Complete the 2 tables using the article attached. See the example for guidance .

KNEE

The effects of repeated intra-articular PRP injections on clinical outcomes of early osteoarthritis of the knee

Alberto Gobbi • Dnyanesh Lad • Georgios Karnatzikos

Received: 11 October 2013 / Accepted: 2 April 2014 / Published online: 20 April 2014

� Springer-Verlag Berlin Heidelberg 2014

Abstract

Purpose To assess the outcome of intra-articular platelet-

rich plasma (PRP) injections into the knee in patients with

early stages of osteoarthritis (OA) and to determine whe-

ther cyclical dosing would affect the end result.

Methods This is a prospective, randomized study in

which 93 patients (119 knees) were followed up for a

minimum of 2 years. Fifty knees were randomly selected

prior to the first injection, to receive a second cycle at the

completion of 1 year. A cycle consisted of three injections,

each given at a monthly interval. The outcome was

assessed using Knee Injury and Osteoarthritis Outcome

Score (KOOS), Visual Analogue Scale (VAS), Tegner and

Marx scoring systems, recorded prior to the first injection

and then at 12, 18 and 24 months.

Results There was a significant improvement in all scores

over time compared to the pre-treatment value (p \ 0.001). At 12 months, both groups showed similar and significant

improvement. At 18 months, except for KOOS (Symptoms)

and Tegner score, all other parameters showed a significant

difference between the two groups in favour of the patients

who had received the second cycle (p \ 0.001). At 2 years, the scores declined in both groups but remained above the

pre-treatment value with no significant difference between

the groups despite the patients with two cycles showing

higher mean values for all the scores.

Conclusion Intra-articular PRP injections into the knee

for symptomatic early stages of OA are a valid treatment

option. There is a significant reduction in pain and

improvement in function after 12 months, which can be

further improved at 18 months by annual repetition of the

treatment. Although the beneficial effects are ill sustained

at 2 years, the results are encouraging when compared to

the pre-treatment function.

Level of evidence II.

Keywords Platelet-rich plasma � Osteoarthritis � Knee � Dosage � Cyclic treatment

Introduction

Osteoarthritis (OA) has a major impact on function and

independence and was estimated to affect 27 million

Americans in 2012 [41]. Orthopaedic surgeons, physicians

and rheumatologists around the globe have been concerned

regarding management of early stage OA in a population

which is now too young or too fit to undergo a total knee

replacement.

In 2007, platelet-rich plasma (PRP) was defined by the

Medical Subject Heading Database as a limited volume of

plasma containing concentrated platelets (minimum

200,000 platelets/lL), growth factors of which enhance wound healing and regeneration. Intra-articular injections

of autologous PRP for chondral lesions have been used for

many years now with encouraging preliminary results [17,

33, 42]. It is based on the intra-articular delivery of

autologous platelet-rich preparations containing a large

pool of growth factors (GFs) and proteins stored in the

alpha granules of platelets. These GFs and proteins have

been implicated in tissue repairing mechanisms and have

A. Gobbi (&) � D. Lad � G. Karnatzikos O.A.S.I. Bioresearch Foundation, Via Amadeo 24,

20133 Milan, Italy

e-mail: [email protected]

D. Lad

e-mail: [email protected]

G. Karnatzikos

e-mail: [email protected]

123

Knee Surg Sports Traumatol Arthrosc (2015) 23:2170–2177

DOI 10.1007/s00167-014-2987-4

been found to take part in the regulation of articular car-

tilage [40]. They are directed at stimulating repair and

replacing damaged cartilage, which is incapable of repair,

given its avascular, aneural and hypocellular nature.

Various growth factors (platelet-derived growth factor,

transforming growth factor beta, vascular endothelial

growth factors), endostatins, platelet factor 4, angiopoie-

tins, and thrombospondin 1 are secreted upon activation of

platelets, and these are involved in the healing process [2].

Moreover, platelets have been identified to have analgesic

properties by releasing protease-activated receptor 4 pep-

tides [3]. However, PRP contains not only platelets but also

plasma with fibrin and other growth factors that influence

healing. The ‘therapeutic dose’ of PRP is considered at a

range of at least 2–6 times higher than the normal platelet

count [12, 26].

Almost all earlier published data regarding PRP injec-

tions for early stages of OA have had short follow-up

periods up to 12 months. Studies having longer follow-ups

are necessary and a more defined therapeutic dosing

schedule must be established. Dosing is important in order

to understand the true potential of PRP, which is a prom-

ising treatment in early stages of OA and a potential means

of delaying or avoiding altogether a metal resurfacing

procedure. No previous studies have looked into the clin-

ical outcomes of cyclical administration of intra-articular

autologous PRP injections into the knee for early stages of

OA.

