Keywords
hip - osteoarthritis - hyaluronic acid - platelet rich plasma - ultrasound - injection
Introduction
Osteoarthritis (OA) is a common, painful condition that affects adults and causes
disability in the United States and Europe. Unfortunately, no agents are available
to halt OA progression. Analgesics and nonsteroidal anti-inflammatory drugs (NSAIDs)
have suboptimal effectiveness, and there is a concern of systemic side effects. A
wide challenge is the development of appropriate and effective therapy in patients
with OA. Currently, the most suitable route for administering OA therapy appears to
be intra-articular injections that allow accumulation of critical doses of the drug
within the damaged area and also reduce the risk of systemic side effects.[1] In the last decade, hyaluronic acid (HA), and more recently, platelet rich plasma
(PRP) injections have been used in the treatment of hip osteoarthritis (OA).[2]
[3]
[4]
[5]
[6]
[7]
[8]
[9]
With progressive aging of the population, the number of patients with hip OA will
increase. The aim of our study was to compare the efficacy of the two most debated
treatments for early hip OA: HA and PRP. Our hypothesis is that differences in clinical
outcomes between HA and PRP are not significant.
Methods
This study was designed as a prospective double-blinded, randomized controlled trial
on patients with hip OA. The study was approved by the local ethics committee of the
University of Sassari.
Participants
All patients provided their consent for using their data. Patients who were confirmed
eligible and agreed to enter the study were randomized and treated with either three intra-articular PRP injections or three intra-articular HA injections.
Inclusion criteria were symptomatic early OA of the hip (Kellgren–Lawrence: grade
0–2) documented by X-ray taken within the past 6 months and age range between 40 and
72 years. Exclusion criteria were previous hip surgery, intra-articular treatments
with steroids within 3 months prior to enrollment in this study, treatments with NSAIDs
within 15 days prior to enrollment, chronic use of NSAIDs (defined as taking NSAIDs
regularly every week for the past 6 months), steroids or chemotherapy drugs, inflammatory
arthritic conditions (e.g., rheumatoid arthritis), and major comorbidities, such as
poorly controlled diabetes, cardiac heart failure, chronic obstructive pulmonary disease,
untreated depression, and blood disorders (thrombophilia, thrombocytopenia, anemia
with hemoglobin < 9 g/dL). Those patients with a positive history of blood disorders
had a cell blood count (CBC) 1 week prior to inclusion in the study. Because this
study utilized an injection technique that may be inaccurate in obese subjects, patients
with a BMI over 30 were also excluded.
The subjects enrolled were comparable in age, sex, BMI, and diagnosis of hip OA. Both
groups had 12 months of follow-up. There was no drop out. In all patients, a 5 to
10 MHz multifrequency linear probe aligned with the long axis of the femoral head
was used.
Interventions
Patients were divided into two groups of 40 patients each.
Patients randomized to group 1 (PRP) received three weekly intra-articular injections
of autologous PRP. The procedure of PRP preparation consisted of a 150-mL venous blood
sample. Then, two centrifugations (first at 1,480 rpm for 6 minutes to separate erythrocytes
and second at 3,400 rpm for 15 minutes to concentrate platelets) produced a unit (20
mL) of PRP. The unit of PRP was divided into four small units of 5 mL each. One unit
was sent to the laboratory for analysis of platelet concentration and for a quality
test, whereas three units were stored at −30°C.
Patients randomized to group 2 (HA) received three weekly intra-articular injections
of hyaluronic acid (Hyalubrix 15 mg/mL, Fidia; Abano Terme, Italy).
Ultrasound-guided intra-articular injections of the hip were performed by the insertion
of a 20- to 22-gauge spinal needle (90–120 mm) under sterile conditions.[9] PRP and HA were injected at the base of the femoral neck, and a complete evacuation
of intra-articular fluid, if present, was performed. The anterosuperior, parasagittal
approach allows for an injection over the femoral head, and the PRP/HA is evenly distributed
on the cartilage of both the femoral head and the acetabulum. Proper needle position
was confirmed by direct visualization of the liquid PRP/HA that was injected.[10]
All the study subjects were blinded to treatment. The principal investigator (C.D.)
was unblinded to treatment and was only involved in the initial assessment of the
patient and actual injections. All the baseline and follow-up visits were performed
by an examiner who was blinded to the treatment throughout the study.
