indi-
cated the regeneration of the articular cartilage. The treatment
strategy of PRP in association with HA injection may be useful to
treat advanced KOA before these patients receive arthroplasty. In
a randomized trial with patients in the different stages of the dis-
ease it is difficult to conclude whether this approach can be applied
to a specific phase of cartilage degeneration [30].
In those who received ozone therapy, there was a significant
improvement of the studied parameters after 1 month and even
more after 3 months.
These results coincided with those of many authors who stated
that ozone diminishes pain and improves function in KOA [14,31–
33]. This short-term effect on symptoms was thought to be due to
the relatively potent anti-inflammatory properties of ozone rather
than intra-articular structural improvement [19]. Another study of
Mishra et al., [34] described that the effectiveness lasted 6 months.
When, PRP and ozone therapies were compared as regards to
VAS and WOMAC score, improvement was achieved with PRP
rather than with ozone in the treatment of KOA. In particular,
ozone gas injection was efficient for only the first month, whereas
the effect of PRP injection lasted for at least 3 months. Many stud-
ies compared PRP and ozone in terms of efficacy [35–37]. The dif-
ferences between various studies in the efficacy of ozone therapy
in KOA may be related to a number of factors including differences
in study populations, severity of disease, and heterogencity of
treatment parameters such as concentration of the ozone, number
of settings and different machine design. Use of different outcome
measures can also prevent direct comparisons between studies.
There are no unanimous criteria for ozone treatment protocols in
KOA including number of doses, concentration, volume or fre-
quency [38]. In contrast, no significant difference between PRP
and ozone has been reported [25]. This differences between vari-
ous studies in the efficacy of PRP due to the application was per-
formed in a single session, other were administered twice at an
interval of 2 weeks/month. Duymus et al. [19] reported in their
study that PRP is superior to hyaluronic acid (HA) and ozone in
the treatment of mild-moderate KOA and is becoming increasingly
widespread. PRP injection alone was effective for achieving at least
12 months of pain-free daily activities. Also, Shen et al. [22] found
that intra-articular PRP injections may be more efficacious in the
treatment of KOA in terms of pain relief and self-reported function
improvement at 3, 6, and 12 months follow-up compared with
other injections, including saline placebo, HA, ozone and
corticosteroids.
This study confirms that PRP is superior to ozone in the treat-
ment of KOA and is an encouraging treatment option. PRP injection
alone was effective for achieving at least 3 months of pain-free
daily activity. This work showed that PRP treatment is safe as no
complications as infection or fever occurred. Patel et al. [25]
reported mild complications as nausea and dizziness which were
of short duration and these complications were not reported in
the current patients.
A larger scale longitudinal study with a longer follow up is rec-
ommended to verify the reached results and combining PRP and
ozone with rehabilitations programs may reveal the optimum
associations of treatment lines for KOA.
In conclusion, this study confirms that PRP is superior to ozone
in the treatment of KOA and is an encouraging treatment option.
PRP injection alone was effective for achieving at least 3 months
of pain-free daily activity.
Conflict of interest
None.
Funding
This research did not receive any specific grant from funding
agencies in the public, commercial, or not-for-profit sectors.
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