The aim of this study was to assess the clinical effects of

intra-articular PRP injections into knees with early stages

of OA with respect to pain, quality of life and return to

activity and to determine whether annual repetition of

treatment with intra-articular autologous PRP injections

into the knee could improve the final outcome.

The hypothesis was that three intra-articular PRP

injections at monthly intervals, repeated annually would

improve the outcome at final follow-up when compared to

a group in whom the treatment was not repeated.

Materials and methods

This is a prospective, randomized study initiated in 2009.

Of 319 patients, 93 (119 knees) that met the inclusion

criteria received intra-articular autologous platelet-rich

plasma (PRP) injections (Regen ACR-C, Regen Lab,

Switzerland) into the knee for early stages of OA (Kell-

gren–Lawrence Grade 1–2) [21] and were systematically

followed up for a minimum of 2 years from the start of

treatment. All the patients were involved with a recrea-

tional sport (jogging, swimming, skiing, bicycling, walking

or trekking) at a non-professional level and had onset of

symptoms within the previous 3 years.

Inclusion criteria

Patients with symptomatic OA of the knees (Kellgren–

Lawrence Grade 1–2 on radiographs) between the ages of

40 and 65 years, having a body mass index (BMI) \30, with stable knees without malalignment or maltracking of

the patella were included in the study. Additional inclusion

criteria were patients having severe pain without relief with

anti-inflammatory agents even after 3 months, normal

blood results and coagulation profile (platelets between

150,000 and 450,000/lL), patients who had not undergone any surgery on the affected knee within 2 years prior to the

first injection and zero, trace or 1? effusion on the grading

scale based on the Stroke test [37].

Exclusion criteria

Patients diagnosed with tricompartmental OA, rheumatoid

arthritis, or concomitant severe hip OA were not included

in the study. A previous high tibial osteotomy or cartilage

transplantation procedure, Grade 2? and 3? effusion in

the knee joint (requiring aspiration) based on the Stroke

test, blood diseases, systemic metabolic disorders, immu-

nodeficiency, Hepatitis B or C, HIV positive status, local

or systemic infection and ingestion of anti-platelet medi-

cations within 7 days prior to the injection and treatment

with intra-articular or oral corticosteroids in the 3 months

prior to the first injection were considered criteria for

exclusion.

Those patients that met the inclusion criteria received a

minimum of 1 cycle of intra-articular PRP injection into

the affected knee. A cycle consisted of three injections,

each given at a monthly interval. Thirty-eight patients (50

knees) were randomly selected using computer generated

random numbers (Research Randomizer � 1997–2013 G. Urbaniak and S. Plous) prior to the first injection, to receive

a second cycle at the completion of 1 year. Between the

cycles, the patients would receive no other intra-articular

injections or oral medications for the knee with the

exception of acetaminophen on an ‘as required’ basis.

Patients were questioned regarding analgesic consumption

and alternative treatments at each follow-up. All patients

underwent physiotherapy at the same centre, with the same

protocol for 4 weeks beginning 1 week after the first

injection to improve quadriceps muscle strength and range

of motion.

Pre-treatment radiographic evaluation included a

standing anteroposterior long-leg radiograph (including

hips and ankles), standing anteroposterior/lateral views of

the knees, skyline patellofemoral and standing 45� flexion knee views and magnetic resonance imaging.

Routine blood investigations were carried out before

treatment, including complete blood count, coagulation

Knee Surg Sports Traumatol Arthrosc (2015) 23:2170–2177 2171

123

profile and screening for transmittable diseases (HIV,

HBsAg).

PRP preparation

Eight millilitre of blood was obtained from the cubital

vein and centrifuged for 5 min at 1,500g centrifugal

force (RCF) and 3,500 revolutions per minute as per the

recommendations of the manufacturer. This system did

not use a second centrifugation process. Centrifugation

of whole venous blood takes advantage of differing

density gradients of the components in blood to con-

centrate platelets. Erythrocytes, which are most dense,

remain as the packed cell layer at the bottom of the

centrifuge container. The buffy coat of white blood cells

is above this while the platelets are at the highest

concentration in the plasma just above the buffy coat

and decrease in concentration towards the top of the

plasma layer. After centrifugation, platelet recovery was

[80 % (twofold increase) and total leucocyte concen- tration was below the normal level-specific granulocyte

depletion [95 % (mostly mononuclear cells being recovered 75 % lymphocytes; 50 % monocytes) in 4 mL