Outcomes Measures
Both groups underwent 6- and 12-month follow-ups consisting of clinical exam and subjective
and functional assessment. WOMAC score,[11] Harris Hip Score,[12] and pain VAS were assessed at the baseline evaluation and at 6 and 12 months after
the last injection.
The primary outcome was a reduction in pain intensity as measured by the WOMAC subscale,[6] which evaluates three items (pain, stiffness, and disability) for a total of 24
points (Likert format, 0–4), and by the 100-mm VAS for pain intensity (lower scores
are associated with less pain). The domain of pain in the traditional Harris hip score,[7] in which higher scores were associated with less pain (out of 44 points), was used
to further assess pain relief.
Secondary efficacy outcomes also included changes in physical function according to
the WOMAC subscale (17 items for a total of 68 points) and the Harris hip score (7
items for a total of 47 points).
Adverse events during and after treatments in the two groups were also recorded and
compared.
Data Analysis
All data were expressed as means and standard deviations. Statistical analysis was
performed by using the SPSS software version 15.0 (SPSS Inc., Chicago, United States).
The Mann–Whitney U-test was used to compare the two groups for all the outcome variables.
A p-value of < 0.05 was considered significant.
Results
No significant differences were observed between the groups for baseline characteristics
([Table 1]).
Table 1
Baseline characteristics of study population (means ± SDs)
|
Baseline characteristics
|
Group 1 (PRP)
|
Group 2 (HA)
|
p-Value
|
|
Age
|
67.3 ± 5.8
|
68 ± 4.6
|
ns
|
|
BMI
|
24.3 ± 3.8
|
25 ± 3.8
|
ns
|
|
OA severity
|
1.5 ± 0.5
|
1.5 ± 0.5
|
ns
|
Abbreviations: HA, hyaluronic acid; ns, nonsignificant; PRP, platelet rich plasma.
There was no drop out at the follow-up visits. Follow-up evaluation revealed a statistically
significant improvement of all clinical scores from baseline evaluation to 6- and
12-month follow-ups in both the treatment groups ([Table 2]).
Table 2
Comparison between groups for outcome scores (means ± SDs)
|
Group 1 (PRP)
|
Group 2 (HA)
|
|
Outcome measure
|
Baseline
|
6 mo
|
12 mo
|
Baseline
|
6 mo
|
12 mo
|
|
WOMAC-pain
|
23.7 ± 2.1
|
7.8 ± 3.8
|
7.4 ± 2.5
|
24 ± 1.9
|
9.7 ± 4.5
|
9 ± 5.6
|
|
WOMAC-stiffness
|
3.8 ± 4.1
|
2.1 ± 3.6
|
2 ± 4.2
|
4.3 ± 5.3
|
3.1 ± 3.2
|
3.1 ± 4.3
|
|
WOMAC-function
|
29.4 ± 2.6
|
12.3 ± 3.6
|
12 ± 3.8
|
28.5 ± 2.5
|
11.3 ± 4.5
|
10.9 ± 4.2
|
|
VAS
|
7.5 ± 2.1
|
6.3 ± 3.3
|
6.4 ± 2.9
|
7.8 ± 1.9
|
6.3 ± 2.9
|
6.1 ± 2.3
|
|
Harris Hip score
|
64 ± 10.3
|
75 ± 11.5
|
78 ± 11.3
|
62 ± 9.8
|
74 ± 12.3
|
75 ± 11.4
|
Abbreviations: HA, hyaluronic acid; PRP, platelet rich plasma; WOMAC, Western Ontario
and McMaster Universities Osteoarthritis Index.
There was a significant reduction from baseline in the WOMAC pain scores at 6-month
follow-up (p = 0.00047 for group 1, p = 0.00063 for group 2) and at 12-month follow-up (p = 0.00607 for group 1, p = 0.00591 for group 2). The results were confirmed by reductions in the VAS scale
(6-month follow-up: p = 0.00062 for group 1, p = 0.00070 for group 2; 12-month follow-up: p = 0.00606 for group 1, p = 0.00654 for group 2) and the Harris pain subscale (6-month follow-up: p = 0.0004 for group 1, p = 0.0006 for group 2; 12-month follow-up: p = 0.0021 for group 1, p = 0.0033 for group 2).