of PRP. Leucocyte poor-PRP (LP-PRP) was obtained

according to Dohan Ehrenfest classification [11] while it

was P2 Bb as per the PAW classification [9]. The PRP was aspirated into a syringe and a topical anaesthetic

skin refrigerant was applied locally before intra-articular

infiltration by a supra-patellar approach using sterile

aseptic precautions. The PRP was activated in vivo

when the platelets were exposed to collagen or von

Willebrand factor, leading to their aggregation. After

treatment, patients were allowed weight bearing, and

local ice application was recommended for 20 min

every 2–3 h for 24 h. Vigorous activities of the knee

were not recommended for 48 h.

Outcome measures

Outcome following treatment was assessed using Knee

Injury and OA Outcome Score (KOOS) [32], Visual

Analogue Scale (VAS) (0 = no pain to 10 = worst pos-

sible pain) [7], Tegner [38] and Marx [25] scoring systems

which were recorded through questionnaires filled by the

patients themselves prior to the first injection and then at

12, 18 and 24 months follow-up. Data were recorded in

SOCRATES TM

(2012 Ortholink PTY Ltd.) orthopaedic

outcomes software.

An institutional review board approved the study (San

Raffaele AISPO at Milan, Italy, with protocol number

20081203/14) and date of approval November 12, 2008.

All patients gave a written informed consent prior to

inclusion in the study.

Statistical analysis

Statistical analysis was performed by an independent stat-

istician using the SPSS software (SPSS 17.0, SPSS, Chi-

cago, IL, USA). The general linear model for repeated

measure test was performed to investigate within time

variations for the continuous variables (KOOS, Marx, VAS)

for all patients and each evaluated subgroup. The evaluated

factors were ‘number of cycles’ and the Greenhouse-Geis-

ser p value is reported. Post hoc test with Bonferroni

adjustment for pair-wise comparisons within time was

performed to investigate the improvement and deterioration

for each variable and between subgroups. The nonpara-

metric Friedman test was performed to detect within time

differences in ordinal variable (Tegner), and the nonpara-

metric Wilcoxon rank test as post hoc was used with a

Bonferroni adjustment of the significant level. To investi-

gate difference in improvement between the evaluated

subgroups, the nonparametric Mann–Whitney U test was

performed. The modified intention to treat analysis was

performed on the originally randomized treatment groups to

rule out bias due to crossover. Reported p values are two-

tailed with an alpha level of 0.05 indicating significance.

Results

The two groups based on cyclical treatment were homo-

geneous by gender (n.s.), age (n.s.), BMI (n.s.) and follow-

up (n.s.). Demographic data are described in Table 1.

Seventy-nine patients (102 knees) were available at final

follow-up: 51 patients (69 knees) in the single cycle group

(group 1) and 28 patients (33 knees) in the two cycles

group (group 2). At 1 year follow-up, 14 patients (17

knees) from group 2 showed significant symptomatic

improvement; these patients did not feel the need for a

second cycle. Since they had received a complete cycle of

injections, they were retained in the study group but results

are reported with patients in group 1. In order to eliminate

any bias generated by this crossover, a modified intention

to treat analysis was performed. No difference was found

between the results reported and the estimated findings

(n.s.). Fourteen patients (17 knees) from group 1 were lost

to follow-up or were excluded. Other than the 10 patients

who crossed over to group 1, no patients were lost to fol-

low-up from group 2 (Fig. 1).

There was a significant improvement in all scores

(KOOS, VAS, Tegner and Marx) at each follow-up com-

pared to the pre-treatment value (p \ 0.001). When com- paring the effect of cyclical treatment, at 12 months, both

groups showed similar and significant improvement.

Results at 18 months, however, showed a significant dif-

ference between the two groups with a greater

2172 Knee Surg Sports Traumatol Arthrosc (2015) 23:2170–2177

123

improvement in results in the patients who had received the

second cycle of injections (p \ 0.001). The only two val- ues which did not vary significantly between the groups at

18 months were KOOS symptoms subscale and Tegner

score.

At 2-year follow-up, the scores had declined from the

18-month value in both the groups. The mean value in both

groups, however, remained significantly above the pre-

treatment value, and no significant difference was found

between the scores in the two groups despite the patients in

group 2 having higher mean values for all the scores

(Fig. 2; Table 2).

Discussion

The most important results of this study are that intra-

articular PRP injections can improve functional outcomes

and reduce pain in patients with early stages of OA of the

knee, and annual repetition of three such injections can

better the results. The beneficial effects of the treatment

peak within 6 months of the injections and subsequently

reduce, and the outcome measures remain significantly

higher than pre-treatment values even 24 months after

treatment.

In many cases, PRP is administered together with other

biological augmentation methods, such as mesenchymal

stem cells [6, 15, 16, 18] or bio-engineered scaffolds [10,

35], making it difficult to assess the net contribution made

by PRP to the outcome. This study investigated PRP as an

isolated entity in the treatment of early stages of OA.

Numerous in vitro and in vivo studies have investigated the

effect of PRP on articular cartilage [1, 4, 5, 24, 27, 28, 30,

34, 36], but no studies have looked into the outcome fol-

lowing cyclical treatment with PRP. Conflicting results

have been seen even in in vivo studies. Serra et al. [34]

Table 1 Demographic data

Values represented as

mean ± SD

Groups No. of males

(knees)

No. of females

(knees)

Age (range

40–65 years)

BMI Follow-up

(in years)

1 Cycle 30 (41) 21 (28) 54.8 ± 1.1 24.3 ± 0.2 2.1 ± 0.2

2 Cycles 20 (24) 8 (9) 54.3 ± 1.4 24.7 ± 0.3 2.2 ± 0.2

Fig. 1 Flow chart showing the patient population included in the study and their distribution along with the lost and excluded cases. M males, F females

Knee Surg Sports Traumatol Arthrosc (2015) 23:2170–2177 2173

123

using 24 New Zealand white rabbits in a control study

failed to show any significant difference when PRP was

used to treat full-thickness cartilage lesions. On the other

hand, histological evidence of cartilage repair has been

demonstrated after just 4 weeks in immunodeficient rats

and sheep [27, 28] with improved cartilage stiffness, jus-

tifying further research into the method of clinical use of

PRP.

Previous clinical studies suggest that PRP is an effective

short term (6 weeks up to 6 months) treatment for chondral

lesions, but there are very few randomized control trials

(RCT). Amongst the clinical studies, in a recently pub-

lished RCT, Patel et al. [31] compared the outcome

following single and double PRP injections compared to a

control group for early OA at 6 weeks, 3 and 6 months.

They concluded that there was a significant improvement

in WOMAC score at all follow-ups when PRP was

administered, with no difference between single and double

injections. Hart et al. [19] in a prospective study of 50

patients administered nine injections in 1 year to assess if

PRP can increase tibiofemoral cartilage regeneration in the

knee. They reported improvement in all scores at

12 months but with no significant cartilage regeneration.

Torrero et al. [39] in a prospective study included patients

aged 18–65 years and reported significant improvement in

the KOOS and VAS score after a single injection up to

Fig. 2 Variation in KOOS score over the course of study at each follow-up. A significant improvement in scores is evident in the 1st

year in both groups, which continues to improve until 18 months for

those patients who received the 2nd cycle. By 2 years, even these

patients show deterioration in results although the final mean is above

the pre-treatment and 1 year mean. KOOS: P pain; S symptoms; ADL

activity of daily living; Sp sports; QOL quality of life

2174 Knee Surg Sports Traumatol Arthrosc (2015) 23:2170–2177

123

6 months after the treatment. In our previous study [17],

significant improvement was demonstrated in IKDC,

KOOS, VAS, Tegner and Marx scores at 12-month follow-

up after two injections administered a month apart. We also

found that patients who had undergone previous cartilage

surgery (such as shaving or microfracture) and presented

with persisting symptoms, showed favorable results, indi-

cating that PRP could be an effective additional therapy.