Disability was significantly reduced from baseline in the self-reported WOMAC subscale
at the 6-month follow-up (p = 0.0142 for group 1, p = 0.0158 for group 2) and at the 12-month follow-up (p = 0.0306 for group 1, p = 0.0402 for group 2) time points. Function was significantly ameliorated also at
the Harris hip score at 6 months (p = 0.0005 for group 1, p = 0.0003 for group 2) and at 12 months (p = 0.0031 for group 1, p = 0.0037 for group 2).
On comparing the two treatments for adverse events, a significantly higher postinjective
pain reaction was observed in group 1 (p = 0.043). However, this reaction was self-limiting within few weeks without compromising
the long-term outcomes. No major complications were reported, neither at 6- or 12-month
follow-up.
Discussion
Hyaluronic acid (HA) produced by synoviocytes, fibroblasts, and chondrocytes, is the
major chemical component of synovial fluid. It is essential for the viscoelastic properties
of the fluid because of high viscosity and has a protective effect on articular cartilage
and soft tissue surfaces of joints. In OA, the concentration and the molecular weight
of HA are reduced, resulting in synovial fluid with lower elasticity and viscosity,
including dilutional effects, reduced hyaluronan synthesis, and free-radical degradation,
which are the factors that contribute to the lower concentrations of HA. When the
viscoelasticity of synovial fluid is reduced, the transmission of mechanical force
to cartilage may increase its susceptibility to mechanical damage. Therefore, the
restoration of normal articular homoeostasis is the rationale for HA injections into
osteoarthritic joints. Besides viscosupplementation, HA is a provider of other positive
biological properties, such as anti-inflammatory and antinociceptive effects, normalization
of endogenous HA synthesis, and chondroprotection.[13]
PRP is a plasma fraction obtained by means of different methods of centrifugation,
with platelet counts above the normal blood values. The basic principle underlying
the PRP therapeutic activity is to deliver a large pool of signaling proteins, such
as growth factors (GFs) and other cytokines, including platelet-derived growth factor
(PDGF), transforming growth factor-1-β (TGF1-β), vascular endothelial growth factor
(VEGF), hepatocyte growth factor (HGF), interleukin-8 (IL-8), chemokine ligand 12
(CXCL12), chemokines, angiopoietin, and matrix metalloproteinases (MMPs) that drive
tissue regeneration mechanisms. These regulatory proteins may be capable of interfering
with various healing mechanisms that influence the inflammatory response, induce cell
migration, proliferation, and modulate angiogenesis.[14]
[15]
The literature describes PRP as a new treatment for joint degenerative pathologies,
and an increasing number of studies show promising results.[16]
[17]
[18] Despite its wide clinical application, only a few reports have documented results
for PRP in the treatment of hip degenerative lesions in the literature.[4]
[5]
[6]
[7]
[8]
The results of this trial suggested a possible effect of platelet concentrate on the
treatment of hip OA, with a clinical subjective improvement but not significantly
better results with respect to HA.
The results of this study also underlined some important aspects related to adequacy
and safety of treatment. PRP did not offer better results compared with HA in this
series. However, it has to be emphasized that the average age of the enrolled patients
was higher than those of other studies, which reported a worse outcome for older patients
treated with PRP.[16]
[17]
The safety of this procedure was confirmed. A higher pain reaction after PRP injection
was found, probably due to the leukocyte content of our platelet concentrate, but
without jeopardizing clinical results up to 1-year follow-up.
Cellularity is one of the most debated aspects when evaluating PRP properties and
the results obtained with its application. In fact, not only platelets but also leukocytes,
monocytes, macrophages, and mast cells are present in many platelet concentrates.
Some authors define PRP as only platelets and attribute better results to leucocyte
depletion, because of the deleterious effects of proteases and reactive oxygen species
released from white cells; others consider them as a source of important cytokines
and enzymes.[19]
[20]
[21]
[22]
[23]
In conclusion, PRP remains a debated treatment for hip OA. Despite its wide application
in clinical practice and the positive findings reported, there is a lack of scientific
background to guide the clinical application of PRP. To avoid indiscriminate and inappropriate
use of PRP, it is important to determine the type of patients who will not benefit
from this treatment. The results of this study suggest that for middle-aged patients
with moderate signs of OA, PRP did not offer better results compared with HA, and
thus it should not be considered as the first-line treatment.