Preliminary reports and results of treatment with PRP have

been encouraging in almost all the studies. However, the

follow-up period has been as short as 5 weeks to

12 months in most studies. Filardo et al. [14] compared a

single spin and double spin method of preparation of PRP

in 144 patients, demonstrating a significant clinical

improvement in both groups with better results in younger

patients. In a comparative study to assess the efficacy of

PRP and hyaluronic acid in 150 patients over 6 months,

Kon et al. [23] showed improved IKDC and VAS scores in

both groups after 2 and 6 months with better results in the

PRP group. In a prospective study including 91 patients, a

follow-up of 24 months has been reported [13, 22]; patients

received three intra-articular PRP injections at monthly

intervals, and all parameters worsened at 2 years with

significantly lower levels of IKDC objective, subjective

and EQ-VAS scores with respect to the 12-month evalua-

tion (IKDC objective fell from 67 to 59 % of normal and

nearly normal knees; IKDC subjective score reduced from

60 to 51 %, though they remained higher than the basal

level). Jang et al. [20] showed deterioration in scores

within the 1st year itself. Unlike the above studies, our

results showed a plateau in the results after 1 year for

patients receiving a single cycle of treatment and deterio-

ration after 18 months of the 1st injection when the treat-

ment was repeated annually. The final follow-up results,

however, continued to remain higher than the baseline pre-

treatment values in both groups and were also higher that

the values obtained by group 1. This difference, however,

was not statistically significant. These findings could be

explained on the following grounds: the factors contained

within PRP may act to inhibit the most notable catabolic

cytokines acting on articular cartilage: interleukin 1b (IL- 1b) and tumour necrosis factor a (TNF-a). The production of these enzymes is under the control of transcription factor

nuclear factor jb (NF-jb). Although PRP does not act directly on NF-jb, the factors stored within a-granules and released with platelet activation may counteract the effects

of NF-jb mediated cartilage degradation [1, 8]. As the injections were administered at monthly intervals, the anti-

cytokinetic effect could have been prolonged and poten-

tially compounded explaining the improved scores even

after 12 months. The cartilage breakdown having been

potentially slowed down, and the administration of the

second cycle of injections may have further improved the

symptomatic response.

The strengths of this study lie in the fact that it is a

prospective, randomized study of a topic which has not yet

been investigated. The study group is large, with a

homogenous patient population and strict inclusion and

exclusion criteria were laid down to eliminate any bias.

Although the results were entirely subjective, all efforts

have been made to eliminate confounding factors which

may have arisen. When reviewing the literature, it was

evident that there was no uniformity in the indications for

which PRP has been used. Although intra-articular PRP

injections have been administered in the knee for degen-

erative cartilage lesions, the age group included in previous

studies has been as wide as 18–81 years [29, 39]. This

study only included patients between the age of 40 and

65 years, who are non-professional athletes in order to

eliminate bias which could occur due to extremes of age. A

detailed description of the PRP and its preparation tech-

nique have been described, to enable further future inves-

tigation and comparison between different types of PRP

and preparation methods.

The limitations of the study are that it was not possible

to have post treatment MRI images for every patient and a

Table 2 Mean values ± SD of VAS, Marx and Tegner scores through the follow-up

Score Group Pre-treatment 12 months p value 18 months p value 24 months p value

VAS 1 4.2 ± 1.8 2.8 ± 1.7 n.s. 2.9 ± 1.8 \0.001 2.6 ± 1.8 n.s. 2 4.3 ± 2.2 3.2 ± 2.2 1.9 ± 1.6 2.1 ± 1.7

Marx 1 3.7 ± 3.6 4.0 ± 3.6 n.s. 5.07 ± 4.2 \0.001 5.96 ± 4.8 n.s. 2 4.7 ± 3.7 5.8 ± 4.3 6.03 ± 3.9 6.88 ± 4.2

Tegner 1 2.9 ± 1.5 3.1 ± 1.3 n.s. 3.44 ± 1.3 n.s. 3.68 ± 1.4 n.s.

2 3.4 ± 1.6 3.2 ± 1.4 3.63 ± 1.2 3.87 ± 1.3

Values are represented as mean ± SD

Groups 1: single cycle; 2: two cycles

VAS Visual Analogue Scale, n.s. not significant

Significant improvement (p \ 0.001) in all the scores at the end of 12 months. The p values are of the comparison between the cycles

Knee Surg Sports Traumatol Arthrosc (2015) 23:2170–2177 2175

123

post treatment arthroscopy and biopsy to assess the status

of cartilage healing could not be obtained. At the start of

the study, 50 knees were assigned to receive a second cycle

of injections, but 10 patients (17 knees) crossed over from

group 2 to group 1 at the end of 1 year, greatly reducing the

patient population in group 2. This could have generated a

bias in the findings but was found to be insignificant on the

intention to treat analysis. A placebo control group would

have provided a key ingredient in this study. However, as it

was proposed as a 2-year study period for patients with

symptomatic, early stages of OA, it was considered

unethical by the review board to leave a certain patient

population in a placebo group untreated.

Conclusion

Intra-articular PRP injections into the knee for symptom-

atic early stages of OA are a valid treatment option. There

is a significant reduction in pain and improvement in

function after 12 months, which can be further improved at

18 months by annual repetition of the treatment. Although

the beneficial effects are ill sustained at 2 years, the results

are encouraging when compared to the pre-treatment

function.

Acknowledgments We would like to thank Mr. Andrea Primo, for his valuable time in helping us with the statistical analysis.

Conflict of interest The authors have no conflict of interests to declare.

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